WO2022143693A1 - Thieno [2, 3-c] pyrrole-4-one derivative - Google Patents

Thieno [2, 3-c] pyrrole-4-one derivative Download PDF

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WO2022143693A1
WO2022143693A1 PCT/CN2021/142174 CN2021142174W WO2022143693A1 WO 2022143693 A1 WO2022143693 A1 WO 2022143693A1 CN 2021142174 W CN2021142174 W CN 2021142174W WO 2022143693 A1 WO2022143693 A1 WO 2022143693A1
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compound
reaction solution
ethyl acetate
mmol
added
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PCT/CN2021/142174
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French (fr)
Chinese (zh)
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吴凌云
赵乐乐
黄维
贾海飞
胡国平
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 WO2022143693A1 publication Critical patent/WO2022143693A1/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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of thieno[2,3-c]pyrrol-4-one derivatives and a preparation method thereof, in particular to a compound represented by formula (I') and a pharmaceutically acceptable salt thereof.
  • CDC7 (cell division cycle 7) is a serine/threonine kinase that plays an important role in regulating the cell cycle.
  • the content of CDC7 remains unchanged in the cell cycle, but it must also bind an important auxiliary protein ASK (activator of S phase kinase) to exert its regulatory function.
  • ASK activator of S phase kinase
  • MCM minichromosome maintenance complex
  • CDC7 The expression level of CDC7 is unchanged in the normal cell cycle, and is regulated by some factors and auxiliary proteins in the cell cycle, and is in a state of dynamic equilibrium.
  • CDC7 is abnormally expressed and overactivated. Since CDC7 is overexpressed in a variety of tumor cells, overexpressed CDC7 can promote the overactivation of MCM2, an important marker of tumor cells, and then promote the abnormal proliferation of tumor cells.
  • CDC7 also showed high expression in all metastatic tumor cells, which also suggested that the abnormally high expression of CDC7 may be closely related to the metastasis of tumor cells.
  • the abnormally high expression and activation of CDC7 also plays a key role in the resistance of tumor cells to chemotherapeutic drugs. CDC7 can further activate the ATR/Chk1 pathway by phosphorylating Claspin to terminate mitosis and repair damaged DNA to protect tumor cells.
  • TAK-931 (WO2011102399A1, WO2018158898A1) developed by Takeda Pharmaceutical has high CDC7 inhibitory activity and high anti-proliferative activity on human colon cancer cells (COLO205 cells), a cell line with high expression of CDC7.
  • -Derived tumor Xenograft a cell line with high expression of CDC7.
  • -Derived tumor Xenograft a cell line with high expression of CDC7.
  • LY3143921 (WO2014143601A1) developed by Eli Lilly is also used as a CDC7 inhibitor. Its CDC7 inhibitory activity is comparable to TAK-931, with a long half-life and high in vivo exposure.
  • the present invention provides a compound represented by formula (I') or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R2;
  • Structural units selected from wherein the each independently optionally substituted with 1, 2 or 3 R3 ;
  • R 1 is selected from H and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a ;
  • R 2 is independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl , -L-4-6-membered heterocycloalkyl and 5-6-membered heteroaryl, wherein the C 1-3 alkyl, C 1-3 alkoxy, 4-6-membered heterocycloalkyl, -L -4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2 or 3 R b ;
  • L is selected from -NH- and -O-;
  • R 3 is each independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally 3 R c replaced;
  • R 4 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally surrounded by 1, 2 or 3 R replaced by d ;
  • Said 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl independently comprise 1, 2, 3 or 4 heterocyclic groups independently selected from -O-, -NH-, -S- and -N- atom or heteroatomic group.
  • the present invention provides a compound represented by formula (I') or a pharmaceutically acceptable salt thereof,
  • Ring A is selected from 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R2;
  • Structural units selected from wherein the each independently optionally substituted with 1, 2 or 3 R3 ;
  • R 1 is selected from H and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a ;
  • R 2 is independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl , -L-4-6-membered heterocycloalkyl and 5-6-membered heteroaryl, wherein the C 1-3 alkyl, C 1-3 alkoxy, 4-6-membered heterocycloalkyl, -L -4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2 or 3 R b ;
  • L is selected from -NH- and -O-;
  • R 3 is each independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally 3 R c replaced;
  • R 4 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally surrounded by 1, 2 or 3 R replaced by d ;
  • Said 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl independently comprise 1, 2, 3 or 4 heterocyclic groups independently selected from -O-, -NH-, -S- and -N- atom or heteroatomic group.
  • Ring A, R 1 , R 3 and R 4 are as defined in the present invention.
  • a carbon atom with "*" is a chiral carbon atom and exists in (R) or (S) single enantiomeric form or enriched in one enantiomeric form.
  • R b are independently selected from F, Cl, Br, -OH, -CH 3 and -OCH 3 , and other variables are as defined in the present invention.
  • R b are independently selected from F, Cl, Br, -OH and -CH 3 , and other variables are as defined in the present invention.
  • R c are independently selected from F, Cl and Br, and other variables are as defined in the present invention.
  • R 1 is selected from H and -CH 3 , and other variables are as defined in the present invention.
  • R 2 is independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -OCH 3 , wherein the -CH 3 , -OCH 3 , Each independently is optionally substituted with 1, 2 or 3 R b , R b and other variables as defined herein.
  • R 2 is independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -OCH 3 , wherein the -CH 3 , -OCH 3 , Each independently is optionally substituted with 1, 2 or 3 R b , R b and other variables as defined herein.
  • R 2 is independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -CH 2 CH 2 OCH 3 , -CHF 2 , -CF 3 , -OCH 3 , Other variables are as defined in the present invention.
  • R 2 are independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -CF 3 , -OCH 3 , Other variables are as defined in the present invention.
  • R 3 are independently selected from H, F, Cl, Br and -CH 3 , wherein the -CH 3 is optionally substituted by 1, 2 or 3 R c , R c and Other variables are as defined in the present invention.
  • R 3 is independently selected from H, -CH 3 and -CF 3 , and other variables are as defined in the present invention.
  • R 4 is selected from H, F, Cl and Br, and other variables are as defined in the present invention.
  • the above ring A is selected from pyridyl, pyrimidinyl and pyridazinyl, wherein said pyridyl, pyrimidinyl and pyridazinyl are each independently optionally substituted with 1, 2 or 3 R2 , R 2 and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from wherein the Each independently is optionally substituted with 1, 2 or 3 R 2 , R 2 and other variables as defined herein.
  • the above-mentioned ring A is selected from R2 and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from R2 and other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • the above-mentioned ring A is selected from Other variables are as defined in the present invention.
  • n is selected from 0, 1, 2 or 3; R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
  • n, R 1 , R 2 , R 3 and R 4 are defined in the present invention.
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the compound of the present invention has good CDC7 inhibitory activity, and has significant inhibitory activity on COLO-205 cells and Capan-1 cells (human pancreatic cancer tumor cells), thereby obtaining excellent tumor growth inhibitory activity, and has in vivo PK ( Pharmacodynamics) has the advantages of long half-life and high exposure, and has a good tumor inhibition effect in the in vivo pharmacodynamic model of human pancreatic cancer cell CAPAN-1 nude mice subcutaneously transplanted.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” result from the inability to rotate freely by double bonds or single bonds of ring carbon atoms.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature.
  • a chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution).
  • proton tautomers also called prototropic tautomers
  • prototropic tautomers include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers, pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in one enantiomer” refer to one of the isomers or pairs
  • the enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • isomeric excess or “enantiomeric excess” refer to the difference between two isomers or relative percentages of two enantiomers. For example, where the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (e.e. value) is 80% .
  • Optically active (R)- and (S)-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art
  • the diastereoisomers were resolved and the pure enantiomers recovered.
  • separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with up to two Rs, with independent options for R in each case.
  • combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
  • the direction of attachment is arbitrary, for example,
  • the linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right. It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
  • Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites in the group can be linked to other groups by chemical bonds.
  • connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group.
  • the chemical bond connecting the site to other groups can be represented by straight solid line bonds straight dotted key or wavy lines express.
  • a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
  • the straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
  • the wavy lines in the phenyl group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
  • C 1-3 alkyl is used to denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) .
  • Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C1-3alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like.
  • Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl” are used interchangeably in the present invention, and the term “5-6 membered heteroaryl” means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2).
  • a 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms denotes a saturated cyclic group consisting of 4 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings.
  • a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule.
  • the 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like.
  • 4-6 membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl,
  • Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membere
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction).
  • a substitution reaction eg, a nucleophilic substitution reaction
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl (TMS),
  • hydroxy protecting group refers to a protecting group suitable for preventing hydroxyl side reactions.
  • Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (eg acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • SXRD single crystal X-ray diffractometry
  • the cultivated single crystal is collected by Bruker D8venture diffractometer
  • the light source is CuK ⁇ radiation
  • the scanning method is as follows: After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
  • the solvent used in the present invention is commercially available.
  • Alloc stands for allyloxycarbonyl
  • SEM stands for trimethylsilylethoxymethyl
  • OTs stands for 4-toluenesulfonyl
  • Boc stands for tert-butoxycarbonyl
  • DCM stands for dichloromethane
  • DIEA represents N,N-diisopropylethylamine
  • MeI represents methyl iodide
  • PE represents petroleum ether
  • EA represents ethyl acetate
  • THF represents tetrahydrofuran
  • EtOH represents ethanol
  • MeOH represents methanol
  • Boc 2 O represents di-tert-butyl dicarbonate ;
  • NH 4 Cl for ammonium chloride
  • T 3 P for 1-propylphosphoric acid tricyclic anhydride
  • Pd/C for palladium/carbon catalyst
  • TMSN 3 for azidotrimethylsilane
  • NCS for N-chlorobutanedi Imide
  • HBr hydrobromic acid
  • DMSO dimethyl sulfoxide
  • DMSO-d 6 stands for deuterated dimethyl sulfoxide
  • CD 3 OD stands for deuterated methanol
  • CDCl 3 stands for deuterated chloroform
  • D 2 O stands for deuterated water
  • BID stands for twice a day.
  • Figure 1 shows the results of in vivo pharmacodynamic experiments of the compounds of the present invention in CAPAN-1 nude mice subcutaneously transplanted tumor model.
  • the present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.
  • reaction solution was added with saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (50 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1 ⁇ 2/1, V/V) to obtain intermediate B-2.
  • MS-ESI calculated [M+H] + 448 and 450, found 448 and 450.
  • the reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1 ⁇ 1/2, V/V) to obtain a mixed crude product of 1a and 1b.
  • the crude product was purified by SFC (separating column: DAICEL).
  • the reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1 ⁇ 1/1, V/V) to obtain a crude mixture of 2a and 2b.
  • the crude product was purified by SFC (separating column: DAICEL).
  • the two compounds were then subjected to SFC (chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5 %-40%) to measure the ee value.
  • SFC chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5 %-40%) to measure the ee value.
  • reaction solution was directly concentrated under reduced pressure, and the residue was separated by thin layer chromatography (petroleum ether/ethyl acetate, 3/1 ⁇ 1/1, V/V) to obtain the crude product of compound 3, which was purified by SFC (separating column: DAICEL CHIRALPAK).
  • SFC separating column: DAICEL CHIRALPAK
  • the two compounds were then subjected to SFC (chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5 %-40%) to measure the ee value.
  • SFC chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5 %-40%) to measure the ee value.
  • the reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1 ⁇ 1/1, V/V) to obtain the crude product, and the crude product was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 25%-25%) to separate compounds 4-6a (the first peak) and 4- 6b (second peak).
  • reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1 ⁇ 1/1, V/V) to obtain the crude product, and the crude product was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 25%-25%) to separate compound 5-2a (the first peak) and compound 5 -2b (second peak).
  • the reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1 ⁇ 1/1, V/V) to obtain the crude product, and the crude product was purified by SFC (separating column: DAICEL CHIRALPAK AD 250mm). ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 40%-40%) to separate compound 6a (the first peak) and compound 6b (the second peak) peaks).
  • the compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
  • the reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1-1/1, V/V) to obtain the crude product, and the crude product was separated by SFC (separating column: DAICEL CHIRALPAK AD 250mm). ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 50%-50%) to separate compounds 7a (the first peak) and 7b (the second peak) peak).
  • reaction solution was added with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL ⁇ 2), the organic phases were combined, the organic phases were washed with saturated brine (50 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1 ⁇ 2/1, V/V) to obtain compound 8-2.
  • MS-ESI calculated [M+H] + 474 and 476, found 474 and 476.
  • the reaction solution was added with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 2), and the organic phases were combined, washed with saturated brine (30 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1-1/1, V/V) to obtain the crude compound.
  • the crude product was separated by SFC (column: DAICEL CHIRALPAK AD 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ethanol solution of 0.1% ammonia water 35%-35%) to obtain compound 8a (first peak) and 8b (second peak).
  • the compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
  • reaction solution was added with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL ⁇ 2), the organic phases were combined, the organic phases were washed with saturated brine (50 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1 ⁇ 2/1, V/V) to obtain compound 9-2.
  • MS-ESI calculated [M+H] + 474 and 476, found 474 and 476.
  • the reaction solution was added with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 2), and the organic phases were combined, washed with saturated brine (30 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1 ⁇ 1/1, V/V) to obtain the crude product.
  • reaction solution was added with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL ⁇ 2), the organic phases were combined, the organic phases were washed with saturated brine (50 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1 ⁇ 2/1, V/V) to obtain compound 10-2.
  • MS-ESI calculated [M+H] + 496 and 498, found 496 and 498.
  • the reaction solution was added with water (30 mL), extracted with ethyl acetate (30 mL ⁇ 2), and the organic phases were combined, washed with saturated brine (30 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1 ⁇ 1/1, V/V) to obtain the crude compound.
  • the crude product was separated by SFC (column: DAICEL CHIRALCEL OJ-H 250mm ⁇ 30mm ⁇ 5 ⁇ m; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ethanol solution of 0.1% ammonia water 30%-30%) to obtain the compound 10a (first peak) and 10b (second peak).
  • the compound was then filtered through SFC (column: Chiralcel OD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: .05% diethylamine in ethanol: 5% -40%) measured ee value.
  • reaction solution was added with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, dried over saturated brine (50 mL), anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1 ⁇ 3/1, V/V) to obtain compound 11-2.
  • MS-ESI calculated [M+H] + 477 and 479, found 477 and 479.
  • reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrated under reduced pressure, the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1 ⁇ 3/1, V/V) to obtain intermediate 11-4. MS-ESI calculated [M+H] + 343 and 345, found 343 and 345.
  • reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1-1/1, V/V) to obtain a crude compound, which was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 45%-45%), compound 11 was isolated.
  • reaction solution was directly concentrated under reduced pressure, and the residue was separated by thin-layer chromatography (petroleum ether/ethyl acetate, 3/1-0/1, V/V) to obtain a crude product, which was subjected to SFC (separating column: DAICEL CHIRALCEL OD- H 250mm ⁇ 30mm ⁇ 5 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 50%-50%), separate compounds 12a (the first peak) and 12b ( the second peak).
  • SFC separating column: DAICEL CHIRALCEL OD- H 250mm ⁇ 30mm ⁇ 5 ⁇ m
  • mobile phase supercritical CO 2 -0.1% ammonia solution in ethanol
  • gradient 0.1% ammonia solution in ethanol 50%-50%)
  • the reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain the crude product of compound 14.
  • the crude product was passed through SFC (column: DAICEL CHIRALPAK AS 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ammonia water 40%-40% ethanol solution), and isolated compounds 14a (the first peak) and 14b (the second peak).
  • the compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
  • reaction solution was added with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 3/1, V/V) to obtain compound 15-2.
  • MS-ESI calculated [M+H] + 468 and 470, found 468 and 470.
  • reaction solution was directly concentrated under reduced pressure, and the residue was separated by thin layer chromatography (dichloromethane/methanol, 100/1 ⁇ 10/1, V/V) to obtain the crude product of compound 15, which was purified by SFC (separating column: DAICEL CHIRALCEL OD). -H 250mm ⁇ 30mm ⁇ 5 ⁇ m; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ammonia water ethanol solution 40%-40%), compound 15 was isolated.
  • reaction solution was added with saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 3/1, V/V) to obtain compound 16-2.
  • MS-ESI calculated [M+H] + 461 and 463, found 461 and 463.
  • reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrated under reduced pressure, the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 3/1, V/V) to obtain intermediate 16-4. MS-ESI calculated [M+H] + 327 and 329, found 327 and 329.
  • reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 0/1, V/V) to obtain the crude compound, which was purified by SFC (separation column: DAICEL CHIRALPAK A 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 45%-45%), separated compounds 16a (first peak) and 16b (second peak) peaks).
  • reaction solution was added with saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (30 mL ⁇ 2), the organic phases were combined, dried with saturated brine (50 mL), anhydrous sodium sulfate, filtered, and concentrated under reduced pressure.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1 ⁇ 3/1, V/V) to obtain compound 17-2.
  • MS-ESI calculated [M+H] + 511 and 513, found 511 and 513.
  • reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1 ⁇ 0/1, V/V) to obtain the crude compound, which was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 30%-30%), compounds 17a (the first peak) and 17b (the first peak) were separated. two peaks).
  • reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was It was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 1/1, V/V) to obtain intermediate 18-3. MS-ESI calculated [M+H] + 339 and 341, found 339 and 341.
  • reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 0/1, V/V) to obtain the crude compound, which was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in isopropanol; gradient: 0.1% ammonia solution in isopropanol 35%-35%), isolated compound 18a (the first peak) and 18b (second peak).
  • reaction solution was added with saturated aqueous ammonium chloride solution (15 mL), extracted with ethyl acetate (50 mL ⁇ 2), the organic phases were combined, the organic phases were washed with saturated brine (50 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1 ⁇ 2/1, V/V) to obtain compound 19-2.
  • MS-ESI calculated [M+H] + 478 and 480, found 478 and 480.
  • the crude product was separated by SFC (column: DAICEL CHIRALPAK AD 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ethanol solution of 0.1% ammonia water 30%-30%) to obtain compound 19a (first peak) and 19b (second peak).
  • the compound was then purified by SFC (chromatographic column: Chiralcel AD-3 150mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
  • the crude compound 20-3 (0.15 g, 0.466 mmol) was dissolved in trifluoroacetic acid (2 mL), N-bromosuccinimide (87 mg, 489 ⁇ mol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid was added dropwise (0.2 mL), the reaction solution was stirred at 0 °C for 1 hour.
  • MS-ESI calculated for [M+H] + 381 and 383 found 381 and 383.
  • the crude product was separated by SFC (column: DAICEL CHIRALPAK AD 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 45%-45% ethanol solution of 0.1% ammonia water) to obtain compound 20a (first peak) and 20b (second peak).
  • the compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
  • the crude product was separated by SFC (column: DAICEL CHIRALCEL OD-H 250mm ⁇ 30mm ⁇ 5 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in methanol; gradient: 0.1% ammonia solution in methanol 45%-45%) to obtain the compound 21 (first peak) and 21b (second peak).
  • the compound was then purified by SFC (chromatographic column: Chiralcel OD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in methanol; gradient: 0.05% diethylamine in methanol: 5%- 40%) measured ee value.
  • reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane/methanol, 30/1 ⁇ 8/1, V/V), and the crude product was purified by SFC (separation column: DAICEL CHIRALPAK AD 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in isopropanol; gradient: 0.1% ammonia solution in isopropanol 40% - 40%), separate compounds 22a (the first peak) and 22b (the first peak). two peaks).
  • the compound was then subjected to SFC (chromatographic column: Chiralcel AD-3 150mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in isopropanol; gradient: 0.05% diethylamine in isopropanol :5%-40%) to measure the ee value.
  • SFC chromatographic column: Chiralcel AD-3 150mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in isopropanol; gradient: 0.05% diethylamine in isopropanol :5%-40%) to measure the ee value.
  • the compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
  • reaction solution was added with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (20 mL ⁇ 2), the organic phases were combined, the organic phases were washed with saturated brine (30 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 3/1, V/V) to obtain compound 24-2.
  • MS-ESI calculated [M+H] + 478 and 480, found 478 and 480.
  • reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was It was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1 ⁇ 1/1, V/V) to obtain intermediate 24-6. MS-ESI calculated [M+H] + 396 and 398, found 396 and 398.
  • reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1 ⁇ 0/1, V/V) to obtain the crude product, which was purified by SFC (separating column: DAICEL CHIRALPAK AS 250mm) ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 50%-50%), compounds 24a (the first peak) and 24b (the second peak) were isolated peaks).
  • the compound was then filtered through SFC (column: Chiralcel AS-3 100mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
  • MS-ESI calculated [M+H] + 395 and 397 found 395 and 397.
  • the crude product was separated by SFC (column: DAICEL CHIRALPAK AD 250mm ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 45%-45% ethanol solution of 0.1% ammonia water) to obtain compound 25a (first peak) and 25b (second peak).
  • the compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
  • reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane/methanol, 100/1 ⁇ 10/1, V/V) to obtain the crude compound, which was purified by SFC (separating column: DAICEL CHIRALCEL OJ 250mm). ⁇ 30mm ⁇ 10 ⁇ m; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 30%-30%), compounds 26a (the first peak) and 26b (the second peak) were isolated peaks).
  • the compound was then filtered through SFC (column: Chiralcel OJ-3 100mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
  • reaction solution was added with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL ⁇ 3), the organic phases were combined, the organic phases were washed with saturated brine (50 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1 ⁇ 3/1, V/V) to obtain compound 27-2.
  • MS-ESI calculated [M+H] + 461 and 463, found 461 and 463.
  • reaction solution was added with water (100 mL), extracted with ethyl acetate (200 mL x 2), the organic phases were combined, washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • Compound 29b was further purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 80 ⁇ 40 mm ⁇ 3 ⁇ m; mobile phase: 0.05% aqueous ammonia solution-acetonitrile; gradient: acetonitrile 20%-50%, 8 min) to obtain compound 29b.
  • SFC chromatographic column: Chiralcel OD-3 100mm ⁇ 4.6mm ⁇ 3 ⁇ m; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%-40 %) to measure the ee value.
  • Methoxymethyltriphenylphosphine chloride (27.4 g, 79.9 mmol) was dissolved in tetrahydrofuran (250 mL), and lithium diisopropylamide (40.0 mL, 2 mol/L of tetrahydrofuran/normal) was added dropwise at -78 °C.
  • reaction solution was added with saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL ⁇ 2), the organic phases were combined, the organic phases were washed with saturated brine (200 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate.
  • the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1 ⁇ 5/1, V/V) to obtain compound 30-2.
  • reaction solution was added with water (20 mL), extracted with ethyl acetate (30 mL x 2), the organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • MS-ESI calculated [M+H] + 395 and 397 found 395 and 397.
  • the reaction solution was added with saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL ⁇ 2), the organic phases were combined, the organic phases were washed with saturated brine (200 mL ⁇ 1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate.
  • the crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 80 ⁇ 40 mm ⁇ 3 ⁇ m; mobile phase: 0.05% aqueous ammonia solution-acetonitrile; gradient: acetonitrile 54%-84%, 8 min) to obtain compound 33-3.
  • MS-ESI calculated [M+H] + 493 and 495, found 493 and 495.
  • reaction solution was added with water (30 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure.
  • CDC7/DBF4 Kinase Assay Kit was purchased from Promega. Nivo Multilabel Analyzer (PerkinElmer).
  • the compound to be tested was diluted 5-fold to the 8th concentration with a row gun, that is, from 10 ⁇ M to 0.13 nM, the concentration of DMSO was 5%, and a double-well experiment was set up.
  • the final concentration gradient of the sample to be tested is 2 ⁇ M diluted to 0.025 nM.
  • the reaction system was placed at 25 degrees for 60 minutes.
  • the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism -Variable slope mode derived).
  • Table 1 provides the inhibitory activity of the compounds of the present invention on CDC7/DBF4 enzymes.
  • 1640 medium, fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Vicente.
  • CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega.
  • COLO205 cell line was purchased from Wuhan Procell Life Technology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
  • COLO205 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 3000 COLO205 cells. Cell plates were incubated overnight in a carbon dioxide incubator.
  • the compounds to be tested were diluted 3-fold to the 8th concentration with a row gun, that is, from 2mM to 920nM, and a double-well experiment was set up.
  • Compound concentrations transferred to cell plates ranged from 10 ⁇ M to 4.57 nM.
  • the cell plates were placed in a carbon dioxide incubator for 3 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • Table 2 provides the inhibitory activity of the compounds of the present invention on the proliferation of COLO205 cells.
  • IMDM Iscove's Modified Dubecco's Medium
  • fetal bovine serum penicillin/streptomycin antibiotics
  • penicillin/streptomycin antibiotics were purchased from Vicente.
  • CellTiter-Glo Cell Viability Chemiluminescence Detection Reagent
  • the Capan-1 cell line was purchased from Wuhan Procell Life Technology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
  • Capan-1 cells were seeded in a white 96-well plate, 80 ⁇ L of cell suspension per well, which contained 6000 Capan-1 cells. Cell plates were incubated overnight in a carbon dioxide incubator.
  • the compound to be tested was diluted 3-fold to the 8th concentration with a row gun, that is, from 2mM to 920nM, and a double-well experiment was set up.
  • Compound concentrations transferred to cell plates ranged from 10 ⁇ M to 4.57 nM.
  • the cell plates were placed in a carbon dioxide incubator for 7 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis.
  • the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode).
  • Table 3 provides the inhibitory activity of the compounds of the present invention on the proliferation of Capan-1 cells.
  • mice Male, 7 weeks old, Viton Lever
  • Intravenous and oral vehicle is a mixed vehicle of 10% dimethyl sulfoxide and 90% 10% hydroxypropyl beta cyclodextrin.
  • This project used four male BALB/c mice, two mice were administered intravenously at a dose of 2 mg/kg, collected at 0h (before administration) and 0.0833, 0.25, 0.5, 1, 2 after administration , 4, 8, 24h plasma samples, the other two mice were given oral gavage at a dose of 2 mg/kg, collected at 0h (before administration) and 0.25, 0.5, 1, 2, 4 after administration, 8, 24h plasma samples, collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain plasma samples, add 4 times the volume of acetonitrile solution containing the internal standard to precipitate the protein, centrifuge the supernatant and add an equal volume of acetonitrile solution.
  • the compounds of the present invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
  • CD-1 or BALB/c mice male, 7-10 weeks old, Viton Lever
  • the rodent pharmacokinetic characteristics of the compounds after intravenous injection and oral administration were tested by standard protocols.
  • the candidate compounds were formulated into clear solutions or suspensions, and were administered to two mice by a single intravenous injection and oral administration.
  • the intravenous vehicle is 10% dimethyl sulfoxide/10% ethanol/40% polyethylene glycol 400/40% aqueous solution, the dosage is 2 mg/kg, and the oral vehicle is 3% dimethyl sulfoxide/5%
  • Polyethylene glycol lauryl stearate/92% aqueous solution was administered at a dose of 10 mg/kg.
  • the compounds of the present invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
  • the pharmacokinetics of the compounds in rodents after intravenous injection and oral administration were tested according to the standard protocol.
  • the candidate compounds were formulated into clear solutions or suspensions, which were administered to two rats by single intravenous injection and oral administration, respectively.
  • the intravenous vehicle is 10% dimethyl sulfoxide/10% ethanol/40% polyethylene glycol 400/40% aqueous solution, the dosage is 5mg/kg, and the oral vehicle is 3% dimethyl sulfoxide/5%
  • Polyethylene glycol lauryl stearate/92% aqueous solution was administered at a dose of 10 mg/kg.
  • the compounds of the present invention have good pharmacokinetic properties in rats, including good oral bioavailability, oral exposure, half-life and clearance rate.
  • the pharmacokinetic characteristics of the compounds after intravenous injection and oral administration were tested by standard protocols.
  • the candidate compounds were formulated into clear solutions or suspensions, and were administered to two dogs by single intravenous injection and oral administration, respectively.
  • the intravenous vehicle is 10% dimethyl sulfoxide/10% ethanol/40% polyethylene glycol 400/40% aqueous solution, the dosage is 2 mg/kg, and the oral vehicle is 3% dimethyl sulfoxide/5%
  • Polyethylene glycol dodecyl stearate/92% aqueous solution was administered at a dose of 5 mg/kg.
  • Human pancreatic cancer cell CAPAN-1 passage 26 cultured in monolayer in vitro, cultured in IMDM medium with 20% fetal bovine serum, 1% double antibody (100 U/mL penicillin, 100 ⁇ g/mL streptomycin and 25 ⁇ g/mL) Amphotericin B) at 37°C, cultured in a 5% CO2 cell incubator, passaged 6 times, and passaged with routine medium exchange.
  • the cell saturation was 80%-90%, cells were digested with trypsin-EDTA, counted, and resuspended in a mixture of PBS and Matrigel (1:1) at a density of 5 x 106 cells/0.2 mL.
  • mice Female BALB/c nude mice (age: 6-8 weeks) were purchased from Shanghai Lingchang Biotechnology Co., Ltd.
  • Each mouse was seeded with 5 ⁇ 10 6 CAPAN-1 cells on the right back of the neck in a seeding volume of 0.2 mL, and the cell suspension was PBS and Matrigel (1:1). When the mean tumor volume reached about 148 mm3 , randomization was used and dosing was started.
  • Tumor diameters were measured with vernier calipers twice a week.
  • TGI percent tumor proliferation rate
  • T/C percent (T RTV : RTV of the treatment group; C RTV : RTV of the negative control group).
  • the experimental results are shown in Figure 1.
  • the compound of the present invention exhibits excellent tumor-inhibiting effect in CAPAN-1 nude mice subcutaneously transplanted tumor model.

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Abstract

The present invention relates to a thieno [2, 3-c] pyrrole-4-one derivative and a preparation method therefor, and in particular to a compound of formula (I') and a pharmaceutically acceptable salt thereof.

Description

噻吩并[2,3-c]吡咯-4-酮衍生物Thieno[2,3-c]pyrrol-4-one derivatives
本申请主张如下优先权：This application claims the following priority:
CN 202011616149.4，2020年12月30日。CN 202011616149.4, December 30, 2020.
技术领域technical field
本发明涉及一类噻吩并[2,3-c]吡咯-4-酮衍生物及其制备方法具体涉及式(I’)所示化合物及其药学上可接受的盐。The present invention relates to a class of thieno[2,3-c]pyrrol-4-one derivatives and a preparation method thereof, in particular to a compound represented by formula (I') and a pharmaceutically acceptable salt thereof.
背景技术Background technique
CDC7(cell division cycle 7)是一种丝氨酸/苏氨酸激酶，在调控细胞周期方面发挥着十分重要的作用。CDC7在细胞周期中CDC7的含量始终保持不变，但它要发挥调控功能还必须结合一个重要的辅助蛋白ASK(activator of S phase kinase)。在细胞核内CDC7-ASK形成复合体后就开始磷酸化激活结合在染色体上的微染色体维持蛋白质(minichromosome maintenance complex，MCM)家族的多个成员如MCM2、MCM4、MCM6，尤其是对MCM2的磷酸化作用最强，而MCM则是细胞周期起始复合物中解旋酶的重要组成部分，最终促进DNA复制的起始和细胞周期的进行。CDC7 (cell division cycle 7) is a serine/threonine kinase that plays an important role in regulating the cell cycle. The content of CDC7 remains unchanged in the cell cycle, but it must also bind an important auxiliary protein ASK (activator of S phase kinase) to exert its regulatory function. After the CDC7-ASK complex is formed in the nucleus, it begins to phosphorylate and activate multiple members of the minichromosome maintenance complex (MCM) family bound to the chromosome, such as MCM2, MCM4, MCM6, especially the phosphorylation of MCM2 It has the strongest effect, and MCM is an important part of the helicase in the cell cycle initiation complex, which ultimately promotes the initiation of DNA replication and the progress of the cell cycle.
CDC7在正常细胞周期中表达水平是不变的，并且受到细胞周期中一些因子和辅助蛋白调控，处于一种动态平衡状态。在肿瘤细胞里由于细胞周期发生紊乱，CDC7是处于异常表达和过度激活状态。由于CDC7在多种肿瘤细胞里过表达，过表达的CDC7可促进肿瘤细胞的重要标记MCM2的过度活化，进而促进了肿瘤细胞的异常增殖。同时，CDC7在所有转移肿瘤细胞里也都显示出高表达，这也提示CDC7的异常高表达与肿瘤细胞的转移可能有密切的联系。CDC7的异常高表达和激活对肿瘤细胞化疗药物抗性也起到很关键的作用，CDC7可以通过磷酸化Claspin来进一步激活ATR/Chk1通路中止有丝分裂、修复受损的DNA来保护肿瘤细胞。The expression level of CDC7 is unchanged in the normal cell cycle, and is regulated by some factors and auxiliary proteins in the cell cycle, and is in a state of dynamic equilibrium. In tumor cells, due to cell cycle disorder, CDC7 is abnormally expressed and overactivated. Since CDC7 is overexpressed in a variety of tumor cells, overexpressed CDC7 can promote the overactivation of MCM2, an important marker of tumor cells, and then promote the abnormal proliferation of tumor cells. At the same time, CDC7 also showed high expression in all metastatic tumor cells, which also suggested that the abnormally high expression of CDC7 may be closely related to the metastasis of tumor cells. The abnormally high expression and activation of CDC7 also plays a key role in the resistance of tumor cells to chemotherapeutic drugs. CDC7 can further activate the ATR/Chk1 pathway by phosphorylating Claspin to terminate mitosis and repair damaged DNA to protect tumor cells.
武田制药开发的TAK-931(WO2011102399A1，WO2018158898A1)作为CDC7抑制剂，其CDC7抑制活性高，对CDC7高表达的细胞系人结肠癌细胞(COLO205细胞)抗增殖活性较高，在25个PDX(Patient-Derived tumor Xenograft)模型中表现出优秀的抑制肿瘤活性，目前已经处在临床二期，但其体内清除率高，半衰期短。礼来公司开发的LY3143921(WO2014143601A1)同样作为CDC7抑制剂，其CDC7抑制活性与TAK-931相当，半衰期长，体内暴露量高，目前已经处在临床一期，但对CDC7高表达的细胞系COLO205细胞抗增殖活性较TAK-931弱。因此研制新一代代谢稳定的CDC7抑制剂，在临床上有需求。As a CDC7 inhibitor, TAK-931 (WO2011102399A1, WO2018158898A1) developed by Takeda Pharmaceutical has high CDC7 inhibitory activity and high anti-proliferative activity on human colon cancer cells (COLO205 cells), a cell line with high expression of CDC7. -Derived tumor Xenograft) model showed excellent tumor-inhibiting activity and is currently in the second clinical phase, but its in vivo clearance rate is high and its half-life is short. LY3143921 (WO2014143601A1) developed by Eli Lilly is also used as a CDC7 inhibitor. Its CDC7 inhibitory activity is comparable to TAK-931, with a long half-life and high in vivo exposure. It is currently in the first clinical phase, but the cell line COLO205 with high expression of CDC7 The antiproliferative activity of cells was weaker than that of TAK-931. Therefore, there is a clinical need to develop a new generation of metabolically stable CDC7 inhibitors.
发明内容SUMMARY OF THE INVENTION
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 PCTCN2021142174-appb-000001
Figure PCTCN2021142174-appb-000001
其中，in,
环A选自5-6元杂芳基，其中所述5-6元杂芳基任选被1、2或3个R 2所取代； Ring A is selected from 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R2;
结构单元
Figure PCTCN2021142174-appb-000002
选自
Figure PCTCN2021142174-appb-000003
其中所述
Figure PCTCN2021142174-appb-000004
分别独立地任选被1、2或3个R 3所取代； Structural units
Figure PCTCN2021142174-appb-000002
selected from
Figure PCTCN2021142174-appb-000003
wherein the
Figure PCTCN2021142174-appb-000004
each independently optionally substituted with 1, 2 or 3 R3 ;
R 1选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a所取代； R 1 is selected from H and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a ;
R 2分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-3烷基、C 1-3烷氧基、4-6元杂环烷基、-L-4-6元杂环烷基和5-6元杂芳基，其中所述C 1-3烷基、C 1-3烷氧基、4-6元杂环烷基、-L-4-6元杂环烷基和5-6元杂芳基分别独立地任选被1、2或3个R b所取代； R 2 is independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl , -L-4-6-membered heterocycloalkyl and 5-6-membered heteroaryl, wherein the C 1-3 alkyl, C 1-3 alkoxy, 4-6-membered heterocycloalkyl, -L -4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2 or 3 R b ;
L选自-NH-和-O-；L is selected from -NH- and -O-;
R 3分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R c所取代； R 3 is each independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally 3 R c replaced;
R 4选自H、F、Cl、Br、I、-OH、-NH 2、-CN和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R d所取代； R 4 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally surrounded by 1, 2 or 3 R replaced by d ;
R a分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； Ra is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN;
R b分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2、-CN、C 1-3烷基和C 1-3烷氧基，其中所述C 1-3烷基和C 1-3烷氧基分别独立地任选被1、2或3个R所取代； R b is independently selected from F, Cl, Br, I, =O, -OH, -NH 2 , -CN, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 Alkyl and C 1-3 alkoxy are each independently optionally substituted with 1, 2 or 3 R;
R c分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； R c is independently selected from F, Cl, Br, I, =O, -OH , -NH and -CN;
R d分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； R d are independently selected from F, Cl, Br, I, =O, -OH, -NH 2 and -CN;
R分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； R is independently selected from F, Cl, Br, I, =O, -OH , -NH and -CN;
所述5-6元杂芳基和4-6元杂环烷基分别独立地包含1、2、3或4个独立选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。Said 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl independently comprise 1, 2, 3 or 4 heterocyclic groups independently selected from -O-, -NH-, -S- and -N- atom or heteroatomic group.
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 PCTCN2021142174-appb-000005
Figure PCTCN2021142174-appb-000005
其中，in,
环A选自5-6元杂芳基，其中所述5-6元杂芳基任选被1、2或3个R 2所取代； Ring A is selected from 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R2;
结构单元
Figure PCTCN2021142174-appb-000006
选自
Figure PCTCN2021142174-appb-000007
其中所述
Figure PCTCN2021142174-appb-000008
分别独立地任选被1、2或3个R 3所取代； Structural units
Figure PCTCN2021142174-appb-000006
selected from
Figure PCTCN2021142174-appb-000007
wherein the
Figure PCTCN2021142174-appb-000008
each independently optionally substituted with 1, 2 or 3 R3 ;
R 1选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a所取代； R 1 is selected from H and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a ;
R 2分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-3烷基、C 1-3烷氧基、4-6元杂环烷基、-L-4-6元杂环烷基和5-6元杂芳基，其中所述C 1-3烷基、C 1-3烷氧基、4-6元杂环烷基、-L-4-6元杂环烷基和5-6 元杂芳基分别独立地任选被1、2或3个R b所取代； R 2 is independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl , -L-4-6-membered heterocycloalkyl and 5-6-membered heteroaryl, wherein the C 1-3 alkyl, C 1-3 alkoxy, 4-6-membered heterocycloalkyl, -L -4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2 or 3 R b ;
L选自-NH-和-O-；L is selected from -NH- and -O-;
R 3分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R c所取代； R 3 is each independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally 3 R c replaced;
R 4选自H、F、Cl、Br、I、-OH、-NH 2、-CN和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R d所取代； R 4 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally surrounded by 1, 2 or 3 R replaced by d ;
R a分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； Ra is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN;
R b分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2、-CN和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R所取代； R b are each independently selected from F, Cl, Br, I, =O, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally replaced by 1, 2 or replaced by 3 Rs;
R c分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； R c is independently selected from F, Cl, Br, I, =O, -OH , -NH and -CN;
R d分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； R d are independently selected from F, Cl, Br, I, =O, -OH, -NH 2 and -CN;
R分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； R is independently selected from F, Cl, Br, I, =O, -OH , -NH and -CN;
所述5-6元杂芳基和4-6元杂环烷基分别独立地包含1、2、3或4个独立选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。Said 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl independently comprise 1, 2, 3 or 4 heterocyclic groups independently selected from -O-, -NH-, -S- and -N- atom or heteroatomic group.
本发明的一些方案中，上述化合物具有式(I)所示结构：In some schemes of the present invention, the above-mentioned compound has the structure shown in formula (I):
Figure PCTCN2021142174-appb-000009
Figure PCTCN2021142174-appb-000009
其中，环A、R 1、R 3和R 4如本发明所定义。 wherein Ring A, R 1 , R 3 and R 4 are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(I-1)所示结构：In some schemes of the present invention, the above-mentioned compound has the structure represented by formula (I-1):
Figure PCTCN2021142174-appb-000010
Figure PCTCN2021142174-appb-000010
其中，环A、R 1、R 3和R 4如本发明所定义； wherein, ring A, R 1 , R 3 and R 4 are as defined in the present invention;
带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。A carbon atom with "*" is a chiral carbon atom and exists in (R) or (S) single enantiomeric form or enriched in one enantiomeric form.
本发明的一些方案中，上述R b分别独立地选自F、Cl、Br、-OH、-CH 3和-OCH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R b are independently selected from F, Cl, Br, -OH, -CH 3 and -OCH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R b分别独立地选自F、Cl、Br、-OH和-CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R b are independently selected from F, Cl, Br, -OH and -CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R c分别独立地选自F、Cl和Br，其他变量如本发明所定义。 In some embodiments of the present invention, the above R c are independently selected from F, Cl and Br, and other variables are as defined in the present invention.
本发明的一些方案中，上述R 1选自H和-CH 3，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 1 is selected from H and -CH 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、-NH 2、-CN、-CH 3、-CH 2CH 3、-OCH 3、
Figure PCTCN2021142174-appb-000011
其中所述 -CH 3、-OCH 3、
Figure PCTCN2021142174-appb-000012
分别独立地任选被1、2或3个R b所取代，R b及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 is independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -OCH 3 ,
Figure PCTCN2021142174-appb-000011
wherein the -CH 3 , -OCH 3 ,
Figure PCTCN2021142174-appb-000012
Each independently is optionally substituted with 1, 2 or 3 R b , R b and other variables as defined herein.
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、-NH 2、-CN、-CH 3、-OCH 3、
Figure PCTCN2021142174-appb-000013
Figure PCTCN2021142174-appb-000014
其中所述-CH 3、-OCH 3、
Figure PCTCN2021142174-appb-000015
Figure PCTCN2021142174-appb-000016
分别独立地任选被1、2或3个R b所取代，R b及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 is independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -OCH 3 ,
Figure PCTCN2021142174-appb-000013
Figure PCTCN2021142174-appb-000014
wherein the -CH 3 , -OCH 3 ,
Figure PCTCN2021142174-appb-000015
Figure PCTCN2021142174-appb-000016
Each independently is optionally substituted with 1, 2 or 3 R b , R b and other variables as defined herein.
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、-NH 2、-CN、-CH 3、-CH 2CH 2OCH 3、-CHF 2、-CF 3、-OCH 3、
Figure PCTCN2021142174-appb-000017
Figure PCTCN2021142174-appb-000018
其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 is independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -CH 2 CH 2 OCH 3 , -CHF 2 , -CF 3 , -OCH 3 ,
Figure PCTCN2021142174-appb-000017
Figure PCTCN2021142174-appb-000018
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 2分别独立地选自H、F、Cl、Br、-NH 2、-CN、-CH 3、-CF 3、-OCH 3、、
Figure PCTCN2021142174-appb-000019
其他变量如本发明所定义。 In some embodiments of the present invention, the above R 2 are independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -CF 3 , -OCH 3 ,
Figure PCTCN2021142174-appb-000019
Other variables are as defined in the present invention.
本发明的一些方案中，上述R 3分别独立地选自H、F、Cl、Br和-CH 3，其中所述-CH 3任选被1、2或3个R c所取代，R c及其他变量如本发明所定义。 In some embodiments of the present invention, the above R 3 are independently selected from H, F, Cl, Br and -CH 3 , wherein the -CH 3 is optionally substituted by 1, 2 or 3 R c , R c and Other variables are as defined in the present invention.
本发明的一些方案中，上述R 3分别独立地选自H、-CH 3和-CF 3，其他变量如本发明所定义。 In some aspects of the present invention, the above R 3 is independently selected from H, -CH 3 and -CF 3 , and other variables are as defined in the present invention.
本发明的一些方案中，上述R 4选自H、F、Cl和Br，其他变量如本发明所定义。 In some embodiments of the present invention, the above R 4 is selected from H, F, Cl and Br, and other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自吡啶基、嘧啶基和哒嗪基，其中所述吡啶基、嘧啶基和哒嗪基分别独立地任选被1、2或3个R 2所取代，R 2及其他变量如本发明所定义。 In some aspects of the present invention, the above ring A is selected from pyridyl, pyrimidinyl and pyridazinyl, wherein said pyridyl, pyrimidinyl and pyridazinyl are each independently optionally substituted with 1, 2 or 3 R2 , R 2 and other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自
Figure PCTCN2021142174-appb-000020
其中所述
Figure PCTCN2021142174-appb-000021
Figure PCTCN2021142174-appb-000022
分别独立地任选被1、2或3个R 2所取代，R 2及其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned ring A is selected from
Figure PCTCN2021142174-appb-000020
wherein the
Figure PCTCN2021142174-appb-000021
Figure PCTCN2021142174-appb-000022
Each independently is optionally substituted with 1, 2 or 3 R 2 , R 2 and other variables as defined herein.
本发明的一些方案中，上述环A选自
Figure PCTCN2021142174-appb-000023
Figure PCTCN2021142174-appb-000024
R 2及其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned ring A is selected from
Figure PCTCN2021142174-appb-000023
Figure PCTCN2021142174-appb-000024
R2 and other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自
Figure PCTCN2021142174-appb-000025
Figure PCTCN2021142174-appb-000026
R 2及其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned ring A is selected from
Figure PCTCN2021142174-appb-000025
Figure PCTCN2021142174-appb-000026
R2 and other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自
Figure PCTCN2021142174-appb-000027
Figure PCTCN2021142174-appb-000028
Figure PCTCN2021142174-appb-000029
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned ring A is selected from
Figure PCTCN2021142174-appb-000027
Figure PCTCN2021142174-appb-000028
Figure PCTCN2021142174-appb-000029
Other variables are as defined in the present invention.
本发明的一些方案中，上述环A选自
Figure PCTCN2021142174-appb-000030
Figure PCTCN2021142174-appb-000031
Figure PCTCN2021142174-appb-000032
Figure PCTCN2021142174-appb-000033
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned ring A is selected from
Figure PCTCN2021142174-appb-000030
Figure PCTCN2021142174-appb-000031
Figure PCTCN2021142174-appb-000032
Figure PCTCN2021142174-appb-000033
Other variables are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(I-2)～(I-6)所示结构：In some schemes of the present invention, the above-mentioned compounds have structures represented by formulas (I-2) to (I-6):
Figure PCTCN2021142174-appb-000034
Figure PCTCN2021142174-appb-000034
其中，n选自0、1、2或3；R 1、R 2、R 3和R 4如本发明所定义。 wherein, n is selected from 0, 1, 2 or 3; R 1 , R 2 , R 3 and R 4 are as defined in the present invention.
本发明的一些方案中，上述化合物具有式(I-2a)～(I-6b)所示结构：In some schemes of the present invention, the above-mentioned compounds have structures represented by formulas (I-2a) to (I-6b):
Figure PCTCN2021142174-appb-000035
Figure PCTCN2021142174-appb-000035
Figure PCTCN2021142174-appb-000036
Figure PCTCN2021142174-appb-000036
其中，n、R 1、R 2、R 3和R 4本发明所定义。 Wherein, n, R 1 , R 2 , R 3 and R 4 are defined in the present invention.
本发明还有一些方案是由上述各变量任意组合而来。There are still some solutions of the present invention which are obtained by any combination of the above variables.
本发明还提供了下式化合物或其药学上可接受的盐，The present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021142174-appb-000037
Figure PCTCN2021142174-appb-000037
Figure PCTCN2021142174-appb-000038
Figure PCTCN2021142174-appb-000038
Figure PCTCN2021142174-appb-000039
Figure PCTCN2021142174-appb-000039
本发明还提供了下式化合物或其药学上可接受的盐，The present invention also provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
Figure PCTCN2021142174-appb-000040
Figure PCTCN2021142174-appb-000040
Figure PCTCN2021142174-appb-000041
Figure PCTCN2021142174-appb-000041
Figure PCTCN2021142174-appb-000042
Figure PCTCN2021142174-appb-000042
Figure PCTCN2021142174-appb-000043
Figure PCTCN2021142174-appb-000043
Figure PCTCN2021142174-appb-000044
Figure PCTCN2021142174-appb-000044
技术效果technical effect
本发明化合物具有良好的CDC7抑制活性，以及对COLO-205细胞、Capan-1细胞(人胰腺癌肿瘤细胞)具有显著的抑制活性，进而获得了优良的抑制肿瘤生长的活性，并且具有体内PK(药物效应动力学)半衰期长、暴露量高等优势，在人胰腺癌细胞CAPAN-1裸小鼠皮下移植瘤的体内药效模型中具有较好的抑瘤效果The compound of the present invention has good CDC7 inhibitory activity, and has significant inhibitory activity on COLO-205 cells and Capan-1 cells (human pancreatic cancer tumor cells), thereby obtaining excellent tumor growth inhibitory activity, and has in vivo PK ( Pharmacodynamics) has the advantages of long half-life and high exposure, and has a good tumor inhibition effect in the in vivo pharmacodynamic model of human pancreatic cancer cell CAPAN-1 nude mice subcutaneously transplanted.
定义和说明Definition and Explanation
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered indeterminate or unclear without specific definitions, but should be understood in its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding commercial product or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。As used herein, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and/or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue , without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
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 salts" refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in neat solution or in a suitable inert solvent. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salts or similar salts. When compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts including, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-toluenesulfonic, citric, tartaric, and methanesulfonic acids; also include salts of amino acids such as arginine, etc. , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain both basic and acidic functional groups and thus can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。The pharmaceutically acceptable salts of the present invention can be synthesized from the acid or base containing parent compound by conventional chemical methods. Generally, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of the two.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and racemic mixtures thereof and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which belong to this within the scope of the invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
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 indicated, 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 terms "cis-trans isomer" or "geometric isomer" result from the inability to rotate freely by double bonds or single bonds of ring 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 indicated, the term "diastereomer" refers to a stereoisomer in which the molecule has two or more chiral centers and the molecules are in a non-mirror-image relationship.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise specified, "(+)" means dextrorotatory, "(-)" means levorotatory, and "(±)" means racemic.
除非另有说明，用楔形实线键
Figure PCTCN2021142174-appb-000045
和楔形虚线键
Figure PCTCN2021142174-appb-000046
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2021142174-appb-000047
和直形虚线键
Figure PCTCN2021142174-appb-000048
表示立体中心的相对构型，用波浪线
Figure PCTCN2021142174-appb-000049
表示楔形实线键
Figure PCTCN2021142174-appb-000050
或楔形虚线键
Figure PCTCN2021142174-appb-000051
或用波浪线
Figure PCTCN2021142174-appb-000052
表示直形实线键
Figure PCTCN2021142174-appb-000053
和直形虚线键
Figure PCTCN2021142174-appb-000054
Use solid wedge keys unless otherwise specified
Figure PCTCN2021142174-appb-000045
and wedge-dotted keys
Figure PCTCN2021142174-appb-000046
Indicate the absolute configuration of a stereocenter, using a straight solid key
Figure PCTCN2021142174-appb-000047
and straight dashed keys
Figure PCTCN2021142174-appb-000048
Indicate the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2021142174-appb-000049
Represents a solid wedge key
Figure PCTCN2021142174-appb-000050
or wedge-dotted key
Figure PCTCN2021142174-appb-000051
or with wavy lines
Figure PCTCN2021142174-appb-000052
Represents a straight solid key
Figure PCTCN2021142174-appb-000053
and straight dashed keys
Figure PCTCN2021142174-appb-000054
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。The compounds of the present invention may exist in particular. Unless otherwise specified, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium and are rapidly interconverted at room temperature. A chemical equilibrium of tautomers can be achieved if tautomers are possible (eg, in solution). For example, proton tautomers (also called prototropic tautomers) include interconversions by migration of protons, such as keto-enol isomerization and imine-ene Amine isomerization. Valence tautomers include interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers, 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 indicated, the terms "enriched in one isomer", "enriched in isomers", "enriched in one enantiomer" or "enriched in one enantiomer" refer to one of the isomers or pairs The enantiomer content is less than 100%, and the isomer or enantiomer content is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
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(e.e.值)为80％。Unless otherwise indicated, the terms "isomeric excess" or "enantiomeric excess" refer to the difference between two isomers or relative percentages of two enantiomers. For example, where the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (e.e. 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)。Optically active (R)- and (S)-isomers, as well as D and L isomers, can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting mixture of diastereomers is separated and the auxiliary group is cleaved to provide pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, followed by conventional methods known in the art The diastereoisomers were resolved and the pure enantiomers recovered. In addition, separation of enantiomers and diastereomers is usually accomplished by the use of chromatography employing a chiral stationary phase, optionally in combination with chemical derivatization (eg, from amines to amino groups) formate).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。 The compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute 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, deuterated drugs can be formed by replacing hydrogen with deuterium, and the bonds formed by deuterium and carbon are stronger than those formed by ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All transformations of the isotopic composition of the compounds of the present invention, whether radioactive or not, are included within the scope of the present invention.
术语“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。The terms "optional" or "optionally" mean that the subsequently described event or circumstance may, but need not, occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. .
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 specified atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable. When the substituent is oxygen (ie =O), it means that two hydrogen atoms are substituted. Oxygen substitution does not occur on aromatic groups. The term "optionally substituted" means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically achievable basis.
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 (eg, 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 may optionally be substituted with up to two Rs, with independent options for R in each case. Furthermore, combinations of substituents and/or variants thereof are permissible only 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 to it 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 does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituents do not indicate through which atom it is attached to the substituted group, such substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be through any one of the pyridine ring The carbon atom is attached to the substituted group.
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 PCTCN2021142174-appb-000055
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 PCTCN2021142174-appb-000056
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 PCTCN2021142174-appb-000057
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 direction of attachment, the direction of attachment is arbitrary, for example,
Figure PCTCN2021142174-appb-000055
The linking group L in the middle is -MW-, at this time -MW- can connect ring A and ring B in the same direction as the reading order from left to right.
Figure PCTCN2021142174-appb-000056
It is also possible to connect ring A and ring B in the opposite direction to the reading order from left to right.
Figure PCTCN2021142174-appb-000057
Combinations of the linking groups, substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
除非另有规定，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2021142174-appb-000058
直形虚线键
Figure PCTCN2021142174-appb-000059
或波浪线
Figure PCTCN2021142174-appb-000060
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2021142174-appb-000061
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2021142174-appb-000062
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连。
Figure PCTCN2021142174-appb-000063
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括
Figure PCTCN2021142174-appb-000064
Figure PCTCN2021142174-appb-000065
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2021142174-appb-000066
仍包括
Figure PCTCN2021142174-appb-000067
这种连接方式的基团，只是在连接1个化学键时，该位点的H会对应减少1个变成相应的一价哌啶基。 Unless otherwise specified, when a group has one or more attachable sites, any one or more sites in the group can be linked to other groups by chemical bonds. When the connection method of the chemical bond is not located, and there is an H atom at the linkable site, when the chemical bond is connected, the number of H atoms at the site will be correspondingly reduced with the number of chemical bonds connected to the corresponding valence. the group. The chemical bond connecting the site to other groups can be represented by straight solid line bonds
Figure PCTCN2021142174-appb-000058
straight dotted key
Figure PCTCN2021142174-appb-000059
or wavy lines
Figure PCTCN2021142174-appb-000060
express. For example, a straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in this group;
Figure PCTCN2021142174-appb-000061
The straight dashed bond in the group indicates that it is connected to other groups through the two ends of the nitrogen atom in the group;
Figure PCTCN2021142174-appb-000062
The wavy lines in the phenyl group indicate connections to other groups through the 1 and 2 carbon atoms in the phenyl group.
Figure PCTCN2021142174-appb-000063
Indicates that any linkable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure PCTCN2021142174-appb-000064
Figure PCTCN2021142174-appb-000065
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure PCTCN2021142174-appb-000066
still includes
Figure PCTCN2021142174-appb-000067
The group in this connection method is only that when one chemical bond is connected, the H at the site will be correspondingly reduced by one to become the corresponding monovalent piperidinyl group.
当某取代基的化学键与连接环上两原子的化学键相交时，说明该取代基可与环上任意原子成键。当某取代基连接的原子并没有指明的时候，该取代基可以与任意原子成键，如果取代基连接的原子在双环或者三环体系中，则说明该取代基可与该体系中任意环的任意原子成键。取代基及/或变量的组合只有在该组合产生稳定的化合物时才被允许。例如，结构单元
Figure PCTCN2021142174-appb-000068
表示其可在环己基或者环戊基上的任意一个位置发生取代。 When the chemical bond of a substituent intersects with the chemical bond connecting two atoms on the ring, it means that the substituent can form a bond with any atom on the ring. When the atom to which a substituent is connected is not specified, the substituent can form a bond with any atom. If the atom to which the substituent is connected is in a bicyclic or tricyclic system, it indicates that the substituent can be bonded to any ring in the system. Any atom forms a bond. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. For example, structural unit
Figure PCTCN2021142174-appb-000068
Indicates that it can be substituted at any position on cyclohexyl or cyclopentyl.
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 denote a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (eg methyl), divalent (eg methylene) or multivalent (eg methine) . Examples of C1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
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 " C1-3alkoxy " refers to those alkyl groups containing 1 to 3 carbon atoms attached to the remainder of the molecule through an oxygen atom. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy and the like. Examples of C 1-3 alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，本发明术语“5-6元杂芳环”和“5-6元杂芳基”可以互换使用，术语“5-6元杂芳基”表示由5至6个环原子组成的具有共轭π电子体系的单环基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子。其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。5-6元杂芳基可通过杂原子或碳原子连接到分子的其余部分。所述5-6元杂芳基包括5元和6元杂芳基。所述5-6元杂芳基的实例包括但不限于吡咯基(包括N-吡咯基、2-吡咯基和3-吡咯基等)、吡唑基(包括2-吡唑基和3-吡唑基等)、咪唑基(包括N-咪唑基、2-咪唑基、4-咪唑基和5-咪唑基等)、噁唑基(包括2-噁唑基、4-噁唑基和5-噁唑基等)、三唑基(1H-1,2,3-三唑基、2H-1,2,3-三唑基、1H-1,2,4-三唑基和4H-1,2,4-三唑基等)、四唑基、异噁唑基(3-异噁唑基、4-异噁唑基和5-异噁唑基等)、噻唑基(包括2-噻唑基、4-噻唑基和5-噻唑基等)、呋喃基(包括2-呋喃基和3-呋喃基等)、噻吩基(包括2-噻吩基和3-噻吩基等)、吡啶基(包括2-吡啶基、3-吡啶基和4-吡啶基等)、吡嗪基或嘧啶基(包括2-嘧啶基和4-嘧啶基等)。 Unless otherwise specified, the terms "5-6 membered heteroaryl ring" and "5-6 membered heteroaryl" are used interchangeably in the present invention, and the term "5-6 membered heteroaryl" means from 5 to 6 ring atoms It is composed of a monocyclic group with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (ie, NO and S(O) p , p is 1 or 2). A 5-6 membered heteroaryl group can be attached to the remainder of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl groups include 5- and 6-membered heteroaryl groups. Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl, etc.), thiazolyl (including 2-thiazolyl , 4-thiazolyl and 5-thiazolyl, etc.), furyl (including 2-furyl and 3-furyl, etc.), thienyl (including 2-thienyl and 3-thienyl, etc.), pyridyl (including 2- -pyridyl, 3-pyridyl and 4-pyridyl, etc.), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl, etc.).
除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉 基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。 Unless otherwise specified, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 4 to 6 ring atoms, respectively, of which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, where the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (ie, NO and S(O) p , p is 1 or 2). It includes monocyclic and bicyclic ring systems, wherein bicyclic ring systems include spiro, paracyclic and bridged rings. Furthermore, with respect to the "4-6 membered heterocycloalkyl", a heteroatom may occupy the position of attachment of the heterocycloalkyl to the remainder of the molecule. The 4-6 membered heterocycloalkyl includes 5-6 membered, 4 membered, 5 membered and 6 membered heterocycloalkyl and the like. Examples of 4-6 membered heterocycloalkyl include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2- piperidinyl and 3-piperidyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), Dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl or homopiperazinyl pyridyl, etc.
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, Cn-n+m or Cn - Cn+m includes any particular instance of n to n+ m carbons, eg C1-12 includes C1 , C2 , C3, C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , also including any range from n to n+ m , eg C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12 , etc.; in the same way, n yuan to n +m-membered means that the number of atoms in the ring is from n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring , 10-membered ring, 11-membered ring, and 12-membered ring, also including any one 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, and 6-10 membered ring, etc.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, a nucleophilic substitution reaction). For example, representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonic acid Esters, etc.; acyloxy, such as acetoxy, trifluoroacetoxy, and the like.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)，2-(三甲基硅)乙氧基甲基(SEM)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl groups, such as alkanoyl groups (eg, acetyl, trichloroacetyl, or trifluoroacetyl); alkoxycarbonyl groups, such as tert-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl groups such as trimethylsilyl (TMS), 2-(trimethylsilyl)ethoxymethyl (SEM) and tert-butyldiphenyl Methylsilyl (TBS) and the like. The term "hydroxy protecting group" refers to a protecting group suitable for preventing hydroxyl side reactions. Representative hydroxy protecting groups include, but are not limited to: alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (eg acetyl); arylmethyl groups such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and the like.
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 enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
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 D8venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2021142174-appb-000069
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 diffractometry (SXRD), the cultivated single crystal is collected by Bruker D8venture diffractometer, the light source is CuKα radiation, and the scanning method is as follows:
Figure PCTCN2021142174-appb-000069
After scanning and collecting relevant data, the crystal structure was further analyzed by the direct method (Shelxs97), and the absolute configuration could be confirmed.
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.
本发明采用下述缩略词：Alloc代表烯丙氧羰基；SEM代表三甲基硅烷基乙氧甲基；OTs代表4-甲苯磺酰基；Boc代表叔丁氧羰基；DCM代表二氯甲烷；DIEA代表N,N-二异丙基乙胺；MeI代表碘甲烷；PE代表石油醚；EA代表乙酸乙酯；THF代表四氢呋喃；EtOH代表乙醇；MeOH代表甲醇；Boc 2O代表二碳酸二叔丁酯；NH 4Cl代表氯化铵；T 3P代表1-丙基磷酸三环酸酐；Pd/C代表钯/碳催化剂；TMSN 3代表叠氮基三甲基硅烷；NCS代表N-氯代丁二酰亚胺；HBr代表氢溴酸；AcOH代表醋酸；HATU代表O-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸盐；DBU代表1,8-二氮杂二环十一碳-7-烯；FA代表甲酸；ACN代表乙腈；TLC代表薄层色谱；HPLC代表高压液相色谱；LCMS代表液质联用色谱；SFC代表超临界流 体色谱法。DMSO代表二甲亚砜；DMSO-d 6代表氘代二甲亚砜；CD 3OD代表氘代甲醇；CDCl 3代表氘代氯仿；D 2O代表氘水；BID代表一日两次。 The following abbreviations are used in the present invention: Alloc stands for allyloxycarbonyl; SEM stands for trimethylsilylethoxymethyl; OTs stands for 4-toluenesulfonyl; Boc stands for tert-butoxycarbonyl; DCM stands for dichloromethane; DIEA Represents N,N-diisopropylethylamine; MeI represents methyl iodide; PE represents petroleum ether; EA represents ethyl acetate; THF represents tetrahydrofuran; EtOH represents ethanol; MeOH represents methanol; Boc 2 O represents di-tert-butyl dicarbonate ; NH 4 Cl for ammonium chloride; T 3 P for 1-propylphosphoric acid tricyclic anhydride; Pd/C for palladium/carbon catalyst; TMSN 3 for azidotrimethylsilane; NCS for N-chlorobutanedi Imide; HBr for hydrobromic acid; AcOH for acetic acid; HATU for O-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate; DBU stands for 1,8-diazabicycloundec-7-ene; FA stands for formic acid; ACN stands for acetonitrile; TLC stands for thin layer chromatography; HPLC stands for high pressure liquid chromatography; Critical Fluid Chromatography. DMSO stands for dimethyl sulfoxide; DMSO-d 6 stands for deuterated dimethyl sulfoxide; CD 3 OD stands for deuterated methanol; CDCl 3 stands for deuterated chloroform; D 2 O stands for deuterated water; BID stands for twice a day.
化合物依据本领域常规命名原则或者使用
Figure PCTCN2021142174-appb-000070
软件命名，市售化合物采用供应商目录名称。 Compounds are named according to conventional nomenclature in the art or are used
Figure PCTCN2021142174-appb-000070
Software naming, commercially available compounds use supplier catalog names.
附图说明Description of drawings
图1为本发明化合物在CAPAN-1裸小鼠皮下移植瘤模型中的体内药效实验结果。Figure 1 shows the results of in vivo pharmacodynamic experiments of the compounds of the present invention in CAPAN-1 nude mice subcutaneously transplanted tumor model.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本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 present invention will be described in detail by the following examples, but it does not mean any unfavorable limitation of the present invention. The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments enumerated below, embodiments formed in combination with other chemical synthesis methods, and those well known to those skilled in the art Equivalent to alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the invention.
中间体AIntermediate A
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000071
Figure PCTCN2021142174-appb-000071
第一步first step
将中间体A-1(9.40g,45.8mmol)溶于三乙胺(60mL),N,N-二甲基甲酰胺(60mL)和甲醇(180mL)中,加入[1,1'-双(二苯基膦基)二茂铁]二氯化钯(3.35g,4.58mmol),反应液在一氧化碳气体保护,压力50psi(磅力每平方英寸),80℃下搅拌12小时。反应液过滤,滤液加水(300mL),乙酸乙酯(150mL×3)萃取,有机相经饱和食盐水洗涤(250mL×3),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,20/1～10/1,V/V)分离得到中间体A-2。 1H NMR(400MHz,CDCl 3)δ7.47(d,J＝5.2Hz,1H),7.36(d,J＝4.8Hz,1H),3.93(s,3H),2.62(s,3H)。 Intermediate A-1 (9.40 g, 45.8 mmol) was dissolved in triethylamine (60 mL), N,N-dimethylformamide (60 mL) and methanol (180 mL), and [1,1'-bis( Diphenylphosphino)ferrocene]palladium dichloride (3.35g, 4.58mmol), the reaction solution was protected by carbon monoxide gas, pressure 50psi (pound force per square inch), and stirred at 80°C for 12 hours. The reaction solution was filtered, water (300 mL) was added to the filtrate, extracted with ethyl acetate (150 mL×3), the organic phase was washed with saturated brine (250 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 20/1～10/1, V/V) to obtain Intermediate A-2. 1 H NMR (400 MHz, CDCl 3 ) δ 7.47 (d, J=5.2 Hz, 1H), 7.36 (d, J=4.8 Hz, 1H), 3.93 (s, 3H), 2.62 (s, 3H).
第二步second step
将中间体A-2(7.9g,42.89mmol)溶于四氢呋喃(80mL)中,加入四异丙氧化钛(24.4g,85.8mmol)和中间体A-3(7.06g,51.5mmol),反应液70℃下搅拌12小时,然后反应液冷却至0℃,缓慢加入硼氢化钠(4.87g,129mmol),反应液20℃下搅拌2小时。反应液加水(100mL)和乙酸乙酯(80mL),过滤,滤液乙酸乙酯(50mL×3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～3/1,V/V)分离得到中间体A-4。MS-ESI计算值[M+H] +334,实测值334。 Intermediate A-2 (7.9 g, 42.89 mmol) was dissolved in tetrahydrofuran (80 mL), titanium tetraisopropoxide (24.4 g, 85.8 mmol) and intermediate A-3 (7.06 g, 51.5 mmol) were added, and the reaction solution was After stirring at 70°C for 12 hours, the reaction solution was cooled to 0°C, sodium borohydride (4.87 g, 129 mmol) was slowly added, and the reaction solution was stirred at 20°C for 2 hours. The reaction solution was added with water (100 mL) and ethyl acetate (80 mL), filtered, the filtrate was extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V) to obtain Intermediate A-4. MS-ESI calculated [M+H] + 334, found 334.
第三步third step
将中间体A-4(9g,26.99mmol)溶于水(30mL)、甲醇(50mL)、四氢呋喃(100mL),加入氢氧化钠(4.32g,107.96mmol),反应液在64℃下搅拌12小时。反应液直接减压浓缩,加入1mol/L稀盐酸至pH＝4,乙酸乙酯(200mL×2)萃取,合并有机相,经饱和食盐水洗涤(50mL×1),用无水硫酸钠干燥,过滤,减压浓缩。得到中间体A-5,未经纯化直接用于下步反应。Intermediate A-4 (9 g, 26.99 mmol) was dissolved in water (30 mL), methanol (50 mL), tetrahydrofuran (100 mL), sodium hydroxide (4.32 g, 107.96 mmol) was added, and the reaction solution was stirred at 64 ° C for 12 hours . The reaction solution was directly concentrated under reduced pressure, 1 mol/L dilute hydrochloric acid was added to pH=4, extracted with ethyl acetate (200 mL×2), the organic phases were combined, washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, Filter and concentrate under reduced pressure. The intermediate A-5 was obtained, which was directly used in the next reaction without purification.
第四步the fourth step
将中间体A-5(10g,34.32mmol)溶于乙酸乙酯(200mL),加入三正丙基环磷酸酐(43.68g,68.64mmol,50％乙酸乙酯溶液)和三乙胺(10.42g,102.96mmol),反应液在25℃下搅拌50分钟。反应液加乙酸乙酯稀释后经水(50mL×2)洗涤,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～3/1,V/V)分离得到中间体A-6。Intermediate A-5 (10 g, 34.32 mmol) was dissolved in ethyl acetate (200 mL), tri-n-propyl cyclic phosphoric anhydride (43.68 g, 68.64 mmol, 50% ethyl acetate solution) and triethylamine (10.42 g were added) , 102.96 mmol), the reaction solution was stirred at 25 ° C for 50 minutes. The reaction solution was diluted with ethyl acetate and washed with water (50 mL×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V) to obtain Intermediate A-6.
第五步the fifth step
将中间体A-6(7.00g,25.61mmol)溶于氯仿(200mL),加入液溴(4.91g,30.73mmol),反应液在25℃下搅拌12小时。反应加饱和亚硫酸钠(20mL),二氯甲烷(200mL)萃取，有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到中间体A。MS-ESI计算值[M+H] +352和354,实测值352和354。 Intermediate A-6 (7.00 g, 25.61 mmol) was dissolved in chloroform (200 mL), liquid bromine (4.91 g, 30.73 mmol) was added, and the reaction solution was stirred at 25° C. for 12 hours. The reaction was added with saturated sodium sulfite (20 mL) and extracted with dichloromethane (200 mL). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain Intermediate A. MS-ESI calculated [M+H] + 352 and 354, found 352 and 354.
中间体BIntermediate B
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000072
Figure PCTCN2021142174-appb-000072
第一步first step
将中间体A(1.8g,5.11mmol)溶于四氢呋喃(20mL),在-78℃下滴加双(三甲基硅)氨基钾(6.13mL,1mol/L的四氢呋喃溶液),在-78℃搅拌0.5小时,加入中间体B-1(1.35g,10.22mmol),反应液在0℃下搅拌1小时。反应液加入饱和氯化铵水溶液(20mL),乙酸乙酯(50mL×3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到中间体B-2。MS-ESI计算值[M+H] +448和450,实测值448和450。 Intermediate A (1.8 g, 5.11 mmol) was dissolved in tetrahydrofuran (20 mL), bis(trimethylsilyl) potassium amide (6.13 mL, 1 mol/L solution in tetrahydrofuran) was added dropwise at -78 °C, and the solution was heated at -78 °C. After stirring for 0.5 hours, intermediate B-1 (1.35 g, 10.22 mmol) was added, and the reaction solution was stirred at 0° C. for 1 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (20 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain intermediate B-2. MS-ESI calculated [M+H] + 448 and 450, found 448 and 450.
第二步second step
将中间体B-2(2.1g,4.68mmol)溶于乙腈(50mL)和水(5mL),后加入硝酸铈铵(7.7g,14.05mmol)反应液在25℃下搅拌12小时。反应液加乙酸乙酯(100mL)稀释，经水(30mL×2)洗涤，水层经乙酸乙酯(50mL×2)萃取,合并有机相经无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到中间体B-3。MS-ESI计算值[M+H] +250,实测值250。 Intermediate B-2 (2.1 g, 4.68 mmol) was dissolved in acetonitrile (50 mL) and water (5 mL), and ceric ammonium nitrate (7.7 g, 14.05 mmol) was added to the reaction solution and stirred at 25° C. for 12 hours. The reaction solution was diluted with ethyl acetate (100 mL), washed with water (30 mL×2), the aqueous layer was extracted with ethyl acetate (50 mL×2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain intermediate B-3. MS-ESI calculated [M+H] + 250, found 250.
第三步third step
将中间体B-3(210mg,802μmol)溶于三氟乙酸(2mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(158mg,0.88mmol)后滴加浓硫酸(0.2mL),反应液在0℃下搅拌1小时。将反应液用饱和碳酸氢钠水溶 液调节pH至8后用乙酸乙酯(40mL×2)萃取,有机相经食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到中间体B。 1H NMR(400MHz,CDCl 3)δ8.96(d,J＝2.8Hz,1H),8.60(d,J＝2.8Hz,1H),7.20(s,1H),1.89(s,3H)。 Intermediate B-3 (210 mg, 802 μmol) was dissolved in trifluoroacetic acid (2 mL), N-bromosuccinimide (158 mg, 0.88 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid ( 0.2 mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (40 mL×2). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Intermediate B was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V). 1 H NMR (400 MHz, CDCl 3 ) δ 8.96 (d, J=2.8 Hz, 1H), 8.60 (d, J=2.8 Hz, 1H), 7.20 (s, 1H), 1.89 (s, 3H).
中间体CIntermediate C
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000073
Figure PCTCN2021142174-appb-000073
第一步first step
将中间体A-2(42.0g,228mmol)溶于四氢呋喃(500mL),加入四异丙基氧钛(129.6g,456mmol)和C-1(41.4g,274mmol)。反应液在70℃下搅拌12小时。将反应液降到0℃,硼氢化钠(17.3g,456mmol)加入到反应液中，反应液在25℃下搅拌2小时。反应液加水(2000mL),过滤，滤液加乙酸乙酯(2000mL×2)萃取,有机相经饱和食盐水洗涤(2000mL×1),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～3/1,V/V)分离得到中间体C-2。MS-ESI计算值[M+H] +348,实测值348。 Intermediate A-2 (42.0 g, 228 mmol) was dissolved in tetrahydrofuran (500 mL) and tetraisopropyltitanium (129.6 g, 456 mmol) and C-1 (41.4 g, 274 mmol) were added. The reaction solution was stirred at 70°C for 12 hours. The reaction solution was lowered to 0 °C, sodium borohydride (17.3 g, 456 mmol) was added to the reaction solution, and the reaction solution was stirred at 25 °C for 2 hours. The reaction solution was added with water (2000 mL), filtered, the filtrate was extracted with ethyl acetate (2000 mL×2), the organic phase was washed with saturated brine (2000 mL×1), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V) to obtain intermediate C-2. MS-ESI calculated [M+H] + 348, found 348.
第二步second step
将中间体C-2(75.1g,216mmol)溶于水(100mL),甲醇(400mL)和四氢呋喃(400mL),加入氢氧化钠(34.6g,864mmol),反应液在60℃下搅拌12小时。反应液直接减压浓缩,加入1mol/L稀盐酸至pH＝3,二氯甲烷(1000mL×3)萃取,合并有机相,有机相经饱和食盐水(1000mL×1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩得到中间体C-3。MS-ESI计算值[M+H] +306,实测值306。 Intermediate C-2 (75.1 g, 216 mmol) was dissolved in water (100 mL), methanol (400 mL) and tetrahydrofuran (400 mL), sodium hydroxide (34.6 g, 864 mmol) was added, and the reaction solution was stirred at 60° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, added 1 mol/L dilute hydrochloric acid to pH=3, extracted with dichloromethane (1000 mL×3), combined the organic phases, washed with saturated brine (1000 mL×1), and washed with anhydrous sodium sulfate. Dry, filter, and concentrate under reduced pressure to obtain intermediate C-3. MS-ESI calculated [M+H] + 306, found 306.
第三步third step
将中间体C-3(57.6g,189mmol)溶于二氯甲烷(600mL),加入三正丙基环磷酸酐(240g,377mmol,50％乙酸乙酯溶液)和三乙胺(38.2g,377mmol),反应液在20℃下搅拌1小时。反应液加水(1000mL),二氯甲烷(1000mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(1000mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到中间体C-4。 1H NMR(400MHz,CDCl 3)δ7.37(d,J＝8.8Hz,1H),7.33-7.29(m,2H),7.25-7.22(m,1H),6.90-6.84(m,2H),5.62-5.55(m,1H),4.77-4.72(m,0.5H),4.33-4.28(m,0.5H),3.80(d,J＝6.8Hz,3H),1.74(t,J＝7.8Hz,3H),1.46(d,J＝6.4Hz,1.5H),1.09(d,J＝6.8Hz,1.5H)。MS-ESI计算值[M+H] +288,实测值288。 Intermediate C-3 (57.6 g, 189 mmol) was dissolved in dichloromethane (600 mL), tri-n-propyl cyclic phosphoric anhydride (240 g, 377 mmol, 50% ethyl acetate solution) and triethylamine (38.2 g, 377 mmol) were added ), and the reaction solution was stirred at 20 °C for 1 hour. The reaction solution was added with water (1000 mL), extracted with dichloromethane (1000 mL×2), and the organic phases were combined, washed with saturated brine (1000 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain intermediate C-4. 1 H NMR (400 MHz, CDCl 3 ) δ 7.37 (d, J=8.8 Hz, 1H), 7.33-7.29 (m, 2H), 7.25-7.22 (m, 1H), 6.90-6.84 (m, 2H), 5.62-5.55(m, 1H), 4.77-4.72(m, 0.5H), 4.33-4.28(m, 0.5H), 3.80(d, J=6.8Hz, 3H), 1.74(t, J=7.8Hz, 3H), 1.46 (d, J=6.4Hz, 1.5H), 1.09 (d, J=6.8Hz, 1.5H). MS-ESI calculated [M+H] + 288, found 288.
第四步the fourth step
将中间体C-4(50.0g,174mmol)溶于氯仿(500mL)中,0℃下加入液溴(33.4g,209mmol),反应液在 25℃下搅拌12小时。反应液加入饱和亚硫酸钠水溶液(500mL),二氯甲烷(500mL×2)萃取,合并有机相,有机相用饱和食盐水(500mL×1)洗涤,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到中间体C。 1H NMR(400MHz,CDCl 3)δ7.60-7.54(m,1H),7.38-7.30(m,2H),7.26-7.22(m,1H),6.89-6.83(m,1H),5.58-5.50(m,1H),4.78-4.75(m,0.5H),4.37-4.32(m,0.5H),3.89(d,J＝6.0Hz,3H),1.76-1.72(m,3H),1.46(d,J＝6.8Hz,1.5H)),1.13(d,J＝6.8Hz,1.5H)。MS-ESI计算值[M+H] +366和368,实测值366和368。 Intermediate C-4 (50.0 g, 174 mmol) was dissolved in chloroform (500 mL), liquid bromine (33.4 g, 209 mmol) was added at 0 °C, and the reaction solution was stirred at 25 °C for 12 hours. The reaction solution was added with saturated aqueous sodium sulfite solution (500 mL), extracted with dichloromethane (500 mL×2), and the organic phases were combined, washed with saturated brine (500 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain Intermediate C. 1 H NMR (400MHz, CDCl 3 ) δ 7.60-7.54 (m, 1H), 7.38-7.30 (m, 2H), 7.26-7.22 (m, 1H), 6.89-6.83 (m, 1H), 5.58-5.50 (m,1H),4.78-4.75(m,0.5H),4.37-4.32(m,0.5H),3.89(d,J=6.0Hz,3H),1.76-1.72(m,3H),1.46(d , J=6.8Hz, 1.5H)), 1.13 (d, J=6.8Hz, 1.5H). MS-ESI calculated [M+H] + 366 and 368, found 366 and 368.
实施例1Example 1
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000074
Figure PCTCN2021142174-appb-000074
第一步first step
将化合物B(124mg,378μmol)和化合物1-1(233mg,756μmol)溶解在1,4-二氧六环(4mL)和水(1mL)中,后向反应液中加入碳酸钾(157mg,1.13mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(28mg,38μmol)。将反应液在氮气保护下加热至80℃反应8小时。反应液减压浓缩,粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,3/1～1/2,V/V)分离得到1a和1b混合粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AD250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液45％-45％),分离得到化合物1a(第一个峰)和1b(第二个峰)。1b经高效液相色谱法(色谱柱:Phenomenex Gemini-NX 80×30mm×3μm；流动相:10mmol/L的碳酸氢铵水溶液-乙腈；梯度:乙腈15％-85％,9min)进一步纯化得到化合物1b。化合物后经SFC(色谱柱:Chiralcel AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Compound B (124 mg, 378 μmol) and compound 1-1 (233 mg, 756 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and potassium carbonate (157 mg, 1.13 mL) was added to the reaction solution. mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 38 μmol). The reaction solution was heated to 80°C under nitrogen protection for 8 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1～1/2, V/V) to obtain a mixed crude product of 1a and 1b. The crude product was purified by SFC (separating column: DAICEL). CHIRALPAK AD250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia water in ethanol; gradient: 0.1% ammonia water in ethanol 45%-45%), compounds 1a (the first peak) and 1b ( the second peak). 1b was further purified by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX 80×30mm×3μm; mobile phase: 10mmol/L aqueous ammonium bicarbonate solution-acetonitrile; gradient: acetonitrile 15%-85%, 9min) to obtain the compound 1b. The compound was then purified by SFC (chromatographic column: Chiralcel AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
化合物1a:e.e.％＝100％,RT＝1.786min。 1H NMR(400MHz,CD 3OD)δ9.01(d,J＝2.8Hz,1H),8.72(d,J＝3.2Hz,1H),7.88(s,0.4H),7.69(s,0.6H)7.13(s,1H),2.44(s,3H),2.00(s,3H)。MS-ESI计算值[M+H] +330,实测值330。 Compound 1a: ee%=100%, RT=1.786 min. 1 H NMR (400MHz, CD 3 OD) δ 9.01 (d, J=2.8Hz, 1H), 8.72 (d, J=3.2Hz, 1H), 7.88 (s, 0.4H), 7.69 (s, 0.6H) ) 7.13(s, 1H), 2.44(s, 3H), 2.00(s, 3H). MS-ESI calculated [M+H] + 330, found 330.
化合物1b:e.e.％＝99％,RT＝2.880min。 1H NMR(400MHz,CD 3OD)δ9.01(d,J＝2.8Hz,1H),8.72(d,J＝3.2Hz,1H),7.86(s,0.4H),7.69(s,0.6H)7.13(s,1H),2.44(s,3H),2.00(s,3H)。MS-ESI计算值[M+H] +330,实测值330。 Compound 1b: ee%=99%, RT=2.880 min. 1 H NMR (400MHz, CD 3 OD) δ 9.01 (d, J=2.8Hz, 1H), 8.72 (d, J=3.2Hz, 1H), 7.86 (s, 0.4H), 7.69 (s, 0.6H) ) 7.13(s, 1H), 2.44(s, 3H), 2.00(s, 3H). MS-ESI calculated [M+H] + 330, found 330.
实施例2Example 2
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000075
Figure PCTCN2021142174-appb-000075
第一步first step
将中间体B(124mg,378μmol)和化合物2-1(99mg,378μmol)溶解在1,4-二氧六环(4mL)和水(1mL)中,后向反应液中加入碳酸钾(157mg,1.13mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(28mg,38μmol)。将反应液在氮气保护下加热至80℃反应8小时。反应液减压浓缩,粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,3/1～1/1,V/V)分离得到2a和2b混合物粗品，粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液35％-35％)分离得到化合物2a(第一个峰)和2b(第二个峰)。两个化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Intermediate B (124 mg, 378 μmol) and compound 2-1 (99 mg, 378 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and potassium carbonate (157 mg, 157 mg, 1 mL) was added to the reaction solution. 1.13 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (28 mg, 38 μmol). The reaction solution was heated to 80°C under nitrogen protection for 8 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 3/1～1/1, V/V) to obtain a crude mixture of 2a and 2b. The crude product was purified by SFC (separating column: DAICEL). CHIRALPAK AD 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 35%-35%) to separate compounds 2a (the first peak) and 2b ( the second peak). The two compounds were then subjected to SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5 %-40%) to measure the ee value.
化合物2a:e.e.％＝100％,RT＝1.193min。 1H NMR(400MHz,CD 3OD)δ9.01(d,J＝2.8Hz,1H),8.73(d,J＝3.6Hz,1H),8.08(s,1H),7.22(s,1H),2.00(s,3H)。MS-ESI计算值[M+H] +384,实测值384。 Compound 2a: ee%=100%, RT=1.193 min. 1 H NMR (400MHz, CD 3 OD) δ 9.01(d, J=2.8Hz, 1H), 8.73(d, J=3.6Hz, 1H), 8.08(s, 1H), 7.22(s, 1H), 2.00 (s, 3H). MS-ESI calculated [M+H] + 384, found 384.
化合物2b:e.e.％＝99％,1.557min。 1H NMR(400MHz,CD 3OD)δ9.02(d,J＝2.8Hz,1H),8.73(d,J＝3.6Hz,1H),8.08(s,1H),7.22(s,1H),2.00(s,3H)。MS-ESI计算值[M+H] +384,实测值384。 Compound 2b: ee%=99%, 1.557 min. 1 H NMR (400MHz, CD 3 OD) δ 9.02(d, J=2.8Hz, 1H), 8.73(d, J=3.6Hz, 1H), 8.08(s, 1H), 7.22(s, 1H), 2.00 (s, 3H). MS-ESI calculated [M+H] + 384, found 384.
实施例3Example 3
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000076
Figure PCTCN2021142174-appb-000076
第一步first step
将中间体B(72.0mg,219μmol)溶于二氧六环(2mL)和水(0.4mL),加入中间体3-1(90.6mg,263μmol),1,1-双(二苯基磷)二茂铁氯化钯(16.1mg,21.9μmol)和碳酸钾(75.8mg,548μmol)。置换氮气三次,反应液在90℃下搅拌12小时。反应液直接减压浓缩,剩余物经过薄层层析法(石油醚/乙酸乙酯,3/1～1/1,V/V)分离得到化合物3粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液50％-50％),分离得到化合物3a(第一个峰)和3b(第二个峰)。两个化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Intermediate B (72.0 mg, 219 μmol) was dissolved in dioxane (2 mL) and water (0.4 mL), and intermediate 3-1 (90.6 mg, 263 μmol), 1,1-bis(diphenylphosphine) was added Ferrocene palladium chloride (16.1 mg, 21.9 μmol) and potassium carbonate (75.8 mg, 548 μmol). The nitrogen was replaced three times, and the reaction solution was stirred at 90 °C for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by thin layer chromatography (petroleum ether/ethyl acetate, 3/1～1/1, V/V) to obtain the crude product of compound 3, which was purified by SFC (separating column: DAICEL CHIRALPAK). AD 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 50%-50%), compounds 3a (the first peak) and 3b ( the second peak). The two compounds were then subjected to SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5 %-40%) to measure the ee value.
化合物3a：e.e.％＝100％,RT＝2.376min。 1H NMR(400MHz,CD3OD)δ9.03(d,J＝2.4Hz,1H),8.73(d,J＝3.6Hz,1H),8.33-8.28(m,2H),7.77(s,1H),7.36(s,1H),7.26-7.23(m,1H),2.03(s,3H)。MS-ESI计算值[M+H]+366,实测值366。 Compound 3a: ee%=100%, RT=2.376 min. 1 H NMR(400MHz, CD3OD)δ9.03(d,J=2.4Hz,1H),8.73(d,J=3.6Hz,1H),8.33-8.28(m,2H),7.77(s,1H), 7.36(s, 1H), 7.26-7.23(m, 1H), 2.03(s, 3H). MS-ESI calculated value [M+H]+366, found 366.
化合物3b：e.e.％＝100％,RT＝3.010min。 1H NMR(400MHz,CD3OD)δ9.03(d,J＝2.4Hz,1H),8.73(d,J＝3.6Hz,1H),8.33-8.28(m,2H),7.77(s,1H),7.36(s,1H),7.26-7.23(m,1H),2.03(s,3H)。MS-ESI计算值[M+H]+366,实测值366。 Compound 3b: ee%=100%, RT=3.010 min. 1 H NMR(400MHz, CD3OD)δ9.03(d,J=2.4Hz,1H),8.73(d,J=3.6Hz,1H),8.33-8.28(m,2H),7.77(s,1H), 7.36(s, 1H), 7.26-7.23(m, 1H), 2.03(s, 3H). MS-ESI calculated value [M+H]+366, found 366.
实施例4Example 4
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000077
Figure PCTCN2021142174-appb-000077
第一步first step
将化合物C(500mg,1.37mmol)溶于四氢呋喃(10mL),在-78℃下滴加双(三甲基硅)氨基钾(2.05mL,1mol/L的四氢呋喃溶液),在-78℃搅拌0.5小时,加入化合物4-1(592mg,2.73mmol),反应液在0℃下搅拌1小时。反应液加入饱和氯化铵水溶液(5mL),乙酸乙酯(15mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～3/1,V/V)分离得到化合物4-2。MS-ESI计算值[M+H] +546和548,实测值546和548。 Compound C (500 mg, 1.37 mmol) was dissolved in tetrahydrofuran (10 mL), bis(trimethylsilyl) potassium amide (2.05 mL, 1 mol/L tetrahydrofuran solution) was added dropwise at -78 °C, and stirred at -78 °C for 0.5 After 1 hour, compound 4-1 (592 mg, 2.73 mmol) was added, and the reaction solution was stirred at 0° C. for 1 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (15 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V) to obtain compound 4-2. MS-ESI calculated [M+H] + 546 and 548, found 546 and 548.
第二步second step
将化合物4-2(120mg,0.22mmol)溶于乙腈(5mL)和水(0.5mL),后加入硝酸铈铵(0.60g,1.09mmol)反应液在25℃下搅拌12小时。反应液加乙酸乙酯(30mL)稀释，经水(10mL×2)洗涤，有机层经无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/-2/1,V/V)分离得到化合物4-3。Compound 4-2 (120 mg, 0.22 mmol) was dissolved in acetonitrile (5 mL) and water (0.5 mL), and ceric ammonium nitrate (0.60 g, 1.09 mmol) was added to the reaction solution and stirred at 25° C. for 12 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with water (10 mL×2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/-2/1, V/V) to obtain compound 4-3.
第三步third step
将化合物4-3(65mg,195μmol)溶于乙酸乙酯(10mL),加入三乙胺(0.2mL)和氢氧化钯(54.9mg,390μmol,10％纯度),氢气置换三次，反应液在50℃下,氢气压力50psi下搅拌12小时。将反应液过滤,滤液减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物4-4。Compound 4-3 (65 mg, 195 μmol) was dissolved in ethyl acetate (10 mL), triethylamine (0.2 mL) and palladium hydroxide (54.9 mg, 390 μmol, 10% purity) were added, hydrogen was replaced three times, and the reaction solution was heated at 50 The mixture was stirred for 12 hours at 50 psi hydrogen pressure. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound 4-4.
第四步the fourth step
将化合物4-4(41mg,137μmol)溶于三氟乙酸(1mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(24mg,0.137mmol)后滴加浓硫酸(0.1mL),反应液在0℃下搅拌1小时。将反应液用饱和碳酸氢钠水溶液调节pH至8后用乙酸乙酯(20mL×2)萃取,有机相经食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到化合物4-5。MS-ESI计算值[M+H] +378和380实测值378和380。 Compound 4-4 (41 mg, 137 μmol) was dissolved in trifluoroacetic acid (1 mL), N-bromosuccinimide (24 mg, 0.137 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid (0.1 mmol) was added dropwise. mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (20 mL×2). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 4-5 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V). MS-ESI calculated [M+H] + 378 and 380 found 378 and 380.
第五步the fifth step
将化合物4-5(22mg,58μmol)和化合物1-1(47mg,153μmol)溶解在1,4-二氧六环(1.2mL)和水(0.3mL)中,后向反应液中加入碳酸钾(32mg,230mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(6mg,7.68μmol)。将反应液在氮气保护下加热至80℃反应5小时。反应液减压浓缩,粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到粗品,后粗品经经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液25％-25％)分离得到化合物4-6a(第一个峰)和4-6b(第二个峰)。 Compound 4-5 (22 mg, 58 μmol) and compound 1-1 (47 mg, 153 μmol) were dissolved in 1,4-dioxane (1.2 mL) and water (0.3 mL), and potassium carbonate was added to the reaction solution. (32 mg, 230 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6 mg, 7.68 μmol). The reaction solution was heated to 80°C under nitrogen protection for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain the crude product, and the crude product was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 25%-25%) to separate compounds 4-6a (the first peak) and 4- 6b (second peak).
第六步Step 6
将化合物4-6a(14mg,29μmol)溶于乙酸乙酯(2mL),后向反应液中加入氯化氢的乙酸乙酯溶液(42μL,4mol/L),将反应液在25℃反应1小时。反应液加阴离子交换树脂中和至中性,过滤，滤液减压浓缩得到粗品,粗品经硅胶薄层层析(石油醚/乙酸乙酯,1/1,V/V,Rf＝0.09)分离得到化合物4a。Compound 4-6a (14 mg, 29 μmol) was dissolved in ethyl acetate (2 mL), and the ethyl acetate solution of hydrogen chloride (42 μL, 4 mol/L) was added to the reaction solution, and the reaction solution was reacted at 25° C. for 1 hour. The reaction solution was neutralized to neutrality by adding anion exchange resin, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel thin layer chromatography (petroleum ether/ethyl acetate, 1/1, V/V, Rf=0.09) to obtain Compound 4a.
化合物4a: 1H NMR(400MHz,CD 3OD)δ9.44(s,1H),9.15(s,1H),7.75(s,1H),7.09(s,1H),2.42(s,3H),2.09(s,3H)。MS-ESI计算值[M+H] +380,实测值380。 Compound 4a: 1 H NMR (400MHz, CD 3 OD) δ 9.44(s, 1H), 9.15(s, 1H), 7.75(s, 1H), 7.09(s, 1H), 2.42(s, 3H), 2.09(s, 3H). MS-ESI calculated [M+H] + 380, found 380.
将化合物4-6b(5mg,10μmol)溶于乙酸乙酯(2mL),后向反应液中加入氯化氢的乙酸乙酯溶液(42μL,4M),将反应液在25℃反应1小时。反应液加阴离子交换树脂中和至中性,过滤，滤液减压浓缩得到粗品,粗品经硅胶薄层层析(石油醚/乙酸乙酯,1/1,V/V,Rf＝0.09)分离得到化合物4b。Compound 4-6b (5 mg, 10 μmol) was dissolved in ethyl acetate (2 mL), hydrogen chloride in ethyl acetate solution (42 μL, 4 M) was added to the reaction solution, and the reaction solution was reacted at 25° C. for 1 hour. The reaction solution was neutralized to neutrality by adding anion exchange resin, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel thin layer chromatography (petroleum ether/ethyl acetate, 1/1, V/V, Rf=0.09) to obtain Compound 4b.
化合物4b: 1H NMR(400MHz,CD 3OD)δ9.44(s,1H),9.15(s,1H),7.74(s,1H),7.09(s,1H),2.42(s,3H),2.09(s,3H)。MS-ESI计算值[M+H] +380,实测值380。 Compound 4b: 1 H NMR (400MHz, CD 3 OD) δ 9.44(s, 1H), 9.15(s, 1H), 7.74(s, 1H), 7.09(s, 1H), 2.42(s, 3H), 2.09(s, 3H). MS-ESI calculated [M+H] + 380, found 380.
实施例5Example 5
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000078
Figure PCTCN2021142174-appb-000078
第一步first step
将化合物4-4(41mg,137μmol)溶于三氟乙酸(1mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(24mg,0.137mmol)后滴加浓硫酸(0.1mL),反应液在0℃下搅拌1小时。将反应液用饱和碳酸氢钠水溶液调节pH至8后用乙酸乙酯(20mL×2)萃取,有机相经食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到化合物5-1。MS-ESI计算值[M+H] +456和458实测值456和458。 Compound 4-4 (41 mg, 137 μmol) was dissolved in trifluoroacetic acid (1 mL), N-bromosuccinimide (24 mg, 0.137 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid (0.1 mmol) was added dropwise. mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (20 mL×2). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 5-1 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V). MS-ESI calculated [M+H] + 456 and 458 found 456 and 458.
第二步second step
将化合物5-1(35mg,77μmol)和化合物1-1(47mg,153μmol)溶解在1,4-二氧六环(1.2mL)和水(0.3mL)中,后向反应液中加入碳酸钾(32mg,230mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(6mg,7.68μmol)。将反应液在氮气保护下加热至80℃反应5小时。反应液减压浓缩,粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到粗品,后粗品经经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液25％-25％)分离得到化合物5-2a(第一个峰)和化合物5-2b(第二个峰)。 Compound 5-1 (35 mg, 77 μmol) and compound 1-1 (47 mg, 153 μmol) were dissolved in 1,4-dioxane (1.2 mL) and water (0.3 mL), and potassium carbonate was added to the reaction solution. (32 mg, 230 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (6 mg, 7.68 μmol). The reaction solution was heated to 80°C under nitrogen protection for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain the crude product, and the crude product was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 25%-25%) to separate compound 5-2a (the first peak) and compound 5 -2b (second peak).
第三步third step
将化合物5-2a(6mg,11μmol)溶于乙酸乙酯(2mL),后向反应液中加入氯化氢的乙酸乙酯溶液(34μL,4mol/L),将反应液在25℃反应1小时。反应液加阴离子交换树脂中和至中性,过滤，滤液减压浓缩得到粗品,粗品经硅胶薄层层析(石油醚/乙酸乙酯,1/1,V/V,Rf＝0.08)分离得到化合物5a。Compound 5-2a (6 mg, 11 μmol) was dissolved in ethyl acetate (2 mL), and the ethyl acetate solution of hydrogen chloride (34 μL, 4 mol/L) was added to the reaction solution, and the reaction solution was reacted at 25° C. for 1 hour. The reaction solution was neutralized to neutrality by adding anion exchange resin, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel thin layer chromatography (petroleum ether/ethyl acetate, 1/1, V/V, Rf=0.08) to obtain Compound 5a.
化合物5a: 1H NMR(400MHz,CD 3OD)δ9.43(s,1H),9.17(s,1H),7.89-7.67(m,1H),2.33(s,3H),2.08(s,3H)。MS-ESI计算值[M+H] +458和460,实测值458和460。 Compound 5a: 1 H NMR (400MHz, CD 3 OD) δ 9.43(s, 1H), 9.17(s, 1H), 7.89-7.67(m, 1H), 2.33(s, 3H), 2.08(s, 3H) ). MS-ESI calculated [M+H] + 458 and 460, found 458 and 460.
将化合物5-2b(3mg,5.4μmol)溶于乙酸乙酯(2mL),后向反应液中加入氯化氢的乙酸乙酯溶液(34μL,4M),将反应液在25℃反应1小时。反应液加阴离子交换树脂中和至中性,过滤，滤液减压浓缩得到粗品,粗品经硅胶薄层层析(石油醚/乙酸乙酯,1/1,V/V,Rf＝0.08)分离得到化合物5b。Compound 5-2b (3 mg, 5.4 μmol) was dissolved in ethyl acetate (2 mL), hydrogen chloride in ethyl acetate solution (34 μL, 4 M) was added to the reaction solution, and the reaction solution was reacted at 25° C. for 1 hour. The reaction solution was neutralized to neutrality by adding anion exchange resin, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by silica gel thin layer chromatography (petroleum ether/ethyl acetate, 1/1, V/V, Rf=0.08) to obtain Compound 5b.
化合物5b: 1H NMR(400MHz,CD 3OD)δ9.43(s,1H),9.17(s,1H),7.89-7.66(m,1H),2.33(s,3H),2.08(s,3H)。MS-ESI计算值[M+H] +458和460,实测值458和460。 Compound 5b: 1 H NMR (400MHz, CD 3 OD) δ 9.43(s, 1H), 9.17(s, 1H), 7.89-7.66(m, 1H), 2.33(s, 3H), 2.08(s, 3H) ). MS-ESI calculated [M+H] + 458 and 460, found 458 and 460.
实施例6Example 6
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000079
Figure PCTCN2021142174-appb-000079
第一步first step
将中间体C(490mg,1.34mmol)溶于四氢呋喃(5mL),在-78℃下滴加双(三甲基硅)氨基钾(2.01mL,1mol/L的四氢呋喃溶液),在-78℃搅拌5分钟,加入化合物6-1(399mg,2.68mmol),反应液在0℃下搅拌1小时。反应液加入饱和氯化铵水溶液(5mL),乙酸乙酯(15mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～3/1,V/V)分离得到化合物6-2。MS-ESI计算值[M+H] +478和480,实测值478和480。 Intermediate C (490 mg, 1.34 mmol) was dissolved in tetrahydrofuran (5 mL), bis(trimethylsilyl) potassium amide (2.01 mL, 1 mol/L tetrahydrofuran solution) was added dropwise at -78 °C, and stirred at -78 °C After 5 minutes, compound 6-1 (399 mg, 2.68 mmol) was added, and the reaction solution was stirred at 0° C. for 1 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (15 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V) to obtain compound 6-2. MS-ESI calculated [M+H] + 478 and 480, found 478 and 480.
第二步second step
将化合物6-2(400mg,0.83mmol)溶于乙腈(10mL)和水(1mL),后加入硝酸铈铵(2.29g,4.18mmol)反应液在25℃下搅拌12小时。反应液加乙酸乙酯(30mL)稀释，经水(10mL×2)洗涤，有机层经无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到化合物6-3。MS-ESI计算值[M+H] +266,实测值266。 Compound 6-2 (400 mg, 0.83 mmol) was dissolved in acetonitrile (10 mL) and water (1 mL), and ceric ammonium nitrate (2.29 g, 4.18 mmol) was added to the reaction solution and stirred at 25° C. for 12 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with water (10 mL×2), the organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 6-3. MS-ESI calculated [M+H] + 266, found 266.
第三步third step
将化合物6-3(40mg,150μmol)溶于四氢呋喃(1mL)和甲醇(0.2mL),加入甲醇钠(40mg,756μmol)，反应液在20℃下搅拌1.5小时。将反应液加阳离子交换树脂中和至pH＝7,过滤,滤液减压浓缩，得到化合物6-4直接用于下步反应。Compound 6-3 (40 mg, 150 μmol) was dissolved in tetrahydrofuran (1 mL) and methanol (0.2 mL), sodium methoxide (40 mg, 756 μmol) was added, and the reaction solution was stirred at 20° C. for 1.5 hours. The reaction solution was neutralized to pH=7 by adding cation exchange resin, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-4, which was directly used in the next reaction.
第四步the fourth step
将化合物6-4(30mg,114μmol)溶于三氟乙酸(1mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(22mg,0.126mmol)后滴加浓硫酸(0.1mL),反应液在0℃下搅拌1小时。将反应液用饱和碳酸氢钠水溶液调节pH至8后用乙酸乙酯(20mL×2)萃取,有机相经食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到化合物6-5。MS-ESI计算值[M+H] +340和342实测值340和342。 Compound 6-4 (30 mg, 114 μmol) was dissolved in trifluoroacetic acid (1 mL), N-bromosuccinimide (22 mg, 0.126 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid (0.1 mmol) was added dropwise. mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (20 mL×2). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 6-5 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V). MS-ESI calculated [M+H] + 340 and 342 found 340 and 342.
第五步the fifth step
将化合物6-5(20mg,59μmol)和化合物1-1(36mg,118μmol)溶解在1,4-二氧六环(1.2mL)和水(0.3mL)中,后向反应液中加入碳酸钾(24mg,176mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(4.3mg,5.9μmol)。将反应液在氮气保护下加热至80℃反应5小时。反应液减压浓缩,粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到粗品,后粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液40％-40％)分离得到化合物6a(第一个峰)和化合物6b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Compound 6-5 (20 mg, 59 μmol) and compound 1-1 (36 mg, 118 μmol) were dissolved in 1,4-dioxane (1.2 mL) and water (0.3 mL), and potassium carbonate was added to the reaction solution. (24 mg, 176 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (4.3 mg, 5.9 μmol). The reaction solution was heated to 80°C under nitrogen protection for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain the crude product, and the crude product was purified by SFC (separating column: DAICEL CHIRALPAK AD 250mm). ×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 40%-40%) to separate compound 6a (the first peak) and compound 6b (the second peak) peaks). The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
化合物6b:e.e.％＝100％,2.169min。 1H NMR(400MHz,CD 3OD)δ8.77(d,J＝1.2Hz,1H),7.87-7.68(m,1H),7.07(s,1H),6.98(s,1H),3.99(s,3H),2.43(s,3H),1.93(s,3H)。MS-ESI计算值[M+H] +342,实测值342。 Compound 6b:ee%=100%, 2.169 min. 1 H NMR (400MHz, CD 3 OD) δ8.77(d, J=1.2Hz, 1H), 7.87-7.68(m, 1H), 7.07(s, 1H), 6.98(s, 1H), 3.99(s , 3H), 2.43 (s, 3H), 1.93 (s, 3H). MS-ESI calculated [M+H] + 342, found 342.
实施例7Example 7
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000080
Figure PCTCN2021142174-appb-000080
第一步first step
将中间体C(500mg,1.37mmol)溶于四氢呋喃(10mL),在-78℃下滴加双(三甲基硅)氨基钾(2.05mL,1mol/L的四氢呋喃溶液),在-78℃搅拌5分钟,加入化合物7-1(456mg,2.73mol),反应液在0℃下搅拌1小时。反应液加入饱和氯化铵水溶液(5mL),乙酸乙酯(15mL×2)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/～3/1,V/V)分离得到化合物7-2。MS-ESI计算值[M+H] +496和498,实测值496和498。 Intermediate C (500 mg, 1.37 mmol) was dissolved in tetrahydrofuran (10 mL), bis(trimethylsilyl) potassium amide (2.05 mL, 1 mol/L tetrahydrofuran solution) was added dropwise at -78 °C, and stirred at -78 °C After 5 minutes, compound 7-1 (456 mg, 2.73 mol) was added, and the reaction solution was stirred at 0° C. for 1 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (15 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/～3/1, V/V) to obtain compound 7-2. MS-ESI calculated [M+H] + 496 and 498, found 496 and 498.
第二步second step
将化合物7-2(450mg,0.905mmol)溶于三氟乙酸(5mL),反应液在75℃下搅拌1小时。反应液减压浓缩后，加饱和碳酸氢水钠溶液中和至pH＝8,乙酸乙酯(20mL×2)萃取，有机层经无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物7-3。MS-ESI计算值[M+H] +284,实测值284。 Compound 7-2 (450 mg, 0.905 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 75° C. for 1 hour. After the reaction solution was concentrated under reduced pressure, saturated aqueous sodium bicarbonate solution was added to neutralize to pH=8, extracted with ethyl acetate (20 mL×2), the organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound 7-3. MS-ESI calculated [M+H] + 284, found 284.
第三步third step
将化合物7-3(160mg,564μmol)溶于四氢呋喃(2mL)和甲醇(0.5mL),加入甲醇钠(152mg,2.82mmol)，反应液在20℃下搅拌2小时。将反应液加阳离子交换树脂中和至pH＝7,过滤,滤液减压浓缩，得到化合物7-4,化合物直接用于下步反应。Compound 7-3 (160 mg, 564 μmol) was dissolved in tetrahydrofuran (2 mL) and methanol (0.5 mL), sodium methoxide (152 mg, 2.82 mmol) was added, and the reaction solution was stirred at 20° C. for 2 hours. The reaction solution was neutralized to pH=7 by adding a cation exchange resin, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 7-4, which was directly used in the next reaction.
第四步the fourth step
将化合物7-4(67mg,241μmol)溶于乙酸(1mL),向加入N-溴代丁二酰亚胺(51mg,0.289mmol),反应液在55℃下搅拌12小时。将反应液用饱和碳酸氢钠水溶液调节pH至8后用乙酸乙酯(30mL×2)萃取,有机相经食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到化合物7-5。MS-ESI计算值[M+H] +358和360实测值358和360。 Compound 7-4 (67 mg, 241 μmol) was dissolved in acetic acid (1 mL), N-bromosuccinimide (51 mg, 0.289 mmol) was added, and the reaction solution was stirred at 55° C. for 12 hours. The reaction solution was adjusted to pH 8 with saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate (30 mL×2). The organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. Compound 7-5 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V). MS-ESI calculated [M+H] + 358 and 360 found 358 and 360.
第五步the fifth step
将化合物7-5(80mg,223μmol)和化合物1-1(138mg,447μmol)溶解在1,4-二氧六环(2mL)和水(0.4mL)中,后向反应液中加入碳酸钾(92mg,670mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(16mg,22μmol)。将反应液在氮气保护下加热至80℃反应5小时。反应液减压浓缩,粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1-1/1,V/V)分离得到粗品,后粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液50％-50％)分 离得到化合物7a(第一个峰)和7b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物7b:e.e.％＝100％,2.292min。 1H NMR(400MHz,CD 3OD)δ8.51(s,1H),7.89-7.68(m,1H),7.11(s,1H),4.07(s,3H),2.46-2.42(m,3H),1.95(s,3H)。MS-ESI计算值[M+H] +360,实测值360。 Compound 7-5 (80 mg, 223 μmol) and compound 1-1 (138 mg, 447 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and potassium carbonate ( 92 mg, 670 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (16 mg, 22 μmol). The reaction solution was heated to 80°C under nitrogen protection for 5 hours. The reaction solution was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1-1/1, V/V) to obtain the crude product, and the crude product was separated by SFC (separating column: DAICEL CHIRALPAK AD 250mm). ×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 50%-50%) to separate compounds 7a (the first peak) and 7b (the second peak) peak). The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 7b: ee%=100%, 2.292 min. 1 H NMR (400MHz, CD 3 OD) δ 8.51(s, 1H), 7.89-7.68(m, 1H), 7.11(s, 1H), 4.07(s, 3H), 2.46-2.42(m, 3H) ,1.95(s,3H). MS-ESI calculated [M+H] + 360, found 360.
实施例8Example 8
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000081
Figure PCTCN2021142174-appb-000081
第一步first step
将中间体C(2.00g,5.46mmol)溶于四氢呋喃(20mL),在-78℃下滴加双(三甲基硅)氨基钾(8.19mL,1mol/L的四氢呋喃溶液),在-78℃搅拌0.5小时,然后加入化合物8-1(1.58g,10.9mmol),反应液在25℃下搅拌0.5小时。反应液加入饱和氯化铵水溶液(50mL),乙酸乙酯(50mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(50mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～2/1,V/V)分离得到化合物8-2。MS-ESI计算值[M+H] +474和476,实测值474和476。 Intermediate C (2.00 g, 5.46 mmol) was dissolved in tetrahydrofuran (20 mL), bis(trimethylsilyl) potassium amide (8.19 mL, 1 mol/L solution in tetrahydrofuran) was added dropwise at -78 °C, and the solution was heated at -78 °C. After stirring for 0.5 hour, compound 8-1 (1.58 g, 10.9 mmol) was added, and the reaction solution was stirred at 25° C. for 0.5 hour. The reaction solution was added with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined, the organic phases were washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～2/1, V/V) to obtain compound 8-2. MS-ESI calculated [M+H] + 474 and 476, found 474 and 476.
第二步second step
将化合物8-2(2.12g,4.47mmol)溶于三氟乙酸(20mL),反应液在90℃下搅拌12小时。反应液直接减压浓缩,加入饱和碳酸氢钠水溶液(50mL)和二氯甲烷(50mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(50mL×1),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物8-3。MS-ESI计算值[M+H] +262,实测值262。 Compound 8-2 (2.12 g, 4.47 mmol) was dissolved in trifluoroacetic acid (20 mL), and the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, extracted with saturated aqueous sodium bicarbonate solution (50 mL) and dichloromethane (50 mL×2), the organic phases were combined, the organic phase was washed with saturated brine (50 mL×1), and the organic phase was washed with anhydrous sulfuric acid Dry over sodium, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 8-3. MS-ESI calculated [M+H] + 262, found 262.
第三步third step
将化合物8-3(1.02g,3.91mmol)溶于三氟乙酸(10mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(766mg,4.30mmol)后滴加浓硫酸(1mL),反应液在0℃下搅拌1小时。向反应液用4mol/L氢氧化钠水溶液(40mL),用二氯甲烷(40mL×2)萃取,有机相经食盐水(40mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物8-4。MS-ESI计算值[M+H] +340和342实测值340和342。 Compound 8-3 (1.02 g, 3.91 mmol) was dissolved in trifluoroacetic acid (10 mL), N-bromosuccinimide (766 mg, 4.30 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid was added dropwise (1 mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was added with 4 mol/L aqueous sodium hydroxide solution (40 mL), extracted with dichloromethane (40 mL×2), the organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 8-4 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V). MS-ESI calculated [M+H] + 340 and 342 found 340 and 342.
第四步the fourth step
将化合物8-4(1.3g,3.32mmol)和化合物1-1(1.02g,3.32mmol)溶解在1,4-二氧六环(10mL)和水(1mL)中,后向反应液中加入磷酸钾(1.76g,8.30mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(243mg,332μmol)。将反应液在氮气保护下加热至80℃反应12小时。反应液加入水(30mL),乙酸乙酯(30mL ×2)萃取,合并有机相,有机相经饱和食盐水洗涤(30mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1-1/1,V/V)分离得到化合物粗品。粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液35％-35％)分离得到化合物8a(第一个峰)和8b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物8b:e.e.％＝100％,RT＝1.833min。 1H NMR(400MHz,CD 3OD)δ8.31(s,1H),8.16(s,1H),7.75(s,1H),7.09(s,1H),4.09(s,3H),2.42(s,3H),1.96(s,3H)。MS-ESI计算值[M+H] +342,实测值342。 Compound 8-4 (1.3 g, 3.32 mmol) and compound 1-1 (1.02 g, 3.32 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), and then added to the reaction solution Potassium phosphate (1.76 g, 8.30 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (243 mg, 332 μmol). The reaction solution was heated to 80°C under nitrogen protection for 12 hours. The reaction solution was added with water (30 mL), extracted with ethyl acetate (30 mL × 2), and the organic phases were combined, washed with saturated brine (30 mL × 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1-1/1, V/V) to obtain the crude compound. The crude product was separated by SFC (column: DAICEL CHIRALPAK AD 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ethanol solution of 0.1% ammonia water 35%-35%) to obtain compound 8a ( first peak) and 8b (second peak). The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 8b: ee%=100%, RT=1.833 min. 1 H NMR (400MHz, CD 3 OD) δ 8.31(s, 1H), 8.16(s, 1H), 7.75(s, 1H), 7.09(s, 1H), 4.09(s, 3H), 2.42(s , 3H), 1.96(s, 3H). MS-ESI calculated [M+H] + 342, found 342.
实施例9Example 9
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000082
Figure PCTCN2021142174-appb-000082
第一步first step
将中间体C(2.00g,5.46mmol)溶于四氢呋喃(20mL),在-78℃下滴加双(三甲基硅)氨基钾(8.19mL,1mol/L的四氢呋喃溶液),在-78℃搅拌0.5小时,然后加入化合物9-1(1.58g,10.9mmol),反应液在25℃下搅拌0.5小时。反应液加入饱和氯化铵水溶液(50mL),乙酸乙酯(50mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(50mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～2/1,V/V)分离得到化合物9-2。MS-ESI计算值[M+H] +474和476,实测值474和476。 Intermediate C (2.00 g, 5.46 mmol) was dissolved in tetrahydrofuran (20 mL), bis(trimethylsilyl) potassium amide (8.19 mL, 1 mol/L solution in tetrahydrofuran) was added dropwise at -78 °C, and the solution was heated at -78 °C. After stirring for 0.5 hour, compound 9-1 (1.58 g, 10.9 mmol) was added, and the reaction solution was stirred at 25° C. for 0.5 hour. The reaction solution was added with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined, the organic phases were washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～2/1, V/V) to obtain compound 9-2. MS-ESI calculated [M+H] + 474 and 476, found 474 and 476.
第二步second step
将化合物9-2(1.87g,3.94mmol)溶于三氟乙酸(20mL),反应液在90℃下搅拌12小时。反应液直接减压浓缩,加入饱和碳酸氢钠水溶液(50mL)和二氯甲烷(50mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(50mL×1),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物9-3。MS-ESI计算值[M+H] +262,实测值262。 Compound 9-2 (1.87 g, 3.94 mmol) was dissolved in trifluoroacetic acid (20 mL), and the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, extracted with saturated aqueous sodium bicarbonate solution (50 mL) and dichloromethane (50 mL×2), the organic phases were combined, the organic phase was washed with saturated brine (50 mL×1), and the organic phase was washed with anhydrous sulfuric acid Dry over sodium, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 9-3. MS-ESI calculated [M+H] + 262, found 262.
第三步third step
将化合物9-3(1.00g,3.83mmol)溶于三氟乙酸(10mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(750mg,4.21mmol)后滴加浓硫酸(1mL),反应液在0℃下搅拌1小时。向反应液加4mol/L氢氧化钠水溶液(40mL),用二氯甲烷(40mL×2)萃取,有机相经食盐水(40mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物9-4。MS-ESI计算值[M+H] +340和342实测值340和342。 Compound 9-3 (1.00 g, 3.83 mmol) was dissolved in trifluoroacetic acid (10 mL), N-bromosuccinimide (750 mg, 4.21 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid was added dropwise (1 mL), the reaction solution was stirred at 0 °C for 1 hour. 4 mol/L aqueous sodium hydroxide solution (40 mL) was added to the reaction solution, extracted with dichloromethane (40 mL×2), the organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 9-4 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V). MS-ESI calculated [M+H] + 340 and 342 found 340 and 342.
第四步the fourth step
将化合物9-4(1.01g,2.97mmol)和化合物1-1(916mg,2.97mmol)溶解在1,4-二氧六环(10mL)和水(1mL)中,后向反应液中加入磷酸钾(1.58g,7.43mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(218mg,297μmol)。将反应液在氮气保护下加热至80℃反应12小时。反应液加入水(30mL),乙酸乙酯(30mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(30mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到粗品。粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的异丙醇溶液；梯度:0.1％氨水的异丙醇溶液45％-45％)分离得到化合物9a(第一个峰)和9b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物9b:e.e.％＝99.1％,RT＝2.131min。 1H NMR(400MHz,CD 3OD)δ8.13(d,J＝3.6Hz,2H),7.77(s,1H),7.09(s,1H),4.11(s,3H),2.44(s,3H),1.92(s,3H)。MS-ESI计算值[M+H] +342,实测值342。 Compound 9-4 (1.01 g, 2.97 mmol) and compound 1-1 (916 mg, 2.97 mmol) were dissolved in 1,4-dioxane (10 mL) and water (1 mL), and phosphoric acid was added to the reaction solution Potassium (1.58 g, 7.43 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (218 mg, 297 μmol). The reaction solution was heated to 80°C under nitrogen protection for 12 hours. The reaction solution was added with water (30 mL), extracted with ethyl acetate (30 mL×2), and the organic phases were combined, washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain the crude product. The crude product was separated by SFC (column: DAICEL CHIRALPAK AD 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in isopropanol; gradient: 0.1% ammonia solution in isopropanol 45%-45%) Compounds 9a (first peak) and 9b (second peak) were obtained. The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 9b: ee%=99.1%, RT=2.131 min. 1 H NMR (400MHz, CD 3 OD) δ 8.13(d, J=3.6Hz, 2H), 7.77(s, 1H), 7.09(s, 1H), 4.11(s, 3H), 2.44(s, 3H) ), 1.92(s, 3H). MS-ESI calculated [M+H] + 342, found 342.
实施例10Example 10
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000083
Figure PCTCN2021142174-appb-000083
第一步first step
将中间体C(1.00g,2.73mmol)溶于四氢呋喃(10mL),在-78℃下滴加双(三甲基硅)氨基钾(4.10mL,1mol/L的四氢呋喃溶液),在-78℃搅拌0.5小时,然后加入化合物10-1(912mg,5.46mmol),反应液在25℃下搅拌0.5小时。反应液加入饱和氯化铵水溶液(50mL),乙酸乙酯(50mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(50mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～2/1,V/V)分离得到化合物10-2。MS-ESI计算值[M+H] +496和498,实测值496和498。 Intermediate C (1.00 g, 2.73 mmol) was dissolved in tetrahydrofuran (10 mL), bis(trimethylsilyl) potassium amide (4.10 mL, 1 mol/L solution in tetrahydrofuran) was added dropwise at -78 °C, and the solution was heated at -78 °C. After stirring for 0.5 hour, compound 10-1 (912 mg, 5.46 mmol) was added, and the reaction solution was stirred at 25° C. for 0.5 hour. The reaction solution was added with saturated aqueous ammonium chloride (50 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined, the organic phases were washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～2/1, V/V) to obtain compound 10-2. MS-ESI calculated [M+H] + 496 and 498, found 496 and 498.
第二步second step
将中间体10-2(1.00g,2.01mmol),10-3(370mg,2.21mmol),碳酸铯(1.31g,4.03mmol)和甲烷磺酸(2-二环己基膦)-3,6-二甲氧基-2,4,6-三异丙基-1,1-联苯)(2-氨基-1,1-联苯-2-基)钯(182mg,201μmol)溶于 1,4-二氧六环(10mL)。将反应液在氮气保护下加热至100℃反应12小时。反应液加入水(30mL),乙酸乙酯(30mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(30mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～2/1,V/V)分离得到化合物10-4。MS-ESI计算值[M+H] +627和629,实测值627和629。 Intermediates 10-2 (1.00 g, 2.01 mmol), 10-3 (370 mg, 2.21 mmol), cesium carbonate (1.31 g, 4.03 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6- Dimethoxy-2,4,6-triisopropyl-1,1-biphenyl)(2-amino-1,1-biphenyl-2-yl)palladium (182 mg, 201 μmol) was dissolved in 1,4 -Dioxane (10 mL). The reaction solution was heated to 100°C under nitrogen protection for 12 hours. The reaction solution was added with water (30 mL), extracted with ethyl acetate (30 mL×2), and the organic phases were combined, washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～2/1, V/V) to obtain compound 10-4. MS-ESI calculated [M+H] + 627 and 629, found 627 and 629.
第三步third step
将化合物10-4(328mg,523μmol)溶于三氟乙酸(5mL),反应液在90℃下搅拌12小时。反应液直接减压浓缩,加入饱和碳酸氢钠水溶液(30mL)和二氯甲烷(30mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(30mL×1),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,0/1,V/V,Rf＝0.4)分离得到化合物10-5。Compound 10-4 (328 mg, 523 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, extracted with saturated aqueous sodium bicarbonate solution (30 mL) and dichloromethane (30 mL×2), the organic phases were combined, the organic phase was washed with saturated brine (30 mL×1), and the organic phase was washed with anhydrous sulfuric acid Dry over sodium, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 0/1, V/V, Rf=0.4) to obtain compound 10-5.
MS-ESI计算值[M+H] +265,实测值265。 MS-ESI calculated [M+H] + 265, found 265.
第四步the fourth step
将化合物10-5(136mg,515μmol)溶于三氟乙酸(5mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(101mg,566μmol)后滴加浓硫酸(0.5mL),反应液在0℃下搅拌1小时。向反应液用4mol/L氢氧化钠水溶液(30mL),用二氯甲烷(30mL×2)萃取,有机相经食盐水(30mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物10-6。MS-ESI计算值[M+H] +343和345实测值343和345。 Compound 10-5 (136 mg, 515 μmol) was dissolved in trifluoroacetic acid (5 mL), N-bromosuccinimide (101 mg, 566 μmol) was added to the reaction solution at 0°C, and concentrated sulfuric acid (0.5 mL) was added dropwise. ), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was added with 4 mol/L aqueous sodium hydroxide solution (30 mL), extracted with dichloromethane (30 mL×2), the organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain the crude product. Compound 10-6 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V). MS-ESI calculated for [M+H] + 343 and 345 found 343 and 345.
第五步the fifth step
将化合物10-6(84.5mg,246μmol)和化合物1-1(75.9mg,246μmol)溶解在1,4-二氧六环(3mL)和水(0.3mL)中,后向反应液中加入磷酸钾(131mg,616μmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(18.0mg,24.6μmol)。将反应液在氮气保护下加热至80℃反应3小时。反应液加入水(30mL),乙酸乙酯(30mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(30mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物粗品。粗品经SFC(分离柱:DAICEL CHIRALCEL OJ-H 250mm×30mm×5μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液30％-30％)分离得到化合物10a(第一个峰)和10b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel OD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物10b:e.e.％＝95.6％,RT＝1.734min。 1H NMR(400MHz,CD 3OD)δ8.15(d,J＝3.6Hz,1H),7.74(s,1H),7.11(s,1H),2.44(s,3H),1.91(s,3H)。MS-ESI计算值[M+H] +345,实测值345。 Compound 10-6 (84.5 mg, 246 μmol) and compound 1-1 (75.9 mg, 246 μmol) were dissolved in 1,4-dioxane (3 mL) and water (0.3 mL), and phosphoric acid was added to the reaction solution. Potassium (131 mg, 616 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (18.0 mg, 24.6 μmol). The reaction solution was heated to 80°C under nitrogen protection for 3 hours. The reaction solution was added with water (30 mL), extracted with ethyl acetate (30 mL×2), and the organic phases were combined, washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain the crude compound. The crude product was separated by SFC (column: DAICEL CHIRALCEL OJ-H 250mm×30mm×5μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ethanol solution of 0.1% ammonia water 30%-30%) to obtain the compound 10a (first peak) and 10b (second peak). The compound was then filtered through SFC (column: Chiralcel OD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: .05% diethylamine in ethanol: 5% -40%) measured ee value. Compound 10b: ee%=95.6%, RT=1.734 min. 1 H NMR (400MHz, CD 3 OD) δ8.15(d, J=3.6Hz, 1H), 7.74(s, 1H), 7.11(s, 1H), 2.44(s, 3H), 1.91(s, 3H) ). MS-ESI calculated [M+H] + 345, found 345.
实施例11Example 11
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000084
Figure PCTCN2021142174-appb-000084
第一步first step
将中间体C(1.00g,2.73mmol)溶于四氢呋喃(10mL),在-78℃下滴加二(三甲基硅)氨基钾1mol/L四氢呋喃溶液(4.1mL),在-78℃搅拌0.5小时,然后加入中间体11-1(808mg,5.46mmol),反应液在25℃下搅拌0.5小时。反应液加入饱和氯化铵水溶液(50mL),乙酸乙酯(50mL x 2)萃取,合并有机相,用饱和食盐水(50mL),无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到化合物11-2。MS-ESI计算值[M+H] +477和479,实测值477和479。 Intermediate C (1.00 g, 2.73 mmol) was dissolved in tetrahydrofuran (10 mL), 1 mol/L tetrahydrofuran solution (4.1 mL) of potassium bis(trimethylsilyl)amide was added dropwise at -78 °C, and stirred at -78 °C for 0.5 hour, then intermediate 11-1 (808 mg, 5.46 mmol) was added, and the reaction was stirred at 25° C. for 0.5 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, dried over saturated brine (50 mL), anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain compound 11-2. MS-ESI calculated [M+H] + 477 and 479, found 477 and 479.
第二步second step
将化合物11-2(890mg,1.86mmol)溶于三氟乙酸(10mL),反应液在90℃下搅拌12小时。反应液直接减压浓缩,加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(20mL x3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物11-3。MS-ESI计算值[M+H] +265,实测值265。 Compound 11-2 (890 mg, 1.86 mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added, saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 11-3. MS-ESI calculated [M+H] + 265, found 265.
第三步third step
将化合物11-3(409mg,1.54mmol)溶于三氟乙酸(6mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(302mg,1.70mmol)后滴加浓硫酸(0.6mL),反应液在0℃下搅拌0.5小时。反应液加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,用乙酸乙酯(10mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到中间体11-4。MS-ESI计算值[M+H] +343和345,实测值343和345。 Compound 11-3 (409 mg, 1.54 mmol) was dissolved in trifluoroacetic acid (6 mL), N-bromosuccinimide (302 mg, 1.70 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid ( 0.6 mL), the reaction solution was stirred at 0 °C for 0.5 h. The reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrated under reduced pressure, the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain intermediate 11-4. MS-ESI calculated [M+H] + 343 and 345, found 343 and 345.
第四步the fourth step
将化合物11-4(420mg,1.22mmol)溶于二氧六环(20mL)和水(4mL),加入中间体1-1(414mg,1.34mmol),1,1-双(二苯基磷)二茂铁氯化钯(89.4mg,122μmol)和磷酸钾(649mg,3.06mmol)。置换氮气三次,反应液在90℃下搅拌4小时。反应液直接减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1-1/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液45％-45％),分离得到化合物11。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物11:e.e.％＝100％,RT＝2.044min。 1H NMR(400MHz,CD3OD)δ7.87-7.67(m,2H),7.50(d,J＝7.6Hz,1H),7.35(d,J＝8.0Hz,1H),7.07(s,1H),2.43(s,3H),1.95(s,3H)。MS-ESI计算值[M+H] +345,实测值345。 Compound 11-4 (420 mg, 1.22 mmol) was dissolved in dioxane (20 mL) and water (4 mL), intermediate 1-1 (414 mg, 1.34 mmol), 1,1-bis(diphenylphosphine) was added Ferrocene palladium chloride (89.4 mg, 122 μmol) and potassium phosphate (649 mg, 3.06 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 90 °C for 4 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1-1/1, V/V) to obtain a crude compound, which was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 45%-45%), compound 11 was isolated. The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 11: ee%=100%, RT=2.044 min. 1 H NMR(400MHz,CD3OD)δ7.87-7.67(m,2H),7.50(d,J=7.6Hz,1H),7.35(d,J=8.0Hz,1H),7.07(s,1H), 2.43(s, 3H), 1.95(s, 3H). MS-ESI calculated [M+H] + 345, found 345.
实施例12Example 12
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000085
Figure PCTCN2021142174-appb-000085
第一步first step
将中间体C(450mg,1.23mmol)和化合物12-1(405mg,2.46mmol)溶于四氢呋喃(15mL),在0℃下滴加二(三甲基硅)氨基钾(1mol/L四氢呋喃溶液,4.30mL),在25℃搅拌2小时。反应液加入饱和氯化铵水溶液(10mL),乙酸乙酯(10mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～3/1,V/V)分离得到化合物12-2。MS-ESI计算值[M+H] +458和460,实测值458和460。 Intermediate C (450 mg, 1.23 mmol) and compound 12-1 (405 mg, 2.46 mmol) were dissolved in tetrahydrofuran (15 mL), and potassium bis(trimethylsilyl)amide (1 mol/L tetrahydrofuran solution was added dropwise at 0 °C, 4.30 mL), stirred at 25°C for 2 hours. The reaction solution was added with saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V) to obtain compound 12-2. MS-ESI calculated [M+H] + 458 and 460, found 458 and 460.
第二步second step
将化合物12-2(220mg,0.480mmol)溶于三氟乙酸(5mL),反应液在90℃下搅拌48小时。反应液直接减压浓缩,加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(20mL x3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物12-3。MS-ESI计算值[M+H] +246,实测值246。 Compound 12-2 (220 mg, 0.480 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 90° C. for 48 hours. The reaction solution was directly concentrated under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added, saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 12-3. MS-ESI calculated [M+H] + 246, found 246.
第三步third step
将化合物12-3(103mg,420μmol)溶于三氟乙酸(5mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(78.5mg,441μmol)后滴加浓硫酸(0.5mL),反应液在0℃下搅拌1小时。加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(10mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗品经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到中间体12-4。MS-ESI计算值[M+H] +324和326实测值324和326。 Compound 12-3 (103 mg, 420 μmol) was dissolved in trifluoroacetic acid (5 mL), N-bromosuccinimide (78.5 mg, 441 μmol) was added to the reaction solution at 0°C, and concentrated sulfuric acid (0.5 mL), the reaction solution was stirred at 0 °C for 1 hour. Water (10 mL) and ethyl acetate (10 mL) were added, saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure . The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain intermediate 12-4. MS-ESI calculated for [M+H] + 324 and 326 found 324 and 326.
第四步the fourth step
将化合物12-4(80.0mg,247μmol)溶于二氧六环(2mL)和水(0.4mL),加入中间体2-5(91.3mg,296μmol),1,1-双(二苯基磷)二茂铁氯化钯(18.1mg,24.7μmol)和磷酸钾(85.3mg,617μmol)。置换氮气三次,反应液在90℃下搅拌12小时。反应液直接减压浓缩,剩余物经过薄层层析法(石油醚/乙酸乙酯,3/1-0/1,V/V)分离得到粗品,粗品经SFC(分离柱:DAICEL CHIRALCEL OD-H 250mm×30mm×5μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液50％-50％),分离得到化合物12a(第一个峰)和12b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel OD-3 50mm×4.6mm×3μm；流动相:超临界CO 2- 0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物12b:e.e.％＝100％,RT＝2.006min。1H NMR(400MHz,CD3OD)δ9.03(s,1H),8.51(s,1H),7.86-7.67(m,1H),7.15(s,1H),2.43(s,3H),2.22(s,3H),2.04(s,3H)。MS-ESI计算值[M+H] +326,实测值326。 Compound 12-4 (80.0 mg, 247 μmol) was dissolved in dioxane (2 mL) and water (0.4 mL), and intermediate 2-5 (91.3 mg, 296 μmol), 1,1-bis(diphenylphosphine) was added ) ferrocene palladium chloride (18.1 mg, 24.7 μmol) and potassium phosphate (85.3 mg, 617 μmol). The nitrogen was replaced three times, and the reaction solution was stirred at 90 °C for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by thin-layer chromatography (petroleum ether/ethyl acetate, 3/1-0/1, V/V) to obtain a crude product, which was subjected to SFC (separating column: DAICEL CHIRALCEL OD- H 250mm×30mm×5μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 50%-50%), separate compounds 12a (the first peak) and 12b ( the second peak). The compound was then purified by SFC (chromatographic column: Chiralcel OD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 - 0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 12b: ee%=100%, RT=2.006 min. 1H NMR(400MHz, CD3OD)δ9.03(s,1H), 8.51(s,1H), 7.86-7.67(m,1H), 7.15(s,1H), 2.43(s,3H), 2.22(s, 3H), 2.04 (s, 3H). MS-ESI calculated [M+H] + 326, found 326.
实施例13Example 13
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000086
Figure PCTCN2021142174-appb-000086
第一步first step
将中间体C(400mg,1.09mmol)溶于四氢呋喃(10mL),在-78℃下滴加二(三甲基硅)氨基钾1M四氢呋喃溶液(1.64mL),在-78℃搅拌0.5小时,然后加入化合物13-1(325mg,2.18mmol),反应液在25℃下搅拌1小时。反应液加入饱和氯化铵水溶液(10mL),乙酸乙酯(20mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物13-2。MS-ESI计算值[M+H] +478和480,实测值478和480。 Intermediate C (400 mg, 1.09 mmol) was dissolved in tetrahydrofuran (10 mL), potassium bis(trimethylsilyl)amide 1M solution in tetrahydrofuran (1.64 mL) was added dropwise at -78 °C, stirred at -78 °C for 0.5 hours, and then Compound 13-1 (325 mg, 2.18 mmol) was added, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (20 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 13-2. MS-ESI calculated [M+H] + 478 and 480, found 478 and 480.
第二步second step
将化合物13-2(470mg,0.982mmol)溶于三氟乙酸(10mL),反应液在90℃下搅拌3小时。反应液直接减压浓缩,加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(20mL x3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物13-3。MS-ESI计算值[M+H] +266,实测值266。 Compound 13-2 (470 mg, 0.982 mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction solution was stirred at 90° C. for 3 hours. The reaction solution was directly concentrated under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added, saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 13-3. MS-ESI calculated [M+H] + 266, found 266.
第三步third step
将化合物13-3(160mg,602μmol)溶于三氟乙酸(4mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(118mg,662μmol)后滴加浓硫酸(0.4mL),反应液在0℃下搅拌1小时。加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至9,乙酸乙酯(20mL x 4)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗品经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到中间体13-4。MS-ESI计算值[M+H] +344和346实测值344和346。 Compound 13-3 (160 mg, 602 μmol) was dissolved in trifluoroacetic acid (4 mL), N-bromosuccinimide (118 mg, 662 μmol) was added to the reaction solution at 0°C, and concentrated sulfuric acid (0.4 mL) was added dropwise. ), the reaction solution was stirred at 0 °C for 1 hour. Water (10 mL) and ethyl acetate (10 mL) were added, saturated aqueous sodium bicarbonate solution was adjusted to pH 9, extracted with ethyl acetate (20 mL x 4), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure . The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain intermediate 13-4. MS-ESI calculated for [M+H] + 344 and 346 found 344 and 346.
第四步the fourth step
将化合物13-4(200mg,580μmol)溶于二氧六环(5mL)和水(1mL),加入化合物1-1(188mg,609μmol),1,1-双(二苯基磷)二茂铁氯化钯(42.5mg,58.0μmol)和磷酸钾(308mg,1.45mmol)。置换氮气三次, 反应液在90℃下搅拌4小时。反应液直接减压浓缩,剩余物经过薄层层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物13-5。MS-ESI计算值[M+H] +446,实测值446。 Compound 13-4 (200 mg, 580 μmol) was dissolved in dioxane (5 mL) and water (1 mL), and compound 1-1 (188 mg, 609 μmol), 1,1-bis(diphenylphosphorus)ferrocene was added. Palladium chloride (42.5 mg, 58.0 μmol) and potassium phosphate (308 mg, 1.45 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 90 °C for 4 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by thin layer chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 13-5. MS-ESI calculated [M+H] + 446, found 446.
第五步the fifth step
将化合物13-5(160mg,359μmol)溶解在甲醇(5mL)后加入氯化氢乙酸乙酯溶液(4moL/L,5.00mL),反应液在25℃下搅拌1小时。反应液直接减压浓缩得到粗品,粗品经SFC(分离柱:DAICEL CHIRALCEL OJ-H 250mm×30mm×5μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液25％-25％),分离得到化合物13a(第一个峰)和13b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel OJ-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物13b:e.e.％＝99.08％,RT＝2.929min。 1H NMR(400MHz,CD 3OD)δ9.10(s,1H),8.78(s,1H),7.89-7.69(m,1H),7.15(s,1H),2.44(s,3H),2.06(s,3H)。MS-ESI计算值[M+H] +346,实测值346。 Compound 13-5 (160 mg, 359 μmol) was dissolved in methanol (5 mL), hydrogen chloride ethyl acetate solution (4 moL/L, 5.00 mL) was added, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the crude product, which was passed through SFC (column: DAICEL CHIRALCEL OJ-H 250mm×30mm×5μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ethanol solution of ammonia water 25%-25%), compounds 13a (the first peak) and 13b (the second peak) were isolated. The compound was then filtered through SFC (column: Chiralcel OJ-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 13b: ee%=99.08%, RT=2.929 min. 1 H NMR (400MHz, CD 3 OD) δ 9.10(s, 1H), 8.78(s, 1H), 7.89-7.69(m, 1H), 7.15(s, 1H), 2.44(s, 3H), 2.06 (s, 3H). MS-ESI calculated [M+H] + 346, found 346.
实施例14Example 14
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000087
Figure PCTCN2021142174-appb-000087
第一步first step
将化合物13-5(160mg,359μmol)溶解在甲醇(5mL)后加入氯化氢乙酸乙酯溶液(4moL/L,5.00mL),反应液在25℃下搅拌1小时。反应液直接减压浓缩得到粗品。将粗品(70.0mg,202μmol)溶解在乙酸乙酯(10mL)后加入氢氧化钯(14.2mg,20.2μmol,纯度：20％)和三乙胺(41.0mg,405μmol),氢气置换三次,反应液在50℃,压力50Psi下搅拌12小时。反应液过滤，滤液直接减压浓缩得到化合物14粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AS 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液40％-40％),分离得到化合物14a(第一个峰)和14b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物14b:e.e.％＝98.66％,RT＝1.922min。 1H NMR(400MHz,CD 3OD)δ9.20(d,J＝0.08Hz,1H),8.77(d,J＝5.2Hz,1H),7.66(dd,J＝1.2,5.2Hz,2H),7.09(s,1H),2.42(s,3H),1.98(s,3H)。MS-ESI计算值[M+H] +312,实测值312。 Compound 13-5 (160 mg, 359 μmol) was dissolved in methanol (5 mL), hydrogen chloride ethyl acetate solution (4 moL/L, 5.00 mL) was added, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure to obtain the crude product. The crude product (70.0 mg, 202 μmol) was dissolved in ethyl acetate (10 mL), palladium hydroxide (14.2 mg, 20.2 μmol, purity: 20%) and triethylamine (41.0 mg, 405 μmol) were added, and the reaction solution was replaced by hydrogen three times. Stir for 12 hours at 50°C and 50 Psi pressure. The reaction solution was filtered, and the filtrate was directly concentrated under reduced pressure to obtain the crude product of compound 14. The crude product was passed through SFC (column: DAICEL CHIRALPAK AS 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ammonia water 40%-40% ethanol solution), and isolated compounds 14a (the first peak) and 14b (the second peak). The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 14b: ee%=98.66%, RT=1.922 min. 1 H NMR (400MHz, CD 3 OD) δ 9.20 (d, J=0.08Hz, 1H), 8.77 (d, J=5.2Hz, 1H), 7.66 (dd, J=1.2, 5.2Hz, 2H), 7.09(s, 1H), 2.42(s, 3H), 1.98(s, 3H). MS-ESI calculated [M+H] + 312, found 312.
实施例15Example 15
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000088
Figure PCTCN2021142174-appb-000088
第一步first step
将化合物C(200mg,0.546mmol)溶于四氢呋喃(10mL),在-78℃下滴加二(三甲基硅)氨基钾1M四氢呋喃溶液819μL),在-78℃搅拌0.5小时,升至0℃,将化合物15-1(151mg,1.09mmol)加入反应液,在25℃下搅拌0.5小时。反应液加入饱和氯化铵水溶液(50mL),乙酸乙酯(50mL x 2)萃取,合并有机相,饱和食盐水洗(50mL),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～3/1,V/V)分离得到化合物15-2。MS-ESI计算值[M+H] +468和470,实测值468和470。 Compound C (200 mg, 0.546 mmol) was dissolved in tetrahydrofuran (10 mL), at -78 °C, potassium bis(trimethylsilyl)amide 1M solution in tetrahydrofuran (819 μL) was added dropwise, stirred at -78 °C for 0.5 hours, and then raised to 0 °C , Compound 15-1 (151 mg, 1.09 mmol) was added to the reaction solution, and the mixture was stirred at 25° C. for 0.5 hours. The reaction solution was added with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～3/1, V/V) to obtain compound 15-2. MS-ESI calculated [M+H] + 468 and 470, found 468 and 470.
第二步second step
将化合物15-2(155mg,0.331mmol)溶于三氟乙酸(2mL),反应液在80℃下搅拌1小时。反应液直接减压浓缩,加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(20mL x3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离得到化合物15-3。MS-ESI计算值[M+H] +256,实测值256。 Compound 15-2 (155 mg, 0.331 mmol) was dissolved in trifluoroacetic acid (2 mL), and the reaction solution was stirred at 80° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added, saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (20 mL×3), the organic phases were combined and dried over anhydrous sodium sulfate , filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 15-3. MS-ESI calculated [M+H] + 256, found 256.
第三步third step
将化合物15-3(77.0mg,302μmol)溶于三氟乙酸(3mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(61.7mg,347μmol)后滴加浓硫酸(0.3mL),反应液在0℃下搅拌0.5小时。加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(10mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗品经过薄层层析法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离得到中间体15-4。MS-ESI计算值[M+H] +334和336实测值334和336。 Compound 15-3 (77.0 mg, 302 μmol) was dissolved in trifluoroacetic acid (3 mL), N-bromosuccinimide (61.7 mg, 347 μmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid ( 0.3 mL), the reaction solution was stirred at 0 °C for 0.5 h. Water (10 mL) and ethyl acetate (10 mL) were added, saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure . The crude product was separated by thin layer chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain intermediate 15-4. MS-ESI calculated for [M+H] + 334 and 336 found 334 and 336.
第四步the fourth step
将化合物15-4(40.0mg,75.4μmol)溶于二氧六环(2mL)和水(0.4mL),加入中间体1-1(27.9mg,90.5μmol),1,1-双(二苯基磷)二茂铁氯化钯(5.52mg,7.54μmol)和磷酸钾(26.1mg,189μmol)。置换氮气三次,反应液在90℃下搅拌12小时。反应液直接减压浓缩,剩余物经过薄层层析法(二氯甲烷/甲醇,100/1～10/1,V/V)分离得到化合物15粗品,粗品经SFC(分离柱:DAICEL CHIRALCEL OD-H 250mm×30mm×5μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液40％-40％),分离得到化合物15。化合物后经SFC(色谱柱:Chiralcel OD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物15:e.e.％＝100％,RT＝1.719min。 1H NMR(400MHz,CD3OD)δ8.02-7.98(m,1H),7.88-7.68(m,3H),7.09(s,1H),2.43(s,3H),1.99(s,3H)。 MS-ESI计算值[M+H] +336,实测值336。 Compound 15-4 (40.0 mg, 75.4 μmol) was dissolved in dioxane (2 mL) and water (0.4 mL), and intermediate 1-1 (27.9 mg, 90.5 μmol), 1,1-bis(diphenyl) was added phosphonium) ferrocene palladium chloride (5.52 mg, 7.54 μmol) and potassium phosphate (26.1 mg, 189 μmol). The nitrogen was replaced three times, and the reaction solution was stirred at 90 °C for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by thin layer chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain the crude product of compound 15, which was purified by SFC (separating column: DAICEL CHIRALCEL OD). -H 250mm×30mm×5μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ammonia water ethanol solution 40%-40%), compound 15 was isolated. The compound was then purified by SFC (chromatographic column: Chiralcel OD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 15: ee%=100%, RT=1.719 min. 1 H NMR (400 MHz, CD3OD) δ 8.02-7.98 (m, 1H), 7.88-7.68 (m, 3H), 7.09 (s, 1H), 2.43 (s, 3H), 1.99 (s, 3H). MS-ESI calculated [M+H] + 336, found 336.
实施例16Example 16
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000089
Figure PCTCN2021142174-appb-000089
第一步first step
将化合物C(800mg,2.18mmol)溶于四氢呋喃(20mL),在-78℃下滴加二(三甲基硅)氨基钾1mol/L四氢呋喃溶液(4.1mL),在-78℃搅拌十分钟,然后在0℃下加入中间体16-1(503mg,4.37mmol),反应液在25℃下搅拌3小时。反应液加入饱和氯化铵水溶液(10mL),乙酸乙酯(10mL x 2)萃取,合并有机相,无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～3/1,V/V)分离得到化合物16-2。MS-ESI计算值[M+H] +461和463,实测值461和463。 Compound C (800 mg, 2.18 mmol) was dissolved in tetrahydrofuran (20 mL), 1 mol/L tetrahydrofuran solution (4.1 mL) of potassium bis(trimethylsilyl)amide was added dropwise at -78 °C, and the mixture was stirred at -78 °C for ten minutes, Then intermediate 16-1 (503 mg, 4.37 mmol) was added at 0°C, and the reaction solution was stirred at 25°C for 3 hours. The reaction solution was added with saturated aqueous ammonium chloride solution (10 mL), extracted with ethyl acetate (10 mL x 2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～3/1, V/V) to obtain compound 16-2. MS-ESI calculated [M+H] + 461 and 463, found 461 and 463.
第二步second step
将化合物16-2(200mg,238μmol)溶于三氟乙酸(5mL),反应液在80℃下搅拌1小时。反应液直接减压浓缩,加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(20mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离得到化合物16-3。Compound 16-2 (200 mg, 238 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 80° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added, saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (20 mL x 3), the organic phases were combined, and anhydrous sodium sulfate was used for extraction. Dry, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 16-3.
第三步third step
将化合物16-3(100mg,403μmol)溶于三氟乙酸(3mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(78.9mg,443μmol)后滴加浓硫酸(0.3mL),反应液在0℃下搅拌1小时。反应液加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,用乙酸乙酯(10mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～3/1,V/V)分离得到中间体16-4。MS-ESI计算值[M+H] +327和329,实测值327和329。 Compound 16-3 (100 mg, 403 μmol) was dissolved in trifluoroacetic acid (3 mL), N-bromosuccinimide (78.9 mg, 443 μmol) was added to the reaction solution at 0°C, and concentrated sulfuric acid (0.3 μmol) was added dropwise. mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrated under reduced pressure, the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～3/1, V/V) to obtain intermediate 16-4. MS-ESI calculated [M+H] + 327 and 329, found 327 and 329.
第四步the fourth step
将化合物16-4(120mg,187μmol)溶于二氧六环(5mL)和水(1mL),加入中间体1-1(63.4mg,206μmol),1,1-双(二苯基磷)二茂铁氯化钯(13.7mg,18.7μmol)和磷酸钾(99.3mg,468μmol)。置换氮气三次,反应液在90℃下搅拌12小时。反应液直接减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～0/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK A 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液45％-45％),分离得到化合物 16a第一个峰)和16b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液；5％-40％)测e.e.值。化合物16b:e.e.％＝100％,RT＝2.057min。 1H NMR(400MHz,CD3OD)δ7.95-7.67(m,2H),7.46(dd,J＝2.4,7.6Hz,1H),7.08(s,1H),6.98(dd,J＝2.4,8.4Hz,1H),2.45-2.41(m,3H),1.95(s,3H)。MS-ESI计算值[M+H] +329,实测值329。 Compound 16-4 (120 mg, 187 μmol) was dissolved in dioxane (5 mL) and water (1 mL), intermediate 1-1 (63.4 mg, 206 μmol), 1,1-bis(diphenylphosphine)di Ferrocene palladium chloride (13.7 mg, 18.7 μmol) and potassium phosphate (99.3 mg, 468 μmol). The nitrogen was replaced three times, and the reaction solution was stirred at 90 °C for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～0/1, V/V) to obtain the crude compound, which was purified by SFC (separation column: DAICEL CHIRALPAK A 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 45%-45%), separated compounds 16a (first peak) and 16b (second peak) peaks). The compound was then purified by SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol; 5%- 40%) measured ee value. Compound 16b: ee%=100%, RT=2.057 min. 1 H NMR(400MHz, CD3OD)δ7.95-7.67(m,2H),7.46(dd,J=2.4,7.6Hz,1H),7.08(s,1H),6.98(dd,J=2.4,8.4Hz , 1H), 2.45-2.41 (m, 3H), 1.95 (s, 3H). MS-ESI calculated [M+H] + 329, found 329.
实施例17Example 17
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000090
Figure PCTCN2021142174-appb-000090
第一步first step
将化合物C(0.2g,0.54mmol)和化合物17-1(198mg,1.1mmol)溶于四氢呋喃(2mL),在-78℃下滴加二(三甲基硅)氨基钾1mol/L四氢呋喃溶液(0.82mL),在-78℃搅拌0.5小时,反应液在25℃下搅拌1小时。反应液加入饱和氯化铵水溶液(5mL),乙酸乙酯(30mL×2)萃取,合并有机相,用饱和食盐水(50mL),无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～3/1,V/V)分离得到化合物17-2。MS-ESI计算值[M+H] +511和513,实测值511和513。 Compound C (0.2 g, 0.54 mmol) and compound 17-1 (198 mg, 1.1 mmol) were dissolved in tetrahydrofuran (2 mL), and 1 mol/L tetrahydrofuran solution of potassium bis(trimethylsilyl)amide was added dropwise at -78 °C ( 0.82 mL), stirred at -78 °C for 0.5 hour, and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (5 mL), extracted with ethyl acetate (30 mL×2), the organic phases were combined, dried with saturated brine (50 mL), anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V) to obtain compound 17-2. MS-ESI calculated [M+H] + 511 and 513, found 511 and 513.
第二步second step
将化合物17-2(175mg,0.34mmol)溶于三氟乙酸(5mL),反应液在75℃下搅拌1小时。反应液直接减压浓缩,饱和氨水调至pH至9,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物17-3。MS-ESI计算值[M+H] +299,实测值299。 Compound 17-2 (175 mg, 0.34 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 75° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure, adjusted to pH 9 with saturated ammonia water, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 17-3. MS-ESI calculated [M+H] + 299, found 299.
第三步third step
将化合物17-3(83mg,0.28mmol)溶于三氟乙酸(2mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(54mg,0.30mmol)后滴加浓硫酸(0.2mL),反应液在0℃下搅拌1.5小时。反应液加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,用乙酸乙酯(30mL×2)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到中间体17-4。MS-ESI计算值[M+H] +377和379,实测值377和379。 Compound 17-3 (83 mg, 0.28 mmol) was dissolved in trifluoroacetic acid (2 mL), N-bromosuccinimide (54 mg, 0.30 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid ( 0.2 mL), the reaction solution was stirred at 0 °C for 1.5 hours. Water (10 mL) and ethyl acetate (10 mL) were added to the reaction solution, the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (30 mL×2), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrated under reduced pressure, the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain intermediate 17-4. MS-ESI calculated [M+H] + 377 and 379, found 377 and 379.
第四步the fourth step
将化合物17-4(110mg,0.24mmol)溶于二氧六环(4mL)和水(1mL),加入化合物1-1(110mg,0.38mmol),1,1-双(二苯基磷)二茂铁氯化钯(17mg,24μmol)和碳酸钾(99mg,0.71mmol)。置换氮气三次,反应液在80℃下搅拌10小时。反应液直接减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～0/1, V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液30％-30％),分离得到化合物17a(第一个峰)和17b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物17b:e.e.％＝99.9％,RT＝1.490min。 1H NMR(400MHz,CD 3OD)δ8.04(t,J＝8.0Hz,1H),7.85(s,0.4H),7.80(d,J＝8.0Hz,1H),7.74(d,J＝8.0Hz,1H),7.65(s,0.6H),7.1(s,1H),2.44-2.39(m,3H),1.99(s,3H)。MS-ESI计算值[M+H] +379,实测值379。 Compound 17-4 (110 mg, 0.24 mmol) was dissolved in dioxane (4 mL) and water (1 mL), compound 1-1 (110 mg, 0.38 mmol), 1,1-bis(diphenylphosphonium)di Ferocene palladium chloride (17 mg, 24 μmol) and potassium carbonate (99 mg, 0.71 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 80 °C for 10 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～0/1, V/V) to obtain the crude compound, which was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 30%-30%), compounds 17a (the first peak) and 17b (the first peak) were separated. two peaks). The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 17b: ee%=99.9%, RT=1.490 min. 1 H NMR (400 MHz, CD 3 OD) δ 8.04 (t, J=8.0 Hz, 1H), 7.85 (s, 0.4H), 7.80 (d, J=8.0 Hz, 1H), 7.74 (d, J= 8.0Hz, 1H), 7.65(s, 0.6H), 7.1(s, 1H), 2.44-2.39(m, 3H), 1.99(s, 3H). MS-ESI calculated [M+H] + 379, found 379.
实施例18Example 18
合成路线：synthetic route:
第一步first step
将化合物16-2(200mg,434μmol)溶于甲醇(3mL),加入甲醇钠(117mg,2.17mmol),在60℃搅拌12小时。反应液直接减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～3/1,V/V)分离得到化合物18-1。MS-ESI计算值[M+H] +473和475,实测值473和475。 Compound 16-2 (200 mg, 434 μmol) was dissolved in methanol (3 mL), sodium methoxide (117 mg, 2.17 mmol) was added, and the mixture was stirred at 60° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～3/1, V/V) to obtain compound 18-1. MS-ESI calculated [M+H] + 473 and 475, found 473 and 475.
第二步second step
将化合物18-1(120mg,254μmol)溶于三氟乙酸(2mL),反应液在90℃下搅拌48小时。反应液直接减压浓缩,加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(10mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离得到化合物18-2。MS-ESI计算值[M+H] +261,实测值261。 Compound 18-1 (120 mg, 254 μmol) was dissolved in trifluoroacetic acid (2 mL), and the reaction solution was stirred at 90° C. for 48 hours. The reaction solution was directly concentrated under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added, saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, and anhydrous sodium sulfate was used for extraction. Dry, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 18-2. MS-ESI calculated [M+H] + 261, found 261.
第三步third step
将化合物18-2(60.0mg,230μmol)溶于三氟乙酸(3mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(45.1mg,254μmol)后滴加浓硫酸(0.3mL),反应液在0℃下搅拌1小时。反应液加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,用乙酸乙酯(10mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离得到中间体18-3。MS-ESI计算值[M+H] +339和341,实测值339和341。 Compound 18-2 (60.0 mg, 230 μmol) was dissolved in trifluoroacetic acid (3 mL), N-bromosuccinimide (45.1 mg, 254 μmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid ( 0.3 mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was It was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain intermediate 18-3. MS-ESI calculated [M+H] + 339 and 341, found 339 and 341.
第四步the fourth step
将化合物18-3(65.0mg,192μmol)溶于二氧六环(2mL)和水(0.4mL),加入中间体1-1(65.0mg,211μmol),1,1-双(二苯基磷)二茂铁氯化钯(14.0mg,19.2μmol)和磷酸钾(102mg,479μmol)。置换氮气三次,反应液在90℃下搅拌12小时。反应液直接减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～0/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的异丙醇溶液；梯度:0.1％氨水的异丙醇溶液35％-35％),分离得到化合物18a(第一个峰)和18b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的异丙醇溶液；梯度:0.05％二乙胺的异丙醇溶液:5％-40％)测e.e.值。化合物18b:e.e.％＝100％,RT＝1.904min。 1H NMR(400MHz,CD3OD)δ7.86-7.61(m,2H),7.11-7.06(m,2H),6.68(d,J＝8.0Hz,1H),4.03(s,3H),2.44-2.40(m,3H),1.94(s,3H)。MS-ESI计算值[M+H] +341,实测值341。 Compound 18-3 (65.0 mg, 192 μmol) was dissolved in dioxane (2 mL) and water (0.4 mL), and intermediate 1-1 (65.0 mg, 211 μmol), 1,1-bis(diphenylphosphine) was added. ) ferrocene palladium chloride (14.0 mg, 19.2 μmol) and potassium phosphate (102 mg, 479 μmol). The nitrogen was replaced three times, and the reaction solution was stirred at 90 °C for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～0/1, V/V) to obtain the crude compound, which was purified by SFC (separating column: DAICEL CHIRALPAK AD). 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in isopropanol; gradient: 0.1% ammonia solution in isopropanol 35%-35%), isolated compound 18a (the first peak) and 18b (second peak). The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in isopropanol; gradient: 0.05% diethylamine in isopropanol :5%-40%) to measure the ee value. Compound 18b: ee%=100%, RT=1.904 min. 1 H NMR (400MHz, CD3OD)δ7.86-7.61(m, 2H), 7.11-7.06(m, 2H), 6.68(d, J=8.0Hz, 1H), 4.03(s, 3H), 2.44-2.40 (m, 3H), 1.94 (s, 3H). MS-ESI calculated [M+H] + 341, found 341.
实施例19Example 19
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000091
Figure PCTCN2021142174-appb-000091
第一步first step
将中间体C(0.75g,2.05mmol)和化合物19-1(0.61g,4.1mmol)溶于四氢呋喃(10mL),在-78℃下滴加双(三甲基硅)氨基钾(3.07mL,1mol/L的四氢呋喃溶液),在-78℃搅拌0.5小时,反应液在25℃下搅拌1小时。反应液加入饱和氯化铵水溶液(15mL),乙酸乙酯(50mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(50mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到化合物19-2。MS-ESI计算值[M+H] +478和480,实测值478和480。 Intermediate C (0.75 g, 2.05 mmol) and compound 19-1 (0.61 g, 4.1 mmol) were dissolved in tetrahydrofuran (10 mL), and bis(trimethylsilyl) potassium amide (3.07 mL, 1 mol/L tetrahydrofuran solution), stirred at -78 °C for 0.5 hour, and the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (15 mL), extracted with ethyl acetate (50 mL×2), the organic phases were combined, the organic phases were washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V) to obtain compound 19-2. MS-ESI calculated [M+H] + 478 and 480, found 478 and 480.
第二步second step
将化合物19-2(0.48g,1mmol)和化合物19-3(88.1mg,1mmol)溶于N,N-二甲基甲酰胺(5mL),在0℃下加入氢化钠(60mg,1.5mmol,60％纯度)后在20℃下搅拌1小时。反应液加水淬灭，乙酸乙酯(30mL)稀释后,经饱和食盐水洗涤(10mL×3),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到化合物19-4。MS-ESI计算值[M+H] +530和532,实测值530和532。 Compound 19-2 (0.48 g, 1 mmol) and compound 19-3 (88.1 mg, 1 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (60 mg, 1.5 mmol, 60% pure) and stirred at 20°C for 1 hour. The reaction solution was quenched by adding water, diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain compound 19-4. MS-ESI calculated [M+H] + 530 and 532, found 530 and 532.
第三步third step
将化合物19-4(0.42g,0.79mmol)溶于三氟乙酸(5mL),反应液在85℃下搅拌12小时。反应液直接减压浓缩,加入饱和碳酸氢钠水溶液(50mL)和乙酸乙酯(30mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(10mL×1),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物19-5。MS-ESI计算值[M+H] +318,实测值318。 Compound 19-4 (0.42 g, 0.79 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 85° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, extracted with saturated aqueous sodium bicarbonate solution (50 mL) and ethyl acetate (30 mL×2), the organic phases were combined, the organic phase was washed with saturated brine (10 mL×1), and the organic phase was washed with anhydrous sulfuric acid Dry over sodium, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound 19-5. MS-ESI calculated [M+H] + 318, found 318.
第四步the fourth step
将化合物19-5(82mg,0.26mmol)溶于三氟乙酸(1mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(50mg,0.28mmol)后滴加浓硫酸(0.1mL),反应液在0℃下搅拌20分钟。向反应液用饱和碳酸氢钠水溶 液调节pH＝8,用乙酸乙酯(30mL×2)萃取,有机相经食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～2/1,V/V)分离得到化合物19-6。MS-ESI计算值[M+H] +396和398实测值396和398。 Compound 19-5 (82 mg, 0.26 mmol) was dissolved in trifluoroacetic acid (1 mL), N-bromosuccinimide (50 mg, 0.28 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid ( 0.1 mL), the reaction solution was stirred at 0 °C for 20 minutes. The reaction solution was adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL×2), the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was subjected to Compound 19-6 was isolated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～2/1, V/V). MS-ESI calculated [M+H] + 396 and 398 found 396 and 398.
第五步the fifth step
将化合物19-6(113mg,285mmol)和化合物1-1(88mg,0.285mmol)溶解在1,4-二氧六环(2mL)和水(0.4mL)中,后向反应液中加入碳酸钾(118mg,0.855mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(21mg,28μmol)。将反应液在氮气保护下加热至80℃反应10小时。反应液减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～0/1,V/V)分离得到化合物粗品。粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液30％-30％)分离得到化合物19a(第一个峰)和19b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Compound 19-6 (113 mg, 285 mmol) and compound 1-1 (88 mg, 0.285 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and potassium carbonate was added to the reaction solution (118 mg, 0.855 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 28 μmol). The reaction solution was heated to 80°C under nitrogen protection for 10 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～0/1, V/V) to obtain the crude compound. The crude product was separated by SFC (column: DAICEL CHIRALPAK AD 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ethanol solution of 0.1% ammonia water 30%-30%) to obtain compound 19a ( first peak) and 19b (second peak). The compound was then purified by SFC (chromatographic column: Chiralcel AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
化合物19a:e.e.％＝99.5％,RT＝5.323min。 1H NMR(400MHz,CD 3OD)δ8.34(s,1H),8.18(s,1H),7.88-7.70(m,1H),7.10(s,1H),5.70-5.68(m,1H),4.17-4.13(m,1H),4.02-3.90(m,3H),2.43-2.39(m,4H),2.24-2.30(m,1H),1.97(s,3H)。MS-ESI计算值[M+H] +398,实测值398。 Compound 19a: ee%=99.5%, RT=5.323 min. 1 H NMR (400MHz, CD 3 OD) δ 8.34(s, 1H), 8.18(s, 1H), 7.88-7.70(m, 1H), 7.10(s, 1H), 5.70-5.68(m, 1H) , 4.17-4.13(m, 1H), 4.02-3.90(m, 3H), 2.43-2.39(m, 4H), 2.24-2.30(m, 1H), 1.97(s, 3H). MS-ESI calculated [M+H] + 398, found 398.
化合物19b:e.e.％＝99.5％,RT＝5.920min。 1H NMR(400MHz,CD 3OD)δ8.34(s,1H),8.18(s,1H),7.90-7.67(m,1H),7.10(s,1H),5.70-5.65(m,1H),4.17-4.11(m,1H),3.99-3.92(m,3H),2.43-2.40(m,4H),2.23-2.20(m,1H),1.96(s,3H)。MS-ESI计算值[M+H] +398,实测值398。 Compound 19b: ee%=99.5%, RT=5.920 min. 1 H NMR (400MHz, CD 3 OD) δ 8.34(s, 1H), 8.18(s, 1H), 7.90-7.67(m, 1H), 7.10(s, 1H), 5.70-5.65(m, 1H) , 4.17-4.11(m, 1H), 3.99-3.92(m, 3H), 2.43-2.40(m, 4H), 2.23-2.20(m, 1H), 1.96(s, 3H). MS-ESI calculated [M+H] + 398, found 398.
实施例20Example 20
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000092
Figure PCTCN2021142174-appb-000092
第一步first step
将化合物19-2(0.12g,0.25mmol)和化合物20-1(87mg,0.50mmol)溶于N,N-二甲基甲酰胺(2mL),在0℃下加入氢化钠(15mg,0.37mmol,60％纯度)后在35℃下搅拌2小时。反应液加水(5mL)淬灭，乙酸乙酯(30mL)稀释后,经饱和食盐水洗涤(10mL×3),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到化合物20-2。Compound 19-2 (0.12 g, 0.25 mmol) and compound 20-1 (87 mg, 0.50 mmol) were dissolved in N,N-dimethylformamide (2 mL), and sodium hydride (15 mg, 0.37 mmol) was added at 0°C , 60% purity) and stirred at 35°C for 2 hours. The reaction solution was quenched by adding water (5 mL), diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain compound 20-2.
第二步second step
将化合物20-2(110mg,178μmol)溶于三氟乙酸(5mL),反应液在85℃下搅拌4小时。反应液直接减压浓缩,加入饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯(30mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(10mL×1),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(二氯甲烷/甲醇,8/1～5/1,V/V)分离得到化合物粗品20-3。MS-ESI计算值[M+H] +303实测值303。 Compound 20-2 (110 mg, 178 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 85° C. for 4 hours. The reaction solution was directly concentrated under reduced pressure, and saturated aqueous sodium bicarbonate solution was added to adjust pH=8, extracted with ethyl acetate (30 mL×2), the organic phases were combined, the organic phase was washed with saturated brine (10 mL×1), and the organic phase was washed with anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol, 8/1～5/1, V/V) to obtain the crude compound 20-3. MS-ESI calculated [M+H] + 303 found 303.
第三步third step
将化合物粗品20-3(0.15g,0.466mmol)溶于三氟乙酸(2mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(87mg,489μmol)后滴加浓硫酸(0.2mL),反应液在0℃下搅拌1小时。反应液用饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯(30mL×2)萃取,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(二氯甲烷/甲醇,20/1～5/1,V/V)分离得到化合物20-4。MS-ESI计算值[M+H] +381和383实测值381和383。 The crude compound 20-3 (0.15 g, 0.466 mmol) was dissolved in trifluoroacetic acid (2 mL), N-bromosuccinimide (87 mg, 489 μmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid was added dropwise (0.2 mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL×2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (dichloromethane/methanol, 20/1～5/1, V/V) to obtain compound 20-4. MS-ESI calculated for [M+H] + 381 and 383 found 381 and 383.
第四步the fourth step
将化合物20-4(111mg,0.29mmol)和化合物1-1(134mg,0.436mmol)溶解在1,4-二氧六环(2mL)和水(0.4mL)中,后向反应液中加入碳酸钾(120mg,0.873mmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(21mg,29μmol)。将反应液在氮气保护下加热至80℃反应10小时。反应液减压浓缩。粗产物经过硅胶柱层析法(二氯甲烷/甲醇,20/1～5/1,V/V)分离得到化合物粗品。粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液45％-45％)分离得到化合物20a(第一个峰)和20b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Compound 20-4 (111 mg, 0.29 mmol) and compound 1-1 (134 mg, 0.436 mmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and carbonic acid was added to the reaction solution. Potassium (120 mg, 0.873 mmol) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (21 mg, 29 μmol). The reaction solution was heated to 80°C under nitrogen protection for 10 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol, 20/1～5/1, V/V) to obtain the crude compound. The crude product was separated by SFC (column: DAICEL CHIRALPAK AD 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 45%-45% ethanol solution of 0.1% ammonia water) to obtain compound 20a ( first peak) and 20b (second peak). The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
化合物20b:e.e.％＝97.7％,RT＝2.181min。 1H NMR(400MHz,CD 3OD)δ8.47(s,1H),8.34(s,1H),7.77(s,1H),7.10(s,1H),5.62-5.58(m,1H),4.68-4.65(m,2H),4.31-4.28(m,2H),2.43(s,3H),1.95-1.94(m,3H)。MS-ESI计算值[M+H] +383,实测值383。 Compound 20b: ee%=97.7%, RT=2.181 min. 1 H NMR (400MHz, CD 3 OD) δ 8.47(s, 1H), 8.34(s, 1H), 7.77(s, 1H), 7.10(s, 1H), 5.62-5.58(m, 1H), 4.68 -4.65(m, 2H), 4.31-4.28(m, 2H), 2.43(s, 3H), 1.95-1.94(m, 3H). MS-ESI calculated [M+H] + 383, found 383.
实施例21Example 21
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000093
Figure PCTCN2021142174-appb-000093
第一步first step
将化合物19-2(0.1g,0.208mmol)和化合物21-1的盐酸盐(46mg,0.42mmol)溶于N,N-二甲基乙酰胺(2mL)后加入N,N-二异丙基乙胺(135mg,1.04mmol),在120℃下搅拌3小时。反应液加乙酸乙酯(30mL)稀释后,经饱和食盐水洗涤(10mL×3),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到化合物21-2。Compound 19-2 (0.1 g, 0.208 mmol) and compound 21-1 hydrochloride (46 mg, 0.42 mmol) were dissolved in N,N-dimethylacetamide (2 mL) and N,N-diisopropyl was added Ethylamine (135 mg, 1.04 mmol), stirred at 120° C. for 3 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain compound 21-2.
第二步second step
将化合物21-2(95mg,184mmol)溶于三氟乙酸(5mL),反应液在85℃下搅拌12小时。反应液直接减压浓缩,饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯萃取(30mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(10mL×1),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,1/1～0/1,V/V)分离得到化合物21-3。MS-ESI计算值[M+H] +303,实测值303。 Compound 21-2 (95 mg, 184 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 85° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL×2), the organic phases were combined, the organic phase was washed with saturated brine (10 mL×1), and the organic phase was washed with anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1～0/1, V/V) to obtain compound 21-3. MS-ESI calculated [M+H] + 303, found 303.
第三步third step
将化合物21-3(50mg,123μmol)溶于三氟乙酸(1mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(23mg,129μmol)后滴加浓硫酸(0.1mL),反应液在0℃下搅拌2小时。反应液经饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯萃取(30mL×2)萃取,有机相经食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,1/1～0/1,V/V)分离得到化合物21-4。MS-ESI计算值[M+H] +381和383实测值381和383。 Compound 21-3 (50 mg, 123 μmol) was dissolved in trifluoroacetic acid (1 mL), N-bromosuccinimide (23 mg, 129 μmol) was added to the reaction solution at 0°C, and concentrated sulfuric acid (0.1 mL) was added dropwise. ), and the reaction solution was stirred at 0 °C for 2 hours. The reaction solution was adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL×2), the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was filtered through silica gel Compound 21-4 was obtained by column chromatography (petroleum ether/ethyl acetate, 1/1～0/1, V/V). MS-ESI calculated for [M+H] + 381 and 383 found 381 and 383.
第四步the fourth step
将化合物21-4(28mg,75μmol)和化合物1-1(34mg,113μmol)溶解在1,4-二氧六环(2mL)和水(0.4mL)中,后向反应液中加入碳酸钾(31mg,226μmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(6mg,7.5μmol)。将反应液在氮气保护下加热至80℃反应10小时。反应液减压浓缩。粗产物经过硅胶柱层析法(二氯甲烷/甲醇,20/1-8/1,V/V)分离得到化合物粗品。粗品经SFC(分离柱:DAICEL CHIRALCEL OD-H 250mm×30mm×5μm；流动相:超临界CO 2-0.1％氨水的甲醇溶液；梯度:0.1％氨水的甲醇溶液45％-45％)分离得到化合物21(第一个峰)和21b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel OD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的甲醇溶液；梯度:0.05％二乙胺的甲醇溶液:5％-40％)测e.e.值。 Compound 21-4 (28 mg, 75 μmol) and compound 1-1 (34 mg, 113 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and potassium carbonate ( 31 mg, 226 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (6 mg, 7.5 μmol). The reaction solution was heated to 80°C under nitrogen protection for 10 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol, 20/1-8/1, V/V) to obtain the crude compound. The crude product was separated by SFC (column: DAICEL CHIRALCEL OD-H 250mm×30mm×5μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in methanol; gradient: 0.1% ammonia solution in methanol 45%-45%) to obtain the compound 21 (first peak) and 21b (second peak). The compound was then purified by SFC (chromatographic column: Chiralcel OD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in methanol; gradient: 0.05% diethylamine in methanol: 5%- 40%) measured ee value.
化合物21b:e.e.％＝100％,RT＝1.763min。 1H NMR(400MHz,CD 3OD)δ7.95(s,1H),7.79-7.69(m,2H),7.07(s,1H),4.79-4.77(m,1H),4.44-4.38(m,2H),3.99-3.91(m,2H),2.43(s,3H),1.90(s,3H)。MS-ESI计算值[M+H] +383,实测值383。 Compound 21b: ee%=100%, RT=1.763 min. 1 H NMR (400MHz, CD 3 OD) δ 7.95(s, 1H), 7.79-7.69(m, 2H), 7.07(s, 1H), 4.79-4.77(m, 1H), 4.44-4.38(m, 2H), 3.99-3.91 (m, 2H), 2.43 (s, 3H), 1.90 (s, 3H). MS-ESI calculated [M+H] + 383, found 383.
实施例22Example 22
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000094
Figure PCTCN2021142174-appb-000094
Figure PCTCN2021142174-appb-000095
Figure PCTCN2021142174-appb-000095
第一步first step
将化合物19-2(0.1g,0.208mmol)和化合物22-1(42mg,0.42mmol)溶于N,N-二甲基乙酰胺(2mL)后加入N,N-二异丙基乙胺(135mg,1.04mmol)，在120℃下搅拌2.5小时。反应液加乙酸乙酯(30mL)稀释后,经饱和食盐水洗涤(10mL×3),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(二氯甲烷/甲醇,50/1～15/1,V/V)分离得到化合物22-2。MS-ESI计算值[M+H] +542和544,实测值542和544。 Compound 19-2 (0.1 g, 0.208 mmol) and compound 22-1 (42 mg, 0.42 mmol) were dissolved in N,N-dimethylacetamide (2 mL) and N,N-diisopropylethylamine ( 135 mg, 1.04 mmol), stirred at 120 °C for 2.5 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol, 50/1～15/1, V/V) to obtain compound 22-2. MS-ESI calculated [M+H] + 542 and 544, found 542 and 544.
第二步second step
将化合物22-2(95mg,0.175mmol)溶于三氟乙酸(5mL),反应液在85℃下搅拌4小时。反应液直接减压浓缩,饱和氨水调节pH＝9,再减压浓缩。粗产物经过硅胶柱层析法(二氯甲烷/甲醇,20/1～8/1,V/V)分离得到化合物22-3。MS-ESI计算值[M+H] +330,实测值330。 Compound 22-2 (95 mg, 0.175 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 85° C. for 4 hours. The reaction solution was directly concentrated under reduced pressure, adjusted to pH=9 with saturated ammonia water, and then concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol, 20/1～8/1, V/V) to obtain compound 22-3. MS-ESI calculated [M+H] + 330, found 330.
第三步third step
将化合物22-3(48mg,0.147mmol)溶于三氟乙酸(1mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(26mg,0.147mmol)后滴加浓硫酸(0.1mL),反应液在0℃下搅拌1小时。反应液经饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯萃取(30mL×5)萃取,有机相经无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,1/1～0/1,V/V)分离得到化合物22-4。MS-ESI计算值[M+H] +408和410实测值408和410。 Compound 22-3 (48 mg, 0.147 mmol) was dissolved in trifluoroacetic acid (1 mL), N-bromosuccinimide (26 mg, 0.147 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid ( 0.1 mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL×5), the organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (petroleum ether). /ethyl acetate, 1/1～0/1, V/V) to obtain compound 22-4. MS-ESI calculated [M+H] + 408 and 410 found 408 and 410.
第四步the fourth step
将化合物22-4(40mg,99μmol)和化合物1-1(46mg,149μmol)溶解在1,4-二氧六环(2mL)和水(0.4mL)中,后向反应液中加入碳酸钾(41mg,297μmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(7.26mg,9.9μmol)。将反应液在氮气保护下加热至80℃反应3小时。反应液减压浓缩。粗产物经过硅胶柱层析法(二氯甲烷/甲醇,30/1～10/1,V/V)分离得到化合物22-5。MS-ESI计算值[M+H] +510,实测值510。 Compound 22-4 (40 mg, 99 μmol) and compound 1-1 (46 mg, 149 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and potassium carbonate ( 41 mg, 297 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium (7.26 mg, 9.9 μmol). The reaction solution was heated to 80°C under nitrogen protection for 3 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol, 30/1～10/1, V/V) to obtain compound 22-5. MS-ESI calculated [M+H] + 510, found 510.
第五步the fifth step
将化合物22-5(29mg,57μmol)溶解在甲醇(3mL)后加入氯化氢甲醇溶液(4moL/L,1.00mL),反应液在25℃下搅拌2小时。反应液直接减压浓缩,经硅胶柱层析法(二氯甲烷/甲醇,30/1～8/1,V/V)分离得到粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的异丙醇溶液；梯度:0.1％氨水的异丙醇溶液40％-40％),分离得到化合物22a(第一个峰)和22b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％ 二乙胺的异丙醇溶液；梯度:0.05％二乙胺的异丙醇溶液:5％-40％)测e.e.值。 Compound 22-5 (29 mg, 57 μmol) was dissolved in methanol (3 mL), hydrogen chloride methanol solution (4 moL/L, 1.00 mL) was added, and the reaction solution was stirred at 25° C. for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (dichloromethane/methanol, 30/1～8/1, V/V), and the crude product was purified by SFC (separation column: DAICEL CHIRALPAK AD 250mm×30mm× 10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in isopropanol; gradient: 0.1% ammonia solution in isopropanol 40% - 40%), separate compounds 22a (the first peak) and 22b (the first peak). two peaks). The compound was then subjected to SFC (chromatographic column: Chiralcel AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in isopropanol; gradient: 0.05% diethylamine in isopropanol :5%-40%) to measure the ee value.
化合物22b:e.e.％＝95％,RT＝6.807min。 1H NMR(400MHz,CD3OD)δ8.18(s,1H),7.98(s,1H),7.87(s,0.4H),7.66(s,0.6H),7.08(s,1H),3.78(s,4H),2.65(s,4H),2.44-2.40(s,6H),1.91(s,3H)。MS-ESI计算值[M+H]+410,实测值410。 Compound 22b: ee%=95%, RT=6.807 min. 1 H NMR(400MHz, CD3OD)δ8.18(s,1H),7.98(s,1H),7.87(s,0.4H),7.66(s,0.6H),7.08(s,1H),3.78(s , 4H), 2.65(s, 4H), 2.44-2.40(s, 6H), 1.91(s, 3H). MS-ESI calculated value [M+H]+410, found 410.
实施例23Example 23
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000096
Figure PCTCN2021142174-appb-000096
第一步first step
将化合物19-2(110mg,0.230mmol)和化合物23-1的盐酸盐(57mg,0.46mmol)溶于N,N-二甲基乙酰胺(2mL)后加入N,N-二异丙基乙胺(149mg,0.2mmol),在120℃下搅拌2.5小时。反应液加乙酸乙酯(30mL)稀释后,经饱和食盐水洗涤(10mL×3),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物23-2直接用于下一步反应。Compound 19-2 (110 mg, 0.230 mmol) and compound 23-1 hydrochloride (57 mg, 0.46 mmol) were dissolved in N,N-dimethylacetamide (2 mL) and N,N-diisopropyl was added Ethylamine (149 mg, 0.2 mmol) was stirred at 120°C for 2.5 hours. The reaction solution was diluted with ethyl acetate (30 mL), washed with saturated brine (10 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product 23-2 was directly used in the next reaction.
第二步second step
将化合物23-2(130mg,0.245mmol)溶于三氟乙酸(5mL),反应液在85℃下搅拌5小时。反应液直接减压浓缩,饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯萃取(30mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(10mL×1),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,1/1～0/1,V/V)分离得到化合物23-3。MS-ESI计算值[M+H] +317,实测值317。 Compound 23-2 (130 mg, 0.245 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 85° C. for 5 hours. The reaction solution was directly concentrated under reduced pressure, adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL×2), the organic phases were combined, the organic phase was washed with saturated brine (10 mL×1), and the organic phase was washed with anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1～0/1, V/V) to obtain compound 23-3. MS-ESI calculated [M+H] + 317, found 317.
第三步third step
将化合物23-3(70mg,208μmol)溶于三氟乙酸(1mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(39mg,218μmol)后滴加浓硫酸(0.1mL),反应液在0℃下搅拌2小时。反应液经饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯萃取(30mL×2)萃取,有机相经食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,1/1～0/1,V/V)分离得到化合物23-4。MS-ESI计算值[M+H] +395和397实测值395和397。 Compound 23-3 (70 mg, 208 μmol) was dissolved in trifluoroacetic acid (1 mL), N-bromosuccinimide (39 mg, 218 μmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid (0.1 mL) was added dropwise. ), and the reaction solution was stirred at 0 °C for 2 hours. The reaction solution was adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL×2), the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was filtered through silica gel Compound 23-4 was obtained by column chromatography (petroleum ether/ethyl acetate, 1/1～0/1, V/V). MS-ESI calculated [M+H] + 395 and 397 found 395 and 397.
第四步the fourth step
将化合物23-4(47mg,120μmol)和化合物1-1(55mg,180μmol)溶解在1,4-二氧六环(2mL)和水(0.4mL)中,后向反应液中加入碳酸钾(50mg,360μmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(8.8mg,12μmol)。将反应液在氮气保护下加热至80℃反应3小时。反应液减压浓缩。粗产物经过硅胶柱层析法(二氯甲烷/甲醇,20/1～10/1,V/V)分离得到化合物23-5。MS-ESI计算值[M+H] +497,实测值497。 Compound 23-4 (47 mg, 120 μmol) and compound 1-1 (55 mg, 180 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and potassium carbonate ( 50 mg, 360 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium (8.8 mg, 12 μmol). The reaction solution was heated to 80°C under nitrogen protection for 3 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol, 20/1～10/1, V/V) to obtain compound 23-5. MS-ESI calculated [M+H] + 497, found 497.
第五步the fifth step
将化合物23-5(17mg,35μmol)溶解在甲醇(3mL)后加入氯化氢甲醇溶液(4moL/L,1.00mL),反应液在25℃下搅拌2小时。反应液直接减压浓缩,粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液醇40％-40％),分离得到化合物23a(第一个峰)和23b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Compound 23-5 (17 mg, 35 μmol) was dissolved in methanol (3 mL), hydrogen chloride methanol solution (4 moL/L, 1.00 mL) was added, and the reaction solution was stirred at 25° C. for 2 hours. The reaction solution was directly concentrated under reduced pressure, and the crude product was passed through SFC (column: DAICEL CHIRALPAK AD 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ammonia water ethanol solution alcohol 40%- 40%), compounds 23a (the first peak) and 23b (the second peak) were isolated. The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
化合物23b:e.e.％＝100％,RT＝2.188min。 1H NMR(400MHz,CD 3OD)δ7.96(s,1H),7.83-7.69(m,2H),7.07(s,1H),4.11-3.99(s,4H),2.43(s,3H),1.90(s,3H),1.58(s,3H)。MS-ESI计算值[M+H] +397,实测值397。 Compound 23b: ee%=100%, RT=2.188 min. 1 H NMR (400MHz, CD 3 OD) δ 7.96(s, 1H), 7.83-7.69(m, 2H), 7.07(s, 1H), 4.11-3.99(s, 4H), 2.43(s, 3H) , 1.90(s, 3H), 1.58(s, 3H). MS-ESI calculated [M+H] + 397, found 397.
实施例24Example 24
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000097
Figure PCTCN2021142174-appb-000097
第一步first step
将中间体C(1.00g,2.73mmol)溶于四氢呋喃(10mL),在-78℃下滴加双(三甲基硅)氨基钾(4.10mL,1mol/L的四氢呋喃溶液),在-78℃搅拌0.5小时,然后在0℃下加入化合物24-1(813mg,5.46mmol),反应 液在25℃下搅拌0.5小时。反应液加入饱和氯化铵水溶液(50mL),乙酸乙酯(20mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(30mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～3/1,V/V)分离得到化合物24-2。MS-ESI计算值[M+H] +478和480,实测值478和480。 Intermediate C (1.00 g, 2.73 mmol) was dissolved in tetrahydrofuran (10 mL), bis(trimethylsilyl) potassium amide (4.10 mL, 1 mol/L solution in tetrahydrofuran) was added dropwise at -78 °C, and the solution was heated at -78 °C. After stirring for 0.5 hour, compound 24-1 (813 mg, 5.46 mmol) was added at 0°C, and the reaction solution was stirred at 25°C for 0.5 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phases were washed with saturated brine (30 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～3/1, V/V) to obtain compound 24-2. MS-ESI calculated [M+H] + 478 and 480, found 478 and 480.
第二步second step
将化合物24-2(147mg,1.67mmol)溶于N,N-二甲基甲酰胺(5mL),在0℃下加入钠氢(50.1mg,1.25mmol,纯度：60％),在0℃搅拌0.5小时,然后加入化合物24-3(400mg,835μmol),反应液在25℃下搅拌1小时。反应液加入水(5mL),乙酸乙酯(10mL x 3)萃取,合并有机相,用饱和食盐水(20mL x 3),无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～3/1,V/V)分离得到化合物24-4。MS-ESI计算值[M+H] +530和532,实测值530和532。 Compound 24-2 (147 mg, 1.67 mmol) was dissolved in N,N-dimethylformamide (5 mL), sodium hydrogen (50.1 mg, 1.25 mmol, purity: 60%) was added at 0 °C, and the mixture was stirred at 0 °C After 0.5 hours, compound 24-3 (400 mg, 835 μmol) was then added, and the reaction solution was stirred at 25° C. for 1 hour. The reaction solution was added with water (5 mL), extracted with ethyl acetate (10 mL x 3), the organic phases were combined, dried over saturated brine (20 mL x 3), anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～3/1, V/V) to obtain compound 24-4. MS-ESI calculated [M+H] + 530 and 532, found 530 and 532.
第三步third step
将化合物24-4(340mg,641μmol)溶于三氟乙酸(10mL),反应液在80℃下搅拌1小时。反应液直接减压浓缩,加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(20mL x 3)萃取,合并有机相,用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离得到化合物24-5。MS-ESI计算值[M+H] +318,实测值318。 Compound 24-4 (340 mg, 641 μmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction solution was stirred at 80° C. for 1 hour. The reaction solution was directly concentrated under reduced pressure, water (10 mL) and ethyl acetate (10 mL) were added, the pH was adjusted to 8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 mL x 3), the organic phases were combined and washed with anhydrous sodium sulfate. Dry, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 24-5. MS-ESI calculated [M+H] + 318, found 318.
第四步the fourth step
将化合物24-5(130mg,410μmol)溶于三氟乙酸(5mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(87.5mg,492μmol)后滴加浓硫酸(0.5mL),反应液在0℃下搅拌1小时。反应液加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,用乙酸乙酯(10mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离得到中间体24-6。MS-ESI计算值[M+H] +396和398,实测值396和398。 Compound 24-5 (130 mg, 410 μmol) was dissolved in trifluoroacetic acid (5 mL), N-bromosuccinimide (87.5 mg, 492 μmol) was added to the reaction solution at 0°C, and concentrated sulfuric acid (0.5 mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was It was concentrated under reduced pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain intermediate 24-6. MS-ESI calculated [M+H] + 396 and 398, found 396 and 398.
第五步the fifth step
将化合物24-6(88.0mg,222μmol)溶于二氧六环(3mL)和水(0.6mL),加入中间体1-1(82.1mg,266μmol),1,1-双(二苯基磷)二茂铁氯化钯(16.3mg,22.2μmol)和磷酸钾(76.7mg,555μmol)。置换氮气三次,反应液在90℃下搅拌12小时。反应液直接减压浓缩,剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,1/1～0/1,V/V)分离得到粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AS 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液50％-50％),分离得到化合物24a(第一个峰)和24b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AS-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Compound 24-6 (88.0 mg, 222 μmol) was dissolved in dioxane (3 mL) and water (0.6 mL), intermediate 1-1 (82.1 mg, 266 μmol), 1,1-bis(diphenylphosphine) was added ) ferrocene palladium chloride (16.3 mg, 22.2 μmol) and potassium phosphate (76.7 mg, 555 μmol). The nitrogen was replaced three times, and the reaction solution was stirred at 90 °C for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1～0/1, V/V) to obtain the crude product, which was purified by SFC (separating column: DAICEL CHIRALPAK AS 250mm) ×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 50%-50%), compounds 24a (the first peak) and 24b (the second peak) were isolated peaks). The compound was then filtered through SFC (column: Chiralcel AS-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
化合物24a:e.e.％＝100％,RT＝2.494min  1H NMR(400MHz,CD3OD)δ8.15(d,J＝2.8Hz,1H),8.13(d,J＝2.8Hz,1H),7.87-7.68(m,1H),7.13(s,1H),5.65-5.63(m,1H),4.06-3.97(m,2H),3.94-3.83(m,2H),2.45(br s,3H),2.30-2.21(m,1H),2.06-2.01(m,1H),1.99(s,3H)。MS-ESI计算值[M+H] +398,实测值398。 Compound 24a: ee%=100%, RT=2.494min 1 H NMR (400MHz, CD3OD) δ 8.15 (d, J=2.8Hz, 1H), 8.13 (d, J=2.8Hz, 1H), 7.87-7.68 (m,1H),7.13(s,1H),5.65-5.63(m,1H),4.06-3.97(m,2H),3.94-3.83(m,2H),2.45(br s,3H),2.30- 2.21(m, 1H), 2.06-2.01(m, 1H), 1.99(s, 3H). MS-ESI calculated [M+H] + 398, found 398.
化合物24b:e.e.％＝99.4％,RT＝3.428min  1H NMR(400MHz,CD 3OD)δ8.15(d,J＝2.8Hz,1H),8.13(d,J＝2.8Hz,1H),7.87-7.68(m,1H),7.13(s,1H),5.67-5.64(m,1H),4.01-3.97(m,1H),3.93-3.85(m,2H),3.77-3.75(m,1H),2.44(s,3H),2.35-2.21(m,2H),1.98(s,3H)。MS-ESI计算值[M+H] +398,实测值398。 Compound 24b: ee%=99.4%, RT=3.428 min 1 H NMR (400 MHz, CD 3 OD) δ 8.15 (d, J=2.8 Hz, 1H), 8.13 (d, J=2.8 Hz, 1H), 7.87 -7.68(m, 1H), 7.13(s, 1H), 5.67-5.64(m, 1H), 4.01-3.97(m, 1H), 3.93-3.85(m, 2H), 3.77-3.75(m, 1H) , 2.44(s, 3H), 2.35-2.21(m, 2H), 1.98(s, 3H). MS-ESI calculated [M+H] + 398, found 398.
实施例25Example 25
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000098
Figure PCTCN2021142174-appb-000098
第一步first step
将化合物11-2(190mg,0.397mmol)和化合物25-1(70mg,0.79mmol)溶于N,N-二甲基甲酰胺(3mL),在0℃下加入氢化钠(63mg,1.59mmol,60％纯度)后在25℃下搅拌12小时。反应液加饱和氯化铵水溶液(10mL)淬灭，乙酸乙酯(30mL)稀释后,经饱和食盐水洗涤(15mL×3),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～3/1,V/V)分离得到化合物25-2。Compound 11-2 (190 mg, 0.397 mmol) and compound 25-1 (70 mg, 0.79 mmol) were dissolved in N,N-dimethylformamide (3 mL), sodium hydride (63 mg, 1.59 mmol, 60% pure) and stirred at 25°C for 12 hours. The reaction solution was quenched with saturated aqueous ammonium chloride solution (10 mL), diluted with ethyl acetate (30 mL), washed with saturated brine (15 mL×3), the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～3/1, V/V) to obtain compound 25-2.
第二步second step
将化合物25-2(100mg,0.189mmol)溶于三氟乙酸(5mL),反应液在75℃下搅拌12小时。反应液直接减压浓缩,饱和碳酸氢钠水溶液调节pH＝9,乙酸乙酯萃取(20mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(10mL×1),有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物25-3。MS-ESI计算值[M+H] +317,实测值317。 Compound 25-2 (100 mg, 0.189 mmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 75° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, adjusted to pH=9 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (20 mL×2), the organic phases were combined, the organic phase was washed with saturated brine (10 mL×1), and the organic phase was washed with anhydrous Dry over sodium sulfate, filter, and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 25-3. MS-ESI calculated [M+H] + 317, found 317.
第三步third step
将化合物25-3(48mg,152μmol)溶于三氟乙酸(2mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(29mg,167μmol)后滴加浓硫酸(0.2mL),反应液在0℃下搅拌4小时。反应液经饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯(30mL×2)萃取,有机相经食盐水(10mL)洗涤,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物25-4。MS-ESI计算值[M+H] +395和397实测值395和397。 Compound 25-3 (48 mg, 152 μmol) was dissolved in trifluoroacetic acid (2 mL), N-bromosuccinimide (29 mg, 167 μmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid (0.2 mL) was added dropwise. ), the reaction solution was stirred at 0 °C for 4 hours. The reaction solution was adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (30 mL×2), the organic phase was washed with brine (10 mL), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was passed through a silica gel column Chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) was used to isolate compound 25-4. MS-ESI calculated [M+H] + 395 and 397 found 395 and 397.
第四步the fourth step
将化合物25-4(30mg,79μmol)和化合物1-1(48mg,158μmol)溶解在1,4-二氧六环(4mL)和水(1mL)中,后向反应液中加入碳酸钾(32mg,237μmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(5.8mg,7.9μmol)。将反应液在氮气保护下加热至80℃反应10小时。反应液减压浓缩。粗产物经过硅胶柱层析法 (石油醚/乙酸乙酯,1/1～0/1,V/V)分离得到粗产物。粗产物经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液45％-45％)分离得到化合物25a(第一个峰)和25b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Compound 25-4 (30 mg, 79 μmol) and compound 1-1 (48 mg, 158 μmol) were dissolved in 1,4-dioxane (4 mL) and water (1 mL), and potassium carbonate (32 mg) was added to the reaction solution. , 237 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (5.8 mg, 7.9 μmol). The reaction solution was heated to 80°C under nitrogen protection for 10 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 1/1～0/1, V/V) to obtain the crude product. The crude product was separated by SFC (column: DAICEL CHIRALPAK AD 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 45%-45% ethanol solution of 0.1% ammonia water) to obtain compound 25a (first peak) and 25b (second peak). The compound was then filtered through SFC (chromatographic column: Chiralcel AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
化合物25a:e.e.％＝99％,RT＝1.718min。 1H NMR(400MHz,CD 3OD)δ7.88(s,0.3H),7.70-7.66(m,1.7H),7.15(d,J＝7.2,1H),7.09(s,1H),6.72(d,J＝7.2,1H),5.72-5.70(m,1H),4.17-4.14(m,1H),4.02-3.93(m,3H),2.46-2.35(m,4H),2.22-2.20(m,1H),1.97(s,3H)。MS-ESI计算值[M+H]+397,实测值397。 Compound 25a: ee%=99%, RT=1.718 min. 1 H NMR (400MHz, CD 3 OD) δ 7.88(s, 0.3H), 7.70-7.66(m, 1.7H), 7.15(d, J=7.2, 1H), 7.09(s, 1H), 6.72( d, J＝7.2, 1H), 5.72-5.70(m, 1H), 4.17-4.14(m, 1H), 4.02-3.93(m, 3H), 2.46-2.35(m, 4H), 2.22-2.20(m , 1H), 1.97(s, 3H). MS-ESI calculated value [M+H]+397, found 397.
化合物25b:e.e.％＝93％,RT＝2.056min。 1H NMR(400MHz,CD 3OD)δ7.88(s,0.3H),7.70-7.66(m,1.7H),7.15(d,J＝7.2,1H),7.09(s,1H),6.72(d,J＝7.2,1H),5.72-5.70(m,1H),4.18-4.14(m,1H),4.00-3.93(m,3H),2.46-2.35(m,4H),2.22-2.19(m,1H),1.95(s,3H)。MS-ESI计算值[M+H]+397,实测值397。 Compound 25b: ee%=93%, RT=2.056 min. 1 H NMR (400MHz, CD 3 OD) δ 7.88(s, 0.3H), 7.70-7.66(m, 1.7H), 7.15(d, J=7.2, 1H), 7.09(s, 1H), 6.72( d, J＝7.2, 1H), 5.72-5.70(m, 1H), 4.18-4.14(m, 1H), 4.00-3.93(m, 3H), 2.46-2.35(m, 4H), 2.22-2.19(m , 1H), 1.95(s, 3H). MS-ESI calculated value [M+H]+397, found 397.
实施例26Example 26
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000099
Figure PCTCN2021142174-appb-000099
第一步first step
将化合物19-2(180mg,390μmol)溶于N,N-二甲基甲酰胺(10mL),加入化合物26-1(64.1mg,585μmol)和碳酸钾(189mg,1.37mmol),反应液在85℃下搅拌12小时。反应液加水(10mL),乙酸乙酯(20mL×3)萃取,合并有机相,有机相经饱和食盐水洗涤(20mL×3),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～1/1,V/V)分离得到化合物26-2。MS-ESI计算值[M+H] +514和516,实测值514和516。 Compound 19-2 (180 mg, 390 μmol) was dissolved in N,N-dimethylformamide (10 mL), compound 26-1 (64.1 mg, 585 μmol) and potassium carbonate (189 mg, 1.37 mmol) were added, and the reaction solution was heated at 85 Stir at °C for 12 hours. The reaction solution was added with water (10 mL), extracted with ethyl acetate (20 mL×3), and the organic phases were combined, washed with saturated brine (20 mL×3), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～1/1, V/V) to obtain compound 26-2. MS-ESI calculated [M+H] + 514 and 516, found 514 and 516.
第二步second step
将化合物26-2(150mg,292μmol)溶于三氟乙酸(5mL),反应液在90℃下搅拌48小时。反应液加水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,乙酸乙酯(10mL x 3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～0/1,V/V)分离得到化合物26-3。MS-ESI计算值[M+H] +302,实测值302。 Compound 26-2 (150 mg, 292 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 90° C. for 48 hours. The reaction solution was added with water (10 mL) and ethyl acetate (10 mL), saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL x 3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, Concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～0/1, V/V) to obtain compound 26-3. MS-ESI calculated [M+H] + 302, found 302.
第三步third step
将化合物26-3(37.0mg,123μmol)溶于三氟乙酸(3mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(24.0mg,135μmol)后滴加浓硫酸(0.3mL),反应液在0℃下搅拌1小时。反应液加入水(10mL)和乙酸乙酯(10mL),饱和碳酸氢钠水溶液调至pH至8,用乙酸乙酯(10mL×3)萃取,合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,100/1～0/1,V/V)分离得到中间体26-4。MS-ESI计算值[M+H] +380和382实测值380和382。 Compound 26-3 (37.0 mg, 123 μmol) was dissolved in trifluoroacetic acid (3 mL), N-bromosuccinimide (24.0 mg, 135 μmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid ( 0.3 mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was added with water (10 mL) and ethyl acetate (10 mL), the saturated aqueous sodium bicarbonate solution was adjusted to pH 8, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was Concentrated under reduced pressure, the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 100/1～0/1, V/V) to obtain intermediate 26-4. MS-ESI calculated [M+H] + 380 and 382 found 380 and 382.
第四步the fourth step
将化合物26-4(20.0mg,52.6μmol)和化合物1-1(24.3mg,78.9μmol)溶解在1,4-二氧六环(2mL)和水(0.4mL)中,后向反应液中加入磷酸钾(27.9mg,131μmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(3.85mg,5.26μmol)。将反应液在氮气保护下加热至90℃反应12小时。反应液直接减压浓缩,剩余物经过硅胶柱层析法(二氯甲烷/甲醇,100/1～10/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALCEL OJ 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液30％-30％),分离得到化合物26a(第一个峰)和26b(第二个峰)。化合物后经SFC(色谱柱:Chiralcel OJ-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。 Compound 26-4 (20.0 mg, 52.6 μmol) and compound 1-1 (24.3 mg, 78.9 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.4 mL), and then added to the reaction solution Potassium phosphate (27.9 mg, 131 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium (3.85 mg, 5.26 μmol) were added. The reaction solution was heated to 90°C under nitrogen protection for 12 hours. The reaction solution was directly concentrated under reduced pressure, and the residue was separated by silica gel column chromatography (dichloromethane/methanol, 100/1～10/1, V/V) to obtain the crude compound, which was purified by SFC (separating column: DAICEL CHIRALCEL OJ 250mm). ×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 30%-30%), compounds 26a (the first peak) and 26b (the second peak) were isolated peaks). The compound was then filtered through SFC (column: Chiralcel OJ-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value.
化合物26b:e.e.％＝98.94％,RT＝3.202min。 1H NMR(400MHz,CD 3OD)δ7.85-7.68(m,1H),7.47(t,J＝8.0Hz,1H),7.04(s,1H),6.79(d,J＝7.2Hz,1H),6.30(d,J＝8.4Hz,1H),4.74-4.69(m,1H),4.33-4.28(m,2H),3.87(dd,J＝4.4,8.4Hz,1H),3.81(dd,J＝4.4,8.4Hz,1H),2.43(s,3H),1.88(s,3H)。MS-ESI计算值[M+H] +382,实测值382。 Compound 26b: ee%=98.94%, RT=3.202 min. 1 H NMR (400MHz, CD 3 OD) δ 7.85-7.68 (m, 1H), 7.47 (t, J=8.0Hz, 1H), 7.04 (s, 1H), 6.79 (d, J=7.2Hz, 1H) ),6.30(d,J＝8.4Hz,1H),4.74-4.69(m,1H),4.33-4.28(m,2H),3.87(dd,J＝4.4,8.4Hz,1H),3.81(dd, J=4.4, 8.4 Hz, 1H), 2.43 (s, 3H), 1.88 (s, 3H). MS-ESI calculated [M+H] + 382, found 382.
实施例27Example 27
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000100
Figure PCTCN2021142174-appb-000100
第一步first step
将中间体C(2.00g,5.46mmol)溶于四氢呋喃(20mL),在25℃下滴加27-1(1.26g,10.9mmol),在0℃搅拌0.17小时,然后在0℃下滴加双(三甲基硅)氨基钾(10.9mL,1mol/L的四氢呋喃溶液),反应液在25℃下搅拌9小时。反应液加入饱和氯化铵水溶液(50mL),乙酸乙酯(50mL×3)萃取,合并有机相,有机相用饱和食盐水洗涤(50mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到化合物27-2。MS-ESI计算值[M+H] +461和463,实测值461和463。 Intermediate C (2.00 g, 5.46 mmol) was dissolved in tetrahydrofuran (20 mL), 27-1 (1.26 g, 10.9 mmol) was added dropwise at 25 °C, stirred at 0 °C for 0.17 hours, and then added dropwise at 0 °C. Potassium (trimethylsilyl)amide (10.9 mL, 1 mol/L tetrahydrofuran solution), the reaction solution was stirred at 25° C. for 9 hours. The reaction solution was added with saturated aqueous ammonium chloride solution (50 mL), extracted with ethyl acetate (50 mL×3), the organic phases were combined, the organic phases were washed with saturated brine (50 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain compound 27-2. MS-ESI calculated [M+H] + 461 and 463, found 461 and 463.
第二步second step
将化合物27-2(500mg,1.08mmol)溶于三氟乙酸(10mL),反应液在80℃下搅拌24小时。反应液直接减压浓缩,剩余加入饱和碳酸氢钠水溶液至pH＝8,乙酸乙酯(10mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物27-3。 1H NMR(400MHz,CD 3OD)δ8.42-8.40(m,1H),7.64-7.59(m,1H),7.59-7.57(m,1H),7.46-7.42(m,1H),7.19(d,J＝5.2Hz,1H),1.96(s,3H)。MS-ESI计算值[M+H] +249,实测值249。 Compound 27-2 (500 mg, 1.08 mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction solution was stirred at 80° C. for 24 hours. The reaction solution was directly concentrated under reduced pressure, the remaining saturated aqueous sodium bicarbonate solution was added to pH=8, extracted with ethyl acetate (10 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 27-3. 1 H NMR (400MHz, CD 3 OD) δ 8.42-8.40 (m, 1H), 7.64-7.59 (m, 1H), 7.59-7.57 (m, 1H), 7.46-7.42 (m, 1H), 7.19 ( d, J=5.2Hz, 1H), 1.96 (s, 3H). MS-ESI calculated [M+H] + 249, found 249.
第三步third step
将化合物27-3(230mg,926μmol)溶于三氟乙酸(2mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(181mg,1.02mmol)后滴加浓硫酸(0.2mL),反应液在0℃下搅拌1小时。反应液加入饱和碳酸氢钠水溶液至pH＝8,乙酸乙酯(10mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到中间体27-4。 1H NMR(400MHz,CD 3OD)δ8.44-8.40(m,1H),7.67-7.61(m,1H),7.47-7.43(m,1H),7.26(s,1H),1.93(s,3H)。MS-ESI计算值[M+H] +327和329,实测值327和329。 Compound 27-3 (230 mg, 926 μmol) was dissolved in trifluoroacetic acid (2 mL), N-bromosuccinimide (181 mg, 1.02 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid (0.2 mmol) was added dropwise. mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was added with saturated aqueous sodium bicarbonate solution to pH=8, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain intermediate 27-4. 1 H NMR (400MHz, CD 3 OD) δ 8.44-8.40(m, 1H), 7.67-7.61(m, 1H), 7.47-7.43(m, 1H), 7.26(s, 1H), 1.93(s, 3H). MS-ESI calculated [M+H] + 327 and 329, found 327 and 329.
第四步the fourth step
将化合物27-4(230mg,703μmol)溶于二氧六环(2mL)和水(0.4mL),加入化合物1-1(238mg,407μmol),1,1-双(二苯基磷)二茂铁氯化钯(51.4mg,70.3μmol)和磷酸钾(373mg,1.76mmol)。置换氮气三次,反应液在100℃下搅拌12小时。反应液减压浓缩。剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～0/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液45％-45％),分离得到化合物27a(第一个峰)和27b(第二个峰)。化合物后经SFC(色谱柱:Chiralpak AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物27b:e.e.％＝100％,RT＝4.877min。 1H NMR(400MHz,CD 3OD)δ8.43-8.41(m,1H),7.91-7.67(m,1H),7.65-7.59(m,1H),7.46-7.42(m,1H),7.13(s,1H),2.45(s,3H),1.98(s,3H)。MS-ESI计算值[M+H] +329,实测值329。 Compound 27-4 (230 mg, 703 μmol) was dissolved in dioxane (2 mL) and water (0.4 mL), and compound 1-1 (238 mg, 407 μmol), 1,1-bis(diphenylphosphonium) dioxin was added Iron palladium chloride (51.4 mg, 70.3 μmol) and potassium phosphate (373 mg, 1.76 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 100 °C for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～0/1, V/V) to obtain a crude product of the compound, which was subjected to SFC (separation column: DAICEL CHIRALPAK AD 250mm×30mm×10μm; Phase: supercritical CO 2 -0.1% aqueous ammonia in ethanol; gradient: 0.1% ammonia in ethanol 45%-45%), compounds 27a (first peak) and 27b (second peak) were isolated. The compound was then filtered through SFC (column: Chiralpak AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 27b: ee%=100%, RT=4.877 min. 1 H NMR (400MHz, CD 3 OD) δ 8.43-8.41 (m, 1H), 7.91-7.67 (m, 1H), 7.65-7.59 (m, 1H), 7.46-7.42 (m, 1H), 7.13 ( s, 1H), 2.45 (s, 3H), 1.98 (s, 3H). MS-ESI calculated [M+H] + 329, found 329.
实施例28Example 28
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000101
Figure PCTCN2021142174-appb-000101
第一步first step
将中间体C(1.72g,4.70mmol)和化合物28-1(1.20g,9.39mmol)溶于N,N-二甲基甲酰胺(10mL),然后向反应液中加入叔丁醇钾(1.05g,9.39mmol),反应液在80℃下搅拌24小时。反应液加入水(50mL),乙酸乙酯(50mL x 2)萃取,合并有机相,用饱和食盐水洗涤(50mL x 3),无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到化合物28-2。MS-ESI计算值[M+H] +457和459,实测值457和459。 Intermediate C (1.72 g, 4.70 mmol) and compound 28-1 (1.20 g, 9.39 mmol) were dissolved in N,N-dimethylformamide (10 mL), and potassium tert-butoxide (1.05 mL) was added to the reaction solution. g, 9.39 mmol), the reaction solution was stirred at 80 °C for 24 hours. The reaction solution was added with water (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain compound 28-2. MS-ESI calculated [M+H] + 457 and 459, found 457 and 459.
第二步second step
将化合物28-2(689mg,1.51mmol)溶于三氟乙酸(10mL),反应液在90℃下搅拌168小时。反应液直接减压浓缩,剩余物加入饱和碳酸氢钠水溶液(50mL),二氯甲烷(50mL x 2)萃取,合并有机相,用饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物28-3。 1H NMR(400MHz,CD 3OD)δ7.62(t,J＝7.6Hz,1H),7.49(d,J＝5.2Hz,1H),7.30(d,J＝7.6Hz,1H),7.16-7.08(m,2H),2.55(s,3H),1.92(s,3H)。MS-ESI计算值[M+H] +245,实测值245。 Compound 28-2 (689 mg, 1.51 mmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction solution was stirred at 90° C. for 168 hours. The reaction solution was directly concentrated under reduced pressure, the residue was added with saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, Filter and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 28-3. 1 H NMR (400MHz, CD 3 OD) δ 7.62 (t, J=7.6Hz, 1H), 7.49 (d, J=5.2Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.16- 7.08 (m, 2H), 2.55 (s, 3H), 1.92 (s, 3H). MS-ESI calculated [M+H] + 245, found 245.
第三步third step
将化合物28-3(350mg,1.43mmol)溶于三氟乙酸(3mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(280mg,1.58mmol)后滴加浓硫酸(0.3mL),反应液在0℃下搅拌1小时。反应液加入4摩尔的氢氧化钠水溶液(20mL),用二氯甲烷(40mL x 2)萃取,用饱和食盐水洗涤(40mL x 1),合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到中间体28-4。 1H NMR(400MHz,CD 3OD)δ7.62(t,J＝7.6Hz,1H),7.30(d,J＝7.6Hz,1H),7.16(s,1H),7.13(d,J＝7.6Hz,1H),2.55(s,3H),1.88(s,3H)。MS-ESI计算值[M+H] +323和325,实测值323和325。 Compound 28-3 (350 mg, 1.43 mmol) was dissolved in trifluoroacetic acid (3 mL), N-bromosuccinimide (280 mg, 1.58 mmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid ( 0.3 mL), the reaction solution was stirred at 0 °C for 1 hour. 4 mol of sodium hydroxide aqueous solution (20 mL) was added to the reaction solution, extracted with dichloromethane (40 mL x 2), washed with saturated brine (40 mL x 1), combined with the organic phases, dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced It was concentrated under pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain intermediate 28-4. 1 H NMR (400MHz, CD 3 OD) δ 7.62 (t, J=7.6Hz, 1H), 7.30 (d, J=7.6Hz, 1H), 7.16 (s, 1H), 7.13 (d, J=7.6 Hz, 1H), 2.55 (s, 3H), 1.88 (s, 3H). MS-ESI calculated [M+H] + 323 and 325, found 323 and 325.
第四步the fourth step
将化合物28-4(450mg,1.39mmol)溶于二氧六环(5mL)和水(1mL),加入化合物1-1(472mg,1.53mmol),1,1-双(二苯基磷)二茂铁氯化钯(102mg,139μmol)和磷酸钾(739mg,3.48mmol)。置换氮气三次,反应液在100℃下搅拌12小时。反应液加入水(20mL),乙酸乙酯(30mL x 2)萃取,合并有机相,用饱和食盐水洗涤(20mL x 1),无水硫酸钠干燥,过滤,减压浓缩。剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～0/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALCEL OD-H 250mm×30mm×5μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液30％-30％),分离得到化合物28a(第一个峰)和28b(第二个峰)。化合物后经SFC(色谱柱:Chiralpak AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物28b:e.e.％＝100％,RT＝2.038min。 1H NMR(400MHz,CD 3OD)δ7.73(s,1H),7.61(t,J＝7.6Hz,1H),7.32(d,J＝7.6Hz,1H),7.12(d,J＝7.6Hz,1H),7.05(s,1H),2.55(s,3H),2.41(s,3H),1.93(s,3H)。MS-ESI计算值[M+H] +325,实测值325。 Compound 28-4 (450 mg, 1.39 mmol) was dissolved in dioxane (5 mL) and water (1 mL), compound 1-1 (472 mg, 1.53 mmol), 1,1-bis(diphenylphosphorus)di Ferocene palladium chloride (102 mg, 139 μmol) and potassium phosphate (739 mg, 3.48 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 100 °C for 12 hours. The reaction solution was added with water (20 mL), extracted with ethyl acetate (30 mL x 2), the organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～0/1, V/V) to obtain a crude product of the compound, which was subjected to SFC (separation column: DAICEL CHIRALCEL OD-H 250mm×30mm×5μm ; Mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 30%-30%), separate compounds 28a (the first peak) and 28b (the second peak). The compound was then filtered through SFC (column: Chiralpak AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 28b: ee%=100%, RT=2.038 min. 1 H NMR (400 MHz, CD 3 OD) δ 7.73 (s, 1H), 7.61 (t, J=7.6 Hz, 1H), 7.32 (d, J=7.6 Hz, 1H), 7.12 (d, J=7.6 Hz, 1H), 7.05(s, 1H), 2.55(s, 3H), 2.41(s, 3H), 1.93(s, 3H). MS-ESI calculated [M+H] + 325, found 325.
实施例29Example 29
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000102
Figure PCTCN2021142174-appb-000102
第一步first step
将化合物11-4(4.90g,14.3mmol)溶于二氧六环(50mL)和水(5mL),加入化合物1-1(6.59g,21.4mmol),1,1-双(二苯基磷)二茂铁氯化钯(1.04g,1.43mmol)和磷酸钾(7.57g,35.7mmol)。置换氮气三次,反应液在100℃下搅拌12小时。反应液加入水(100mL),乙酸乙酯(200mL x 2)萃取,合并有机相,用饱和食盐水洗涤(200mL x 1),无水硫酸钠干燥,过滤,减压浓缩。剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～0/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALCEL OD-H 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液35％-35％),分离得到化合物29a(第一个峰)和29b(第二个峰)。化合物29b再经高效液相色谱法(色谱柱:Phenomenex C18 80×40mm×3μm；流动相:0.05％的氨水溶液-乙腈；梯度:乙腈20％-50％,8min)进一步纯化得到化合物29b。后经SFC(色谱柱:Chiralcel OD-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物29b:e.e.％＝97.22％,RT＝5.275min。 1H NMR(400MHz,CD 3OD)δ8.26-7.96(m,1H),7.89-7.61(m,2H),7.52(d,J＝7.6Hz,1H),7.32(d,J＝7.6Hz,1H),7.07(s,1H),2.72(s,3H),2.41(s,3H),2.03(s,3H)。MS-ESI计算值[M+H] +391,实测值391。 Compound 11-4 (4.90 g, 14.3 mmol) was dissolved in dioxane (50 mL) and water (5 mL), compound 1-1 (6.59 g, 21.4 mmol), 1,1-bis(diphenylphosphine) was added ) ferrocene palladium chloride (1.04 g, 1.43 mmol) and potassium phosphate (7.57 g, 35.7 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 100 °C for 12 hours. The reaction solution was added with water (100 mL), extracted with ethyl acetate (200 mL x 2), the organic phases were combined, washed with saturated brine (200 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～0/1, V/V) to obtain a crude product of the compound, which was subjected to SFC (separation column: DAICEL CHIRALCEL OD-H 250mm×30mm×10μm ; Mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 35%-35%), separate compounds 29a (the first peak) and 29b (the second peak). Compound 29b was further purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 80×40 mm×3 μm; mobile phase: 0.05% aqueous ammonia solution-acetonitrile; gradient: acetonitrile 20%-50%, 8 min) to obtain compound 29b. After SFC (chromatographic column: Chiralcel OD-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%-40 %) to measure the ee value. Compound 29b: ee%=97.22%, RT=5.275 min. 1 H NMR (400MHz, CD 3 OD) δ 8.26-7.96 (m, 1H), 7.89-7.61 (m, 2H), 7.52 (d, J=7.6Hz, 1H), 7.32 (d, J=7.6Hz) , 1H), 7.07(s, 1H), 2.72(s, 3H), 2.41(s, 3H), 2.03(s, 3H). MS-ESI calculated [M+H] + 391, found 391.
实施例30Example 30
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000103
Figure PCTCN2021142174-appb-000103
第一步first step
将甲氧基甲基三苯基氯化膦(27.4g,79.9mmol)溶于四氢呋喃(250mL),在-78℃下滴加二异丙基氨基锂(40.0mL,2mol/L的四氢呋喃/正庚烷(V/V＝12/25)溶液),在-78℃搅拌0.5小时,然后在-78℃下加入化合物30-1(5.00g,40.0mmol),反应液在25℃下搅拌11.5小时。反应液加入饱和氯化铵水溶液(200mL),乙酸乙酯(200mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(200mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～5/1,V/V)分离得到化合物30-2。 1H NMR(400MHz,CD 3OD)δ7.72(q,J＝8.0Hz,1H),7.62(d,J＝12.4Hz,1H),7.04(dd,J＝2.4,7.6Hz,1H),6.69(dd,J＝2.4,7.6Hz,1H),5.85(d,J＝12.4Hz,1H),3.72(s,3H)。 Methoxymethyltriphenylphosphine chloride (27.4 g, 79.9 mmol) was dissolved in tetrahydrofuran (250 mL), and lithium diisopropylamide (40.0 mL, 2 mol/L of tetrahydrofuran/normal) was added dropwise at -78 °C. Heptane (V/V=12/25) solution), stirred at -78 °C for 0.5 hours, then added compound 30-1 (5.00 g, 40.0 mmol) at -78 °C, and the reaction solution was stirred at 25 °C for 11.5 hours . The reaction solution was added with saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL×2), the organic phases were combined, the organic phases were washed with saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～5/1, V/V) to obtain compound 30-2. 1 H NMR (400 MHz, CD 3 OD) δ 7.72 (q, J=8.0 Hz, 1H), 7.62 (d, J=12.4 Hz, 1H), 7.04 (dd, J=2.4, 7.6 Hz, 1H), 6.69 (dd, J=2.4, 7.6 Hz, 1H), 5.85 (d, J=12.4 Hz, 1H), 3.72 (s, 3H).
第二步second step
将化合物30-2(1.70g,11.1mmol)溶于甲醇(20mL),向反应液中加入湿钯碳(200mg,10％纯度),反应液在50帕斯卡氢气氛围、25℃下搅拌12小时。反应液过滤,滤液减压浓缩。得到化合物30-3。 1H NMR(400MHz,CD 3OD)δ7.84(q,J＝8.0Hz,1H),7.20(dd,J＝2.4,7.6Hz,1H),6.88(dd,J＝2.4,7.6Hz,1H),3.73(t,J＝6.4Hz,2H),3.32(s,3H),2.96(t,J＝6.4Hz,2H)。 Compound 30-2 (1.70 g, 11.1 mmol) was dissolved in methanol (20 mL), wet palladium on carbon (200 mg, 10% purity) was added to the reaction solution, and the reaction solution was stirred at 50 Pascal hydrogen atmosphere at 25° C. for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. Compound 30-3 was obtained. 1 H NMR (400 MHz, CD 3 OD) δ 7.84 (q, J=8.0 Hz, 1H), 7.20 (dd, J=2.4, 7.6 Hz, 1H), 6.88 (dd, J=2.4, 7.6 Hz, 1H) ), 3.73(t, J=6.4Hz, 2H), 3.32(s, 3H), 2.96(t, J=6.4Hz, 2H).
第三步third step
将中间体C(688mg,1.88mmol)和化合物30-3(583mg,3.76mmol)溶于N,N-二甲基甲酰胺(10mL),然后向反应液中加入叔丁醇钾(422mg,3.76mmol),反应液在80℃下搅拌24小时。反应液加入水(50mL),乙酸乙酯(50mL x 2)萃取,合并有机相,用饱和食盐水洗涤(50mL x 3),无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到化合物30-4。MS-ESI计算值[M+H] +501和503,实测值501和503。 Intermediate C (688 mg, 1.88 mmol) and compound 30-3 (583 mg, 3.76 mmol) were dissolved in N,N-dimethylformamide (10 mL), and potassium tert-butoxide (422 mg, 3.76 mmol) was added to the reaction solution. mmol), the reaction solution was stirred at 80 °C for 24 hours. The reaction solution was added with water (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 3), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain compound 30-4. MS-ESI calculated [M+H] + 501 and 503, found 501 and 503.
第四步the fourth step
将化合物30-4(493mg,983μmol)溶于三氟乙酸(5mL),反应液在90℃下搅拌12小时。反应液直接减压浓缩,剩余物加入饱和碳酸氢钠水溶液(50mL),二氯甲烷(50mL x 2)萃取,合并有机相,用饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物30-5。 1H NMR(400MHz,CD 3OD)δ7.52(d,J＝5.2Hz,1H),7.50-7.44(m,1H),7.15(d,J＝5.2Hz,1H),6.62(d,J＝7.2Hz,1H),6.54(d,J＝8.4Hz,1H),3.86(s,3H),2.68-2.57(m,1H),2.42-2.29(m,3H),1.61(s,3H)。MS-ESI计算值[M+H] +289,实测值289。 Compound 30-4 (493 mg, 983 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, the residue was added with saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, Filter and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 30-5. 1 H NMR (400 MHz, CD 3 OD) δ 7.52 (d, J=5.2 Hz, 1H), 7.50-7.44 (m, 1H), 7.15 (d, J=5.2 Hz, 1H), 6.62 (d, J =7.2Hz,1H),6.54(d,J=8.4Hz,1H),3.86(s,3H),2.68-2.57(m,1H),2.42-2.29(m,3H),1.61(s,3H) . MS-ESI calculated [M+H] + 289, found 289.
第五步the fifth step
将化合物30-5(230mg,798μmol)溶于三氟乙酸(3mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(156mg,877μmol)后滴加浓硫酸(0.3mL),反应液在0℃下搅拌1小时。反应液加入4摩尔的氢氧化钠水溶液(20mL),用二氯甲烷(40mL x 2)萃取,合并有机相,用饱和食盐水洗涤(40mL x 1),无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物30-6。 1H NMR(400MHz,CD 3OD)δ7.47(t,J＝7.6Hz,1H),7.19(s,1H),6.61(d,J＝7.2Hz,1H),6.55(d,J＝8.0Hz,1H),3.87(s,3H),2.67-2.58(m,1H),2.44-2.29(m,3H),1.59(s,3H)。MS-ESI计算值[M+H] +367和369,实测值367和369。 Compound 30-5 (230 mg, 798 μmol) was dissolved in trifluoroacetic acid (3 mL), N-bromosuccinimide (156 mg, 877 μmol) was added to the reaction solution at 0°C, and concentrated sulfuric acid (0.3 mL) was added dropwise. ), the reaction solution was stirred at 0 °C for 1 hour. 4 mol of sodium hydroxide aqueous solution (20 mL) was added to the reaction solution, extracted with dichloromethane (40 mL x 2), the organic phases were combined, washed with saturated brine (40 mL x 1), dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced It was concentrated under pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound 30-6. 1 H NMR (400 MHz, CD 3 OD) δ 7.47 (t, J=7.6 Hz, 1H), 7.19 (s, 1H), 6.61 (d, J=7.2 Hz, 1H), 6.55 (d, J=8.0 Hz, 1H), 3.87(s, 3H), 2.67-2.58(m, 1H), 2.44-2.29(m, 3H), 1.59(s, 3H). MS-ESI calculated [M+H] + 367 and 369, found 367 and 369.
第六步Step 6
将化合物30-6(200mg,545μmol)溶于二氧六环(5mL)和水(1mL),加入化合物1-1(185mg,599μmol),1,1-双(二苯基磷)二茂铁氯化钯(39.9mg,54.5μmol)和磷酸钾(289mg,1.36mmol)。置换氮气三次, 反应液在100℃下搅拌12小时。反应液加入水(20mL),乙酸乙酯(30mL x 2)萃取,合并有机相,用饱和食盐水(20mL x 1)洗涤,无水硫酸钠干燥,过滤,减压浓缩。剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～0/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALCEL OD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液35％-35％),分离得到化合物30a(第一个峰)和30b(第二个峰)。化合物后经SFC(色谱柱:Chiralpak AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物30b:e.e.％＝100％,RT＝1.903min。 1H NMR(400MHz,CD 3OD)δ7.93-7.57(m,1H),7.45(t,J＝7.6Hz,1H),7.07(s,1H),6.62(d,J＝7.6Hz,1H),6.52(d,J＝8.4Hz,1H),3.86(s,3H),2.72-2.60(m,1H),2.48-2.31(m,6H),1.62(s,3H)。MS-ESI计算值[M+H] +369,实测值369。 Compound 30-6 (200 mg, 545 μmol) was dissolved in dioxane (5 mL) and water (1 mL), compound 1-1 (185 mg, 599 μmol), 1,1-bis(diphenylphosphonium)ferrocene was added Palladium chloride (39.9 mg, 54.5 μmol) and potassium phosphate (289 mg, 1.36 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 100 °C for 12 hours. The reaction solution was added with water (20 mL), extracted with ethyl acetate (30 mL x 2), the organic phases were combined, washed with saturated brine (20 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～0/1, V/V) to obtain a crude product of the compound, which was subjected to SFC (separation column: DAICEL CHIRALCEL OD 250mm×30mm×10μm; flow Phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 35%-35%), compounds 30a (first peak) and 30b (second peak) were isolated. The compound was then filtered through SFC (column: Chiralpak AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 30b: ee%=100%, RT=1.903 min. 1 H NMR (400MHz, CD 3 OD) δ 7.93-7.57 (m, 1H), 7.45 (t, J=7.6Hz, 1H), 7.07 (s, 1H), 6.62 (d, J=7.6Hz, 1H) ), 6.52(d, J=8.4Hz, 1H), 3.86(s, 3H), 2.72-2.60(m, 1H), 2.48-2.31(m, 6H), 1.62(s, 3H). MS-ESI calculated [M+H] + 369, found 369.
实施例31Example 31
合成路线:synthetic route:
Figure PCTCN2021142174-appb-000104
Figure PCTCN2021142174-appb-000104
第一步first step
将化合物31-1(229mg,2.60mmol)溶于N,N-二甲基甲酰胺(6mL)中,加入氢化钠(260mg,6.50mmol,60％纯度),反应液在氮气保护下降温至0℃反应0.5小时。在0℃将中间体27-2(600mg,1.30mmol)加入到反应液中,反应液在氮气保护,60℃下搅拌12小时。反应液加入饱和氯化铵水溶液(30mL)淬灭，乙酸乙酯(30mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物31-2。MS-ESI计算值[M+H] +529和531,实测值529和531。 Compound 31-1 (229 mg, 2.60 mmol) was dissolved in N,N-dimethylformamide (6 mL), sodium hydride (260 mg, 6.50 mmol, 60% purity) was added, and the reaction solution was warmed to 0 under nitrogen protection °C reaction for 0.5 hours. Intermediate 27-2 (600 mg, 1.30 mmol) was added to the reaction solution at 0°C, and the reaction solution was stirred at 60°C for 12 hours under nitrogen protection. The reaction solution was quenched by adding saturated aqueous ammonium chloride solution (30 mL), extracted with ethyl acetate (30 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 31-2. MS-ESI calculated [M+H] + 529 and 531, found 529 and 531.
第二步second step
将化合物31-2(190mg,359μmol)溶于三氟乙酸(10mL),反应液在80℃下搅拌48小时。反应液直接减压浓缩,饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯萃取(10mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物31-3。MS-ESI计算值[M+H] +317,实测值317。 Compound 31-2 (190 mg, 359 μmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction solution was stirred at 80° C. for 48 hours. The reaction solution was directly concentrated under reduced pressure, adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL×3), and the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 31-3. MS-ESI calculated [M+H] + 317, found 317.
第三步third step
将化合物31-3(110mg,348μmol)溶于三氟乙酸(1mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(68.1mg,382μmol)后滴加浓硫酸(0.1mL),反应液在0℃下搅拌1小时。反应液经饱和碳酸氢钠水溶液调节pH＝8,乙酸乙酯(10mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～0/1,V/V)分离得到化合物31-4。MS-ESI计算值[M+H] +395和397实测值395和397。 Compound 31-3 (110 mg, 348 μmol) was dissolved in trifluoroacetic acid (1 mL), N-bromosuccinimide (68.1 mg, 382 μmol) was added to the reaction solution at 0°C, and concentrated sulfuric acid (0.1 mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was adjusted to pH=8 with saturated aqueous sodium bicarbonate solution, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the crude product was subjected to silica gel column chromatography (Petroleum ether/ethyl acetate, 5/1～0/1, V/V) to obtain compound 31-4. MS-ESI calculated [M+H] + 395 and 397 found 395 and 397.
第四步the fourth step
将化合物31-4(108mg,273μmol)和化合物1-1(92.5mg,300μmol)溶解在1,4-二氧六环(2mL)和水(0.3mL)中,后向反应液中加入磷酸钾(145mg,682μmol)和[1,1'-双(二苯基膦基)二茂铁]二氯化钯(20.0mg,27.3μmol)。将反应液在氮气保护下加热至100℃反应12小时。反应液减压浓缩。粗产物经过硅胶柱层析法(二氯甲烷/甲醇,20/1～10/1,V/V)分离得到粗产物。粗产物经SFC(分离柱:DAICEL CHIRALCEL OD-H 250mm×30mm×5μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液40％-40％)分离得到化合物31a(第二个峰)和31b(第一个峰)。化合物后经SFC(色谱柱:Chiralcel OD-3 100mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物31b:e.e.％＝100％,RT＝4.171min。 1H NMR(400MHz,CD 3OD)δ8.13(dd,J＝1.2,4.4Hz,1H),7.93-7.58(m,1H),7.43(dd,J＝1.2,8.4Hz,1H),7.34(dd,J＝4.4,8.4Hz,1H),7.10(s,1H),5.21-5.16(m,1H),4.14-4.07(m,1H),4.04-3.98(m,1H),3.96-3.90(m,1H),3.88-3.82(m,1H),2.45(s,3H),2.34-2.25(m,1H),2.09-2.02(m,1H),1.96(s,3H)。MS-ESI计算值[M+H] +397,实测值397。 Compound 31-4 (108 mg, 273 μmol) and compound 1-1 (92.5 mg, 300 μmol) were dissolved in 1,4-dioxane (2 mL) and water (0.3 mL), and potassium phosphate was added to the reaction solution. (145 mg, 682 μmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloride palladium (20.0 mg, 27.3 μmol). The reaction solution was heated to 100°C under nitrogen protection for 12 hours. The reaction solution was concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (dichloromethane/methanol, 20/1～10/1, V/V) to obtain the crude product. The crude product was separated by SFC (column: DAICEL CHIRALCEL OD-H 250mm×30mm×5μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 40%-40% ethanol solution of 0.1% ammonia water) Compounds 31a (second peak) and 31b (first peak). The compound was then filtered through SFC (column: Chiralcel OD-3 100mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 31b: ee%=100%, RT=4.171 min. 1 H NMR (400 MHz, CD 3 OD) δ 8.13 (dd, J=1.2, 4.4 Hz, 1H), 7.93-7.58 (m, 1H), 7.43 (dd, J=1.2, 8.4 Hz, 1H), 7.34 (dd, J=4.4, 8.4Hz, 1H), 7.10(s, 1H), 5.21-5.16(m, 1H), 4.14-4.07(m, 1H), 4.04-3.98(m, 1H), 3.96-3.90 (m, 1H), 3.88-3.82 (m, 1H), 2.45 (s, 3H), 2.34-2.25 (m, 1H), 2.09-2.02 (m, 1H), 1.96 (s, 3H). MS-ESI calculated [M+H] + 397, found 397.
实施例32Example 32
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000105
Figure PCTCN2021142174-appb-000105
第一步first step
将中间体C(1.50g,4.10mmol)和32-1(1.08g,8.19mmol)溶于四氢呋喃(20mL),在0℃下滴加双(三甲基硅)氨基钾(6.14mL,1mol/L的四氢呋喃溶液),反应液在0℃下搅拌10分钟,然后25℃下搅拌1小时。反应液加入饱和氯化铵水溶液(200mL),乙酸乙酯(200mL×2)萃取,合并有机相,有机相用饱和食盐水洗涤(200mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到化合物32-2。MS-ESI计算值[M+H] +477和479,实测值477和479。 Intermediate C (1.50 g, 4.10 mmol) and 32-1 (1.08 g, 8.19 mmol) were dissolved in tetrahydrofuran (20 mL), and bis(trimethylsilyl) potassium amide (6.14 mL, 1 mol/ L of tetrahydrofuran solution), the reaction solution was stirred at 0 °C for 10 minutes and then at 25 °C for 1 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL × 2), the organic phases were combined, washed with saturated brine (200 mL × 1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain compound 32-2. MS-ESI calculated [M+H] + 477 and 479, found 477 and 479.
第二步second step
将化合物32-2(300mg,628μmol)溶于三氟乙酸(10mL),反应液在80℃下搅拌35小时。反应液直接减压浓缩,剩余加入饱和碳酸氢钠水溶液至pH＝8,乙酸乙酯(20mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物32-3。MS-ESI计算值[M+H] +265,实测值265。 Compound 32-2 (300 mg, 628 μmol) was dissolved in trifluoroacetic acid (10 mL), and the reaction solution was stirred at 80° C. for 35 hours. The reaction solution was directly concentrated under reduced pressure, the remaining saturated aqueous sodium bicarbonate solution was added to pH=8, extracted with ethyl acetate (20 mL×3), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 32-3. MS-ESI calculated [M+H] + 265, found 265.
第三步third step
将化合物32-3(114mg,431μmol)溶于三氟乙酸(1mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(84.3mg,474μmol)后滴加浓硫酸(0.1mL),反应液在0℃下搅拌1小时。反应液加入饱和碳酸氢钠水溶液至pH＝8,乙酸乙酯(10mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到中间体32-4。 1H NMR(400MHz,CD 3OD)δ8.44-8.40(m,1H),7.67-7.61(m,1H),7.47-7.43(m,1H),7.26(s,1H),1.93(s,3H)。MS-ESI计算值[M+H] +343和345,实测值343和345。 Compound 32-3 (114 mg, 431 μmol) was dissolved in trifluoroacetic acid (1 mL), N-bromosuccinimide (84.3 mg, 474 μmol) was added to the reaction solution at 0 °C, and concentrated sulfuric acid (0.1 mL), the reaction solution was stirred at 0 °C for 1 hour. The reaction solution was added with saturated aqueous sodium bicarbonate solution to pH=8, extracted with ethyl acetate (10 mL×3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain intermediate 32-4. 1 H NMR (400MHz, CD 3 OD) δ 8.44-8.40(m, 1H), 7.67-7.61(m, 1H), 7.47-7.43(m, 1H), 7.26(s, 1H), 1.93(s, 3H). MS-ESI calculated [M+H] + 343 and 345, found 343 and 345.
第四步the fourth step
将化合物32-4(127mg,370μmol)溶于二氧六环(2mL)和水(0.3mL),加入化合物1-1(125mg,407μmol),1,1-双(二苯基磷)二茂铁氯化钯(27.0mg,37.0μmol)和磷酸钾(196mg,924μmol)。置换氮气三次,反应液在100℃下搅拌12小时。反应液减压浓缩。剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～0/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的异丙醇溶液；梯度:0.1％氨水的异丙醇溶液50％-50％),分离得到化合物32a(第一个峰)和32b(第二个峰)。化合物后经SFC(色谱柱:Chiralpak AD-3 50mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的异丙醇溶液；梯度:0.05％二乙胺的异丙醇溶液:5％-40％)测e.e.值。化合物32b:e.e.％＝99.90％,RT＝2.432min。 1H NMR(400MHz,CD 3OD)δ8.51(dd,J＝1.2,4.4Hz,1H),7.87-7.61(m,2H),7.35(dd,J＝4.4,8.0Hz,1H),7.11(s,1H),2.43(s,3H),2.04(s,3H)。MS-ESI计算值[M+H] +345,实测值345。 Compound 32-4 (127 mg, 370 μmol) was dissolved in dioxane (2 mL) and water (0.3 mL), and compound 1-1 (125 mg, 407 μmol), 1,1-bis(diphenylphosphonium) dioxin was added Iron palladium chloride (27.0 mg, 37.0 μmol) and potassium phosphate (196 mg, 924 μmol). The nitrogen was replaced three times, and the reaction solution was stirred at 100 °C for 12 hours. The reaction solution was concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～0/1, V/V) to obtain a crude product of the compound, which was subjected to SFC (separation column: DAICEL CHIRALPAK AD 250mm×30mm×10μm; Phase: supercritical CO 2 -0.1% ammonia solution in isopropanol; gradient: 0.1% ammonia solution in isopropanol 50%-50%), separate compounds 32a (the first peak) and 32b (the second peak) ). The compound was then filtered through SFC (chromatographic column: Chiralpak AD-3 50mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in isopropanol; gradient: 0.05% diethylamine in isopropanol :5%-40%) to measure the ee value. Compound 32b: ee%=99.90%, RT=2.432 min. 1 H NMR (400 MHz, CD 3 OD) δ 8.51 (dd, J=1.2, 4.4 Hz, 1H), 7.87-7.61 (m, 2H), 7.35 (dd, J=4.4, 8.0 Hz, 1H), 7.11 (s, 1H), 2.43 (s, 3H), 2.04 (s, 3H). MS-ESI calculated [M+H] + 345, found 345.
实施例33Example 33
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000106
Figure PCTCN2021142174-appb-000106
第一步first step
将化合物33-1(4.80g,38.4mmol)溶于三氯甲烷(100mL),在0℃下滴加二乙氨基三氟化硫(6.83mL,51.6mmol),反应液在氮气保护,25℃下搅拌12小时。反应液加入饱和碳酸氢钠水溶液(50mL),二氯甲烷(50mL×3)萃取,合并有机相,有机相用无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～3/1,V/V)分离得到中间体33-2。 1H NMR(400MHz,CDCl 3)δ8.12(q,J＝7.6Hz,1H),7.61(dd,J＝1.6,7.6Hz,1H),7.23(d,J＝8.0Hz,1H),6.80(s,0.25H),6.66(s,0.5H),6.52(s,0.25H)。MS-ESI计算值[M+H] +148,实测值148。 Compound 33-1 (4.80 g, 38.4 mmol) was dissolved in chloroform (100 mL), diethylaminosulfur trifluoride (6.83 mL, 51.6 mmol) was added dropwise at 0 °C, the reaction solution was under nitrogen protection, 25 °C under stirring for 12 hours. The reaction solution was added with saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL×3), the organic phases were combined, the organic phases were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～3/1, V/V) to obtain intermediate 33-2. 1 H NMR (400 MHz, CDCl 3 ) δ 8.12 (q, J=7.6 Hz, 1H), 7.61 (dd, J=1.6, 7.6 Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.80 (s, 0.25H), 6.66 (s, 0.5H), 6.52 (s, 0.25H). MS-ESI calculated [M+H] + 148, found 148.
第二步second step
将中间体C(1.20g,3.28mmol)和化合物33-2(964mg,6.55mmol)溶于四氢呋喃(15mL),在0℃下滴加双(三甲基硅)氨基钾(4.91mL,1mol/L的四氢呋喃溶液),在0℃搅拌10分钟,然后反应液在25℃下搅拌1小时。反应液加入饱和氯化铵水溶液(200mL),乙酸乙酯(200mL×2)萃取,合并有机相,有机相经饱和食盐水洗涤(200mL×1),用无水硫酸钠干燥,过滤,减压浓缩。粗品经高效液相色谱法(色谱柱:Phenomenex C18 80×40mm×3μm；流动相:0.05％的氨水溶液-乙腈；梯度:乙腈54％-84％,8min)纯化得到化合物33-3。MS-ESI计算值[M+H] +493和495,实测值493和495。 Intermediate C (1.20 g, 3.28 mmol) and compound 33-2 (964 mg, 6.55 mmol) were dissolved in tetrahydrofuran (15 mL), and bis(trimethylsilyl) potassium amide (4.91 mL, 1 mol/mol) was added dropwise at 0 °C. L of tetrahydrofuran solution), stirred at 0 °C for 10 minutes, and then the reaction solution was stirred at 25 °C for 1 hour. The reaction solution was added with saturated aqueous ammonium chloride solution (200 mL), extracted with ethyl acetate (200 mL×2), the organic phases were combined, the organic phases were washed with saturated brine (200 mL×1), dried over anhydrous sodium sulfate, filtered, and reduced in pressure. concentrate. The crude product was purified by high performance liquid chromatography (chromatographic column: Phenomenex C18 80×40 mm×3 μm; mobile phase: 0.05% aqueous ammonia solution-acetonitrile; gradient: acetonitrile 54%-84%, 8 min) to obtain compound 33-3. MS-ESI calculated [M+H] + 493 and 495, found 493 and 495.
第三步third step
将化合物33-3(450mg,912μmol)溶于三氟乙酸(5mL),反应液在90℃下搅拌12小时。反应液直接减压浓缩,剩余物加入饱和碳酸氢钠水溶液(50mL),二氯甲烷(50mL×2)萃取,合并有机相,用饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。粗产物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～1/1,V/V)分离得到化合物33-4。 1H NMR(400MHz,CDCl 3)δ7.89-7.77(m,1H),7.69-7.51(m,2H),7.38(d,J＝5.0Hz,1H),7.26-7.15(m,2H),6.80(s,0.25H),6.66(s,0.5H),6.52(s,0.25H),2.01(s,3H)。MS-ESI计算值[M+H] +281,实测值281。 Compound 33-3 (450 mg, 912 μmol) was dissolved in trifluoroacetic acid (5 mL), and the reaction solution was stirred at 90° C. for 12 hours. The reaction solution was directly concentrated under reduced pressure, the residue was added with saturated aqueous sodium bicarbonate solution (50 mL), extracted with dichloromethane (50 mL × 2), the organic phases were combined, washed with saturated brine (50 mL × 1), dried over anhydrous sodium sulfate, Filter and concentrate under reduced pressure. The crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～1/1, V/V) to obtain compound 33-4. 1 H NMR (400 MHz, CDCl 3 ) δ 7.89-7.77 (m, 1H), 7.69-7.51 (m, 2H), 7.38 (d, J=5.0 Hz, 1H), 7.26-7.15 (m, 2H), 6.80(s, 0.25H), 6.66(s, 0.5H), 6.52(s, 0.25H), 2.01(s, 3H). MS-ESI calculated [M+H] + 281, found 281.
第四步the fourth step
将化合物33-4(250mg,892μmol)溶于三氟乙酸(3mL),在0℃下向反应液中加入N-溴代丁二酰亚胺(175mg,981μmol)后滴加浓硫酸(0.3mL),反应液在0℃下搅拌1小时。反应液加入4摩尔的氢氧化钠水溶液(20mL),用二氯甲烷(40mL x 2)萃取,用饱和食盐水洗涤(40mL×1),合并有机相,无水硫酸钠干燥,过滤,滤液减压浓缩,粗品经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到中间体33-5。MS-ESI计算值[M+H] +359和361,实测值359和361。 Compound 33-4 (250 mg, 892 μmol) was dissolved in trifluoroacetic acid (3 mL), N-bromosuccinimide (175 mg, 981 μmol) was added to the reaction solution at 0°C, and concentrated sulfuric acid (0.3 mL) was added dropwise. ), the reaction solution was stirred at 0 °C for 1 hour. 4 mol of sodium hydroxide aqueous solution (20 mL) was added to the reaction solution, extracted with dichloromethane (40 mL x 2), washed with saturated brine (40 mL x 1), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was reduced. It was concentrated under pressure, and the crude product was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain intermediate 33-5. MS-ESI calculated [M+H] + 359 and 361, found 359 and 361.
第五步the fifth step
将化合物33-5(210mg,583μmol)溶于二氧六环(5mL)和水(1mL),加入化合物1-1(198mg,642μmol),1,1-双(二苯基磷)二茂铁氯化钯(42.7mg,58.3μmol)和磷酸钾(310mg,1.46mmol)。置换氮气三次,反应液在100℃下搅拌12小时。反应液加入水(20mL),乙酸乙酯(30mL×2)萃取,合并有机相,用饱和食盐水洗涤(20mL×1),无水硫酸钠干燥,过滤,减压浓缩。剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,5/1～0/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALCEL OD-H 250mm×30mm×5μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液30％-30％),分离得到化合物33a(第二个峰)和33b(第一个峰)。化合物后经SFC(色谱柱:Chiralcel OD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物 33b:e.e.％＝99.68％,RT＝4.541min。 1H NMR(400MHz,CD 3OD)δ7.96(t,J＝8.0Hz,1H),7.88-7.64(m,2H),7.60(d,J＝7.6Hz,1H),7.07(s,1H),6.89(s,0.25H),6.75(s,0.5H),6.61(s,0.25H),2.42(s,3H),1.98(s,3H)。MS-ESI计算值[M+H] +361,实测值361。 Compound 33-5 (210 mg, 583 μmol) was dissolved in dioxane (5 mL) and water (1 mL), compound 1-1 (198 mg, 642 μmol), 1,1-bis(diphenylphosphonium)ferrocene was added Palladium chloride (42.7 mg, 58.3 μmol) and potassium phosphate (310 mg, 1.46 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 100 °C for 12 hours. The reaction solution was added with water (20 mL), extracted with ethyl acetate (30 mL×2), the organic phases were combined, washed with saturated brine (20 mL×1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 5/1～0/1, V/V) to obtain a crude product of the compound, which was subjected to SFC (separation column: DAICEL CHIRALCEL OD-H 250mm×30mm×5μm ; Mobile phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 30%-30%), separate compounds 33a (the second peak) and 33b (the first peak). The compound was then purified by SFC (column: Chiralcel OD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%- 40%) measured ee value. Compound 33b: ee%=99.68%, RT=4.541 min. 1 H NMR (400 MHz, CD 3 OD) δ 7.96 (t, J=8.0 Hz, 1H), 7.88-7.64 (m, 2H), 7.60 (d, J=7.6 Hz, 1H), 7.07 (s, 1H) ), 6.89(s, 0.25H), 6.75(s, 0.5H), 6.61(s, 0.25H), 2.42(s, 3H), 1.98(s, 3H). MS-ESI calculated [M+H] + 361, found 361.
实施例34Example 34
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000107
Figure PCTCN2021142174-appb-000107
第一步first step
将化合物16-4(890mg,2.72mmol)溶于二氧六环(10mL)和水(2mL),加入化合物34-1(880mg,2.99mmol),1,1-双(二苯基磷)二茂铁氯化钯(199mg,272μmol)和磷酸钾(1.44g,6.80mmol)。置换氮气三次,反应液在100℃下搅拌12小时。反应液加入水(30mL),乙酸乙酯(50mL x 2)萃取,合并有机相,用饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物粗品,粗品经SFC(分离柱:DAICEL CHIRALPAK AD 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液55％-55％),分离得到化合物34a(第一个峰)和34b(第二个峰)。后经SFC(色谱柱:ChiralPak AD-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物34b:e.e.％＝100％,RT＝3.918min。 1H NMR(400MHz,CD 3OD)δ8.05-7.74(m,3H),7.45(dd,J＝2.0,8.0Hz,1H),7.15(s,1H),6.98(dd,J＝2.0,8.0Hz,1H),1.94(s,3H)。MS-ESI计算值[M+H] +315,实测值315。 Compound 16-4 (890 mg, 2.72 mmol) was dissolved in dioxane (10 mL) and water (2 mL), compound 34-1 (880 mg, 2.99 mmol), 1,1-bis(diphenylphosphorus)di Ferrocene palladium chloride (199 mg, 272 μmol) and potassium phosphate (1.44 g, 6.80 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 100 °C for 12 hours. The reaction solution was added with water (30 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain a crude product of the compound, which was subjected to SFC (separation column: DAICEL CHIRALPAK AD 250mm×30mm×10μm; Phase: supercritical CO 2 -0.1% ammonia solution in ethanol; gradient: 0.1% ammonia solution in ethanol 55%-55%), compounds 34a (first peak) and 34b (second peak) were isolated. After SFC (chromatographic column: ChiralPak AD-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%-40 %) to measure the ee value. Compound 34b: ee%=100%, RT=3.918 min. 1 H NMR (400 MHz, CD 3 OD) δ 8.05-7.74 (m, 3H), 7.45 (dd, J=2.0, 8.0 Hz, 1H), 7.15 (s, 1H), 6.98 (dd, J=2.0, 8.0Hz, 1H), 1.94 (s, 3H). MS-ESI calculated [M+H] + 315, found 315.
实施例35Example 35
合成路线：synthetic route:
Figure PCTCN2021142174-appb-000108
Figure PCTCN2021142174-appb-000108
第一步first step
将化合物16-4(890mg,2.72mmol)溶于二氧六环(10mL)和水(2mL),加入化合物3-1(936mg,2.72mmol),1,1-双(二苯基磷)二茂铁氯化钯(199mg,272μmol)和磷酸钾(1.44g,6.80mmol)。置换氮气三次,反应液在100℃下搅拌12小时。反应液加入水(30mL),乙酸乙酯(50mL x 2)萃取,合并有机相,用饱和 食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。剩余物经过硅胶柱层析法(石油醚/乙酸乙酯,10/1～1/1,V/V)分离得到化合物35-1。MS-ESI计算值[M-56+H] +409,实测值409。 Compound 16-4 (890 mg, 2.72 mmol) was dissolved in dioxane (10 mL) and water (2 mL), compound 3-1 (936 mg, 2.72 mmol), 1,1-bis(diphenylphosphine)di Ferrocene palladium chloride (199 mg, 272 μmol) and potassium phosphate (1.44 g, 6.80 mmol). The nitrogen was replaced three times, and the reaction solution was stirred at 100 °C for 12 hours. The reaction solution was added with water (30 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was separated by silica gel column chromatography (petroleum ether/ethyl acetate, 10/1～1/1, V/V) to obtain compound 35-1. MS-ESI calculated [M-56+H] + 409, found 409.
第二步second step
将化合物35-1(514mg,1.11mmol)溶于乙酸乙酯(10mL),加入盐酸乙酸乙酯(4M,831μL),反应液在25℃下搅拌2小时。反应液加入饱和碳酸氢钠水溶液(50mL),乙酸乙酯(50mL x 2)萃取,合并有机相,用饱和食盐水洗涤(50mL x 1),无水硫酸钠干燥,过滤,减压浓缩。剩余物经SFC(分离柱:DAICEL CHIRALCEL OJ 250mm×30mm×10μm；流动相:超临界CO 2-0.1％氨水的乙醇溶液；梯度:0.1％氨水的乙醇溶液35％-35％),分离得到化合物35a(第一个峰)和35b(第二个峰)。后经SFC(色谱柱:Chiralpak AS-3 150mm×4.6mm×3μm；流动相:超临界CO 2-0.05％二乙胺的乙醇溶液；梯度:0.05％二乙胺的乙醇溶液:5％-40％)测e.e.值。化合物35b:e.e.％＝87.1％,RT＝3.697min。 1H NMR(400MHz,CD 3OD)δ8.37-8.23(m,2H),7.93(q,J＝8.0Hz,1H),7.74(s,1H),7.48(dd,J＝2.0,8.0Hz,1H),7.29(s,1H),7.23(dd,J＝4.8,8.0Hz,1H),6.98(dd,J＝2.0,8.0Hz,1H),1.97(s,3H)。MS-ESI计算值[M+H] +365,实测值365。 Compound 35-1 (514 mg, 1.11 mmol) was dissolved in ethyl acetate (10 mL), ethyl acetate hydrochloride (4 M, 831 μL) was added, and the reaction solution was stirred at 25° C. for 2 hours. The reaction solution was added with saturated aqueous sodium bicarbonate solution (50 mL), extracted with ethyl acetate (50 mL x 2), the organic phases were combined, washed with saturated brine (50 mL x 1), dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was subjected to SFC (separation column: DAICEL CHIRALCEL OJ 250mm×30mm×10μm; mobile phase: supercritical CO 2 -0.1% ethanol solution of ammonia water; gradient: 0.1% ethanol solution of ammonia water 35%-35%) to obtain the compound 35a (first peak) and 35b (second peak). After SFC (chromatographic column: Chiralpak AS-3 150mm×4.6mm×3μm; mobile phase: supercritical CO 2 -0.05% diethylamine in ethanol; gradient: 0.05% diethylamine in ethanol: 5%-40 %) to measure the ee value. Compound 35b: ee%=87.1%, RT=3.697 min. 1 H NMR (400 MHz, CD 3 OD) δ 8.37-8.23 (m, 2H), 7.93 (q, J=8.0 Hz, 1H), 7.74 (s, 1H), 7.48 (dd, J=2.0, 8.0 Hz , 1H), 7.29 (s, 1H), 7.23 (dd, J=4.8, 8.0 Hz, 1H), 6.98 (dd, J=2.0, 8.0 Hz, 1H), 1.97 (s, 3H). MS-ESI calculated [M+H] + 365, found 365.
生物学活性：Biological activity:
实验例1:CDC7/DBF4酶活性的抑制效应测试Experimental example 1: Inhibitory effect test of CDC7/DBF4 enzymatic activity
实验材料：Experimental Materials:
CDC7/DBF4激酶检测试剂盒购自Promega。Nivo多标记分析仪(PerkinElmer)。CDC7/DBF4 Kinase Assay Kit was purchased from Promega. Nivo Multilabel Analyzer (PerkinElmer).
实验方法：experimental method:
将待测化合物用排枪进行5倍稀释至第8个浓度，即从10μM稀释至0.13nM，DMSO浓度为5％，设置双复孔实验。向微孔板中加入1μL各浓度梯度待测化合物、2μL CDC7/DBF4酶(6.25ng)和2μL底物(0.2μg/μL PDKtide)和10μM ATP(腺嘌呤核苷三磷酸)的混合物，此时待测样品终浓度梯度为2μM稀释至0.025nM。反应体系置于25度反应60分钟。反应结束后，每孔加入5μL ADP-Glo试剂，25度继续反应40分钟，结束反应后每孔加入10μL的激酶检测试剂，25度反应30分钟后采用多标记分析仪读数化学发光，积分时间0.5秒。The compound to be tested was diluted 5-fold to the 8th concentration with a row gun, that is, from 10 μM to 0.13 nM, the concentration of DMSO was 5%, and a double-well experiment was set up. A mixture of 1 μL of each concentration gradient of the compound to be tested, 2 μL of CDC7/DBF4 enzyme (6.25 ng), 2 μL of substrate (0.2 μg/μL PDKtide) and 10 μM ATP (adenosine triphosphate) was added to the microplate. The final concentration gradient of the sample to be tested is 2 μM diluted to 0.025 nM. The reaction system was placed at 25 degrees for 60 minutes. After the reaction, 5 μL of ADP-Glo reagent was added to each well, and the reaction was continued at 25 degrees for 40 minutes. After the reaction, 10 μL of kinase detection reagent was added to each well. After 30 minutes of reaction at 25 degrees, the multi-label analyzer was used to read the chemiluminescence, and the integration time was 0.5 second.
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)。表1提供了本发明化合物对CDC7/DBF4酶的抑制活性。 Using the equation (Sample-Min)/(Max-Min)×100% to convert the raw data into inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters (log(inhibitor) vs.response in GraphPad Prism -Variable slope mode derived). Table 1 provides the inhibitory activity of the compounds of the present invention on CDC7/DBF4 enzymes.
表1本发明化合物对CDC7/DBF4酶活性抑制效应IC 50值测试结果 Table 1 Test results of IC 50 value of the compounds of the present invention on the inhibitory effect of CDC7/DBF4 enzyme activity
受试化合物test compound 1b1b 3b3b 4a4a 8b8b 9b9b 10b10b 1111 12b12b 13b13b 14b14b 1515 16b16b
IC 50(nM) IC50 (nM) 4.34.3 2.692.69 4.724.72 4.644.64 2.32.3 4.054.05 1.71.7 4.294.29 3.93.9 3.93.9 3.23.2 2.82.8
受试化合物test compound 17b17b 18b18b 24a24a 24b24b 25a25a 25b25b 26b26b 27b27b 28b28b 29b29b 31b31b 32b32b
IC 50(nM) IC50 (nM) 4.34.3 2.92.9 3.593.59 2.852.85 2.562.56 2.362.36 3.623.62 3.463.46 2.082.08 1.751.75 2.832.83 3.443.44
结论：本发明化合物对CDC7/DBF4有较强的抑制活性。Conclusion: The compounds of the present invention have strong inhibitory activity on CDC7/DBF4.
实验例2:COLO205细胞活性的抑制效应测试Experimental example 2: Inhibitory effect test of COLO205 cell activity
实验材料：Experimental Materials:
1640培养基，胎牛血清，盘尼西林/链霉素抗生素购自维森特。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。COLO205细胞系购自武汉普诺赛(Procell)生命科技有限公司。Nivo多标记分析仪(PerkinElmer)。1640 medium, fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Vicente. CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega. COLO205 cell line was purchased from Wuhan Procell Life Technology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
实验方法：experimental method:
将COLO205细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含3000个COLO205细胞。细胞板置于二氧化碳培养箱中过夜培养。COLO205 cells were seeded in a white 96-well plate, 80 μL of cell suspension per well, which contained 3000 COLO205 cells. Cell plates were incubated overnight in a carbon dioxide incubator.
将待测化合物用排枪进行3倍稀释至第8个浓度，即从2mM稀释至920nM，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4.57nM。细胞板置于二氧化碳培养箱中培养3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。The compounds to be tested were diluted 3-fold to the 8th concentration with a row gun, that is, from 2mM to 920nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 μM to 4.57 nM. The cell plates were placed in a carbon dioxide incubator for 3 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of this cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.
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。Add 25 μL 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. Read using a multi-label analyzer.
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)。表2提供了本发明化合物对COLO205细胞增殖的抑制活性。 Using the equation (Sample-Min)/(Max-Min)×100% to convert the raw data into inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode). Table 2 provides the inhibitory activity of the compounds of the present invention on the proliferation of COLO205 cells.
表2本发明化合物对COLO205细胞活性的抑制效应IC 50值测试结果 Table 2 Test results of IC 50 value of the inhibitory effect of the compounds of the present invention on the activity of COLO205 cells
受试化合物test compound 3b3b 8b8b 9b9b 1111 1515 16b16b 17b17b 18b18b 24a24a
IC 50(nM) IC50 (nM) 780780 810810 210210 730730 590590 170170 410410 3030 110110
受试化合物test compound 24b24b 25a25a 25b25b 26b26b 27b27b 28b28b 29b29b 31b31b 32b32b
IC 50(nM) IC50 (nM) 6060 2525 4747 408408 403403 140140 4343 467467 442442
结论：本发明化合物对COLO205细胞显示出良好的抑制活性。Conclusion: The compounds of the present invention show good inhibitory activity on COLO205 cells.
实验例3:Capan-1细胞活性的抑制效应测试Experimental example 3: Inhibitory effect test of Capan-1 cell activity
实验材料：Experimental Materials:
IMDM(Iscove’s Modified Dubecco’s Medium)培养基，胎牛血清，盘尼西林/链霉素抗生素购自维森特。CellTiter-Glo(细胞活率化学发光检测试剂)试剂购自Promega。Capan-1细胞系购自武汉普诺赛(Procell)生命科技有限公司。Nivo多标记分析仪(PerkinElmer)。IMDM (Iscove's Modified Dubecco's Medium) medium, fetal bovine serum, penicillin/streptomycin antibiotics were purchased from Vicente. CellTiter-Glo (Cell Viability Chemiluminescence Detection Reagent) reagent was purchased from Promega. The Capan-1 cell line was purchased from Wuhan Procell Life Technology Co., Ltd. Nivo Multilabel Analyzer (PerkinElmer).
实验方法：experimental method:
将Capan-1细胞种于白色96孔板中，80μL细胞悬液每孔，其中包含6000个Capan-1细胞。细胞板置于二氧化碳培养箱中过夜培养。Capan-1 cells were seeded in a white 96-well plate, 80 μL of cell suspension per well, which contained 6000 Capan-1 cells. Cell plates were incubated overnight in a carbon dioxide incubator.
将待测化合物用排枪进行3倍稀释至第8个浓度，即从2mM稀释至920nM，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4.57nM。细胞板置于二氧化碳培养箱中培养7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。The compound to be tested was diluted 3-fold to the 8th concentration with a row gun, that is, from 2mM to 920nM, and a double-well experiment was set up. Add 78 μL of medium to the middle plate, and then transfer 2 μL of each well of the compound to the middle plate according to the corresponding position. After mixing, transfer 20 μL of each well to the cell plate. Compound concentrations transferred to cell plates ranged from 10 μM to 4.57 nM. The cell plates were placed in a carbon dioxide incubator for 7 days. Another cell plate was prepared, and the signal value was read on the day of drug addition as the maximum value (Max value in the following equation) to participate in data analysis. Add 25 μL of cell viability chemiluminescence detection reagent to each well of the cell plate, and incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read using a multi-label analyzer.
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)。表3提供了本发明化合物对Capan-1细胞增殖的抑制活性。 Using the equation (Sample-Min)/(Max-Min)×100% to convert the raw data into inhibition rate, the IC 50 value can be obtained by curve fitting with four parameters ("log(inhibitor) vs. response--Variable slope" mode). Table 3 provides the inhibitory activity of the compounds of the present invention on the proliferation of Capan-1 cells.
表3本发明化合物对Capan-1细胞活性的抑制效应IC 50值测试结果 Table 3 Test results of IC 50 value of the inhibitory effect of the compounds of the present invention on the activity of Capan-1 cells
受试化合物test compound 1b1b 8b8b 9b9b 1111 13b13b 1515 16b16b 18b18b
IC 50(nM) IC50 (nM) 644644 678678 8989 230230 710710 797797 232232 7272
结论：本发明化合物对Capan-1细胞显示出良好的抑制活性。Conclusion: The compounds of the present invention show good inhibitory activity on Capan-1 cells.
实验例4:药代动力学评价Experimental Example 4: Pharmacokinetic Evaluation
实验材料：Experimental Materials:
BALB/c小鼠(雄性,7周龄,维通利华)BALB/c mice (male, 7 weeks old, Viton Lever)
实验操作：Experimental operation:
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征,实验中候选化合物配成澄清溶液,给予小鼠单次静脉注射及口服给药。静注及口服溶媒为10％二甲基亚砜与90％的10％的羟丙基β环糊精配成的混合溶媒。该项目使用四只雄性BALB/c小鼠,两只小鼠进行静脉注射给药,给药剂量为2mg/kg,收集0h(给药前)和给药后0.0833,0.25,0.5,1,2,4,8,24h的血浆样品,另外两只小鼠口服灌胃给药,给药剂量为2mg/kg,收集0h(给药前)和给药后0.25、0.5,1,2,4,8,24h的血浆样品,收集24小时内的全血样品,3000g离心15分钟,分离上清得血浆样品,加入4倍体积含内标的乙腈溶液沉淀蛋白,离心取上清液加入等倍体积的水再离心取上清进样,以LC-MS/MS分析方法定量分析血药浓度,并计算药代参数,如达峰浓度(C max),清除率(CL),半衰期(T 1/2),组织分布(Vdss),药时曲线下面积(AUC 0-last),生物利用度(F)等。表4提供了本发明化合物的药代动力学的测试结果。实验结果如表4。 The pharmacokinetic characteristics of the compounds in rodents after intravenous injection and oral administration were tested by standard protocols. In the experiment, the candidate compounds were formulated into clear solutions and administered to mice by a single intravenous injection and oral administration. Intravenous and oral vehicle is a mixed vehicle of 10% dimethyl sulfoxide and 90% 10% hydroxypropyl beta cyclodextrin. This project used four male BALB/c mice, two mice were administered intravenously at a dose of 2 mg/kg, collected at 0h (before administration) and 0.0833, 0.25, 0.5, 1, 2 after administration , 4, 8, 24h plasma samples, the other two mice were given oral gavage at a dose of 2 mg/kg, collected at 0h (before administration) and 0.25, 0.5, 1, 2, 4 after administration, 8, 24h plasma samples, collect whole blood samples within 24 hours, centrifuge at 3000g for 15 minutes, separate the supernatant to obtain plasma samples, add 4 times the volume of acetonitrile solution containing the internal standard to precipitate the protein, centrifuge the supernatant and add an equal volume of acetonitrile solution. The water was centrifuged and the supernatant was injected into the sample, and the blood drug concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters, such as peak concentration (C max ), clearance rate (CL), half-life (T 1/2 ), were calculated. ), tissue distribution (Vdss), area under the drug-time curve (AUC 0-last ), bioavailability (F), etc. Table 4 provides the results of testing the pharmacokinetics of the compounds of the present invention. The experimental results are shown in Table 4.
表4本发明化合物的药代动力学测试结果Table 4 Pharmacokinetic test results of the compounds of the present invention
Figure PCTCN2021142174-appb-000109
Figure PCTCN2021142174-appb-000109
结论：本发明化合物具有良好的药代动力学性质，包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。Conclusion: The compounds of the present invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
实验例5:化合物小鼠药代动力学评价Experimental Example 5: Pharmacokinetic Evaluation of Compounds in Mice
实验材料：Experimental Materials:
CD-1或BALB/c小鼠(雄性,7～10周龄,维通利华)CD-1 or BALB/c mice (male, 7-10 weeks old, Viton Lever)
实验操作：Experimental operation:
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液或混悬液,分别给予两只小鼠单次静脉注射及口服给药。静注溶媒为10％二甲基亚砜/10％乙醇/40％聚乙二醇400/40％的水溶液,给药剂量为2mg/kg,口服溶媒为3％二甲基亚砜/5％聚乙二醇十二羟基硬脂酸酯/92％水溶液给药剂量为10mg/kg。收集24小时内的全血样品至商品化EDTA2K抗凝管中,3200g离心10分钟,分离上清得血浆样品,加入含内标的乙腈溶液沉淀蛋白,离心取上清液加入等倍体积的水再离心取上清进样,以LC-MS/MS分析方法定量分析血药浓度,并计算药代参数,如表观分布容积,清除率,半衰期,药时曲线下面积等。实验结果如表5。The rodent pharmacokinetic characteristics of the compounds after intravenous injection and oral administration were tested by standard protocols. In the experiment, the candidate compounds were formulated into clear solutions or suspensions, and were administered to two mice by a single intravenous injection and oral administration. The intravenous vehicle is 10% dimethyl sulfoxide/10% ethanol/40% polyethylene glycol 400/40% aqueous solution, the dosage is 2 mg/kg, and the oral vehicle is 3% dimethyl sulfoxide/5% Polyethylene glycol lauryl stearate/92% aqueous solution was administered at a dose of 10 mg/kg. Collect whole blood samples within 24 hours into commercial EDTA2K anticoagulant tubes, centrifuge at 3200g for 10 minutes, separate the supernatant to obtain plasma samples, add acetonitrile solution containing internal standard to precipitate proteins, centrifuge the supernatant and add an equal volume of water for refilling. The supernatant was centrifuged and injected, and the plasma concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters, such as apparent volume of distribution, clearance rate, half-life, and area under the drug-time curve, were calculated. The experimental results are shown in Table 5.
表5本发明化合物的药代动力学测试结果Table 5 Pharmacokinetic test results of the compounds of the present invention
Figure PCTCN2021142174-appb-000110
Figure PCTCN2021142174-appb-000110
结论：本发明化合物具有良好的药代动力学性质，包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。Conclusion: The compounds of the present invention have good pharmacokinetic properties, including good oral bioavailability, oral exposure, half-life and clearance rate.
实验例6：化合物大鼠药代动力学评价Experimental Example 6: Evaluation of compound pharmacokinetics in rats
实验目的：测试化合物在SD大鼠体内药代动力学Experimental purpose: To test the pharmacokinetics of the compound in SD rats
实验材料：Experimental Materials:
SD大鼠(雄性,7～10周龄,维通利华)SD rats (male, 7-10 weeks old, Viton Lever)
实验操作：Experimental operation:
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征,实验中候选化合物配成澄清溶液或混悬液,分别给予两只大鼠单次静脉注射及口服给药。静注溶媒为10％二甲基亚砜/10％乙醇/40％聚乙二醇400/40％的水溶液,给药剂量为5mg/kg,口服溶媒为3％二甲基亚砜/5％聚乙二醇十二羟基硬脂酸酯/92％水溶液给药剂量为10mg/kg。收集24小时内的全血样品至商品化EDTA2K抗凝管中,3200g离心10分钟,分离上清得血浆样品,加入含内标的乙腈溶液沉淀蛋白,离心取上清液加入等倍体积的水再离心取上清进样,以LC-MS/MS分析方法定量分析血药浓度,并计算药代参数,如表观分布容积、清除率、半衰期、药时曲线下面积等。实验结果如表6。The pharmacokinetics of the compounds in rodents after intravenous injection and oral administration were tested according to the standard protocol. In the experiment, the candidate compounds were formulated into clear solutions or suspensions, which were administered to two rats by single intravenous injection and oral administration, respectively. The intravenous vehicle is 10% dimethyl sulfoxide/10% ethanol/40% polyethylene glycol 400/40% aqueous solution, the dosage is 5mg/kg, and the oral vehicle is 3% dimethyl sulfoxide/5% Polyethylene glycol lauryl stearate/92% aqueous solution was administered at a dose of 10 mg/kg. Collect whole blood samples within 24 hours into commercial EDTA2K anticoagulant tubes, centrifuge at 3200g for 10 minutes, separate the supernatant to obtain plasma samples, add acetonitrile solution containing internal standard to precipitate proteins, centrifuge the supernatant and add an equal volume of water for refilling. The supernatant was collected by centrifugation, and the plasma concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters, such as apparent volume of distribution, clearance rate, half-life, and area under the drug-time curve, were calculated. The experimental results are shown in Table 6.
表6药代动力学测试结果Table 6 Pharmacokinetic test results
Figure PCTCN2021142174-appb-000111
Figure PCTCN2021142174-appb-000111
结论：本发明化合物在大鼠中具有良好的药代动力学性质，包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。Conclusion: The compounds of the present invention have good pharmacokinetic properties in rats, including good oral bioavailability, oral exposure, half-life and clearance rate.
实验例7：化合物犬药代动力学评价Experimental Example 7: Canine Pharmacokinetic Evaluation of Compounds
实验目的：测试化合物在犬体内药代动力学Objective: To test the pharmacokinetics of the compound in dogs
实验材料：Experimental Materials:
比格犬(雄性,≥6月龄)Beagle (male, ≥6 months old)
实验操作：Experimental operation:
以标准方案测试化合物静脉注射及口服给药后的犬药代特征,实验中候选化合物配成澄清溶液或混悬液,分别给予两只犬单次静脉注射及口服给药。静注溶媒为10％二甲基亚砜/10％乙醇/40％聚乙二醇400/40％的水溶液,给药剂量为2mg/kg,口服溶媒为3％二甲基亚砜/5％聚乙二醇十二羟基硬脂酸酯/92％水溶液给药剂量为5mg/kg。收集24小时内的全血样品至商品化EDTA2K抗凝管中,3200g离心10分钟,分离上清得血浆样品,加入含内标的乙腈溶液沉淀蛋白,离心取上清液加入等倍体积的水再离心取上清进样,以LC-MS/MS分析方法定量分析血药浓度,并计算药代参数,如表观分布容积、清除率、半衰期、药时曲线下面积等。结论：本发明化合物在犬中具有良好的药代动力学性质，包括良好的口服生物利用度,口服暴露量,半衰期和清除率等。The pharmacokinetic characteristics of the compounds after intravenous injection and oral administration were tested by standard protocols. In the experiment, the candidate compounds were formulated into clear solutions or suspensions, and were administered to two dogs by single intravenous injection and oral administration, respectively. The intravenous vehicle is 10% dimethyl sulfoxide/10% ethanol/40% polyethylene glycol 400/40% aqueous solution, the dosage is 2 mg/kg, and the oral vehicle is 3% dimethyl sulfoxide/5% Polyethylene glycol dodecyl stearate/92% aqueous solution was administered at a dose of 5 mg/kg. Collect whole blood samples within 24 hours into commercial EDTA2K anticoagulant tubes, centrifuge at 3200g for 10 minutes, separate the supernatant to obtain plasma samples, add acetonitrile solution containing internal standard to precipitate proteins, centrifuge the supernatant and add an equal volume of water for refilling. The supernatant was collected by centrifugation, and the plasma concentration was quantitatively analyzed by LC-MS/MS analysis method, and the pharmacokinetic parameters, such as apparent volume of distribution, clearance rate, half-life, and area under the drug-time curve, were calculated. Conclusion: The compounds of the present invention have good pharmacokinetic properties in dogs, including good oral bioavailability, oral exposure, half-life and clearance rate.
实验例8：化合物在人胰腺癌细胞CAPAN-1裸小鼠皮下移植瘤模型的体内药效评价Experimental Example 8: In vivo efficacy evaluation of compounds in human pancreatic cancer cell CAPAN-1 nude mice subcutaneously transplanted tumor model
细胞培养：Cell Culture:
人胰腺癌细胞CAPAN-1第26代，体外单层培养，培养条件为IMDM培养基中加20％胎牛血清，1％双抗(100U/mL青霉素，100μg/mL链霉素和25μg/mL两性霉素B)，温度为37℃，在5％CO 2细胞培养箱中培养，传代6次，常规换液传代。当细胞饱和度为80％-90％时，细胞用胰酶-EDTA消化，计数，重悬于PBS和Matrigel(1:1)混合液，密度为5×10 6个细胞/0.2mL。 Human pancreatic cancer cell CAPAN-1 passage 26, cultured in monolayer in vitro, cultured in IMDM medium with 20% fetal bovine serum, 1% double antibody (100 U/mL penicillin, 100 μg/mL streptomycin and 25 μg/mL) Amphotericin B) at 37°C, cultured in a 5% CO2 cell incubator, passaged 6 times, and passaged with routine medium exchange. When the cell saturation was 80%-90%, cells were digested with trypsin-EDTA, counted, and resuspended in a mixture of PBS and Matrigel (1:1) at a density of 5 x 106 cells/0.2 mL.
实验动物：Experimental animals:
雌性BALB/c裸小鼠(周龄：6-8周)，购自上海灵畅生物科技有限公司。Female BALB/c nude mice (age: 6-8 weeks) were purchased from Shanghai Lingchang Biotechnology Co., Ltd.
模型制备：Model preparation:
在每只小鼠的右侧颈背部接种5×10 6个CAPAN-1细胞，接种体积为0.2mL，细胞悬液为PBS和Matrigel(1:1)。肿瘤平均体积达到约148mm 3时，采用随机分组，开始给药。 Each mouse was seeded with 5×10 6 CAPAN-1 cells on the right back of the neck in a seeding volume of 0.2 mL, and the cell suspension was PBS and Matrigel (1:1). When the mean tumor volume reached about 148 mm3 , randomization was used and dosing was started.
给药方案：见表7。Dosing regimen: see Table 7.
表7实验动物分组及给药方案Table 7 Grouping and dosing schedule of experimental animals
Figure PCTCN2021142174-appb-000112
Figure PCTCN2021142174-appb-000112
肿瘤测量和实验指标：Tumor measurements 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：TV＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。 Tumor diameters were measured with vernier calipers twice a week. The calculation formula of tumor volume is: TV=0.5a×b 2 , a and b represent the long and short diameters 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(％)＝T RTV/C RTV×100％(T RTV：治疗组RTV；C RTV：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＝V t/V 0，其中V 0是分组时(即D0)测量所得肿瘤体积RTV的平均值，V t为某一次测量时的肿瘤体积RTV的平均值，T RTV与C RTV取同一天数据。实验结果见图1。 The antitumor efficacy of the compounds was evaluated by TGI (%) or relative tumor proliferation rate T/C (%). Relative tumor proliferation rate T/C (%) = T RTV /C RTV × 100% (T RTV : RTV of the treatment group; C RTV : RTV of the negative control group). The relative tumor volume (RTV) is calculated according to the results of tumor measurement, and the calculation formula is RTV=V t /V 0 , where V 0 is the average value of tumor volume RTV measured during grouping (ie, D0 ), V t It is the average value of tumor volume RTV at a certain measurement, and the data of T RTV and C RTV are taken on the same day. The experimental results are shown in Figure 1.
实验结论：本发明化合物在CAPAN-1裸小鼠皮下移植瘤模型中展现出优异的抑瘤效果。Experimental conclusion: The compound of the present invention exhibits excellent tumor-inhibiting effect in CAPAN-1 nude mice subcutaneously transplanted tumor model.

Claims (19)

  1. 式(I’)化合物或其药学上可接受的盐，A compound of formula (I') or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2021142174-appb-100001
    Figure PCTCN2021142174-appb-100001
    其中，in,
    环A选自5-6元杂芳基，其中所述5-6元杂芳基任选被1、2或3个R 2所取代； Ring A is selected from 5-6 membered heteroaryl, wherein said 5-6 membered heteroaryl is optionally substituted with 1, 2 or 3 R2;
    结构单元
    Figure PCTCN2021142174-appb-100002
    选自
    Figure PCTCN2021142174-appb-100003
    其中所述
    Figure PCTCN2021142174-appb-100004
    分别独立地任选被1、2或3个R 3所取代；     Structural units
    Figure PCTCN2021142174-appb-100002
    selected from
    Figure PCTCN2021142174-appb-100003
    wherein the
    Figure PCTCN2021142174-appb-100004
    each independently optionally substituted with 1, 2 or 3 R3 ;
    R 1选自H和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R a所取代； R 1 is selected from H and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally substituted with 1, 2 or 3 R a ;
    R 2分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN、C 1-3烷基、C 1-3烷氧基、4-6元杂环烷基、-L-4-6元杂环烷基和5-6元杂芳基，其中所述C 1-3烷基、C 1-3烷氧基、4-6元杂环烷基、-L-4-6元杂环烷基和5-6元杂芳基分别独立地任选被1、2或3个R b所取代； R 2 is independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN, C 1-3 alkyl, C 1-3 alkoxy, 4-6 membered heterocycloalkyl , -L-4-6-membered heterocycloalkyl and 5-6-membered heteroaryl, wherein the C 1-3 alkyl, C 1-3 alkoxy, 4-6-membered heterocycloalkyl, -L -4-6 membered heterocycloalkyl and 5-6 membered heteroaryl are each independently optionally substituted with 1, 2 or 3 R b ;
    L选自-NH-和-O-；L is selected from -NH- and -O-;
    R 3分别独立地选自H、F、Cl、Br、I、-OH、-NH 2、-CN和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R c所取代； R 3 is each independently selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally 3 R c replaced;
    R 4选自H、F、Cl、Br、I、-OH、-NH 2、-CN和C 1-3烷基，其中所述C 1-3烷基任选被1、2或3个R d所取代； R 4 is selected from H, F, Cl, Br, I, -OH, -NH 2 , -CN and C 1-3 alkyl, wherein said C 1-3 alkyl is optionally surrounded by 1, 2 or 3 R replaced by d ;
    R a分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； Ra is independently selected from F, Cl, Br, I, =O, -OH, -NH2 and -CN;
    R b分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2、-CN、C 1-3烷基和C 1-3烷氧基，其中所述C 1-3烷基和C 1-3烷氧基分别独立地任选被1、2或3个R所取代； R b is independently selected from F, Cl, Br, I, =O, -OH, -NH 2 , -CN, C 1-3 alkyl and C 1-3 alkoxy, wherein the C 1-3 Alkyl and C 1-3 alkoxy are each independently optionally substituted with 1, 2 or 3 R;
    R c分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； R c is independently selected from F, Cl, Br, I, =O, -OH , -NH and -CN;
    R d分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； R d are independently selected from F, Cl, Br, I, =O, -OH, -NH 2 and -CN;
    R分别独立地选自F、Cl、Br、I、＝O、-OH、-NH 2和-CN； R is independently selected from F, Cl, Br, I, =O, -OH , -NH and -CN;
    所述5-6元杂芳基和4-6元杂环烷基分别独立地包含1、2、3或4个独立选自-O-、-NH-、-S-和-N-的杂原子或杂原子团。Said 5-6 membered heteroaryl and 4-6 membered heterocycloalkyl independently comprise 1, 2, 3 or 4 heterocyclic groups independently selected from -O-, -NH-, -S- and -N- atom or heteroatomic group.
  2. 根据权利要求1所述的化合物或其药学上可接受的盐，其所述化合物具有式(I)所示结构：The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I):
    Figure PCTCN2021142174-appb-100005
    Figure PCTCN2021142174-appb-100005
    其中，环A、R 1、R 3和R 4如权利要求1所定义。 wherein Ring A, R 1 , R 3 and R 4 are as defined in claim 1 .
  3. 根据权利要求2所述的化合物或其药学上可接受的盐，其所述化合物具有式(I-1)所示结构：The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has a structure represented by formula (I-1):
    Figure PCTCN2021142174-appb-100006
    Figure PCTCN2021142174-appb-100006
    其中，环A、R 1、R 3和R 4如权利要求2所定义； wherein Ring A, R 1 , R 3 and R 4 are as defined in claim 2;
    带“*”的碳原子为手性碳原子，以(R)或(S)单一对映体形式或富含一种对映体形式存在。A carbon atom with "*" is a chiral carbon atom and exists in (R) or (S) single enantiomeric form or enriched in one enantiomeric form.
  4. 根据权利要求1～3任一项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、-OH、-CH 3和-OCH 3。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R b is independently selected from F, Cl, Br, -OH, -CH 3 and -OCH 3 .
  5. 根据权利要求1～3任一项所述的化合物或其药学上可接受的盐，其中，R c分别独立地选自F、Cl和Br。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R c is independently selected from F, Cl and Br.
  6. 根据权利要求1～3任一项所述的化合物或其药学上可接受的盐，其中，R 1选自H和-CH 3。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 is selected from H and -CH 3 .
  7. 根据权利要求1～3任一项所述的化合物或其药学上可接受的盐，其中，R 2分别独立地选自H、F、Cl、Br、-NH 2、-CN、-CH 3、-CH 2CH 3、-OCH 3、
    Figure PCTCN2021142174-appb-100007
    Figure PCTCN2021142174-appb-100008
    其中所述-CH 3、-OCH 3、
    Figure PCTCN2021142174-appb-100009
    Figure PCTCN2021142174-appb-100010
    分别独立地任选被1、2或3个R b所取代。     The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -CH 2 CH 3 , -OCH 3 ,
    Figure PCTCN2021142174-appb-100007
    Figure PCTCN2021142174-appb-100008
    wherein the -CH 3 , -OCH 3 ,
    Figure PCTCN2021142174-appb-100009
    Figure PCTCN2021142174-appb-100010
    are each independently optionally substituted with 1, 2 or 3 R b .
  8. 根据权利要求7所述的化合物或其药学上可接受的盐，其中，R 2分别独立地选自H、F、Cl、Br、-NH 2、-CN、-CH 3、-CH 2CH 2OCH 3、-CHF 2、-CF 3、-OCH 3、
    Figure PCTCN2021142174-appb-100011
    Figure PCTCN2021142174-appb-100012
    The compound of claim 7 or a pharmaceutically acceptable salt thereof, wherein R 2 is independently selected from H, F, Cl, Br, -NH 2 , -CN, -CH 3 , -CH 2 CH 2 OCH 3 , -CHF 2 , -CF 3 , -OCH 3 ,
    Figure PCTCN2021142174-appb-100011
    Figure PCTCN2021142174-appb-100012
  9. 根据权利要求1～3任一项所述的化合物或其药学上可接受的盐，其中，R 3分别独立地选自H、F、Cl、Br和-CH 3，其中所述-CH 3任选被1、2或3个R c所取代。 The compound according to any one of claims 1 to 3 or a pharmaceutically acceptable salt thereof, wherein R 3 is independently selected from H, F, Cl, Br and -CH 3 , wherein -CH 3 is any Select is replaced by 1, 2 or 3 Rcs.
  10. 根据权利要求5或9所述的化合物或其药学上可接受的盐，其中，R 3分别独立地选自H、-CH 3和-CF 3。 The compound of claim 5 or 9, or a pharmaceutically acceptable salt thereof, wherein R 3 is independently selected from H, -CH 3 and -CF 3 .
  11. 根据权利要求1～3任一项所述的化合物或其药学上可接受的盐，其中，R 4选自H、F、Cl和Br。 The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 4 is selected from H, F, Cl and Br.
  12. 根据权利要求1～3任一项所述的化合物或其药学上可接受的盐，其中，环A选自吡啶基、嘧啶基和哒嗪基，其中所述吡啶基、嘧啶基和哒嗪基分别独立地任选被1、2或3个R 2所取代。 The compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from the group consisting of pyridyl, pyrimidinyl and pyridazinyl, wherein said pyridyl, pyrimidinyl and pyridazinyl are each independently optionally substituted with 1, 2 or 3 R 2 .
  13. 根据权利要求12所述的化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2021142174-appb-100013
    其中所述
    Figure PCTCN2021142174-appb-100014
    分别独立地任选被1、2或3个R 2所取代。     The compound of claim 12, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from
    Figure PCTCN2021142174-appb-100013
    wherein the
    Figure PCTCN2021142174-appb-100014
    are each independently optionally substituted with 1, 2 or 3 R 2 .
  14. 根据权利要求13所述的化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2021142174-appb-100015
    Figure PCTCN2021142174-appb-100016
    The compound of claim 13, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from
    Figure PCTCN2021142174-appb-100015
    Figure PCTCN2021142174-appb-100016
  15. 根据权利要求8或14任一项所述的化合物或其药学上可接受的盐，其中，环A选自
    Figure PCTCN2021142174-appb-100017
    Figure PCTCN2021142174-appb-100018
    The compound of any one of claims 8 or 14, or a pharmaceutically acceptable salt thereof, wherein Ring A is selected from
    Figure PCTCN2021142174-appb-100017
    Figure PCTCN2021142174-appb-100018
  16. 根据权利要求2所述的化合物或其药学上可接受的盐，其所述化合物具有式(I-2)～(I-6)所示结构：The compound according to claim 2 or a pharmaceutically acceptable salt thereof, wherein the compound has the structures represented by the formulae (I-2) to (I-6):
    Figure PCTCN2021142174-appb-100019
    Figure PCTCN2021142174-appb-100019
    其中，n选自0、1、2或3；R 1、R 2、R 3和R 4如权利要求2所定义。 wherein n is selected from 0, 1, 2 or 3; R 1 , R 2 , R 3 and R 4 are as defined in claim 2 .
  17. 根据权利要求16所述的化合物或其药学上可接受的盐，其所述化合物具有式(I-2a)～(I-6b)所示结构：The compound according to claim 16 or a pharmaceutically acceptable salt thereof, wherein the compound has the structures represented by formulae (I-2a) to (I-6b):
    Figure PCTCN2021142174-appb-100020
    Figure PCTCN2021142174-appb-100020
    其中，n、R 1、R 2、R 3和R 4如权利要求16所定义。 wherein n, R 1 , R 2 , R 3 and R 4 are as defined in claim 16 .
  18. 下式化合物或其药学上可接受的盐：A compound of the following formula or a pharmaceutically acceptable salt thereof:
    Figure PCTCN2021142174-appb-100021
    Figure PCTCN2021142174-appb-100021
    Figure PCTCN2021142174-appb-100022
    Figure PCTCN2021142174-appb-100022
    Figure PCTCN2021142174-appb-100023
    Figure PCTCN2021142174-appb-100023
  19. 根据权利要求18所述的化合物或其药学上可接受的盐，其化合物为The compound according to claim 18 or a pharmaceutically acceptable salt thereof, which is
    Figure PCTCN2021142174-appb-100024
    Figure PCTCN2021142174-appb-100024
    Figure PCTCN2021142174-appb-100025
    Figure PCTCN2021142174-appb-100025
    Figure PCTCN2021142174-appb-100026
    Figure PCTCN2021142174-appb-100026
    Figure PCTCN2021142174-appb-100027
    Figure PCTCN2021142174-appb-100027
    Figure PCTCN2021142174-appb-100028
    Figure PCTCN2021142174-appb-100028
PCT/CN2021/142174 2020-12-30 2021-12-28 Thieno [2, 3-c] pyrrole-4-one derivative WO2022143693A1 (en)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
CN107074874A (en) * 2014-12-22 2017-08-18 伊莱利利公司 Erk inhibitor
WO2019223632A1 (en) * 2018-05-22 2019-11-28 Js Innomed Holdings Ltd. Heterocyclic compounds as kinase inhibitors, compositions comprising the heterocyclic compound, and methods of use thereof
WO2020192750A1 (en) * 2019-03-28 2020-10-01 江苏恒瑞医药股份有限公司 Thienoheterocyclic derivative, preparation method therefor and medical use thereof

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Publication number Priority date Publication date Assignee Title
CN107074874A (en) * 2014-12-22 2017-08-18 伊莱利利公司 Erk inhibitor
WO2019223632A1 (en) * 2018-05-22 2019-11-28 Js Innomed Holdings Ltd. Heterocyclic compounds as kinase inhibitors, compositions comprising the heterocyclic compound, and methods of use thereof
WO2020192750A1 (en) * 2019-03-28 2020-10-01 江苏恒瑞医药股份有限公司 Thienoheterocyclic derivative, preparation method therefor and medical use thereof

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