WO2022247862A1 - Benzospiroheterocyclic derivative, and use thereof - Google Patents

Benzospiroheterocyclic derivative, and use thereof Download PDF

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Publication number
WO2022247862A1
WO2022247862A1 PCT/CN2022/095009 CN2022095009W WO2022247862A1 WO 2022247862 A1 WO2022247862 A1 WO 2022247862A1 CN 2022095009 W CN2022095009 W CN 2022095009W WO 2022247862 A1 WO2022247862 A1 WO 2022247862A1
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compound
alkyl
ethyl acetate
stirred
pharmaceutically acceptable
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PCT/CN2022/095009
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French (fr)
Chinese (zh)
Inventor
陈新海
姜奋
胡国平
张丽
胡伯羽
陈兆国
王晶晶
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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Priority to CN202280037913.3A priority Critical patent/CN117377656A/en
Publication of WO2022247862A1 publication Critical patent/WO2022247862A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/56—Amides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/96—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings spiro-condensed with carbocyclic rings or ring systems

Definitions

  • the present invention relates to a class of benzospiro heterocyclic derivatives and applications thereof, in particular to compounds represented by formula (II) or pharmaceutically acceptable salts thereof.
  • PGE2 Prostaglandin E2
  • the body produces high concentrations of PGE2 in an inflammatory state, causing inflammation, edema and pain.
  • PGE2 is also involved in various physiological and/or pathological symptoms, such as hyperalgesia, uterine contraction, digestive tract peristalsis, inhibition of gastric acid secretion, and lowering of blood pressure.
  • PGE2 has four receptors (EP1, EP2, EP3, EP4), among which EP4 plays an important role in the biological effects mediated by PGE2. Studies have shown that PGE2/EP4 is closely related to the occurrence and development of tumors. Tumor tissue will secrete more PGE2.
  • PGE2 and EP4 can activate PKA and phosphorylate the transcription factor CREB; PKA can also increase the activity of WNT/ ⁇ -catenin and NOTCH pathways by inhibiting GSK3; EP4 can also activate non-canonical PI3K/Akt and ERK signaling pathways.
  • the abnormality of the above signaling pathways can promote cell survival, proliferation and metastasis, and promote the occurrence and development of tumors.
  • PGE2 can promote the differentiation of immunosuppressive cells through the EP4 receptor, inhibit the anti-tumor effect of immune effector cells, and mediate the immunosuppressive effect of the tumor microenvironment. In recent years, the application of EP4 selective antagonists in tumor immunotherapy has received attention.
  • EP4 selective antagonists can inhibit the differentiation of monocytes into immunosuppressive cells, reduce immunosuppressive cells in tumor tissues, such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages, and increase tumor tissue Antitumor immune cells, such as dendritic cells (DCs), T cells, and M1 macrophages, reverse the immune suppression in the tumor microenvironment.
  • tumor tissues such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages
  • Antitumor immune cells such as dendritic cells (DCs), T cells, and M1 macrophages, reverse the immune suppression in the tumor microenvironment.
  • ONO-4578 (patent: WO2016111347, CN107108480) is one of them, and is currently conducting phase I/II clinical trials of single drug or in combination with PD1 monoclonal antibody for the treatment of solid tumors.
  • EP4 selective antagonists have great application prospects and clinical value in the treatment of tumors, inflammation, pain and other diseases
  • the present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • L 1 is selected from 5-6 membered heteroaryl
  • R 1 is selected from C 1-3 haloalkyl, C 1-3 alkylthio, The 5-6 membered heteroaryl, C 1-3 alkylthio, each independently optionally substituted by 1, 2 or 3 halogens;
  • L is selected from C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl- C 0-3 alkyl-, the C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3 -6 cycloalkyl-C 0-3 alkyl-are independently optionally substituted by 1, 2 or 3 R e ;
  • E 1 is selected from -O-, -S- and -NR 6 -;
  • R 2 , R 4 and R 6 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 3 is selected from C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5-10 membered bicyclic heterocycloalkyl, the C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5-
  • the 10-membered bicyclic heterocycloalkyl group is independently optionally substituted by 1, 2 or 3 R b ;
  • R 5 is selected from C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl Cycloalkyl is independently optionally substituted by 1, 2 or 3 Rc ;
  • each R a and each R e are independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • Each R is independently selected from H, F, Cl, Br and I;
  • n is selected from 0, 1 and 2;
  • hetero of the 5-10 membered bicyclic heterocycloalkyl and 5-6 membered heteroaryl independently represent 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and A heteroatom or heteroatom group of N;
  • L 2 is selected from C 1-3 alkoxy, C 1-3 alkane Amino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-, the C 1-3 alkoxy, C 1-3 alkylamino , C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl- are independently optionally substituted by 1, 2 or 3 R e .
  • R 2 is selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally replaced by 1 , 2 or 3 R a substitutions, R a and other variables are as defined in the present invention.
  • R 2 is selected from H, and other variables are as defined in the present invention.
  • the above-mentioned R 3 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , spiro[2,2]pentyl, spiro[2,3 ]hexyl, spiro[3,3]heptanyl, bicyclo[3.1.0]hexyl and bicyclo[1.1.1]pentanyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3.
  • Pentyl is optionally substituted with 1, 2 or 3 Rb , Rb and other variables are as defined herein.
  • R 3 is selected from spiro[2,2]pentyl, spiro[2,3]hexyl, spiro[3,3]heptanyl, bicyclo[3.1.0]hexyl Alkyl and bicyclo[1.1.1]pentanyl, the spiro[2,2]pentanyl, spiro[2,3]hexyl, spiro[3,3]heptanyl, bicyclo[3.1.0 ]hexyl and bicyclo[1.1.1]pentanyl are optionally substituted with 1, 2 or 3 Rb , Rb and other variables are as defined herein.
  • R 4 is selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally replaced by 1 , 2 or 3 R a substitutions, R a and other variables are as defined in the present invention.
  • R 4 is selected from H, and other variables are as defined in the present invention.
  • the above-mentioned R is selected from C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolyl, azepine Cyclobutyl, azepanyl and morpholinyl, the C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolyl , azetidinyl, azetidinyl and morpholinyl are optionally substituted with 1, 2 or 3 Rc , Rc and other variables are as defined herein.
  • the above-mentioned R is selected from C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolyl, azepine Cyclobutyl and azacyclopentyl, the C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolyl, azacyclic Butyl and azacyclopentyl are optionally substituted with 1, 2 or 3 Rc , Rc and other variables are as defined herein.
  • R 5 is selected from -CH(CH 3 ) 2 , -C(CH 3 ) 3 and Other variables are as defined herein.
  • Other variables are as defined herein.
  • R 1 is selected from CF 3 , SCH 3
  • L is selected from pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, isothienyl, oxazolyl and Oxadiazolyl
  • Azolyl and oxadiazolyl are optionally substituted with 1, 2 or 3 halogens, other variables being as defined herein.
  • the above-mentioned structural units selected from Other variables are as defined herein.
  • the above-mentioned L is selected from propyl, butyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl, Other variables are as defined herein.
  • the above-mentioned structural units selected from R 3 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , wherein CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are respectively independently optionally substituted by 1, 2 or 3 R b , at this time, L is selected from R b and other variables are as defined herein.
  • the above-mentioned E 1 is selected from -O-, and other variables are as defined in the present invention.
  • n is selected from 0, and other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 1 , L 1 and E 1 are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • R is selected from C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl, said C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl are independently optionally replaced by 1, 2 or 3 R b is substituted, and the C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl are bicyclic;
  • R 2 , R 4 and R 5 are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • Ring A is selected from 5-6 membered heteroaryls
  • R 1 is selected from C 1-3 haloalkyl, C 1-3 alkylthio,
  • R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • R 2 is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 3 is selected from C 1-5 alkyl, said C 1-5 alkyl is optionally substituted by 1, 2 or 3 R b ;
  • L 2 is selected from C 1-5 heteroalkyl and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-, the C 1-5 heteroalkyl and -C 0- 3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-are independently optionally substituted by 1, 2 or 3 R e ;
  • each R a , each R b and each Re is as defined herein.
  • the present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
  • E 1 is selected from -O-, -S- and -NR 6 -;
  • R 2 , R 4 and R 6 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 3 is selected from C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl, said C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl are bicyclic, optionally surrounded by 1, 2 or 3 R b replaces;
  • R 5 is selected from C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl Cycloalkyl is optionally substituted by 1, 2 or 3 R ;
  • Each R a is independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • Each R is independently selected from H, F, Cl, Br and I;
  • the "5-10 membered heterocycloalkyl” contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N;
  • the "4-6 membered heterocycloalkyl” contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
  • the present invention also provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
  • L is selected from C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl- C 0-3 alkyl-, the C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3 -6 cycloalkyl-C 0-3 alkyl-are independently optionally substituted by 1, 2 or 3 R e ;
  • E 1 is selected from -O-, -S- and -NR 6 -;
  • R 2 , R 4 and R 6 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
  • R 3 is selected from C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5-10 membered bicyclic heterocycloalkyl, the C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5-
  • the 10-membered bicyclic heterocycloalkyl group is independently optionally substituted by 1, 2 or 3 R b ;
  • R 5 is selected from C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl Cycloalkyl is independently optionally substituted by 1, 2 or 3 Rc ;
  • each R a and each R e are independently selected from H, F, Cl, Br, I, OH and NH 2 ;
  • Each R is independently selected from H, F, Cl, Br and I;
  • n is selected from 0, 1 and 2;
  • the 5-10 membered bicyclic heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N;
  • the 4-6 membered heterocycloalkyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N;
  • L 2 is selected from C 1-3 alkoxy, C 1-3 alkane Amino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-, the C 1-3 alkoxy, C 1-3 alkylamino , C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl- are independently optionally substituted by 1, 2 or 3 R e .
  • the present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
  • the compound of the present invention has strong antagonistic activity to human source EP4, has good pharmacokinetic properties, and exhibits a certain tumor inhibitory effect when monotherapy, and has significantly better than corresponding monotherapy when combined with oxaliplatin. Tumor suppressive effect of drug therapy.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either 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 the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; also salts of amino acids such as arginine and the like , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus be converted into
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • 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 both.
  • the compounds provided herein also exist in prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them to the compounds of the present invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms.
  • the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention.
  • the compounds of the invention may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • enantiomer or “optical isomer” refer to stereoisomers that are mirror images of each other.
  • cis-trans isomers or “geometric isomers” arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
  • diastereoisomer refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
  • keys with wedge-shaped solid lines and dotted wedge keys Indicates the absolute configuration of a stereocenter, with a straight solid-line bond and straight dashed keys Indicates the relative configuration of the stereocenter, with a wavy line Indicates wedge-shaped solid-line bond or dotted wedge key or with tilde Indicates a straight solid line key and straight dashed keys
  • tautomer or “tautomeric form” means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • proton tautomers include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons.
  • keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in an isomer”, “enriched in an isomer”, “enriched in an enantiomer” or “enantiomerically enriched” refer to one of the isomers or enantiomers
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. 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 compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C).
  • heavy hydrogen can be used to replace hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • “Optional” or “optionally” means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where it does not.
  • 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 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 realizable basis.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations 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.
  • substituent 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 enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
  • linking group listed does not indicate its linking direction
  • its linking direction is arbitrary, for example,
  • the connecting 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 to form It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
  • any one or more sites of the group can be linked to other groups through chemical bonds.
  • connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group.
  • the chemical bonds that the site connects with other groups can use straight solid line bonds Straight dotted key or tilde express.
  • the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dotted line bond indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
  • C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12 etc.; C 0-3 includes C 0 , C 1.
  • C 2 and C 3 also include any range from n to n+m, where C 0 means that the group does not exist; similarly, n-membered to n+m-membered means that the number of atoms on the ring is from n to n +m, for example, 3-12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings and 12-membered rings , also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring , 6-8 membered ring and 6-10 membered ring, etc.
  • C 1-5 alkyl by itself or in combination with other terms is used to indicate a linear or branched saturated hydrocarbon group consisting of 1 to 5 carbon atoms.
  • the C 1-5 alkyl group includes C 1-4 , C 1-3 , C 1-2 , C 2-5 , C 2-4 and C 5 alkyl, etc.; it can be monovalent (such as methyl) , bivalent (such as methylene) or multivalent (such as methine).
  • C 1-5 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl) and so on.
  • C 1-3 alkyl by itself or in combination with other terms is used to indicate a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), and the like.
  • C 0-3 alkyl by itself or in combination with other terms is used to indicate the absence of such a group, or to indicate a straight or branched chain of saturated hydrocarbons consisting of 1 to 3 carbon atoms group.
  • the C 0-3 alkyl group includes C 0 (that is, the group does not exist), and also includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkyl groups, etc.; It can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine).
  • Examples of C 0-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n - propyl and isopropyl), and the like.
  • C 1-3 haloalkyl is used by itself or in combination with other terms to denote monohaloalkyl and polyhaloalkyl groups containing 1 to 3 carbon atoms.
  • the C 1-3 haloalkyl includes C 1-2 , C 2-3 , C 3 , C 2 and C 1 haloalkyl and the like.
  • Examples of C 1-3 haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl and the like.
  • C1-3 alkoxy is used by itself or in combination with other terms to denote those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. It can be monovalent (eg -OCH3 ), divalent (eg -OCH2- ) or multivalent.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 1-3 alkylamino is used by itself or in combination with other terms to denote those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group. It can be monovalent (eg -NHCH3 ), divalent (eg -NHCH2- ) or multivalent.
  • the C 1-3 alkylamino group includes C 1-2 , C 2-3 , C 3 and C 2 alkylamino groups and the like.
  • C 1-3 alkylamino examples include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 (CH 3 ) 2 etc.
  • C 1-3 alkylthio is used by itself or in combination with other terms to denote those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through a sulfur atom. It can be monovalent (eg -SCH3 ), divalent (eg -SCH2- ) or multivalent.
  • the C 1-3 alkylthio group includes C 1-2 , C 2-3 , C 3 and C 2 alkylthio groups and the like. Examples of C 1-3 alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 and the like.
  • C 3-6 cycloalkyl by itself or in combination with other terms is used to indicate a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, so
  • the C 3-6 cycloalkyl group includes C 3-5 , C 4-5 and C 5-6 cycloalkyl groups; it may be monovalent, divalent or multivalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • C 5-10 cycloalkyl by itself or in combination with other terms is used to indicate a saturated cyclic hydrocarbon group consisting of 5 to 10 carbon atoms, including monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include spiro, fused and bridged rings.
  • the C 5-10 cycloalkyl group includes C 5-6 , C 5-8 , C 5-10 , C 6-8 , C 6-10 or C 8-10 etc.; it can be monovalent, divalent or polyvalent.
  • C 5-10 cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2,2]pentyl, norbornyl, [2.2.2]bicyclooctane Wait.
  • C 5-10 bicyclic cycloalkyl by itself or in combination with other terms is used to indicate a saturated cyclic hydrocarbon group consisting of 5 to 10 carbon atoms, which is a bicyclic ring system, including spiro rings , parallel rings and bridge rings.
  • the bicyclic C 5-10 bicyclic cycloalkyl group includes C 5-6 , C 5-8 , C 5- 10 , C 6-8 , C 6-10 or C 8-10 etc.; it can be monovalent, divalent price or multiple.
  • Examples of C 5-10 bicyclic cycloalkyl include, but are not limited to, spiro[2,2]pentanyl, norbornyl, [2.2.2]bicyclooctane and the like.
  • the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings.
  • the 5-10 membered heterocycloalkyl group includes 5-6, 5-8, 5-10, 6-8, 6-10, 8-10, 6, 8 and 10 Cycloalkyl etc.
  • Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl,
  • the term "5-10 membered bicyclic heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 ring atoms, whose 1, 2, 3 or 4 ring Atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It is a bicyclic ring system including spiro, fused and bridged rings.
  • a heteroatom may occupy the linking position of the heterocycloalkyl to the rest of the molecule.
  • the 5-10 membered bicyclic heterocycloalkyl group includes 5-6, 5-8, 5-10, 6-8, 6-10, 8-10, 6, 8 and 10 Bicyclic heterocycloalkyl, etc. Examples of 5-10 membered bicyclic heterocycloalkyl include, but are not limited to Wait.
  • 4-6 membered heterocycloalkyl by itself or in combination with other terms denotes a saturated monocyclic group consisting of 4 to 6 ring atoms, 1, 2 or 3 of which are independently Heteroatoms selected from O, S, and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , where p is 1 or 2).
  • a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule.
  • the 4-6 membered heterocycloalkyl group includes 4-5 membered, 4-membered, 5-membered, 6-membered and other heterocycloalkyl groups.
  • 4-6 membered heterocycloalkyl groups include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophene-2 -yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3- piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholin
  • the terms “5-6-membered heteroaryl ring” and “5-6-membered heteroaryl” in the present invention can be used interchangeably, and the term “5-6-membered heteroaryl” means that there are 5 to 6 ring atoms A monocyclic group with a conjugated ⁇ -electron system, 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 , where p is 1 or 2).
  • the 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl 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.
  • the structure of the compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuK ⁇ radiation, and the scanning method is: After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
  • SXRD single crystal X-ray diffraction
  • PGE2 stands for prostaglandin E2
  • EP4 stands for PGE2 receptor 4
  • SFC supercritical fluid chromatography chiral separation
  • CO2 stands for carbon dioxide.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
  • the solvent used in the present invention is commercially available.
  • Compounds are named according to the conventional naming principles in this field or using The software is named, and the commercially available compounds adopt the supplier catalog name.
  • reaction solution was quenched with saturated ammonium chloride aqueous solution (100mL) at 10-20°C, diluted with water (70mL), extracted with dichloromethane (150mL*2), combined organic phases, and washed with saturated sodium chloride solution ( 100mL*1), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound A-3.
  • Diiodhydantoin 46.79g, 0.54eq
  • concentrated sulfuric acid 2.39g, 1.30mL, 0.107eq
  • methanol 50mL
  • 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (16.84g, 0.2eq) and palladium acetate (9.21g, 0.2eq) were added to compound C-1 (23.58 g, 0.5eq) in tetrahydrofuran (40mL), and the prepared zinc reagent reaction solution was added dropwise to the mixture at 0°C. It was then stirred at 25°C for 12 hours. 80 mL of saturated aqueous ammonium chloride solution was added to the reaction mixture, diluted with 100 mL of water, and the mixture was extracted with ethyl acetate (200 mL*2).
  • intermediate B 0.1g, 1eq
  • compound 2-1 60mg, hydrochloride, 1.07eq
  • acetonitrile 2mL
  • tetrahydrofuran 2mL
  • diisopropyl Ethylamine 0.21eq
  • 4-dimethylaminopyridine 10mg, 0.21eq
  • added tri-n-propyl cyclic phosphoric anhydride 50% mass fraction in ethyl acetate, 0.5mL, 2.2 eq
  • the reaction mixture was stirred at 20-25° C. for 10 hours.
  • intermediate B 0.1g, 1eq
  • compound 3-1 50mg, 1.10eq, hydrochloride
  • diisopropyl Ethylamine 73.92mg, 99.62 ⁇ L, 1.5eq
  • 4-dimethylaminopyridine 46.58mg, 1eq
  • added tri-n-propyl cyclic phosphoric anhydride 50% mass fraction in ethyl acetate solution, 0.68mL, 3eq
  • compound 3-3 (65mg, 1eq) and intermediate C (48.18mg, 1eq) were dissolved in a mixed solvent of acetonitrile (1mL) and tetrahydrofuran (1mL), and diisopropylethylamine (40.21mg, 54.20 ⁇ L, 1.5eq) and 4-dimethylaminopyridine (25.34mg, 1eq), stirred for 10 minutes, added tri-n-propyl cyclic phosphoric anhydride (50% mass fraction in ethyl acetate solution, 0.37mL, 3eq), The reaction mixture was stirred at 20°C for 2 hours.
  • Diphenylphosphoryl azide (1.02g, 1.16eq) was added to compound 4-1 (0.4g, 1eq), diisopropylethylamine (0.7mL, 1.27eq) and tert-butanol (1.00mL, 3.30eq ) in toluene (10 mL), the mixture was stirred at 25°C for 30 minutes, then heated to 110°C and stirred for 10 hours.
  • Tri-n-propyl cyclic phosphoric anhydride (T 3 P, 11.63g, 10.87mL, 50% ethyl acetate solution, 3eq) was added at 20°C, and the reaction solution was stirred at 20°C for 2 hours.
  • the reaction solution was concentrated under reduced pressure, diluted with water (3 mL), extracted with ethyl acetate (4 mL*2), the organic phases were combined, washed with saturated brine (3 mL*2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • Compound 7-7 was separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) isopropanol]; B% : 20%-20%) to obtain compound 7-7a.
  • SFC detection conditions: Chromatographic column: Chiralpak AD-3 50 ⁇ 4.6mm ID, 3 ⁇ m; mobile phase: phase A: CO 2 , phase B: isopropanol (0.05% diethylamine); gradient: B%: 5% ⁇ 40%; flow rate: 3mL/min, retention time 1.636min, ee 100%.
  • MS m/z 518.3 [M+H] + .
  • Methyl 2-methylpropionate (10g, 11.22mL, 1eq) was added into 200mL of anhydrous tetrahydrofuran, cooled to -70°C and replaced with nitrogen, and lithium diisopropylamide (LDA) was added dropwise at -70°C ( 2M, 73.43mL, 1.5eq), stirred at -70 ⁇ -40°C for 30 minutes.
  • LDA lithium diisopropylamide
  • Compound 8-1 (20.16g, 1.05eq) was dissolved in 50mL of tetrahydrofuran, and added dropwise to the reaction system at -70°C, then naturally heated to 20°C and stirred for 1 hour.
  • n-Hexane solution and triethylamine (7.05g, 9.70mL, 2.06eq), control the internal temperature at 5-10°C during the dropwise addition, then stir at 0-10°C for 1 hour, and stir at 20-30°C for 10 hours in the reaction solution
  • Add 80 mL of ethyl acetate, stir for 15 minutes, filter with celite, and concentrate the filtrate to obtain a crude product, which is separated by column chromatography (petroleum ether: ethyl acetate 5:1 ⁇ 3:1) to obtain compound 8-5.
  • Compound 8-6 (1.8g, 1eq) was added to 15mL of trifluoroacetic anhydride, and the solution was cooled to 3°C, and nitric acid (3.77g, 2.69mL, 65% content, 5eq) was added dropwise within 15 minutes to the reaction system, control the internal temperature not to exceed 20°C, and then stir at 3-20°C for 15 minutes.
  • reaction solution was concentrated under reduced pressure, diluted with water (15 mL), extracted with ethyl acetate (10 mL*2), the organic phases were combined, washed with saturated brine (15 mL*1), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • reaction solution was adjusted to pH 6-7 with saturated aqueous citric acid solution, concentrated under reduced pressure, diluted with water (6 mL), extracted with ethyl acetate (5 mL*2), combined organic phases, and washed with saturated brine (20 mL*1 ), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was prepared and separated by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3 ⁇ m; mobile phase: [water (10mM ammonium bicarbonate)- Acetonitrile]; B (acetonitrile)%: 14%-44%, 8min) was purified to obtain compound 8a.
  • reaction solution was concentrated under reduced pressure, diluted with water (13mL) and ethyl acetate extraction (14mL), extracted with ethyl acetate (14mL*2), the organic phases were combined, washed with saturated brine (16mL*1), and dried over anhydrous sodium sulfate , the filtrate was concentrated under reduced pressure to obtain the crude product, which was prepared and separated by high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10 ⁇ m; mobile phase: [water (0.1% triethylamine)-acetonitrile]; acetonitrile%: 52 %-82%) to isolate compound 9-11a.
  • Extract with ethyl acetate (20mL*3) adjust the pH of the aqueous phase to about 3 with 2N dilute hydrochloric acid, extract with ethyl acetate (20mL*3), wash with water (50mL*3) and saturated brine (50mL*3) , dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to remove the solvent to obtain compound 10-3.
  • compound 11-1 (5g, 1eq) was dissolved in anhydrous tetrahydrofuran (100mL), and methyl 3-hydroxypropionate (4.70g, 1.5eq) was added, cooled to 0-5°C, and added in batches Sodium hydride (1.20g, 60% content, 1eq), the temperature was controlled at 0-10°C, and the addition was completed in 1 hour, and the reactant was stirred at 0-5°C for 0.5 hour.
  • compound 11-4a (0.5g, 1eq) was dissolved in concentrated hydrochloric acid (3mL) and glacial acetic acid (3mL), and the reactant was stirred at 40-60°C for 1 hour, cooled, and diluted with water (60mL) under stirring , a solid precipitated out, filtered under reduced pressure, collected the solid, dried in vacuo, and then separated and purified by preparative thin-layer chromatography (10% methanol/dichloromethane) to obtain compound 11a.
  • Fuming nitric acid (4.11g, 3eq) was added to concentrated sulfuric acid (20mL) at 0°C, followed by compound 12-2 (4.77g, 1eq), and the system was stirred at 0°C for 1 hour.
  • the reaction system was poured into ice water (200 mL) at 0°C, the system was stirred at 0°C for 0.5 hours, filtered, and the filter cake was collected and dried under reduced pressure to obtain compound 12-3.
  • Compound 12-5 was separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10 ⁇ m); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; B%: 30%-30%) to give compound 12-5a.
  • MS: m/z 506.2 [M+H] + .
  • trimethylsulfoxide iodide 49.2g, 1.5eq was dissolved in dimethylsulfoxide (500mL), sodium tert-butoxide (21.43g, 1.50eq) was added, and the mixture was heated at 20-25°C Stir for 2 hours.
  • Compound 14-2 (30.0 g, 1 eq) was added, and the reaction solution was stirred at 20-25° C. for 30 hours.
  • reaction solution was poured into saturated aqueous ammonium chloride solution (400mL), stirred, extracted with ethyl acetate (300mL*3), the organic layers were combined, washed with water (300mL*2), saturated aqueous sodium chloride solution (300mL*1) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness.
  • Compound 14-8 (4.1g, 1eq) was dissolved in a mixed solvent of isopropanol (50mL) and water (10mL), iron powder (4.40g, 5eq) and ammonium chloride (4.21g, 5eq) were added, and the reaction The mixture was stirred at 90-100°C for 10 hours.
  • Example 14a Concentrate below 35°C to remove tetrahydrofuran, cool the residue in an ice-water bath, adjust the pH value to 2-3 with 2N dilute hydrochloric acid while stirring, a solid precipitates, collect the solid by filtration under reduced pressure, rinse with water (10 mL), dry, add acetonitrile and water A mixed solvent (20 mL, 1:1) was shaken in an ultrasonic apparatus for 5 minutes, filtered, the solid was rinsed with a mixed solvent of acetonitrile and water (10 mL, 1:1), and the filter cake was dried in vacuum to obtain Example 14a.
  • reaction solution was concentrated under reduced pressure, diluted with water (12 mL), extracted with ethyl acetate (10 mL*2), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product.
  • reaction solution was quenched by adding 10 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (5 mL*2), combined the organic phases, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 17- 3.
  • reaction solution was quenched by adding 10 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (5 mL*2), combined the organic phases, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 17- 4.
  • reaction solution was quenched by adding 10 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (5 mL*2), combined the organic phases, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 17- 5.
  • Compound 18-2 (2.5g, 1.0eq), diboronic acid indachidol ester (2.50g, 1.2eq), potassium phosphate (5.00g, 2.9eq) and [1,1'-bis(diphenylphosphino ) ferrocene]palladium dichloride dichloromethane complex (375.00mg, 0.06eq) was added to 40mL of dioxane, replaced with nitrogen three times, heated to 110-120°C and stirred for 10 hours.
  • Compound 18-3 (0.5g, 1.0eq) and compound 18-4 (380.08mg, 1.5eq) were added to a mixed solvent of 10mL dioxane and 3mL water, and potassium carbonate (385.81mg, 2.0eq ) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (227.96mg, 0.2eq), stirred for 10 minutes, heated to 90°C and stirred for 1 hour.
  • reaction solution was adjusted to pH 5 with 4N dilute hydrochloric acid, diluted with 5 mL of water, extracted with ethyl acetate (4 mL*2), the ethyl acetate layer was washed with saturated aqueous sodium chloride solution (4 mL*2), dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated to obtain compound 21-5.
  • reaction solution was concentrated under reduced pressure, diluted with water (5 mL), extracted with ethyl acetate (4 mL*2), the organic phases were combined, washed with saturated aqueous sodium chloride solution (4 mL*2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure
  • the 0.6mM test compound was serially diluted 3 times and 10 points with ECHO, and 900nL was transferred to the compound plate.
  • Run the FLIPR instrument software add 10 ⁇ L of the test compound to the cell plate according to the set program, and read the fluorescence signal.
  • GraphPad Prism 5.0 software was used to calculate the IC 50 of the compound on the calcium flow inhibition of PGE2 receptor EP4, that is, the drug concentration when the Ca 2+ flow in cells stably expressing EP4 receptor was inhibited by half.
  • Table 1 The results of the in vitro enzyme activity screening test of the compounds of the present invention
  • the compound of the present invention has strong antagonistic activity to human EP4.
  • test compound was dissolved in a solvent of 5% DMSO/10% Solutol/85% water, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use.
  • Balb/c male mice weighing 17 to 25 grams were selected, and the solution of the candidate compound was administered intravenously or orally, at doses of 1 mg/kg or 2 mg/kg, respectively.
  • Whole blood was collected at a certain time point, and plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.3.
  • C max maximum drug concentration
  • T 1/2 half-life
  • V dss apparent volume of distribution
  • Cl drug clearance
  • AUC 0-last area under the time curve
  • F bioavailability
  • "--" Refers to untested or unavailable data.
  • test compound was dissolved in a solvent of 5% DMSO/10% Solutol/85% water, vortexed and sonicated, and a clear or nearly clear solution of corresponding concentration was prepared.
  • Male SD rats with a body weight of about 250 g were selected, and the candidate compound solution was administered intravenously or orally, at doses of 1 mg/kg or 10 mg/kg, respectively.
  • Whole blood was collected at a certain time point, and plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.3.
  • C max maximum drug concentration
  • T 1/2 half-life
  • V dss apparent volume of distribution
  • Cl drug clearance
  • AUC 0-last area under the time curve
  • F bioavailability
  • "--" Refers to untested or unavailable data.
  • mice Female BALB/c mice, 6-8 weeks old, weighing 19-22 grams; supplier: Shanghai Lingchang Biotechnology Co., Ltd.
  • Mouse colon cancer CT-26 cells were cultured in vitro under the conditions of McCoy's 5a medium plus 10% fetal bovine serum, 100 U/mL penicillin and 100 ⁇ g/mL streptomycin, at 37°C in a 5% CO 2 incubator. Routine digestion with trypsin-EDTA was performed twice a week for passaging. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
  • PO oral administration
  • IP intraperitoneal injection
  • BID twice a day
  • 20D 20 days
  • PG-D0, D7 mean administration once on day 0 and day 7 after the start of administration.
  • the compound was formulated as a 0.5 mg/mL solution in 5% DMSO/10% Solutol/85% water.
  • Oxaliplatin was formulated into a 0.75 mg/mL solution, and the vehicle was 5% glucose solution.
  • the experimental index is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameters were measured with vernier calipers three times a week.
  • the calculation formulas of tumor volume (V), relative tumor volume (relative tumor volume, RTV), tumor growth inhibition rate TGI (%) and relative tumor proliferation rate T/C (%) are as follows. ) or T/C (%) evaluation:
  • V 0.5a ⁇ b 2
  • a and b represent the long diameter and short diameter of the tumor respectively;
  • V 0 is the average tumor volume measured during group administration (i.e., day 0), and V t is the average tumor volume during a certain measurement;
  • TGI (%) [1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group)/(Average tumor volume at the end of treatment of vehicle control group-Average at the beginning of treatment of vehicle control group Tumor volume)] ⁇ 100%;
  • T/C (%) T RTV /C RTV ⁇ 100%
  • T RTV represents the RTV of the treatment group
  • C RTV represents the RTV of the vehicle control group
  • the data of T RTV and C RTV are taken on the same day.
  • Table 5 Evaluation results of the antitumor efficacy of the compounds of the present invention on the subcutaneous transplantation tumor model of mouse colon cancer CT-26 cells
  • the compound of the present invention exhibits a certain tumor growth inhibitory effect in monotherapy, and the combined therapy with oxaliplatin has a significantly better tumor inhibitory effect than the corresponding monotherapy.

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Abstract

The present invention relates to a benzospiroheterocyclic derivative of formula (II) and a pharmaceutically acceptable salt thereof.

Description

苯并螺杂环衍生物及其应用Benzospiro heterocyclic derivatives and their applications
本发明主张如下优先权：The present invention claims the following priority:
CN202110594877.8，申请日：2021年05月28日；CN202110594877.8, application date: May 28, 2021;
CN202110672952.8，申请日：2021年06月17日；CN202110672952.8, application date: June 17, 2021;
CN202210394271.4，申请日：2022年04月14日。CN202210394271.4, application date: April 14, 2022.
技术领域technical field
本发明涉及一类苯并螺杂环衍生物及其应用，具体涉及式(II)所示化合物或其药学上可接受的盐。The present invention relates to a class of benzospiro heterocyclic derivatives and applications thereof, in particular to compounds represented by formula (II) or pharmaceutically acceptable salts thereof.
背景技术Background technique
前列腺素E2(PGE2)广泛参与机体免疫调节。机体在炎症状态下产生高浓度的PGE2，引起炎症、水肿和疼痛。PGE2还参与各种生理和/或病理症状，如痛觉过敏、子宫收缩、消化道蠕动、抑制胃酸分泌、降低血压等。PGE2有4种受体(EP1、EP2、EP3、EP4)，其中EP4在PGE2介导的生物学效应中发挥着重要作用。研究表明PGE2/EP4与肿瘤的发生发展有密切关系。肿瘤组织会分泌较多的PGE2。PGE2与EP4结合，可以激活PKA，磷酸化转录因子CREB；PKA也可以通过抑制GSK3，上调WNT/β-catenin和NOTCH通路活性；EP4还可激活非经典的PI3K/Akt、ERK信号通路。上述信号通路的异常可以促进细胞的存活、增殖和转移，促进肿瘤的发生发展。此外，PGE2可以通过EP4受体促进免疫抑制性细胞分化，抑制免疫效应细胞的抗肿瘤作用，介导肿瘤微环境的免疫抑制作用。近年来，EP4选择性拮抗剂在肿瘤免疫治疗中的应用受到重视。研究证实，EP4选择性拮抗剂可以抑制单核细胞向免疫抑制性细胞分化，减少肿瘤组织中免疫抑制性的细胞，如髓源抑制性细胞(MDSCs)和M2型巨噬细胞，增加肿瘤组织中的抗肿瘤免疫细胞，如树突状细胞(DCs)、T细胞和M1型巨噬细胞，进而逆转肿瘤微环境免疫抑制。目前已有多个EP4选择性拮抗剂处于针对肿瘤、炎症、疼痛等疾病治疗的临床试验阶段。ONO-4578(专利：WO2016111347、CN107108480)是其中之一，目前正在开展单药或与PD1单抗联用于实体瘤治疗的临床I/II期试验。EP4选择性拮抗剂在肿瘤、炎症、疼痛等疾病的治疗方面有很大的应用前景和临床价值，因此，有必要开发结构新颖的EP4选择性拮抗剂用于上述疾病的治疗。Prostaglandin E2 (PGE2) is widely involved in immune regulation of the body. The body produces high concentrations of PGE2 in an inflammatory state, causing inflammation, edema and pain. PGE2 is also involved in various physiological and/or pathological symptoms, such as hyperalgesia, uterine contraction, digestive tract peristalsis, inhibition of gastric acid secretion, and lowering of blood pressure. PGE2 has four receptors (EP1, EP2, EP3, EP4), among which EP4 plays an important role in the biological effects mediated by PGE2. Studies have shown that PGE2/EP4 is closely related to the occurrence and development of tumors. Tumor tissue will secrete more PGE2. The combination of PGE2 and EP4 can activate PKA and phosphorylate the transcription factor CREB; PKA can also increase the activity of WNT/β-catenin and NOTCH pathways by inhibiting GSK3; EP4 can also activate non-canonical PI3K/Akt and ERK signaling pathways. The abnormality of the above signaling pathways can promote cell survival, proliferation and metastasis, and promote the occurrence and development of tumors. In addition, PGE2 can promote the differentiation of immunosuppressive cells through the EP4 receptor, inhibit the anti-tumor effect of immune effector cells, and mediate the immunosuppressive effect of the tumor microenvironment. In recent years, the application of EP4 selective antagonists in tumor immunotherapy has received attention. Studies have confirmed that EP4 selective antagonists can inhibit the differentiation of monocytes into immunosuppressive cells, reduce immunosuppressive cells in tumor tissues, such as myeloid-derived suppressor cells (MDSCs) and M2 macrophages, and increase tumor tissue Antitumor immune cells, such as dendritic cells (DCs), T cells, and M1 macrophages, reverse the immune suppression in the tumor microenvironment. Currently, several EP4 selective antagonists are in clinical trials for the treatment of tumors, inflammation, pain and other diseases. ONO-4578 (patent: WO2016111347, CN107108480) is one of them, and is currently conducting phase I/II clinical trials of single drug or in combination with PD1 monoclonal antibody for the treatment of solid tumors. EP4 selective antagonists have great application prospects and clinical value in the treatment of tumors, inflammation, pain and other diseases. Therefore, it is necessary to develop EP4 selective antagonists with novel structures for the treatment of the above diseases.
发明内容Contents of the invention
本发明提供了式(II)所示化合物或其药学上可接受的盐，The present invention provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022095009-appb-000001
Figure PCTCN2022095009-appb-000001
其中，in,
结构单元
Figure PCTCN2022095009-appb-000002
选自
Figure PCTCN2022095009-appb-000003
Structural units
Figure PCTCN2022095009-appb-000002
selected from
Figure PCTCN2022095009-appb-000003
或者，L 1选自5-6元杂芳基，R 1选自C 1-3卤代烷基、C 1-3烷硫基、
Figure PCTCN2022095009-appb-000004
所述5-6元杂芳基、C 1-3烷硫基、
Figure PCTCN2022095009-appb-000005
分别独立地任选被1、2或3个卤素取代； Or, L 1 is selected from 5-6 membered heteroaryl, R 1 is selected from C 1-3 haloalkyl, C 1-3 alkylthio,
Figure PCTCN2022095009-appb-000004
The 5-6 membered heteroaryl, C 1-3 alkylthio,
Figure PCTCN2022095009-appb-000005
each independently optionally substituted by 1, 2 or 3 halogens;
L 2选自C 1-5烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-，所述C 1-5烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-分别独立地任选被1、2或3个R e取代； L is selected from C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl- C 0-3 alkyl-, the C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3 -6 cycloalkyl-C 0-3 alkyl-are independently optionally substituted by 1, 2 or 3 R e ;
E 1选自-O-、-S-和-NR 6-； E 1 is selected from -O-, -S- and -NR 6 -;
R 2、R 4和R 6分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 2 , R 4 and R 6 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
R 3选自C 1-5烷基、C 5-10双环环烷基和5-10元双环杂环烷基，所述C 1-5烷基、C 5-10双环环烷基和5-10元双环杂环烷基分别独立地任选被1、2或3个R b取代； R 3 is selected from C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5-10 membered bicyclic heterocycloalkyl, the C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5- The 10-membered bicyclic heterocycloalkyl group is independently optionally substituted by 1, 2 or 3 R b ;
R 5选自C 1-5烷基、C 3-6环烷基和4-6元杂环烷基，所述C 1-5烷基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R c取代； R 5 is selected from C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl Cycloalkyl is independently optionally substituted by 1, 2 or 3 Rc ;
或者，R 4和R 5相连，使结构单元-N(R 4)-C(＝O)-R 5为4-6元杂环烷基，所述4-6元杂环烷基任选被1、2或3个R d取代； Alternatively, R 4 and R 5 are connected, so that the structural unit -N(R 4 )-C(=O)-R 5 is a 4-6 membered heterocycloalkyl group, and the 4-6 membered heterocycloalkyl group is optionally 1, 2 or 3 R d substitutions;
各R a和各R e分别独立地选自H、F、Cl、Br、I、OH和NH 2； each R a and each R e are independently selected from H, F, Cl, Br, I, OH and NH 2 ;
各R b、各R c和各R d分别独立地选自H、F、Cl、Br、I、OH、＝O、NH 2、-C 1-3烷基-OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代； Each R b , each R c and each R d is independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , -C 1-3 alkyl-OH and C 1-3 alkyl , the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
各R分别独立地选自H、F、Cl、Br和I；Each R is independently selected from H, F, Cl, Br and I;
n选自0、1和2；n is selected from 0, 1 and 2;
所述5-10元双环杂环烷基和5-6元杂芳基的“杂”分别独立地表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团；The "hetero" of the 5-10 membered bicyclic heterocycloalkyl and 5-6 membered heteroaryl independently represent 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and A heteroatom or heteroatom group of N;
所述4-6元杂环烷基的“杂”表示1、2或3个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团；The "hetero" of the 4-6 membered heterocycloalkyl means 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N;
条件是，当
Figure PCTCN2022095009-appb-000006
选自
Figure PCTCN2022095009-appb-000007
R 3选自C 1-5烷基，所述C 1-5烷基任选被1、2或3个R b取代时，L 2选自C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-，所述C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-分别独立地任选被1、2或3个R e取代。 The condition is that when
Figure PCTCN2022095009-appb-000006
selected from
Figure PCTCN2022095009-appb-000007
R 3 is selected from C 1-5 alkyl, and when said C 1-5 alkyl is optionally substituted by 1, 2 or 3 R b , L 2 is selected from C 1-3 alkoxy, C 1-3 alkane Amino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-, the C 1-3 alkoxy, C 1-3 alkylamino , C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl- are independently optionally substituted by 1, 2 or 3 R e .
在本发明的一些方案中，上述各R b、各R c和各R d分别独立地选自H、F、OH、＝O、NH 2、-CH 2OH和CH 3，所述-CH 2OH和CH 3任选被1、2或3个R取代，R及其他变量如本发明所定义。 In some solutions of the present invention, each of the above-mentioned R b , each R c and each R d is independently selected from H, F, OH, =O, NH 2 , -CH 2 OH and CH 3 , and the -CH 2 OH and CH3 are optionally substituted with 1, 2 or 3 R, R and other variables are as defined herein.
在本发明的一些方案中，上述各R b、各R c和各R d分别独立地选自H、F、OH、＝O、NH 2、CH 3、CF 3和-CH 2OH，其他变量如本发明所定义。 In some solutions of the present invention, each of the above-mentioned R b , each R c and each R d is independently selected from H, F, OH, =O, NH 2 , CH 3 , CF 3 and -CH 2 OH, and other variables as defined herein.
在本发明的一些方案中，上述R 2选自H、CH 3、CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3和CH(CH 3) 2任选被1、2或3个R a取代，R a及其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 2 is selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally replaced by 1 , 2 or 3 R a substitutions, R a and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 2选自H，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R 2 is selected from H, and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 3选自CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、螺[2，2]戊烷基、螺[2，3]己烷基、螺[3，3]庚烷基、双环[3.1.0]己烷基和双环[1.1.1]戊烷基，所述CH 3、CH 2CH 3、CH 2CH 2CH 3、CH(CH 3) 2、螺[2，2]戊烷基、螺[2，3]己烷基、螺[3，3]庚烷基、双环[3.1.0]己烷基和双环[1.1.1]戊烷基任选被1、2或3个R b取代，R b及其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 3 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH(CH 3 ) 2 , spiro[2,2]pentyl, spiro[2,3 ]hexyl, spiro[3,3]heptanyl, bicyclo[3.1.0]hexyl and bicyclo[1.1.1]pentanyl, the CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3. CH(CH 3 ) 2 , spiro[2,2]pentyl, spiro[2,3]hexyl, spiro[3,3]heptyl, bicyclo[3.1.0]hexyl and bicyclo [1.1.1] Pentyl is optionally substituted with 1, 2 or 3 Rb , Rb and other variables are as defined herein.
在本发明的一些方案中，上述R 3选自螺[2，2]戊烷基、螺[2，3]己烷基、螺[3，3]庚烷基、双环[3.1.0]己烷基和双环[1.1.1]戊烷基，所述螺[2，2]戊烷基、螺[2，3]己烷基、螺[3，3]庚烷基、双环[3.1.0]己烷基和双环[1.1.1]戊烷基任选被1、2或3个R b取代，R b及其他变量如本发明所定义。 In some schemes of the present invention, the above R 3 is selected from spiro[2,2]pentyl, spiro[2,3]hexyl, spiro[3,3]heptanyl, bicyclo[3.1.0]hexyl Alkyl and bicyclo[1.1.1]pentanyl, the spiro[2,2]pentanyl, spiro[2,3]hexyl, spiro[3,3]heptanyl, bicyclo[3.1.0 ]hexyl and bicyclo[1.1.1]pentanyl are optionally substituted with 1, 2 or 3 Rb , Rb and other variables are as defined herein.
在本发明的一些方案中，上述R 3选自
Figure PCTCN2022095009-appb-000008
其他变量如本发明所定义。 In some schemes of the present invention, above-mentioned R 3 is selected from
Figure PCTCN2022095009-appb-000008
Other variables are as defined herein.
在本发明的一些方案中，上述R 3选自
Figure PCTCN2022095009-appb-000009
Figure PCTCN2022095009-appb-000010
其他变量如本发明所定义。 In some schemes of the present invention, above-mentioned R 3 is selected from
Figure PCTCN2022095009-appb-000009
Figure PCTCN2022095009-appb-000010
Other variables are as defined herein.
在本发明的一些方案中，上述R 4选自H、CH 3、CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3和CH(CH 3) 2任选被1、2或3个R a取代，R a及其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 4 is selected from H, CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 , and the CH 3 , CH 2 CH 3 and CH(CH 3 ) 2 are optionally replaced by 1 , 2 or 3 R a substitutions, R a and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 4选自H，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R 4 is selected from H, and other variables are as defined in the present invention.
在本发明的一些方案中，上述R 5选自C 1-3烷基、叔丁基、环丙基、环丁基、环戊基、氧杂环丁基、氧 杂环戊基、氮杂环丁基、氮杂环戊基和吗啡啉基，所述C 1-3烷基、叔丁基、环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基、氮杂环戊基和吗啡啉基任选被1、2或3个R c取代，R c及其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned R is selected from C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolyl, azepine Cyclobutyl, azepanyl and morpholinyl, the C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolyl , azetidinyl, azetidinyl and morpholinyl are optionally substituted with 1, 2 or 3 Rc , Rc and other variables are as defined herein.
在本发明的一些方案中，上述R 5选自C 1-3烷基、叔丁基、环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基和氮杂环戊基，所述C 1-3烷基、叔丁基、环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基和氮杂环戊基任选被1、2或3个R c取代，R c及其他变量如本发明所定义。 In some schemes of the present invention, the above-mentioned R is selected from C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolyl, azepine Cyclobutyl and azacyclopentyl, the C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl, oxolyl, azacyclic Butyl and azacyclopentyl are optionally substituted with 1, 2 or 3 Rc , Rc and other variables are as defined herein.
在本发明的一些方案中，上述R 5选自-CH(CH 3) 2、-C(CH 3) 3和
Figure PCTCN2022095009-appb-000011
其他变量如本发明所定义。 In some aspects of the present invention, the above-mentioned R 5 is selected from -CH(CH 3 ) 2 , -C(CH 3 ) 3 and
Figure PCTCN2022095009-appb-000011
Other variables are as defined herein.
在本发明的一些方案中，上述R 4和R 5相连，使结构单元-N(R 4)-C(＝O)-R 5为
Figure PCTCN2022095009-appb-000012
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R 4 and R 5 are connected, so that the structural unit -N(R 4 )-C(=O)-R 5 is
Figure PCTCN2022095009-appb-000012
Other variables are as defined herein.
在本发明的一些方案中，上述R 1选自-C(＝O)-NH(R 3)、-NH-C(＝O)-R 5和
Figure PCTCN2022095009-appb-000013
In some aspects of the present invention, the above-mentioned R 1 is selected from -C(=O)-NH(R 3 ), -NH-C(=O)-R 5 and
Figure PCTCN2022095009-appb-000013
在本发明的一些方案中，上述结构单元-L 1-R 1选自
Figure PCTCN2022095009-appb-000014
Figure PCTCN2022095009-appb-000015
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units -L 1 -R 1 are selected from
Figure PCTCN2022095009-appb-000014
Figure PCTCN2022095009-appb-000015
Other variables are as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022095009-appb-000016
选自
Figure PCTCN2022095009-appb-000017
Figure PCTCN2022095009-appb-000018
Figure PCTCN2022095009-appb-000019
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022095009-appb-000016
selected from
Figure PCTCN2022095009-appb-000017
Figure PCTCN2022095009-appb-000018
Figure PCTCN2022095009-appb-000019
Other variables are as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022095009-appb-000020
选自
Figure PCTCN2022095009-appb-000021
Figure PCTCN2022095009-appb-000022
Figure PCTCN2022095009-appb-000023
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022095009-appb-000020
selected from
Figure PCTCN2022095009-appb-000021
Figure PCTCN2022095009-appb-000022
Figure PCTCN2022095009-appb-000023
Other variables are as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022095009-appb-000024
选自
Figure PCTCN2022095009-appb-000025
Figure PCTCN2022095009-appb-000026
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022095009-appb-000024
selected from
Figure PCTCN2022095009-appb-000025
Figure PCTCN2022095009-appb-000026
Other variables are as defined herein.
在本发明的一些方案中，上述R 1选自CF 3、SCH 3、
Figure PCTCN2022095009-appb-000027
L 1选自吡啶基、嘧啶基、吡嗪基、哒嗪基、吡唑基、咪唑基、吡咯基、三唑基、四唑基、噻唑基、噻吩基、异噻吩基、噁唑基和噁二唑基，所述吡啶基、嘧啶基、吡嗪基、哒嗪基、吡唑基、咪唑基、吡咯基、三唑基、四唑基、噻唑基、噻吩基、异噻吩基、噁唑基和噁二唑基任选被1、2或3个卤素取代，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned R 1 is selected from CF 3 , SCH 3 ,
Figure PCTCN2022095009-appb-000027
L is selected from pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, isothienyl, oxazolyl and Oxadiazolyl, the pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, pyrazolyl, imidazolyl, pyrrolyl, triazolyl, tetrazolyl, thiazolyl, thienyl, isothienyl, oxadiazolyl Azolyl and oxadiazolyl are optionally substituted with 1, 2 or 3 halogens, other variables being as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022095009-appb-000028
选自
Figure PCTCN2022095009-appb-000029
Figure PCTCN2022095009-appb-000030
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022095009-appb-000028
selected from
Figure PCTCN2022095009-appb-000029
Figure PCTCN2022095009-appb-000030
Other variables are as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022095009-appb-000031
选自
Figure PCTCN2022095009-appb-000032
Figure PCTCN2022095009-appb-000033
Figure PCTCN2022095009-appb-000034
Figure PCTCN2022095009-appb-000035
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022095009-appb-000031
selected from
Figure PCTCN2022095009-appb-000032
Figure PCTCN2022095009-appb-000033
Figure PCTCN2022095009-appb-000034
Figure PCTCN2022095009-appb-000035
Other variables are as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022095009-appb-000036
选自
Figure PCTCN2022095009-appb-000037
Figure PCTCN2022095009-appb-000038
Figure PCTCN2022095009-appb-000039
其他变量如本发明所定义。在本发明的一些方案中，上述L 2选自丙基、丁基、1，1-二甲基丙基、2，2-二甲基丙基、
Figure PCTCN2022095009-appb-000040
Figure PCTCN2022095009-appb-000041
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022095009-appb-000036
selected from
Figure PCTCN2022095009-appb-000037
Figure PCTCN2022095009-appb-000038
Figure PCTCN2022095009-appb-000039
Other variables are as defined herein. In some schemes of the present invention, the above-mentioned L is selected from propyl, butyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,
Figure PCTCN2022095009-appb-000040
Figure PCTCN2022095009-appb-000041
Other variables are as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022095009-appb-000042
选自
Figure PCTCN2022095009-appb-000043
R 3选自CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2分别独立地任选被1、2或3个R b取代，此时，L 2选自
Figure PCTCN2022095009-appb-000044
Figure PCTCN2022095009-appb-000045
R b及其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022095009-appb-000042
selected from
Figure PCTCN2022095009-appb-000043
R 3 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , wherein CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are respectively independently optionally substituted by 1, 2 or 3 R b , at this time, L is selected from
Figure PCTCN2022095009-appb-000044
Figure PCTCN2022095009-appb-000045
R b and other variables are as defined herein.
在本发明的一些方案中，上述结构单元
Figure PCTCN2022095009-appb-000046
选自
Figure PCTCN2022095009-appb-000047
此时，-L 2-COOH选自
Figure PCTCN2022095009-appb-000048
Figure PCTCN2022095009-appb-000049
其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned structural units
Figure PCTCN2022095009-appb-000046
selected from
Figure PCTCN2022095009-appb-000047
At this point, -L 2 -COOH is selected from
Figure PCTCN2022095009-appb-000048
Figure PCTCN2022095009-appb-000049
Other variables are as defined herein.
在本发明的一些方案中，上述E 1选自-O-，其他变量如本发明所定义。 In some solutions of the present invention, the above-mentioned E 1 is selected from -O-, and other variables are as defined in the present invention.
在本发明的一些方案中，上述n选自0，其他变量如本发明所定义。In some solutions of the present invention, the above n is selected from 0, and other variables are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
Figure PCTCN2022095009-appb-000050
Figure PCTCN2022095009-appb-000050
其中，R 1、L 1和E 1如本发明所定义。 Wherein, R 1 , L 1 and E 1 are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
Figure PCTCN2022095009-appb-000051
Figure PCTCN2022095009-appb-000051
其中，in,
R 3选自C 5-10环烷基和5-10元杂环烷基，所述C 5-10环烷基和5-10元杂环烷基分别独立地任选被1、2或3个R b取代，且所述C 5-10环烷基和5-10元杂环烷基为双环； R is selected from C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl, said C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl are independently optionally replaced by 1, 2 or 3 R b is substituted, and the C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl are bicyclic;
R 2、R 4和R 5如本发明所定义。 R 2 , R 4 and R 5 are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
Figure PCTCN2022095009-appb-000052
Figure PCTCN2022095009-appb-000052
其中，R 2、R 3、R 4和R 5如本发明所定义。 Wherein, R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
Figure PCTCN2022095009-appb-000053
Figure PCTCN2022095009-appb-000053
其中，in,
环A选自5-6元杂芳基；Ring A is selected from 5-6 membered heteroaryls;
R 1选自C 1-3卤代烷基、C 1-3烷硫基、
Figure PCTCN2022095009-appb-000054
R 1 is selected from C 1-3 haloalkyl, C 1-3 alkylthio,
Figure PCTCN2022095009-appb-000054
R 2、R 3、R 4和R 5如本发明所定义。 R 2 , R 3 , R 4 and R 5 are as defined in the present invention.
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
Figure PCTCN2022095009-appb-000055
Figure PCTCN2022095009-appb-000055
其中，in,
R 2选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 2 is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
R 3选自C 1-5烷基，所述C 1-5烷基任选被1、2或3个R b取代； R 3 is selected from C 1-5 alkyl, said C 1-5 alkyl is optionally substituted by 1, 2 or 3 R b ;
L 2选自C 1-5杂烷基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-，所述C 1-5杂烷基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-分别独立地任选被1、2或3个R e取代； L 2 is selected from C 1-5 heteroalkyl and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-, the C 1-5 heteroalkyl and -C 0- 3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-are independently optionally substituted by 1, 2 or 3 R e ;
各R a、各R b和各R e如本发明所定义。 Each R a , each R b and each Re is as defined herein.
本发明还提供了式(I)化合物或其药学上可接受的盐，The present invention also provides a compound of formula (I) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022095009-appb-000056
Figure PCTCN2022095009-appb-000056
其中，in,
当L 1选自单键时，R 1选自-C(＝O)-NR 2R 3； When L 1 is selected from single bonds, R 1 is selected from -C(=O)-NR 2 R 3 ;
当L 1选自-CH 2-时，R 1选自-N(R 4)-C(＝O)-R 5； When L 1 is selected from -CH 2 -, R 1 is selected from -N(R 4 )-C(=O)-R 5 ;
E 1选自-O-、-S-和-NR 6-； E 1 is selected from -O-, -S- and -NR 6 -;
R 2、R 4和R 6分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 2 , R 4 and R 6 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
R 3选自C 5-10环烷基和5-10元杂环烷基，所述C 5-10环烷基和5-10元杂环烷基为双环，任选被1、2或3个 R b取代； R 3 is selected from C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl, said C 5-10 cycloalkyl and 5-10 membered heterocycloalkyl are bicyclic, optionally surrounded by 1, 2 or 3 R b replaces;
R 5选自C 1-5烷基、C 3-6环烷基和4-6元杂环烷基，所述C 1-5烷基、C 3-6环烷基和4-6元杂环烷基任选被1、2或3个R c取代； R 5 is selected from C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl Cycloalkyl is optionally substituted by 1, 2 or 3 R ;
或者，R 4和R 5相连，使结构单元-N(R 4)-C(＝O)-R 5为4-6元杂环烷基，所述4-6元杂环烷基任选被1、2或3个R d取代； Alternatively, R 4 and R 5 are connected, so that the structural unit -N(R 4 )-C(=O)-R 5 is a 4-6 membered heterocycloalkyl group, and the 4-6 membered heterocycloalkyl group is optionally 1, 2 or 3 R d substitutions;
各R a分别独立地选自H、F、Cl、Br、I、OH和NH 2； Each R a is independently selected from H, F, Cl, Br, I, OH and NH 2 ;
各R b、R c和R d分别独立地选自H、F、C1、Br、I、OH、＝O、NH 2、-C 1-3烷基-OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代； Each R b , R c and R d are independently selected from H, F, C1, Br, I, OH, =O, NH 2 , -C 1-3 alkyl-OH and C 1-3 alkyl, so The C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
各R分别独立地选自H、F、Cl、Br和I；Each R is independently selected from H, F, Cl, Br and I;
所述“5-10元杂环烷基”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；The "5-10 membered heterocycloalkyl" contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N;
所述“4-6元杂环烷基”包含1、2或3个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团。The "4-6 membered heterocycloalkyl" contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N.
本发明还提供了式(II)所示化合物或其药学上可接受的盐，The present invention also provides a compound represented by formula (II) or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022095009-appb-000057
Figure PCTCN2022095009-appb-000057
其中，in,
结构单元
Figure PCTCN2022095009-appb-000058
选自
Figure PCTCN2022095009-appb-000059
Structural units
Figure PCTCN2022095009-appb-000058
selected from
Figure PCTCN2022095009-appb-000059
L 2选自C 1-5烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-，所述C 1-5烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-分别独立地任选被1、2或3个R e取代； L is selected from C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl- C 0-3 alkyl-, the C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3 -6 cycloalkyl-C 0-3 alkyl-are independently optionally substituted by 1, 2 or 3 R e ;
E 1选自-O-、-S-和-NR 6-； E 1 is selected from -O-, -S- and -NR 6 -;
R 2、R 4和R 6分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 2 , R 4 and R 6 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
R 3选自C 1-5烷基、C 5-10双环环烷基和5-10元双环杂环烷基，所述C 1-5烷基、C 5-10双环环烷基和5-10元双环杂环烷基分别独立地任选被1、2或3个R b取代； R 3 is selected from C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5-10 membered bicyclic heterocycloalkyl, the C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5- The 10-membered bicyclic heterocycloalkyl group is independently optionally substituted by 1, 2 or 3 R b ;
R 5选自C 1-5烷基、C 3-6环烷基和4-6元杂环烷基，所述C 1-5烷基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R c取代； R 5 is selected from C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl Cycloalkyl is independently optionally substituted by 1, 2 or 3 Rc ;
或者，R 4和R 5相连，使结构单元-N(R 4)-C(＝O)-R 5为4-6元杂环烷基，所述4-6元杂环烷基任选被1、2或3个R d取代； Alternatively, R 4 and R 5 are connected, so that the structural unit -N(R 4 )-C(=O)-R 5 is a 4-6 membered heterocycloalkyl group, and the 4-6 membered heterocycloalkyl group is optionally 1, 2 or 3 R d substitutions;
各R a和各R e分别独立地选自H、F、Cl、Br、I、OH和NH 2； each R a and each R e are independently selected from H, F, Cl, Br, I, OH and NH 2 ;
各R b、各R c和各R d分别独立地选自H、F、Cl、Br、I、OH、＝O、NH 2、-C 1-3烷基-OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代； Each R b , each R c and each R d is independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , -C 1-3 alkyl-OH and C 1-3 alkyl , the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
各R分别独立地选自H、F、Cl、Br和I；Each R is independently selected from H, F, Cl, Br and I;
n选自0、1和2；n is selected from 0, 1 and 2;
所述5-10元双环杂环烷基包含1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团；The 5-10 membered bicyclic heterocycloalkyl group contains 1, 2, 3 or 4 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N;
所述4-6元杂环烷基包含1、2或3个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团；The 4-6 membered heterocycloalkyl group contains 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N;
条件是，当
Figure PCTCN2022095009-appb-000060
选自
Figure PCTCN2022095009-appb-000061
R 3选自C 1-5烷基，所述C 1-5烷基任选被1、2或3个R b取代时，L 2选自C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-，所述C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-分别独立地任选被1、2或3个R e取代。 The condition is that when
Figure PCTCN2022095009-appb-000060
selected from
Figure PCTCN2022095009-appb-000061
R 3 is selected from C 1-5 alkyl, and when said C 1-5 alkyl is optionally substituted by 1, 2 or 3 R b , L 2 is selected from C 1-3 alkoxy, C 1-3 alkane Amino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-, the C 1-3 alkoxy, C 1-3 alkylamino , C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl- are independently optionally substituted by 1, 2 or 3 R e .
本发明还有一些方案是由上述各变量任意组合而来。Some schemes of the present invention are formed by any combination of the above-mentioned variables.
本发明提供了下式化合物或其药学上可接受的盐，The present invention provides a compound of the following formula or a pharmaceutically acceptable salt thereof,
Figure PCTCN2022095009-appb-000062
Figure PCTCN2022095009-appb-000062
Figure PCTCN2022095009-appb-000063
Figure PCTCN2022095009-appb-000063
在本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自，In some aspects of the present invention, the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from,
Figure PCTCN2022095009-appb-000064
Figure PCTCN2022095009-appb-000064
Figure PCTCN2022095009-appb-000065
Figure PCTCN2022095009-appb-000065
Figure PCTCN2022095009-appb-000066
Figure PCTCN2022095009-appb-000066
Figure PCTCN2022095009-appb-000067
Figure PCTCN2022095009-appb-000067
Figure PCTCN2022095009-appb-000068
Figure PCTCN2022095009-appb-000068
技术效果technical effect
本发明化合物对人源EP4有较强的拮抗活性，具有良好的药代动力学性质，且单药治疗时展现了一定的肿瘤抑制效果，和奥沙利铂联合治疗时具有显著优于对应单药治疗的肿瘤抑制效果。The compound of the present invention has strong antagonistic activity to human source EP4, has good pharmacokinetic properties, and exhibits a certain tumor inhibitory effect when monotherapy, and has significantly better than corresponding monotherapy when combined with oxaliplatin. Tumor suppressive effect of drug therapy.
定义和说明Definition and Description
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。Unless otherwise stated, the following terms and phrases used herein are intended to have the following meanings. A specific term or phrase should not be considered indeterminate or unclear if it is not specifically defined, but should be understood according to its ordinary meaning. When a trade name appears herein, it is intended to refer to its corresponding trade name or its active ingredient. The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。The term "pharmaceutically acceptable salt" refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. When compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either 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 functionalities, acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent. Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; also salts of amino acids such as arginine and the like , and salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups and can thus 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 parent compound containing acid groups or bases by conventional chemical methods. In general, such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
除了盐的形式，本发明所提供的化合物还存在前药形式。本文所描述的化合物的前药容易地在生理条件下发生化学变化从而转化成本发明的化合物。此外，前体药物可以在体内环境中通过化学或生化方法被转换到本发明的化合物。In addition to salt forms, the compounds provided herein also exist in prodrug forms. Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them to the compounds of the present invention. In addition, prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.
本发明的某些化合物可以以非溶剂化形式或者溶剂化形式存在，包括水合物形式。一般而言，溶剂化形式与非溶剂化的形式相当，都包含在本发明的范围之内。Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the invention may exist in particular 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 their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention. Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise stated, the terms "enantiomer" or "optical isomer" refer to stereoisomers that are mirror images of each other.
除非另有说明，术语“顺反异构体”或者“几何异构体”系由因双键或者成环碳原子单键不能自由旋转而引起。Unless otherwise stated, the terms "cis-trans isomers" or "geometric isomers" arise from the inability to rotate freely due to the double bond or the single bond of the carbon atoms forming the ring.
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 "diastereoisomer" refers to stereoisomers whose molecules have two or more chiral centers and which are not mirror images of the molecules.
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。Unless otherwise stated, "(D)" or "(+)" means dextrorotation, "(L)" or "(-)" means levorotation, and "(DL)" or "(±)" means racemization.
除非另有说明，用楔形实线键
Figure PCTCN2022095009-appb-000069
和楔形虚线键
Figure PCTCN2022095009-appb-000070
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2022095009-appb-000071
和直形虚线键
Figure PCTCN2022095009-appb-000072
表示立体中心的相对构型，用波浪线
Figure PCTCN2022095009-appb-000073
表示楔形实线键
Figure PCTCN2022095009-appb-000074
或楔形虚线键
Figure PCTCN2022095009-appb-000075
或用波浪线
Figure PCTCN2022095009-appb-000076
表示直形实线键
Figure PCTCN2022095009-appb-000077
和直形虚线键
Figure PCTCN2022095009-appb-000078
Unless otherwise noted, keys with wedge-shaped solid lines
Figure PCTCN2022095009-appb-000069
and dotted wedge keys
Figure PCTCN2022095009-appb-000070
Indicates the absolute configuration of a stereocenter, with a straight solid-line bond
Figure PCTCN2022095009-appb-000071
and straight dashed keys
Figure PCTCN2022095009-appb-000072
Indicates the relative configuration of the stereocenter, with a wavy line
Figure PCTCN2022095009-appb-000073
Indicates wedge-shaped solid-line bond
Figure PCTCN2022095009-appb-000074
or dotted wedge key
Figure PCTCN2022095009-appb-000075
or with tilde
Figure PCTCN2022095009-appb-000076
Indicates a straight solid line key
Figure PCTCN2022095009-appb-000077
and straight dashed keys
Figure PCTCN2022095009-appb-000078
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。Compounds of the invention may exist specific. Unless otherwise stated, the term "tautomer" or "tautomeric form" means that isomers with different functional groups are in dynamic equilibrium at room temperature and are rapidly interconvertible. If tautomerism is possible (eg, in solution), then chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via migration of a proton, such as keto-enol isomerization and imine-ene Amine isomerization. Valence isomers (valence tautomers) involve interconversions by recombination of some bonding electrons. A specific example of keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise stated, the terms "enriched in an isomer", "enriched in an isomer", "enriched in an enantiomer" or "enantiomerically enriched" refer to one of the isomers or enantiomers The content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or Greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体 过量(ee值)为80％。Unless otherwise stated, the terms "isomer excess" or "enantiomeric excess" refer to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the other isomer or enantiomer is 10%, then the isomer or enantiomeric excess (ee value) is 80% .
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。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。“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。 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 invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture 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 diastereoisomeric salt is formed with an appropriate optically active acid or base, and then a diastereomeric salt is formed by a conventional method known in the art. Diastereomeric resolution is performed and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. 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 compounds. For example, compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). For another example, heavy hydrogen can be used to replace hydrogen to form deuterated drugs. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with 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 changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention. "Optional" or "optionally" means that the subsequently described event or circumstance can but need not occur, and that the description includes instances where said event or circumstance occurs and instances where 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 a substituent is oxygen (ie =0), it means that two hydrogen atoms are replaced. 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 realizable 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 is independent at each occurrence. Thus, for example, if a group is substituted with 0-2 R, said group may optionally be substituted with up to two R, with independent options for each occurrence of R. Also, combinations of substituents and/or variations 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 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 enumerated substituent does not indicate which atom it is connected to the substituted group, this substituent can be bonded through any atom, for example, pyridyl as a substituent can be connected to any atom on the pyridine ring. The carbon atom is attached to the group being substituted.
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 PCTCN2022095009-appb-000079
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 PCTCN2022095009-appb-000080
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 PCTCN2022095009-appb-000081
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 linking group listed does not indicate its linking direction, its linking direction is arbitrary, for example,
Figure PCTCN2022095009-appb-000079
The connecting 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 to form
Figure PCTCN2022095009-appb-000080
It can also be formed by connecting loop A and loop B in the opposite direction to the reading order from left to right
Figure PCTCN2022095009-appb-000081
Combinations of the described linking groups, substituents and/or variations 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 PCTCN2022095009-appb-000082
直形虚线键
Figure PCTCN2022095009-appb-000083
或波浪线
Figure PCTCN2022095009-appb-000084
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 PCTCN2022095009-appb-000085
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 PCTCN2022095009-appb-000086
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 PCTCN2022095009-appb-000087
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 PCTCN2022095009-appb-000088
Figure PCTCN2022095009-appb-000089
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2022095009-appb-000090
仍包括
Figure PCTCN2022095009-appb-000091
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 linkable sites, any one or more sites of the group can be linked to other groups through chemical bonds. When the connection method of the chemical bond is not positioned, and there is an H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will decrease correspondingly with the number of chemical bonds connected to become the corresponding valence group. The chemical bonds that the site connects with other groups can use straight solid line bonds
Figure PCTCN2022095009-appb-000082
Straight dotted key
Figure PCTCN2022095009-appb-000083
or tilde
Figure PCTCN2022095009-appb-000084
express. For example, the straight-shaped solid-line bond in -OCH3 indicates that it is connected to other groups through the oxygen atom in the group;
Figure PCTCN2022095009-appb-000085
The straight dotted line bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
Figure PCTCN2022095009-appb-000086
The wavy lines in indicate that the 1 and 2 carbon atoms in the phenyl group are connected to other groups;
Figure PCTCN2022095009-appb-000087
Indicates that any connectable site on the piperidinyl group can be connected to other groups through a chemical bond, including at least
Figure PCTCN2022095009-appb-000088
Figure PCTCN2022095009-appb-000089
These 4 connection methods, even if the H atom is drawn on -N-, but
Figure PCTCN2022095009-appb-000090
still include
Figure PCTCN2022095009-appb-000091
For groups with this connection method, only when a chemical bond is connected, the H at this site will be reduced by one to become the corresponding monovalent piperidinyl group.
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；C 0-3包括C 0、C 1、C 2和C 3，也包括n至n+m中的任何一个范围，其中C 0表示该基团不存在；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环和6-10元环等。 Unless otherwise specified, C n-n+m or C n -C n+m includes any specific instance of n to n+m carbons, for example C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 and C 12 , also including any range from n to n+m, for example, C 1-12 includes C 1-3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 and C 9-12 etc.; C 0-3 includes C 0 , C 1. C 2 and C 3 also include any range from n to n+m, where C 0 means that the group does not exist; similarly, n-membered to n+m-membered means that the number of atoms on the ring is from n to n +m, for example, 3-12-membered rings include 3-membered rings, 4-membered rings, 5-membered rings, 6-membered rings, 7-membered rings, 8-membered rings, 9-membered rings, 10-membered rings, 11-membered rings and 12-membered rings , also includes any range from n to n+m, for example, 3-12-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring, 5-7-membered ring, 6-7-membered ring , 6-8 membered ring and 6-10 membered ring, etc.
除非另有规定，术语“C 1-5烷基”本身或者与其他术语联合，用于表示直链或支链的由1至5个碳原子 组成的饱和碳氢基团。所述C 1-5烷基包括C 1-4、C 1-3、C 1-2、C 2-5、C 2-4和C 5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 1-5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)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)等。 Unless otherwise specified, the term "C 1-5 alkyl" by itself or in combination with other terms is used to indicate a linear or branched saturated hydrocarbon group consisting of 1 to 5 carbon atoms. The C 1-5 alkyl group includes C 1-4 , C 1-3 , C 1-2 , C 2-5 , C 2-4 and C 5 alkyl, etc.; it can be monovalent (such as methyl) , bivalent (such as methylene) or multivalent (such as methine). Examples of C 1-5 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , s-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl) and so on.
除非另有规定，术语“C 1-3烷基”本身或者与其他术语联合，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" by itself or in combination with other terms is used to indicate a linear or branched saturated hydrocarbon group consisting of 1 to 3 carbon atoms. The C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) . Examples of C 1-3 alkyl 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 0-3烷基”本身或者与其他术语联合，用于表示该基团不存在，或者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 0-3烷基包括C 0(即该基团不存在)，还包括C 1-3、C 1-2、C 2-3、C 1、C 2和C 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 0- 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 0-3 alkyl" by itself or in combination with other terms is used to indicate the absence of such a group, or to indicate a straight or branched chain of saturated hydrocarbons consisting of 1 to 3 carbon atoms group. The C 0-3 alkyl group includes C 0 (that is, the group does not exist), and also includes C 1-3 , C 1-2 , C 2-3 , C 1 , C 2 and C 3 alkyl groups, etc.; It can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine). Examples of C 0-3 alkyl 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卤代烷基”本身或者与其他术语联合，用于表示包含1至3个碳原子的单卤代烷基和多卤代烷基。所述C 1-3卤代烷基包括C 1-2、C 2-3、C 3、C 2和C 1卤代烷基等。C 1-3卤代烷基的实例包括但不限于三氟甲基、三氯甲基、2，2，2-三氟乙基、五氟乙基、五氯乙基、3-溴丙基等。 Unless otherwise specified, the term "C 1-3 haloalkyl" is used by itself or in combination with other terms to denote monohaloalkyl and polyhaloalkyl groups containing 1 to 3 carbon atoms. The C 1-3 haloalkyl includes C 1-2 , C 2-3 , C 3 , C 2 and C 1 haloalkyl and the like. Examples of C 1-3 haloalkyl include, but are not limited to, trifluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, pentafluoroethyl, pentachloroethyl, 3-bromopropyl and the like.
除非另有规定，术语“C 1-3烷氧基”本身或者与其他术语联合，用于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。其可以是一价(如-OCH 3)、二价(如-OCH 2-)或者多价。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 " C1-3 alkoxy" is used by itself or in combination with other terms to denote those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an oxygen atom. It can be monovalent (eg -OCH3 ), divalent (eg -OCH2- ) or multivalent. The C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like. Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
除非另有规定，术语“C 1-3烷氨基”本身或者与其他术语联合，用于表示通过氨基连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。其可以是一价(如-NHCH 3)、二价(如-NHCH 2-)或者多价。所述C 1-3烷氨基包括C 1-2、C 2-3、C 3和C 2烷氨基等。C 1-3烷氨基的实例包括但不限于-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 3)CH 2CH 3、-NHCH 2CH 2CH 3、-NHCH 2(CH 3) 2等。 Unless otherwise specified, the term "C 1-3 alkylamino" is used by itself or in combination with other terms to denote those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through an amino group. It can be monovalent (eg -NHCH3 ), divalent (eg -NHCH2- ) or multivalent. The C 1-3 alkylamino group includes C 1-2 , C 2-3 , C 3 and C 2 alkylamino groups and the like. Examples of C 1-3 alkylamino include, but are not limited to, -NHCH 3 , -N(CH 3 ) 2 , -NHCH 2 CH 3 , -N(CH 3 )CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 3 , - NHCH 2 (CH 3 ) 2 etc.
除非另有规定，术语“C 1-3烷硫基”本身或者与其他术语联合，用于表示通过硫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。其可以是一价(如-SCH 3)、二价(如-SCH 2-)或者多价。所述C 1-3烷硫基包括C 1-2、C 2-3、C 3和C 2烷硫基等。C 1-3烷硫基的实例包括但不限于-SCH 3、-SCH 2CH 3、-SCH 2CH 2CH 3、-SCH 2(CH 3) 2等等。 Unless otherwise specified, the term "C 1-3 alkylthio" is used by itself or in combination with other terms to denote those alkyl groups containing 1 to 3 carbon atoms attached to the rest of the molecule through a sulfur atom. It can be monovalent (eg -SCH3 ), divalent (eg -SCH2- ) or multivalent. The C 1-3 alkylthio group includes C 1-2 , C 2-3 , C 3 and C 2 alkylthio groups and the like. Examples of C 1-3 alkylthio include, but are not limited to, -SCH 3 , -SCH 2 CH 3 , -SCH 2 CH 2 CH 3 , -SCH 2 (CH 3 ) 2 and the like.
除非另有规定，“C 3-6环烷基”本身或者与其他术语联合，用于表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。 Unless otherwise specified, "C 3-6 cycloalkyl" by itself or in combination with other terms is used to indicate a saturated cyclic hydrocarbon group composed of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system, so The C 3-6 cycloalkyl group includes C 3-5 , C 4-5 and C 5-6 cycloalkyl groups; it may be monovalent, divalent or multivalent. Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
除非另有规定，“C 5-10环烷基”本身或者与其他术语联合，用于表示由5至10个碳原子组成的饱和环状碳氢基团，其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。所述C 5-10环烷基包括C 5-6、C 5-8、C 5-10、C 6-8、C 6-10或C 8-10等；其可以是一价、二价或者多价。C 5-10环烷基的实例包括，但不限于，环戊基、环己基、环庚基、螺[2，2]戊烷基、降冰片烷基、[2.2.2]二环辛烷等。 Unless otherwise specified, "C 5-10 cycloalkyl" by itself or in combination with other terms is used to indicate a saturated cyclic hydrocarbon group consisting of 5 to 10 carbon atoms, including monocyclic, bicyclic and tricyclic systems, wherein bicyclic and tricyclic systems include spiro, fused and bridged rings. The C 5-10 cycloalkyl group includes C 5-6 , C 5-8 , C 5-10 , C 6-8 , C 6-10 or C 8-10 etc.; it can be monovalent, divalent or polyvalent. Examples of C 5-10 cycloalkyl groups include, but are not limited to, cyclopentyl, cyclohexyl, cycloheptyl, spiro[2,2]pentyl, norbornyl, [2.2.2]bicyclooctane Wait.
除非另有规定，“C 5-10双环环烷基”本身或者与其他术语联合，用于表示由5至10个碳原子组成的饱和环状碳氢基团，其为双环体系，包括螺环、并环和桥环。所述双环C 5-10双环环烷基包括C 5-6、C 5-8、C 5- 10、C 6-8、C 6-10或C 8-10等；其可以是一价、二价或者多价。C 5-10双环环烷基的实例包括，但不限于，螺[2，2]戊烷基、降冰片烷基、[2.2.2]二环辛烷等。 Unless otherwise specified, "C 5-10 bicyclic cycloalkyl" by itself or in combination with other terms is used to indicate a saturated cyclic hydrocarbon group consisting of 5 to 10 carbon atoms, which is a bicyclic ring system, including spiro rings , parallel rings and bridge rings. The bicyclic C 5-10 bicyclic cycloalkyl group includes C 5-6 , C 5-8 , C 5- 10 , C 6-8 , C 6-10 or C 8-10 etc.; it can be monovalent, divalent price or multiple. Examples of C 5-10 bicyclic cycloalkyl include, but are not limited to, spiro[2,2]pentanyl, norbornyl, [2.2.2]bicyclooctane and the like.
除非另有规定，术语“5-10元杂环烷基”本身或者与其他术语联合分别表示由5至10个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环、双环和三环体系，其中双环和三环体系包括螺环、并环和桥环。此外，就该“5-10元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述5-10元杂环烷基包括5-6元、5-8元、5-10元、6-8元、6-10元、8-10元、6元、8元和10元杂环烷基等。5-10元杂环烷基的实例包括但不限于吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1，2-噁嗪基、1，2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基等。 Unless otherwise specified, the term "5-10 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 ring atoms, respectively, whose 1, 2, 3 or 4 ring atoms is a heteroatom independently selected from O, S, and N, and the remainder is carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It includes monocyclic, bicyclic and tricyclic ring systems, wherein bicyclic and tricyclic ring systems include spiro, merged and bridged rings. In addition, as for the "5-10 membered heterocycloalkyl group", a heteroatom may occupy the attachment position of the heterocycloalkyl group to the rest of the molecule. The 5-10 membered heterocycloalkyl group includes 5-6, 5-8, 5-10, 6-8, 6-10, 8-10, 6, 8 and 10 Cycloalkyl etc. Examples of 5-10 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.) , tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1 -piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazole Alkyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, etc.
除非另有规定，术语“5-10元双环杂环烷基”本身或者与其他术语联合分别表示由5至10个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其为双环体系，包括螺环、并环和桥环。此外，就该“5-10元双环杂环烷基”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5-10元双环杂环烷基包括5-6元、5-8元、5-10元、6-8元、6-10元、8-10元、6元、8元和10元双环杂环烷基等。5-10元双环杂环烷基的实例包括但不限于
Figure PCTCN2022095009-appb-000092
Figure PCTCN2022095009-appb-000093
等。 Unless otherwise specified, the term "5-10 membered bicyclic heterocycloalkyl" by itself or in combination with other terms denotes a saturated cyclic group consisting of 5 to 10 ring atoms, whose 1, 2, 3 or 4 ring Atoms are heteroatoms independently selected from O, S, and N, and the remainder are carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). It is a bicyclic ring system including spiro, fused and bridged rings. In addition, as for the "5-10 membered bicyclic heterocycloalkyl", a heteroatom may occupy the linking position of the heterocycloalkyl to the rest of the molecule. The 5-10 membered bicyclic heterocycloalkyl group includes 5-6, 5-8, 5-10, 6-8, 6-10, 8-10, 6, 8 and 10 Bicyclic heterocycloalkyl, etc. Examples of 5-10 membered bicyclic heterocycloalkyl include, but are not limited to
Figure PCTCN2022095009-appb-000092
Figure PCTCN2022095009-appb-000093
Wait.
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单环基团，其1、2或3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)。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4-5元、4元、5元、6元等杂环烷基。4-6元杂环烷基的实例包括但不限于氧杂环丁基、氮杂环丁基、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、六氢哒嗪基等。 Unless otherwise specified, the term "4-6 membered heterocycloalkyl" by itself or in combination with other terms denotes a saturated monocyclic group consisting of 4 to 6 ring atoms, 1, 2 or 3 of which are independently Heteroatoms selected from O, S, and N, the remainder being carbon atoms, wherein the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , where p is 1 or 2). With respect to the "4-6 membered heterocycloalkyl", a heteroatom may occupy the attachment position of the heterocycloalkyl to the rest of the molecule. The 4-6 membered heterocycloalkyl group includes 4-5 membered, 4-membered, 5-membered, 6-membered and other heterocycloalkyl groups. Examples of 4-6 membered heterocycloalkyl groups include, but are not limited to, oxetanyl, azetidinyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophene (including tetrahydrothiophene-2 -yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3- piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxane, dioxane Thianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, 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" in the present invention can be used interchangeably, and the term "5-6-membered heteroaryl" means that there are 5 to 6 ring atoms A monocyclic group with a conjugated π-electron system, 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 , where p is 1 or 2). The 5-6 membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5 and 6 membered heteroaryl. Examples of the 5-6 membered heteroaryl groups include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl 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 pyrimidyl (including 2-pyrimidyl and 4-pyrimidyl, etc.).
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2022095009-appb-000094
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 compounds of the present invention can be confirmed by conventional methods known to those skilled in the art. If the present invention involves the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art. For example, in single crystal X-ray diffraction (SXRD), the cultured single crystal is collected with a Bruker D8 venture diffractometer to collect diffraction intensity data, the light source is CuKα radiation, and the scanning method is:
Figure PCTCN2022095009-appb-000094
After scanning and collecting relevant data, the absolute configuration can be confirmed by further analyzing the crystal structure by direct method (Shelxs97).
缩略语：PGE2代表前列腺素E2；EP4代表PGE2受体4；SFC代表超临界流体色谱手性分离，CO 2代表二氧化碳。 Abbreviations: PGE2 stands for prostaglandin E2; EP4 stands for PGE2 receptor 4; SFC stands for supercritical fluid chromatography chiral separation, and CO2 stands for carbon dioxide.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention.
本发明所使用的溶剂可经市售获得。化合物依据本领域常规命名原则或者使用
Figure PCTCN2022095009-appb-000095
软件命名，市售化合物采用供应商目录名称。 The solvent used in the present invention is commercially available. Compounds are named according to the conventional naming principles in this field or using
Figure PCTCN2022095009-appb-000095
The software is named, and the commercially available compounds adopt the supplier catalog name.
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 through examples below, but it does not imply any unfavorable limitation to 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 listed below, the embodiments formed by combining them with other chemical synthesis methods, and the methods well known to those skilled in the art Equivalent alternatives, preferred embodiments include but are not limited to the examples of the present invention. Various changes and modifications to the specific embodiments of the invention will be apparent to those skilled in the art without departing from the spirit and scope of the invention.
参考例1中间体A的合成Synthesis of Reference Example 1 Intermediate A
Figure PCTCN2022095009-appb-000096
Figure PCTCN2022095009-appb-000096
第一步first step
将甲基三苯基溴化膦(145.00g，1.20eq)加入四氢呋喃(500mL)中，氮气氛围下于-5～0℃搅拌下滴加双(三甲基硅基)胺基锂(LiHMDS)(1M，404.97mL，1.2eq)，滴加完成后于0～20℃搅拌1小时，降温至-5℃。称取化合物A-1(50g，1eq)溶于四氢呋喃(50mL)中，并于-5～0℃搅拌下将该溶液滴加至反应体系，滴加完成后缓慢升温至20℃，于20℃搅拌1小时。将反应液冷却到-5～0℃，用饱和氯化铵水溶液(100mL)淬灭，加入水(50mL)稀释，乙酸乙酯萃取(150mL*2)，合并有机相，用饱和氯化钠溶液洗涤(100mL*1)，无水硫酸钠干燥，滤液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝30∶1～10∶1)纯化得到化合物A-2。Add methyltriphenylphosphine bromide (145.00g, 1.20eq) into tetrahydrofuran (500mL), and add lithium bis(trimethylsilyl)amide (LiHMDS) dropwise under nitrogen atmosphere at -5～0°C with stirring (1M, 404.97mL, 1.2eq), stirred at 0-20°C for 1 hour after the dropwise addition, and cooled to -5°C. Weigh compound A-1 (50g, 1eq) and dissolve it in tetrahydrofuran (50mL), and add the solution dropwise to the reaction system at -5 ~ 0°C with stirring, and slowly raise the temperature to 20°C after the addition is completed, and at 20°C Stir for 1 hour. Cool the reaction solution to -5~0°C, quench with saturated ammonium chloride aqueous solution (100mL), add water (50mL) to dilute, extract with ethyl acetate (150mL*2), combine the organic phases, and wash with saturated sodium chloride solution After washing (100 mL*1), drying over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 30:1 ~ 10:1) to obtain compound A-2.
第二步second step
氮气氛围下将化合物A-2(28.9g，1eq)，(S，S)-2，6-双(4-异丙基-2-噁唑啉-2-基)吡啶(5.96g，0.1eq)和(对异丙甲苯)二氯化钌(II)二聚体(6.05g，0.05eq)加入二氯甲烷(500mL)中，并于20℃下搅拌30分钟。取重氮乙酸乙酯(35.62g，1.5eq)溶于二氯甲烷(60mL)中，搅拌下将该溶液滴加至反应体系，滴加完成后于20℃搅拌1小时。将反应液在10～20℃下用饱和氯化铵水溶液(100mL)淬灭，加入水(70mL)稀释，二氯甲烷萃取(150mL*2)，合并有机相，用饱和氯化钠溶液洗涤(100mL*1)，无水硫酸钠干燥，滤液减压浓缩得到化合物A-3。MS：m/z 233.2[M+H] +。 Compound A-2 (28.9g, 1eq), (S, S)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)pyridine (5.96g, 0.1eq ) and (p-cymene)ruthenium(II) dichloride dimer (6.05g, 0.05eq) were added to dichloromethane (500mL) and stirred at 20°C for 30 minutes. Ethyl diazoacetate (35.62 g, 1.5 eq) was dissolved in dichloromethane (60 mL), and the solution was added dropwise to the reaction system with stirring, and stirred at 20° C. for 1 hour after the dropwise addition was completed. The reaction solution was quenched with saturated ammonium chloride aqueous solution (100mL) at 10-20°C, diluted with water (70mL), extracted with dichloromethane (150mL*2), combined organic phases, and washed with saturated sodium chloride solution ( 100mL*1), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound A-3. MS: m/z 233.2 [M+H] + .
第三步third step
氮气氛围下于0℃将二碘海因(46.79g，0.54eq)和浓硫酸(2.39g，1.30mL，0.107eq)加入化合物A-3(52.98g，1eq)的甲醇(50mL)溶液中，0℃下搅拌1.5小时，升温至20℃继续搅拌2小时。反应液减压浓缩，加入乙酸乙酯(50mL)和饱和碳酸氢钠水溶液(30mL)稀释，乙酸乙酯萃取(40mL*2)，合并有机相，用饱和氯化钠溶液洗涤(80mL*1)，无水硫酸钠干燥，滤液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝30∶1～10∶1)纯化得到化合物A-4。MS：m/z 359.0[M+H] +。 Diiodhydantoin (46.79g, 0.54eq) and concentrated sulfuric acid (2.39g, 1.30mL, 0.107eq) were added to a solution of compound A-3 (52.98g, 1eq) in methanol (50mL) at 0°C under nitrogen atmosphere, Stir at 0°C for 1.5 hours, then raise the temperature to 20°C and continue stirring for 2 hours. The reaction solution was concentrated under reduced pressure, diluted by adding ethyl acetate (50mL) and saturated aqueous sodium bicarbonate solution (30mL), extracted with ethyl acetate (40mL*2), combined the organic phases, and washed with saturated sodium chloride solution (80mL*1) , dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 30:1 ~ 10:1) to obtain compound A-4. MS: m/z 359.0 [M+H] + .
第四步the fourth step
将化合物A-4(20g，1eq)，醋酸钠(13.74g，3eq)和[1，1’-双(二苯基膦基)二茂铁]二氯化钯(2.04g，0.05eq)加入N，N-二甲基甲酰胺(100mL)中，于80℃，一氧化碳(50Psi)气氛下搅拌反应6小时。反应液冷却，倒入饱和碳酸钾(250mL)溶液中，20℃搅拌10分钟，用2N稀盐酸调节pH值至3～4，乙酸乙酯萃取(150mL*2)，合并有机相，用饱和氯化钠溶液洗涤(60mL*1)，无水硫酸钠干燥，滤液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝5∶1～2∶1)纯化得到中间体A。Compound A-4 (20g, 1eq), sodium acetate (13.74g, 3eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (2.04g, 0.05eq) were added In N,N-dimethylformamide (100 mL), the reaction was stirred for 6 hours at 80° C. under an atmosphere of carbon monoxide (50 Psi). The reaction solution was cooled, poured into saturated potassium carbonate (250mL) solution, stirred at 20°C for 10 minutes, adjusted the pH value to 3-4 with 2N dilute hydrochloric acid, extracted with ethyl acetate (150mL*2), combined the organic phases, and washed with saturated chlorine Washed with sodium chloride solution (60 mL*1), dried over anhydrous sodium sulfate, concentrated the filtrate under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 5:1~2:1) to obtain intermediate A.
参考例2中间体B的合成Synthesis of Reference Example 2 Intermediate B
Figure PCTCN2022095009-appb-000097
Figure PCTCN2022095009-appb-000097
第一步first step
将化合物A-3(7g，1eq)和二碘海因(6.18g，0.54eq)加入甲醇(40mL)中，并于0℃下加入浓硫酸(322.00mg，175.00μL，0.11eq)，0℃搅拌0.5小时后，升温至70℃搅拌12小时。反应液中加入乙酸乙酯(100mL)和饱和碳酸氢钠水溶液(35mL)稀释，乙酸乙酯萃取(50mL*2)，合并有机相，用饱和氯化钠溶液(150mL*1)洗涤，无水硫酸钠干燥，滤液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝30∶1-10∶1)分离得到化合物B-1。Compound A-3 (7g, 1eq) and diiodohydantoin (6.18g, 0.54eq) were added to methanol (40mL), and concentrated sulfuric acid (322.00mg, 175.00μL, 0.11eq) was added at 0°C, After stirring for 0.5 hours, the temperature was raised to 70° C. and stirred for 12 hours. Add ethyl acetate (100mL) and saturated aqueous sodium bicarbonate (35mL) to the reaction solution to dilute, extract with ethyl acetate (50mL*2), combine the organic phases, wash with saturated sodium chloride solution (150mL*1), anhydrous After drying over sodium sulfate, the filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 30:1-10:1) to obtain compound B-1.
第二步second step
将化合物B-1(7g，1eq)和醋酸钠(5.01g，3eq)加入N，N-二甲基甲酰胺(30mL)中，并于20℃下加入[1，1’-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(830.54mg，0.05eq)，氮气置换后，升温至80℃，在一氧化碳气氛(50Psi)下搅拌5小时。反应液冷却后将其倒入100mL饱和碳酸钾水溶液中，50mL乙酸乙酯稀释，搅拌下滴加2N稀盐酸调节pH值至2-3，水相用乙酸乙酯萃取(50mL*2)，合并有机相，用饱和氯化钠溶液(150mL*4)洗涤，无水硫酸钠干燥，滤液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝5∶1-3∶1)分离得到中间体B。 1H NMR(400MHz，CDCl 3)δ＝10.38(br s，1H)，7.83(br s，1H)，7.47(br s，1H)，6.85(br d，J＝6.3Hz，1H)，4.34-4.18(m，2H)，3.72(s，3H)，2.21-2.04(m，3H)，1.72-1.63(m，2H)。 Compound B-1 (7g, 1eq) and sodium acetate (5.01g, 3eq) were added to N,N-dimethylformamide (30mL), and [1,1'-bis(diphenyl Phosphine)ferrocene]dichloropalladium dichloromethane complex (830.54mg, 0.05eq), after nitrogen replacement, the temperature was raised to 80°C, and stirred for 5 hours under a carbon monoxide atmosphere (50Psi). After the reaction liquid is cooled, pour it into 100mL saturated potassium carbonate aqueous solution, dilute with 50mL ethyl acetate, add 2N dilute hydrochloric acid dropwise under stirring to adjust the pH value to 2-3, extract the aqueous phase with ethyl acetate (50mL*2), combine The organic phase was washed with saturated sodium chloride solution (150mL*4), dried over anhydrous sodium sulfate, the filtrate was concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 5:1-3:1) to obtain intermediate Body B. 1 H NMR (400MHz, CDCl 3 ) δ=10.38 (br s, 1H), 7.83 (br s, 1H), 7.47 (br s, 1H), 6.85 (br d, J=6.3Hz, 1H), 4.34- 4.18 (m, 2H), 3.72 (s, 3H), 2.21-2.04 (m, 3H), 1.72-1.63 (m, 2H).
参考例3中间体C的合成Synthesis of Reference Example 3 Intermediate C
Figure PCTCN2022095009-appb-000098
Figure PCTCN2022095009-appb-000098
第一步first step
在氮气流下，将碘(5.20g，0.1eq)加至锌粉(50g，3.73eq)的N，N-二甲基甲酰胺溶液中(140mL)，将该 混合物搅拌10分钟。滴加4-溴丁酸乙酯(40g，29.41mL，1eq)后，将该混合物在95℃搅拌4小时以制备锌试剂。在氮气流下，将2-二环己基膦基-2′，6′-二甲氧基联苯(16.84g，0.2eq)和乙酸钯(9.21g，0.2eq)加至化合物C-1(23.58g，0.5eq)的四氢呋喃(40mL)溶液中，并于0℃将制备的锌试剂反应液滴加至该混合物中。然后在25℃搅拌12小时。将80mL饱和氯化铵水溶液加至该反应混合物中，加入100mL水稀释，并将该混合物用乙酸乙酯(200mL*2)萃取。将有机层用饱和氯化钠溶液(200mL*1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩得粗品。经柱层析(石油醚∶乙酸乙酯＝30∶1～10∶1)纯化得到化合物C-2。Under nitrogen flow, iodine (5.20 g, 0.1 eq) was added to a solution (140 mL) of zinc powder (50 g, 3.73 eq) in N,N-dimethylformamide, and the mixture was stirred for 10 minutes. After ethyl 4-bromobutyrate (40 g, 29.41 mL, 1 eq) was added dropwise, the mixture was stirred at 95° C. for 4 hours to prepare a zinc reagent. Under a stream of nitrogen, 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (16.84g, 0.2eq) and palladium acetate (9.21g, 0.2eq) were added to compound C-1 (23.58 g, 0.5eq) in tetrahydrofuran (40mL), and the prepared zinc reagent reaction solution was added dropwise to the mixture at 0°C. It was then stirred at 25°C for 12 hours. 80 mL of saturated aqueous ammonium chloride solution was added to the reaction mixture, diluted with 100 mL of water, and the mixture was extracted with ethyl acetate (200 mL*2). The organic layer was washed with saturated sodium chloride solution (200 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product. Compound C-2 was obtained after purification by column chromatography (petroleum ether: ethyl acetate = 30:1-10:1).
第二步second step
将盐酸羟胺(32.50g，1eq)加至化合物C-2(125g，1eq)的N，N-二甲基甲酰胺(400mL)溶液中，并将该混合物在50℃搅拌1小时。加入乙酰氯(41.12g，37.38mL，1.12eq)，将该混合物在90℃搅拌2小时。将反应混合物加至500mL冰水中，搅拌10分钟，用乙酸乙酯(200mL*2)萃取。将有机层用饱和氯化钠溶液(200mL*1)洗涤，用无水硫酸钠干燥，过滤，滤液减压浓缩。粗品经柱层析(石油醚∶乙酸乙酯＝20∶1-5∶1)纯化得到化合物C-3。Hydroxylamine hydrochloride (32.50 g, 1 eq) was added to a solution of compound C-2 (125 g, 1 eq) in N,N-dimethylformamide (400 mL), and the mixture was stirred at 50° C. for 1 hr. Acetyl chloride (41.12 g, 37.38 mL, 1.12 eq) was added, and the mixture was stirred at 90° C. for 2 hours. The reaction mixture was added to 500 mL of ice water, stirred for 10 minutes, and extracted with ethyl acetate (200 mL*2). The organic layer was washed with saturated sodium chloride solution (200 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The crude product was purified by column chromatography (petroleum ether:ethyl acetate=20:1-5:1) to obtain compound C-3.
第三步third step
将钯碳(8g，10％含量)加至化合物C-3(80g，1eq)的乙醇(400mL)溶液中，并将该混合物在20～25℃，氢气氛围下(15psi)搅拌9小时。将该反应混合物用硅藻土过滤，滤液浓缩得到粗品。经柱层析(石油醚∶乙酸乙酯＝10∶1～3∶1)分离得到中间体C。MS：m/z 233.2[M+H] +。 Palladium on carbon (8 g, 10% content) was added to a solution of compound C-3 (80 g, 1 eq) in ethanol (400 mL), and the mixture was stirred at 20˜25° C. under hydrogen atmosphere (15 psi) for 9 hours. The reaction mixture was filtered through celite, and the filtrate was concentrated to give the crude product. Intermediate C was obtained by separation by column chromatography (petroleum ether: ethyl acetate = 10:1 ~ 3:1). MS: m/z 233.2 [M+H] + .
参考例4中间体D和Da的合成Synthesis of Reference Example 4 Intermediate D and Da
Figure PCTCN2022095009-appb-000099
Figure PCTCN2022095009-appb-000099
第一步first step
将中间体A(8g，1eq)和异丙胺(2.57g，3.73mL，1.5eq)加入乙腈(40mL)中，降温至0℃加入二异丙基乙胺(5.61g，7.57mL，1.5eq)，搅拌10分钟后加入三正丙基环磷酸酐(T 3P，55.28g，51.66mL，50％含量的乙酸乙酯溶液，3eq)，搅拌2小时。反应液减压浓缩，加入水(34mL)稀释，乙酸乙酯萃取(23mL*2)，合并有机相，用饱和食盐水洗涤(23mL*1)，无水硫酸钠干燥，滤液减压浓缩得到化合物D-1。MS：m/z 318.2[M+H] +。 Add intermediate A (8g, 1eq) and isopropylamine (2.57g, 3.73mL, 1.5eq) into acetonitrile (40mL), cool down to 0°C and add diisopropylethylamine (5.61g, 7.57mL, 1.5eq) After stirring for 10 minutes, tri-n-propyl cyclic phosphoric anhydride (T 3 P, 55.28 g, 51.66 mL, 50% content in ethyl acetate, 3 eq) was added, and stirred for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (34mL), extracted with ethyl acetate (23mL*2), the organic phases were combined, washed with saturated brine (23mL*1), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain the compound D-1. MS: m/z 318.2 [M+H] + .
第二步second step
将化合物D-1(4.3g，1eq)加入四氢呋喃(20mL)和甲醇(20mL)混合溶剂中，搅拌下加入一水合氢氧化锂(1.71g，3eq)的水(5mL)溶液，并于25℃下搅拌1小时。反应液浓缩，用饱和柠檬酸水溶液调节反应体系pH值至5，水相用乙酸乙酯萃取(40mL*2)，合并有机相，用饱和食盐水洗(35mL*2)，无水硫 酸钠干燥，滤液减压浓缩。剩余物用高效液相色谱法制备分离(色谱柱：Phenomenex luna C18 150*40mm*15μm；流动相：[水(0.1％三氟乙酸)-乙腈]；乙腈％：22％-52％)得到中间体D。MS：m/z 290.1[M+H] +。 Compound D-1 (4.3g, 1eq) was added into a mixed solvent of tetrahydrofuran (20mL) and methanol (20mL), and a solution of lithium hydroxide monohydrate (1.71g, 3eq) in water (5mL) was added under stirring, and heated at 25°C Stir for 1 hour. The reaction solution was concentrated, and the pH value of the reaction system was adjusted to 5 with saturated aqueous citric acid solution, the aqueous phase was extracted with ethyl acetate (40 mL*2), the organic phases were combined, washed with saturated brine (35 mL*2), dried over anhydrous sodium sulfate, The filtrate was concentrated under reduced pressure. The residue was prepared and separated by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*40mm*15 μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile%: 22%-52%) to obtain intermediate Body D. MS: m/z 290.1 [M+H] + .
第三步third step
中间体D经SFC分离(分离条件：色谱柱：DAICEL CHIRALPAK IG(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)异丙醇]；B％：50％-50％)得到中间体Da。SFC检测条件：色谱柱：Chiralpak IG-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.801min，ee＝100％。MS：m/z 290.2[M+H] +。 Intermediate D was separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK IG (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) isopropanol]; B%: 50%-50%) to give the intermediate Da. SFC detection conditions: Chromatographic column: Chiralpak IG-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 1.801min, ee=100%. MS: m/z 290.2 [M+H] + .
实施例1Example 1
Figure PCTCN2022095009-appb-000100
Figure PCTCN2022095009-appb-000100
第一步first step
0℃下向化合物1-1(0.6g，1eq)，邻苯二甲酰亚胺(1.17g，1.3eq)和三苯基膦(2.0g，1.25eq)的四氢呋喃 溶液中滴加偶氮二羧酸二异丙酯(1.56g，1.5mL，1.26eq)。滴加完毕后，反应混合物在0℃下搅拌1小时，然后在25℃下搅拌10小时。向反应液中加入40mL水和100mL乙酸乙酯，分出有机层并依次用水(40mL)和饱和氯化钠水溶液(40mL)洗涤，无水硫酸钠干燥。过滤，滤液减压浓缩，剩余物经柱层析(石油醚∶乙酸乙酯＝15∶1～10∶1)分离得到化合物1-2。At 0°C, add azodicarbonate dropwise in a tetrahydrofuran solution of compound 1-1 (0.6g, 1eq), phthalimide (1.17g, 1.3eq) and triphenylphosphine (2.0g, 1.25eq). Diisopropyl carboxylate (1.56 g, 1.5 mL, 1.26 eq). After the addition was complete, the reaction mixture was stirred at 0°C for 1 hour and then at 25°C for 10 hours. 40 mL of water and 100 mL of ethyl acetate were added to the reaction solution, and the organic layer was separated and washed with water (40 mL) and saturated aqueous sodium chloride solution (40 mL) successively, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was separated by column chromatography (petroleum ether: ethyl acetate = 15:1-10:1) to obtain compound 1-2.
第二步second step
将化合物1-2(1.1g，1eq)溶于乙醇(20mL)中，加入水合肼(0.5mL，2.1eq)。混合物在90～100℃搅拌16小时。冷却到室温，过滤，向滤液中滴加4M盐酸/1，4-二氧六环溶液(2mL)，搅拌30分钟，过滤，滤液减压浓缩至干，得到化合物1-3(0.8g，盐酸盐粗品)直接用于下一步反应。 1H NMR(400MHz，DMSO-d 6)δ＝8.25(brs，3H)，3.15-3.05(m，1H)，2.08-2.03(m，2H)，1.85-1.74(m，2H)，1.32-1.27(m，2H)，0.37-0.30(m，1H)，0.23-0.19(m，1H)。 Compound 1-2 (1.1 g, 1 eq) was dissolved in ethanol (20 mL), and hydrazine hydrate (0.5 mL, 2.1 eq) was added. The mixture was stirred at 90-100°C for 16 hours. Cool to room temperature, filter, add 4M hydrochloric acid/1,4-dioxane solution (2mL) dropwise to the filtrate, stir for 30 minutes, filter, and the filtrate is concentrated to dryness under reduced pressure to obtain compound 1-3 (0.8g, salt salt crude product) was directly used in the next reaction. 1 H NMR (400MHz, DMSO-d 6 ) δ=8.25 (brs, 3H), 3.15-3.05 (m, 1H), 2.08-2.03 (m, 2H), 1.85-1.74 (m, 2H), 1.32-1.27 (m, 2H), 0.37-0.30 (m, 1H), 0.23-0.19 (m, 1H).
第三步third step
将化合物1-3(0.18g，盐酸盐粗品，1.0eq)和中间体A(0.3g，0.8eq)溶于四氢呋喃(5mL)和乙腈(5mL)的混合溶剂中，加入二异丙基乙胺(1.2mL)和4-二甲氨基吡啶(DMAP)(33mg，0.2eq)，在20～25℃搅拌10分钟后加入三正丙基环磷酸酐(T 3P，1.20mL，50％含量的乙酸乙酯溶液，3eq)，反应液继续搅拌10小时。加入50mL乙酸乙酯稀释，依次用水(30mL*2)和饱和氯化钠水溶液(30mL*1)，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物经制备薄层色谱(石油醚/乙酸乙酯/二氯甲烷/甲醇＝15∶15∶9∶1)分离纯化得到化合物1-4。LCMS：m/z 356.2[M+H] +。 Compound 1-3 (0.18g, crude hydrochloride, 1.0eq) and intermediate A (0.3g, 0.8eq) were dissolved in a mixed solvent of tetrahydrofuran (5mL) and acetonitrile (5mL), and diisopropylethyl Amine (1.2mL) and 4-dimethylaminopyridine (DMAP) (33mg, 0.2eq), stirred at 20-25°C for 10 minutes, then added tri-n-propyl cyclic phosphoric anhydride (T 3 P, 1.20mL, 50% content ethyl acetate solution, 3eq), and the reaction solution was stirred for 10 hours. Add 50mL of ethyl acetate for dilution, followed by water (30mL*2) and saturated aqueous sodium chloride solution (30mL*1), the organic layer was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to preparative thin-layer chromatography ( Petroleum ether/ethyl acetate/dichloromethane/methanol=15:15:9:1) separation and purification to obtain compound 1-4. LCMS: m/z 356.2 [M+H] + .
第四步the fourth step
将化合物1-4(0.17g，1eq)溶于四氢呋喃(2mL)中，加入一水合氢氧化锂(60mg，3eq)的水(1mL)溶液，反应液在15～20℃搅拌10小时。减压浓缩除去四氢呋喃，剩余物用2N稀盐酸溶液处理至pH值为1，浓缩至干得到化合物1-5的粗品直接用于下一步反应。LCMS：m/z 328.1[M+H] +。 Compound 1-4 (0.17g, 1eq) was dissolved in tetrahydrofuran (2mL), a solution of lithium hydroxide monohydrate (60mg, 3eq) in water (1mL) was added, and the reaction solution was stirred at 15-20°C for 10 hours. The tetrahydrofuran was removed by concentration under reduced pressure, the residue was treated with 2N dilute hydrochloric acid solution to pH 1, and concentrated to dryness to obtain the crude compound 1-5, which was directly used in the next reaction. LCMS: m/z 328.1 [M+H] + .
第五步the fifth step
将化合物1-5(0.15g，1eq)和中间体C(0.12g，1.1eq)溶于乙腈(2mL)和四氢呋喃(2mL)的混合溶剂中，加入二异丙基乙胺(0.4mL)和4-二甲氨基吡啶(15mg，0.27eq)，混合物在15～20℃搅拌10分钟后加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，0.8mL，3eq)，反应混合物继续搅拌10小时。加入60mL乙酸乙酯稀释，用水(50mL*2)和饱和氯化钠水溶液(50mL*1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液减压浓缩。所得粗品加入5mL乙醇，超声震荡3分钟，过滤，滤饼用1mL乙醇淋洗，干燥，再经SFC分离(分离条件：色谱柱：DAICEL CHIRALCELOJ(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；B％：60％-60％)得到化合物1-6a。LCMS：m/z 542.3[M+H] +，SFC分析条件：色谱柱：Chiralcel OJ-350×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min， 保留时间为1.525min。 Compound 1-5 (0.15g, 1eq) and Intermediate C (0.12g, 1.1eq) were dissolved in a mixed solvent of acetonitrile (2mL) and tetrahydrofuran (2mL), and diisopropylethylamine (0.4mL) and 4-Dimethylaminopyridine (15mg, 0.27eq), the mixture was stirred at 15-20°C for 10 minutes, and then tri-n-propyl cyclic phosphoric anhydride (50% mass fraction in ethyl acetate, 0.8mL, 3eq) was added, and the reaction The mixture was stirred for an additional 10 hours. Add 60 mL of ethyl acetate for dilution, wash with water (50 mL*2) and saturated aqueous sodium chloride solution (50 mL*1), dry the organic layer over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Add 5 mL of ethanol to the obtained crude product, oscillate ultrasonically for 3 minutes, filter, rinse the filter cake with 1 mL of ethanol, dry, and then separate by SFC (separation conditions: chromatographic column: DAICEL CHIRALCELOJ (250mm*30mm, 10 μm); mobile phase: Phase A: CO 2 , phase B: [(0.1% ammonia)methanol]; B%: 60%-60%) to obtain compound 1-6a. LCMS: m/z 542.3[M+H] + , SFC analysis conditions: chromatographic column: Chiralcel OJ-350×4.6mm ID, 3μm, mobile phase: A phase: CO 2 , B phase: methanol (0.05% diethylamine ); gradient: B%: 5% to 40%; flow rate: 3mL/min, retention time: 1.525min.
第六步step six
将化合物1-6a(100mg，1eq)溶于四氢呋喃(2mL)中，加入一水合氢氧化锂(24mg，3.1eq)的水(1mL)溶液，反应混合物在20℃搅拌10小时。减压浓缩除去四氢呋喃，剩余物用2N稀盐酸调节pH为1，加入2mL水，过滤，收集滤饼得到化合物1a。SFC分析条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为2.045min，ee＝93.6％。 1H NMR(400MHz，DMSO-d 6)δ＝10.34(brs，1H)，8.29(d，J＝8Hz，1H)，8.00(s，1H)，7.59(d，J＝8.1Hz，1H)，7.53(d，J＝8.0Hz，1H)，7.43(s，1H)，7.39(d，J＝8.0Hz，1H)，6.82(d，J＝8.4Hz，1H)，4.31-4.28(m，1H)，7.16-4.06(m，1H)，4.05-3.98(m，1H)，2.74(t，J＝7.2Hz，1H)，2.66(t，J＝8.0Hz，2H)，2.18-2.07(m，4H)，2.03-1.97(m，2H)，1.80-1.67(m，5H)，1.54(t，J＝4.8Hz，1H)，1.30-1.22(m，1H)，0.36-0.30(m，1H)，0.24-0.21(m，1H)。LCMS：m/z 514.2[M+H] +。 Compound 1-6a (100mg, 1eq) was dissolved in tetrahydrofuran (2mL), a solution of lithium hydroxide monohydrate (24mg, 3.1eq) in water (1mL) was added, and the reaction mixture was stirred at 20°C for 10 hours. Concentrate under reduced pressure to remove tetrahydrofuran, adjust the pH of the residue to 1 with 2N dilute hydrochloric acid, add 2 mL of water, filter, and collect the filter cake to obtain compound 1a. SFC analysis conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 2.045min, ee=93.6%. 1 H NMR (400MHz, DMSO-d 6 ) δ = 10.34 (brs, 1H), 8.29 (d, J = 8Hz, 1H), 8.00 (s, 1H), 7.59 (d, J = 8.1Hz, 1H), 7.53(d, J=8.0Hz, 1H), 7.43(s, 1H), 7.39(d, J=8.0Hz, 1H), 6.82(d, J=8.4Hz, 1H), 4.31-4.28(m, 1H ), 7.16-4.06(m, 1H), 4.05-3.98(m, 1H), 2.74(t, J=7.2Hz, 1H), 2.66(t, J=8.0Hz, 2H), 2.18-2.07(m, 4H), 2.03-1.97(m, 2H), 1.80-1.67(m, 5H), 1.54(t, J=4.8Hz, 1H), 1.30-1.22(m, 1H), 0.36-0.30(m, 1H) , 0.24-0.21 (m, 1H). LCMS: m/z 514.2 [M+H] + .
化合物1a经单晶X射线衍射法(SXRD)确证绝对构型为：The absolute configuration of compound 1a was confirmed by single crystal X-ray diffraction (SXRD):
Figure PCTCN2022095009-appb-000101
Figure PCTCN2022095009-appb-000101
实施例2Example 2
Figure PCTCN2022095009-appb-000102
Figure PCTCN2022095009-appb-000102
第一步first step
20℃下，将中间体B(0.1g，1eq)和化合物2-1(60mg，盐酸盐，1.07eq)溶于乙腈(2mL)和四氢呋喃(2mL)的混合溶剂中，加入二异丙基乙胺(0.4mL，6eq)和4-二甲氨基吡啶(10mg，0.21eq)，搅拌10分钟，加 入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，0.5mL，2.2eq)，反应混合物在20～25℃搅拌10小时。加30mL乙酸乙酯稀释，依次用水(20mL*2)和饱和氯化钠水溶液(30mL*1)洗涤，有机层用无水硫酸钠干燥，过滤，滤液浓缩，剩余物用制备薄层色谱纯化(石油醚/乙酸乙酯＝2∶1)得到化合物2-2。LCMS：m/z 356.2[M+H] +。 At 20°C, intermediate B (0.1g, 1eq) and compound 2-1 (60mg, hydrochloride, 1.07eq) were dissolved in a mixed solvent of acetonitrile (2mL) and tetrahydrofuran (2mL), and diisopropyl Ethylamine (0.4mL, 6eq) and 4-dimethylaminopyridine (10mg, 0.21eq), stirred for 10 minutes, added tri-n-propyl cyclic phosphoric anhydride (50% mass fraction in ethyl acetate, 0.5mL, 2.2 eq), the reaction mixture was stirred at 20-25° C. for 10 hours. Dilute with 30 mL of ethyl acetate, wash with water (20 mL*2) and saturated aqueous sodium chloride solution (30 mL*1) successively, dry the organic layer over anhydrous sodium sulfate, filter, concentrate the filtrate, and purify the residue by preparative thin-layer chromatography ( Petroleum ether/ethyl acetate=2:1) to obtain compound 2-2. LCMS: m/z 356.2 [M+H] + .
第二步second step
将化合物2-2(0.105g，1eq)溶于四氢呋喃(2mL)中，加入一水合氢氧化锂(38mg，3eq)的水(1mL)溶液，反应混合液在20～25℃搅拌10小时。减压浓缩除去四氢呋喃，剩余物用2N稀盐酸调pH到1，减压浓缩至干，得到化合物2-3粗品直接用于下一步反应。LCMS：m/z 342.1[M+H] +。 Compound 2-2 (0.105g, 1eq) was dissolved in tetrahydrofuran (2mL), a solution of lithium hydroxide monohydrate (38mg, 3eq) in water (1mL) was added, and the reaction mixture was stirred at 20-25°C for 10 hours. Concentrate under reduced pressure to remove tetrahydrofuran, adjust the pH of the residue to 1 with 2N dilute hydrochloric acid, and concentrate to dryness under reduced pressure to obtain the crude compound 2-3, which is directly used in the next reaction. LCMS: m/z 342.1 [M+H] + .
第三步third step
将化合物2-3(0.1g，1eq)和中间体C(75mg，1.1eq)溶于四氢呋喃(1.5mL)和乙腈(1.5mL)的混合溶剂中，加入二异丙基乙胺(0.3mL，5.9eq)和4-二甲氨基吡啶(8mg，0.2eq)，然后加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，0.6mL，3.4eq)，反应混合液在20～25℃搅拌10小时。加30mL乙酸乙酯稀释，依次用水(20mL*2)和饱和氯化钠水溶液(20mL*1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物用制备薄层色谱纯化(石油醚/乙酸乙酯＝1∶1)得到化合物2-4。LCMS：m/z 556.4[M+H] +。 Compound 2-3 (0.1g, 1eq) and intermediate C (75mg, 1.1eq) were dissolved in a mixed solvent of tetrahydrofuran (1.5mL) and acetonitrile (1.5mL), and diisopropylethylamine (0.3mL, 5.9eq) and 4-dimethylaminopyridine (8mg, 0.2eq), then add tri-n-propyl cyclic phosphoric acid anhydride (mass fraction is 50% ethyl acetate solution, 0.6mL, 3.4eq), the reaction mixture is at 20 Stir at ~25°C for 10 hours. Add 30 mL of ethyl acetate to dilute, wash with water (20 mL*2) and saturated aqueous sodium chloride solution (20 mL*1) successively, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative thin-layer chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 2-4. LCMS: m/z 556.4 [M+H] + .
第四步the fourth step
将化合物2-4(100mg，1eq)溶于四氢呋喃(3mL)中，加入一水合氢氧化锂(23mg，3eq)的水(1.5mL)溶液，反应在20℃搅拌2小时。减压浓缩除去四氢呋喃，加2N稀盐酸调pH值到1，加入2mL水，搅拌5分钟，抽滤，滤饼用2mL水淋洗，收集固体，减压干燥后经制备薄层色谱纯化(二氯甲烷/甲醇＝15∶1)，再经SFC分离(分离条件：色谱柱：DAICEL CHIRALCEL OJ(250mm*30mm，10μm)；流动相：A相：二氧化碳，B相：[(0.1％氨水)甲醇]；B％：50％-50％)得到化合物2a。SFC分析条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为2.236min，ee＝100％。 1H NMR(400MHz，CD 3OD)δ＝8.06(s，1H)，7.60(dd，J＝8.8，2.0Hz，1H)，7.50-7.47(m，2H)，7.44(d，J＝8.4Hz，1H)，6.84(d，J＝8.4Hz，1H)，4.40-4.23(m，3H)，2.77-2.67(m，3H)，2.48-2.41(m，2H)，2.37-2.33(m，2H)，2.30-2.20(m，2H)，2.16-1.97(m，6H)，1.92-1.80(m，4H)，1.77-1.68(m，2H)。LCMS：m/z 528.2[M+H] +。 Compound 2-4 (100mg, 1eq) was dissolved in tetrahydrofuran (3mL), a solution of lithium hydroxide monohydrate (23mg, 3eq) in water (1.5mL) was added, and the reaction was stirred at 20°C for 2 hours. Concentrate under reduced pressure to remove tetrahydrofuran, add 2N dilute hydrochloric acid to adjust the pH to 1, add 2 mL of water, stir for 5 minutes, filter with suction, rinse the filter cake with 2 mL of water, collect the solid, dry under reduced pressure and purify by preparative thin-layer chromatography (2 Chloromethane/methanol=15:1), and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: A phase: carbon dioxide, B phase: [(0.1% ammonia water) methanol ]; B%: 50%-50%) to obtain compound 2a. SFC analysis conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 2.236min, ee=100%. 1 H NMR (400MHz, CD 3 OD) δ=8.06(s, 1H), 7.60(dd, J=8.8, 2.0Hz, 1H), 7.50-7.47(m, 2H), 7.44(d, J=8.4Hz , 1H), 6.84(d, J=8.4Hz, 1H), 4.40-4.23(m, 3H), 2.77-2.67(m, 3H), 2.48-2.41(m, 2H), 2.37-2.33(m, 2H ), 2.30-2.20 (m, 2H), 2.16-1.97 (m, 6H), 1.92-1.80 (m, 4H), 1.77-1.68 (m, 2H). LCMS: m/z 528.2 [M+H] + .
实施例3Example 3
Figure PCTCN2022095009-appb-000103
Figure PCTCN2022095009-appb-000103
Figure PCTCN2022095009-appb-000104
Figure PCTCN2022095009-appb-000104
第一步first step
20℃下，将中间体B(0.1g，1eq)和化合物3-1(50mg，1.10eq，盐酸盐)溶于乙腈(3mL)和四氢呋喃(3mL)的混合溶剂中，加入二异丙基乙胺(73.92mg，99.62μL，1.5eq)和4-二甲氨基吡啶(46.58mg，1eq)，搅拌10分钟，加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，0.68mL，3eq)，反应混合物在20℃搅拌2小时。反应液浓缩，加3mL水稀释，用乙酸乙酯萃取(4mL*2)，乙酸乙酯层用饱和氯化钠水溶液洗涤(3mL*2)，无水硫酸钠干燥，过滤，滤液浓缩得到化合物3-2。MS：m/z 328.2[M+H] +。 At 20°C, intermediate B (0.1g, 1eq) and compound 3-1 (50mg, 1.10eq, hydrochloride) were dissolved in a mixed solvent of acetonitrile (3mL) and tetrahydrofuran (3mL), and diisopropyl Ethylamine (73.92mg, 99.62μL, 1.5eq) and 4-dimethylaminopyridine (46.58mg, 1eq), stirred for 10 minutes, added tri-n-propyl cyclic phosphoric anhydride (50% mass fraction in ethyl acetate solution, 0.68mL, 3eq), the reaction mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated, diluted with 3 mL of water, extracted with ethyl acetate (4 mL*2), the ethyl acetate layer was washed with saturated aqueous sodium chloride solution (3 mL*2), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 3 -2. MS: m/z 328.2 [M+H] + .
第二步second step
将化合物3-2(85mg，1eq)溶于四氢呋喃(3mL)中，加入三甲基硅醇钾(99.93mg，3eq)，反应混合液在20℃搅拌2小时。反应液用2N稀盐酸调pH到5，加2mL水稀释，用乙酸乙酯萃取(2mL*2)，乙酸乙酯层用5mL饱和氯化钠水溶液洗，无水硫酸钠干燥，过滤，滤液浓缩得到化合物3-3。MS：m/z 314.1[M+H] +。 Compound 3-2 (85mg, 1eq) was dissolved in tetrahydrofuran (3mL), potassium trimethylsiliconate (99.93mg, 3eq) was added, and the reaction mixture was stirred at 20°C for 2 hours. The pH of the reaction solution was adjusted to 5 with 2N dilute hydrochloric acid, diluted with 2 mL of water, extracted with ethyl acetate (2 mL*2), the ethyl acetate layer was washed with 5 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated Compound 3-3 was obtained. MS: m/z 314.1 [M+H] + .
第三步third step
20℃下，将化合物3-3(65mg，1eq)和中间体C(48.18mg，1eq)溶于乙腈(1mL)和四氢呋喃(1mL)混合溶剂中，加入二异丙基乙胺(40.21mg，54.20μL，1.5eq)和4-二甲氨基吡啶(25.34mg，1eq)，搅拌10分钟，加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，0.37mL，3eq)，反应混合物在20℃搅拌2小时。反应液浓缩，加3mL水稀释，用乙酸乙酯萃取(4mL*2)，乙酸乙酯层用饱和氯化钠水溶液洗涤(3mL*2)，无水硫酸钠干燥，过滤，滤液浓缩，粗品经薄层色谱(石油醚∶乙酸乙酯＝1∶1)纯化，再经SFC分离(分离条件：色谱柱：DAICEL CHIRALPAK AD(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)异丙醇]；B％：25％-25％)得到化合物3-4a。SFC分析条件：色谱柱：Chiralpak AD-3 50×4.6mm I.D.，3μm流动相：A相：CO 2，B相：异丙醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.807min。MS：m/z 528.3[M+H] +。 At 20°C, compound 3-3 (65mg, 1eq) and intermediate C (48.18mg, 1eq) were dissolved in a mixed solvent of acetonitrile (1mL) and tetrahydrofuran (1mL), and diisopropylethylamine (40.21mg, 54.20 μL, 1.5eq) and 4-dimethylaminopyridine (25.34mg, 1eq), stirred for 10 minutes, added tri-n-propyl cyclic phosphoric anhydride (50% mass fraction in ethyl acetate solution, 0.37mL, 3eq), The reaction mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated, diluted with 3 mL of water, extracted with ethyl acetate (4 mL*2), the ethyl acetate layer was washed with saturated aqueous sodium chloride (3 mL*2), dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the crude product was Purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:1), and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase : [(0.1% ammonia) isopropanol]; B%: 25%-25%) to obtain compound 3-4a. SFC analysis conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm Mobile phase: Phase A: CO 2 , Phase B: isopropanol (0.05% diethylamine); Gradient: B%: 5%～40 %; Flow rate: 3mL/min, retention time is 1.807min. MS: m/z 528.3 [M+H] + .
第四步the fourth step
将化合物3-4a(45mg，1eq)溶于四氢呋喃(2mL)中，加入三甲基硅醇钾(32.83mg，3eq)，反应混合液在20℃搅拌2小时。反应液用2N稀盐酸调pH到5，加2mL水稀释，用乙酸乙酯萃取(2mL*2)，乙酸乙酯层用5mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液浓缩，粗品经制备薄层色谱(石油醚/乙酸乙酯＝1∶2)分离得到化合物3a。SFC分析条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为2.094min，ee＝98.9％。 1H NMR(400MHz，CDCl 3)δ＝9.85(s，1H)，8.81(s，1H)，7.91(s，1H)，7.20-7.18(m，2H)，7.13-7.12(m，1H)，6.73-6.58(m，2H)，4.46(br d，J＝10.6Hz，1H)，4.29-4.26(m，1H)，3.70-3.68(m，1H)，3.50-3.49(m，1H)，2.64(br t，J＝8.4Hz，2H)，2.58-2.48(m，1H)，2.46(s，1H)，2.45-2.35(m，1H)，2.18(br d，J＝4.3Hz，1H)，2.11-2.04(m，2H)，2.03-1.91(m，1H)，1.80-1.78(m，1H)，1.74-1.59(m，2H)，1.47(dd，J＝4.4，5.6Hz，1H)，1.19-1.15(m，2H)。MS：m/z 500.2[M+H] +。 Compound 3-4a (45mg, 1eq) was dissolved in tetrahydrofuran (2mL), potassium trimethylsiliconate (32.83mg, 3eq) was added, and the reaction mixture was stirred at 20°C for 2 hours. The reaction solution was adjusted to pH 5 with 2N dilute hydrochloric acid, diluted with 2 mL of water, extracted with ethyl acetate (2 mL*2), the ethyl acetate layer was washed with 5 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated , the crude product was separated by preparative thin-layer chromatography (petroleum ether/ethyl acetate=1:2) to obtain compound 3a. SFC analysis conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 2.094min, ee=98.9%. 1 H NMR (400MHz, CDCl 3 ) δ=9.85(s, 1H), 8.81(s, 1H), 7.91(s, 1H), 7.20-7.18(m, 2H), 7.13-7.12(m, 1H), 6.73-6.58(m, 2H), 4.46(br d, J=10.6Hz, 1H), 4.29-4.26(m, 1H), 3.70-3.68(m, 1H), 3.50-3.49(m, 1H), 2.64 (br t, J=8.4Hz, 2H), 2.58-2.48(m, 1H), 2.46(s, 1H), 2.45-2.35(m, 1H), 2.18(br d, J=4.3Hz, 1H), 2.11-2.04(m, 2H), 2.03-1.91(m, 1H), 1.80-1.78(m, 1H), 1.74-1.59(m, 2H), 1.47(dd, J=4.4, 5.6Hz, 1H), 1.19-1.15 (m, 2H). MS: m/z 500.2 [M+H] + .
实施例4Example 4
Figure PCTCN2022095009-appb-000105
Figure PCTCN2022095009-appb-000105
第一步first step
将叠氮磷酸二苯酯(1.02g，1.16eq)加入到化合物4-1(0.4g，1eq)，二异丙基乙胺(0.7mL，1.27eq)和 叔丁醇(1.00mL，3.30eq)的甲苯(10mL)溶液中，混合物在25℃搅拌30分钟后加热到110℃搅拌10小时。反应液冷却，加50mL乙酸乙酯稀释，依次用40mL水和40mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物经柱层析(石油醚/乙酸乙酯＝15/1～10/1)纯化得到化合物4-2。 1H NMR(400MHz，CDCl 3)δ＝4.50(br s，1H)，2.37(br s，1H)，2.08-1.98(m，6H)，1.41(s，9H)，0.82-0.78(m，1H)，0.35(br s，1H)。 Diphenylphosphoryl azide (1.02g, 1.16eq) was added to compound 4-1 (0.4g, 1eq), diisopropylethylamine (0.7mL, 1.27eq) and tert-butanol (1.00mL, 3.30eq ) in toluene (10 mL), the mixture was stirred at 25°C for 30 minutes, then heated to 110°C and stirred for 10 hours. The reaction solution was cooled, diluted with 50 mL of ethyl acetate, washed successively with 40 mL of water and 40 mL of saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the residue was subjected to column chromatography (petroleum ether/ethyl acetate =15/1～10/1) to obtain compound 4-2. 1 H NMR (400MHz, CDCl 3 ) δ=4.50(br s, 1H), 2.37(br s, 1H), 2.08-1.98(m, 6H), 1.41(s, 9H), 0.82-0.78(m, 1H ), 0.35 (br s, 1H).
第二步second step
将化合物4-2(0.13g，1eq)溶于二氯甲烷(2mL)中，滴加4M盐酸乙酸乙酯溶液(1mL，3.07eq)，反应混合物在15～20℃搅拌10小时。反应液减压浓缩得到化合物4-3(盐酸盐)粗品。 1H NMR(400MHz，DMSO)δ＝8.20(br s，3H)，2.44-2.39(m，1H)，2.14-2.17(m，1H)，2.11-2.02(m，5H)，0.85-0.81(m，1H)，0.75-0.72(m，1H)。 Compound 4-2 (0.13g, 1eq) was dissolved in dichloromethane (2mL), 4M hydrochloric acid ethyl acetate solution (1mL, 3.07eq) was added dropwise, and the reaction mixture was stirred at 15-20°C for 10 hours. The reaction solution was concentrated under reduced pressure to obtain the crude compound 4-3 (hydrochloride). 1 H NMR (400MHz, DMSO) δ=8.20(br s, 3H), 2.44-2.39(m, 1H), 2.14-2.17(m, 1H), 2.11-2.02(m, 5H), 0.85-0.81(m , 1H), 0.75-0.72 (m, 1H).
第三步third step
将化合物4-3(80mg，1eq，盐酸盐)和中间体A(0.14g，0.85eq)溶于乙腈(1.5mL)和四氢呋喃(1.5mL)混合溶剂中，加入二异丙基乙胺(0.5mL)和4-二甲氨基吡啶(16mg，0.22eq)，然后加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，1.1mL，3.1eq)，反应混合物在20℃搅拌90分钟。加20mL乙酸乙酯稀释，依次用水(20mL*2)和饱和氯化钠水溶液洗涤(20mL*1)，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物经制备薄层色谱(石油醚/乙酸乙酯/二氯甲烷/甲醇＝90∶30∶36∶4)得到化合物4-4。Compound 4-3 (80mg, 1eq, hydrochloride) and intermediate A (0.14g, 0.85eq) were dissolved in acetonitrile (1.5mL) and tetrahydrofuran (1.5mL) mixed solvent, diisopropylethylamine ( 0.5mL) and 4-dimethylaminopyridine (16mg, 0.22eq), then added tri-n-propyl cyclic phosphoric anhydride (mass fraction is 50% ethyl acetate solution, 1.1mL, 3.1eq), the reaction mixture at 20 ℃ Stir for 90 minutes. Add 20mL of ethyl acetate to dilute, wash with water (20mL*2) and saturated aqueous sodium chloride solution (20mL*1) successively, dry over anhydrous sodium sulfate, filter, the filtrate is concentrated under reduced pressure, and the residue is subjected to preparative thin-layer chromatography (petroleum ether /ethyl acetate/dichloromethane/methanol=90:30:36:4) to obtain compound 4-4.
第四步the fourth step
将化合物4-4(0.14g，1eq)溶于四氢呋喃(4mL)中，加入一水合氢氧化锂(50mg，3eq)的水(1mL)溶液，反应混合物在20～25℃搅拌40小时。减压浓缩除去四氢呋喃，剩余物用2N稀盐酸调pH为1，减压浓缩得到化合物4-5直接用于下一步反应。LCMS：m/z 328.2[M+H] +。 Compound 4-4 (0.14g, 1eq) was dissolved in tetrahydrofuran (4mL), a solution of lithium hydroxide monohydrate (50mg, 3eq) in water (1mL) was added, and the reaction mixture was stirred at 20-25°C for 40 hours. Concentrate under reduced pressure to remove tetrahydrofuran, adjust the pH of the residue to 1 with 2N dilute hydrochloric acid, and concentrate under reduced pressure to obtain compound 4-5, which is directly used in the next reaction. LCMS: m/z 328.2 [M+H] + .
第五步the fifth step
将化合物4-5(0.12g，1eq)和中间体C(0.093g，1.09eq)溶于四氢呋喃(1.5mL)和乙腈(1.5mL)的混合溶剂中，加入二异丙基乙胺(0.3mL，4.70eq)和4-二甲氨基吡啶(9mg，0.2eq)，混合物在20℃搅拌10分钟，然后加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，0.6mL，2.75eq)，反应液在20～30℃搅拌36小时。减压浓缩，剩余物加入20mL乙酸乙酯，依次用水(20mL*2)和饱和氯化钠水溶液(20mL*1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物经制备薄层色谱(石油/乙酸乙酯＝2∶1)纯化，然后经SFC分离(分离条件：色谱柱：DAICEL CHIRALPAK AS(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)乙醇]；B％：60％-60％)得到化合物4-6a和化合物4-6b。SFC分析条件：色谱柱：Chiralpak AS-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：乙醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，化合物4-6a的保留时间为1.619min，化合物4-6b的保留时间为1.999min。 Compound 4-5 (0.12g, 1eq) and intermediate C (0.093g, 1.09eq) were dissolved in a mixed solvent of tetrahydrofuran (1.5mL) and acetonitrile (1.5mL), and diisopropylethylamine (0.3mL , 4.70eq) and 4-dimethylaminopyridine (9mg, 0.2eq), the mixture was stirred at 20°C for 10 minutes, then added tri-n-propyl cyclic phosphoric anhydride (50% mass fraction in ethyl acetate, 0.6mL, 2.75eq), and the reaction solution was stirred at 20-30°C for 36 hours. Concentrate under reduced pressure, add 20mL ethyl acetate to the residue, wash with water (20mL*2) and saturated aqueous sodium chloride solution (20mL*1) successively, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and prepare the residue Purified by layer chromatography (petroleum/ethyl acetate=2:1), and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AS (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [ (0.1% ammonia water) ethanol]; B%: 60%-60%) to obtain compound 4-6a and compound 4-6b. SFC analysis conditions: chromatographic column: Chiralpak AS-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: ethanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, the retention time of compound 4-6a was 1.619min, and the retention time of compound 4-6b was 1.999min.
第六步step six
将化合物4-6a(10mg，1eq)溶于四氢呋喃(0.5mL)，加入一水合氢氧化锂(2.32mg，3eq)的水(0.2mL)溶液，反应液在20～25℃搅拌10小时。反应液浓缩，剩余物用2N稀盐酸调pH为1，加1mL水，搅拌10分钟，减压过滤收集滤饼，干燥得到化合物4a。 1H NMR(400MHz，CD 3OD)δ＝8.08(s，1H)，7.59(dd，J＝8.0，2.0Hz，1H)，7.54(d，J＝2.0Hz，1H)，7.49(dd，J＝8.0，2.0Hz，1H)，7.43(d，J＝8.0Hz，1H)，6.84(d，J＝8.4Hz，1H)，4.39-4.34(m，1H)，4.31-4.26(m，1H)，2.78-2.67(m，4H)，2.39(t，J＝7.2Hz，2H)，2.26-2.16(m，5H)，2.07-1.98(m，3H)，1.86-1.82(m，2H)，1.75-1.71(m，2H)，0.94-0.90(m，1H)，0.72-0.69(m，1H)。LCMS：m/z 514.4[M+H] +。SFC分析条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为2.029min，ee＝93.4％。 Compound 4-6a (10mg, 1eq) was dissolved in tetrahydrofuran (0.5mL), a solution of lithium hydroxide monohydrate (2.32mg, 3eq) in water (0.2mL) was added, and the reaction solution was stirred at 20-25°C for 10 hours. The reaction solution was concentrated, the residue was adjusted to pH 1 with 2N dilute hydrochloric acid, 1 mL of water was added, stirred for 10 minutes, the filter cake was collected by filtration under reduced pressure, and dried to obtain compound 4a. 1 H NMR (400MHz, CD 3 OD) δ = 8.08 (s, 1H), 7.59 (dd, J = 8.0, 2.0Hz, 1H), 7.54 (d, J = 2.0Hz, 1H), 7.49 (dd, J =8.0, 2.0Hz, 1H), 7.43(d, J=8.0Hz, 1H), 6.84(d, J=8.4Hz, 1H), 4.39-4.34(m, 1H), 4.31-4.26(m, 1H) , 2.78-2.67(m, 4H), 2.39(t, J=7.2Hz, 2H), 2.26-2.16(m, 5H), 2.07-1.98(m, 3H), 1.86-1.82(m, 2H), 1.75 -1.71 (m, 2H), 0.94-0.90 (m, 1H), 0.72-0.69 (m, 1H). LCMS: m/z 514.4 [M+H] + . SFC analysis conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 2.029min, ee=93.4%.
将化合物4-6b(10mg，1eq)溶于四氢呋喃(0.5mL)，加入一水合氢氧化锂(3mg，3.9eq)的水(0.2mL)溶液，反应液在20～25℃搅拌10小时。反应液浓缩，剩余物用2N稀盐酸调pH为1，加1mL水，搅拌10分钟，减压过滤收集滤饼，干燥得到化合物4b。 1H NMR(400MHz，CD 3OD)δ＝8.04(s，1H)，7.59(dd，J＝8.4，2.0Hz，1H)，7.52-7.48(m，2H)，7.44(d，J＝8.0Hz，1H)，6.85(d，J＝8.4Hz，1H)，4.40-4.35(m，1H)，4.30-4.24(m，1H)，2.77-2.65(m，4H)，2.37(t，J＝7.2Hz，2H)，2.26-2.17(m，5H)，2.08-2.00(m，3H)，1.88-1.81(m，2H)，1.77-1.70(m，2H)，0.94-0.90(m，1H)，0.72-0.69(m，1H)。LCMS：m/z 514.4[M+H] +。SFC检测条件：色谱柱：Chiralpak IC-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：40％；流速：3mL/min，保留时间为0.770min，ee＝100％。 Compound 4-6b (10mg, 1eq) was dissolved in tetrahydrofuran (0.5mL), a solution of lithium hydroxide monohydrate (3mg, 3.9eq) in water (0.2mL) was added, and the reaction solution was stirred at 20-25°C for 10 hours. The reaction solution was concentrated, the residue was adjusted to pH 1 with 2N dilute hydrochloric acid, 1 mL of water was added, stirred for 10 minutes, the filter cake was collected by filtration under reduced pressure, and dried to obtain compound 4b. 1 H NMR (400MHz, CD 3 OD) δ=8.04(s, 1H), 7.59(dd, J=8.4, 2.0Hz, 1H), 7.52-7.48(m, 2H), 7.44(d, J=8.0Hz , 1H), 6.85(d, J=8.4Hz, 1H), 4.40-4.35(m, 1H), 4.30-4.24(m, 1H), 2.77-2.65(m, 4H), 2.37(t, J=7.2 Hz, 2H), 2.26-2.17(m, 5H), 2.08-2.00(m, 3H), 1.88-1.81(m, 2H), 1.77-1.70(m, 2H), 0.94-0.90(m, 1H), 0.72-0.69 (m, 1H). LCMS: m/z 514.4 [M+H] + . SFC detection conditions: chromatographic column: Chiralpak IC-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 40%; flow rate: 3mL/min, retention time 0.770min, ee=100%.
实施例5Example 5
Figure PCTCN2022095009-appb-000106
Figure PCTCN2022095009-appb-000106
第一步first step
将中间体B(0.1g，1eq)和化合物5-1(35mg，1.1eq)加入乙腈(2mL)和四氢呋喃(2mL)的混合溶剂中，加入二异丙基乙胺(0.4mL)和4-二甲氨基吡啶(10mg，0.2eq)，搅拌10分钟，加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，0.5mL，2.2eq)，反应液在20～25℃回流反应10小时。加入乙酸乙酯(30mL)稀释，依次用水(20mL*2)和饱和氯化钠水溶液(30mL*1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓 缩，剩余物经制备薄层色谱分离纯化(石油醚/乙酸乙酯＝2∶1)得化合物5-2。LCMS：m/z 328.2[M+H] +。 Intermediate B (0.1g, 1eq) and compound 5-1 (35mg, 1.1eq) were added to a mixed solvent of acetonitrile (2mL) and tetrahydrofuran (2mL), diisopropylethylamine (0.4mL) and 4- Dimethylaminopyridine (10mg, 0.2eq), stirred for 10 minutes, added tri-n-propyl cyclic phosphoric anhydride (50% ethyl acetate solution, 0.5mL, 2.2eq), and the reaction solution was refluxed at 20-25°C React for 10 hours. Add ethyl acetate (30mL) to dilute, wash with water (20mL*2) and saturated aqueous sodium chloride solution (30mL*1) successively, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and separate the residue by preparative thin-layer chromatography Purification (petroleum ether/ethyl acetate=2:1) gave compound 5-2. LCMS: m/z 328.2 [M+H] + .
第二步second step
将化合物5-2(75mg，1eq)溶于四氢呋喃(2mL)中，加入一水合氢氧化锂(30mg，3.1eq)的水(1mL)溶液，反应液在20～25℃搅拌10小时。减压浓缩除去四氢呋喃，剩余物用2N稀盐酸调pH约为1，浓缩至干，得到化合物5-3粗品直接用于下一步反应。LCMS：m/z 314.0[M+H] +。 Compound 5-2 (75mg, 1eq) was dissolved in tetrahydrofuran (2mL), a solution of lithium hydroxide monohydrate (30mg, 3.1eq) in water (1mL) was added, and the reaction solution was stirred at 20-25°C for 10 hours. Concentrate under reduced pressure to remove tetrahydrofuran, adjust the pH of the residue to about 1 with 2N dilute hydrochloric acid, and concentrate to dryness to obtain the crude compound 5-3, which is directly used in the next reaction. LCMS: m/z 314.0 [M+H] + .
第三步third step
将化合物5-3(70mg，1eq)和中间体C(57mg，1.1eq)加入四氢呋喃(1.5mL)和乙腈(1.5mL)的混合溶剂中，加入二异丙基乙胺(0.2mL，5.1eq)和4-二甲氨基吡啶(6mg，0.2eq)，再加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，0.4mL，3.0eq)，反应液在20～25℃搅拌10小时。加入乙酸乙酯(30mL)稀释，依次用水(20mL*2)和饱和氯化钠水溶液(20mL*1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物经制备薄层色谱纯化(石油醚/乙酸乙酯＝1∶1)得到化合物5-4。Compound 5-3 (70mg, 1eq) and Intermediate C (57mg, 1.1eq) were added to a mixed solvent of tetrahydrofuran (1.5mL) and acetonitrile (1.5mL), and diisopropylethylamine (0.2mL, 5.1eq ) and 4-dimethylaminopyridine (6mg, 0.2eq), then added tri-n-propyl cyclic phosphoric anhydride (50% ethyl acetate solution, 0.4mL, 3.0eq), and the reaction solution was heated at 20-25°C Stir for 10 hours. Add ethyl acetate (30mL) to dilute, wash with water (20mL*2) and saturated aqueous sodium chloride solution (20mL*1) successively, dry over anhydrous sodium sulfate, filter, concentrate the filtrate under reduced pressure, and purify the residue by preparative thin-layer chromatography (petroleum ether/ethyl acetate=1:1) to obtain compound 5-4.
第四步the fourth step
将化合物5-4(100mg，1eq)溶于四氢呋喃(3mL)中，加入一水合氢氧化锂(24mg，3eq)的水(1.5mL)溶液，反应在20～25℃搅拌10小时。减压浓缩除去四氢呋喃，用2N稀盐酸调pH约为1，加水，搅拌5分钟，过滤，滤饼用2mL水淋洗，收集固体，干燥，再经SFC分离(分离条件：色谱柱：DAICEL CHIRALCEL OD(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；B％：45％-45％)得到化合物5a和化合物5b。 Compound 5-4 (100mg, 1eq) was dissolved in tetrahydrofuran (3mL), a solution of lithium hydroxide monohydrate (24mg, 3eq) in water (1.5mL) was added, and the reaction was stirred at 20-25°C for 10 hours. Concentrate under reduced pressure to remove tetrahydrofuran, adjust the pH to about 1 with 2N dilute hydrochloric acid, add water, stir for 5 minutes, filter, rinse the filter cake with 2 mL of water, collect the solid, dry, and then separate by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: phase A: CO 2 , phase B: [(0.1% ammonia)methanol]; B%: 45%-45%) to obtain compound 5a and compound 5b.
化合物5a(SFC检测条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为2.077min，ee＝99.4％)： 1H NMR(400MHz，CD 3OD)δ＝8.02(d，J＝1.6Hz，1H)，7.57(d，J＝8.4，2.0Hz，1H)，7.47-7.45(m，2H)，7.42(d，J＝8.0Hz，1H)，6.82(d，J＝8.4Hz，1H)，4.37-4.32(m，1H)，4.27-4.24(m，1H)，3.17-3.14(m，1H)，2.74-2.64(m，3H)，2.33-2.29(m，2H)，2.25-2.15(m，2H)，1.86-1.79(m，2H)，1.76-1.66(m，2H)，1.32-1.28(m，1H)，1.14-1.11(m，1H)，1.06-1.02(m，1H)，0.98-0.93(m，1H)，0.89-0.84(m，1H)，0.84-0.80(m，1H)。LCMS：m/z500.0[M+H] +。 Compound 5a (SFC detection conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3 μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% ~40%; flow rate: 3mL/min, retention time 2.077min, ee=99.4%): 1 H NMR (400MHz, CD 3 OD) δ=8.02(d, J=1.6Hz, 1H), 7.57(d, J=8.4, 2.0Hz, 1H), 7.47-7.45(m, 2H), 7.42(d, J=8.0Hz, 1H), 6.82(d, J=8.4Hz, 1H), 4.37-4.32(m, 1H ), 4.27-4.24(m, 1H), 3.17-3.14(m, 1H), 2.74-2.64(m, 3H), 2.33-2.29(m, 2H), 2.25-2.15(m, 2H), 1.86-1.79 (m, 2H), 1.76-1.66(m, 2H), 1.32-1.28(m, 1H), 1.14-1.11(m, 1H), 1.06-1.02(m, 1H), 0.98-0.93(m, 1H) , 0.89-0.84 (m, 1H), 0.84-0.80 (m, 1H). LCMS: m/z 500.0 [M+H] + .
化合物5b(SFC检测条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为2.264min，ee＝100％)： 1H NMR(400MHz，CD 3OD)δ＝8.04(d，J＝1.6Hz，1H)，7.58(d，J＝8.4，2.0Hz，1H)，7.47-7.44(m，2H)，7.42(d，J＝8.0Hz，1H)，6.82(d，J＝8.4Hz，1H)，4.38-4.31(m，1H)，4.28-4.23(m，1H)，3.18-3.14(m，1H)，2.80-2.67(m，3H)，2.31-2.15(m，4H)，1.88-1.79(m，2H)，1.75-1.67(m，2H)，1.31-1.28(m，1H)，1.14-1.11(m，1H)，1.06-1.02(m，1H)，0.98-0.93(m，1H)，0.88-0.84(m，1H)，0.83-0.80(m，1H)。LCMS：m/z 500.0[M+H] +。 Compound 5b (SFC detection conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3 μm, mobile phase: A phase: CO 2 , B phase: methanol (0.05% diethylamine); gradient: B%: 5% ~40%; flow rate: 3mL/min, retention time 2.264min, ee=100%): 1 H NMR (400MHz, CD 3 OD) δ=8.04(d, J=1.6Hz, 1H), 7.58(d, J=8.4, 2.0Hz, 1H), 7.47-7.44(m, 2H), 7.42(d, J=8.0Hz, 1H), 6.82(d, J=8.4Hz, 1H), 4.38-4.31(m, 1H ), 4.28-4.23(m, 1H), 3.18-3.14(m, 1H), 2.80-2.67(m, 3H), 2.31-2.15(m, 4H), 1.88-1.79(m, 2H), 1.75-1.67 (m, 2H), 1.31-1.28(m, 1H), 1.14-1.11(m, 1H), 1.06-1.02(m, 1H), 0.98-0.93(m, 1H), 0.88-0.84(m, 1H) , 0.83-0.80 (m, 1H). LCMS: m/z 500.0 [M+H] + .
实施例6Example 6
Figure PCTCN2022095009-appb-000107
Figure PCTCN2022095009-appb-000107
第一步first step
将化合物6-1(2.5g，1eq)和三氟甲基三甲基硅烷(7.04g，2.5eq)溶解于干燥的四氢呋喃(20mL)中，于20℃加入碘化钠(1.49g，0.5eq)，搅拌10分钟，升温至70℃，反应液在70℃反应12小时。加28mL水和28mL乙酸乙酯，分出有机层，用40mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物6-2。Compound 6-1 (2.5g, 1eq) and trifluoromethyltrimethylsilane (7.04g, 2.5eq) were dissolved in dry tetrahydrofuran (20mL), and sodium iodide (1.49g, 0.5eq ), stirred for 10 minutes, heated up to 70°C, and the reaction solution was reacted at 70°C for 12 hours. Add 28 mL of water and 28 mL of ethyl acetate, separate the organic layer, wash with 40 mL of saturated aqueous sodium chloride, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 6-2.
第二步second step
将化合物6-2(1.8g，1eq)溶于甲醇(5mL)和四氢呋喃(10mL)中，加入一水合氢氧化锂(1.29g，3eq)的5mL水溶液。混合物在20℃搅拌12小时。加入1M的HCl溶液(20mL)，10mL水稀释，二氯甲烷萃取两次，每次20mL，分出有机层，用30mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物6-3。Compound 6-2 (1.8g, 1eq) was dissolved in methanol (5mL) and tetrahydrofuran (10mL), and a 5mL aqueous solution of lithium hydroxide monohydrate (1.29g, 3eq) was added. The mixture was stirred at 20°C for 12 hours. Add 1M HCl solution (20mL), dilute with 10mL water, extract twice with dichloromethane, 20mL each time, separate the organic layer, wash with 30mL saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure Compound 6-3 was obtained.
第三步third step
将化合物6-3(0.5g，1eq)和三乙胺(624.11mg，2eq)溶于甲苯(5mL)中，降温至0℃，加入叠氮磷酸二苯酯(DPPA)(1.70g，2eq)，在0～20℃搅拌1小时后升温至90℃，搅拌2小时，加入苄醇(667mg，2eq)，反应液继续搅拌12小时。反应液过滤，滤液减压浓缩得到化合物6-4。Compound 6-3 (0.5g, 1eq) and triethylamine (624.11mg, 2eq) were dissolved in toluene (5mL), cooled to 0°C, and diphenylphosphoryl azide (DPPA) (1.70g, 2eq) was added , stirred at 0-20°C for 1 hour, then heated to 90°C, stirred for 2 hours, added benzyl alcohol (667mg, 2eq), and the reaction solution continued to stir for 12 hours. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-4.
第四步the fourth step
将化合物6-4(0.4g，1eq)溶于乙腈(5mL)中，于25℃加入三甲基碘硅烷(299mg，1eq)，反应液在25℃搅拌30分钟。随后加入三乙胺(151mg，1eq)，继续搅拌30分钟。向反应液中加入5mL饱和碳酸氢钠溶液，2mL水稀释，二氯甲烷萃取两次，每次4mL，分出有机层，用10mL饱和氯化钠水溶液洗涤，无水 硫酸钠干燥，过滤，滤液减压浓缩得到化合物6-5。Compound 6-4 (0.4g, 1eq) was dissolved in acetonitrile (5mL), and iodotrimethylsilane (299mg, 1eq) was added at 25°C, and the reaction solution was stirred at 25°C for 30 minutes. Triethylamine (151 mg, 1 eq) was then added and stirring continued for 30 minutes. Add 5mL saturated sodium bicarbonate solution to the reaction solution, dilute with 2mL water, extract twice with dichloromethane, 4mL each time, separate the organic layer, wash with 10mL saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and the filtrate Concentration under reduced pressure gave compound 6-5.
第五步the fifth step
将化合物6-5(0.2g，1eq)和中间体B(292mg，0.74eq)溶于乙腈(5mL)和四氢呋喃(3mL)混合溶剂中，加入4-二甲氨基吡啶(DMAP)(184mg，1eq)和二异丙基乙胺(291mg，1.5eq)，混合物在20℃搅拌10分钟后加入三正丙基环磷酸酐(T 3P，2.87g，50％含量的乙酸乙酯溶液，3eq)，反应混合物继续搅拌2小时。加10mL水稀释，用乙酸乙酯萃取2次，每次4mL，8mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物6-6。LCMS：m/z 378.1[M+H] +。 Compound 6-5 (0.2g, 1eq) and intermediate B (292mg, 0.74eq) were dissolved in acetonitrile (5mL) and tetrahydrofuran (3mL) in a mixed solvent, and 4-dimethylaminopyridine (DMAP) (184mg, 1eq ) and diisopropylethylamine (291mg, 1.5eq), the mixture was stirred at 20°C for 10 minutes and tri-n-propyl cyclic phosphoric anhydride (T 3 P, 2.87g, 50% content of ethyl acetate solution, 3eq) was added , the reaction mixture was stirred for an additional 2 hours. It was diluted with 10 mL of water, extracted twice with ethyl acetate, 4 mL each time, washed with 8 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-6. LCMS: m/z 378.1 [M+H] + .
第六步step six
将化合物6-6(0.3g，1eq)溶于甲醇(5mL)和四氢呋喃(5mL)中，加入一水合氢氧化锂(100mg，3eq)的3mL水溶液。混合物在20℃搅拌1.5小时。加入2M的HCl溶液(5mL)，10mL水稀释，二氯甲烷萃取两次，每次4mL，分出有机层，用8mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物6-7。LCMS：m/z 364.1[M+H] +。 Compound 6-6 (0.3g, 1eq) was dissolved in methanol (5mL) and tetrahydrofuran (5mL), and a 3mL aqueous solution of lithium hydroxide monohydrate (100mg, 3eq) was added. The mixture was stirred at 20°C for 1.5 hours. Add 2M HCl solution (5mL), dilute with 10mL water, extract twice with dichloromethane, 4mL each time, separate the organic layer, wash with 8mL saturated aqueous sodium chloride solution, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure Compound 6-7 was obtained. LCMS: m/z 364.1 [M+H] + .
第七步step seven
将化合物6-7(0.22g，1eq)和中间体C(141mg，1eq)溶于乙腈(5mL)和四氢呋喃(3mL)的混合溶剂中，加入4-二甲氨基吡啶(DMAP)(74mg，1eq)和二异丙基乙胺(117mg，1.5eq)，混合物在20℃搅拌10分钟后，加入三正丙基环磷酸酐(T 3P，1.16g，50％含量的乙酸乙酯溶液，3eq)，反应混合物继续搅拌2小时。加5mL水稀释，用乙酸乙酯萃取2次，每次4mL，再用12mL饱和氯化钠水溶洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物6-8。LCMS：m/z 578.2[M+H] +。 Compound 6-7 (0.22g, 1eq) and Intermediate C (141mg, 1eq) were dissolved in a mixed solvent of acetonitrile (5mL) and tetrahydrofuran (3mL), and 4-dimethylaminopyridine (DMAP) (74mg, 1eq ) and diisopropylethylamine (117mg, 1.5eq), after the mixture was stirred at 20°C for 10 minutes, tri-n-propyl cyclic phosphoric anhydride (T 3 P, 1.16g, 50% content of ethyl acetate solution, 3eq ), and the reaction mixture was stirred for 2 hours. It was diluted with 5 mL of water, extracted twice with 4 mL of ethyl acetate, washed with 12 mL of saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain compound 6-8. LCMS: m/z 578.2 [M+H] + .
第八步eighth step
将化合物6-8(62mg，1eq)溶于四氢呋喃(3mL)和甲醇(3mL)的混合溶剂中，加入一水合氢氧化锂(13.5mg，3eq)溶于水(1mL)的溶液，反应混合物在20℃搅拌2小时。减压浓缩移除四氢呋喃，剩余物用2N稀盐酸调节pH为1，加入5mL水稀释，乙酸乙酯萃取两次，每次4mL，分出有机层，用12mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到粗品，经高效液相色谱法制备分离(色谱柱：Phenomenex Synergi Polar-RP 100*25mm*4μm；流动相：[水(0.1％三氟乙酸)-乙腈]；乙腈％：62％-82％)纯化，再经SFC拆分(分离条件：色谱柱：DAICEL CHIRALCEL OD(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；B％：60％-60％)得到化合物6a。LCMS：m/z 550.4[M+H] +。SFC分析条件：色谱柱：OD 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为2.133min。LCMS：m/z 550.4[M+H] +； 1H NMR(400MHz，CDCl 3)δ＝9.85(s，1H)，8.80(d，J＝1.3Hz，1H)，7.84(d，J＝2.0Hz，1H)，7.21(d，J＝1.5Hz，1H)，7.12(d，J＝7.5Hz，2H)，6.73(d，J＝8.5Hz，1H)，5.84(brd，J＝6.6Hz，1H)，4.50-4.39(m，2H)，4.30-4.22(m，1H)，3.50-3.47(m，1H)，2.68-2.60(m，2H)， 2.57-2.47(m，1H)，2.45-2.40(m，1H)，2.39-2.29(m，2H)，2.12-2.03(m，2H)，1.68(br d，J＝2.1Hz，1H)，1.65(br d，J＝2.0Hz，1H)，1.61(br d，J＝2.3Hz，1H)，1.50-1.47(m，1H)，1.35-1.29(m，2H)，0.86-0.76(m，1H)，0.69-0.59(m，1H)。 Compound 6-8 (62mg, 1eq) was dissolved in a mixed solvent of tetrahydrofuran (3mL) and methanol (3mL), and a solution of lithium hydroxide monohydrate (13.5mg, 3eq) dissolved in water (1mL) was added, and the reaction mixture was Stir at 20°C for 2 hours. Concentrate under reduced pressure to remove tetrahydrofuran, adjust the pH of the residue to 1 with 2N dilute hydrochloric acid, add 5 mL of water to dilute, extract twice with ethyl acetate, 4 mL each time, separate the organic layer, wash with 12 mL of saturated aqueous sodium chloride solution, anhydrous Sodium sulfate was dried, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was prepared and separated by high performance liquid chromatography (chromatographic column: Phenomenex Synergi Polar-RP 100*25mm*4μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile ]; acetonitrile%: 62%-82%) purification, and then SFC resolution (separation conditions: chromatographic column: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [( 0.1% ammonia water) methanol]; B%: 60%-60%) to obtain compound 6a. LCMS: m/z 550.4 [M+H] + . SFC analysis conditions: chromatographic column: OD 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% ~ 40%; flow rate: 3mL/min, the retention time is 2.133min. LCMS: m/z 550.4[M+H] + ; 1 H NMR (400MHz, CDCl 3 ) δ=9.85(s, 1H), 8.80(d, J=1.3Hz, 1H), 7.84(d, J=2.0 Hz, 1H), 7.21(d, J=1.5Hz, 1H), 7.12(d, J=7.5Hz, 2H), 6.73(d, J=8.5Hz, 1H), 5.84(brd, J=6.6Hz, 1H), 4.50-4.39(m, 2H), 4.30-4.22(m, 1H), 3.50-3.47(m, 1H), 2.68-2.60(m, 2H), 2.57-2.47(m, 1H), 2.45- 2.40(m, 1H), 2.39-2.29(m, 2H), 2.12-2.03(m, 2H), 1.68(br d, J=2.1Hz, 1H), 1.65(br d, J=2.0Hz, 1H) , 1.61 (br d, J=2.3Hz, 1H), 1.50-1.47 (m, 1H), 1.35-1.29 (m, 2H), 0.86-0.76 (m, 1H), 0.69-0.59 (m, 1H).
实施例7Example 7
Figure PCTCN2022095009-appb-000108
Figure PCTCN2022095009-appb-000108
第一步first step
将二异丙胺(7.16g，10mL，1.2eq)加至20mL四氢呋喃，降温至0℃，滴加正丁基锂(2.5M，28mL，1.19eq)，于0℃搅拌15分钟制得二异丙基氨基锂(LDA)溶液，降温至-68℃备用。将化合物7-2(6.0g，6.73mL，1eq)加至15mL四氢呋喃，降温至-68℃，滴加制得的LDA溶液，于-68℃搅拌30分钟，随后滴加化合物7-1(15.57g，9mL，1.00eq)，于-68℃搅拌15分钟，移除冷却浴，缓慢升温至20℃继续搅拌10小时。滴加100mL饱和氯化铵水溶液，乙酸乙酯萃取(100mL×2)，合并有机相，水(100mL)洗涤，饱和食盐水(100mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，经柱层析(石油醚∶乙酸乙酯＝100∶1～50∶1)分离得到化合物7-3。 1H NMR(400MHz，CDCl 3)δ7.35-7.27(m，1H)，7.18-7.14(m，1H)，7.02(d，J＝8.4Hz， 1H)，6.97(d，J＝8.4Hz，1H)，3.60(s，3H)，2.49-2.37(m，2H)，1.80-1.67(m，2H)，1.17(s，6H)。 Add diisopropylamine (7.16g, 10mL, 1.2eq) to 20mL tetrahydrofuran, cool down to 0°C, add n-butyllithium (2.5M, 28mL, 1.19eq) dropwise, and stir at 0°C for 15 minutes to obtain diisopropylamine Lithium amide (LDA) solution was cooled to -68°C for later use. Compound 7-2 (6.0g, 6.73mL, 1eq) was added to 15mL of tetrahydrofuran, cooled to -68°C, the prepared LDA solution was added dropwise, stirred at -68°C for 30 minutes, and then compound 7-1 (15.57 g, 9mL, 1.00eq), stirred at -68°C for 15 minutes, removed the cooling bath, slowly raised the temperature to 20°C and continued to stir for 10 hours. Add dropwise 100mL saturated aqueous ammonium chloride solution, extract with ethyl acetate (100mL×2), combine the organic phases, wash with water (100mL), wash with saturated brine (100mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, pass through the column Compound 7-3 was obtained by chromatography (petroleum ether: ethyl acetate = 100:1 to 50:1). 1 H NMR (400MHz, CDCl 3 ) δ7.35-7.27(m, 1H), 7.18-7.14(m, 1H), 7.02(d, J=8.4Hz, 1H), 6.97(d, J=8.4Hz, 1H), 3.60(s, 3H), 2.49-2.37(m, 2H), 1.80-1.67(m, 2H), 1.17(s, 6H).
第二步second step
将化合物7-3(2.4g，1eq)加至20mL氮甲基吡咯烷酮中，于20℃加入氰化亚铜(2.26g，3eq)，20℃搅拌10分钟后将该溶液加热至180℃搅拌4小时。冷却至室温，搅拌下将反应液倒入60mL冷水中，乙酸乙酯萃取(15mL*2)，合并有机相，水(15mL*2)洗涤，饱和食盐水(30mL*1)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，经柱层析(石油醚∶乙酸乙酯＝20∶1～8∶1)分离得到化合物7-4。MS：m/z 232.3[M+H] +， 1H NMR(400MHz，CDCl 3)δ＝7.35-7.29(m，1H)，7.18-7.13(m，1H)，7.03(d，J＝8.3Hz，1H)，6.97(d，J＝8.3Hz，1H)，3.60(s，3H)，2.47-2.38(m，2H)，1.77-1.70(m，2H)，1.17(s，6H)。 Add compound 7-3 (2.4g, 1eq) to 20mL nitrogen methyl pyrrolidone, add cuprous cyanide (2.26g, 3eq) at 20°C, stir at 20°C for 10 minutes, then heat the solution to 180°C and stir for 4 Hour. Cool to room temperature, pour the reaction solution into 60 mL of cold water with stirring, extract with ethyl acetate (15 mL*2), combine the organic phases, wash with water (15 mL*2), wash with saturated brine (30 mL*1), and anhydrous sulfuric acid Dry over sodium, filter, concentrate the filtrate, and separate by column chromatography (petroleum ether: ethyl acetate = 20:1 ~ 8:1) to obtain compound 7-4. MS: m/z 232.3[M+H] + , 1 H NMR (400MHz, CDCl 3 ) δ=7.35-7.29(m, 1H), 7.18-7.13(m, 1H), 7.03(d, J=8.3Hz , 1H), 6.97 (d, J=8.3Hz, 1H), 3.60 (s, 3H), 2.47-2.38 (m, 2H), 1.77-1.70 (m, 2H), 1.17 (s, 6H).
第三步third step
将化合物7-4(1.6g，1eq)加至10mL三氟乙酸酐中，并将该溶液降温至0～5℃，15分钟内滴加硝酸(2.10g，1.5mL，65％含量，3.13eq)至反应体系，控制内温不超过10℃，随后于0～10℃搅拌30分钟。反应液中加入30克冰水和30mL饱和碳酸氢钠溶液，于0～10℃搅拌30分钟，乙酸乙酯萃取(15mL*2)，合并有机相，饱和食盐水(15mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物7-5。Compound 7-4 (1.6g, 1eq) was added to 10mL of trifluoroacetic anhydride, and the solution was cooled to 0-5°C, and nitric acid (2.10g, 1.5mL, 65% content, 3.13eq ) into the reaction system, control the internal temperature not to exceed 10°C, and then stir at 0-10°C for 30 minutes. Add 30 g of ice water and 30 mL of saturated sodium bicarbonate solution to the reaction solution, stir at 0-10°C for 30 minutes, extract with ethyl acetate (15 mL*2), combine the organic phases, wash with saturated brine (15 mL*2), and remove Dry over sodium sulfate, filter, and concentrate the filtrate to obtain compound 7-5.
第四步the fourth step
将化合物7-5(1.5g，1eq)和氯化铵(871.21mg，3eq)加入乙醇(20mL)和水(10mL)中，氮气保护下加入铁粉(1.52g，5eq)，于20℃下搅拌10分钟，随后加热至75℃搅拌12小时。反应液经硅藻土过滤，滤液减压浓缩，加入水(13mL)稀释，乙酸乙酯萃取(15mL*2)，合并有机相，用饱和食盐水洗(10mL*2)，无水硫酸钠干燥，滤液减压浓缩得到化合物7-6。MS：m/z 247.1[M+H] +。 1H NMR(400MHz，CDCl 3)δ＝7.06(d，J＝7.7Hz，1H)，6.96(dd，J＝1.4，7.6Hz，1H)，6.90(d，J＝1.3Hz，1H)，4.38(br s，2H)，3.73(s，3H)，2.52-2.43(m，2H)，1.80-1.69(m，2H)，1.31-1.24(s，6H)。 Compound 7-5 (1.5g, 1eq) and ammonium chloride (871.21mg, 3eq) were added to ethanol (20mL) and water (10mL), iron powder (1.52g, 5eq) was added under nitrogen protection, and at 20°C Stir for 10 minutes, then heat to 75°C and stir for 12 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, diluted with water (13 mL), extracted with ethyl acetate (15 mL*2), the organic phases were combined, washed with saturated brine (10 mL*2), dried over anhydrous sodium sulfate, The filtrate was concentrated under reduced pressure to obtain compound 7-6. MS: m/z 247.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ = 7.06 (d, J = 7.7Hz, 1H), 6.96 (dd, J = 1.4, 7.6Hz, 1H), 6.90 (d, J = 1.3Hz, 1H), 4.38 (br s, 2H), 3.73 (s, 3H), 2.52-2.43 (m, 2H), 1.80-1.69 (m, 2H), 1.31-1.24 (s, 6H).
第五步the fifth step
将化合物7-6(2.29g，1.3eq)和中间体D(1.5g，1eq)溶解于10mL乙腈和10mL四氢呋喃中，于20℃加入二异丙基乙胺(1.57g，2.12mL，2eq)和4-二甲氨基吡啶(DMAP)(148.80mg，0.2eq)，反应液在氮气保护下于20℃搅拌10分钟。20℃加入三正丙基环磷酸酐(T 3P，11.63g，10.87mL，50％含量的乙酸乙酯溶液，3eq)，反应液在20℃下搅拌2个小时。反应液减压浓缩，加入水(3mL)稀释，乙酸乙酯萃取(4mL*2)，合并有机相，用饱和食盐水洗(3mL*2)，无水硫酸钠干燥，滤液减压浓缩得到粗品，经高效液相色谱法制备分离(色谱柱：Phenomenex Synergi Max-RP 250*50mm*10μm；流动相：[水(0.1％三氟乙酸)-乙腈]；乙腈％：45％-75％，35min)纯化得到化合物7-7。 Compound 7-6 (2.29g, 1.3eq) and intermediate D (1.5g, 1eq) were dissolved in 10mL of acetonitrile and 10mL of tetrahydrofuran, and diisopropylethylamine (1.57g, 2.12mL, 2eq) was added at 20°C and 4-dimethylaminopyridine (DMAP) (148.80mg, 0.2eq), and the reaction solution was stirred at 20°C for 10 minutes under nitrogen protection. Tri-n-propyl cyclic phosphoric anhydride (T 3 P, 11.63g, 10.87mL, 50% ethyl acetate solution, 3eq) was added at 20°C, and the reaction solution was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (3 mL), extracted with ethyl acetate (4 mL*2), the organic phases were combined, washed with saturated brine (3 mL*2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product. Prepared and separated by high performance liquid chromatography (chromatographic column: Phenomenex Synergi Max-RP 250*50mm*10μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile%: 45%-75%, 35min) Purification affords compound 7-7.
第六步step six
化合物7-7经SFC分离(分离条件：色谱柱：DAICEL CHIRALPAK AD(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)异丙醇]；B％：20％-20％)得到化合物7-7a。SFC检测条件：色谱柱：Chiralpak AD-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：异丙醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.636min，ee＝100％。MS：m/z 518.3[M+H] +。 Compound 7-7 was separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) isopropanol]; B% : 20%-20%) to obtain compound 7-7a. SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: isopropanol (0.05% diethylamine); gradient: B%: 5%～ 40%; flow rate: 3mL/min, retention time 1.636min, ee=100%. MS: m/z 518.3 [M+H] + .
第七步step seven
于20℃下向化合物7-7a(2.2g，1eq)的四氢呋喃(20mL)溶液中加入三甲基硅醇钾(1.64g，3eq)，反应液在氮气保护下于20℃下搅拌12个小时。反应液用2N稀盐酸调节反应体系pH值至5，加入水(20mL)稀释，乙酸乙酯萃取(20mL*2)，合并有机相，用饱和食盐水洗(25mL*1)，无水硫酸钠干燥，滤液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝3∶1～0∶1)分离得到化合物7a。SFC检测条件：色谱柱：Chiralpak AD-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.409min，ee＝97.2％。MS：m/z 504.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ＝9.85(s，1H)，8.79(s，1H)，7.85(s，1H)，7.18(br s，1H)，7.10(d，J＝7.8Hz，1H)，6.73(br d，J＝8.3Hz，1H)，5.95(br d，J＝7.6Hz，1H)，4.46(d，J＝10.4Hz，1H)，4.29-4.18(m，2H)，3.48(dd，J＝6.5，8.2Hz，1H)，2.62(br t，J＝8.5Hz，2H)，2.23-1.99(m，2H)，1.84-1.63(m，1H)，1.56-1.42(m，2H)，1.29(s，3H)，1.21-1.18(m，10H)。 Add potassium trimethylsilanolate (1.64g, 3eq) to a solution of compound 7-7a (2.2g, 1eq) in tetrahydrofuran (20mL) at 20°C, and the reaction solution was stirred at 20°C under nitrogen protection for 12 hours . Adjust the pH of the reaction system to 5 with 2N dilute hydrochloric acid, add water (20mL) to dilute, extract with ethyl acetate (20mL*2), combine the organic phases, wash with saturated brine (25mL*1), and dry over anhydrous sodium sulfate , the filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 3:1 ~ 0:1) to obtain compound 7a. SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 1.409min, ee=97.2%. MS: m/z 504.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ=9.85(s, 1H), 8.79(s, 1H), 7.85(s, 1H), 7.18(br s, 1H), 7.10(d, J=7.8Hz, 1H ), 6.73 (br d, J=8.3Hz, 1H), 5.95 (br d, J=7.6Hz, 1H), 4.46 (d, J=10.4Hz, 1H), 4.29-4.18 (m, 2H), 3.48 (dd, J=6.5, 8.2Hz, 1H), 2.62(br t, J=8.5Hz, 2H), 2.23-1.99(m, 2H), 1.84-1.63(m, 1H), 1.56-1.42(m, 2H), 1.29 (s, 3H), 1.21-1.18 (m, 10H).
实施例8Example 8
Figure PCTCN2022095009-appb-000109
Figure PCTCN2022095009-appb-000109
Figure PCTCN2022095009-appb-000110
Figure PCTCN2022095009-appb-000110
第一步first step
将2-甲基丙酸甲酯(10g，11.22mL，1eq)加入200mL无水四氢呋喃中，降温至-70℃并用氮气置换，于-70℃下滴加二异丙基氨基锂(LDA)(2M，73.43mL，1.5eq)，-70～-40℃搅拌30分钟。将化合物8-1(20.16g，1.05eq)溶于50mL四氢呋喃，于-70℃下滴加至反应体系，后自然升温至20℃搅拌1小时。反应液用饱和氯化铵水溶液(200mL)淬灭，于25℃下搅拌10分钟，乙酸乙酯萃取(80mL*3)，合并有机相，用饱和食盐水洗(60mL*2)，无水硫酸钠干燥，滤液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝10∶1～5∶1)分离得到化合物8-2。Methyl 2-methylpropionate (10g, 11.22mL, 1eq) was added into 200mL of anhydrous tetrahydrofuran, cooled to -70°C and replaced with nitrogen, and lithium diisopropylamide (LDA) was added dropwise at -70°C ( 2M, 73.43mL, 1.5eq), stirred at -70～-40°C for 30 minutes. Compound 8-1 (20.16g, 1.05eq) was dissolved in 50mL of tetrahydrofuran, and added dropwise to the reaction system at -70°C, then naturally heated to 20°C and stirred for 1 hour. The reaction solution was quenched with saturated ammonium chloride aqueous solution (200mL), stirred at 25°C for 10 minutes, extracted with ethyl acetate (80mL*3), combined the organic phases, washed with saturated brine (60mL*2), anhydrous sodium sulfate After drying, the filtrate was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 10:1 ~ 5:1) to obtain compound 8-2.
第二步second step
将化合物8-2(10g，1eq)加入甲醇(20mL)和四氢呋喃(30mL)混合溶剂中，取一水合氢氧化锂(5.79g，3eq)溶于水(10mL)中，搅拌下将该溶液加至反应体系，并于25℃下搅拌12小时。反应液减压浓缩，用2N稀盐酸水溶液调节反应体系pH值至5，乙酸乙酯萃取(50mL*2)，合并有机相，用饱和食盐水洗(50mL*1)，无水硫酸钠干燥，滤液减压浓缩得到化合物8-3。Compound 8-2 (10g, 1eq) was added into a mixed solvent of methanol (20mL) and tetrahydrofuran (30mL), and lithium hydroxide monohydrate (5.79g, 3eq) was dissolved in water (10mL), and the solution was added to to the reaction system and stirred at 25°C for 12 hours. The reaction solution was concentrated under reduced pressure, the pH value of the reaction system was adjusted to 5 with 2N dilute hydrochloric acid aqueous solution, extracted with ethyl acetate (50mL*2), the organic phases were combined, washed with saturated brine (50mL*1), dried over anhydrous sodium sulfate, and the filtrate Concentration under reduced pressure gave compound 8-3.
第三步third step
将化合物8-3(7.5g，1eq)和N，N-二甲基甲酰胺(47.50mg，50.00μL，0.018eq)加至100mL二氯甲烷，降温至0℃，滴加草酰氯(9.37g，6.46mL，2eq)，于0～20℃搅拌1小时。反应液浓缩得化合物8-4。Compound 8-3 (7.5g, 1eq) and N,N-dimethylformamide (47.50mg, 50.00μL, 0.018eq) were added to 100mL of dichloromethane, cooled to 0°C, and oxalyl chloride (9.37g , 6.46mL, 2eq), stirred at 0-20°C for 1 hour. The reaction solution was concentrated to obtain compound 8-4.
第四步the fourth step
将化合物8-4(7.5g，1eq)加至200mL二氯甲烷，降温至0～5℃，30分钟内依次滴加(三甲基硅烷基)重氮甲烷(2M，33.83mL，2eq)的正己烷溶液和三乙胺(7.05g，9.70mL，2.06eq)，滴加过程控制内温在5～10℃，随后于0～10℃搅拌1小时，20～30℃搅拌10小时反应液中加入80mL乙酸乙酯，搅拌15分钟，硅藻土过滤，滤液浓缩得粗品，经柱层析(石油醚∶乙酸乙酯＝5∶1～3∶1)分离得到化合物8-5。Compound 8-4 (7.5g, 1eq) was added to 200mL of dichloromethane, cooled to 0-5°C, and (trimethylsilyl) diazomethane (2M, 33.83mL, 2eq) was added dropwise within 30 minutes. n-Hexane solution and triethylamine (7.05g, 9.70mL, 2.06eq), control the internal temperature at 5-10°C during the dropwise addition, then stir at 0-10°C for 1 hour, and stir at 20-30°C for 10 hours in the reaction solution Add 80 mL of ethyl acetate, stir for 15 minutes, filter with celite, and concentrate the filtrate to obtain a crude product, which is separated by column chromatography (petroleum ether: ethyl acetate = 5:1 ~ 3:1) to obtain compound 8-5.
第五步the fifth step
暗黑环境下将化合物8-5(4.6g，1eq)加至50mL甲醇和50mL二氧六环中，称取苯甲酸银(695.22mg，0.15eq)溶于三乙胺(11.67g，16.06mL，5.7eq)，并将该溶液于0～5℃滴加至反应体系，随后于0～5℃搅拌12小时。反应液中加入30mL乙酸乙酯，搅拌15分钟，硅藻土过滤，滤液浓缩得粗品，经制备薄层色谱(石油醚∶乙酸乙酯＝6∶1～3∶1)分离得到化合物8-6。Add compound 8-5 (4.6g, 1eq) to 50mL of methanol and 50mL of dioxane in a dark environment, weigh silver benzoate (695.22mg, 0.15eq) and dissolve it in triethylamine (11.67g, 16.06mL, 5.7eq), and the solution was added dropwise to the reaction system at 0-5°C, followed by stirring at 0-5°C for 12 hours. Add 30 mL of ethyl acetate to the reaction solution, stir for 15 minutes, filter through celite, and concentrate the filtrate to obtain a crude product, which is separated by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 6:1 ~ 3:1) to obtain compound 8-6 .
第六步step six
将化合物8-6(1.8g，1eq)加至15mL三氟乙酸酐中，并将该溶液降温至3℃，15分钟内滴加硝酸(3.77g，2.69mL，65％含量，5eq)至反应体系，控制内温不超过20℃，随后于3～20℃搅拌15分钟。反应液中加入30mL冰水，乙酸乙酯萃取(20mL*2)，合并有机相，依次用水(20mL*1)，饱和碳酸氢钠溶液(20mL*2)，饱和食盐水(30mL*1)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物8-7。Compound 8-6 (1.8g, 1eq) was added to 15mL of trifluoroacetic anhydride, and the solution was cooled to 3°C, and nitric acid (3.77g, 2.69mL, 65% content, 5eq) was added dropwise within 15 minutes to the reaction system, control the internal temperature not to exceed 20°C, and then stir at 3-20°C for 15 minutes. Add 30mL of ice water to the reaction solution, extract with ethyl acetate (20mL*2), combine the organic phases, wash with water (20mL*1), saturated sodium bicarbonate solution (20mL*2), and saturated brine (30mL*1) successively , dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 8-7.
第七步step seven
将化合物8-7(1g，1eq)加入乙醇(20mL)中，氮气保护下加入湿钯碳(0.2g，10％含量)，接入氢气球，置换3次后于25℃、15Psi下搅拌2小时，反应液经硅藻土过滤，滤液减压浓缩，经高效液相色谱法制备分离(色谱柱：Phenomenex luna C18 150*40mm*15μm；流动相：[水(0.1％三氟乙酸)-乙腈]；乙腈％：37％-67％，10min)纯化得到化合物8-8。MS：m/z 247.2[M+H] +。 Add compound 8-7 (1g, 1eq) into ethanol (20mL), add wet palladium carbon (0.2g, 10% content) under nitrogen protection, insert a hydrogen balloon, replace it three times, and stir at 25°C and 15Psi for 2 Hours, the reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and separated by high performance liquid chromatography (chromatographic column: Phenomenex luna C18 150*40mm*15 μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile ]; acetonitrile%: 37%-67%, 10min) purification to obtain compound 8-8. MS: m/z 247.2 [M+H] + .
第八步eighth step
将中间体Da(300mg，1eq)加入N，N-二甲基甲酰胺(10mL)中，降温至0℃加入二异丙基乙胺(201.01mg，270.91μL，1.5eq)，搅拌10分钟后加入1-(3-二甲氨基丙基)-3-乙基碳二亚胺盐酸盐(EDCI)(397.55mg，2eq)和1-羟基苯并三唑(HOBt)(280.21mg，2eq)，并于0℃下搅拌30分钟。随后加入化合物8-8(255.39mg，1eq)，于0～20℃下搅拌1小时。反应液减压浓缩，加入水(15mL)稀释，乙酸乙酯萃取(10mL*2)，合并有机相，用饱和食盐水洗(15mL*1)，无水硫酸钠干燥，滤液减压浓缩得到粗品，粗品经柱层析(石油醚∶乙酸乙酯＝5∶1～3∶1)分离得到化合物8-9a。MS：m/z 518.4[M+H] +。 Add the intermediate Da (300mg, 1eq) into N,N-dimethylformamide (10mL), cool down to 0°C, add diisopropylethylamine (201.01mg, 270.91μL, 1.5eq), and stir for 10 minutes Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) (397.55mg, 2eq) and 1-hydroxybenzotriazole (HOBt) (280.21mg, 2eq) , and stirred at 0°C for 30 minutes. Then compound 8-8 (255.39mg, 1eq) was added, and stirred at 0-20°C for 1 hour. The reaction solution was concentrated under reduced pressure, diluted with water (15 mL), extracted with ethyl acetate (10 mL*2), the organic phases were combined, washed with saturated brine (15 mL*1), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated by column chromatography (petroleum ether: ethyl acetate = 5:1 ~ 3:1) to obtain compound 8-9a. MS: m/z 518.4 [M+H] + .
第九步Ninth step
将化合物8-9a(90mg，99.45％纯度，1eq)加入四氢呋喃(5mL)中，搅拌下加入三甲基硅醇钾(66.55mg，3eq)，并于25℃下搅拌12小时。反应液用饱和柠檬酸水溶液调节反应体系pH值至6-7，减压浓缩，加入水(6mL)稀释，乙酸乙酯萃取(5mL*2)，合并有机相，用饱和食盐水洗(20mL*1)，无水硫酸钠干燥，滤液减压浓缩得粗品，经高效液相色谱法制备分离(色谱柱：Phenomenex Gemini-NX C18 75*30mm*3μm；流动相：[水(10mM碳酸氢铵)-乙腈]；B(乙腈)％：14％-44％，8min)纯化得到化合物8a。SFC检测条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.695min，ee＝100％。MS：m/z 504.3[M+H] +。 1H NMR(400MHz，CDCl 3)δ＝10.12(br s，1H)，8.76(s，1H)，7.78(s，1H)，7.19-7.16(m，2H)，7.14-7.10(m，1H)，6.73(d，J＝8.4Hz，1H)，5.97(br d，J＝7.7Hz，1H)，4.45(br d，J＝10.6Hz，1H)，4.32-4.13(m，2H)，3.29(br s，1H)，2.94(br s，1H)，2.80(br d，J＝13.2Hz，1H)，2.24(br s，2H)，2.17-2.03(m，2H)，1.48-1.45(m，1H)，1.21-1.18(m，7H)，0.95(s，3H)，0.89(s，3H)。 Compound 8-9a (90mg, 99.45% purity, 1eq) was added to tetrahydrofuran (5mL), potassium trimethylsiliconate (66.55mg, 3eq) was added with stirring, and stirred at 25°C for 12 hours. The reaction solution was adjusted to pH 6-7 with saturated aqueous citric acid solution, concentrated under reduced pressure, diluted with water (6 mL), extracted with ethyl acetate (5 mL*2), combined organic phases, and washed with saturated brine (20 mL*1 ), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product, which was prepared and separated by high performance liquid chromatography (chromatographic column: Phenomenex Gemini-NX C18 75*30mm*3 μm; mobile phase: [water (10mM ammonium bicarbonate)- Acetonitrile]; B (acetonitrile)%: 14%-44%, 8min) was purified to obtain compound 8a. SFC detection conditions: Chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm Mobile phase: A phase: CO 2 , B phase: methanol (0.05% diethylamine); Gradient: B%: 5% ~ 40%; Flow rate: 3 mL/min, retention time 1.695 min, ee=100%. MS: m/z 504.3 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ=10.12(br s, 1H), 8.76(s, 1H), 7.78(s, 1H), 7.19-7.16(m, 2H), 7.14-7.10(m, 1H) , 6.73(d, J=8.4Hz, 1H), 5.97(br d, J=7.7Hz, 1H), 4.45(br d, J=10.6Hz, 1H), 4.32-4.13(m, 2H), 3.29( br s, 1H), 2.94(br s, 1H), 2.80(br d, J=13.2Hz, 1H), 2.24(br s, 2H), 2.17-2.03(m, 2H), 1.48-1.45(m, 1H), 1.21-1.18 (m, 7H), 0.95 (s, 3H), 0.89 (s, 3H).
实施例9Example 9
Figure PCTCN2022095009-appb-000111
Figure PCTCN2022095009-appb-000111
第一步first step
将化合物9-1(4g，1eq)加入甲醇(80mL)中，氮气保护下加入氯化亚砜(7.38g，4.50mL，2.5eq)，于0～25℃下搅拌6小时。反应液减压浓缩得到化合物9-2。Compound 9-1 (4g, 1eq) was added into methanol (80mL), and thionyl chloride (7.38g, 4.50mL, 2.5eq) was added under nitrogen protection, and stirred at 0-25°C for 6 hours. The reaction solution was concentrated under reduced pressure to obtain compound 9-2.
第二步second step
将化合物9-2(4.5g，1eq)加入四氢呋喃(90mL)中，冷却至0℃，氮气保护下加入氢化钠(2.57g，60％含量，2.5eq)和碘甲烷(12.76g，5.60mL，3.5eq)，于0～25℃下搅拌6小时，反应液用饱和氯化铵水溶液(10mL)淬灭，于25℃下搅拌10分钟，乙酸乙酯萃取(20mL*3)，合并有机相，用饱和食盐水洗(20mL*1)，无水硫酸钠干燥，滤液减压浓缩得到化合物9-3。MS：m/z 204.2[M+H] +。 Add compound 9-2 (4.5g, 1eq) into tetrahydrofuran (90mL), cool to 0°C, add sodium hydride (2.57g, 60% content, 2.5eq) and methyl iodide (12.76g, 5.60mL, 3.5eq), stirred at 0-25°C for 6 hours, quenched the reaction solution with saturated ammonium chloride aqueous solution (10mL), stirred at 25°C for 10 minutes, extracted with ethyl acetate (20mL*3), combined the organic phases, Wash with saturated brine (20 mL*1), dry over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure to obtain compound 9-3. MS: m/z 204.2 [M+H] + .
第三步third step
将化合物9-3(2.5g，1eq)加入异丙醇(50mL)和水(5mL)的混合溶剂中，加入一水合氢氧化锂(2.06g，4eq)，于25℃下搅拌4小时，反应液用1N稀盐酸溶液调节pH至5，加入20mL水稀释，乙酸乙酯萃 取(20mL*3)，合并有机相，用饱和食盐水洗(20mL*1)，无水硫酸钠干燥，滤液减压浓缩得到化合物9-4。MS：m/z 190.0[M+H] +。 Add compound 9-3 (2.5g, 1eq) into a mixed solvent of isopropanol (50mL) and water (5mL), add lithium hydroxide monohydrate (2.06g, 4eq), stir at 25°C for 4 hours, and react The solution was adjusted to pH 5 with 1N dilute hydrochloric acid solution, diluted with 20 mL of water, extracted with ethyl acetate (20 mL*3), the organic phases were combined, washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure Compound 9-4 was obtained. MS: m/z 190.0 [M+H] + .
第四步the fourth step
将化合物9-4(2.5g，1eq)加入四氢呋喃(25mL)中，25℃加入N，N′-羰基二咪唑(2.36g，1.1eq)并搅拌1小时，随后加入水(5mL)和硼氢化钠(1.50g，3eq)，于25℃下继续搅拌1小时，反应液用饱和氯化铵水溶液(20mL)淬灭，加入20mL水稀释，乙酸乙酯萃取(20mL*3)，合并有机相，用饱和食盐水洗(20mL*1)，无水硫酸钠干燥，滤液减压浓缩得到化合物9-5。MS：m/z 176.1[M+H] +。 Compound 9-4 (2.5g, 1eq) was added in tetrahydrofuran (25mL), N, N'-carbonyldiimidazole (2.36g, 1.1eq) was added at 25°C and stirred for 1 hour, then water (5mL) was added and hydroboration Sodium (1.50g, 3eq), continued to stir at 25°C for 1 hour, quenched the reaction solution with saturated aqueous ammonium chloride (20mL), diluted with 20mL of water, extracted with ethyl acetate (20mL*3), combined the organic phases, Wash with saturated brine (20 mL*1), dry over anhydrous sodium sulfate, and concentrate the filtrate under reduced pressure to obtain compound 9-5. MS: m/z 176.1 [M+H] + .
第五步the fifth step
将化合物9-5(3.2g，1eq)加入二氯甲烷(32mL)中，25℃加入戴斯-马丁氧化剂(15.49g，11.31mL，2eq)并搅拌3小时。反应液用饱和硫代硫酸钠水溶液淬灭，加入20mL水稀释，二氯甲烷萃取(20mL*3)，合并有机相，用饱和碳酸氢钠(20mL*1)洗涤，饱和食盐水洗(20mL*1)，无水硫酸钠干燥，滤液减压浓缩得到化合物9-6。Compound 9-5 (3.2g, 1eq) was added into dichloromethane (32mL), and Dess-Martin oxidizer (15.49g, 11.31mL, 2eq) was added at 25°C and stirred for 3 hours. The reaction solution was quenched with saturated aqueous sodium thiosulfate solution, diluted with 20 mL of water, extracted with dichloromethane (20 mL*3), combined organic phases, washed with saturated sodium bicarbonate (20 mL*1), washed with saturated brine (20 mL*1 ), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 9-6.
第六步step six
将化合物9-6(2g，1eq)和磷酰基乙酸三乙酯(2.72g，2.41mL，1.05eq)加入N，N-二甲基甲酰胺(18mL)中，冷却至0℃，加入氢化钠(461.87mg，60％含量，1eq)并于0℃搅拌1小时，反应液用饱和氯化铵水溶液(20mL)淬灭，加入20mL水稀释，乙酸乙酯萃取(20mL*3)，合并有机相，用饱和食盐水洗(20mL*1)，无水硫酸钠干燥，滤液减压浓缩得到化合物9-7。MS：m/z 244.1[M+H] +。 Add compound 9-6 (2g, 1eq) and triethyl phosphoroacetate (2.72g, 2.41mL, 1.05eq) into N,N-dimethylformamide (18mL), cool to 0°C, add sodium hydride (461.87mg, 60% content, 1eq) and stirred at 0°C for 1 hour, the reaction solution was quenched with saturated ammonium chloride aqueous solution (20mL), diluted with 20mL water, extracted with ethyl acetate (20mL*3), and the organic phases were combined , washed with saturated brine (20 mL*1), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 9-7. MS: m/z 244.1 [M+H] + .
第七步step seven
将化合物9-7(2g，1eq)加入四氢呋喃(20mL)中，氮气保护下加入三(三苯基膦)氯化铑(I)(760.55mg，0.1eq)，通入氢气，置换多次后于45℃、50Psi下搅拌8小时。反应液经硅藻土过滤，滤液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝6∶1)分离得到化合物9-8。 1H NMR(400MHz，CDCl 3)δ＝7.14(d，J＝8.4Hz，2H)，7.04(d，J＝7.6Hz，2H)，3.97(q，J＝7.1Hz，2H)，2.01-1.94(m，2H)，1.91-1.84(m，2H)，1.23(s，6H)，1.12(t，J＝7.2Hz，3H)。 Compound 9-7 (2g, 1eq) was added to tetrahydrofuran (20mL), and tris(triphenylphosphine)rhodium(I) chloride (760.55mg, 0.1eq) was added under the protection of nitrogen, and hydrogen gas was introduced, and after several replacements Stir at 45°C, 50 Psi for 8 hours. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated under reduced pressure, and compound 9-8 was obtained by column chromatography (petroleum ether: ethyl acetate = 6:1). 1 H NMR (400MHz, CDCl 3 ) δ = 7.14 (d, J = 8.4Hz, 2H), 7.04 (d, J = 7.6Hz, 2H), 3.97 (q, J = 7.1Hz, 2H), 2.01-1.94 (m, 2H), 1.91-1.84 (m, 2H), 1.23 (s, 6H), 1.12 (t, J=7.2Hz, 3H).
第八步eighth step
将化合物9-8(1.78g，1eq)加至10mL三氟乙酸酐中，并将该溶液降温至3℃，15分钟内滴加硝酸(10.37g，7.41mL，65％含量，14.74eq)至反应体系，控制内温不超过20℃，随后于3～20℃搅拌15分钟。反应液中缓慢加入50mL饱和碳酸氢钠水溶液，乙酸乙酯萃取(30mL*2)，合并有机相，饱和食盐水(50mL*1)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物9-9。Compound 9-8 (1.78g, 1eq) was added to 10mL of trifluoroacetic anhydride, and the solution was cooled to 3°C, and nitric acid (10.37g, 7.41mL, 65% content, 14.74eq) was added dropwise within 15 minutes to In the reaction system, the internal temperature was controlled not to exceed 20°C, and then stirred at 3-20°C for 15 minutes. Slowly add 50 mL of saturated aqueous sodium bicarbonate solution to the reaction solution, extract with ethyl acetate (30 mL*2), combine the organic phases, wash with saturated brine (50 mL*1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 9- 9.
第九步Ninth step
将化合物9-9(1.1g，1eq)加入甲醇(10mL)和水(10mL)中，氮气保护下加入二碳酸二叔丁酯(826.95 mg，870.47μL，1eq)，铁粉(1.06g，5eq)和氯化铵(405.35mg，2eq)，反应液升温至85℃搅拌2小时，反应液经硅藻土过滤，滤饼用5mL甲醇洗涤，向所得滤液中加入6mL 4N盐酸甲醇溶液搅拌30分钟，收集析出的固体干燥后得到化合物9-10(盐酸盐粗品)。Compound 9-9 (1.1g, 1eq) was added to methanol (10mL) and water (10mL), and di-tert-butyl dicarbonate (826.95 mg, 870.47μL, 1eq), iron powder (1.06g, 5eq ) and ammonium chloride (405.35mg, 2eq), the reaction solution was warmed up to 85°C and stirred for 2 hours, the reaction solution was filtered through diatomaceous earth, the filter cake was washed with 5mL of methanol, and 6mL of 4N methanolic hydrochloric acid was added to the resulting filtrate and stirred for 30 minutes , the precipitated solid was collected and dried to obtain compound 9-10 (crude hydrochloride).
第十步tenth step
将中间体Da(0.6g，1eq)和化合物9-10(0.8g，盐酸盐粗品)加入乙腈(10mL)中，降温至0℃加入二异丙基乙胺(402.02mg，541.81μL，1.5eq)和4-二甲氨基吡啶(DMAP)(253.35mg，1eq)，搅拌10分钟后加入三正丙基环磷酸酐(T 3P，3.96g，3.70mL，50％含量的乙酸乙酯溶液，3eq)，并于0～20℃下搅拌2小时。反应液减压浓缩，加入水(13mL)和乙酸乙酯萃取(14mL)稀释，乙酸乙酯萃取(14mL*2)，合并有机相，用饱和食盐水洗(16mL*1)，无水硫酸钠干燥，滤液减压浓缩得到粗品，粗品经高效液相色谱法制备分离(色谱柱：Phenomenex Synergi C18 150*25mm*10μm；流动相：[水(0.1％三乙胺)-乙腈]；乙腈％：52％-82％)分离得到化合物9-11a。 Intermediate Da (0.6g, 1eq) and compound 9-10 (0.8g, crude hydrochloride) were added to acetonitrile (10mL), cooled to 0°C and diisopropylethylamine (402.02mg, 541.81μL, 1.5 eq) and 4-dimethylaminopyridine (DMAP) (253.35mg, 1eq), after stirring for 10 minutes, tri-n-propyl cyclic phosphoric anhydride (T 3 P, 3.96g, 3.70mL, 50% content of ethyl acetate solution , 3eq), and stirred at 0-20°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (13mL) and ethyl acetate extraction (14mL), extracted with ethyl acetate (14mL*2), the organic phases were combined, washed with saturated brine (16mL*1), and dried over anhydrous sodium sulfate , the filtrate was concentrated under reduced pressure to obtain the crude product, which was prepared and separated by high performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10 μm; mobile phase: [water (0.1% triethylamine)-acetonitrile]; acetonitrile%: 52 %-82%) to isolate compound 9-11a.
第十一步Eleventh step
将化合物9-11a(0.1g，1eq)加入四氢呋喃(5mL)中，搅拌下加入三甲基硅醇钾(71.95mg，3eq)，并于25℃下搅拌1小时。反应液加入水(3mL)稀释，用2N稀盐酸调节反应体系pH值至5，乙酸乙酯萃取(5mL*2)，合并有机相，用饱和食盐水洗(8mL*1)，无水硫酸钠干燥，滤液减压浓缩得化合物9a。SFC检测条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％，流速：3mL/min，保留时间：1.190min，ee＝100％。MS：m/z 504.2[M+H] +。 1H NMR(400MHz，DMSO-d6)δ＝8.92(d，J＝7.8Hz，1H)，8.47-8.42(m，1H)，7.54(d，J＝1.9Hz，1H)，7.49(dd，J＝2.0，8.5Hz，1H)，7.37-7.31(m，1H)，7.30-7.24(m，1H)，6.71(d，J＝8.4Hz，1H)，4.20(br t，J＝5.1Hz，2H)，4.07-3.94(m，1H)，3.29(br t，J＝7.3Hz，1H)，3.07(br d，J＝13.1Hz，1H)，2.74(br d，J＝12.8Hz，1H)，2.10-2.03(m，2H)，1.37-1.30(m，2H)，1.16-1.08(m，6H)，0.92(s，3H)，0.84(s，3H)。 Compound 9-11a (0.1g, 1eq) was added into tetrahydrofuran (5mL), potassium trimethylsiliconate (71.95mg, 3eq) was added with stirring, and stirred at 25°C for 1 hour. Add water (3mL) to the reaction solution to dilute, adjust the pH of the reaction system to 5 with 2N dilute hydrochloric acid, extract with ethyl acetate (5mL*2), combine the organic phases, wash with saturated brine (8mL*1), and dry over anhydrous sodium sulfate , and the filtrate was concentrated under reduced pressure to obtain compound 9a. SFC detection conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% , flow rate: 3 mL/min, retention time: 1.190 min, ee=100%. MS: m/z 504.2 [M+H] + . 1 H NMR (400MHz, DMSO-d6) δ = 8.92 (d, J = 7.8Hz, 1H), 8.47-8.42 (m, 1H), 7.54 (d, J = 1.9Hz, 1H), 7.49 (dd, J =2.0, 8.5Hz, 1H), 7.37-7.31(m, 1H), 7.30-7.24(m, 1H), 6.71(d, J=8.4Hz, 1H), 4.20(br t, J=5.1Hz, 2H ), 4.07-3.94(m, 1H), 3.29(br t, J=7.3Hz, 1H), 3.07(br d, J=13.1Hz, 1H), 2.74(br d, J=12.8Hz, 1H), 2.10-2.03 (m, 2H), 1.37-1.30 (m, 2H), 1.16-1.08 (m, 6H), 0.92 (s, 3H), 0.84 (s, 3H).
实施例10Example 10
Figure PCTCN2022095009-appb-000112
Figure PCTCN2022095009-appb-000112
Figure PCTCN2022095009-appb-000113
Figure PCTCN2022095009-appb-000113
第一步first step
将无水二异丙胺(4.18mL，1.56eq)溶于四氢呋喃中(50mL)，用氮气置换反应瓶中的空气三次，在-70℃向反应液中加入正丁基锂(2.5M，9.09mL，1.2eq)，反应液在-70～-40℃搅拌0.5小时。将反应液冷却至-70～-60℃，将环丙甲酸叔丁酯(3.23g，1.2.eq)缓慢滴加到反应瓶中，反应液在-70～-60℃搅拌4小时。在-70～-60℃将化合物10-1(5g，1eq)滴加到反应液中，反应液在25～30℃搅拌5小时。用水(20mL)淬灭反应液，减压浓缩除去溶剂，剩余物用水(20mL)稀释，用乙酸乙酯(20mL*3)萃取，用饱和食盐水(20mL*2)洗涤，用无水硫酸钠干燥。过滤，减压浓缩除去溶剂，剩余物通过柱层析(石油醚∶乙酸乙酯＝1∶0～10∶1)分离纯化得到化合物10-2。Anhydrous diisopropylamine (4.18mL, 1.56eq) was dissolved in tetrahydrofuran (50mL), the air in the reaction flask was replaced with nitrogen three times, and n-butyl lithium (2.5M, 9.09mL , 1.2eq), and the reaction solution was stirred at -70～-40°C for 0.5 hours. The reaction solution was cooled to -70~-60°C, tert-butyl cyclopropanate (3.23g, 1.2.eq) was slowly added dropwise into the reaction flask, and the reaction solution was stirred at -70~-60°C for 4 hours. Compound 10-1 (5 g, 1 eq) was added dropwise to the reaction solution at -70~-60°C, and the reaction solution was stirred at 25~30°C for 5 hours. Quench the reaction solution with water (20mL), concentrate under reduced pressure to remove the solvent, dilute the residue with water (20mL), extract with ethyl acetate (20mL*3), wash with saturated brine (20mL*2), wash with anhydrous sodium sulfate dry. Filtration, concentration under reduced pressure to remove the solvent, the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 1:0 ~ 10:1) to obtain compound 10-2.
第二步second step
将化合物10-2(1.2g，1eq)溶于N-甲基吡咯烷酮(10mL)，再向反应液中加入氰化亚铜(660.90mg，2eq)，反应液在190℃搅拌2小时。将反应液冷却至25～30℃，用水(50mL)和乙酸乙酯(20mL)稀释，再加入25-28％氨水(5mL)，然后在25～30℃搅拌15分钟。用乙酸乙酯(20mL*3)萃取，水相用2N稀盐酸调节pH约为3，用乙酸乙酯(20mL*3)萃取，用水(50mL*3)和饱和食盐水(50mL*3)洗涤，用无水硫酸钠干燥。过滤，减压浓缩除去溶剂得到化合物10-3。Compound 10-2 (1.2g, 1eq) was dissolved in N-methylpyrrolidone (10mL), then cuprous cyanide (660.90mg, 2eq) was added to the reaction solution, and the reaction solution was stirred at 190°C for 2 hours. The reaction solution was cooled to 25-30°C, diluted with water (50mL) and ethyl acetate (20mL), and 25-28% ammonia water (5mL) was added, then stirred at 25-30°C for 15 minutes. Extract with ethyl acetate (20mL*3), adjust the pH of the aqueous phase to about 3 with 2N dilute hydrochloric acid, extract with ethyl acetate (20mL*3), wash with water (50mL*3) and saturated brine (50mL*3) , dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to remove the solvent to obtain compound 10-3.
第三步third step
将化合物10-3(360mg，1eq)溶于甲醇(4mL)，再向反应液中缓慢滴加二氯亚砜(242.65μL，2eq)，反应液在25～30℃搅拌5小时。减压浓缩反应液除去溶剂，剩余物加水(20mL)，用乙酸乙酯(10mL*3)萃取，萃取液用无水硫酸钠干燥。过滤，减压浓缩滤液除去溶剂，剩余物用薄层色谱(石油醚∶乙酸乙酯＝5∶1)分离纯化得到化合物10-4。Compound 10-3 (360mg, 1eq) was dissolved in methanol (4mL), and thionyl chloride (242.65μL, 2eq) was slowly added dropwise to the reaction solution, and the reaction solution was stirred at 25-30°C for 5 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, the residue was added with water (20 mL), extracted with ethyl acetate (10 mL*3), and the extract was dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to remove the solvent, and the residue was separated and purified by thin layer chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 10-4.
第四步the fourth step
将化合物10-4(120mg，1eq)溶于三氟乙酸酐(3mL)，在0℃下向反应液中加入65％硝酸(144.97μL，4eq)，反应液在0℃搅拌0.5小时。将反应液倒入冰水(20mL)中，用乙酸乙酯(10mL*3)萃取，用饱和碳酸氢钠(20mL*3)和饱和食盐水(20mL*2)洗涤，用无水硫酸钠干燥。过滤，减压浓缩滤液得到化合物10-5。Compound 10-4 (120mg, 1eq) was dissolved in trifluoroacetic anhydride (3mL), 65% nitric acid (144.97μL, 4eq) was added to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 0.5 hours. Pour the reaction solution into ice water (20 mL), extract with ethyl acetate (10 mL*3), wash with saturated sodium bicarbonate (20 mL*3) and saturated brine (20 mL*2), and dry over anhydrous sodium sulfate . After filtration, the filtrate was concentrated under reduced pressure to obtain compound 10-5.
第五步the fifth step
将化合物10-5(120mg，1eq)溶于乙醇(3mL)和水(3mL)，向反应瓶中加入铁粉(122.17mg，5eq)和氯化铵(117.02mg，5eq)，用氮气置换反应瓶中的空气三次，反应液在80℃搅拌10小时。冷却反应液至25～30℃，过滤，用乙酸乙酯(20mL)洗涤滤饼，滤液减压浓缩除去有机溶剂，剩余物用水(20mL)稀释，用乙酸乙酯(10mL*3)萃取，用无水硫酸钠干燥。过滤，减压浓缩滤液得到化合物10-6。MS：m/z 245.2[M+H] +。 Compound 10-5 (120mg, 1eq) was dissolved in ethanol (3mL) and water (3mL), iron powder (122.17mg, 5eq) and ammonium chloride (117.02mg, 5eq) were added to the reaction flask, and the reaction was replaced with nitrogen The air in the bottle was three times, and the reaction solution was stirred at 80°C for 10 hours. Cool the reaction solution to 25-30°C, filter, wash the filter cake with ethyl acetate (20mL), concentrate the filtrate under reduced pressure to remove the organic solvent, dilute the residue with water (20mL), extract with ethyl acetate (10mL*3), and use Dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 10-6. MS: m/z 245.2 [M+H] + .
第六步step six
将中间体Da(95mg，1eq)和化合物10-6(84.22mg，1.05eq)溶于四氢呋喃(4mL)和乙腈(4mL)混合溶剂中，再向反应液中加入二异丙基乙胺(285.96μL，5eq)和4-二甲氨基吡啶(DMAP)(20.06mg，0.5eq)，反应液在25～30℃搅拌10分钟，将三正丙基环磷酸酐(T 3P，781μL，50％含量的乙酸乙酯溶液，4eq)加到反应液中，反应液在25～30℃搅拌5小时。减压浓缩反应液除去溶剂，剩余物用水(10mL)稀释，用乙酸乙酯(10mL*3)萃取，用饱和食盐水(10mL*2)洗涤，用无水硫酸钠干燥。过滤，减压浓缩滤液得到化合物10-7a粗品。MS：m/z 516.3[M+H] +。 Intermediate Da (95mg, 1eq) and compound 10-6 (84.22mg, 1.05eq) were dissolved in a mixed solvent of tetrahydrofuran (4mL) and acetonitrile (4mL), and diisopropylethylamine (285.96 μL, 5eq) and 4-dimethylaminopyridine (DMAP) (20.06mg, 0.5eq), the reaction solution was stirred at 25～30°C for 10 minutes, tri-n-propyl cyclic phosphoric anhydride (T 3 P, 781μL, 50% content of ethyl acetate solution, 4eq) was added to the reaction solution, and the reaction solution was stirred at 25-30°C for 5 hours. The reaction solution was concentrated under reduced pressure to remove the solvent, and the residue was diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), washed with saturated brine (10 mL*2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain the crude compound 10-7a. MS: m/z 516.3 [M+H] + .
第七步step seven
将化合物10-7a(165mg，1eq)溶于四氢呋喃(10mL)，再向反应液中加入三甲基硅醇钾(49.26mg，1.2eq)，用氮气置换反应瓶中的空气三次，反应液在50℃搅拌7小时。用水(20mL)稀释反应液，用2N稀盐酸调节pH至5，用乙酸乙酯(20mL*3)萃取，用饱和食盐水(20mL*2)洗涤，用无水硫酸钠干燥。过滤，减压浓缩滤液除去溶剂。剩余物通过高效液相色谱法制备分离(分离条件：色谱柱：3_Phenomenex Luna C18 75*30mm*3μm；流动相：[水(0.05％盐酸)-乙腈]；乙腈％：58％-78％)纯化得到化合物10a。SFC检测条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度B％：5％～40％，流速：3mL/min，保留时间为1.921min，ee＝100％。MS：m/z 502.2[M+H] +。 1H NMR(400MHz，CDCl 3)δ10.20(s，1H)，8.90(d，J＝1.2Hz，1H)，7.95(d，J＝2.0Hz，1H)，7.25(d，J＝8.0Hz，2H)，7.14(d，J＝8.0Hz，1H)，6.81(d，J＝8.4Hz，1H)，5.99(br d，J＝7.6Hz，1H)，4.55(dt，J＝10.4，3.2Hz，1H)，4.39-4.21(m，2H)，3.65(dd，J＝8.4，6.4Hz，1H)，2.91-2.69(m，2H)，2.24-2.09(m，2H)，1.61-1.53(m，2H)，1.51-1.34(m，4H)，1.26(dd，J＝6.8，4.0Hz，6H)，0.95-0.80(m，2H)。 Compound 10-7a (165mg, 1eq) was dissolved in tetrahydrofuran (10mL), then potassium trimethylsilanolate (49.26mg, 1.2eq) was added to the reaction solution, and the air in the reaction flask was replaced with nitrogen three times, and the reaction solution was Stir at 50°C for 7 hours. The reaction solution was diluted with water (20 mL), adjusted to pH 5 with 2N dilute hydrochloric acid, extracted with ethyl acetate (20 mL*3), washed with saturated brine (20 mL*2), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to remove the solvent. The residue was prepared and separated by high performance liquid chromatography (separation conditions: chromatographic column: 3_Phenomenex Luna C18 75*30mm*3μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 58%-78%) purification Compound 10a was obtained. SFC detection conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient B%: 5% to 40%, Flow rate: 3 mL/min, retention time 1.921 min, ee=100%. MS: m/z 502.2 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ10.20(s, 1H), 8.90(d, J=1.2Hz, 1H), 7.95(d, J=2.0Hz, 1H), 7.25(d, J=8.0Hz , 2H), 7.14(d, J=8.0Hz, 1H), 6.81(d, J=8.4Hz, 1H), 5.99(br d, J=7.6Hz, 1H), 4.55(dt, J=10.4, 3.2 Hz, 1H), 4.39-4.21(m, 2H), 3.65(dd, J=8.4, 6.4Hz, 1H), 2.91-2.69(m, 2H), 2.24-2.09(m, 2H), 1.61-1.53( m, 2H), 1.51-1.34 (m, 4H), 1.26 (dd, J=6.8, 4.0 Hz, 6H), 0.95-0.80 (m, 2H).
实施例11Example 11
Figure PCTCN2022095009-appb-000114
Figure PCTCN2022095009-appb-000114
第一步first step
氮气保护下，将化合物11-1(5g，1eq)溶于无水四氢呋喃(100mL)中，加入3-羟基丙酸甲酯(4.70g，1.5eq)，冷却到0～5℃，分批加入氢化钠(1.20g，60％含量，1eq)，控制温度在0～10℃，1小时加完，反应物在0～5℃搅拌0.5小时。倒入饱和氯化铵水溶液(200mL)中，此时混合物pH值约为7，加乙酸乙酯萃取2次，每次200mL，有机层合并用饱和氯化钠水溶液(200mL)洗，硫酸钠干燥，过滤，滤液减压浓缩得到化合物11-2。 1H NMR(400MHz，CDCl 3)δ＝8.14(d，J＝2.0Hz，1H)，7.82(dd，J＝8.8，2.0Hz，1H)，7.23(d，J＝8.8Hz，1H)，4.47(t，J＝6.0Hz，2H)，3.75(s，3H)，2.90(t，J＝6.0Hz，2H)。 Under the protection of nitrogen, compound 11-1 (5g, 1eq) was dissolved in anhydrous tetrahydrofuran (100mL), and methyl 3-hydroxypropionate (4.70g, 1.5eq) was added, cooled to 0-5°C, and added in batches Sodium hydride (1.20g, 60% content, 1eq), the temperature was controlled at 0-10°C, and the addition was completed in 1 hour, and the reactant was stirred at 0-5°C for 0.5 hour. Pour into saturated ammonium chloride aqueous solution (200mL), at this time the pH value of the mixture is about 7, add ethyl acetate to extract twice, each time 200mL, the combined organic layers are washed with saturated sodium chloride aqueous solution (200mL), and dried over sodium sulfate , filtered, and the filtrate was concentrated under reduced pressure to obtain compound 11-2. 1 H NMR (400MHz, CDCl 3 ) δ = 8.14 (d, J = 2.0Hz, 1H), 7.82 (dd, J = 8.8, 2.0Hz, 1H), 7.23 (d, J = 8.8Hz, 1H), 4.47 (t, J=6.0Hz, 2H), 3.75(s, 3H), 2.90(t, J=6.0Hz, 2H).
第二步second step
将化合物11-2(3.5g，1eq)溶于四氢呋喃(50mL)中，氮气保护下加入湿钯碳(0.5g，10％含量)，氢气置换3次后，反应物在0～20℃下搅拌15小时。过滤，用乙酸乙酯(20mL)淋洗，滤液减压浓缩至干，剩余物经柱层析(石油醚∶乙酸乙酯＝5∶1～5∶3)纯化得到化合物11-3。 1H NMR(400MHz，CDCl 3)δ＝7.04(dd，J＝8.4，2.0Hz，1H)，6.92(d，J＝2.0Hz，1H)，6.82(d，J＝8.4Hz，1H)，4.32(t，J＝6.0Hz，2H)，3.75(s，3H)，2.86(t，J＝6.0Hz，2H)。 Compound 11-2 (3.5g, 1eq) was dissolved in tetrahydrofuran (50mL), and wet palladium carbon (0.5g, 10% content) was added under nitrogen protection. After hydrogen replacement for 3 times, the reactant was stirred at 0-20°C 15 hours. After filtering, rinse with ethyl acetate (20 mL), the filtrate was concentrated to dryness under reduced pressure, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 5:1 ~ 5:3) to obtain compound 11-3. 1 H NMR (400MHz, CDCl 3 ) δ = 7.04 (dd, J = 8.4, 2.0Hz, 1H), 6.92 (d, J = 2.0Hz, 1H), 6.82 (d, J = 8.4Hz, 1H), 4.32 (t, J=6.0Hz, 2H), 3.75(s, 3H), 2.86(t, J=6.0Hz, 2H).
第三步third step
氮气保护下将中间体Da(1.0g，1eq)溶于无水四氢呋喃(20mL)中，冷却到0℃，加入二异丙基乙胺(1.80mL，2.99eq)，然后滴加氯甲酸异丁酯(500.01μL，1.1eq)，混合物在20℃搅拌2小时，加入化合物11- 3(0.7g，0.92eq)，反应物在40～50℃搅拌12小时。冷却，加水(40mL)淬灭，加乙酸乙酯萃取(40mL*2)，有机层依次用水(40mL)，饱和氯化钠水溶液(40mL)洗涤，硫酸钠干燥，过滤，滤液减压浓缩，剩余物经柱层析(石油醚∶乙酸乙酯＝1∶1～2∶3)得到化合物11-4a。MS：m/z 492.3[M+H] +。 Under the protection of nitrogen, the intermediate Da (1.0g, 1eq) was dissolved in anhydrous tetrahydrofuran (20mL), cooled to 0°C, diisopropylethylamine (1.80mL, 2.99eq) was added, and then isobutyl chloroformate was added dropwise Ester (500.01μL, 1.1eq), the mixture was stirred at 20°C for 2 hours, compound 11-3 (0.7g, 0.92eq) was added, and the reaction was stirred at 40-50°C for 12 hours. Cool, add water (40mL) to quench, add ethyl acetate to extract (40mL*2), the organic layer was washed with water (40mL), saturated aqueous sodium chloride solution (40mL) successively, dried over sodium sulfate, filtered, the filtrate was concentrated under reduced pressure, and the remaining The compound 11-4a was obtained by column chromatography (petroleum ether: ethyl acetate = 1:1 ~ 2:3). MS: m/z 492.3 [M+H] + .
第四步the fourth step
氮气保护下，将化合物11-4a(0.5g，1eq)溶于浓盐酸(3mL)和冰醋酸(3mL)中，反应物在40～60℃搅拌1小时，冷却，搅拌下加水(60mL)稀释，固体析出，减压过滤，收集固体，真空干燥后再经制备薄层色谱(10％甲醇/二氯甲烷)分离纯化得到化合物11a。MS：m/z 478.4[M+H] +； 1H NMR(400MHz，DMSO-d 6)δ＝12.41(brs，1H)，9.79(s，1H)，8.31(d，J＝2.0Hz，1H)，8.06(d，J＝8.0Hz，1H)，7.64(dd，J＝8.0，2.0Hz，1H)，7.51(dd，J＝8.4，2.0Hz，1H)，7.41(d，J＝1.2Hz，1H)，7.26(d，J＝8.8Hz，1H)，6.83(d，J＝8.4Hz，1H)，4.31(t，J＝6.0Hz，3H)，4.11-4.04(m，2H)，2.78(t，J＝6.0Hz，2H)，2.67(t，J＝6.0Hz，1H)，2.16-2.11(m，2H)，1.81-1.78(m，1H)，1.60-1.57(m，1H)，1.16(dd，J＝6.8，2.0Hz，6H)。 Under nitrogen protection, compound 11-4a (0.5g, 1eq) was dissolved in concentrated hydrochloric acid (3mL) and glacial acetic acid (3mL), and the reactant was stirred at 40-60°C for 1 hour, cooled, and diluted with water (60mL) under stirring , a solid precipitated out, filtered under reduced pressure, collected the solid, dried in vacuo, and then separated and purified by preparative thin-layer chromatography (10% methanol/dichloromethane) to obtain compound 11a. MS: m/z 478.4[M+H] + ; 1 H NMR (400MHz, DMSO-d 6 ) δ=12.41(brs, 1H), 9.79(s, 1H), 8.31(d, J=2.0Hz, 1H ), 8.06(d, J=8.0Hz, 1H), 7.64(dd, J=8.0, 2.0Hz, 1H), 7.51(dd, J=8.4, 2.0Hz, 1H), 7.41(d, J=1.2Hz , 1H), 7.26(d, J=8.8Hz, 1H), 6.83(d, J=8.4Hz, 1H), 4.31(t, J=6.0Hz, 3H), 4.11-4.04(m, 2H), 2.78 (t, J=6.0Hz, 2H), 2.67(t, J=6.0Hz, 1H), 2.16-2.11(m, 2H), 1.81-1.78(m, 1H), 1.60-1.57(m, 1H), 1.16 (dd, J=6.8, 2.0Hz, 6H).
实施例12Example 12
Figure PCTCN2022095009-appb-000115
Figure PCTCN2022095009-appb-000115
Figure PCTCN2022095009-appb-000116
Figure PCTCN2022095009-appb-000116
第一步first step
在0℃下向氢化钠(720.94mg，60％含量，1.2eq)的甲苯(20mL)溶剂中加入化合物12-1(2.00g，1eq)，反应体系在25℃下搅拌3小时。再在0℃下向反应体系加入溴乙酸乙酯(3.26g，1.3eq)，反应体系在25℃下搅拌2小时。向反应液中加入氯化铵水溶液(20mL)淬灭，用乙酸乙酯(40mL*3)萃取三次，合并有机相依次用饱和食盐水(30mL*1)洗涤。收集有机相用无水硫酸钠干燥，过滤浓缩得到化合物12-2。MS：m/z＝220.2[M+H] +。 Compound 12-1 (2.00 g, 1 eq) was added to sodium hydride (720.94 mg, 60% content, 1.2 eq) in toluene (20 mL) at 0°C, and the reaction system was stirred at 25°C for 3 hours. Ethyl bromoacetate (3.26 g, 1.3 eq) was added to the reaction system at 0°C, and the reaction system was stirred at 25°C for 2 hours. Aqueous ammonium chloride solution (20 mL) was added to the reaction solution to quench, extracted three times with ethyl acetate (40 mL*3), and the combined organic phases were washed successively with saturated brine (30 mL*1). The collected organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 12-2. MS: m/z = 220.2 [M+H] + .
第二步second step
在0℃下向浓硫酸(20mL)中加入发烟硝酸(4.11g，3eq)，然后加入化合物12-2(4.77g，1eq)，体系在0℃下搅拌1小时。在0℃下将反应体系倒入冰水(200mL)中，体系在0℃下搅拌0.5小时，过滤，收集滤饼减压干燥得到化合物12-3。 1H NMR(400MHz，CDCl 3)δ＝8.36-8.32(m，1H)，8.08(d，J＝8.4Hz，1H)，7.90-7.85(m，1H)，5.01(s，2H)，4.31-4.17(m，4H)，1.24(t，J＝7.2Hz，3H)。 Fuming nitric acid (4.11g, 3eq) was added to concentrated sulfuric acid (20mL) at 0°C, followed by compound 12-2 (4.77g, 1eq), and the system was stirred at 0°C for 1 hour. The reaction system was poured into ice water (200 mL) at 0°C, the system was stirred at 0°C for 0.5 hours, filtered, and the filter cake was collected and dried under reduced pressure to obtain compound 12-3. 1 H NMR (400MHz, CDCl 3 ) δ=8.36-8.32(m, 1H), 8.08(d, J=8.4Hz, 1H), 7.90-7.85(m, 1H), 5.01(s, 2H), 4.31- 4.17 (m, 4H), 1.24 (t, J=7.2Hz, 3H).
第三步third step
向化合物12-3(2.00g，1eq)的无水四氢呋喃(20mL)溶剂中，加入湿钯碳(200mg，10％含量，1eq)，该混合物在氢气(15Psi)条件下于20℃搅拌6小时。将该反应液过滤，滤饼用乙酸乙酯(30mL)洗涤，收集滤液，在减压下浓缩得到化合物12-4。MS：m/z＝235.0[M+H] +。 To compound 12-3 (2.00g, 1eq) in anhydrous tetrahydrofuran (20mL) solvent, add wet palladium carbon (200mg, 10% content, 1eq), the mixture was stirred at 20°C under hydrogen (15Psi) for 6 hours . The reaction solution was filtered, the filter cake was washed with ethyl acetate (30 mL), the filtrate was collected, and concentrated under reduced pressure to obtain compound 12-4. MS: m/z = 235.0 [M+H] + .
第四步the fourth step
在0℃下向化合物12-4(294.71mg，1.3eq)的乙腈(3mL)溶液中加入三正丙基环磷酸酐(T 3P，1.85g，50％含量的乙酸乙酯溶液，3eq)，二异丙基乙胺(375mg，3eq)和中间体D(0.28g，1eq)，该混合物在0～20℃下搅拌2小时。将该反应液浓缩除去乙腈，粗品经制备薄层色谱分离(石油醚∶乙酸乙酯＝1∶1)，然后通过高效液相色谱法制备分离纯化(分离条件：色谱柱：3_Phenomenex Luna C18 75*30mm*3μm；流动相：[水(0.05％盐酸)-乙腈]；B(乙腈)％：49％-69％)得到化合物12-5。 To a solution of compound 12-4 (294.71mg, 1.3eq) in acetonitrile (3mL) was added tri-n-propyl cyclic phosphoric anhydride (T 3 P, 1.85g, 50% content in ethyl acetate, 3eq) at 0°C , diisopropylethylamine (375mg, 3eq) and intermediate D (0.28g, 1eq), the mixture was stirred at 0-20°C for 2 hours. The reaction solution was concentrated to remove acetonitrile, and the crude product was separated by preparative thin-layer chromatography (petroleum ether: ethyl acetate=1:1), and then separated and purified by high-performance liquid chromatography (separation conditions: chromatographic column: 3_Phenomenex Luna C18 75* 30mm*3μm; mobile phase: [water (0.05% hydrochloric acid)-acetonitrile]; B (acetonitrile)%: 49%-69%) to obtain compound 12-5.
第五步the fifth step
化合物12-5再通过SFC分离(分离条件：色谱柱：DAICEL CHIRALPAK AD(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)乙醇]；B％：30％-30％)得到化合物12-5a。SFC检测条件：色谱柱：Chiralpak AD-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：乙醇(0.05％二乙胺)；梯度B％：5％～40％，流 速：3mL/min)保留时间为1.901min，ee＝100％。MS：m/z＝506.2[M+H] +。 Compound 12-5 was separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water) ethanol]; B%: 30%-30%) to give compound 12-5a. SFC detection conditions: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: ethanol (0.05% diethylamine); gradient B%: 5% to 40%, Flow rate: 3mL/min) The retention time is 1.901min, ee=100%. MS: m/z = 506.2 [M+H] + .
第六步step six
向化合物12-5a(60mg，1eq)的四氢呋喃(5mL)，甲醇(3mL)和水(3mL)溶液中，加入一水合氢氧化锂(14.94mg，3eq)，该混合物在25℃下搅拌2小时。将该反应液浓缩除去溶剂，水相用盐酸(1M)调节pH至5，减压浓缩后，通过高效液相色谱法制备分离(色谱柱：3_Phenomenex Luna C18 75*30mm*3μm；流动相：[水(0.05％盐酸)-乙腈]；乙腈％：46％-66％)，得到化合物12a。SFC检测条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％，流速：3mL/min，保留时间1.620min，ee＝100％。MS：m/z＝478.4[M+H] +。 1H NMR(400MHz，DMSO-d 6)δ＝10.03(s，1H)，8.12-8.00(m，2H)，7.67-7.61(m，3H)，7.42(d，J＝2.0Hz，1H)，6.84(d，J＝8.6Hz，1H)，4.65-4.53(m，2H)，4.35-4.27(m，1H)，4.17-4.04(m，4H)，2.18-2.07(m，2H)，1.79(dd，J＝4.8，7.8Hz，1H)，1.59(t，J＝5.6Hz，1H)，1.17(d，J＝6.8Hz，6H)。 To a solution of compound 12-5a (60mg, 1eq) in tetrahydrofuran (5mL), methanol (3mL) and water (3mL), was added lithium hydroxide monohydrate (14.94mg, 3eq), and the mixture was stirred at 25°C for 2 hours . The reaction solution was concentrated to remove the solvent, the aqueous phase was adjusted to pH 5 with hydrochloric acid (1M), concentrated under reduced pressure, and separated by high performance liquid chromatography (chromatographic column: 3_Phenomenex Luna C18 75*30mm*3 μm; mobile phase: [ Water (0.05% hydrochloric acid)-acetonitrile]; acetonitrile%: 46%-66%) to obtain compound 12a. SFC detection conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% , flow rate: 3mL/min, retention time 1.620min, ee=100%. MS: m/z = 478.4 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ=10.03(s, 1H), 8.12-8.00(m, 2H), 7.67-7.61(m, 3H), 7.42(d, J=2.0Hz, 1H), 6.84(d, J=8.6Hz, 1H), 4.65-4.53(m, 2H), 4.35-4.27(m, 1H), 4.17-4.04(m, 4H), 2.18-2.07(m, 2H), 1.79( dd, J = 4.8, 7.8 Hz, 1H), 1.59 (t, J = 5.6 Hz, 1H), 1.17 (d, J = 6.8 Hz, 6H).
实施例13Example 13
Figure PCTCN2022095009-appb-000117
Figure PCTCN2022095009-appb-000117
第一步first step
将化合物11-1(2g，1eq)和化合物13-1(2.42g，1.5eq)溶于四氢呋喃(20mL)，反应瓶中的空气用氮气置 换三次。在0℃下将氢化钠(722.35mg，60％含量，1.5eq)加入到反应液中，反应液在0℃下搅拌2小时。反应液用冰水(30mL)淬灭，用乙酸乙酯(20mL*3)萃取，用饱和食盐水(50mL*2)洗涤，用无水硫酸钠干燥。过滤，减压浓缩除去溶剂，剩余物用柱层析(石油醚∶乙酸乙酯＝5∶1～3∶1)分离纯化得到化合物13-2。Compound 11-1 (2 g, 1 eq) and compound 13-1 (2.42 g, 1.5 eq) were dissolved in tetrahydrofuran (20 mL), and the air in the reaction flask was replaced with nitrogen three times. Sodium hydride (722.35mg, 60% content, 1.5eq) was added to the reaction solution at 0°C, and the reaction solution was stirred at 0°C for 2 hours. The reaction solution was quenched with ice water (30 mL), extracted with ethyl acetate (20 mL*3), washed with saturated brine (50 mL*2), and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure to remove the solvent, the residue was separated and purified by column chromatography (petroleum ether: ethyl acetate = 5:1 ~ 3:1) to obtain compound 13-2.
第二步second step
将化合物13-2(2g，1eq)溶于乙醇(20mL)和水(20mL)的混合溶剂，再向反应液中加入铁粉(1.99g，5eq)和氯化铵(1.91g，5eq)，用氮气置换反应瓶中的空气三次，反应液在80℃搅拌10小时。过滤，用乙酸乙酯(30mL)洗涤滤饼，滤液减压浓缩除去溶剂。剩余物用水(20mL)和乙酸乙酯(20mL)稀释，用乙酸乙酯(20mL*3)萃取，用无水硫酸钠干燥。过滤，减压浓缩滤液得到化合物13-3。MS：m/z 251.1[M+H] +。 Compound 13-2 (2g, 1eq) was dissolved in a mixed solvent of ethanol (20mL) and water (20mL), then iron powder (1.99g, 5eq) and ammonium chloride (1.91g, 5eq) were added to the reaction solution, The air in the reaction bottle was replaced with nitrogen three times, and the reaction solution was stirred at 80° C. for 10 hours. After filtration, the filter cake was washed with ethyl acetate (30 mL), and the filtrate was concentrated under reduced pressure to remove the solvent. The residue was diluted with water (20 mL) and ethyl acetate (20 mL), extracted with ethyl acetate (20 mL*3), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain compound 13-3. MS: m/z 251.1 [M+H] + .
第三步third step
将化合物13-3(200mg，1eq)溶于乙腈(2mL)和四氢呋喃(2mL)，再向反应液中加入中间体D(173.03mg，1eq)，4-二甲氨基吡啶(DMAP)(42.23mg，0.5eq)和二异丙基乙胺(602.03μL，5eq)，反应液在20～25℃搅拌10分钟。再将三正丙基环磷酸酐(T 3P，1.64mL，50％含量的乙酸乙酯溶液，4eq)加入到反应液中，反应液在50℃搅拌3小时。减压浓缩除去溶剂，剩余物用水(20mL)和乙酸乙酯(10mL)稀释，用乙酸乙酯(10mL*3)萃取，用饱和食盐水(20mL*3)洗涤，用无水硫酸钠干燥。过滤，减压浓缩除去溶剂，剩余物先经过柱层析(石油醚∶乙酸乙酯＝5∶1～2∶1)纯化得到化合物13-4。 Compound 13-3 (200mg, 1eq) was dissolved in acetonitrile (2mL) and tetrahydrofuran (2mL), and intermediate D (173.03mg, 1eq), 4-dimethylaminopyridine (DMAP) (42.23mg , 0.5eq) and diisopropylethylamine (602.03μL, 5eq), and the reaction solution was stirred at 20-25°C for 10 minutes. Then, tri-n-propyl cyclic phosphoric anhydride (T 3 P, 1.64 mL, 50% solution in ethyl acetate, 4 eq) was added to the reaction solution, and the reaction solution was stirred at 50° C. for 3 hours. The solvent was removed by concentration under reduced pressure, and the residue was diluted with water (20 mL) and ethyl acetate (10 mL), extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL*3), and dried over anhydrous sodium sulfate. Filtration, concentration under reduced pressure to remove the solvent, the residue was first purified by column chromatography (petroleum ether: ethyl acetate = 5:1 ~ 2:1) to obtain compound 13-4.
第四步the fourth step
化合物13-4通过SFC分离(分离条件：色谱柱：DAICEL CHIRALPAK AD-H(250mm*30mm，5μm)；流动相：A相：CO 2，B相：[(0.1％氨水)异丙醇]；梯度：B％：35％-35％)得到化合物13-4a。SFC检测条件：色谱柱：Chiralpak AD-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：异丙醇(0.05％二乙胺)；梯度：B％：5％～40％，流速：3mL/min，保留时间为1.842min，ee＝100％。MS：m/z 522.4[M+H] +。 Compound 13-4 was separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD-H (250mm*30mm, 5μm); mobile phase: phase A: CO 2 , phase B: [(0.1% ammonia water) isopropanol]; Gradient: B%: 35%-35%) gave compound 13-4a. SFC detection conditions: Chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: isopropanol (0.05% diethylamine); gradient: B%: 5%～ 40%, flow rate: 3mL/min, retention time 1.842min, ee=100%. MS: m/z 522.4 [M+H] + .
第五步the fifth step
将化合物13-4a(65mg，1eq)溶于浓盐酸(1mL，96.30eq)和冰醋酸(1mL，140.32eq)，反应液在50℃搅拌1小时。反应液用水(10mL)稀释，用乙酸乙酯(10mL*3)萃取，用饱和食盐水(20mL*3)洗涤，用无水硫酸钠干燥。过滤，减压浓缩除去溶剂。剩余物通过制备薄层色谱(石油醚∶乙酸乙酯＝1∶1)分离纯化得到化合物13a。SFC检测条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％，流速：3mL/min，保留时间1.968min，ee＝100％。MS：m/z 494.4[M+H] +。 1H NMR(400MHz，CDCl 3)δ＝10.13(s，1H)，9.00(d，J＝2.0Hz，1H)，7.93(d，J＝2.4Hz，1H)，7.69(d，J＝8.0Hz，1H)，7.26-7.24(m，1H)，6.83(d，J＝8.40Hz，1H)，6.01(br d，J＝7.6Hz，1H)，4.53(dt，J＝10.8，3.2Hz，1H)，4.38-4.23(m，2H)，3.68(dd，J＝8.4，6.4Hz，1H)，3.04-2.93(m，2H)，2.69-2.49(m，2H)，2.25-2.12(m，2H)，1.61-1.59(m，2H)，1.28(dd，J＝6.4，4.0Hz，6H)。 Compound 13-4a (65mg, 1eq) was dissolved in concentrated hydrochloric acid (1mL, 96.30eq) and glacial acetic acid (1mL, 140.32eq), and the reaction solution was stirred at 50°C for 1 hour. The reaction solution was diluted with water (10 mL), extracted with ethyl acetate (10 mL*3), washed with saturated brine (20 mL*3), and dried over anhydrous sodium sulfate. Filter and concentrate under reduced pressure to remove the solvent. The residue was separated and purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 13a. SFC detection conditions: Chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% , flow rate: 3 mL/min, retention time 1.968 min, ee=100%. MS: m/z 494.4 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ=10.13(s, 1H), 9.00(d, J=2.0Hz, 1H), 7.93(d, J=2.4Hz, 1H), 7.69(d, J=8.0Hz , 1H), 7.26-7.24(m, 1H), 6.83(d, J=8.40Hz, 1H), 6.01(br d, J=7.6Hz, 1H), 4.53(dt, J=10.8, 3.2Hz, 1H ), 4.38-4.23(m, 2H), 3.68(dd, J=8.4, 6.4Hz, 1H), 3.04-2.93(m, 2H), 2.69-2.49(m, 2H), 2.25-2.12(m, 2H ), 1.61-1.59 (m, 2H), 1.28 (dd, J=6.4, 4.0Hz, 6H).
实施例14Example 14
Figure PCTCN2022095009-appb-000118
Figure PCTCN2022095009-appb-000118
第一步first step
将化合物14-1(30g，1eq)和膦酰基乙酸三乙酯(53.11g，47.0mL，1.04eq)加入干燥的N，N-二甲基乙酰胺(240mL)中，冷却到0℃，缓慢加入氢化钠(9.15g，60％含量，1eq)，控制温度在10℃以下，30分钟加完。反应液在0～10℃搅拌1小时，搅拌下将反应液倒入冰水(400mL)中，有固体析出，过滤，用水(100mL)淋洗，收集固体，真空干燥得到化合物14-2。 1H NMR(400MHz，CDCl 3)δ＝7.69-7.60(m，5H)，6.52(d，J＝16.0Hz，1H)，4.28(q，J＝7.2Hz，2H)，1.35(t，J＝7.2Hz，3H)。 Add compound 14-1 (30g, 1eq) and triethyl phosphonoacetate (53.11g, 47.0mL, 1.04eq) into dry N,N-dimethylacetamide (240mL), cool to 0°C, slowly Sodium hydride (9.15 g, 60% content, 1 eq) was added, the temperature was controlled below 10° C., and the addition was completed in 30 minutes. The reaction solution was stirred at 0-10°C for 1 hour. The reaction solution was poured into ice water (400 mL) while stirring. Solids precipitated, filtered, rinsed with water (100 mL), collected solids, and dried in vacuo to obtain compound 14-2. 1 H NMR (400MHz, CDCl 3 ) δ=7.69-7.60(m, 5H), 6.52(d, J=16.0Hz, 1H), 4.28(q, J=7.2Hz, 2H), 1.35(t, J= 7.2Hz, 3H).
第二步second step
氮气保护下，将三甲基碘化亚砜(49.2g，1.5eq)溶于二甲基亚砜(500mL)中，加入叔丁醇钠(21.43g，1.50eq)，混合物在20～25℃下搅拌2小时。加入化合物14-2(30.0g，1eq)，反应液在20～25℃搅拌30小时。将反应液倒入饱和氯化铵水溶液(400mL)中，搅拌，用乙酸乙酯萃取(300mL*3)，有机层合并，用水洗(300mL*2)，饱和氯化钠水溶液(300mL*1)洗涤，无水硫酸钠干燥，过滤，滤液浓缩至干。剩余物经柱层析纯化(石油醚∶乙酸乙酯＝10∶1～5∶1)得到化合物14-3。 1H NMR(400MHz，CDCl 3)δ＝7.59(d，J＝8.4Hz，2H)，7.20(d，J＝8.4Hz，2H)，4.20(d，J＝7.2Hz，2H)，2.58-2.53(m，1H)，1.99-1.95(m，1H)，1.73-1.68(m，1H)，1.38 -1.34(m，1H)，1.30(t，J＝7.2Hz，3H)。 Under nitrogen protection, trimethylsulfoxide iodide (49.2g, 1.5eq) was dissolved in dimethylsulfoxide (500mL), sodium tert-butoxide (21.43g, 1.50eq) was added, and the mixture was heated at 20-25°C Stir for 2 hours. Compound 14-2 (30.0 g, 1 eq) was added, and the reaction solution was stirred at 20-25° C. for 30 hours. The reaction solution was poured into saturated aqueous ammonium chloride solution (400mL), stirred, extracted with ethyl acetate (300mL*3), the organic layers were combined, washed with water (300mL*2), saturated aqueous sodium chloride solution (300mL*1) Washed, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to dryness. The residue was purified by column chromatography (petroleum ether:ethyl acetate=10:1~5:1) to obtain compound 14-3. 1 H NMR (400MHz, CDCl 3 ) δ=7.59(d, J=8.4Hz, 2H), 7.20(d, J=8.4Hz, 2H), 4.20(d, J=7.2Hz, 2H), 2.58-2.53 (m, 1H), 1.99-1.95 (m, 1H), 1.73-1.68 (m, 1H), 1.38-1.34 (m, 1H), 1.30 (t, J=7.2Hz, 3H).
第三步third step
将化合物14-3(7.0g，1eq)溶于甲醇(50mL)和四氢呋喃(50mL)中，加入一水合氢氧化锂(4.20g，3.08eq)的水(20mL)溶液，反应液在20～25℃搅拌1小时。减压浓缩除去有机溶剂，剩余物用1N稀盐酸调pH值约2～3，搅拌，减压过滤收集固体，减压干燥得到化合物14-4。Compound 14-3 (7.0g, 1eq) was dissolved in methanol (50mL) and tetrahydrofuran (50mL), and a solution of lithium hydroxide monohydrate (4.20g, 3.08eq) in water (20mL) was added. °C and stirred for 1 hour. Concentrate under reduced pressure to remove the organic solvent, adjust the pH of the residue to about 2-3 with 1N dilute hydrochloric acid, stir, collect the solid by filtration under reduced pressure, and dry under reduced pressure to obtain compound 14-4.
第四步the fourth step
将化合物14-4(6.0g，1eq)溶于四氢呋喃(60mL)中，冷却到0℃，加入草酰氯(5.8mL，2.07eq)和催化量的N，N-二甲基甲酰胺(117.13mg，123.30μL，0.05eq)，反应在0～20℃搅拌2小时。将反应浓缩至干，分散至甲苯(10mL)后旋干得到化合物14-5。Compound 14-4 (6.0g, 1eq) was dissolved in tetrahydrofuran (60mL), cooled to 0°C, oxalyl chloride (5.8mL, 2.07eq) and a catalytic amount of N,N-dimethylformamide (117.13mg , 123.30 μL, 0.05eq), the reaction was stirred at 0-20°C for 2 hours. The reaction was concentrated to dryness, dispersed in toluene (10 mL) and spin-dried to obtain compound 14-5.
第五步the fifth step
将化合物14-5(6.6g，1eq)溶于二氯甲烷(60mL)中，冷却到0～5℃，加入三甲基硅重氮甲烷(2M，31.5mL，1.96eq)的正己烷溶液，然后滴加三乙胺(9.2mL，2.06eq)，控制温度在5～10℃，10分钟加完。反应液在0～10℃搅拌1小时，然后在20～30℃搅拌10小时。加水(60mL)淬灭反应，加二氯甲烷(40mL)萃取，萃取液用饱和氯化钠(50mL)洗，无水硫酸钠干燥，过滤，滤液浓缩干得到化合物14-6。 1H NMR(400MHz，CDCl 3)δ＝7.57(d，J＝8.4Hz，2H)，7.18(d，J＝8.4Hz，2H)，5.44(brs，1H)，2.68-2.63(m，1H)，1.92(br s，1H)，1.86-1.81(m，1H)，1.42-1.39(m，1H)。 Compound 14-5 (6.6g, 1eq) was dissolved in dichloromethane (60mL), cooled to 0-5°C, and a n-hexane solution of trimethylsilyldiazomethane (2M, 31.5mL, 1.96eq) was added, Then triethylamine (9.2mL, 2.06eq) was added dropwise, the temperature was controlled at 5-10°C, and the addition was completed in 10 minutes. The reaction solution was stirred at 0-10°C for 1 hour, then at 20-30°C for 10 hours. Add water (60 mL) to quench the reaction, add dichloromethane (40 mL) to extract, the extract is washed with saturated sodium chloride (50 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate is concentrated to dryness to obtain compound 14-6. 1 H NMR (400MHz, CDCl 3 ) δ=7.57(d, J=8.4Hz, 2H), 7.18(d, J=8.4Hz, 2H), 5.44(brs, 1H), 2.68-2.63(m, 1H) , 1.92 (br s, 1H), 1.86-1.81 (m, 1H), 1.42-1.39 (m, 1H).
第六步step six
将化合物14-6(4.9g，1eq)溶于甲醇(50mL)和1，4-二氧六环(50mL)的混合溶剂中，反应瓶遮光并冷却到0℃，缓慢滴加苯甲酸银(0.8g，0.15eq)的三乙胺(18.4mL，5.7eq)溶液，反应液升温到20～25℃并搅拌10小时。加乙酸乙酯(100mL)稀释，搅拌15分钟，经硅藻土过滤，滤液减压浓缩，剩余物柱层析(石油醚∶乙酸乙酯＝5∶1～3∶1)纯化得到化合物14-7。Compound 14-6 (4.9g, 1eq) was dissolved in a mixed solvent of methanol (50mL) and 1,4-dioxane (50mL), the reaction bottle was shielded from light and cooled to 0°C, and silver benzoate ( 0.8g, 0.15eq) in triethylamine (18.4mL, 5.7eq) solution, the reaction solution was warmed up to 20-25°C and stirred for 10 hours. Dilute with ethyl acetate (100 mL), stir for 15 minutes, filter through celite, concentrate the filtrate under reduced pressure, and purify the residue by column chromatography (petroleum ether: ethyl acetate = 5:1 ~ 3:1) to obtain compound 14- 7.
第七步step seven
将化合物14-7(3.6g，1eq)溶于三氟乙酸酐(50mL)中，冷却到3℃，缓慢滴加硝酸(5mL，65％含量，4.32eq)，15分钟加完，控制温度在20℃以下，反应液在冰水浴中搅拌15分钟。搅拌下倒入碎冰(100g)中，用乙酸乙酯萃取(100Ml*2)，有机层依次用水洗涤(100mL*1)，饱和碳酸氢钠水溶液洗涤(100mL*2)，饱和氯化钠水溶液洗涤(100mL*1)，无水硫酸钠干燥，过滤，滤液减压浓缩至干得到化合物14-8。 1H NMR(400MHz，CDCl 3)δ＝8.15(d，J＝1.2Hz，1H)，7.79(dd，J＝8.4，1.2Hz，1H)，7.40(d，J＝8.4，Hz，1H)，3.74(s，3H)，2.58-2.46(m，2H)，2.36-2.31(m，1H)，1.55-1.42(m，1H)，1.17-1.10(m，2H). Compound 14-7 (3.6g, 1eq) was dissolved in trifluoroacetic anhydride (50mL), cooled to 3°C, nitric acid (5mL, 65% content, 4.32eq) was slowly added dropwise for 15 minutes, and the temperature was controlled at Below 20°C, the reaction solution was stirred in an ice-water bath for 15 minutes. Pour into crushed ice (100g) with stirring, extract with ethyl acetate (100Ml*2), wash the organic layer with water (100mL*1), saturated aqueous sodium bicarbonate (100mL*2), and saturated aqueous sodium chloride Wash (100 mL*1), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to dryness under reduced pressure to obtain compound 14-8. 1 H NMR (400MHz, CDCl 3 ) δ = 8.15 (d, J = 1.2Hz, 1H), 7.79 (dd, J = 8.4, 1.2Hz, 1H), 7.40 (d, J = 8.4, Hz, 1H), 3.74(s, 3H), 2.58-2.46(m, 2H), 2.36-2.31(m, 1H), 1.55-1.42(m, 1H), 1.17-1.10(m, 2H).
第八步eighth step
将化合物14-8(4.1g，1eq)溶于异丙醇(50mL)和水(10mL)的混合溶剂中，加入铁粉(4.40g，5eq)和氯化 铵(4.21g，5eq)，反应物在90～100℃搅拌10小时。冷却，加入乙酸乙酯(100mL)，搅拌15分钟，经硅藻土过滤，滤液依次用水(100mL)和饱和氯化钠(100mL)洗涤，硫酸钠干燥，过滤，减压浓缩，经柱层析(石油醚∶乙酸乙酯＝5∶1～3∶1)纯化，再经SFC分离(分离条件：色谱柱：DAICEL CHIRALPAK AD(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；梯度：B％：40％-40％)得到化合物14-9。SFC检测条件：色谱柱：Chiralpak IG-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％，流速：3mL/min，保留时间2.054min。 1H NMR(400MHz，CDCl 3)δ＝7.09(d，J＝8.0Hz，1H)，6.94(dd，J＝8.0，1.2Hz，1H)，6.89(d，J＝1.2，Hz，1H)，4.74(brs，2H)，3.78(s，3H)，2.95(dd，J＝16.8，4.0Hz，1H)，2.06(t，J＝7.6Hz，1H)，1.69-1.64(m，1H)，1.20-1.14(m，1H)，1.10-1.06(m，1H)，0.83-0.78(m，1H)。 Compound 14-8 (4.1g, 1eq) was dissolved in a mixed solvent of isopropanol (50mL) and water (10mL), iron powder (4.40g, 5eq) and ammonium chloride (4.21g, 5eq) were added, and the reaction The mixture was stirred at 90-100°C for 10 hours. Cool, add ethyl acetate (100mL), stir for 15 minutes, filter through diatomaceous earth, wash the filtrate with water (100mL) and saturated sodium chloride (100mL) successively, dry over sodium sulfate, filter, concentrate under reduced pressure, and pass column chromatography (petroleum ether: ethyl acetate = 5:1 ~ 3:1), and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALPAK AD (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B Phase: [(0.1% ammonia)methanol]; Gradient: B%: 40%-40%) to give compound 14-9. SFC detection conditions: Chromatographic column: Chiralpak IG-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% , flow rate: 3mL/min, retention time 2.054min. 1 H NMR (400MHz, CDCl 3 ) δ = 7.09 (d, J = 8.0Hz, 1H), 6.94 (dd, J = 8.0, 1.2Hz, 1H), 6.89 (d, J = 1.2, Hz, 1H), 4.74(brs, 2H), 3.78(s, 3H), 2.95(dd, J=16.8, 4.0Hz, 1H), 2.06(t, J=7.6Hz, 1H), 1.69-1.64(m, 1H), 1.20 -1.14 (m, 1H), 1.10-1.06 (m, 1H), 0.83-0.78 (m, 1H).
第九步Ninth step
将中间体Da(510mg，1eq)和化合物14-9(300.00mg，0.74eq)溶于乙腈(5mL)和四氢呋喃(5mL)混合溶剂中，加入二异丙基乙胺(1.60mL，5.21eq)和4-二甲氨基吡啶(DMAP)(43.00mg，0.2eq)，混合物在25℃搅拌10分钟，然后滴加三正丙基环磷酸酐(T 3P，4.20mL，50％含量的乙酸乙酯溶液，4.0eq)，10分钟加完，滴加过程中，反应液温度升至35℃，加毕，反应液搅拌1小时。加水(100mL)淬灭反应，搅拌10分钟，有固体析出，减压过滤收集固体，用乙醇打浆(20mL*2)，过滤，滤饼干燥得到化合物14-10a。MS：m/z 502.2[M+H] +。 Intermediate Da (510mg, 1eq) and compound 14-9 (300.00mg, 0.74eq) were dissolved in acetonitrile (5mL) and tetrahydrofuran (5mL) mixed solvent, diisopropylethylamine (1.60mL, 5.21eq) was added and 4-dimethylaminopyridine (DMAP) (43.00mg, 0.2eq), the mixture was stirred at 25°C for 10 minutes, then tri-n-propyl cyclic phosphoric anhydride (T 3 P, 4.20mL, 50% content of ethyl acetate Ester solution, 4.0eq), the addition was completed in 10 minutes. During the dropwise addition, the temperature of the reaction solution rose to 35°C. After the addition was complete, the reaction solution was stirred for 1 hour. Add water (100 mL) to quench the reaction, stir for 10 minutes, and a solid precipitates out. The solid is collected by filtration under reduced pressure, slurried with ethanol (20 mL*2), filtered, and the filter cake is dried to obtain compound 14-10a. MS: m/z 502.2 [M+H] + .
第十步tenth step
将化合物14-10a(0.84g，1eq)悬浮于四氢呋喃(10mL)中，25℃下，缓慢滴加一水合氢氧化锂(103.76mg，2.95eq)的水(10mL)溶液，控制反应液温度在30℃以下，10分钟加完，反应液在25℃搅拌1小时。在35℃以下浓缩除去四氢呋喃，剩余物用冰水浴冷却，搅拌下用2N稀盐酸调pH值2～3，析出固体，减压过滤收集固体，用水(10mL)淋洗，干燥，加乙腈和水的混合溶剂(20mL，1∶1)，在超声仪中震荡5分钟，过滤，固体用乙腈和水的混合溶剂(10mL，1∶1)淋洗，滤饼真空干燥得到实施例14a。手性高效液相色谱检测检测条件：色谱柱：Chiralpak IE-3 50×4.6mm I.D.，3μm；流动相：A相：庚烷(0.05％二乙胺)，B相：乙醇(0.05％二乙胺)；梯度：B％：25％，流速：1mL/min，保留时间8.601min，ee＝100％。MS：m/z 488.4[M+H] +。 1H NMR(400MHz，DMSO-d 6)δ＝12.24(brs，1H)，10.04(s，1H)，8.11(d，J＝8.0Hz，1H)，7.98(d，J＝1.2Hz，1H)，7.64(dd，J＝8.4，2.0Hz，1H)，7.51(dd，J＝8.0，1.6Hz，1H)，7.44(d，J＝8.4，1.6Hz，1H)，7.18(d，J＝8.4Hz，1H)，6.84(d，J＝8.4Hz，1H)，4.35-4.30(m，1H)，4.16-4.05(m，2H)，2.59(t，J＝6.8Hz，1H)，2.45(dd，J＝17.2，6.8Hz，1H)，2.30(dd，J＝16.8，7.6Hz，1H)，2.17-2.10(m，2H)，1.95-1.90(m，1H)，1.78-1.75(m，1H)，1.61-1.59(m，1H)，1.36-1.28(m，1H)，1.17(d，J＝6.4Hz，6H)，1.10-0.94(m，1H)，0.91-0.86(m，1H)。 Compound 14-10a (0.84g, 1eq) was suspended in tetrahydrofuran (10mL), at 25°C, a solution of lithium hydroxide monohydrate (103.76mg, 2.95eq) in water (10mL) was slowly added dropwise, and the temperature of the reaction solution was controlled at Below 30°C, the addition was completed in 10 minutes, and the reaction solution was stirred at 25°C for 1 hour. Concentrate below 35°C to remove tetrahydrofuran, cool the residue in an ice-water bath, adjust the pH value to 2-3 with 2N dilute hydrochloric acid while stirring, a solid precipitates, collect the solid by filtration under reduced pressure, rinse with water (10 mL), dry, add acetonitrile and water A mixed solvent (20 mL, 1:1) was shaken in an ultrasonic apparatus for 5 minutes, filtered, the solid was rinsed with a mixed solvent of acetonitrile and water (10 mL, 1:1), and the filter cake was dried in vacuum to obtain Example 14a. Chiral high-performance liquid chromatography detection detection conditions: chromatographic column: Chiralpak IE-3 50 × 4.6mm ID, 3 μm; mobile phase: A phase: heptane (0.05% diethylamine), B phase: ethanol (0.05% diethylamine amine); gradient: B%: 25%, flow rate: 1 mL/min, retention time 8.601 min, ee=100%. MS: m/z 488.4 [M+H] + . 1 H NMR (400MHz, DMSO-d 6 ) δ=12.24(brs, 1H), 10.04(s, 1H), 8.11(d, J=8.0Hz, 1H), 7.98(d, J=1.2Hz, 1H) , 7.64(dd, J=8.4, 2.0Hz, 1H), 7.51(dd, J=8.0, 1.6Hz, 1H), 7.44(d, J=8.4, 1.6Hz, 1H), 7.18(d, J=8.4 Hz, 1H), 6.84(d, J=8.4Hz, 1H), 4.35-4.30(m, 1H), 4.16-4.05(m, 2H), 2.59(t, J=6.8Hz, 1H), 2.45(dd , J=17.2, 6.8Hz, 1H), 2.30(dd, J=16.8, 7.6Hz, 1H), 2.17-2.10(m, 2H), 1.95-1.90(m, 1H), 1.78-1.75(m, 1H ), 1.61-1.59 (m, 1H), 1.36-1.28 (m, 1H), 1.17 (d, J=6.4Hz, 6H), 1.10-0.94 (m, 1H), 0.91-0.86 (m, 1H).
实施例15Example 15
Figure PCTCN2022095009-appb-000119
Figure PCTCN2022095009-appb-000119
第一步first step
将化合物15-1(5g，1eq)加至40mL N，N-二甲基甲酰胺中，25℃下加入氰化亚铜(2.96g，1.5eq)，于25℃搅拌10分钟，升温至170℃搅拌2小时。将冷却后的反应液加至40mL冰水中，加入15mL氨水，水相用乙酸乙酯萃取(60mL*2)，合并有机相，饱和食盐水(25mL*4)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，制备薄层色谱(石油醚/乙酸乙酯＝5∶1-3∶1)纯化得到化合物15-2。 1H NMR(400MHz，CDCl 3)δ＝8.13(d，J＝2.1Hz，1H)，7.63(dd，J＝2.2，8.7Hz，1H)，7.02(d，J＝8.6Hz，1H)，4.57(t，J＝6.4Hz，2H)，2.81(t，J＝6.4Hz，2H)。 Add compound 15-1 (5g, 1eq) to 40mL N,N-dimethylformamide, add cuprous cyanide (2.96g, 1.5eq) at 25°C, stir at 25°C for 10 minutes, and heat up to 170 °C and stirred for 2 hours. Add the cooled reaction solution to 40 mL of ice water, add 15 mL of ammonia water, extract the aqueous phase with ethyl acetate (60 mL*2), combine the organic phases, wash with saturated brine (25 mL*4), dry over anhydrous sodium sulfate, and filter , the filtrate was concentrated, and purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=5:1-3:1) to obtain compound 15-2. 1 H NMR (400MHz, CDCl 3 ) δ = 8.13 (d, J = 2.1Hz, 1H), 7.63 (dd, J = 2.2, 8.7Hz, 1H), 7.02 (d, J = 8.6Hz, 1H), 4.57 (t, J=6.4Hz, 2H), 2.81 (t, J=6.4Hz, 2H).
第二步second step
将化合物15-2(4g，1eq)加至盛有25mL无水甲醇的氢化瓶中，于20℃加入钯碳(2g，10％含量)，氩气置换三次，氢气置换三次后控制氢气气压为50Psi，升温至45℃搅拌12小时。冷却后过滤，滤液浓缩，制备薄层色谱(石油醚/乙酸乙酯＝5∶1)纯化得到化合物15-3。 1H NMR(400MHz，CDCl 3)δ＝7.59(d，J＝1.6Hz，1H)，7.19(dd，J＝2.3，8.5Hz，1H)，6.78(d，J＝8.5Hz，1H)，4.41(t，J＝6.4Hz，2H)，2.70(t，J＝6.4Hz，2H)，2.21(s，2H)。 Compound 15-2 (4g, 1eq) was added to a hydrogenation bottle filled with 25mL of anhydrous methanol, palladium carbon (2g, 10% content) was added at 20°C, argon was replaced three times, and after three hydrogen replacements, the hydrogen pressure was controlled to be 50Psi, heated to 45°C and stirred for 12 hours. After cooling, it was filtered, the filtrate was concentrated, and purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=5:1) to obtain compound 15-3. 1 H NMR (400MHz, CDCl 3 ) δ = 7.59 (d, J = 1.6Hz, 1H), 7.19 (dd, J = 2.3, 8.5Hz, 1H), 6.78 (d, J = 8.5Hz, 1H), 4.41 (t, J=6.4Hz, 2H), 2.70(t, J=6.4Hz, 2H), 2.21(s, 2H).
第三步third step
将化合物15-3(1.89g，1eq)和2-甲基丙酸(1.41g，1.48mL，1.5eq)溶于四氢呋喃(10mL)和乙腈(10mL)中，加入二异丙基乙胺(2.07g，2.79mL，1.5eq)和4-二甲氨基吡啶(1.30g，1eq)，在25℃搅拌10分钟，然后 加入三正丙基环磷酸酐(T 3P，20.36g，19mL，50％含量的乙酸乙酯溶液，3eq)，反应混合液在25℃搅拌1小时。反应液减压浓缩得到化合物15-4。 Compound 15-3 (1.89g, 1eq) and 2-methylpropionic acid (1.41g, 1.48mL, 1.5eq) were dissolved in tetrahydrofuran (10mL) and acetonitrile (10mL), and diisopropylethylamine (2.07 g, 2.79mL, 1.5eq) and 4-dimethylaminopyridine (1.30g, 1eq), stirred at 25°C for 10 minutes, then added tri-n-propyl cyclic phosphoric anhydride (T 3 P, 20.36g, 19mL, 50% content of ethyl acetate solution, 3eq), and the reaction mixture was stirred at 25°C for 1 hour. The reaction solution was concentrated under reduced pressure to obtain compound 15-4.
第四步the fourth step
将甲基三苯基溴化磷(5.20g，2eq)加入四氢呋喃(15mL)中，降温至-5～0℃，氮气保护下加入双(三甲基硅基)胺基锂(LiHMDS)(1M，18.20mL，2.5eq)，于0～20℃下搅拌30分钟，再次降温至-5～0℃，滴加化合物15-4(1.8g，1eq)的15mL四氢呋喃溶液，缓慢升温至20℃搅拌1小时。反应液中加入20mL饱和氯化铵水溶液淬灭，加入水(20mL)稀释，乙酸乙酯萃取(15mL*2)，合并有机相，用饱和食盐水(25mL)洗涤，无水硫酸钠干燥，滤液减压浓缩得到化合物15-5。Add methyltriphenylphosphine bromide (5.20g, 2eq) into tetrahydrofuran (15mL), cool down to -5～0°C, add lithium bis(trimethylsilyl)amide (LiHMDS) (1M , 18.20mL, 2.5eq), stirred at 0-20°C for 30 minutes, cooled down to -5-0°C again, added dropwise 15mL tetrahydrofuran solution of compound 15-4 (1.8g, 1eq), slowly heated to 20°C and stirred 1 hour. Add 20 mL of saturated ammonium chloride aqueous solution to the reaction solution to quench, add water (20 mL) to dilute, extract with ethyl acetate (15 mL*2), combine organic phases, wash with saturated brine (25 mL), dry over anhydrous sodium sulfate, and filtrate Concentration under reduced pressure gave compound 15-5.
第五步the fifth step
将化合物15-5(1.2g，1eq)加入二氯甲烷(30mL)中，氮气置换后于20℃加入(S，S)-2，6-双(4-异丙基-2-噁唑啉-2-基)吡啶(1.47g，1eq)和(对异丙甲苯)二氯化钌(II)二聚体(3.00g，1eq)，搅拌30分钟后加入重氮乙酸乙酯(23.36g，21.4mL，41.9eq)的30mL二氯甲烷溶液，搅拌1小时。反应液过滤，滤液减压浓缩得到化合物15-6。MS：m/z 332.1[M+H] +。 Add compound 15-5 (1.2g, 1eq) into dichloromethane (30mL), and add (S,S)-2,6-bis(4-isopropyl-2-oxazoline) at 20°C after nitrogen replacement -2-yl)pyridine (1.47g, 1eq) and (p-cymene) ruthenium (II) dichloride dimer (3.00g, 1eq), after stirring for 30 minutes, ethyl diazoacetate (23.36g, 21.4mL, 41.9eq) in 30mL of dichloromethane solution, stirred for 1 hour. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 15-6. MS: m/z 332.1 [M+H] + .
第六步step six
将化合物15-6(0.48g，1eq)溶于四氢呋喃(5mL)中，加入三甲基硅醇钾(557.4mg，3eq)，反应混合液在50℃搅拌0.5小时。反应液用2N稀盐酸调pH到5，加5mL水稀释，用乙酸乙酯萃取(5mL*2)，乙酸乙酯层用10mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物15-7。MS：m/z 304.1[M+H] +。 Compound 15-6 (0.48g, 1eq) was dissolved in tetrahydrofuran (5mL), potassium trimethylsiliconate (557.4mg, 3eq) was added, and the reaction mixture was stirred at 50°C for 0.5 hours. The pH of the reaction solution was adjusted to 5 with 2N dilute hydrochloric acid, diluted with 5 mL of water, extracted with ethyl acetate (5 mL*2), the ethyl acetate layer was washed with 10 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated Compound 15-7 was obtained. MS: m/z 304.1 [M+H] + .
第七步step seven
将化合物15-7(0.6g，1eq)和二异丙基乙胺(383.4mg，517μL，1.5eq)加至10mL N，N-二甲基甲酰胺中，并将该溶液降温至0℃，加入2-(7-氮杂苯并三氮唑)-N，N，N′，N′-四甲基脲六氟磷酸盐(HATU)(752mg，1eq)至反应体系，于0℃搅拌10分钟，加入中间体C(459.4mg，1eq)，于0～20℃搅拌1小时。反应液中加入20mL水，乙酸乙酯萃取(7mL*2)，合并有机相，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，经高效液相色谱法制备分离纯化(分离条件：色谱柱：Phenomenex Synergi C18 150*25mm*10μm；流动相：[水(0.1％三氟乙酸)-乙腈]；乙腈％：56％-86％)，然后再通过SFC分离(分离条件：色谱柱：DAICEL CHIRALPAK AS(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)乙醇]；B％：35％-35％)得到化合物15-8a。SFC检测条件：色谱柱：Chiralpak AS-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：乙醇(0.05％二乙胺)；梯度：B％：5％～40％，流速：3mL/min，保留时间为1.616min，ee＝100％。MS：m/z 518.3[M+H] +。 Compound 15-7 (0.6g, 1eq) and diisopropylethylamine (383.4mg, 517μL, 1.5eq) were added to 10mL of N,N-dimethylformamide, and the solution was cooled to 0°C, Add 2-(7-azabenzotriazole)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU) (752mg, 1eq) to the reaction system, stir at 0°C for 10 minutes, Intermediate C (459.4mg, 1eq) was added and stirred at 0-20°C for 1 hour. Add 20 mL of water to the reaction solution, extract with ethyl acetate (7 mL*2), combine the organic phases, wash with saturated brine (15 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and prepare separation and purification by high performance liquid chromatography ( Separation conditions: chromatographic column: Phenomenex Synergi C18 150*25mm*10 μ m; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; acetonitrile%: 56%-86%), and then separated by SFC (separation conditions: Chromatographic column: DAICEL CHIRALPAK AS (250mm*30mm, 10μm); mobile phase: phase A: CO 2 , phase B: [(0.1% ammonia) ethanol]; B%: 35%-35%) to obtain compound 15-8a. SFC detection conditions: Chromatographic column: Chiralpak AS-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: ethanol (0.05% diethylamine); gradient: B%: 5% to 40% , flow rate: 3mL/min, retention time 1.616min, ee=100%. MS: m/z 518.3 [M+H] + .
第八步eighth step
将化合物15-8a(0.25g，1eq)溶于四氢呋喃(4mL)和甲醇(4mL)的混合溶剂中，加入氢氧化锂(34.7mg，3eq)的水(1mL)溶液，反应在20℃搅拌2小时。反应液用饱和柠檬酸水溶液调节pH值至5，乙酸乙酯萃取(5mL*2)，合并有机相，用饱和食盐水洗涤(10mL*1)，无水硫酸钠干燥，滤液减压浓缩，经制备薄层色谱(石油醚/乙酸乙酯＝0∶1)分离得到化合物15a。SFC检测条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％，流速：3mL/min，保留时间为2.039min，ee＝100％。MS：m/z 490.3[M+H] +。 1H NMR(400MHz，CDCl 3)δ＝9.83(s，1H)，8.76(s，1H)，7.84(s，1H)，7.22-7.14(m，2H)，7.09(d，J＝8.0Hz，1H)，6.71(d，J＝8.4Hz，1H)，6.24(br s，1H)，4.43(br d，J＝10.8Hz，1H)，4.25-4.22(m，1H)，3.46(br t，J＝7.3Hz，1H)，3.28-3.10(m，2H)，2.60(br t，J＝8.3Hz，2H)，2.54-2.30(m，2H)，2.12-1.98(m，2H)，1.80(tt，J＝6.7，13.3Hz，1H)，1.63(br s，2H)，1.45(br t，J＝4.9Hz，1H)，1.17-1.12(m，2H)，0.88(br d，J＝6.6Hz，6H)。 Compound 15-8a (0.25g, 1eq) was dissolved in a mixed solvent of tetrahydrofuran (4mL) and methanol (4mL), a solution of lithium hydroxide (34.7mg, 3eq) in water (1mL) was added, and the reaction was stirred at 20°C for 2 Hour. The pH of the reaction solution was adjusted to 5 with saturated aqueous citric acid, extracted with ethyl acetate (5 mL*2), the organic phases were combined, washed with saturated brine (10 mL*1), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure. Compound 15a was obtained by preparative thin layer chromatography (petroleum ether/ethyl acetate=0:1). SFC detection conditions: Chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% , flow rate: 3 mL/min, retention time 2.039 min, ee=100%. MS: m/z 490.3 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ=9.83(s, 1H), 8.76(s, 1H), 7.84(s, 1H), 7.22-7.14(m, 2H), 7.09(d, J=8.0Hz, 1H), 6.71(d, J=8.4Hz, 1H), 6.24(br s, 1H), 4.43(br d, J=10.8Hz, 1H), 4.25-4.22(m, 1H), 3.46(br t, J=7.3Hz, 1H), 3.28-3.10(m, 2H), 2.60(br t, J=8.3Hz, 2H), 2.54-2.30(m, 2H), 2.12-1.98(m, 2H), 1.80( tt, J=6.7, 13.3Hz, 1H), 1.63(br s, 2H), 1.45(br t, J=4.9Hz, 1H), 1.17-1.12(m, 2H), 0.88(br d, J=6.6 Hz, 6H).
实施例16Example 16
Figure PCTCN2022095009-appb-000120
Figure PCTCN2022095009-appb-000120
第一步first step
将化合物16-1(1g，1eq)加至15mL N-甲基吡咯烷酮中，20℃下加入氰化亚铜(863mg，9.6mmol，3eq)，于20℃搅拌10分钟，升温至180℃搅拌4小时。将冷却后的反应液加至30mL冰水中搅拌10分钟，析出固体过滤，水相用乙酸乙酯萃取(15mL*2)，合并有机相，饱和食盐水(20mL*3)洗涤，无水硫酸钠干燥， 过滤，滤液浓缩干后与过滤得到的固体合并得到化合物16-2。 1H NMR(400MHz，CDCl 3)δ＝7.38(dd，J＝2.0，8.5Hz，1H)，7.00(d，J＝1.8Hz，1H)，6.88(d，J＝8.6Hz，1H)，4.40-4.32(m，1H)，4.31-4.22(m，1H)，4.21-4.17(m，2H)，2.26-2.19(m，2H)，2.14-2.07(m，1H)，1.62-1.55(m，1H)，1.31-1.27(m，3H)，1.11(t，J＝7.2Hz，1H)。 Compound 16-1 (1g, 1eq) was added to 15mL of N-methylpyrrolidone, cuprous cyanide (863mg, 9.6mmol, 3eq) was added at 20°C, stirred at 20°C for 10 minutes, then heated to 180°C and stirred for 4 Hour. The cooled reaction liquid was added to 30 mL of ice water and stirred for 10 minutes, the precipitated solid was filtered, the aqueous phase was extracted with ethyl acetate (15 mL*2), the organic phases were combined, washed with saturated brine (20 mL*3), anhydrous sodium sulfate After drying and filtering, the filtrate was concentrated to dryness and combined with the filtered solid to obtain compound 16-2. 1 H NMR (400MHz, CDCl 3 ) δ = 7.38 (dd, J = 2.0, 8.5Hz, 1H), 7.00 (d, J = 1.8Hz, 1H), 6.88 (d, J = 8.6Hz, 1H), 4.40 -4.32(m, 1H), 4.31-4.22(m, 1H), 4.21-4.17(m, 2H), 2.26-2.19(m, 2H), 2.14-2.07(m, 1H), 1.62-1.55(m, 1H), 1.31-1.27 (m, 3H), 1.11 (t, J=7.2Hz, 1H).
第二步second step
将化合物16-2(0.7g，1eq)加至盛有10mL无水甲醇的氢化瓶中，于20℃加入钯碳(1g，10％含量)，氩气置换三次，氢气置换三次后控制氢气气压为50Psi，升温至50℃搅拌2小时。反应液冷却，过滤，滤液浓缩得到化合物16-3粗品。Add compound 16-2 (0.7g, 1eq) to a hydrogenation bottle filled with 10mL of anhydrous methanol, add palladium carbon (1g, 10% content) at 20°C, replace with argon three times, and control the hydrogen pressure after three replacements with hydrogen to 50Psi, the temperature was raised to 50°C and stirred for 2 hours. The reaction liquid was cooled, filtered, and the filtrate was concentrated to obtain the crude compound 16-3.
第三步third step
将化合物16-3(0.3g，1eq)加至10mL二氯甲烷，降温至0℃，滴加三乙胺(174.3mg，240μL，1.5eq)，于0℃搅拌10分钟，滴加三甲基乙酰氯(276.9mg，283μL，2eq)的10mL二氯甲烷溶液，于0～20℃搅拌12小时。将反应液倒入12mL水中，乙酸乙酯萃取(12mL*2)，合并有机相，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物16-4。MS：m/z 346.3[M+H] +。 Compound 16-3 (0.3g, 1eq) was added to 10mL of dichloromethane, cooled to 0°C, triethylamine (174.3mg, 240μL, 1.5eq) was added dropwise, stirred at 0°C for 10 minutes, trimethylamine was added dropwise Acetyl chloride (276.9mg, 283μL, 2eq) in 10mL of dichloromethane was stirred at 0-20°C for 12 hours. The reaction solution was poured into 12 mL of water, extracted with ethyl acetate (12 mL*2), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 16-4. MS: m/z 346.3 [M+H] + .
第四步the fourth step
将化合物16-4(0.4g，1eq)溶于四氢呋喃(15mL)中，在20℃加入三甲基硅醇钾(743mg，5eq)，反应混合液升温至50℃搅拌2小时。反应液用2N稀盐酸调pH到5，加20mL水稀释，用乙酸乙酯萃取(12mL*2)，乙酸乙酯层用15mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物16-5。MS：m/z 318.2[M+H] +。 Compound 16-4 (0.4g, 1eq) was dissolved in tetrahydrofuran (15mL), potassium trimethylsiliconate (743mg, 5eq) was added at 20°C, and the reaction mixture was heated to 50°C and stirred for 2 hours. The reaction solution was adjusted to pH 5 with 2N dilute hydrochloric acid, diluted with 20 mL of water, extracted with ethyl acetate (12 mL*2), the ethyl acetate layer was washed with 15 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated Compound 16-5 was obtained. MS: m/z 318.2 [M+H] + .
第五步the fifth step
将化合物16-5(0.4g，1eq)和中间体C(351mg，1.2eq)溶于四氢呋喃(5mL)和乙腈(5mL)中，加入二异丙基乙胺(244mg，329μL，1.5eq)和4-二甲氨基吡啶(154mg，1eq)，在20℃搅拌10分钟，然后加入三正丙基环磷酸酐(T 3P，2.41g，2.25mL，50％含量的乙酸乙酯溶液，3eq)，反应混合液在20℃搅拌2小时。反应液减压浓缩，加入水(12mL)稀释，乙酸乙酯萃取(10mL*2)，合并有机相，用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，滤液减压浓缩得到粗品。粗品经制备薄层色谱分离纯化(石油醚/乙酸乙酯＝1∶2)，再经SFC分离(分离条件：色谱柱：Daicel ChiralPak IG(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)乙醇]；B％：40％-40％)得到化合物16-6a。SFC检测条件：色谱柱：Chiralpak AD-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度B％：5％～40％，流速：3mL/min，保留时间为1.680min。MS：m/z 532.4[M+H] +。 Compound 16-5 (0.4g, 1eq) and intermediate C (351mg, 1.2eq) were dissolved in tetrahydrofuran (5mL) and acetonitrile (5mL), diisopropylethylamine (244mg, 329μL, 1.5eq) was added and 4-Dimethylaminopyridine (154mg, 1eq), stirred at 20°C for 10 minutes, then added tri-n-propyl cyclic phosphoric anhydride (T 3 P, 2.41g, 2.25mL, 50% content in ethyl acetate solution, 3eq) , and the reaction mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (12 mL), extracted with ethyl acetate (10 mL*2), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product. The crude product was separated and purified by preparative thin-layer chromatography (petroleum ether/ethyl acetate=1:2), and then separated by SFC (separation conditions: chromatographic column: Daicel ChiralPak IG (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , Phase B: [(0.1% ammonia water) ethanol]; B%: 40%-40%) to obtain compound 16-6a. SFC detection conditions: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient B%: 5% to 40%, Flow rate: 3mL/min, retention time 1.680min. MS: m/z 532.4 [M+H] + .
第六步step six
将化合物16-6a(0.4g，1eq)加入四氢呋喃(10mL)中，搅拌下加入三甲基硅醇钾(269.6mg，3eq)，并于20℃下搅拌2小时。用2N稀盐酸水溶液调节反应体系pH值至5，加入12mL水稀释，水相用乙酸乙酯萃 取(10mL*2)，合并有机相，用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，滤液减压浓缩，经制备薄层色谱(二氯甲烷/甲醇＝10∶1)纯化得到化合物16a。SFC检测条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％，流速：3mL/min，保留时间为1.521min，ee＝100％。MS：m/z 504.3[M+H] +。 1H NMR(400MHz，CDCl 3)δ＝9.85(br s，1H)，8.79(br s，1H)，7.86(br s，1H)，7.30-7.20(m，2H)，7.12(br s，1H)，6.76(d，J＝8.4Hz，1H)，6.19(br s，1H)，4.50-4.45(m，1H)，4.29-4.24(m，1H)，3.48(br s，1H)，3.28(br s，1H)，3.13(br s，1H)，2.63(br s，2H)，2.56-2.31(m，2H)，2.19-2.04(m，2H)，1.49(br s，2H)，1.19(br s，2H)，0.90(s，9H)。 Compound 16-6a (0.4g, 1eq) was added into tetrahydrofuran (10mL), potassium trimethylsiliconate (269.6mg, 3eq) was added with stirring, and stirred at 20°C for 2 hours. Adjust the pH value of the reaction system to 5 with 2N dilute hydrochloric acid aqueous solution, add 12 mL of water to dilute, extract the aqueous phase with ethyl acetate (10 mL*2), combine the organic phases, wash with saturated brine (15 mL), and dry over anhydrous sodium sulfate. The filtrate was concentrated under reduced pressure, and purified by preparative thin-layer chromatography (dichloromethane/methanol=10:1) to obtain compound 16a. SFC detection conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% , flow rate: 3 mL/min, retention time 1.521 min, ee=100%. MS: m/z 504.3 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ=9.85 (br s, 1H), 8.79 (br s, 1H), 7.86 (br s, 1H), 7.30-7.20 (m, 2H), 7.12 (br s, 1H ), 6.76(d, J=8.4Hz, 1H), 6.19(br s, 1H), 4.50-4.45(m, 1H), 4.29-4.24(m, 1H), 3.48(br s, 1H), 3.28( br s, 1H), 3.13(br s, 1H), 2.63(br s, 2H), 2.56-2.31(m, 2H), 2.19-2.04(m, 2H), 1.49(br s, 2H), 1.19( br s, 2H), 0.90 (s, 9H).
实施例17Example 17
Figure PCTCN2022095009-appb-000121
Figure PCTCN2022095009-appb-000121
第一步first step
将化合物15-1(4g，1eq)和甲基硼酸(2.11g，2eq)加至25mL二氧六环和5mL水中，20℃下加入碳酸钾(7.30g，3eq)和二(三苯基膦)二氯化钯(2.47g，3.52mmol，0.2eq)，于20℃搅拌10分钟，升温至90℃搅拌1小时。将冷却后的反应液过滤，水相用乙酸乙酯萃取(28mL*2)，合并有机相，饱和食盐水(15mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物17-1。 1H NMR(400MHz，CDCl 3)δ＝7.70(d，J＝1.5Hz，1H)，7.33-7.26(m，1H)，6.89(dd，J＝3.7，8.6Hz，1H)，4.56-4.48(m，2H)，2.83-2.79(m，2H)，2.32(s，3H)。 Compound 15-1 (4g, 1eq) and methylboronic acid (2.11g, 2eq) were added to 25mL dioxane and 5mL water, potassium carbonate (7.30g, 3eq) and bis(triphenylphosphine) were added at 20°C ) palladium dichloride (2.47g, 3.52mmol, 0.2eq), stirred at 20°C for 10 minutes, then raised the temperature to 90°C and stirred for 1 hour. The cooled reaction solution was filtered, the aqueous phase was extracted with ethyl acetate (28 mL*2), the organic phases were combined, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 17-1. 1 H NMR (400MHz, CDCl 3 ) δ = 7.70 (d, J = 1.5Hz, 1H), 7.33-7.26 (m, 1H), 6.89 (dd, J = 3.7, 8.6Hz, 1H), 4.56-4.48 ( m, 2H), 2.83-2.79 (m, 2H), 2.32 (s, 3H).
第二步second step
将化合物17-1(0.2g，1eq)加至盛有5mL 1，2-二氯乙烷的反应瓶中，于20℃加入N-溴代丁二酰亚胺(219mg，1eq)和偶氮二异丁腈(40.5mg，0.2eq)，20℃搅拌10分钟，升温至75℃搅拌2小时。反应液冷却，过滤，滤液浓缩，制备薄层色谱(石油醚/乙酸乙酯＝5∶1)纯化得到化合物17-2。 1H NMR(400MHz，CDCl 3)δ＝7.84(d，J＝2.4Hz，1H)，7.45(dd，J＝2.4，8.6Hz，1H)，6.90(d，J＝8.5Hz，1H)，4.48(t，J＝6.4Hz，2H)，4.40(s，2H)，2.75(t，J＝6.4Hz，2H)。 Compound 17-1 (0.2g, 1eq) was added to a reaction flask containing 5mL of 1,2-dichloroethane, and N-bromosuccinimide (219mg, 1eq) and azo Diisobutyronitrile (40.5mg, 0.2eq), stirred at 20°C for 10 minutes, then raised to 75°C and stirred for 2 hours. The reaction liquid was cooled, filtered, the filtrate was concentrated, and purified by preparative thin layer chromatography (petroleum ether/ethyl acetate=5:1) to obtain compound 17-2. 1 H NMR (400MHz, CDCl 3 ) δ = 7.84 (d, J = 2.4Hz, 1H), 7.45 (dd, J = 2.4, 8.6Hz, 1H), 6.90 (d, J = 8.5Hz, 1H), 4.48 (t, J=6.4Hz, 2H), 4.40(s, 2H), 2.75(t, J=6.4Hz, 2H).
第三步third step
将2-吡咯烷酮(53mg，1.5eq)溶于四氢呋喃(5mL)中，降温至0℃，加入氢化钠(33mg，60％含量，2eq)，在0～20℃搅拌30分钟，然后加入化合物17-2(0.1g，1eq)的3mL四氢呋喃溶液，反应混合液在0～20℃搅拌2小时。反应液中加入10mL饱和氯化铵水溶液淬灭，乙酸乙酯萃取(5mL*2)，合并有机相，用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，滤液减压浓缩得到化合物17-3。 1H NMR(400MHz，CDCl 3)δ＝7.82(d，J＝2.4Hz，1H)，7.46(dd，J＝2.4，8.4Hz，1H)，6.92(d，J＝8.8Hz，1H)，4.59(s，2H)，4.47(t，J＝6.4Hz，2H)，4.05(q，J＝7.1Hz，2H)，2.75(t，J＝6.4Hz，2H)，1.19(t，J＝7.2Hz，2H)，1.14(d，J＝6.1Hz，2H)。 Dissolve 2-pyrrolidone (53mg, 1.5eq) in tetrahydrofuran (5mL), cool down to 0°C, add sodium hydride (33mg, 60% content, 2eq), stir at 0-20°C for 30 minutes, then add compound 17- 2 (0.1g, 1eq) was dissolved in 3mL of tetrahydrofuran, and the reaction mixture was stirred at 0-20°C for 2 hours. The reaction solution was quenched by adding 10 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (5 mL*2), combined the organic phases, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 17- 3. 1 H NMR (400MHz, CDCl 3 ) δ = 7.82 (d, J = 2.4Hz, 1H), 7.46 (dd, J = 2.4, 8.4Hz, 1H), 6.92 (d, J = 8.8Hz, 1H), 4.59 (s, 2H), 4.47(t, J=6.4Hz, 2H), 4.05(q, J=7.1Hz, 2H), 2.75(t, J=6.4Hz, 2H), 1.19(t, J=7.2Hz , 2H), 1.14 (d, J = 6.1 Hz, 2H).
第四步the fourth step
将甲基三苯基溴化磷(105mg，2eq)加入四氢呋喃(5mL)中，降温至-5～0℃，氮气保护下加入叔丁醇钾(33mg，2eq)，于0～20℃下搅拌30分钟，再次降温至-5～0℃，滴加化合物17-3(36mg，1eq)的3mL四氢呋喃溶液，0～20℃搅拌2小时。反应液中加入10mL饱和氯化铵水溶液淬灭，乙酸乙酯萃取(5mL*2)，合并有机相，用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，滤液减压浓缩得到化合物17-4。Add methyltriphenylphosphine bromide (105mg, 2eq) into tetrahydrofuran (5mL), cool down to -5~0°C, add potassium tert-butoxide (33mg, 2eq) under nitrogen protection, and stir at 0~20°C After 30 minutes, the temperature was lowered to -5~0°C again, a solution of compound 17-3 (36 mg, 1 eq) in 3 mL tetrahydrofuran was added dropwise, and stirred at 0~20°C for 2 hours. The reaction solution was quenched by adding 10 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (5 mL*2), combined the organic phases, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 17- 4.
第五步the fifth step
将化合物17-4(38mg，1eq)加入二氯甲烷(3mL)中，氮气置换后于20℃加入(S，S)-2，6-双(4-异丙基-2-噁唑啉-2-基)吡啶(23.5mg，0.5eq)和(对异丙甲苯)二氯化钌(II)二聚体(48mg，0.5eq)，搅拌30分钟后加入重氮乙酸乙酯(53.5mg，49μL，3eq)的1mL二氯甲烷溶液，搅拌1小时。反应液中加入10mL饱和氯化铵水溶液淬灭，乙酸乙酯萃取(5mL*2)，合并有机相，用饱和食盐水(15mL)洗涤，无水硫酸钠干燥，滤液减压浓缩得到化合物17-5。Compound 17-4 (38mg, 1eq) was added to dichloromethane (3mL), and after nitrogen replacement, (S,S)-2,6-bis(4-isopropyl-2-oxazoline- 2-yl)pyridine (23.5mg, 0.5eq) and (p-cymene) ruthenium (II) dichloride dimer (48mg, 0.5eq), after stirring for 30 minutes, ethyl diazoacetate (53.5mg, 49 μL, 3eq) in 1 mL of dichloromethane, stirred for 1 hour. The reaction solution was quenched by adding 10 mL of saturated aqueous ammonium chloride solution, extracted with ethyl acetate (5 mL*2), combined the organic phases, washed with saturated brine (15 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 17- 5.
第六步step six
将化合物17-5(56mg，1eq)溶于四氢呋喃(3mL)中，加入三甲基硅醇钾(65mg，3eq)，反应混合液在25℃搅拌30分钟。反应液用2N稀盐酸调pH到5，加4mL水稀释，用乙酸乙酯萃取(2mL*2)，乙酸乙酯层用5mL饱和氯化钠水溶液洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物17-6。MS：m/z 302.1[M+H] +。第七步 Compound 17-5 (56mg, 1eq) was dissolved in tetrahydrofuran (3mL), potassium trimethylsiliconate (65mg, 3eq) was added, and the reaction mixture was stirred at 25°C for 30 minutes. The reaction solution was adjusted to pH 5 with 2N dilute hydrochloric acid, diluted with 4 mL of water, extracted with ethyl acetate (2 mL*2), the ethyl acetate layer was washed with 5 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated Compound 17-6 was obtained. MS: m/z 302.1 [M+H] + . step seven
将化合物17-6(50mg，1eq)和中间体C(38.5mg，1eq)溶于四氢呋喃(1mL)和乙腈(2mL)中，加入二异丙基乙胺(32mg，43μL，1.5eq)和4-二甲氨基吡啶(20mg，1eq)，在20℃搅拌10分钟，然后加入三正丙基环磷酸酐(T 3P，317mg，296μL，50％含量的乙酸乙酯溶液，3eq)，反应混合液在20℃搅拌2小时。反应液减压浓缩，加入水(2mL)稀释，乙酸乙酯萃取(2mL*2)，合并有机相，用饱和食盐水(5mL)洗涤，无水硫酸钠干燥，滤液减压浓缩得到化合物17-7粗品。MS：m/z 516.4[M+H] +。 Compound 17-6 (50mg, 1eq) and intermediate C (38.5mg, 1eq) were dissolved in tetrahydrofuran (1mL) and acetonitrile (2mL), and diisopropylethylamine (32mg, 43μL, 1.5eq) and 4 -Dimethylaminopyridine (20mg, 1eq), stirred at 20°C for 10 minutes, then added tri-n-propyl cyclic phosphoric anhydride (T 3 P, 317mg, 296μL, 50% content of ethyl acetate solution, 3eq), and the reaction was mixed The solution was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (2 mL), extracted with ethyl acetate (2 mL*2), the organic phases were combined, washed with saturated brine (5 mL), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain compound 17- 7 crude products. MS: m/z 516.4 [M+H] + .
第八步eighth step
将化合物17-7(38mg，1eq)溶于四氢呋喃(1mL)中，加入三甲基硅醇钾(28mg，3eq)，反应在20℃搅 拌1小时。反应液用2N稀盐酸调节pH值至5，加入2mL水稀释，乙酸乙酯萃取(2mL*2)，合并有机相，用饱和食盐水(5mL*1)洗涤，无水硫酸钠干燥，滤液减压浓缩，经制备薄层色谱(石油醚/乙酸乙酯＝0∶1)纯化，再经SFC分离(分离条件：色谱柱：Daicel ChiralPak AD(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；B％：35％-35％)得到化合物17a。SFC检测条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm；流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％，流速：3mL/min，保留时间为1.382min，ee＝97.4％。MS：m/z 488.1[M+H] +。 1H NMR(400MHz，CDCl 3)δ＝9.90(s，1H)，8.84(s，1H)，7.50(d，J＝1.8Hz，1H)，7.26(d，J＝1.5Hz，1H)，7.22(br d，J＝1.9Hz，1H)，7.20(s，1H)，6.79(d，J＝8.4Hz，1H)，4.48-4.45(m，1H)，4.29-4.22(m，1H)，3.73-3.65(m，2H)，3.64-3.55(m，2H)，3.54-3.41(m，2H)，2.79-2.57(m，2H)，2.57-2.31(m，2H)，2.16-2.10(m，2H)，1.73-1.67(m，2H)，1.61-1.60(m，1H)，1.31-1.28(m，2H)，1.28-1.25(m，2H)。 Compound 17-7 (38mg, 1eq) was dissolved in tetrahydrofuran (1mL), potassium trimethylsiliconate (28mg, 3eq) was added, and the reaction was stirred at 20°C for 1 hour. The reaction solution was adjusted to pH 5 with 2N dilute hydrochloric acid, diluted with 2 mL of water, extracted with ethyl acetate (2 mL*2), the organic phases were combined, washed with saturated brine (5 mL*1), dried over anhydrous sodium sulfate, and the filtrate was reduced to Concentrated under reduced pressure, purified by preparative thin-layer chromatography (petroleum ether/ethyl acetate=0:1), and then separated by SFC (separation conditions: chromatographic column: Daicel ChiralPak AD (250mm*30mm, 10 μm); mobile phase: Phase A: CO 2 , phase B: [(0.1% ammonia)methanol]; B%: 35%-35%) gave compound 17a. SFC detection conditions: Chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm; mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% , flow rate: 3mL/min, retention time 1.382min, ee=97.4%. MS: m/z 488.1 [M+H] + . 1 H NMR (400MHz, CDCl 3 ) δ=9.90(s, 1H), 8.84(s, 1H), 7.50(d, J=1.8Hz, 1H), 7.26(d, J=1.5Hz, 1H), 7.22 (br d, J=1.9Hz, 1H), 7.20(s, 1H), 6.79(d, J=8.4Hz, 1H), 4.48-4.45(m, 1H), 4.29-4.22(m, 1H), 3.73 -3.65(m, 2H), 3.64-3.55(m, 2H), 3.54-3.41(m, 2H), 2.79-2.57(m, 2H), 2.57-2.31(m, 2H), 2.16-2.10(m, 2H), 1.73-1.67 (m, 2H), 1.61-1.60 (m, 1H), 1.31-1.28 (m, 2H), 1.28-1.25 (m, 2H).
实施例18Example 18
Figure PCTCN2022095009-appb-000122
Figure PCTCN2022095009-appb-000122
第一步first step
将甲基三苯基溴化膦(35.40g，1.5eq)加入四氢呋喃(50mL)中，并于-5～0℃搅拌下滴加双(三甲基硅基)胺基锂(1M，99.10mL，1.5eq)，滴加完成后于0～20℃搅拌1小时，降温至-5℃。称取化合物15-1(15g，1.0eq)溶于四氢呋喃(20mL)中，并于-5～0℃搅拌下将该溶液滴加至反应体系，滴加完成后缓慢升温至20℃，于20℃搅拌1小时。将反应液冷却到-5～0℃，用饱和氯化铵水溶液(100mL)淬灭，加 入水(50mL)稀释，乙酸乙酯萃取(150mL*2)，合并有机相，用饱和食盐水洗(100mL*1)，无水硫酸钠干燥，滤液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝30∶1～10∶1)纯化得到化合物18-1。 1H NMR(400MHz，CDCl 3)δ＝7.58(d，J＝2.3Hz，1H)，7.23-7.09(m，1H)，6.65(d，J＝8.7Hz，1H)，5.42(s，1H)，4.86(s，1H)，4.24-4.04(m，2H)，2.68-2.47(m，2H)。 Add methyltriphenylphosphine bromide (35.40g, 1.5eq) into tetrahydrofuran (50mL), and add lithium bis(trimethylsilyl)amide (1M, 99.10mL) dropwise with stirring at -5～0°C , 1.5eq), after the dropwise addition was completed, stir at 0-20°C for 1 hour, then cool down to -5°C. Weighed compound 15-1 (15g, 1.0eq) and dissolved it in tetrahydrofuran (20mL), and added the solution dropwise to the reaction system at -5~0°C with stirring, and slowly raised the temperature to 20°C after the addition was completed. °C and stirred for 1 hour. The reaction solution was cooled to -5～0°C, quenched with saturated ammonium chloride aqueous solution (100mL), diluted with water (50mL), extracted with ethyl acetate (150mL*2), combined organic phases, washed with saturated brine (100mL *1), dried over anhydrous sodium sulfate, concentrated the filtrate under reduced pressure, and purified by column chromatography (petroleum ether: ethyl acetate = 30:1 ~ 10:1) to obtain compound 18-1. 1 H NMR (400MHz, CDCl 3 ) δ=7.58(d, J=2.3Hz, 1H), 7.23-7.09(m, 1H), 6.65(d, J=8.7Hz, 1H), 5.42(s, 1H) , 4.86 (s, 1H), 4.24-4.04 (m, 2H), 2.68-2.47 (m, 2H).
第二步second step
将化合物18-1(11.5g，1.0eq)，(S，S)-2，6-双(4-异丙基-2-噁唑啉-2-基)吡啶(1.54g，0.1eq)和(对异丙甲苯)二氯化钌(II)二聚体(1.56g，0.05eq)加入二氯甲烷(100mL)中，并于20℃下搅拌30分钟。取重氮乙酸乙酯(35.62g，296.54mmol，1.5eq)溶于二氯甲烷(30mL)中，搅拌下将该溶液滴加至反应体系，滴加完成后于20℃搅拌12小时。将反应液减压浓缩，经柱层析(石油醚∶乙酸乙酯＝30∶1～10∶1)分离得到化合物18-2。Compound 18-1 (11.5g, 1.0eq), (S, S)-2,6-bis(4-isopropyl-2-oxazolin-2-yl)pyridine (1.54g, 0.1eq) and (p-Cymene) Ruthenium(II) dichloride dimer (1.56 g, 0.05 eq) was added to dichloromethane (100 mL), and stirred at 20° C. for 30 minutes. Ethyl diazoacetate (35.62g, 296.54mmol, 1.5eq) was dissolved in dichloromethane (30mL), and the solution was added dropwise to the reaction system with stirring, and stirred at 20°C for 12 hours after the dropwise addition was completed. The reaction solution was concentrated under reduced pressure and separated by column chromatography (petroleum ether: ethyl acetate = 30:1-10:1) to obtain compound 18-2.
第三步third step
将化合物18-2(2.5g，1.0eq)，联硼酸嚬哪醇酯(2.50g，1.2eq)，磷酸钾(5.00g，2.9eq)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(375.00mg，0.06eq)加至40mL二氧六环，氮气置换三次，升温至110～120℃搅拌10小时。反应液冷却，加入100mL乙酸乙酯稀释，硅藻土过滤，20mL乙酸乙酯淋洗，滤液用水洗两次，每次70mL，饱和食盐水(70mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，经柱层析(石油醚∶乙酸乙酯＝15∶1～10∶1)分离得到化合物18-3。MS：m/z 359.2[M+H] +。 Compound 18-2 (2.5g, 1.0eq), diboronic acid indachidol ester (2.50g, 1.2eq), potassium phosphate (5.00g, 2.9eq) and [1,1'-bis(diphenylphosphino ) ferrocene]palladium dichloride dichloromethane complex (375.00mg, 0.06eq) was added to 40mL of dioxane, replaced with nitrogen three times, heated to 110-120°C and stirred for 10 hours. The reaction solution was cooled, diluted with 100 mL of ethyl acetate, filtered with diatomaceous earth, rinsed with 20 mL of ethyl acetate, washed twice with water, 70 mL each time, washed with saturated brine (70 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate Concentrate and separate by column chromatography (petroleum ether: ethyl acetate = 15:1 ~ 10:1) to obtain compound 18-3. MS: m/z 359.2 [M+H] + .
第四步the fourth step
将化合物18-3(0.5g，1.0eq)和化合物18-4(380.08mg，1.5eq)加至10mL二氧六环和3mL水的混合溶剂中，25℃加入碳酸钾(385.81mg，2.0eq)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯二氯甲烷络合物(227.96mg，0.2eq)，搅拌10分钟，升温至90℃搅拌1小时。反应液加入5mL水稀释，乙酸乙酯萃取两次，每次12mL，合并有机相，饱和食盐水(25mL*1)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到中间体18-5。MS：m/z 378.3[M+H] +。 Compound 18-3 (0.5g, 1.0eq) and compound 18-4 (380.08mg, 1.5eq) were added to a mixed solvent of 10mL dioxane and 3mL water, and potassium carbonate (385.81mg, 2.0eq ) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium dichloromethane complex (227.96mg, 0.2eq), stirred for 10 minutes, heated to 90°C and stirred for 1 hour. The reaction solution was diluted with 5 mL of water, extracted twice with 12 mL of ethyl acetate each time, the organic phases were combined, washed with saturated brine (25 mL*1), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain Intermediate 18-5. MS: m/z 378.3 [M+H] + .
第五步the fifth step
将化合物18-5(0.32g，1.0eq)溶于四氢呋喃(10mL)中，在25℃加入三甲基硅醇钾(326.37mg，3.0eq)，反应混合液于25℃搅拌2小时。反应液用2N稀盐酸调pH到5，加12mL水稀释，用乙酸乙酯萃取2次，每次12mL，乙酸乙酯层用15mL饱和氯化钠水溶液洗，无水硫酸钠干燥，过滤，滤液浓缩得到中间体18-6。MS：m/z 350.1[M+H] +。 Compound 18-5 (0.32g, 1.0eq) was dissolved in tetrahydrofuran (10mL), potassium trimethylsilanolate (326.37mg, 3.0eq) was added at 25°C, and the reaction mixture was stirred at 25°C for 2 hours. The reaction solution was adjusted to pH 5 with 2N dilute hydrochloric acid, diluted with 12 mL of water, extracted twice with ethyl acetate, 12 mL each time, the ethyl acetate layer was washed with 15 mL of saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and the filtrate Concentration affords Intermediate 18-6. MS: m/z 350.1 [M+H] + .
第六步step six
将化合物18-6(0.23g，1.0eq)和中间体C(183.53mg，1.2eq)溶于四氢呋喃(5mL)和乙腈(5mL)的混合溶剂中，加入4-二甲氨基吡啶(80.44mg，1eq)和二异丙基乙胺(127.65mg，172μL，1.5eq)，在20℃搅拌10分 钟，然后加入三正丙基环磷酸酐(T 3P，质量分数为50％的乙酸乙酯溶液，1.17mL，3.0eq)，反应混合液在20℃搅拌2小时。反应液减压浓缩，加入水(3mL)稀释，乙酸乙酯萃取(4mL*2)，合并有机相，用饱和食盐水洗(3mL*2)，无水硫酸钠干燥，滤液减压浓缩得到粗品，经制备高效液相色谱(色谱柱：Phenomenex Synergi C18 150*25mm*10μm；流动相：[水(0.1％三氟乙酸)-乙腈]；梯度：乙腈％：70％-100％)纯化得到化合物18-7。MS：m/z 564.2[M+H] +。 Compound 18-6 (0.23g, 1.0eq) and Intermediate C (183.53mg, 1.2eq) were dissolved in a mixed solvent of tetrahydrofuran (5mL) and acetonitrile (5mL), and 4-dimethylaminopyridine (80.44mg, 1eq) and diisopropylethylamine (127.65mg, 172μL, 1.5eq), stirred at 20°C for 10 minutes, then added tri-n-propyl cyclic phosphoric anhydride (T 3 P, 50% mass fraction in ethyl acetate solution , 1.17mL, 3.0eq), the reaction mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (3 mL), extracted with ethyl acetate (4 mL*2), the organic phases were combined, washed with saturated brine (3 mL*2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure to obtain a crude product. Compound 18 was purified by preparative high-performance liquid chromatography (column: Phenomenex Synergi C18 150*25mm*10 μm; mobile phase: [water (0.1% trifluoroacetic acid)-acetonitrile]; gradient: acetonitrile%: 70%-100%) -7. MS: m/z 564.2 [M+H] + .
第七步step seven
将化合物18-7(0.13g，1.0eq)加入四氢呋喃(2mL)中，搅拌下加入三甲基硅醇钾(79.38mg，3.0eq)，并于25℃下搅拌2小时。用2N稀盐酸水溶液调节反应体系pH值至5，加入2mL水稀释，水相用乙酸乙酯萃取(2mL*2)，合并有机相，用饱和食盐水洗(5mL*1)，无水硫酸钠干燥，滤液减压浓缩，经制备薄层色谱(二氯甲烷∶甲醇＝10∶1)纯化和SFC分离(分离条件：色谱柱：DAICEL CHIRALCEL OD-H(250mm*30mm，5μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；梯度：B％：35％-35％)得到化合物18a。SFC分析条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：异丙醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.502min，ee＝86.05％。 1H NMR(400MHz，CDCl 3)δ＝9.79(br s，1H)，8.68(s，1H)，7.91(t，J＝7.8Hz，1H)，7.69(d，J＝7.8Hz，1H)，7.59(d，J＝7.7Hz，1H)，7.42(d，J＝2.0Hz，1H)，7.38-7.34(m，1H)，7.22-7.20(m，1H)，7.13(d，J＝8.0Hz，1H)，6.86(d，J＝8.4Hz，1H)，4.34-4.28(m，1H)，4.26-4.20(m，1H)，3.20(br s，1H)，2.92-2.80(m，1H)，2.55-2.43(m，1H)，2.41-2.31(m，2H)，2.17-2.05(m，2H)，1.28(br d，J＝8.1Hz，2H)，0.81(br s，2H)。MS：m/z 536.2[M+H] +。 Compound 18-7 (0.13g, 1.0eq) was added into tetrahydrofuran (2mL), potassium trimethylsiliconate (79.38mg, 3.0eq) was added with stirring, and stirred at 25°C for 2 hours. Adjust the pH of the reaction system to 5 with 2N dilute hydrochloric acid aqueous solution, add 2 mL of water to dilute, extract the aqueous phase with ethyl acetate (2 mL*2), combine the organic phases, wash with saturated brine (5 mL*1), and dry over anhydrous sodium sulfate , the filtrate was concentrated under reduced pressure, purified by preparative thin-layer chromatography (dichloromethane:methanol=10:1) and separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OD-H (250mm*30mm, 5 μm); mobile phase: A Phase: CO 2 , Phase B: [(0.1% ammonia)methanol]; Gradient: B%: 35%-35%) to give compound 18a. SFC analysis conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: isopropanol (0.05% diethylamine); gradient: B%: 5%～ 40%; flow rate: 3mL/min, retention time 1.502min, ee=86.05%. 1 H NMR (400MHz, CDCl 3 ) δ=9.79(br s, 1H), 8.68(s, 1H), 7.91(t, J=7.8Hz, 1H), 7.69(d, J=7.8Hz, 1H), 7.59(d, J=7.7Hz, 1H), 7.42(d, J=2.0Hz, 1H), 7.38-7.34(m, 1H), 7.22-7.20(m, 1H), 7.13(d, J=8.0Hz , 1H), 6.86(d, J=8.4Hz, 1H), 4.34-4.28(m, 1H), 4.26-4.20(m, 1H), 3.20(br s, 1H), 2.92-2.80(m, 1H) , 2.55-2.43 (m, 1H), 2.41-2.31 (m, 2H), 2.17-2.05 (m, 2H), 1.28 (br d, J=8.1Hz, 2H), 0.81 (br s, 2H). MS: m/z 536.2 [M+H] + .
实施例19Example 19
Figure PCTCN2022095009-appb-000123
Figure PCTCN2022095009-appb-000123
Figure PCTCN2022095009-appb-000124
Figure PCTCN2022095009-appb-000124
第一步first step
将化合物B-1(200mg，1.0eq)溶解在1，4-二氧六环(5mL)和水(0.5mL)的混合溶剂中，在氮气保护下，向反应液中加入化合物19-1(166.43mg，1.5eq)、磷酸钾(370.08mg，3.0eq)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯(85.05mg，0.2eq)，混合物在氮气氛围下加热至80℃，搅拌2小时。反应液浓缩，剩余物经柱层析(石油醚∶乙酸乙酯＝20/1～15/1)纯化得到化合物19-2。MS：m/z 364.0[M+H] +。 Compound B-1 (200 mg, 1.0 eq) was dissolved in a mixed solvent of 1,4-dioxane (5 mL) and water (0.5 mL), and compound 19-1 ( 166.43mg, 1.5eq), potassium phosphate (370.08mg, 3.0eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (85.05mg, 0.2eq), the mixture was under nitrogen It was heated to 80° C. under atmosphere, and stirred for 2 hours. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether: ethyl acetate = 20/1-15/1) to obtain compound 19-2. MS: m/z 364.0 [M+H] + .
第二步second step
将化合物19-2(100mg，1.0eq)溶解在水(0.5mL)、四氢呋喃(0.5mL)和甲醇(0.5mL)的混合溶剂中，加入氢氧化锂(19.77mg，3.0eq)，混合物在15℃下搅拌2小时。反应结束后，用2N稀盐酸调pH到7，混合物浓缩后用二氯甲烷(10mL*3)萃取，合并有机相，浓缩得到化合物19-3。MS：m/z 350.1[M+H] +。 Compound 19-2 (100mg, 1.0eq) was dissolved in a mixed solvent of water (0.5mL), tetrahydrofuran (0.5mL) and methanol (0.5mL), lithium hydroxide (19.77mg, 3.0eq) was added, and the mixture was Stir at °C for 2 hours. After the reaction, the pH was adjusted to 7 with 2N dilute hydrochloric acid, the mixture was concentrated and extracted with dichloromethane (10 mL*3), the organic phases were combined and concentrated to obtain compound 19-3. MS: m/z 350.1 [M+H] + .
第三步third step
将化合物19-3(140mg，1.0eq)加入到四氢呋喃(2mL)和乙腈(2mL)的混合溶剂中，然后向体系中加入中间体C(93.10mg，1.0eq)、4-二甲氨基吡啶(4.90mg，0.1eq)、三乙胺(121.67mg，3.0eq)和三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，715μL，3.0eq)，混合物在15℃下搅拌2小时。向反应体系中加水(10mL)，用乙酸乙酯(10mL*3)萃取，合并有机相，用饱和氯化钠水溶液(5mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，剩余物用制备高效液相色谱(色谱柱：Phenomenex Synergi C18 150*25mm*10μm；流动相：[水(0.225％甲酸)-乙腈]；梯度：乙腈％：56％-89％)纯化，再经SFC分离(分离条件：色谱柱：DAICEL CHIRALCEL OD(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)异丙醇]；梯度：B％：35％-35％)得到化合物19-4a。SFC分析条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：异丙醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.876min，ee＝97.61％。MS：m/z 564.1[M+H] +。 Compound 19-3 (140mg, 1.0eq) was added to a mixed solvent of tetrahydrofuran (2mL) and acetonitrile (2mL), then Intermediate C (93.10mg, 1.0eq), 4-dimethylaminopyridine ( 4.90mg, 0.1eq), triethylamine (121.67mg, 3.0eq) and tri-n-propyl cyclic phosphoric acid anhydride (mass fraction is 50% ethyl acetate solution, 715 μ L, 3.0eq), the mixture was stirred at 15 ℃ for 2 Hour. Add water (10 mL) to the reaction system, extract with ethyl acetate (10 mL*3), combine the organic phases, wash with saturated aqueous sodium chloride solution (5 mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and prepare the residue with High performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10 μm; Mobile phase: [water (0.225% formic acid)-acetonitrile]; Gradient: acetonitrile%: 56%-89%) Purification, then SFC separation (separation Conditions: Chromatographic column: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: phase A: CO 2 , phase B: [(0.1% ammonia water) isopropanol]; gradient: B%: 35%-35%) Compound 19-4a was obtained. SFC analysis conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: isopropanol (0.05% diethylamine); gradient: B%: 5%～ 40%; flow rate: 3mL/min, retention time 1.876min, ee=97.61%. MS: m/z 564.1 [M+H] + .
第四步the fourth step
将化合物19-4a(50mg，1eq)溶解在甲醇(1mL)、水(1mL)和四氢呋喃(1mL)的混合溶剂中，向体系中加入氢氧化锂(6.37mg，3.0eq)，混合物在15℃下搅拌2小时。反应结束后，体系用4N盐酸调pH至7，加水(5mL)，用乙酸乙酯(10mL*3)萃取，合并有机相，浓缩，剩余物用薄层色谱(石油醚∶乙酸乙酯＝1∶1)纯化得到化合物19a。SFC分析条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相： 甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.613min，ee＝96.22％。 1H NMR(400MHz，CDCl 3)δ＝9.62(s，1H)，8.90(d，J＝1.2Hz，1H)，8.6(brs，1H)，8.08(dd，J＝8.0，1.6Hz，1H)，7.74(d，J＝8.0Hz，1H)，7.35(dd，J＝8.4，2.0Hz，1H)，7.27-7.21(m，3H)，6.95(d，J＝8.4Hz，1H)，4.50(dt，J＝10.8，3.2Hz，1H)，4.32(td，J＝11.2，2.0Hz，1H)，2.92-2.83(m，2H)，2.68-2.55(m，3H)，2.43-2.37(m，1H)，2.33-2.25(m，1H)，1.95-1.85(m，1H)，1.72-1.63(m，2H)，1.49-1.46(m，1H)。MS：m/z 536.3[M+H] +。 Compound 19-4a (50mg, 1eq) was dissolved in a mixed solvent of methanol (1mL), water (1mL) and tetrahydrofuran (1mL), lithium hydroxide (6.37mg, 3.0eq) was added to the system, and the mixture was heated at 15° C. Stir for 2 hours. After the reaction, the pH of the system was adjusted to 7 with 4N hydrochloric acid, water (5 mL) was added, extracted with ethyl acetate (10 mL*3), the organic phases were combined, concentrated, and the residue was analyzed by thin-layer chromatography (petroleum ether: ethyl acetate = 1 : 1) Compound 19a was obtained by purification. SFC analysis conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 1.613min, ee=96.22%. 1 H NMR (400MHz, CDCl 3 ) δ=9.62(s, 1H), 8.90(d, J=1.2Hz, 1H), 8.6(brs, 1H), 8.08(dd, J=8.0, 1.6Hz, 1H) , 7.74(d, J=8.0Hz, 1H), 7.35(dd, J=8.4, 2.0Hz, 1H), 7.27-7.21(m, 3H), 6.95(d, J=8.4Hz, 1H), 4.50( dt, J=10.8, 3.2Hz, 1H), 4.32(td, J=11.2, 2.0Hz, 1H), 2.92-2.83(m, 2H), 2.68-2.55(m, 3H), 2.43-2.37(m, 1H), 2.33-2.25 (m, 1H), 1.95-1.85 (m, 1H), 1.72-1.63 (m, 2H), 1.49-1.46 (m, 1H). MS: m/z 536.3 [M+H] + .
实施例20Example 20
Figure PCTCN2022095009-appb-000125
Figure PCTCN2022095009-appb-000125
第一步first step
将化合物18-3(208.19mg，1.0eq)溶解在1，4-二氧六环(5mL)和水(0.5mL)的混合溶剂中，在氮气的保护下，向反应液中加入化合物20-1(177.91mg，1.5eq)、磷酸钾(370.08mg，3.0eq)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯(85.05mg，0.2eq)，混合物在氮气的氛围下加热至80℃，搅拌2小时。反应液浓缩后经柱层析(石油醚∶乙酸乙酯＝20∶1～15∶1)纯化得到化合物20-2。MS：m/z 356.0[M+H] +。 Compound 18-3 (208.19mg, 1.0eq) was dissolved in a mixed solvent of 1,4-dioxane (5mL) and water (0.5mL), and compound 20- 1 (177.91mg, 1.5eq), potassium phosphate (370.08mg, 3.0eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (85.05mg, 0.2eq), mixture It was heated to 80° C. under a nitrogen atmosphere, and stirred for 2 hours. The reaction solution was concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 20:1-15:1) to obtain compound 20-2. MS: m/z 356.0 [M+H] + .
第二步second step
将化合物20-2(100mg，1.0eq)溶解在水(0.5mL)、四氢呋喃(0.5mL)和甲醇(0.5mL)的混合溶剂中，加入氢氧化锂(20.21mg，3.0eq)，混合物在15℃下搅拌2小时。反应液用2N稀盐酸调pH到7，混合物浓缩后用二氯甲烷(10mL*3)萃取，合并后的有机相浓缩得到化合物20-3。MS：m/z 328.1[M+H] +。 Compound 20-2 (100mg, 1.0eq) was dissolved in a mixed solvent of water (0.5mL), tetrahydrofuran (0.5mL) and methanol (0.5mL), lithium hydroxide (20.21mg, 3.0eq) was added, and the mixture was Stir at °C for 2 hours. The pH of the reaction solution was adjusted to 7 with 2N dilute hydrochloric acid, the mixture was concentrated and extracted with dichloromethane (10 mL*3), and the combined organic phase was concentrated to obtain compound 20-3. MS: m/z 328.1 [M+H] + .
第三步third step
将化合物20-3(110mg，1.0eq)加入到四氢呋喃(2mL)和乙腈(2mL)的混合溶剂中，然后向体系中加入中间体C(78.04mg，1.0eq)、4-二甲氨基吡啶(4.10mg，0.1eq)、三乙胺(101.99mg，3.0eq)和三正丙基环 磷酸酐(质量分数为50％的乙酸乙酯溶液，0.6mL，3.0eq)，混合物在15℃下搅拌2小时。向反应体系中加水(10mL)，用乙酸乙酯(10mL*3)萃取，合并后的有机相用饱和氯化钠水溶液(5mL)洗涤，硫酸钠干燥，过滤，滤液浓缩，残留物用制备高效液相色谱纯化(色谱柱：Phenomenex Synergi C18 150*25mm*10μm；流动相：[水(0.225％甲酸)-乙腈]；梯度：乙腈％：58％-89％)，再用SFC分离(分离条件：色谱柱：DAICEL CHIRALCEL OD(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；梯度：B％：45％-45％)得到化合物20-4a。SFC分析条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：异丙醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为2.227min，ee＝100％。MS：m/z 542.3[M+H] +。 Compound 20-3 (110mg, 1.0eq) was added to a mixed solvent of tetrahydrofuran (2mL) and acetonitrile (2mL), and then Intermediate C (78.04mg, 1.0eq), 4-dimethylaminopyridine ( 4.10mg, 0.1eq), triethylamine (101.99mg, 3.0eq) and tri-n-propyl cyclic phosphoric anhydride (50% mass fraction in ethyl acetate, 0.6mL, 3.0eq), the mixture was stirred at 15°C 2 hours. Add water (10mL) to the reaction system, extract with ethyl acetate (10mL*3), wash the combined organic phase with saturated aqueous sodium chloride solution (5mL), dry over sodium sulfate, filter, concentrate the filtrate, and use the residue to prepare high-efficiency Purified by liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: acetonitrile%: 58%-89%), and then separated by SFC (separation conditions : Chromatographic column: DAICEL CHIRALCEL OD (250mm*30mm, 10μm); mobile phase: phase A: CO 2 , phase B: [(0.1% ammonia water) methanol]; gradient: B%: 45%-45%) to obtain compound 20 -4a. SFC analysis conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: isopropanol (0.05% diethylamine); gradient: B%: 5%～ 40%; flow rate: 3mL/min, retention time 2.227min, ee=100%. MS: m/z 542.3 [M+H] + .
第四步the fourth step
将化合物20-4a(40.00mg，1.0eq)溶解在甲醇(1mL)、水(1mL)和四氢呋喃(1mL)的混合溶剂中，向体系中加入氢氧化锂(5.19mg，3.0eq)，混合物在15℃下搅拌2小时。反应体系用4N盐酸调pH至7，加水(5mL)，用乙酸乙酯(10mL*3)萃取，合并后的有机相浓缩，残留物用薄层色谱(石油醚∶乙酸乙酯＝1∶1)纯化得到化合物20a。SFC分析条件：色谱柱：Chiralpak AD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：40％；流速：3mL/min，保留时间为2.245min，ee＝89.23％。 1H NMR(400MHz，CDCl 3)δ＝9.31(brs，1H)，8.87(s，1H)，8.68(s，1H)，7.73(d，J＝8.4Hz，1H)，7.23-7.14(m，5H)，6.84(d，J＝8.4Hz，1H)，4.45(dt，J＝10.8，3.2Hz，1H)，4.25(td，J＝11.2，2.4Hz，1H)，3.61-3.42(m，1H)，2.92-2.88(m，1H)，2.81(td，J＝13.2，3.6Hz，1H)，2.64-2.46(m，5H)，2.35-2.20(m，2H)，1.88-1.79(m，1H)，1.66-1.59(m，2H)，1.44-1.41(m，1H)。MS：m/z 514.3[M+H]] +。 Compound 20-4a (40.00mg, 1.0eq) was dissolved in a mixed solvent of methanol (1mL), water (1mL) and tetrahydrofuran (1mL), lithium hydroxide (5.19mg, 3.0eq) was added to the system, and the mixture was Stir at 15°C for 2 hours. The pH of the reaction system was adjusted to 7 with 4N hydrochloric acid, water (5 mL) was added, extracted with ethyl acetate (10 mL*3), the combined organic phase was concentrated, and the residue was analyzed by thin layer chromatography (petroleum ether: ethyl acetate = 1:1 ) purification to obtain compound 20a. SFC analysis conditions: chromatographic column: Chiralpak AD-3 50×4.6mm ID, 3 μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 40%; flow rate: 3mL/min, retention time 2.245min, ee=89.23%. 1 H NMR (400MHz, CDCl 3 ) δ=9.31(brs, 1H), 8.87(s, 1H), 8.68(s, 1H), 7.73(d, J=8.4Hz, 1H), 7.23-7.14(m, 5H), 6.84(d, J=8.4Hz, 1H), 4.45(dt, J=10.8, 3.2Hz, 1H), 4.25(td, J=11.2, 2.4Hz, 1H), 3.61-3.42(m, 1H ), 2.92-2.88(m, 1H), 2.81(td, J=13.2, 3.6Hz, 1H), 2.64-2.46(m, 5H), 2.35-2.20(m, 2H), 1.88-1.79(m, 1H ), 1.66-1.59 (m, 2H), 1.44-1.41 (m, 1H). MS: m/z 514.3 [M+H]] + .
实施例21Example 21
Figure PCTCN2022095009-appb-000126
Figure PCTCN2022095009-appb-000126
Figure PCTCN2022095009-appb-000127
Figure PCTCN2022095009-appb-000127
第一步first step
将化合物21-1(2g，1.0eq)和化合物21-2(1.31g，1.5eq)加至25mL四氢呋喃中，20℃下加入三苯基磷(4.52g，1.5eq)，搅拌30分钟。滴加偶氮二甲酸二异丙酯(3.49g，3.35mL，1.5eq)，于20℃搅拌12小时。将反应液倒入15mL水中，乙酸乙酯萃取(15mL*2)，合并有机相，饱和氯化钠水溶液(30mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩，经薄层色谱(石油醚∶乙酸乙酯＝20∶1)纯化得到化合物21-3。 1H NMR(400MHz，CDCl 3)δ＝7.71-7.57(m，1H)，7.31-7.23(m，1H)，6.74(d，J＝8.8Hz，1H)，4.57-4.34(t，J＝4.8Hz，2H)，3.82-3.65(t，J＝4.8Hz，2H)，3.45(s，3H)。MS：m/z 233.9[M+H] +。 Compound 21-1 (2g, 1.0eq) and compound 21-2 (1.31g, 1.5eq) were added to 25mL of tetrahydrofuran, triphenylphosphine (4.52g, 1.5eq) was added at 20°C, and stirred for 30 minutes. Diisopropyl azodicarboxylate (3.49 g, 3.35 mL, 1.5 eq) was added dropwise, and stirred at 20° C. for 12 hours. Pour the reaction solution into 15mL water, extract with ethyl acetate (15mL*2), combine the organic phases, wash with saturated aqueous sodium chloride solution (30mL), dry over anhydrous sodium sulfate, filter, concentrate the filtrate, and perform thin-layer chromatography (petroleum ether). : ethyl acetate=20:1) to obtain compound 21-3. 1 H NMR (400MHz, CDCl 3 ) δ=7.71-7.57(m, 1H), 7.31-7.23(m, 1H), 6.74(d, J=8.8Hz, 1H), 4.57-4.34(t, J=4.8 Hz, 2H), 3.82-3.65 (t, J=4.8Hz, 2H), 3.45 (s, 3H). MS: m/z 233.9 [M+H] + .
第二步second step
将化合物18-3(0.5g，1.0eq)和化合物21-3(485.87mg，1.5eq)加至10mL二氧六环和4mL水的混合溶剂中，25℃下加入碳酸钾(578.71mg，3.0eq)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯(510.64mg，0.5eq)，搅拌10分钟，升温至90℃搅拌2小时。反应液中加入5mL水稀释，乙酸乙酯萃取(4mL*2)，合并有机相，饱和氯化钠水溶液(4mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物21-4。MS：m/z 384.2[M+H] +。 Compound 18-3 (0.5g, 1.0eq) and compound 21-3 (485.87mg, 1.5eq) were added to a mixed solvent of 10mL dioxane and 4mL water, and potassium carbonate (578.71mg, 3.0 eq) and [1,1′-bis(diphenylphosphino)ferrocene]palladium dichloride (510.64mg, 0.5eq), stirred for 10 minutes, heated to 90°C and stirred for 2 hours. Add 5 mL of water to the reaction solution for dilution, extract with ethyl acetate (4 mL*2), combine the organic phases, wash with saturated aqueous sodium chloride solution (4 mL*2), dry over anhydrous sodium sulfate, filter, and concentrate the filtrate to obtain compound 21-4. MS: m/z 384.2 [M+H] + .
第三步third step
将化合物21-4(0.4g，1.0eq)溶于四氢呋喃(2mL)和甲醇(2mL)的混合溶剂中，在25℃下加入一水合氢氧化锂(131.32mg，3.0eq)的1mL水溶液，反应混合液于25℃搅拌2小时。反应液用4N稀盐酸调pH到5，加5mL水稀释，用乙酸乙酯萃取(4mL*2)，乙酸乙酯层用饱和氯化钠水溶液(4mL*2)洗涤，无水硫酸钠干燥，过滤，滤液浓缩得到化合物21-5。MS：m/z 356.2[M+H] +。 Compound 21-4 (0.4g, 1.0eq) was dissolved in a mixed solvent of tetrahydrofuran (2mL) and methanol (2mL), and a 1mL aqueous solution of lithium hydroxide monohydrate (131.32mg, 3.0eq) was added at 25°C to react The mixture was stirred at 25°C for 2 hours. The reaction solution was adjusted to pH 5 with 4N dilute hydrochloric acid, diluted with 5 mL of water, extracted with ethyl acetate (4 mL*2), the ethyl acetate layer was washed with saturated aqueous sodium chloride solution (4 mL*2), dried over anhydrous sodium sulfate, After filtration, the filtrate was concentrated to obtain compound 21-5. MS: m/z 356.2 [M+H] + .
第四步the fourth step
将化合物21-5(306.00mg，1.0eq)和中间体C(0.2g，1.0eq)溶于四氢呋喃(2mL)和乙腈(3mL)的混合溶剂中，加入二异丙基乙胺(166.92mg，225μL，1.5eq)和4-二甲氨基吡啶(105.19mg，1.0eq)，在20℃搅拌10分钟，然后加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，1.54mL，3.0eq)，反应混合液在 20℃搅拌2小时。反应液减压浓缩，加入水(5mL)稀释，乙酸乙酯萃取(4mL*2)，合并有机相，用饱和氯化钠水溶液(4mL*2)洗涤，无水硫酸钠干燥，滤液减压浓缩得到粗品，经制备薄层色谱(石油醚∶乙酸乙酯＝1∶1)纯化，再经SFC分离(分离条件：色谱柱：DAICEL CHIRALCEL OJ(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；梯度：B％：35％-35％)得到化合物21-6a。SFC分析条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.932min，ee＝100％。MS：m/z 570.4[M+H] +。 Compound 21-5 (306.00mg, 1.0eq) and intermediate C (0.2g, 1.0eq) were dissolved in a mixed solvent of tetrahydrofuran (2mL) and acetonitrile (3mL), and diisopropylethylamine (166.92mg, 225μL, 1.5eq) and 4-dimethylaminopyridine (105.19mg, 1.0eq), stirred at 20°C for 10 minutes, then added tri-n-propyl cyclic phosphoric anhydride (50% ethyl acetate solution, 1.54mL , 3.0eq), the reaction mixture was stirred at 20°C for 2 hours. The reaction solution was concentrated under reduced pressure, diluted with water (5 mL), extracted with ethyl acetate (4 mL*2), the organic phases were combined, washed with saturated aqueous sodium chloride solution (4 mL*2), dried over anhydrous sodium sulfate, and the filtrate was concentrated under reduced pressure The crude product was obtained, purified by preparative thin-layer chromatography (petroleum ether: ethyl acetate = 1:1), and separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OJ (250mm*30mm, 10 μm); mobile phase: phase A: CO 2 , phase B: [(0.1% ammonia)methanol]; gradient: B%: 35%-35%) gave compound 21-6a. SFC analysis conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 1.932min, ee=100%. MS: m/z 570.4 [M+H] + .
第五步the fifth step
将化合物21-6a(85mg，1.0eq)加入四氢呋喃(5mL)中，搅拌下加入三甲基硅醇钾(57.43mg，3.0eq)，并于25℃下搅拌1小时。用2N稀盐酸调节反应体系pH值至5，加入20mL水稀释，水相用乙酸乙酯萃取(20mL*2)，合并有机相，用饱和氯化钠水溶液(25mL*1)洗涤，无水硫酸钠干燥，滤液减压浓缩，经薄层色谱(石油醚∶乙酸乙酯＝1∶1)纯化得到化合物21a。SFC分析条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.967min，ee＝100％。 1H NMR(400MHz，CDCl 3)δ＝8.88(s，1H)，8.79-8.65(m，2H)，8.28(br d，J＝6.9Hz，1H)，7.31-7.28(m，2H)，7.24-7.20(m，1H)，7.11(br s，1H)，6.97(d，J＝8.4Hz，1H)，4.74(br s，2H)，4.45-4.25(m，2H)，3.86(br s，2H)，3.45(s，3H)，2.97-2.83(m，1H)，2.82-2.63(m，3H)，2.58-2.44(m，2H)，2.43-2.36(m，2H)，1.91-1.79(m，2H)，1.77(br d，J＝4.9Hz，1H)，1.57-1.49(m，1H)。MS：m/z 542.2[M+H] +。 Compound 21-6a (85mg, 1.0eq) was added to tetrahydrofuran (5mL), potassium trimethylsiliconate (57.43mg, 3.0eq) was added with stirring, and stirred at 25°C for 1 hour. Use 2N dilute hydrochloric acid to adjust the pH value of the reaction system to 5, add 20 mL of water to dilute, extract the aqueous phase with ethyl acetate (20 mL*2), combine the organic phases, wash with saturated aqueous sodium chloride solution (25 mL*1), and anhydrous sulfuric acid After drying over sodium, the filtrate was concentrated under reduced pressure, and purified by thin layer chromatography (petroleum ether: ethyl acetate = 1:1) to obtain compound 21a. SFC analysis conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 1.967min, ee=100%. 1 H NMR (400MHz, CDCl 3 ) δ=8.88(s, 1H), 8.79-8.65(m, 2H), 8.28(br d, J=6.9Hz, 1H), 7.31-7.28(m, 2H), 7.24 -7.20(m, 1H), 7.11(br s, 1H), 6.97(d, J=8.4Hz, 1H), 4.74(br s, 2H), 4.45-4.25(m, 2H), 3.86(br s, 2H), 3.45(s, 3H), 2.97-2.83(m, 1H), 2.82-2.63(m, 3H), 2.58-2.44(m, 2H), 2.43-2.36(m, 2H), 1.91-1.79( m, 2H), 1.77 (br d, J = 4.9 Hz, 1H), 1.57-1.49 (m, 1H). MS: m/z 542.2 [M+H] + .
实施例22Example 22
Figure PCTCN2022095009-appb-000128
Figure PCTCN2022095009-appb-000128
第一步first step
将化合物22-1(118.62mg，1.0eq)溶解在N，N-二甲基甲酰胺(8mL)中，在氮气保护下向反应液中加入化合物B-1(300mg，1.0eq)、碘化亚铜(33.20mg，0.2eq)、N，N-二甲基乙二胺(30.74mg，0.4eq)和碳酸钾(361.43mg，3.0eq)，将混合物在氮气的氛围下加热至130℃，并搅拌10小时。向反应体系中加水(20mL)，用乙酸乙酯(20mL*3)萃取，合并后的有机相依次用水(15mL*3)和饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到的残留物经薄层色谱(石油醚∶乙酸乙酯＝5∶1)纯化得到化合物22-2。MS：m/z 353.2[M+H] +。 Compound 22-1 (118.62mg, 1.0eq) was dissolved in N,N-dimethylformamide (8mL), and compound B-1 (300mg, 1.0eq), iodide Cuprous (33.20mg, 0.2eq), N,N-dimethylethylenediamine (30.74mg, 0.4eq) and potassium carbonate (361.43mg, 3.0eq), the mixture was heated to 130°C under nitrogen atmosphere, and stirred for 10 hours. Add water (20mL) to the reaction system, extract with ethyl acetate (20mL*3), wash the combined organic phase with water (15mL*3) and saturated aqueous sodium chloride solution (20mL) successively, dry over anhydrous sodium sulfate, filter , the residue obtained after the filtrate was concentrated was purified by thin layer chromatography (petroleum ether: ethyl acetate = 5:1) to obtain compound 22-2. MS: m/z 353.2 [M+H] + .
第二步second step
将化合物22-2(150mg，1.0eq)溶解在水(2mL)、四氢呋喃(2mL)和甲醇(2mL)的混合溶剂中，加入一水合氢氧化锂(53.60mg，3.0eq)，混合物在20℃下搅拌3小时。用1N稀盐酸调pH到7，混合物浓缩后加水(5mL)，用乙酸乙酯(10mL*3)萃取，合并后的有机相用饱和氯化钠水溶液(10mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩后得到化合物22-3。MS：m/z 339.2[M+H] +。 Compound 22-2 (150mg, 1.0eq) was dissolved in a mixed solvent of water (2mL), tetrahydrofuran (2mL) and methanol (2mL), lithium hydroxide monohydrate (53.60mg, 3.0eq) was added, and the mixture was heated at 20°C Stirring was continued for 3 hours. Adjust the pH to 7 with 1N dilute hydrochloric acid, concentrate the mixture, add water (5 mL), extract with ethyl acetate (10 mL*3), wash the combined organic phase with saturated aqueous sodium chloride (10 mL), and dry over anhydrous sodium sulfate. After filtration, the filtrate was concentrated to obtain compound 22-3. MS: m/z 339.2 [M+H] + .
第三步third step
将化合物22-3(100mg，1.0eq)加入到四氢呋喃(2mL)和乙腈(2mL)的混合溶剂中，然后向体系中加入中间体C(68.66mg，1.0eq)、4-二甲氨基吡啶(3.61mg，0.1eq)、三乙胺(123.44μL，3.0eq)和三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，527μL，3.0eq)。混合物在20℃下搅拌3小时。向反应体系中加水(15mL)，用乙酸乙酯(10mL*3)萃取，合并后的有机相用饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤，滤液浓缩。剩余物用制备高效液相色谱(色谱柱：Phenomenex Synergi C18 150*25mm*10μm；流动相：[水(0.225％甲酸)-乙腈]；梯度：B％：56％-95％)纯化，再用SFC分离(分离条件：色谱柱：DAICEL CHIRALCEL OJ(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；梯度：B％：35％-35％)得到化合物22-4a。SFC分析条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.464min，ee＝91.46％。MS：m/z 553.3[M+H] +。 Compound 22-3 (100mg, 1.0eq) was added to a mixed solvent of tetrahydrofuran (2mL) and acetonitrile (2mL), and then Intermediate C (68.66mg, 1.0eq), 4-dimethylaminopyridine ( 3.61mg, 0.1eq), triethylamine (123.44μL, 3.0eq) and tri-n-propyl cyclic phosphoric anhydride (50% mass fraction in ethyl acetate, 527μL, 3.0eq). The mixture was stirred at 20°C for 3 hours. Water (15 mL) was added to the reaction system, extracted with ethyl acetate (10 mL*3), the combined organic phases were washed with saturated aqueous sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by preparative high-performance liquid chromatography (chromatographic column: Phenomenex Synergi C18 150*25mm*10 μm; mobile phase: [water (0.225% formic acid)-acetonitrile]; gradient: B%: 56%-95%), and then used SFC separation (separation conditions: chromatographic column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: phase A: CO 2 , phase B: [(0.1% ammonia water) methanol]; gradient: B%: 35%-35 %) to obtain compound 22-4a. SFC analysis conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 1.464min, ee=91.46%. MS: m/z 553.3 [M+H] + .
第四步the fourth step
将化合物22-4a(60mg，1.0eq)溶解在甲醇(1mL)、水(1mL)和四氢呋喃(1mL)的混合溶剂中，向体系中加入一水合氢氧化锂(13.67mg，3.0eq)，混合物在20℃下搅拌3小时。反应结束后，体系用2N稀盐酸调pH至5，混合物浓缩后加水(10mL)，用乙酸乙酯(20mL*3)萃取，合并后的有机相用饱和氯化钠水溶液(20mL)洗涤，无水硫酸钠干燥，过滤后将滤液浓缩，所得残留物溶解在乙醇(3mL)中，加入水(20mL)中，有固体析出，过滤，滤饼干燥得到化合物22a。SFC分析条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.833min，ee＝91.41％。 1H NMR(400MHz，CDCl 3)δ＝10.64(brs，1H)，9.27(s，1H)，8.13(s，1H)，8.04(brs，1H)， 7.59(dd，J＝8.8，2.4Hz，1H)，7.50(dd，J＝8.0，1.2Hz，1H)，7.39-7.36(m，2H)，6.95(d，J＝8.8Hz，1H)，4.35-4.30(m，1H)，4.16-4.12(m，1H)，2.81(s，1H)，2.71-2.63(m，2H)，2.20-2.09(m，2H)，2.05-1.99(m，2H)，1.81-1.77(m，1H)，1.69-1.66(m，2H)，1.59-1.56(m，1H)。MS：m/z 525.3[M+H] +。 Compound 22-4a (60mg, 1.0eq) was dissolved in a mixed solvent of methanol (1mL), water (1mL) and tetrahydrofuran (1mL), and lithium hydroxide monohydrate (13.67mg, 3.0eq) was added to the system, and the mixture Stir at 20°C for 3 hours. After the reaction, the pH of the system was adjusted to 5 with 2N dilute hydrochloric acid, the mixture was concentrated, added water (10 mL), extracted with ethyl acetate (20 mL*3), and the combined organic phases were washed with saturated aqueous sodium chloride (20 mL). Dry over sodium sulfate, filter and concentrate the filtrate, dissolve the obtained residue in ethanol (3 mL), add water (20 mL), solid precipitates, filter, and dry the filter cake to obtain compound 22a. SFC analysis conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 1.833min, ee=91.41%. 1 H NMR (400MHz, CDCl 3 ) δ=10.64(brs, 1H), 9.27(s, 1H), 8.13(s, 1H), 8.04(brs, 1H), 7.59(dd, J=8.8, 2.4Hz, 1H), 7.50(dd, J=8.0, 1.2Hz, 1H), 7.39-7.36(m, 2H), 6.95(d, J=8.8Hz, 1H), 4.35-4.30(m, 1H), 4.16-4.12 (m, 1H), 2.81(s, 1H), 2.71-2.63(m, 2H), 2.20-2.09(m, 2H), 2.05-1.99(m, 2H), 1.81-1.77(m, 1H), 1.69 -1.66 (m, 2H), 1.59-1.56 (m, 1H). MS: m/z 525.3 [M+H] + .
实施例23Example 23
Figure PCTCN2022095009-appb-000129
Figure PCTCN2022095009-appb-000129
第一步first step
将化合物23-1(2.0g，1eq)溶于乙醇(24mL)和四氢呋喃(8mL)的混合溶剂中，冷却到0℃，加入硼氢化钠(0.17g，0.4eq)，反应物在冰水浴中(0～10℃)搅拌45分钟。反应液中加二氯甲烷(20mL)和水(20mL)稀释，搅拌，分液，水层再用二氯甲烷萃取(20mL*2)，有机层合并，用饱和氯化钠水溶液洗涤(30mL*1)，无水硫酸钠干燥，过滤，减压浓缩得到化合物23-2直接用于下一步反应。 1H NMR(400MHz，CDCl 3)δ＝8.64(s，1H)，7.85(d，J＝8.0Hz，1H)，7.22(d，J＝8.0Hz，1H)，4.74(s，2H)，3.07(br s，1H)。 Compound 23-1 (2.0g, 1eq) was dissolved in a mixed solvent of ethanol (24mL) and tetrahydrofuran (8mL), cooled to 0°C, sodium borohydride (0.17g, 0.4eq) was added, and the reactant was placed in an ice-water bath (0-10°C) and stirred for 45 minutes. Add dichloromethane (20mL) and water (20mL) to the reaction solution to dilute, stir, separate the layers, extract the aqueous layer with dichloromethane (20mL*2), combine the organic layers, wash with saturated aqueous sodium chloride (30mL* 1), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain compound 23-2, which was directly used in the next reaction. 1 H NMR (400MHz, CDCl 3 ) δ=8.64(s, 1H), 7.85(d, J=8.0Hz, 1H), 7.22(d, J=8.0Hz, 1H), 4.74(s, 2H), 3.07 (br s, 1H).
第二步second step
将氢化钠(0.205g，60％含量，1eq)悬浮于N，N-二甲基甲酰胺(8mL)中，冷却到0℃，滴加化合物23-2(0.8g，1eq)的N，N-二甲基甲酰胺(4mL)溶液，搅拌15分钟后，缓慢滴加碘甲烷(0.3mL，1.1eq)的N，N-二甲基甲酰胺(4mL)溶液，控制温度低于5℃。加毕，反应混合物缓慢升温到20℃搅拌15小时。将反应液倒入20mL饱 和氯化钠水溶液中，用乙酸乙酯萃取(20mL*2)，有机层合并，依次用水(20mL*2)，饱和氯化钠水溶液(20mL*1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩得到化合物23-3直接用于下一步反应。 1H NMR(400MHz，CDCl 3)δ＝8.61(d，J＝2.4Hz，1H)，7.83(dd，J＝8.4，2.4Hz，1H)，7.34(d，J＝8.4Hz，1H)，4.53(s，2H)，3.47(s，3H)。 Sodium hydride (0.205g, 60% content, 1eq) was suspended in N,N-dimethylformamide (8mL), cooled to 0°C, and compound 23-2 (0.8g, 1eq) was added dropwise in N,N -Dimethylformamide (4mL) solution, after stirring for 15 minutes, slowly add iodomethane (0.3mL, 1.1eq) in N,N-dimethylformamide (4mL) solution dropwise, controlling the temperature below 5°C. After the addition was complete, the reaction mixture was slowly warmed to 20°C and stirred for 15 hours. Pour the reaction solution into 20mL saturated aqueous sodium chloride solution, extract with ethyl acetate (20mL*2), combine the organic layers, wash with water (20mL*2), saturated aqueous sodium chloride solution (20mL*1) successively, and anhydrous Dry over sodium sulfate, filter, and concentrate the filtrate under reduced pressure to obtain compound 23-3, which is directly used in the next reaction. 1 H NMR (400MHz, CDCl 3 ) δ = 8.61 (d, J = 2.4Hz, 1H), 7.83 (dd, J = 8.4, 2.4Hz, 1H), 7.34 (d, J = 8.4Hz, 1H), 4.53 (s, 2H), 3.47 (s, 3H).
第三步third step
将化合物23-3(0.1g，1eq)和化合物18-3(0.17g，0.96eq)加入1，4-二氧六环(4mL)和水(1mL)的混合溶剂中，加入磷酸钾(0.21g，2eq)和[1，1′-双(二苯基膦基)二茂铁]二氯化钯(0.02g，0.055eq)，反应液用氮气置换数次后加热到80～90℃搅拌13小时。冷却，加20mL乙酸乙酯稀释，依次用水(20mL*2)和饱和氯化钠水溶液(10mL*1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物经制备薄层色谱(石油醚∶乙酸乙酯＝1∶1)纯化得化合物23-4。Add compound 23-3 (0.1g, 1eq) and compound 18-3 (0.17g, 0.96eq) into a mixed solvent of 1,4-dioxane (4mL) and water (1mL), add potassium phosphate (0.21 g, 2eq) and [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (0.02g, 0.055eq), the reaction solution was replaced with nitrogen several times and then heated to 80-90°C and stirred 13 hours. Cool, add 20 mL of ethyl acetate to dilute, wash with water (20 mL*2) and saturated aqueous sodium chloride solution (10 mL*1) successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, and the residue is subjected to preparative thin-layer chromatography ( Petroleum ether: ethyl acetate = 1:1) to obtain compound 23-4.
第四步the fourth step
将化合物23-4(0.052g，1eq)溶于四氢呋喃(2mL)中，加入一水合氢氧化锂(19mg，3eq)的水(0.5mL)溶液，反应液在20℃搅拌12小时。反应液减压浓缩，剩余物用2N稀盐酸调pH值到2，再次减压浓缩得到化合物23-5粗品直接用于下一步反应。Compound 23-4 (0.052g, 1eq) was dissolved in tetrahydrofuran (2mL), a solution of lithium hydroxide monohydrate (19mg, 3eq) in water (0.5mL) was added, and the reaction solution was stirred at 20°C for 12 hours. The reaction solution was concentrated under reduced pressure, and the residue was adjusted to pH 2 with 2N dilute hydrochloric acid, and concentrated under reduced pressure again to obtain the crude compound 23-5, which was directly used in the next reaction.
第五步the fifth step
将化合物23-5(0.05g，1eq)和中间体C(0.04g，1.1eq)溶于乙腈(2mL)和四氢呋喃(2mL)的混合溶剂中，加入二异丙基乙胺(0.14mL，5.2eq)和4-二甲氨基吡啶(4mg，0.21eq)，然后加入三正丙基环磷酸酐(质量分数为50％的乙酸乙酯溶液，0.3mL，3.2eq)，反应液在20℃搅拌10小时。加20mL乙酸乙酯稀释，依次用水(10mL*2)和饱和氯化钠水溶液(10mL*1)洗涤，无水硫酸钠干燥，过滤，滤液减压浓缩，剩余物经制备薄层色谱(石油醚∶乙酸乙酯＝3∶1)纯化，再经SFC分离(分离条件：色谱柱：DAICEL CHIRALCEL OJ(250mm*30mm，10μm)；流动相：A相：CO 2，B相：[(0.1％氨水)甲醇]；梯度：B％：30％-30％)得到化合物23-6a。SFC分析条件：色谱柱：Chiralcel OJ-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.632min。MS：m/z 540.3[M+H] +。 Compound 23-5 (0.05g, 1eq) and intermediate C (0.04g, 1.1eq) were dissolved in a mixed solvent of acetonitrile (2mL) and tetrahydrofuran (2mL), and diisopropylethylamine (0.14mL, 5.2 eq) and 4-dimethylaminopyridine (4mg, 0.21eq), then add tri-n-propyl cyclic phosphoric acid anhydride (mass fraction is 50% ethyl acetate solution, 0.3mL, 3.2eq), and the reaction solution is stirred at 20°C 10 hours. Add 20 mL of ethyl acetate to dilute, wash with water (10 mL*2) and saturated aqueous sodium chloride solution (10 mL*1) successively, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure, and the residue is subjected to preparative thin-layer chromatography (petroleum ether : ethyl acetate=3:1), and then separated by SFC (separation conditions: chromatographic column: DAICEL CHIRALCEL OJ (250mm*30mm, 10μm); mobile phase: A phase: CO 2 , B phase: [(0.1% ammonia water )methanol]; Gradient: B%: 30%-30%) to obtain compound 23-6a. SFC analysis conditions: chromatographic column: Chiralcel OJ-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time is 1.632min. MS: m/z 540.3 [M+H] + .
第六步step six
将化合物23-6a(45mg，1eq)溶于四氢呋喃(1mL)中，加入一水合氢氧化锂(10.5mg，3eq)的0.5mL水溶液，反应在20℃搅拌10小时。减压浓缩除去四氢呋喃，加1N稀盐酸调pH值到5～6，减压浓缩至干，剩余物加入二氯甲烷和甲醇的混合溶剂(5mL，体积比10∶1)中，过滤，滤液减压浓缩至干得到化合物23a。SFC分析条件：色谱柱：Chiralcel OD-3 50×4.6mm I.D.，3μm，流动相：A相：CO 2，B相：甲醇(0.05％二乙胺)；梯度：B％：5％～40％；流速：3mL/min，保留时间为1.831min，ee＝98.55％。 1H NMR(400MHz，DMSO-d 6)δ＝9.90(s，1H)，8.89(s，1H)，8.18(s，1H)，7.88(s，1H)，7.58-7.48(m，3H)，7.42(d，J＝8.4Hz，1H)，7.26(s， 1H)，6.94(d，J＝8.0Hz，1H)，4.57(s，2H)，4.34-4.31(m，1H)，4.15-4.08(m，1H)，3.39(s，3H)，2.72-2.59(m，3H)，2.20(t，J＝7.2Hz，2H)，2.16-2.12(m，2H)，1.94-1.91(m，1H)，1.77-1.70(m，2H)，1.57(t，J＝6.8Hz，1H)。MS：m/z 512.4[M+H] +。 Compound 23-6a (45mg, 1eq) was dissolved in tetrahydrofuran (1mL), a 0.5mL aqueous solution of lithium hydroxide monohydrate (10.5mg, 3eq) was added, and the reaction was stirred at 20°C for 10 hours. Concentrate under reduced pressure to remove tetrahydrofuran, add 1N dilute hydrochloric acid to adjust the pH value to 5-6, concentrate under reduced pressure to dryness, add the residue to a mixed solvent of dichloromethane and methanol (5mL, volume ratio 10:1), filter, and the filtrate Concentrate to dryness under reduced pressure to obtain compound 23a. SFC analysis conditions: chromatographic column: Chiralcel OD-3 50×4.6mm ID, 3μm, mobile phase: phase A: CO 2 , phase B: methanol (0.05% diethylamine); gradient: B%: 5% to 40% ; Flow rate: 3mL/min, retention time 1.831min, ee=98.55%. 1 H NMR (400MHz, DMSO-d 6 ) δ=9.90(s, 1H), 8.89(s, 1H), 8.18(s, 1H), 7.88(s, 1H), 7.58-7.48(m, 3H), 7.42(d, J=8.4Hz, 1H), 7.26(s, 1H), 6.94(d, J=8.0Hz, 1H), 4.57(s, 2H), 4.34-4.31(m, 1H), 4.15-4.08 (m, 1H), 3.39(s, 3H), 2.72-2.59(m, 3H), 2.20(t, J=7.2Hz, 2H), 2.16-2.12(m, 2H), 1.94-1.91(m, 1H ), 1.77-1.70 (m, 2H), 1.57 (t, J=6.8Hz, 1H). MS: m/z 512.4 [M+H] + .
生物测试数据biological test data
实验例1钙流方法检测化合物对人源EP4的拮抗活性Experimental Example 1 Calcium flux method to detect the antagonistic activity of compounds on human EP4
实验步骤和方法：Experimental steps and methods:
取对数生长期的EP4/HEK293培养细胞，用DPBS缓冲液(杜氏磷酸缓冲液)清洗，加入适量0.05％的EDTA-胰酶放置于37℃二氧化碳培养箱中消化，1～2分钟取出细胞加入培养基终止消化。反复吹打分散细胞后离心收取细胞，以每孔20,000个细胞，20μL的密度种入384孔多聚赖氨酸包被细胞板，5％CO 2，37℃培养箱孵育过夜。 Take the EP4/HEK293 cultured cells in the logarithmic growth phase, wash them with DPBS buffer (Duchener's phosphate buffer), add an appropriate amount of 0.05% EDTA-trypsin, place them in a 37°C carbon dioxide incubator for digestion, take out the cells for 1 to 2 minutes and add Media terminates digestion. After repeated pipetting to disperse the cells, the cells were collected by centrifugation, and 20,000 cells per well were seeded into a 384-well polylysine-coated cell plate at a density of 20 μL, and incubated overnight in a 37°C incubator with 5% CO 2 .
第二天每孔加入20μL 2×Fluo-4 Direct TM缓冲液，5％CO 2，37℃培养箱孵育50分钟，室温放置细胞10min。将0.2mM前列腺素E2用ECHO(纳升级声波移液系统)做4倍10个点的梯度稀释，并转移900nL到细胞板。添加30μL实验用缓冲盐溶液至细胞板中，1000rpm离心1min。运行FLIPR(实时荧光成像分析系统)仪器软件，按照设定程序，加入10μL实验用缓冲盐溶液，读取荧光信号。然后再加入10μL激动剂参考化合物，读取荧光信号，计算EC 80，准备6×EC 80浓度的激动剂。 On the second day, 20 μL of 2×Fluo-4 Direct TM buffer solution was added to each well, 5% CO 2 , incubated in a 37° C. incubator for 50 minutes, and the cells were placed at room temperature for 10 minutes. 0.2mM prostaglandin E2 was diluted 4 times and 10 points with ECHO (nanoliter acoustic wave pipetting system), and transferred 900nL to the cell plate. Add 30 μL of experimental buffered saline solution to the cell plate, and centrifuge at 1000 rpm for 1 min. Run FLIPR (real-time fluorescence imaging analysis system) instrument software, add 10 μL experimental buffer saline solution according to the set procedure, and read the fluorescence signal. Then add 10 μL agonist reference compound, read the fluorescence signal, calculate EC 80 , and prepare agonist with 6×EC 80 concentration.
将0.6mM受试化合物用ECHO做3倍10个点的梯度稀释，并转移900nL至化合物板。添加30μL实验用缓冲盐溶液至化合物板中，1000rpm离心1min。运行FLIPR仪器软件，按照设定程序，添加10μL受试化合物到细胞板中，读取荧光信号。再添加10μL 6×EC 80浓度的激动剂到细胞板中，读取荧光信号。 The 0.6mM test compound was serially diluted 3 times and 10 points with ECHO, and 900nL was transferred to the compound plate. Add 30 μL of experimental buffered saline solution to the compound plate, and centrifuge at 1000 rpm for 1 min. Run the FLIPR instrument software, add 10 μL of the test compound to the cell plate according to the set program, and read the fluorescence signal. Add 10 μL of agonist at a concentration of 6×EC 80 to the cell plate, and read the fluorescent signal.
应用GraphPad Prism 5.0软件计算化合物对PGE2受体EP4的钙流抑制的IC 50，即在稳定表达EP4受体的细胞内Ca 2+流动被抑制一半时的药物浓度。 GraphPad Prism 5.0 software was used to calculate the IC 50 of the compound on the calcium flow inhibition of PGE2 receptor EP4, that is, the drug concentration when the Ca 2+ flow in cells stably expressing EP4 receptor was inhibited by half.
实验结果：实验结果见表1。Experimental results: The experimental results are shown in Table 1.
表1：本发明化合物体外酶活性筛选试验结果Table 1: The results of the in vitro enzyme activity screening test of the compounds of the present invention
化合物compound EP4 IC 50(nM) EP4 IC50 (nM) 化合物compound EP4 IC 50(nM) EP4 IC50 (nM)
化合物1aCompound 1a 88 化合物13aCompound 13a 1414
化合物2aCompound 2a 24twenty four 化合物14aCompound 14a 1818
化合物3aCompound 3a 3434 化合物15aCompound 15a 44
化合物4aCompound 4a 3535 化合物16aCompound 16a 1717
化合物4bCompound 4b 4040 化合物18aCompound 18a 1818
化合物5aCompound 5a 22twenty two 化合物19aCompound 19a 55
化合物5bCompound 5b 22twenty two 化合物20aCompound 20a 55
化合物7aCompound 7a 66 化合物21aCompound 21a 1111
化合物10aCompound 10a 99 化合物22aCompound 22a 77
化合物11aCompound 11a 1313 化合物23aCompound 23a 1818
化合物12aCompound 12a 1313 ---- ----
结论：本发明化合物对人源EP4有较强拮抗活性。Conclusion: the compound of the present invention has strong antagonistic activity to human EP4.
实验例2小鼠药代动力学性质评价Experimental Example 2 Mouse Pharmacokinetic Properties Evaluation
实验方法：受试化合物溶于5％DMSO/10％Solutol/85％水的溶媒中，涡旋并超声，制备得到相应浓度的澄清溶液，微孔滤膜过滤后备用。选取17至25克的Balb/c雄性小鼠，静脉或口服给予候选化合物溶液，剂量分别为1mg/kg或2mg/kg。收集一定时间点的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin 6.3计算药代动力学参数。Experimental method: the test compound was dissolved in a solvent of 5% DMSO/10% Solutol/85% water, vortexed and sonicated to prepare a clear solution of corresponding concentration, which was filtered through a microporous membrane for use. Balb/c male mice weighing 17 to 25 grams were selected, and the solution of the candidate compound was administered intravenously or orally, at doses of 1 mg/kg or 2 mg/kg, respectively. Whole blood was collected at a certain time point, and plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.3.
实验结果：测试结果见表2。Experimental results: The test results are shown in Table 2.
表2：本发明化合物小鼠血浆中的药物代谢动力学(PK)参数Table 2: Pharmacokinetic (PK) parameters in mouse plasma of compounds of the present invention
Figure PCTCN2022095009-appb-000130
Figure PCTCN2022095009-appb-000130
注：C max，最大药物浓度；T 1/2，半衰期；V dss，表观分布容积；Cl，药物清除率；AUC 0-last，时间曲线下面积；F，生物利用度；“--”是指未测试或未获得数据。 Note: C max , maximum drug concentration; T 1/2 , half-life; V dss , apparent volume of distribution; Cl, drug clearance; AUC 0-last , area under the time curve; F, bioavailability; "--" Refers to untested or unavailable data.
实验结论：本发明化合物具有良好的小鼠体内药代动力学性质。Experimental conclusion: the compound of the present invention has good pharmacokinetic properties in mice.
实验例3大鼠药代动力学性质评价Experimental Example 3 Pharmacokinetic Properties Evaluation in Rats
实验方法：受试化合物溶于5％DMSO/10％Solutol/85％水的溶媒中，涡旋并超声，制备得到相应浓度的澄清或近似澄清溶液。选取体重约250g的雄性SD大鼠，静脉或口服给予候选化合物溶液，剂量分别为1mg/kg或10mg/kg。收集一定时间点的全血，制备得到血浆，以LC-MS/MS方法分析药物浓度，并用Phoenix WinNonlin 6.3计算药代动力学参数。Experimental method: the test compound was dissolved in a solvent of 5% DMSO/10% Solutol/85% water, vortexed and sonicated, and a clear or nearly clear solution of corresponding concentration was prepared. Male SD rats with a body weight of about 250 g were selected, and the candidate compound solution was administered intravenously or orally, at doses of 1 mg/kg or 10 mg/kg, respectively. Whole blood was collected at a certain time point, and plasma was prepared, and the drug concentration was analyzed by LC-MS/MS method, and the pharmacokinetic parameters were calculated by Phoenix WinNonlin 6.3.
实验结果：测试结果见表3。Experimental results: The test results are shown in Table 3.
表3：本发明化合物大鼠血浆中的药物代谢动力学(PK)参数Table 3: Pharmacokinetic (PK) parameters in rat plasma of compounds of the present invention
Figure PCTCN2022095009-appb-000131
Figure PCTCN2022095009-appb-000131
Figure PCTCN2022095009-appb-000132
Figure PCTCN2022095009-appb-000132
注：C max，最大药物浓度；T 1/2，半衰期；V dss，表观分布容积；Cl，药物清除率；AUC 0-last，时间曲线下面积；F，生物利用度；“--”是指未测试或未获得数据。 Note: C max , maximum drug concentration; T 1/2 , half-life; V dss , apparent volume of distribution; Cl, drug clearance; AUC 0-last , area under the time curve; F, bioavailability; "--" Refers to untested or unavailable data.
实验结论：本发明化合物具有良好的大鼠体内药代动力学性质。Experimental conclusion: the compound of the present invention has good in vivo pharmacokinetic properties in rats.
实验例4小鼠结肠癌CT-26细胞皮下移植肿瘤BALB/c小鼠模型中的体内药效学研究Experimental Example 4 In vivo pharmacodynamic study of mouse colon cancer CT-26 cells subcutaneously transplanted into tumor BALB/c mouse model
实验目的：研究本发明化合物在CT-26细胞皮下移植肿瘤BALB/c小鼠模型中的单药及与化疗药物奥沙利铂(Oxaliplatin)联用的抗肿瘤效果。Experimental purpose: To study the anti-tumor effect of the compound of the present invention as a single drug and in combination with chemotherapy drug Oxaliplatin in CT-26 cell subcutaneously transplanted tumor BALB/c mouse model.
实验动物：雌性BALB/c小鼠，6-8周龄，体重19-22克；供应商：上海灵畅生物科技有限公司Experimental animals: female BALB/c mice, 6-8 weeks old, weighing 19-22 grams; supplier: Shanghai Lingchang Biotechnology Co., Ltd.
实验方法与步骤：Experimental method and steps:
(1)细胞培养(1) Cell culture
小鼠结肠癌CT-26细胞体外培养，培养条件为McCoy’s 5a培养基加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃，5％CO 2培养箱培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％～90％，数量到达要求时，收取细胞，计数，接种。 Mouse colon cancer CT-26 cells were cultured in vitro under the conditions of McCoy's 5a medium plus 10% fetal bovine serum, 100 U/mL penicillin and 100 μg/mL streptomycin, at 37°C in a 5% CO 2 incubator. Routine digestion with trypsin-EDTA was performed twice a week for passaging. When the cell saturation is 80%-90% and the number reaches the requirement, the cells are collected, counted, and inoculated.
(2)肿瘤细胞接种及分组(2) Tumor cell inoculation and grouping
将0.1mL(3×10 5个)CT-26细胞皮下接种于每只小鼠的右后肢，在接种后第9天肿瘤体积达到约61mm 3时开始分组给药，分组及给药方案见下表4。 Subcutaneously inoculate 0.1 mL (3×10 5 cells) of CT-26 cells into the right hind limb of each mouse, and start administration in groups when the tumor volume reaches about 61 mm 3 on the 9th day after inoculation. The grouping and administration schedule are as follows Table 4.
表4：动物分组及给药方案Table 4: Animal grouping and dosing regimen
Figure PCTCN2022095009-appb-000133
Figure PCTCN2022095009-appb-000133
注：PO表示口服；IP表示腹腔注射；BID表示每天两次；20D表示20天；PG-D0，D7表示开始给药后第0天和第7天各给药1次。Note: PO means oral administration; IP means intraperitoneal injection; BID means twice a day; 20D means 20 days; PG-D0, D7 mean administration once on day 0 and day 7 after the start of administration.
(3)化合物的配制(3) Compound preparation
将化合物配制成0.5mg/mL的溶液，溶媒为5％DMSO/10％Solutol/85％水。将奥沙利铂配制成0.75 mg/mL的溶液，溶媒为5％葡萄糖溶液。The compound was formulated as a 0.5 mg/mL solution in 5% DMSO/10% Solutol/85% water. Oxaliplatin was formulated into a 0.75 mg/mL solution, and the vehicle was 5% glucose solution.
(4)肿瘤测量和实验指标(4) Tumor measurement and experimental indicators
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周三次用游标卡尺测量肿瘤直径。肿瘤体积(V)、相对肿瘤体积(relative tumor volume，RTV)、肿瘤生长抑制率TGI(％)和相对肿瘤增殖率T/C(％)的计算公式如下，化合物的抑瘤疗效用TGI(％)或T/C(％)评价：The experimental index is to investigate whether tumor growth is inhibited, delayed or cured. Tumor diameters were measured with vernier calipers three times a week. The calculation formulas of tumor volume (V), relative tumor volume (relative tumor volume, RTV), tumor growth inhibition rate TGI (%) and relative tumor proliferation rate T/C (%) are as follows. ) or T/C (%) evaluation:
V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径； V=0.5a×b 2 , a and b represent the long diameter and short diameter of the tumor respectively;
RTV＝V t/V 0，其中V 0是分组给药时(即第0天)测量所得平均肿瘤体积，V t为某一次测量时的平均肿瘤体积； RTV=V t /V 0 , where V 0 is the average tumor volume measured during group administration (i.e., day 0), and V t is the average tumor volume during a certain measurement;
TGI(％)＝[1-(某处理组给药结束时平均瘤体积-该处理组开始给药时平均瘤体积)/(溶媒对照组治疗结束时平均瘤体积-溶媒对照组开始治疗时平均瘤体积)]×100％；TGI (%)=[1-(Average tumor volume at the end of administration of a certain treatment group-Average tumor volume at the beginning of administration of this treatment group)/(Average tumor volume at the end of treatment of vehicle control group-Average at the beginning of treatment of vehicle control group Tumor volume)] × 100%;
T/C(％)＝T RTV/C RTV×100％，T RTV表示治疗组RTV，C RTV表示溶媒对照组RTV，T RTV与C RTV取同一天数据。 T/C (%)=T RTV /C RTV ×100%, T RTV represents the RTV of the treatment group, C RTV represents the RTV of the vehicle control group, and the data of T RTV and C RTV are taken on the same day.
试验结果：结果见表5。Test results: the results are shown in Table 5.
表5：本发明化合物对小鼠结肠癌CT-26细胞皮下移植肿瘤模型的抑瘤药效评价结果Table 5: Evaluation results of the antitumor efficacy of the compounds of the present invention on the subcutaneous transplantation tumor model of mouse colon cancer CT-26 cells
(基于给药后第20天肿瘤体积计算得出)(calculated based on tumor volume on day 20 after administration)
组别group 肿瘤体积＊(mm 3)(第20天) Tumor volume*(mm 3 )(Day 20) T/C(％)T/C(%) TGI(％)TGI(%)
溶媒组Vehicle group 2193±3192193±319 ---- ----
奥沙利铂(7.5mg/kg)Oxaliplatin (7.5mg/kg) 1407±3471407±347 57.757.7 36.936.9
化合物1a(5mg/kg)Compound 1a (5mg/kg) 1495±4351495±435 56.356.3 32.832.8
化合物1a(5mg/kg)+奥沙利铂(7.5mg/kg)Compound 1a (5mg/kg) + Oxaliplatin (7.5mg/kg) 474±96474±96 18.618.6 80.780.7
注：“--”不需计算；“*”：平均值±SEM，n＝7。Note: "--" does not need to be calculated; "*": mean ± SEM, n = 7.
结论：本发明化合物单药治疗时展现了一定的抑制肿瘤生长的效果，和奥沙利铂联合治疗具有显著优于对应单药治疗的肿瘤抑制效果。Conclusion: The compound of the present invention exhibits a certain tumor growth inhibitory effect in monotherapy, and the combined therapy with oxaliplatin has a significantly better tumor inhibitory effect than the corresponding monotherapy.

Claims (23)

  1. 式(II)化合物或其药学上可接受的盐，a compound of formula (II) or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022095009-appb-100001
    Figure PCTCN2022095009-appb-100001
    其中，in,
    结构单元
    Figure PCTCN2022095009-appb-100002
    选自
    Figure PCTCN2022095009-appb-100003
    Structural units
    Figure PCTCN2022095009-appb-100002
    selected from
    Figure PCTCN2022095009-appb-100003
    或者，L 1选自5-6元杂芳基，R 1选自C 1-3卤代烷基、C 1-3烷硫基、
    Figure PCTCN2022095009-appb-100004
    所述5-6元杂芳基、C 1-3烷硫基、
    Figure PCTCN2022095009-appb-100005
    分别独立地任选被1、2或3个卤素取代；     Or, L 1 is selected from 5-6 membered heteroaryl, R 1 is selected from C 1-3 haloalkyl, C 1-3 alkylthio,
    Figure PCTCN2022095009-appb-100004
    The 5-6 membered heteroaryl, C 1-3 alkylthio,
    Figure PCTCN2022095009-appb-100005
    each independently optionally substituted by 1, 2 or 3 halogens;
    L 2选自C 1-5烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-，所述C 1-5烷基、C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-分别独立地任选被1、2或3个R e取代； L is selected from C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl- C 0-3 alkyl-, the C 1-5 alkyl, C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3 -6 cycloalkyl-C 0-3 alkyl-are independently optionally substituted by 1, 2 or 3 R e ;
    E 1选自-O-、-S-和-NR 6-； E 1 is selected from -O-, -S- and -NR 6 -;
    R 2、R 4和R 6分别独立地选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 2 , R 4 and R 6 are independently selected from H and C 1-3 alkyl, and the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
    R 3选自C 1-5烷基、C 5-10双环环烷基和5-10元双环杂环烷基，所述C 1-5烷基、C 5-10双环环烷基和5-10元双环杂环烷基分别独立地任选被1、2或3个R b取代； R 3 is selected from C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5-10 membered bicyclic heterocycloalkyl, the C 1-5 alkyl, C 5-10 bicyclic cycloalkyl and 5- The 10-membered bicyclic heterocycloalkyl group is independently optionally substituted by 1, 2 or 3 R b ;
    R 5选自C 1-5烷基、C 3-6环烷基和4-6元杂环烷基，所述C 1-5烷基、C 3-6环烷基和4-6元杂环烷基分别独立地任选被1、2或3个R c取代； R 5 is selected from C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl, the C 1-5 alkyl, C 3-6 cycloalkyl and 4-6 membered heterocycloalkyl Cycloalkyl is independently optionally substituted by 1, 2 or 3 Rc ;
    或者，R 4和R 5相连，使结构单元-N(R 4)-C(＝O)-R 5为4-6元杂环烷基，所述4-6元杂环烷基任选被1、2或3个R d取代； Alternatively, R 4 and R 5 are connected, so that the structural unit -N(R 4 )-C(=O)-R 5 is a 4-6 membered heterocycloalkyl group, and the 4-6 membered heterocycloalkyl group is optionally 1, 2 or 3 R d substitutions;
    各R a和各R e分别独立地选自H、F、Cl、Br、I、OH和NH 2； each R a and each R e are independently selected from H, F, Cl, Br, I, OH and NH 2 ;
    各R b、各R c和各R d分别独立地选自H、F、Cl、Br、I、OH、＝O、NH 2、-C 1-3烷基-OH和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R取代； Each R b , each R c and each R d is independently selected from H, F, Cl, Br, I, OH, =O, NH 2 , -C 1-3 alkyl-OH and C 1-3 alkyl , the C 1-3 alkyl is optionally substituted by 1, 2 or 3 R;
    各R分别独立地选自H、F、Cl、Br和I；Each R is independently selected from H, F, Cl, Br and I;
    n选自0、1和2；n is selected from 0, 1 and 2;
    所述5-10元双环杂环烷基和5-6元杂芳基的“杂”分别独立地表示1、2、3或4个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团；The "hetero" of the 5-10 membered bicyclic heterocycloalkyl and 5-6 membered heteroaryl independently represent 1, 2, 3 or 4 independently selected from -O-, -NH-, -S- and A heteroatom or heteroatom group of N;
    所述4-6元杂环烷基的“杂”表示1、2或3个独立选自-O-、-NH-、-S-和N的杂原子或杂原子团；The "hetero" of the 4-6 membered heterocycloalkyl means 1, 2 or 3 heteroatoms or heteroatom groups independently selected from -O-, -NH-, -S- and N;
    条件是，当
    Figure PCTCN2022095009-appb-100006
    选自
    Figure PCTCN2022095009-appb-100007
    R 3选自C 1-5烷基，所述C 1-5烷基任选被1、2或3个R b取代时，L 2选自C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-，所述C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-分别独立地任选被1、2或3个R e取代。     The condition is that when
    Figure PCTCN2022095009-appb-100006
    selected from
    Figure PCTCN2022095009-appb-100007
    R 3 is selected from C 1-5 alkyl, and when said C 1-5 alkyl is optionally substituted by 1, 2 or 3 R b , L 2 is selected from C 1-3 alkoxy, C 1-3 alkane Amino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-, the C 1-3 alkoxy, C 1-3 alkylamino , C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl- are independently optionally substituted by 1, 2 or 3 R e .
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，各R b、R c和R d分别独立地选自H、F、OH、＝O、NH 2、-CH 2OH和CH 3，所述-CH 2OH和CH 3任选被1、2或3个R取代。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein each R b , R c and R d are independently selected from H, F, OH, =O, NH 2 , -CH 2 OH and CH 3 , the -CH 2 OH and CH 3 are optionally substituted by 1, 2 or 3 R.
  3. 根据权利要求2所述化合物或其药学上可接受的盐，其中，各R b、R c和R d分别独立地选自H、F、OH、＝O、NH 2、CH 3、CF 3和-CH 2OH。 The compound or a pharmaceutically acceptable salt thereof according to claim 2, wherein each R b , R c and R d are independently selected from H, F, OH, =O, NH 2 , CH 3 , CF 3 and -CH2OH .
  4. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 2选自H。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from H.
  5. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 3选自螺[2，2]戊烷基、螺[2，3]己烷基、螺[3，3]庚烷基、双环[3.1.0]己烷基和双环[1.1.1]戊烷基，所述螺[2，2]戊烷基、螺[2，3]己烷基、螺[3，3]庚烷基、双环[3.1.0]己烷基和双环[1.1.1]戊烷基任选被1、2或3个R b取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from spiro[2,2]pentyl, spiro[2,3]hexyl, spiro[3,3]heptane base, bicyclo[3.1.0]hexyl and bicyclo[1.1.1]pentyl, the spiro[2,2]pentyl, spiro[2,3]hexyl, spiro[3,3] Heptyl, bicyclo[3.1.0]hexyl and bicyclo[1.1.1]pentanyl are optionally substituted with 1, 2 or 3 R b .
  6. 根据权利要求5所述化合物或其药学上可接受的盐，其中，R 3选自
    Figure PCTCN2022095009-appb-100008
    Figure PCTCN2022095009-appb-100009
    The compound or a pharmaceutically acceptable salt thereof according to claim 5, wherein R is selected from
    Figure PCTCN2022095009-appb-100008
    Figure PCTCN2022095009-appb-100009
  7. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4选自H。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from H.
  8. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 5选自C 1-3烷基、叔丁基、环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基和氮杂环戊基，所述C 1-3烷基、叔丁基、环丙基、环丁基、环戊基、氧杂环丁基、氧杂环戊基、氮杂环丁基和氮杂环戊基任选被1、2或3个R c取代。 The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R is selected from C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetanyl , oxolyl, azetidinyl and azetidinyl, the C 1-3 alkyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, oxetyl, Oxolyl, azetidinyl and azetidinyl are optionally substituted with 1, 2 or 3 Rc .
  9. 根据权利要求8所述化合物或其药学上可接受的盐，其中，R 5选自-CH(CH 3) 2、-C(CH 3) 3和
    Figure PCTCN2022095009-appb-100010
    The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from -CH(CH 3 ) 2 , -C(CH 3 ) 3 and
    Figure PCTCN2022095009-appb-100010
  10. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 4和R 5相连，使结构单元-N(R 4)-C(＝O)-R 5为
    Figure PCTCN2022095009-appb-100011
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein, R 4 and R 5 are connected, so that the structural unit -N(R 4 )-C(=O)-R 5 is
    Figure PCTCN2022095009-appb-100011
  11. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022095009-appb-100012
    选自
    Figure PCTCN2022095009-appb-100013
    Figure PCTCN2022095009-appb-100014
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2022095009-appb-100012
    selected from
    Figure PCTCN2022095009-appb-100013
    Figure PCTCN2022095009-appb-100014
  12. 根据权利要求11所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022095009-appb-100015
    选自
    Figure PCTCN2022095009-appb-100016
    Figure PCTCN2022095009-appb-100017
    The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2022095009-appb-100015
    selected from
    Figure PCTCN2022095009-appb-100016
    Figure PCTCN2022095009-appb-100017
  13. 根据权利要求11所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022095009-appb-100018
    选自
    Figure PCTCN2022095009-appb-100019
    Figure PCTCN2022095009-appb-100020
    The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2022095009-appb-100018
    selected from
    Figure PCTCN2022095009-appb-100019
    Figure PCTCN2022095009-appb-100020
  14. 根据权利要求1所述化合物或其药学上可接受的盐，其中，L 2选自丙基、丁基、1，1-二甲基丙基、2，2-二甲基丙基、
    Figure PCTCN2022095009-appb-100021
    Figure PCTCN2022095009-appb-100022
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein L is selected from propyl, butyl, 1,1-dimethylpropyl, 2,2-dimethylpropyl,
    Figure PCTCN2022095009-appb-100021
    Figure PCTCN2022095009-appb-100022
  15. 根据权利要求1所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022095009-appb-100023
    选自
    Figure PCTCN2022095009-appb-100024
    R 3选自CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2，所述CH 3、CH 2CH 3、CH 2CH 2CH 3和CH(CH 3) 2分别独立地任选被1、2或3个R b取代，此时，L 2选自
    Figure PCTCN2022095009-appb-100025
    Figure PCTCN2022095009-appb-100026
    The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein the structural unit
    Figure PCTCN2022095009-appb-100023
    selected from
    Figure PCTCN2022095009-appb-100024
    R 3 is selected from CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 , wherein CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 and CH(CH 3 ) 2 are respectively independently optionally substituted by 1, 2 or 3 R b , at this time, L is selected from
    Figure PCTCN2022095009-appb-100025
    Figure PCTCN2022095009-appb-100026
  16. 根据权利要求15所述化合物或其药学上可接受的盐，其中，结构单元
    Figure PCTCN2022095009-appb-100027
    选自
    Figure PCTCN2022095009-appb-100028
    此时，结构单元-L 2-COOH选自
    Figure PCTCN2022095009-appb-100029
    Figure PCTCN2022095009-appb-100030
    The compound or a pharmaceutically acceptable salt thereof according to claim 15, wherein the structural unit
    Figure PCTCN2022095009-appb-100027
    selected from
    Figure PCTCN2022095009-appb-100028
    In this case, the structural unit -L 2 -COOH is selected from
    Figure PCTCN2022095009-appb-100029
    Figure PCTCN2022095009-appb-100030
  17. 根据权利要求1所述化合物或其药学上可接受的盐，其中，E 1选自-O-。 The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein E is selected from -O-.
  18. 根据权利要求1所述化合物或其药学上可接受的盐，其中，n选自0。The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein n is selected from 0.
  19. 根据权利要求1～18任意一项所述化合物或其药学上可接受的盐，其选自，According to any one of claims 1-18, the compound or a pharmaceutically acceptable salt thereof is selected from the group consisting of:
    Figure PCTCN2022095009-appb-100031
    Figure PCTCN2022095009-appb-100031
    其中，R 1、L 1和E 1如权利要求1～18任意一项所定义。 Wherein, R 1 , L 1 and E 1 are as defined in any one of claims 1-18.
  20. 根据权利要求19所述的化合物或其药学上可接受的盐，其选自，The compound according to claim 19 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of,
    Figure PCTCN2022095009-appb-100032
    Figure PCTCN2022095009-appb-100032
    其中，in,
    环A选自5-6元杂芳基；Ring A is selected from 5-6 membered heteroaryl;
    R 1选自C 1-3卤代烷基、C 1-3烷硫基、
    Figure PCTCN2022095009-appb-100033
    R 1 is selected from C 1-3 haloalkyl, C 1-3 alkylthio,
    Figure PCTCN2022095009-appb-100033
    R 2、R 3、R 4和R 5如权利要求19所定义。 R 2 , R 3 , R 4 and R 5 are as defined in claim 19 .
  21. 根据权利要求1所述的化合物或其药学上可接受的盐，其选自，The compound according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of,
    Figure PCTCN2022095009-appb-100034
    Figure PCTCN2022095009-appb-100034
    其中，in,
    R 2选自H和C 1-3烷基，所述C 1-3烷基任选被1、2或3个R a取代； R 2 is selected from H and C 1-3 alkyl, said C 1-3 alkyl is optionally substituted by 1, 2 or 3 R a ;
    R 3选自C 1-5烷基，所述C 1-5烷基任选被1、2或3个R b取代； R 3 is selected from C 1-5 alkyl, said C 1-5 alkyl is optionally substituted by 1, 2 or 3 R b ;
    L 2选自C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-，所述C 1-3烷氧基、C 1-3烷氨基、C 1-3烷硫基和-C 0-3烷基-C 3-6环烷基-C 0-3烷基-分别独立地任选被1、2或3个R e取代； L is selected from C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl- , the C 1-3 alkoxy, C 1-3 alkylamino, C 1-3 alkylthio and -C 0-3 alkyl-C 3-6 cycloalkyl-C 0-3 alkyl-respectively independently optionally substituted by 1, 2 or 3 Re ;
    n、各R a、各R b和各R e如权利要求1所定义。 n, each R a , each R b and each R e are as defined in claim 1 .
  22. 下式所示化合物或其药学上可接受的盐，A compound represented by the following formula or a pharmaceutically acceptable salt thereof,
    Figure PCTCN2022095009-appb-100035
    Figure PCTCN2022095009-appb-100035
    Figure PCTCN2022095009-appb-100036
    Figure PCTCN2022095009-appb-100036
  23. 根据权利要求22所述化合物或其药学上可接受的盐，其选自，The compound or pharmaceutically acceptable salt thereof according to claim 22, which is selected from the group consisting of:
    Figure PCTCN2022095009-appb-100037
    Figure PCTCN2022095009-appb-100037
    Figure PCTCN2022095009-appb-100038
    Figure PCTCN2022095009-appb-100038
    Figure PCTCN2022095009-appb-100039
    Figure PCTCN2022095009-appb-100039
    Figure PCTCN2022095009-appb-100040
    Figure PCTCN2022095009-appb-100040
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JP2018123108A (en) * 2017-02-03 2018-08-09 小野薬品工業株式会社 Stable crystal of tricyclic spiro compound
CN109475520A (en) * 2016-07-07 2019-03-15 小野药品工业株式会社 Combination comprising EP4 antagonist and immunologic test point inhibitor
US20190125720A1 (en) * 2017-11-01 2019-05-02 Ono Pharmaceutical Co., Ltd. Method for treating brain tumors

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JP2018021013A (en) * 2016-07-07 2018-02-08 小野薬品工業株式会社 Pharmaceutical application
CN109475520A (en) * 2016-07-07 2019-03-15 小野药品工业株式会社 Combination comprising EP4 antagonist and immunologic test point inhibitor
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