WO2024099398A1 - Class of sulfonamide compounds containing ortho-fused heterocycle and use thereof - Google Patents

Class of sulfonamide compounds containing ortho-fused heterocycle and use thereof Download PDF

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WO2024099398A1
WO2024099398A1 PCT/CN2023/130794 CN2023130794W WO2024099398A1 WO 2024099398 A1 WO2024099398 A1 WO 2024099398A1 CN 2023130794 W CN2023130794 W CN 2023130794W WO 2024099398 A1 WO2024099398 A1 WO 2024099398A1
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compound
mmol
added
solution
present
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PCT/CN2023/130794
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Chinese (zh)
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胡利红
刘希乐
张路
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南京明德新药研发有限公司
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Publication of WO2024099398A1 publication Critical patent/WO2024099398A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • A61K31/497—Non-condensed pyrazines containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D221/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00
    • C07D221/02—Heterocyclic compounds containing six-membered rings having one nitrogen atom as the only ring hetero atom, not provided for by groups C07D211/00 - C07D219/00 condensed with carbocyclic rings or ring systems
    • C07D221/20—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to the field of pharmaceutical chemistry, and in particular to a class of sulfonamide compounds containing heterocyclic rings and applications thereof in preparing drugs for treating related diseases.
  • Mitotic enzymes are widely used clinically as targets for tumor therapy, and many anti-mitotic drugs are clinically used, such as microtubule-targeting agents, which can stabilize microtubules or prevent microtubule assembly.
  • microtubules are an important component of the mitotic spindle, and the disruption of microtubule dynamics by these drugs leads to mitotic arrest and inhibition of cancer cell growth.
  • microtubule-targeting agents are widely used as standard therapies for the treatment of a variety of cancers, these drugs have significant toxicity, including bone marrow suppression and neurotoxicity, due to damage to normal cells. Therefore, it is of great significance to develop new mitotic enzymes as therapeutic targets to prevent cancer cell proliferation and improve safety.
  • Kinesin is a type of mitotic enzyme that plays an important role in the dynamics of spindle assembly, chromosome separation, centriole separation, etc.
  • Mitotic kinesin is a motor protein that uses ATP hydrolysis to move along microtubule filaments and coordinate proper bipolar spindle formation, chromosome alignment and separation.
  • inhibitors of mitotic kinesin Eg5 and CENP-E have no significant clinical therapeutic effects and have target mechanism toxicity.
  • KIF18A kinesin-like protein 18A
  • KIF18A is a kinesin expressed in the G2/M phase of the cell cycle and is a member of the kinesin-8 family of kinesins. In metaphase of cell division, it mainly regulates chromosome positioning and spindle length. KIF18A is believed to control chromosome positioning and spindle tension by affecting the dynamics of the plus end of the centromere microtubules. KIF18A deficiency leads to spindle elongation, chromosome misalignment, and activation of mitotic checkpoints, and its overexpression leads to the formation of multipolar spindles.
  • KIF18A is overexpressed in a variety of tumors, such as breast cancer, ovarian cancer, and colon cancer; it is associated with tumor grade and degree of metastasis. Abnormal cell cycle regulation and chromosomal instability are common characteristics of solid tumors, and chromosomally unstable cells are more sensitive to anti-mitotic treatment. In chromosomally unstable cancer cells, KIF18A knockdown is associated with impaired cell division (including activation of spindle assembly checkpoints, formation of multipolar spindles, and induction of cell apoptosis), but does not affect the division of normal cells and cancer cells with normal karyotypes.
  • KIF18A small molecule inhibitors of KIF18A can effectively and selectively target cancer cells with CIN features while largely sparing normal Therefore, the development of KIF18A small molecule inhibitors is of great research significance for cancer treatment.
  • the present invention provides a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl, wherein the 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl are each independently optionally substituted by 1 or 2 R a ;
  • Ring A is selected from C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, and the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b ;
  • T1 and T2 are each independently selected from N, C and CH;
  • X 1 , X 2 and X 3 are each independently selected from N and CR c ;
  • R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl and OC 1-3 alkyl, wherein the C 1-3 alkyl and OC 1-3 alkyl are independently optionally substituted with 1, 2 and 3 R, respectively;
  • R 5 is selected from 5-8 membered heterocycloalkyl and C 5-8 membered cycloalkenyl, wherein the 5-8 membered heterocycloalkyl and C 5-8 membered cycloalkenyl are each independently optionally substituted by 1, 2, 3 or 4 R d ;
  • Ra , Rb , Rc and Rd are independently selected from H, F, Cl, Br, OH, NH2, CN, C1-3 alkyl and OC1-3 alkyl, wherein the C1-3 alkyl and OC1-3 alkyl are independently optionally substituted with 1 , 2 and 3 Rs, respectively;
  • R is selected from H, F, Cl, Br, OH, NH2 and CN.
  • the present invention also provides a compound of formula (II-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl, wherein the 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl are each independently optionally substituted by 1 or 2 R a ;
  • Ring A is selected from C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, and the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b ;
  • T1 and T2 are each independently selected from N, C and CH;
  • X 1 , X 2 and X 3 are each independently selected from N and CR c ;
  • R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl and OC 1-3 alkyl, wherein the C 1-3 alkyl and OC 1-3 alkyl are independently optionally substituted with 1, 2 and 3 R, respectively;
  • Ra , Rb and Rc are independently selected from H, F, Cl, Br, OH, NH2 , CN, C1-3 alkyl and OC1-3 alkyl, wherein the C1-3 alkyl and OC1-3 alkyl are independently optionally substituted with 1, 2 and 3 Rs, respectively;
  • R is selected from H, F, Cl, Br, OH, NH2 and CN.
  • the present invention also provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
  • Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocyclic aryl, wherein the 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocyclic aryl are selected from The 6-membered heteroaryl group is optionally substituted by 1 or 2 R a ;
  • Ring A is selected from C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, wherein the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R b ;
  • T1 and T2 are each independently selected from N, C and CH;
  • X 1 , X 2 and X 3 are each independently selected from N and CR c ;
  • R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl and OC 1-3 alkyl, wherein the C 1-3 alkyl and OC 1-3 alkyl are optionally substituted with 1, 2 and 3 R;
  • Ra , Rb and Rc are independently selected from H, F, Cl, Br, OH, NH2 , CN, C1-3 alkyl and OC1-3 alkyl, wherein the C1-3 alkyl and OC1-3 alkyl are optionally substituted with 1, 2 and 3 R;
  • R is selected from H, F, Cl, Br, OH, NH2 and CN.
  • each of the above Ra is independently selected from H, F and CH 3 , and other variables are as defined in the present invention.
  • each R b is independently selected from H, F and CH 3 , and other variables are as defined in the present invention.
  • each R c is independently selected from H, F and CH 3 , and other variables are as defined in the present invention.
  • each of the above R d is independently selected from H, F and CH 3 , and other variables are as defined in the present invention.
  • R 1 , R 2 , R 3 and R 4 are independently selected from H and CH 3 , and other variables are as defined in the present invention.
  • R 1 is selected from H and CH 3 , and other variables are as defined in the present invention.
  • R 1 is selected from H, and other variables are as defined in the present invention.
  • R 1 is selected from CH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from H and CH 3 , 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.
  • R 2 is selected from CH 3 , and other variables are as defined in the present invention.
  • R 3 is selected from H and CH 3 , and other variables are as defined in the present invention.
  • R 3 is selected from H, and other variables are as defined in the present invention.
  • R 3 is selected from CH 3 , and other variables are as defined in the present invention.
  • R 4 is selected from H and CH 3 , 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.
  • R 4 is selected from CH 3 , and other variables are as defined in the present invention.
  • R 5 is selected from 5-8 membered heterocycloalkyl
  • the 5-8 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
  • R 5 is selected from C 5-8 membered cycloalkenyl
  • the C 5-8 membered cycloalkenyl is optionally substituted by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
  • R 5 is selected from Said are each independently optionally substituted with 1, 2, 3 or 4 R d , and other variables are as defined herein.
  • R 5 is selected from Said are each independently optionally substituted with 1, 2, 3 or 4 R d , and other variables are as defined herein.
  • T1 is selected from N, and other variables are as defined in the present invention.
  • T1 is selected from C
  • other variables are as defined in the present invention.
  • T1 is selected from CH
  • other variables are as defined in the present invention.
  • T 2 is selected from N, and other variables are as defined in the present invention.
  • T 2 is selected from C, and other variables are as defined in the present invention.
  • T 2 is selected from CH
  • other variables are as defined in the present invention.
  • the ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
  • the ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
  • the ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
  • the ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
  • the ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
  • the ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
  • the ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
  • ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
  • ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
  • ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
  • the ring A is selected from Other variables are as defined in the present invention.
  • the ring A is selected from Other variables are as defined in the present invention.
  • the ring B is selected from a 5-membered heteroaryl group, and the 5-membered heteroaryl group is optionally substituted by 1 or 2 Ras , and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from a 6-membered heteroaryl group, and the 6-membered heteroaryl group is optionally substituted by 1 or 2 Ras , and other variables are as defined in the present invention.
  • the ring B is selected from a 5-membered heteroaryl alkenyl group, the 5-membered heteroaryl alkenyl group is optionally substituted by 1 or 2 R a , and other variables are as defined in the present invention.
  • the ring B is selected from a 6-membered heteroaryl alkenyl group, the 6-membered heteroaryl alkenyl group is optionally substituted by 1 or 2 R a , and other variables are as defined in the present invention.
  • the above structural unit Selected from Said are each independently optionally substituted by 1 or 2 Ra , and other variables are as defined herein.
  • the above compound is selected from formula (IA), (IB), (IC), (ID) and (II-A)
  • the present invention provides the following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof,
  • the second aspect of the present invention provides a pharmaceutical composition, which comprises an effective dose of the compound defined in any of the above technical solutions, its stereoisomers or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
  • the third aspect of the present invention provides the use of the compound defined in any of the above technical solutions, its stereoisomer or pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a drug for treating a disease related to KIF18A.
  • the above-mentioned KIF18A-related diseases refer to triple-negative breast cancer, ovarian cancer or colorectal cancer.
  • the fourth aspect of the present invention also provides a method for treating a disease associated with KIF18A in a subject in need thereof, comprising providing the subject with an effective dose of the compound defined in any of the above technical solutions, its stereoisomer or its pharmaceutically acceptable salt or pharmaceutical composition.
  • the present invention also provides the following biological testing method:
  • RPMI 1640 medium was purchased from VivaCell, fetal bovine serum was purchased from ExCell, and penicillin-streptomycin solution was purchased from Giboco.
  • Cell-Titer Glo reagent was purchased from Promega (1 kit, catalog number G7573). Plate reader: Envision (PerkinElmer).
  • the cells in the logarithmic growth phase were harvested and counted using a platelet counter.
  • the cell viability was detected by trypan blue exclusion method to ensure that the cell viability was above 90%, and the cell concentration was adjusted; the cells in the 96-well plate were cultured overnight at 37°C, 5% CO 2 , and 95% humidity, and the drug solution was prepared.
  • the drug solution was added to the 96-well plate inoculated with cells, and the cells in the 96-well plate with the drug added were cultured for 96 hours at 37°C, 5% CO 2 , and 95% humidity.
  • Cell activity was detected by CellTiter-Glo luminescence method, and the corresponding fluorescence value RLU per well was obtained by SpectraMax Paradigm reading.
  • Inhibition Rate (Inh%) 100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100%. Then, the inhibition rate curve was plotted using GraphPad Prism software and the IC 50 value was calculated.
  • the compounds of the present invention have strong anti-proliferation activity against NIH:OVCAR3 cells.
  • the compound of the present invention has strong KIF18A inhibitory activity, and its antiproliferative activity (IC 50 ) value on NIH:OVCAR3 cells is 0 ⁇ 100nmol, preferably 0 ⁇ 60nmol, more preferably 0.1 ⁇ 40nmol, further preferably 0.1 ⁇ 20nmol, most preferably 0.1 ⁇ 10nmol.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.
  • salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, 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. All of these isomers and their mixtures are included within the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of one another.
  • cis-trans isomers or “geometric isomers” arises from the inability of a double bond or single bond forming a ring carbon atom to rotate freely.
  • diastereomer refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
  • the key is a solid wedge. and dotted wedge key
  • a straight solid bond To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key
  • a wavy line Denotes a solid wedge bond or dotted wedge key
  • use a wavy line Represents a straight solid bond or straight dashed key
  • tautomer or “tautomeric form” refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved.
  • proton tautomers also called prototropic tautomers
  • Valence tautomers include interconversions via reorganization of some of the bonding electrons.
  • keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “enriched in one isomer”, “isomerically enriched”, “enriched in one enantiomer” or “enantiomerically enriched” mean that the content of one isomer or enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or greater than or equal to 96%, or greater than or equal to 97%, or greater than or equal to 98%, or greater than or equal to 99%, or greater than or equal to 99.5%, or greater than or equal to 99.6%, or greater than or equal to 99.7%, or greater than or equal to 99.8%, or greater than or equal to 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.
  • Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered.
  • the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).
  • the compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound.
  • the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ).
  • deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • any variable e.g., R
  • its definition at each occurrence is independent.
  • the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • 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 listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
  • linking group L When the linking group is listed without specifying its linking direction, its linking direction is arbitrary, for example,
  • the connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, substituents, and/or variations thereof are permissible only if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds to become a group with a corresponding valence.
  • the chemical bond connecting the site to other groups can be a straight solid bond.
  • the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.
  • C 1-3 alkyl is used to represent a straight 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 polyvalent (such as methine).
  • Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.
  • C 5-8 cycloalkenyl means a partially unsaturated cyclic hydrocarbon group consisting of 5 to 8 carbon atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings, and any ring of this system is non-aromatic.
  • the C 5-8 cycloalkenyl includes C 5-6 , C 5-7 , C 6-7 , C 6-8 , C 7-8 , C 5 , C 6 , C 7 or C 8 cycloalkenyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 5-8 cycloalkenyl include, but are not limited to, cyclohexenyl, cyclohexadienyl, wait.
  • C 3-8 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings.
  • the C 3-8 cycloalkyl includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent.
  • Examples of C 3-8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, etc.
  • the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), and the carbon atoms may be optionally oxidized (i.e., CO). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings.
  • heteroatoms may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule.
  • the 3-8 membered heterocycloalkyl includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 5-7 membered, 5-8 membered, 4 membered, 5 membered, 6 membered, 7 membered and 8 membered heterocycloalkyl, etc.
  • 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dimethoxybenzene ...
  • the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), and the carbon atom may be optionally oxidized (i.e., CO). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings.
  • heteroatoms may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule.
  • the 5-6 membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyl.
  • 5-6 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydro
  • the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), and the carbon atoms may be optionally oxidized (i.e., CO).
  • the bicyclic ring system includes spirocyclic, paracyclic and bridged rings, and any ring of this system is non-aromatic.
  • heteroatoms may occupy the connection position of the heterocycloalkenyl group to the rest of the molecule.
  • the 5-6 membered heterocycloalkenyl group includes 5-membered and 6-membered heterocycloalkenyl groups, etc. Examples of 5-6 membered heterocycloalkenyl groups include, but are not limited to
  • 5-6 membered heteroaromatic ring and “5-6 membered heteroaryl” are used interchangeably.
  • the term “5-6 membered heteroaryl” refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated ⁇ electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms.
  • the nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl.
  • Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl 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), 1-H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-
  • Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9 , C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 .
  • n-membered to n+m-membered means that the number of atoms in the ring is n to n+m
  • 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and 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.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction).
  • a substitution reaction e.g., a nucleophilic substitution reaction.
  • representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.
  • alkyl groups such as methyl, ethyl and tert-butyl
  • acyl groups such as alkanoyl (e.g., acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (
  • supercritical fluid chromatography for example, supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 ⁇ m); mobile phase: [0.1% ammonia-ethanol]; ethanol%: 48%-78%, 7 min, where 7 min refers to the time required for the ethanol concentration to increase from 48% to 78%.
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
  • 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 relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art.
  • single crystal X-ray diffraction (SXRD) is used to determine the absolute configuration of the compounds.
  • the single crystal was collected using a Bruker D8venture diffractometer to collect diffraction intensity data.
  • the light source was CuK ⁇ radiation and the scanning mode was ⁇ / ⁇ scanning.
  • the crystal structure was further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.
  • the solvent used in the present invention can be obtained commercially.
  • the present invention uses the following abbreviations: FA represents formic acid; HBr represents hydrogen bromide; HPLC represents high performance liquid chromatography; Xphos represents 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl; PDDF represents 1,1′-bis(diphenylphosphino)ferrocene; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd(OAc) 2 represents palladium acetate; Pd(dba) 2 represents bis(dibenzylideneacetone)palladium; Pd(dppf)Cl 2 represents [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium; PE represents petroleum ether; EA represents ethyl acetate; DMF represents N,N-di
  • bromoacetaldehyde diethyl acetal (19.57 g, 99.28 mmol) and 48% HBr aqueous solution (79.24 g, 470.07 mmol) were added to a solution of compound 1B (4.85 g, 16.55 mmol) in ethanol (40 ml) . After the addition was completed, the temperature was raised to 100 ° C and stirred for 30 minutes to terminate the reaction.
  • tert-butyl carbamate 2.2 g, 18.92 mmol
  • XPhos 601.28 mg, 1.26 mmol
  • Pd(OAc) 2 (283.17 mg, 1.26 mmol)
  • cesium carbonate 5.14 g, 15.77 mmol
  • Nitrogen was replaced 3-4 times, and the mixture was stirred at 110°C for 12 hours.
  • compound 1-3 29.57 mg, 236.32 ⁇ mol
  • potassium phosphate 75.24 mg, 354.48 ⁇ mol
  • cuprous iodide 22.50 mg, 118.16 ⁇ mol
  • trans-N,N-dimethylcyclohexyl-1,2-diamine 8.4 mg, 59.08 ⁇ mol
  • DMF 3 ml
  • Nitrogen was replaced 3-4 times, and the mixture was stirred at 100°C for 12 hours.
  • Purified water (20 ml) was added to the reaction solution, and ethyl acetate (20 ml x 2) was added for extraction.
  • PE:EA 50:1 to 10:1
  • bromoacetaldehyde diethyl acetal 14.50 g, 73.59 mmol was added to a solution of compound 2B (6.1 g, 24.53 mmol) in 1,4-dioxane (30 ml) and water (15 ml). After the addition was completed, the temperature was raised to 100°C and stirred for 12 hours. After the reaction was completed, the reaction solution was dried under reduced pressure, slurried with tetrahydrofuran (200 ml) for 1 hour, filtered, and the filter cake was dried to obtain compound 2C.
  • thionyl chloride (1.48 g, 12.44 mmol) and catalytic amount of DMF (1 drop) were added to compound 1-2 (1.11 g, 3.11 mmol) in dichloromethane (20 ml), and the mixture was stirred at 20-30°C for 0.5 hours.
  • dichloromethane (20 ml) and potassium phosphate (1.32 g, 6.21 mmol) were added to the crude product, and compound 2E (1.17 g, 3.11 mmol) and N,N-diisopropylethylamine (1.61 g, 12.43 mmol) were slowly added to the above solution, and stirred at 20-30°C for 12 hours.
  • compound 1-3 (114.07 mg, 911.51 ⁇ mol), potassium phosphate (290.23 mg, 1.37 mmol), cuprous iodide (86.8 mg, 455.76 ⁇ mol), trans-N,N-dimethylcyclohexyl-1,2-diamine (32.41 mg, 227.88 ⁇ mol) were added to a DMF (5 ml) solution of compound 2F (270 mg, 455.76 ⁇ mol). Nitrogen was replaced 3-4 times, and the mixture was stirred at 100°C for 12 hours. Purified water (150 ml) was added to the reaction solution, and ethyl acetate (100 ml) was added for extraction.
  • thionyl chloride (980.31 mg, 8.24 mmol) was added to a solution of compound 1-2 (735.80 mg, 2.06 mmol) in dichloromethane (10 ml), and the mixture was stirred at 26°C for 0.5 hours.
  • the mixture was concentrated under reduced pressure, dichloromethane (10 ml) and potassium phosphate (1.00 g, 4.72 mmol) were added to the crude product, and a solution of compound 3I (400 mg, 1.57 mmol) and N,N-diisopropylethylamine (610.01 mg, 4.72 mmol) in dichloromethane (3 ml) was slowly added to the above solution, and stirred at 20°C for 12 hours.
  • compound 1-3 126.54 mg, 1.01 mmol
  • potassium phosphate 321.94 mg, 1.52 mmol
  • cuprous iodide 96.28 mg, 505.55 micromol
  • trans-N,N-dimethylcyclohexyl-1,2-diamine 35.95 mg, 252.78 micromol
  • DMF 4 ml
  • Saturated brine (30 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml x 2).
  • thionyl chloride (2.46 g, 20.64 mmol) was added to a solution of compound 1-2 (1.84 g, 5.16 mmol) in dichloromethane (30 ml), and the mixture was stirred at 26°C for 0.5 hours.
  • dichloromethane (20 ml) and potassium phosphate (2.19 g, 10.32 mmol) were added to the crude product, and a solution of compound 4D (1 g, 3.44 mmol) and N,N-diisopropylethylamine (2.67 g, 20.64 mmol) in dichloromethane (5 ml) was slowly added to the above solution, and stirred at 26°C for 12 hours.
  • compound 1-3 126.54 mg, 1.01 mmol
  • potassium phosphate 321.94 mg, 1.52 mmol
  • cuprous iodide 96.28 mg, 505.55 mmol
  • trans-N,N-dimethylcyclohexyl-1,2-diamine 35.95 mg, 252.78 mmol
  • Nitrogen was replaced three times, and the mixture was stirred at 100°C for 12 hours.
  • Saturated brine (30 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml x 2).
  • bromoacetaldehyde diethyl acetal 39.30 g, 199.42 mmol
  • 48% HBr aqueous solution 59.60 g, 353.58 mmol
  • the temperature was raised to 100 ° C. and stirred for 30 minutes to complete the reaction.
  • saturated sodium hydroxide aqueous solution 100 ml was added to the reaction solution to quench, and ethyl acetate (200 ml) was used for extraction.
  • tert-butyl carbamate (2.43 g, 20.76 mmol), XPhos (1.32 g, 2.77 mmol), Pd(OAc) 2 (621.31 mg, 2.77 mmol) and cesium carbonate (11.27 g, 34.59 mmol) were added to a solution of compound 5B (4 g, 13.84 mmol) in 1,4-dioxane (50 ml) .
  • the nitrogen atmosphere was replaced 3-4 times, and the mixture was stirred at 110°C for 16 hours.
  • compound 1-3 (53.22 mg, 425.25 ⁇ mol), potassium phosphate (135.40 mg, 637.88 ⁇ mol), cuprous iodide (40.49 mg, 212.63 ⁇ mol), trans-N,N-dimethylcyclohexyl-1,2-diamine (15.12 mg, 106.31 ⁇ mol) were added to a DMF (3 ml) solution of compound 5E (0.12 g, 212.63 ⁇ mol). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 100°C for 12 hours. Water (20 ml) was added to the reaction solution, and ethyl acetate (20 ml x 3) was added for extraction.
  • tert-butyl carbamate (827.91 mg, 7.07 mmol), XPhos (449.21 mg, 942.28 ⁇ mol), Pd(OAc) 2 (211.55 mg, 942.28 ⁇ mol) and cesium carbonate (3.84 g, 11.78 mmol) were added to a solution of compound 6B (1.4 g, 4.71 mmol) in 1,4-dioxane (20 ml) . The nitrogen atmosphere was replaced three times, and the mixture was stirred at 110°C for 16 hours.
  • compound 1-3 (61.21 mg, 489.13 ⁇ mol), potassium phosphate (155.74 mg, 733.70 ⁇ mol), cuprous iodide (46.58 mg, 244.57 ⁇ mol), trans-N,N-dimethylcyclohexyl-1,2-diamine (17.39 mg, 122.28 ⁇ mol) were added to a DMF (4 ml) solution of compound 6E (140 mg, 244.57 ⁇ mol). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 100°C for 12 hours. Water (20 ml) was added to the reaction solution, and ethyl acetate (20 ml ⁇ 3) was added for extraction.
  • compound 1-3 75.80 mg, 605.68 ⁇ mol
  • potassium phosphate (192.85 mg, 908.51 ⁇ mol)
  • cuprous iodide 57.68 mg, 302.84 ⁇ mol
  • trans-N,N-dimethylcyclohexyl-1,2-diamine 21.54 mg, 151.42 ⁇ mol
  • the nitrogen atmosphere was replaced three times, and the mixture was stirred at 100°C for 12 hours.
  • Saturated brine (30 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml x 2).
  • tert-butyl carbamate (2.07 g, 17.67 mmol), XPhos (1.12 g, 2.36 mmol), Pd(OAc) 2 (528.80 mg, 2.36 mmol) and cesium carbonate (9.59 g, 29.44 mmol) were added to a solution of compound 8A (3.90 g, 11.78 mmol) in 1,4-dioxane (40 ml) .
  • the nitrogen atmosphere was replaced three times and the mixture was stirred at 110°C for 12 hours.
  • compound 1-3 (106.48 mg, 850.86 ⁇ mol), potassium phosphate (270.92 mg, 1.28 mmol), cuprous iodide (81.02 mg, 425.43 ⁇ mol), trans-N,N-dimethylcyclohexyl-1,2-diamine (30.26 mg, 2112.71 ⁇ mol) were added to a DMF (4 ml) solution of compound 8D (258 mg, 425.23 ⁇ mol). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 100°C for 12 hours. Saturated brine (30 ml) was added to the reaction solution, and extracted with ethyl acetate (30 ml x 2).
  • bromoacetaldehyde diethyl acetal (19.65 g, 99.71 mmol) and 48% HBr aqueous solution (29.80 g, 176.79 mmol) were added to a solution of compound 10A (4.8 g, 18.53 mmol) in ethanol (80 ml) and water (40 ml) .
  • the temperature was raised to 100 ° C and stirred for 30 minutes to terminate the reaction.
  • saturated sodium hydroxide aqueous solution (80 ml) was added to the reaction solution to quench, and ethyl acetate (100 ml) was used for extraction.
  • tert-butyl carbamate (1.80 g, 15.36 mmol)
  • XPhos (1 g, 2.10 mmol
  • Pd(OAc) 2 0.5 g, 2.23 mmol
  • cesium carbonate 8.6 g, 26.39 mmol
  • compound 1-3 (90 mg, 719.16 ⁇ mol), potassium phosphate (228 mg, 1.07 mmol), cuprous iodide (68 mg, 357.05 ⁇ mol), trans-N,N-dimethylcyclohexyl-1,2-diamine (26 mg, 182.79 ⁇ mol) were added to a DMF (4 ml) solution of compound 10E (0.2 g, 358.16 ⁇ mol). The nitrogen was replaced three times, and the mixture was stirred at 100°C for 12 hours. Water (20 ml) was added to the reaction solution, and ethyl acetate (20 ml ⁇ 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.
  • tert-butyl carbamate 910.34 mg, 7.77 mmol
  • XPhos 493.92 mg, 1.04 mmol
  • Pd(OAc) 2 232.61 mg, 1.04 mmol
  • cesium carbonate 4.22 g, 12.95 mmol
  • compound 1-3 (12.28 mg, 102.30 ⁇ mol), potassium phosphate (42.25 mg, 199.04 ⁇ mol), cuprous iodide (12.80 mg, 67.22 ⁇ mol), trans-N,N-dimethylcyclohexyl-1,2-diamine (5.12 mg, 36.00 ⁇ mol) were added to a DMF (2 ml) solution of compound 11H (40 mg, 66.29 ⁇ mol). Nitrogen was replaced three times, and the mixture was stirred at 100°C for 12 hours. Water (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml x 2).
  • compound 9-1 (592.21 mg, 3.03 mmol), potassium phosphate (965.82 mg, 4.55 mmol), cuprous iodide (288.85 mg, 1.52 mmol), and the reaction mixture were added to a solution of compound 4E (900 mg, 1.52 mmol) in DMF (4 ml).
  • the mixture was replaced with nitrogen three times and stirred at 100°C for 12 hours. Water (30 ml) was added to the reaction solution, and it was extracted with ethyl acetate (30 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated.
  • Potassium tert-butoxide (32.33 g, 288.13 mmol) was added to a solution of methyltriphenylphosphine iodide (116.47 g, 288.13 mmol) in dimethyl sulfoxide (450 ml), and the mixture was stirred at 25°C for 0.5 hours.
  • a solution of compound 13A (30 g, 192.09 mmol) in toluene (75 ml) was added dropwise to the above mixture at 0°C, and the reaction solution was stirred at 25°C for 4 hours.
  • RPMI 1640 medium was purchased from VivaCell, fetal bovine serum was purchased from ExCell, and penicillin-streptomycin solution was purchased from Giboco.
  • Cell-Titer Glo reagent was purchased from Promega (1 kit, catalog number G7573). Plate reader: Envision (PerkinElmer).
  • Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was detected using the trypan blue exclusion method to ensure that the cell viability was above 90%, and the cell concentration was adjusted; the cells in the 96-well plate were cultured overnight at 37°C, 5% CO 2 , and 95% humidity.
  • Prepare drug solution add drug solution to 96-well plate seeded with cells, place cells in 96-well plate with drug added at 37°C, 5% CO 2 , 95% humidity for 96 hours, detect cell activity by CellTiter-Glo luminescence method, and read SpectraMax Paradigm to obtain the corresponding fluorescence value RLU per well.
  • Inhibition Rate (Inh%) 100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100%. Then, use GraphPad Prism software to draw inhibition rate curve and calculate IC 50 value.
  • the compounds of the present invention have strong anti-proliferation activity against NIH:OVCAR3 cells.

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Abstract

Disclosed in the present invention are a class of sulfonamide compounds containing an ortho-fused heterocycle and the use thereof, and specifically disclosed is a compound of formula (II), a stereoisomer or a pharmaceutically acceptable salt thereof.

Description

一类含并杂环的磺酰胺类化合物及其应用A class of sulfonamide compounds containing heterocyclic rings and their application
本发明主张如下优先权The present invention claims the following priority
申请号：CN202211407231.5，申请日：2022年11月10日；Application number: CN202211407231.5, application date: November 10, 2022;
申请号：CN202310469318.3，申请日：2023年4月26日。Application number: CN202310469318.3, application date: April 26, 2023.
技术领域Technical Field
本发明涉及药物化学领域，具体涉及一类含并杂环的磺酰胺类化合物及其在制备治疗相关疾病的药物中的应用。The present invention relates to the field of pharmaceutical chemistry, and in particular to a class of sulfonamide compounds containing heterocyclic rings and applications thereof in preparing drugs for treating related diseases.
背景技术Background technique
细胞周期调控改变及染色体不稳定是许多人类恶性肿瘤的常见特征。有丝分裂酶作为肿瘤治疗靶标，临床应用广泛，很多抗有丝分裂药物得到临床应用，如微管靶向剂，可以稳定微管或阻止微管组装。微管是有丝分裂纺锤体的重要组成部分，这些药物对微管动力学的破坏导致有丝分裂停滞和癌细胞生长的抑制。尽管微管靶向剂被广泛用作治疗多种癌症的标准疗法，但由于对正常细胞的损害，这些药物具有显着的毒性，包括骨髓抑制和神经毒性。因此，开发新型的有丝分裂酶作为治疗靶标，阻止癌细胞增殖，提高安全性，具有重要意义。Altered cell cycle regulation and chromosomal instability are common features of many human malignancies. Mitotic enzymes are widely used clinically as targets for tumor therapy, and many anti-mitotic drugs are clinically used, such as microtubule-targeting agents, which can stabilize microtubules or prevent microtubule assembly. Microtubules are an important component of the mitotic spindle, and the disruption of microtubule dynamics by these drugs leads to mitotic arrest and inhibition of cancer cell growth. Although microtubule-targeting agents are widely used as standard therapies for the treatment of a variety of cancers, these drugs have significant toxicity, including bone marrow suppression and neurotoxicity, due to damage to normal cells. Therefore, it is of great significance to develop new mitotic enzymes as therapeutic targets to prevent cancer cell proliferation and improve safety.
驱动蛋白是有丝分裂酶的一种，在纺锤体的组装、染色体的分离、中心粒分离等动力学过程中发挥重要角色。有丝分裂驱动蛋白是利用ATP水解，沿微管细丝定向移动并协调适当的双极纺锤体形成、染色体排列和分离的运动蛋白。其中有丝分裂驱动蛋白Eg5和CENP-E的抑制剂在临床治疗效果不显著，且具有靶点机制毒性。Kinesin is a type of mitotic enzyme that plays an important role in the dynamics of spindle assembly, chromosome separation, centriole separation, etc. Mitotic kinesin is a motor protein that uses ATP hydrolysis to move along microtubule filaments and coordinate proper bipolar spindle formation, chromosome alignment and separation. Among them, inhibitors of mitotic kinesin Eg5 and CENP-E have no significant clinical therapeutic effects and have target mechanism toxicity.
KIF18A(kinesin-like protein 18A)是一种在细胞周期的G2/M期表达的驱动蛋白，是驱动蛋白kinesin-8家族中的一员。在细胞分裂中期，主要调控染色体定位及纺锤体长度。KIF18A被认为通过影响着丝点微管正端的动力学来控制染色体定位和纺锤体的张力。KIF18A缺失会导致纺锤体变长、染色体错位和有丝分裂检查点的激活，它的过表达导致多极纺锤体的形成。KIF18A在多种肿瘤中过表达，如乳腺癌、卵巢癌、结肠癌等；与肿瘤级别及转移程度相关。细胞周期调控异常及染色体不稳定是实体瘤的常见特征，染色体不稳定细胞对抗有丝分裂治疗更加敏感。在染色体不稳定癌细胞中，KIF18A敲低与细胞分裂受损具有相关性(包括纺锤体组装检查点激活、多极纺锤体形成，诱导细胞凋亡)，但不影响正常细胞及正常染色体组型癌细胞的分裂。临床前研究显示，染色体不稳定细胞中微管动力学的改变使其特别依赖KIF18A来减少着丝粒-微管的周转及限制微管的生长。在缺乏KIF18A活性的情况下，染色体不稳定细胞中着丝粒-微管附着和中心体完整性的维持受到损害，随后导致有丝分裂阻滞和中心体碎裂的延长，从而抑制细胞增殖。KIF18A (kinesin-like protein 18A) is a kinesin expressed in the G2/M phase of the cell cycle and is a member of the kinesin-8 family of kinesins. In metaphase of cell division, it mainly regulates chromosome positioning and spindle length. KIF18A is believed to control chromosome positioning and spindle tension by affecting the dynamics of the plus end of the centromere microtubules. KIF18A deficiency leads to spindle elongation, chromosome misalignment, and activation of mitotic checkpoints, and its overexpression leads to the formation of multipolar spindles. KIF18A is overexpressed in a variety of tumors, such as breast cancer, ovarian cancer, and colon cancer; it is associated with tumor grade and degree of metastasis. Abnormal cell cycle regulation and chromosomal instability are common characteristics of solid tumors, and chromosomally unstable cells are more sensitive to anti-mitotic treatment. In chromosomally unstable cancer cells, KIF18A knockdown is associated with impaired cell division (including activation of spindle assembly checkpoints, formation of multipolar spindles, and induction of cell apoptosis), but does not affect the division of normal cells and cancer cells with normal karyotypes. Preclinical studies have shown that altered microtubule dynamics in chromosomally unstable cells make them particularly dependent on KIF18A to reduce centromere-microtubule turnover and limit microtubule growth. In the absence of KIF18A activity, maintenance of centromere-microtubule attachment and centrosome integrity in chromosomally unstable cells is impaired, subsequently leading to prolonged mitotic arrest and centrosome fragmentation, thereby inhibiting cell proliferation.
KIF18A的小分子抑制剂能够有效地选择性靶向具有CIN特征的癌细胞，同时在很大程度上不影响正 常体细胞的分裂。因此，开发KIF18A小分子抑制剂对于癌症治疗，具有重要的研究意义。Small molecule inhibitors of KIF18A can effectively and selectively target cancer cells with CIN features while largely sparing normal Therefore, the development of KIF18A small molecule inhibitors is of great research significance for cancer treatment.
发明内容Summary of the invention
本发明一方面提供式(II)化合物、其立体异构体或其药学上可接受的盐，
In one aspect, the present invention provides a compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
其中，in,
环B选自5-6元杂环烷基、5-6元杂环烯基和5-6元杂环芳基，所述5-6元杂环烷基、5-6元杂环烯基和5-6元杂环芳基分别独立地任选被1或2个Ra取代；Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl, wherein the 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl are each independently optionally substituted by 1 or 2 R a ;
环A选自C3-8环烷基和3-8元杂环烷基，所述C3-8环烷基和3-8元杂环烷基分别独立地任选被1、2、3或4个Rb取代；Ring A is selected from C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, and the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b ;
T1和T2各自独立选自N、C和CH； T1 and T2 are each independently selected from N, C and CH;
X1、X2和X3各自独立选自N和CRc；X 1 , X 2 and X 3 are each independently selected from N and CR c ;
R1、R2、R3和R4分别独立地选自H、F、Cl、Br、OH、NH2、CN、C1-3烷基和OC1-3烷基，其中所述C1-3烷基和OC1-3烷基分别独立地任选被1、2和3个R取代；R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl and OC 1-3 alkyl, wherein the C 1-3 alkyl and OC 1-3 alkyl are independently optionally substituted with 1, 2 and 3 R, respectively;
R5选自5-8元杂环烷基和C5-8元环烯基，所述5-8元杂环烷基和C5-8元环烯基分别独立地任选被1、2、3或4个Rd取代；R 5 is selected from 5-8 membered heterocycloalkyl and C 5-8 membered cycloalkenyl, wherein the 5-8 membered heterocycloalkyl and C 5-8 membered cycloalkenyl are each independently optionally substituted by 1, 2, 3 or 4 R d ;
Ra、Rb、Rc和Rd分别独立地选自H、F、Cl、Br、OH、NH2、CN、C1-3烷基和OC1-3烷基，其中所述C1-3烷基和OC1-3烷基分别独立地任选被1、2和3个R取代； Ra , Rb , Rc and Rd are independently selected from H, F, Cl, Br, OH, NH2, CN, C1-3 alkyl and OC1-3 alkyl, wherein the C1-3 alkyl and OC1-3 alkyl are independently optionally substituted with 1 , 2 and 3 Rs, respectively;
R选自H、F、Cl、Br、OH、NH2和CN。R is selected from H, F, Cl, Br, OH, NH2 and CN.
本发明还提供式(II-1)化合物、其立体异构体或其药学上可接受的盐，
The present invention also provides a compound of formula (II-1), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
其中，in,
环B选自5-6元杂环烷基、5-6元杂环烯基和5-6元杂环芳基，所述5-6元杂环烷基、5-6元杂环烯基和5-6元杂环芳基分别独立地任选被1或2个Ra取代；Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl, wherein the 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl are each independently optionally substituted by 1 or 2 R a ;
环A选自C3-8环烷基和3-8元杂环烷基，所述C3-8环烷基和3-8元杂环烷基分别独立地任选被1、2、3或4个Rb取代；Ring A is selected from C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, and the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b ;
T1和T2各自独立选自N、C和CH； T1 and T2 are each independently selected from N, C and CH;
X1、X2和X3各自独立选自N和CRc；X 1 , X 2 and X 3 are each independently selected from N and CR c ;
R1、R2、R3和R4分别独立地选自H、F、Cl、Br、OH、NH2、CN、C1-3烷基和OC1-3烷基，其中所述C1-3烷基和OC1-3烷基分别独立地任选被1、2和3个R取代；R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl and OC 1-3 alkyl, wherein the C 1-3 alkyl and OC 1-3 alkyl are independently optionally substituted with 1, 2 and 3 R, respectively;
Ra、Rb和Rc分别独立地选自H、F、Cl、Br、OH、NH2、CN、C1-3烷基和OC1-3烷基，其中所述C1-3烷基和OC1-3烷基分别独立地任选被1、2和3个R取代； Ra , Rb and Rc are independently selected from H, F, Cl, Br, OH, NH2 , CN, C1-3 alkyl and OC1-3 alkyl, wherein the C1-3 alkyl and OC1-3 alkyl are independently optionally substituted with 1, 2 and 3 Rs, respectively;
R选自H、F、Cl、Br、OH、NH2和CN。R is selected from H, F, Cl, Br, OH, NH2 and CN.
本发明还提供式(I)化合物、其立体异构体或其药学上可接受的盐，
The present invention also provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
其中，in,
环B选自5-6元杂环烷基、5-6元杂环烯基和5-6元杂环芳基，所述5-6元杂环烷基、5-6元杂环烯基和5- 6元杂环芳基任选被1或2个Ra取代；Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocyclic aryl, wherein the 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocyclic aryl are selected from The 6-membered heteroaryl group is optionally substituted by 1 or 2 R a ;
环A选自C3-8环烷基和3-8元杂环烷基，所述C3-8环烷基和3-8元杂环烷基任选被1、2、3或4个Rb取代；Ring A is selected from C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, wherein the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are optionally substituted by 1, 2, 3 or 4 R b ;
T1和T2各自独立选自N、C和CH； T1 and T2 are each independently selected from N, C and CH;
X1、X2和X3各自独立选自N和CRc；X 1 , X 2 and X 3 are each independently selected from N and CR c ;
R1、R2、R3和R4分别独立地选自H、F、Cl、Br、OH、NH2、CN、C1-3烷基和OC1-3烷基，其中所述C1-3烷基和OC1-3烷基任选被1、2和3个R取代；R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl and OC 1-3 alkyl, wherein the C 1-3 alkyl and OC 1-3 alkyl are optionally substituted with 1, 2 and 3 R;
Ra、Rb和Rc分别独立地选自H、F、Cl、Br、OH、NH2、CN、C1-3烷基和OC1-3烷基，其中所述C1-3烷基和OC1-3烷基任选被1、2和3个R取代； Ra , Rb and Rc are independently selected from H, F, Cl, Br, OH, NH2 , CN, C1-3 alkyl and OC1-3 alkyl, wherein the C1-3 alkyl and OC1-3 alkyl are optionally substituted with 1, 2 and 3 R;
R选自H、F、Cl、Br、OH、NH2和CN。R is selected from H, F, Cl, Br, OH, NH2 and CN.
在本发明的一些技术方案中，其中，上述各Ra独立地选自H、F和CH3，其他变量如本发明所定义。In some technical solutions of the present invention, each of the above Ra is independently selected from H, F and CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述各Rb独立地选自H、F和CH3，其他变量如本发明所定义。In some technical solutions of the present invention, each R b is independently selected from H, F and CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述各Rc独立地选自H、F和CH3，其他变量如本发明所定义。In some technical solutions of the present invention, each R c is independently selected from H, F and CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述各Rd独立地选自H、F和CH3，其他变量如本发明所定义。In some technical solutions of the present invention, each of the above R d is independently selected from H, F and CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R1、R2、R3和R4分别独立地选自H和CH3，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 1 , R 2 , R 3 and R 4 are independently selected from H and CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R1选自H和CH3，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 1 is selected from H and CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R1选自H，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 1 is selected from H, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R1选自CH3，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 1 is selected from CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R2选自H和CH3，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 2 is selected from H and CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R2选自H，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 2 is selected from H, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R2选自CH3，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 2 is selected from CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R3选自H和CH3，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 3 is selected from H and CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R3选自H，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 3 is selected from H, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R3选自CH3，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 3 is selected from CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R4选自H和CH3，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 4 is selected from H and CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R4选自H，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 4 is selected from H, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R4选自CH3，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 4 is selected from CH 3 , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R5选自5-8元杂环烷基，所述5-8元杂环烷基任选被1、2、3或4个Rd取代，其他变量如本发明所定义。 In some technical schemes of the present invention, wherein the above R 5 is selected from 5-8 membered heterocycloalkyl, the 5-8 membered heterocycloalkyl is optionally substituted by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R5选自C5-8元环烯基，所述C5-8元环烯基任选被1、2、3或4个Rd取代，其他变量如本发明所定义。In some technical schemes of the present invention, wherein the above R 5 is selected from C 5-8 membered cycloalkenyl, the C 5-8 membered cycloalkenyl is optionally substituted by 1, 2, 3 or 4 R d , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述R5选自所述分别独立地任选被1、2、3或4个Rd取代，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 5 is selected from Said are each independently optionally substituted with 1, 2, 3 or 4 R d , and other variables are as defined herein.
在本发明的一些技术方案中，其中，上述R5选自所述分别独立地任选被1、2、3或4个Rd取代，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 5 is selected from Said are each independently optionally substituted with 1, 2, 3 or 4 R d , and other variables are as defined herein.
在本发明的一些技术方案中，其中，上述R5选自其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above R 5 is selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述T1选自N，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above T1 is selected from N, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述T1选自C，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above T1 is selected from C, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述T1选自CH，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above T1 is selected from CH, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述T2选自N，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above T 2 is selected from N, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述T2选自C，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above T 2 is selected from C, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述T2选自CH，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above T 2 is selected from CH, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述X1选自N，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above X1 is selected from N, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述X1选自CRc，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above X 1 is selected from CR c , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述X2选自N，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above X2 is selected from N, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述X2选自CRc，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above X 2 is selected from CR c , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述X3选自N，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above X 3 is selected from N, and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述X3选自CRc，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the above X 3 is selected from CR c , and other variables are as defined in the present invention.
在本发明的一些技术方案中，上述环A选自 所述任选被1、2、3或4个Rb取代，其他变量如本发明所定义。In some technical solutions of the present invention, the ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
在本发明的一些技术方案中，上述环A选自 所述分别独立地任选被1、2、3或4个Rb取代，其他变量如本发明所定义。In some technical solutions of the present invention, the ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
在本发明的一些技术方案中，上述环A选自 所述 任选被1、2、3或4个Rb取代，其他变量如本发明所定义。In some technical solutions of the present invention, the ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
在本发明的一些技术方案中，上述环A选自 所述 任选被1、2、3或4个Rb取代，其他变量如本发明所定义。 In some technical solutions of the present invention, the ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
在本发明的一些技术方案中，上述环A选自 所述 分别独立地任选被1、2、3或4个Rb取代，其他变量如本发明所定义。In some technical solutions of the present invention, the ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
在本发明的一些技术方案中，上述环A选自所述 分别独立地任选被1、2、3或4个Rb取代，其他变量如本发明所定义。In some technical solutions of the present invention, the ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
在本发明的一些技术方案中，上述环A选自所述任选被1、2、3或4个Rb取代，其他变量如本发明所定义。In some technical solutions of the present invention, the ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
在本发明的一些技术方案中，其中，上述环A选自 所述任选被1、2、3或4个Rb取代，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the ring A is selected from Said Optionally substituted with 1, 2, 3 or 4 R b , and the other variables are as defined herein.
在本发明的一些技术方案中，其中，上述环A选自 所述 分别独立地任选被1、2、3或4个Rb取代，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
在本发明的一些技术方案中，其中，上述环A选自 所述 分别独立地任选被1、2、3或4个Rb取代，其他变量如本发明所定义。In some technical solutions of the present invention, wherein the ring A is selected from Said Rb is optionally substituted with 1, 2, 3 or 4 Rb, respectively, and the other variables are as defined herein.
在本发明的一些技术方案中，上述环A选自 其他变量如本发明所定义。In some technical solutions of the present invention, the ring A is selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，上述环A选自 其他变量如本发明所定义。In some technical solutions of the present invention, the ring A is selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述环A选自 其他变量如本发明所定义。In some technical solutions of the present invention, wherein the ring A is selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述环A选自 其他变量如本发明所定义。 In some technical solutions of the present invention, wherein the ring A is selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述环A选自其他变量如本发明所定义。In some technical solutions of the present invention, wherein the ring A is selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述环B选自5元杂芳基，所述5元杂芳基任选被1或2个Ra取代，其他变量如本发明所定义。In some technical solutions of the present invention, the ring B is selected from a 5-membered heteroaryl group, and the 5-membered heteroaryl group is optionally substituted by 1 or 2 Ras , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述环B选自6元杂芳基，所述6元杂芳基任选被1或2个Ra取代，其他变量如本发明所定义。In some technical solutions of the present invention, the above-mentioned ring B is selected from a 6-membered heteroaryl group, and the 6-membered heteroaryl group is optionally substituted by 1 or 2 Ras , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述环B选自5元杂芳烯基，所述5元杂芳烯基任选被1或2个Ra取代，其他变量如本发明所定义。In some technical solutions of the present invention, the ring B is selected from a 5-membered heteroaryl alkenyl group, the 5-membered heteroaryl alkenyl group is optionally substituted by 1 or 2 R a , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述环B选自6元杂芳烯基，所述6元杂芳烯基任选被1或2个Ra取代，其他变量如本发明所定义。In some technical solutions of the present invention, the ring B is selected from a 6-membered heteroaryl alkenyl group, the 6-membered heteroaryl alkenyl group is optionally substituted by 1 or 2 R a , and other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述结构单元选自 所述 分别独立地任选被1或2个Ra取代，其他变量如本发明所定义。In some technical solutions of the present invention, the above structural unit Selected from Said are each independently optionally substituted by 1 or 2 Ra , and other variables are as defined herein.
在本发明的一些技术方案中，其中，上述结构单元选自 其他变量如本发明所定义。In some technical solutions of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述结构单元选自 其他变量如本发明所定义。In some technical solutions of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述结构单元选自 其他变量如本发明所定义。In some technical solutions of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述结构单元选自 其他变量如本发明所定义。In some technical solutions of the present invention, the above structural unit Selected from Other variables are as defined in the present invention.
在本发明的一些技术方案中，其中，上述化合物选自式(I-A)，(I-B)，(I-C)，(I-D)和(II-A)
In some technical solutions of the present invention, the above compound is selected from formula (IA), (IB), (IC), (ID) and (II-A)
其他变量如本发明所定义。Other variables are as defined in the present invention.
本发明还有一些技术方案由上述变量自由组合而来。Some other technical solutions of the present invention are obtained by freely combining the above variables.
本发明提供如下化合物、其立体异构体或其药学上可接受的盐，


The present invention provides the following compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof,


本发明第二方面提供一种药物组合物，所述药物组合物包含有效剂量的上述任意技术方案限定的化合物、其立体异构体或其药学上可接受的盐和药学上可接受的载体。The second aspect of the present invention provides a pharmaceutical composition, which comprises an effective dose of the compound defined in any of the above technical solutions, its stereoisomers or pharmaceutically acceptable salts thereof and a pharmaceutically acceptable carrier.
本发明第三方面提供上述任意技术方案限定的化合物、其立体异构体或其药学上可接受的盐或药物组合物在制备治疗与KIF18A相关疾病的药物中的应用。The third aspect of the present invention provides the use of the compound defined in any of the above technical solutions, its stereoisomer or pharmaceutically acceptable salt or pharmaceutical composition in the preparation of a drug for treating a disease related to KIF18A.
在本发明的一些技术方案中，上述与KIF18A相关疾病是指三阴性乳腺癌、卵巢癌或结直肠癌。In some technical schemes of the present invention, the above-mentioned KIF18A-related diseases refer to triple-negative breast cancer, ovarian cancer or colorectal cancer.
本发明第四方面还提供一种在需要的受试者中治疗与KIF18A相关的疾病的方法，包括向受试者提供有效剂量的上述任意技术方案所限定的化合物、其立体异构体或其药学上可接受的盐或药物组合物。The fourth aspect of the present invention also provides a method for treating a disease associated with KIF18A in a subject in need thereof, comprising providing the subject with an effective dose of the compound defined in any of the above technical solutions, its stereoisomer or its pharmaceutically acceptable salt or pharmaceutical composition.
本发明还提供如下生物测试方法：The present invention also provides the following biological testing method:
测试例1：NIH:OVCAR3细胞的抗增殖活性测试Test Example 1: Antiproliferative Activity Test of NIH:OVCAR3 Cells
实验材料：Experimental Materials:
RPMI 1640培养基购自VivaCell，胎牛血清购自ExCell，青霉素-链霉素溶液购自Giboco。Cell-Titer Glo reagent购自Promega(1kit，货号G7573)。读板仪器：Envision(PerkinElmer)。RPMI 1640 medium was purchased from VivaCell, fetal bovine serum was purchased from ExCell, and penicillin-streptomycin solution was purchased from Giboco. Cell-Titer Glo reagent was purchased from Promega (1 kit, catalog number G7573). Plate reader: Envision (PerkinElmer).
实验方法：experimental method:
收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上，调整细胞浓度；将96孔板中的细胞置于37℃、5％CO2、95％湿度条件下培养过夜，配制药物溶液，在接种有细胞的96孔板中加入药物溶液，将已加药的96孔板中的细胞置于37℃、5％CO2、95％湿度条件下继续培养96小时，CellTiter-Glo发光法细胞活性检测，SpectraMax Paradigm读数得出对应的每孔荧光值RLU。细胞增殖抑制率数据采用下列公式来处理：Inhibition Rate(Inh％)＝100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100％。然后用GraphPad Prism软件作抑制率曲线图并计算IC50值。The cells in the logarithmic growth phase were harvested and counted using a platelet counter. The cell viability was detected by trypan blue exclusion method to ensure that the cell viability was above 90%, and the cell concentration was adjusted; the cells in the 96-well plate were cultured overnight at 37°C, 5% CO 2 , and 95% humidity, and the drug solution was prepared. The drug solution was added to the 96-well plate inoculated with cells, and the cells in the 96-well plate with the drug added were cultured for 96 hours at 37°C, 5% CO 2 , and 95% humidity. Cell activity was detected by CellTiter-Glo luminescence method, and the corresponding fluorescence value RLU per well was obtained by SpectraMax Paradigm reading. The cell proliferation inhibition rate data were processed using the following formula: Inhibition Rate (Inh%) = 100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100%. Then, the inhibition rate curve was plotted using GraphPad Prism software and the IC 50 value was calculated.
实验结论：本发明化合物对NIH:OVCAR3细胞均具有较强的抗增殖活性。Experimental conclusion: The compounds of the present invention have strong anti-proliferation activity against NIH:OVCAR3 cells.
技术效果Technical Effects
本发明化合物具有较强的KIF18A抑制活性，其对NIH:OVCAR3细胞的抗增殖活性(IC50)值为0 ～100nmol，优选为0～60nmol，更有选为0.1～40nmol，再优选为0.1～20nmol，最优选为0.1～10nmol。The compound of the present invention has strong KIF18A inhibitory activity, and its antiproliferative activity (IC 50 ) value on NIH:OVCAR3 cells is 0 ～100nmol, preferably 0～60nmol, more preferably 0.1～40nmol, further preferably 0.1～20nmol, most preferably 0.1～10nmol.
定义与说明Definition and Explanation
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。Unless otherwise specified, the following terms and phrases used herein are intended to have the following meanings. A particular term or phrase should not be considered to be uncertain or unclear in the absence of a special definition, but should be understood according to its ordinary meaning. When a trade name appears in this article, it is intended to refer to its corresponding commercial product or its active ingredient.
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。The term "pharmaceutically acceptable" as used herein refers to those compounds, materials, compositions and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response or other problems or complications, commensurate with a reasonable benefit/risk ratio.
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物接触的方式获得碱加成盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。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 salts of the compounds of the present invention, prepared from compounds with specific substituents discovered by the present invention and relatively non-toxic acids or bases. When the compounds of the present invention contain relatively acidic functional groups, base addition salts can be obtained by contacting such compounds with a sufficient amount of base in a pure solution or a suitable inert solvent. When the compounds of the present invention contain relatively basic functional groups, acid addition salts can be obtained by contacting such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent. Certain specific compounds of the present invention contain basic and acidic functional groups and can be converted into either base or acid addition salts.
本发明的药学上可接受的盐可由含有酸根或碱基的母体化合物通过常规化学方法合成。一般情况下，这样的盐的制备方法是：在水或有机溶剂或两者的混合物中，经由游离酸或碱形式的这些化合物与化学计量的适当的碱或酸反应来制备。Pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid radicals or bases. Generally, the preparation method of such salts is: in water or an organic solvent or a mixture of the two, these compounds in free acid or base form are reacted with a stoichiometric amount of an appropriate base or acid to prepare.
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。The compounds of the present invention may exist in specific geometric or stereoisomeric forms. The present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers, (D)-isomers, (L)-isomers, and racemic mixtures and other mixtures thereof, 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. All of these isomers and their mixtures are included within the scope of the present invention.
除非另有说明，术语“对映异构体”或者“旋光异构体”是指互为镜像关系的立体异构体。Unless otherwise indicated, the term "enantiomer" or "optical isomer" refers to stereoisomers that are mirror images of one another.
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 indicated, the term "cis-trans isomers" or "geometric isomers" arises from the inability of a double bond or single bond forming a ring carbon atom to rotate freely.
除非另有说明，术语“非对映异构体”是指分子具有两个或多个手性中心，并且分子间为非镜像的关系的立体异构体。Unless otherwise indicated, the term "diastereomer" refers to stereoisomers that have two or more chiral centers and that are not mirror images of each other.
除非另有说明，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。Unless otherwise indicated, "(+)" indicates dextrorotatory, "(-)" indicates levorotatory, and "(±)" indicates racemic.
除非另有说明，用楔形实线键和楔形虚线键表示一个立体中心的绝对构型，用直形实线键和直形虚线键表示立体中心的相对构型，用波浪线表示楔形实线键 或楔形虚线键或用波浪线表示直形实线键或直形虚线键 Unless otherwise specified, the key is a solid wedge. and dotted wedge key To indicate the absolute configuration of a stereocenter, use a straight solid bond. and straight dashed key To indicate the relative configuration of a stereocenter, use a wavy line Denotes a solid wedge bond or dotted wedge key Or use a wavy line Represents a straight solid bond or straight dashed key
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。Unless otherwise indicated, the term "tautomer" or "tautomeric form" refers to isomers of different functional groups that are in dynamic equilibrium at room temperature and can readily interconvert. If tautomerism is possible (such as in solution), chemical equilibrium of the tautomers can be achieved. For example, proton tautomers (also called prototropic tautomers) include interconversions via proton migration, such as keto-enol isomerization and imine-enamine isomerization. Valence tautomers include interconversions via reorganization of some of the bonding electrons. A specific example of keto-enol tautomerism is the interconversion between pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
除非另有说明，术语“富含一种异构体”、“异构体富集”、“富含一种对映体”或者“对映体富集”指其中一种异构体或对映体的含量小于100％，并且，该异构体或对映体的含量大于等于60％，或者大于等于70％，或者大于等于80％，或者大于等于90％，或者大于等于95％，或者大于等于96％，或者大于等于97％，或者大于等于98％，或者大于等于99％，或者大于等于99.5％，或者大于等于99.6％，或者大于等于99.7％，或者大于等于99.8％，或者大于等于99.9％。Unless otherwise indicated, the terms "enriched in one isomer", "isomerically enriched", "enriched in one enantiomer" or "enantiomerically enriched" mean that the content of one isomer or 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 indicated, the term "isomer excess" or "enantiomeric excess" refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90% and the content of the other isomer or enantiomer is 10%, the isomer or enantiomeric excess (ee value) is 80%.
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。Optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide the pure desired enantiomer. Alternatively, when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), a diastereomeric salt is formed with an appropriate optically active acid or base, and then the diastereoisomers are separated by conventional methods known in the art, and then the pure enantiomer is recovered. In addition, the separation of enantiomers and diastereomers is usually accomplished by using chromatography, which uses a chiral stationary phase and is optionally combined with a chemical derivatization method (for example, a carbamate is generated from an amine).
本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚(3H)，碘-125(125I)或C-14(14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。The compounds of the present invention may contain non-natural proportions of atomic isotopes on one or more atoms constituting the compound. For example, the compound may be labeled with a radioactive isotope, such as tritium ( 3H ), iodine-125 ( 125I ) or C-14 ( 14C ). For another example, deuterated drugs may be formed by replacing hydrogen with heavy hydrogen. The bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon. Compared with undeuterated drugs, deuterated drugs have the advantages of reducing toxic side effects, increasing drug stability, enhancing therapeutic effects, and extending the biological half-life of drugs. All isotopic composition changes of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。 The terms "optional" or "optionally" mean that the subsequently described event or circumstance may but need not occur, and that the description includes instances where said event or circumstance occurs and instances 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。The term "substituted" means that any one or more hydrogen atoms on a particular atom are replaced by a substituent, which may include deuterium and hydrogen variants, as long as the valence state of the particular atom is normal and the substituted compound is stable. When the substituent is oxygen (i.e., =O), it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
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 "optionally substituted" means that the group may be substituted or unsubstituted, and unless otherwise specified, the type and number of the substituents may be any on the basis of what is chemically feasible.
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 (e.g., R) occurs more than once in a compound's composition or structure, its definition at each occurrence is independent. Thus, for example, if a group is substituted with 0-2 Rs, the group may be optionally substituted with up to two Rs, and each occurrence of R is an independent choice. In addition, combinations of substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
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 it connects are directly connected. For example, when L in A-L-Z represents a single bond, it means that the structure is actually A-Z.
当一个取代基为空缺时，表示该取代基是不存在的，比如A-X中X为空缺时表示该结构实际上是A。当所列举的取代基中没有指明其通过哪一个原子连接到被取代的基团上时，这种取代基可以通过其任何原子相键合，例如，吡啶基作为取代基可以通过吡啶环上任意一个碳原子连接到被取代的基团上。When a substituent is vacant, it means that the substituent does not exist. For example, when X in A-X is vacant, it means that the structure is actually A. When the listed substituent does not specify which atom it is connected to the substituted group through, the substituent can be bonded through any atom of it. For example, pyridyl as a substituent can be connected to the substituted group through any carbon atom on the pyridine ring.
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，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 is listed without specifying its linking direction, its linking direction is arbitrary, for example, The connecting group L is -MW-, in which case -MW- can connect ring A and ring B in the same direction as the reading order from left to right to form You can also connect ring A and ring B in the opposite direction of the reading order from left to right to form Combinations of linkers, 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直形虚线键或波浪线表示。例如-OCH3中的直形实线键表示通过该基团中的氧原子与其他基团相连；中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连； 表示该哌啶基上的任意可连接位点可以通过1个化学键与其他基团相连，至少包括 这4种连接方式，即使-N-上画出了H原子，但是仍包括这种连接方式的基团，只是在连接1个化学键时，该位点的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 connectable sites, any one or more sites of the group can be connected to other groups through chemical bonds. When the chemical bond connection mode is non-positional and there are H atoms at the connectable sites, when the chemical bonds are connected, the number of H atoms at the site will decrease accordingly with the number of connected chemical bonds to become a group with a corresponding valence. The chemical bond connecting the site to other groups can be a straight solid bond. Straight dotted key or wavy line For example, the straight solid bond in -OCH 3 indicates that it is connected to other groups through the oxygen atom in the group; The straight dashed bond in the group indicates that the two ends of the nitrogen atom in the group are connected to other groups; The wavy line in the phenyl group indicates that it is connected to other groups through the carbon atoms at positions 1 and 2 in the phenyl group; It means that any connectable site on the piperidine group can be connected to other groups through one chemical bond, including at least These four connection methods, even if the H atom is drawn on -N-, Still includes For groups connected in this way, when one chemical bond is connected, the H at that site will be reduced by one and become a corresponding monovalent piperidine group.
除非另有规定，术语“C1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C1- 3烷基包括C1-2和C2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C1-3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。Unless otherwise specified, the term "C 1-3 alkyl" is used to represent a straight 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 polyvalent (such as methine). Examples of C 1-3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), etc.
除非另有规定，“C5-8环烯基”表示包含至少一个碳-碳双键的由5至8个碳原子组成的部分不饱和的环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。所述C5-8环烯基包括C5-6、C5-7、C6-7、C6-8、C7-8、C5、C6、C7或C8环烯基等；其可以是一价、二价或者多价。C5-8环烯基的实例包括但不限于，环己烯基、环己二烯基、等。Unless otherwise specified, "C 5-8 cycloalkenyl" means a partially unsaturated cyclic hydrocarbon group consisting of 5 to 8 carbon atoms containing at least one carbon-carbon double bond, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings, and any ring of this system is non-aromatic. The C 5-8 cycloalkenyl includes C 5-6 , C 5-7 , C 6-7 , C 6-8 , C 7-8 , C 5 , C 6 , C 7 or C 8 cycloalkenyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 5-8 cycloalkenyl include, but are not limited to, cyclohexenyl, cyclohexadienyl, wait.
除非另有规定，“C3-8环烷基”表示由3至8个碳原子组成的饱和环状碳氢基团，其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。所述C3-8环烷基包括C3-6、C3-5、C4-8、C4-6、C4-5、C5-8或C5-6环烷基等；其可以是一价、二价或者多价。C3-8环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基、环庚基、降冰片烷基等。Unless otherwise specified, "C 3-8 cycloalkyl" means a saturated cyclic hydrocarbon group consisting of 3 to 8 carbon atoms, including monocyclic and bicyclic systems, wherein the bicyclic system includes spirocyclic, fused and bridged rings. The C 3-8 cycloalkyl includes C 3-6 , C 3-5 , C 4-8 , C 4-6 , C 4-5 , C 5-8 or C 5-6 cycloalkyl, etc.; it can be monovalent, divalent or polyvalent. Examples of C 3-8 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, etc.
除非另有规定，术语“3-8元杂环烷基”本身或者与其他术语联合分别表示由3至8个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)，碳原子可任选被氧化(即CO)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“3-8元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述3-8元杂环烷基包括3-6元、3-5元、4-6元、5-6元、5-7元、5-8元、4元、5元、6元、7元和8元杂环烷基等。3-8元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二 噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基、高哌啶基或二氧杂环庚烷基、等。Unless otherwise specified, the term "3-8 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 3 to 8 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), and the carbon atoms may be optionally oxidized (i.e., CO). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings. In addition, with respect to the "3-8 membered heterocycloalkyl", heteroatoms may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 3-8 membered heterocycloalkyl includes 3-6 membered, 3-5 membered, 4-6 membered, 5-6 membered, 5-7 membered, 5-8 membered, 4 membered, 5 membered, 6 membered, 7 membered and 8 membered heterocycloalkyl, etc. Examples of 3-8 membered heterocycloalkyl groups include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dimethoxybenzene ... Thianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or dioxepanyl, wait.
除非另有规定，术语“5-6元杂环烷基”本身或者与其他术语联合分别表示由5至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O)p，p是1或2)，碳原子可任选被氧化(即CO)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“5-6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5-6元杂环烷基包括5元和6元杂环烷基。5-6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、六氢哒嗪基等。Unless otherwise specified, the term "5-6 membered heterocycloalkyl" by itself or in combination with other terms refers to a saturated cyclic group consisting of 5 to 6 ring atoms, 1, 2, 3 or 4 of which are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), and the carbon atom may be optionally oxidized (i.e., CO). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, fused and bridged rings. In addition, with respect to the "5-6 membered heterocycloalkyl", heteroatoms may occupy the position at which the heterocycloalkyl is connected to the rest of the molecule. The 5-6 membered heterocycloalkyl includes 5-membered and 6-membered heterocycloalkyl. Examples of 5-6 membered heterocycloalkyl groups include, but are not limited to, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothiophenyl (including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuranyl (including tetrahydrofuran-2-yl, etc.), tetrahydropyranyl, piperidinyl (including 1-piperidinyl, 2-piperidinyl and 3-piperidinyl, etc.), piperazinyl (including 1-piperazinyl and 2-piperazinyl, etc.), morpholinyl (including 3-morpholinyl and 4-morpholinyl, etc.), dioxanyl, dithianyl, isoxazolidinyl, isothiazolidinyl, 1,2-oxazinyl, 1,2-thiazinyl, hexahydropyridazinyl, etc.
除非另有规定，术语“5-6元杂环烯基”本身或者与其他术语联合分别表示包含至少一个碳-碳双键的由5至6个环原子组成的部分不饱和的环状基团，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)，碳原子可任选被氧化(即CO)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环，此体系的任意环都是非芳香性的。此外，就该“5-6元杂环烯基”而言，杂原子可以占据杂环烯基与分子其余部分的连接位置。所述5-6元杂环烯基包括5元和6元杂环烯基等。5-6元杂环烯基的实例包括但不限于 Unless otherwise specified, the term "5-6 membered heterocycloalkenyl" by itself or in combination with other terms refers to a partially unsaturated cyclic group consisting of 5 to 6 ring atoms containing at least one carbon-carbon double bond, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms, wherein the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may be optionally oxidized (i.e., NO and S(O) p , p is 1 or 2), and the carbon atoms may be optionally oxidized (i.e., CO). It includes monocyclic and bicyclic ring systems, wherein the bicyclic ring system includes spirocyclic, paracyclic and bridged rings, and any ring of this system is non-aromatic. In addition, with respect to the "5-6 membered heterocycloalkenyl", heteroatoms may occupy the connection position of the heterocycloalkenyl group to the rest of the molecule. The 5-6 membered heterocycloalkenyl group includes 5-membered and 6-membered heterocycloalkenyl groups, etc. Examples of 5-6 membered heterocycloalkenyl groups include, but are not limited to
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 heteroaromatic ring" and "5-6 membered heteroaryl" are used interchangeably. The term "5-6 membered heteroaryl" refers to a monocyclic group consisting of 5 to 6 ring atoms with a conjugated π electron system, wherein 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. The nitrogen atom is optionally quaternized, and the nitrogen and sulfur heteroatoms are optionally oxidized (i.e., NO and S(O) p , p is 1 or 2). The 5-6 membered heteroaryl can be connected to the rest of the molecule via a heteroatom or a carbon atom. The 5-6 membered heteroaryl includes 5-membered and 6-membered heteroaryl. Examples of the 5-6 membered heteroaryl group include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl 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), 1-H-1,2,4-triazolyl, etc.), tetrazolyl, isoxazolyl (3-isoxazolyl, 4-isoxazolyl and 5-isoxazolyl), thiazolyl (including 2-thiazolyl, 4-thiazolyl and 5-thiazolyl), furyl (including 2-furyl and 3-furyl), thienyl (including 2-thienyl and 3-thienyl), pyridyl (including 2-pyridyl, 3-pyridyl and 4-pyridyl), pyrazinyl or pyrimidinyl (including 2-pyrimidinyl and 4-pyrimidinyl).
除非另有规定，Cn-n+m或Cn-Cn+m包括n至n+m个碳的任何一种具体情况，例如C1-12包括C1、C2、C3、C4、C5、C6、C7、C8、C9、C10、C11、和C12，也包括n至n+m中的任何一个范围，例如C1-12包括C1- 3、C1-6、C1-9、C3-6、C3-9、C3-12、C6-9、C6-12、和C9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。Unless otherwise specified, Cn-n+m or Cn - Cn+m includes any specific case of n to n+m carbon atoms, for example, C1-12 includes C1 , C2 , C3 , C4 , C5 , C6 , C7 , C8 , C9 , C10 , C11 , and C12 , and also includes any range from n to n+m, for example, C1-12 includes C1-3 , C1-6 , C1-9 , C3-6 , C3-9 , C3-12 , C6-9 , C6-12 , and C13 . 9-12 , etc.; similarly, n-membered to n+m-membered means that the number of atoms in the ring is n to n+m, for example, 3-12-membered ring includes 3-membered ring, 4-membered ring, 5-membered ring, 6-membered ring, 7-membered ring, 8-membered ring, 9-membered ring, 10-membered ring, 11-membered ring, and 12-membered ring, and 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.
术语“离去基团”是指可以被另一种官能团或原子通过取代反应(例如亲核取代反应)所取代的官能团或原子。例如，代表性的离去基团包括三氟甲磺酸酯；氯、溴、碘；磺酸酯基，如甲磺酸酯、甲苯磺酸酯、对溴苯磺酸酯、对甲苯磺酸酯等；酰氧基，如乙酰氧基、三氟乙酰氧基等等。The term "leaving group" refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (e.g., a nucleophilic substitution reaction). For example, representative leaving groups include trifluoromethanesulfonate; chlorine, bromine, iodine; sulfonate groups, such as mesylate, tosylate, p-brosylate, p-toluenesulfonate, etc.; acyloxy groups, such as acetoxy, trifluoroacetoxy, etc.
术语“保护基”包括但不限于“氨基保护基”、“羟基保护基”或“巯基保护基”。术语“氨基保护基”是指适合用于阻止氨基氮位上副反应的保护基团。代表性的氨基保护基包括但不限于：甲酰基；酰基，例如链烷酰基(如乙酰基、三氯乙酰基或三氟乙酰基)；烷氧基羰基，如叔丁氧基羰基(Boc)；芳基甲氧羰基，如苄氧羰基(Cbz)和9-芴甲氧羰基(Fmoc)；芳基甲基，如苄基(Bn)、三苯甲基(Tr)、1,1-二-(4'-甲氧基苯基)甲基；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。术语“羟基保护基”是指适合用于阻止羟基副反应的保护基。代表性羟基保护基包括但不限于：烷基，如甲基、乙基和叔丁基；酰基，例如链烷酰基(如乙酰基)；芳基甲基，如苄基(Bn)，对甲氧基苄基(PMB)、9-芴基甲基(Fm)和二苯基甲基(二苯甲基，DPM)；甲硅烷基，如三甲基甲硅烷基(TMS)和叔丁基二甲基甲硅烷基(TBS)等等。The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for preventing side reactions at the amino nitrogen position. Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butyloxycarbonyl (Boc); arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-bis-(4'-methoxyphenyl)methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), etc. The term "hydroxy protecting group" refers to a protecting group suitable for preventing side reactions of the hydroxyl group. Representative hydroxy protecting groups include, but are not limited to, alkyl groups such as methyl, ethyl and tert-butyl; acyl groups such as alkanoyl (e.g., acetyl); arylmethyl groups such as benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS), and the like.
除非另有说明，超临界流体色谱的条件，例如，超临界流体色谱(色谱柱：DAICEL CHIRALPAK AS(250mm*30mm,10μm)；流动相:[0.1％氨水-乙醇]；乙醇％:48％-78％,7min，其中7min表示的是乙醇浓度从48％增加到78％所需要的时间。Unless otherwise stated, the conditions of supercritical fluid chromatography, for example, supercritical fluid chromatography (chromatographic column: DAICEL CHIRALPAK AS (250 mm*30 mm, 10 μm); mobile phase: [0.1% ammonia-ethanol]; ethanol%: 48%-78%, 7 min, where 7 min refers to the time required for the ethanol concentration to increase from 48% to 78%.
本发明的化合物可以通过本领域技术人员所熟知的多种合成方法来制备，包括下面列举的具体实施方式、其与其他化学合成方法的结合所形成的实施方式以及本领域技术上人员所熟知的等同替换方式，优选的实施方式包括但不限于本发明的实施例。The compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, embodiments formed by combining them with other chemical synthetic methods, and equivalent substitutions well known to those skilled in the art. Preferred embodiments include but are not limited to the examples of the present invention.
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养 出的单晶用Bruker D8venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：φ/ω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 relates to the absolute configuration of the compounds, the absolute configuration can be confirmed by conventional technical means in the art. For example, single crystal X-ray diffraction (SXRD) is used to determine the absolute configuration of the compounds. The single crystal was collected using a Bruker D8venture diffractometer to collect diffraction intensity data. The light source was CuKα radiation and the scanning mode was φ/ω scanning. After collecting the relevant data, the crystal structure was further analyzed using the direct method (Shelxs97) to confirm the absolute configuration.
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：FA代表甲酸；HBr代表溴化氢；HPLC代表高效液相色谱；Xphos代表2-二叔丁基膦-2′,4′,6′-三异丙基联苯；PDDF代表1,1'-双(二苯基膦)二茂铁；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；Pd(OAc)2代表醋酸钯；Pd(dba)2代表双(二亚芐基丙酮)钯；Pd(dppf)Cl2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；PE代表石油醚；EA代表乙酸乙酯；DMF代表N,N-二甲基甲酰胺。The solvent used in the present invention can be obtained commercially. The present invention uses the following abbreviations: FA represents formic acid; HBr represents hydrogen bromide; HPLC represents high performance liquid chromatography; Xphos represents 2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl; PDDF represents 1,1′-bis(diphenylphosphino)ferrocene; Xantphos represents 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; Pd(OAc) 2 represents palladium acetate; Pd(dba) 2 represents bis(dibenzylideneacetone)palladium; Pd(dppf)Cl 2 represents [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium; PE represents petroleum ether; EA represents ethyl acetate; DMF represents N,N-dimethylformamide.
化合物依据本领域常规命名原则或者使用软件命名，市售化合物采用供应商目录名称。Compounds are named according to the conventional nomenclature in the art or using The software names were used, and commercially available compounds were named using the supplier's catalog names.
具体实施方式Detailed ways
下面通过实施例对本发明进行详细描述，但并不意味着对本发明任何不利限制。本文已经详细地描述了本发明，其中也公开了其具体实施例方式，对本领域的技术人员而言，在不脱离本发明精神和范围的情况下针对本发明具体实施方式进行各种变化和改进将是显而易见的。The present invention is described in detail below by way of examples, but it is not intended to impose any adverse limitations on the present invention. The present invention has been described in detail herein, and specific embodiments thereof are also disclosed therein. It will be apparent to those skilled in the art that various changes and modifications can be made to the specific embodiments of the present invention without departing from the spirit and scope of the present invention.
实施例1
Example 1
步骤1：化合物1B的合成Step 1: Synthesis of compound 1B
氮气保护下，向化合物1A(5克,19.77毫摩尔)的乙腈(25毫升)溶液中加入化合物1-1(4.67克,29.66毫摩尔)和N,N-二异丙基乙胺(7.67克,59.31毫摩尔)。加入完毕，升温至85℃，搅拌12小时， 反应结束。将反应液加入水(80毫升)，乙酸乙酯(80毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝100:1至10:1)得到化合物1B。Under nitrogen protection, add compound 1-1 (4.67 g, 29.66 mmol) and N,N-diisopropylethylamine (7.67 g, 59.31 mmol) to a solution of compound 1A (5 g, 19.77 mmol) in acetonitrile (25 ml). After the addition is complete, heat to 85°C and stir for 12 hours. After the reaction was completed, the reaction solution was added to water (80 mL), extracted with ethyl acetate (80 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=100:1 to 10:1) to obtain compound 1B.
1HNMR(400MHz,DMSO-d6)δppm 7.72(s,1H),6.30(s,2H),3.16(t,J＝5.50Hz,4H),2.24-2.07(m,4H)。LCMS(ESI):m/z:293.1[M+1]。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 7.72 (s, 1H), 6.30 (s, 2H), 3.16 (t, J=5.50 Hz, 4H), 2.24-2.07 (m, 4H). LCMS (ESI): m/z: 293.1 [M+1].
步骤2：化合物1C的合成Step 2: Synthesis of Compound 1C
氮气保护下，向化合物1B(4.85克，16.55毫摩尔)的乙醇(40毫升)溶液中加入溴乙醛缩二乙醇(19.57克，99.28毫摩尔)和48％HBr水溶液(79.24克，470.07毫摩尔)。加入完毕，升温至100℃，搅拌30分钟，反应结束。冰浴下，向反应液中加入饱和氢氧化钠水溶液(40毫升)淬灭，乙酸乙酯(100毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝100:1至50:1)得到化合物1C。Under nitrogen protection, bromoacetaldehyde diethyl acetal (19.57 g, 99.28 mmol) and 48% HBr aqueous solution (79.24 g, 470.07 mmol) were added to a solution of compound 1B (4.85 g, 16.55 mmol) in ethanol (40 ml) . After the addition was completed, the temperature was raised to 100 ° C and stirred for 30 minutes to terminate the reaction. Under ice bath, saturated sodium hydroxide aqueous solution (40 ml) was added to the reaction solution to quench, and ethyl acetate (100 ml × 2) was extracted, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: EA = 100: 1 to 50: 1) to obtain compound 1C.
1HNMR(400MHz,CDCl3)δppm 7.65(s,1H),7.53(d,J＝0.86Hz,1H),7.47(d,J＝0.86Hz,1H),4.55-4.39(m,4H),2.23-2.00(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.65 (s, 1H), 7.53 (d, J=0.86 Hz, 1H), 7.47 (d, J=0.86 Hz, 1H), 4.55-4.39 (m, 4H), 2.23-2.00 (m, 4H).
LCMS(ESI):m/z:317.0[M+1]。LCMS (ESI): m/z: 317.0 [M+1].
步骤3：化合物1D的合成Step 3: Synthesis of Compound 1D
氮气保护下,向化合物1C(2克，6.31毫摩尔)的1,4-二氧六环(30毫升)溶液中加入氨基甲酸叔丁酯(2.2克，18.92毫摩尔)、XPhos(601.28毫克，1.26毫摩尔)、Pd(OAc)2(283.17毫克，1.26毫摩尔)和碳酸铯(5.14克，15.77毫摩尔)。氮气置换3-4次，混合物于110℃搅拌12小时。反应液减压抽滤，滤液加入水(200毫升),用乙酸乙酯(200毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝100:1至50:1)得到化合物1D。Under nitrogen protection, tert-butyl carbamate (2.2 g, 18.92 mmol), XPhos (601.28 mg, 1.26 mmol), Pd(OAc) 2 (283.17 mg, 1.26 mmol) and cesium carbonate (5.14 g, 15.77 mmol) were added to a solution of compound 1C (2 g, 6.31 mmol) in 1,4-dioxane (30 ml) . Nitrogen was replaced 3-4 times, and the mixture was stirred at 110°C for 12 hours. The reaction solution was filtered under reduced pressure, water (200 ml) was added to the filtrate, and it was extracted with ethyl acetate (200 ml x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=100:1 to 50:1) to obtain compound 1D.
1HNMR(400MHz,CDCl3)δppm 8.20(s,1H),7.48(dd,J＝12.10,0.86Hz,2H),6.64(br,1H),4.44-4.34(m,4H),2.17-2.01(m,4H),1.53(s,9H)。LCMS(ESI):m/z:354.3[M+1]。 1 HNMR (400MHz,CDCl 3 )δppm 8.20(s,1H),7.48(dd,J＝12.10,0.86Hz,2H),6.64(br,1H),4.44-4.34(m,4H),2.17-2.01( m, 4H), 1.53 (s, 9H). LCMS (ESI): m/z: 354.3 [M+1].
步骤4：化合物1E的合成Step 4: Synthesis of Compound 1E
氮气保护下，0℃向化合物1D(600毫克，1.70毫摩尔)的DMF(5毫升)溶液中缓慢加入钠氢(135.82毫克，3.40毫摩尔)，混合物于0℃搅拌30分钟。向化合物1-2(910.82毫克，2.55毫摩尔)的二氯甲烷(20毫升)中分别加入氯化亚砜(1.21克，10.20毫摩尔)和催化量DMF(1滴)，混合物于20-30℃搅拌30分钟。减压浓缩，粗品溶于DMF(8毫升)缓慢加入上述化合物1D的反应溶液中，20-30℃搅拌12小时。反应液中加入水溶液(50毫升)，加入乙酸乙酯萃取(50毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝30:1至5:1)得到化合物1E。Under nitrogen protection, sodium hydrogen (135.82 mg, 3.40 mmol) was slowly added to a solution of compound 1D (600 mg, 1.70 mmol) in DMF (5 ml) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Thionyl chloride (1.21 g, 10.20 mmol) and a catalytic amount of DMF (1 drop) were added to a solution of compound 1-2 (910.82 mg, 2.55 mmol) in dichloromethane (20 ml), and the mixture was stirred at 20-30°C for 30 minutes. After concentration under reduced pressure, the crude product was dissolved in DMF (8 ml) and slowly added to the reaction solution of the above compound 1D, and stirred at 20-30°C for 12 hours. Aqueous solution (50 ml) was added to the reaction solution, and ethyl acetate was added for extraction (50 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA＝30:1 to 5:1) to obtain compound 1E.
1HNMR(400MHz,CDCl3)δppm 7.62-7.58(m,2H),7.55-7.52(m,1H),7.45-7.39(m,2H),7.18(d,J＝7.88Hz,1H),4.43-4.37(m,4H),3.19-3.06(m,4H),2.15-2.06(m,4H),2.06-1.32(m,4H),1.29(s,9H),0.41-0.32(m,4H)。LCMS(ESI):m/z:693.1[M+1]。 1 HNMR (400MHz,CDCl 3 )δppm 7.62-7.58(m,2H),7.55-7.52(m,1H),7.45-7.39(m,2H),7.18(d,J＝7.88Hz,1H),4.43- 4.37(m,4H),3.19-3.06(m,4H),2.15-2.06(m,4H),2.06-1.32(m,4H),1.29(s,9H),0.41-0.32(m,4H). LCMS (ESI): m/z: 693.1 [M+1].
步骤5：化合物1F的合成Step 5: Synthesis of Compound 1F
氮气保护下，向化合物1E(200毫克，288.79微摩尔)的二氯甲烷(5毫升)溶液中缓慢滴加三氟乙酸(1毫升，13.46毫摩尔)，混合物于20-30℃搅拌1小时。反应液中加入水溶液(20毫升)，加入乙酸乙酯萃取(10毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝50:1至10:1)得到化合物1F。Under nitrogen protection, trifluoroacetic acid (1 ml, 13.46 mmol) was slowly added dropwise to a solution of compound 1E (200 mg, 288.79 μmol) in dichloromethane (5 ml), and the mixture was stirred at 20-30°C for 1 hour. Aqueous solution (20 ml) was added to the reaction solution, and ethyl acetate was added for extraction (10 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=50:1 to 10:1) to obtain compound 1F.
1H NMR(400MHz,CDCl3)δppm 12.90(s,1H),8.84(s,1H),8.01(d,J＝8.68Hz,1H),7.71-7.65(m,2H),7.58-7.53(m,2H),4.49-4.44(m,4H),3.14-3.03(m,4H),2.18-2.09(m,4H),1.57-1.50(m,4H),0.44(s,4H)。LCMS(ESI):m/z:593.2[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 12.90 (s, 1H), 8.84 (s, 1H), 8.01 (d, J＝8.68 Hz, 1H), 7.71-7.65 (m, 2H), 7.58-7.53 (m , 2H), 4.49-4.44(m, 4H), 3.14-3.03(m, 4H), 2.18-2.09(m, 4H), 1.57-1.50(m, 4H), 0.44(s, 4H). LCMS (ESI): m/z: 593.2 [M+1].
步骤6：化合物1的合成Step 6: Synthesis of compound 1
氮气保护下，向化合物1F(70毫克，118.16微摩尔)的DMF(3毫升)溶液中加入化合物1-3(29.57毫克，236.32微摩尔)、磷酸钾(75.24毫克，354.48微摩尔)、碘化亚铜(22.50毫克，118.16微摩尔)、反式N,N-二甲基环己基-1,2-二胺(8.4毫克，59.08微摩尔)。氮气置换3-4次，混合物于100℃搅拌12小时。反应液中加入纯化水(20毫升)，加入乙酸乙酯(20毫升×2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动相：水(0.225％FA)-乙腈，梯度：52％-82％乙腈；洗脱10分钟)分离得到化合物1。Under nitrogen protection, compound 1-3 (29.57 mg, 236.32 μmol), potassium phosphate (75.24 mg, 354.48 μmol), cuprous iodide (22.50 mg, 118.16 μmol), trans-N,N-dimethylcyclohexyl-1,2-diamine (8.4 mg, 59.08 μmol) were added to a DMF (3 ml) solution of compound 1F (70 mg, 118.16 μmol). Nitrogen was replaced 3-4 times, and the mixture was stirred at 100°C for 12 hours. Purified water (20 ml) was added to the reaction solution, and ethyl acetate (20 ml x 2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 52%-82% acetonitrile; elution within 10 minutes) to obtain compound 1.
1HNMR(400MHz,CD3OD)δppm 8.79(s,1H),8.11(d,J＝8.68Hz,1H),7.82(d,J＝0.86Hz,1H),7.53(d,J＝0.86Hz,1H),7.32(d,J＝2.08Hz,1H),7.15(dd,J＝8.68,2.08Hz,1H),4.37(t,J＝5.56Hz,4H),3.96(t,J＝6.17Hz,2H),3.38(t,J＝6.17Hz,2H),3.11-3.02(m,4H),2.20-2.07(m,4H),2.04(s,4H),0.44(s,4H)；LCMS(ESI)m/z:590.2[M+1]。 1 H NMR (400 MHz, CD 3 OD) δ ppm 8.79 (s, 1H), 8.11 (d, J = 8.68 Hz, 1H), 7.82 (d, J = 0.86 Hz, 1H), 7.53 (d, J = 0.86 Hz, 1H), 7.32 (d, J = 2.08 Hz, 1H), 7.15 (dd, J = 8.68, 2.08 Hz, 1H), 4.37 (t, J = 5.56 Hz, 4H), 3.96 (t, J = 6.17 Hz, 2H), 3.38 (t, J = 6.17 Hz, 2H), 3.11-3.02 (m, 4H), 2.20-2.07 (m, 4H), 2.04 (s, 4H), 0.44 (s, 4H); LCMS (ESI) m/z: 590.2 [M+1].
实施例2

Example 2

步骤1：化合物2B的合成Step 1: Synthesis of compound 2B
氮气保护下，向化合物2A(5克,30.49毫摩尔)的二氧六环(30毫升)溶液中加入化合物1-1(7.21克,45.73毫摩尔)和N,N-二异丙基乙胺(19.70克,152.45毫摩尔)。加入完毕，升温至80℃，搅拌12小时，反应结束。将反应液加入水(80毫升)，乙酸乙酯(80毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝50:1至10:1)得到化合物2B。Under nitrogen protection, compound 1-1 (7.21 g, 45.73 mmol) and N,N-diisopropylethylamine (19.70 g, 152.45 mmol) were added to a solution of compound 2A (5 g, 30.49 mmol) in dioxane (30 ml) under nitrogen protection. After the addition was completed, the temperature was raised to 80°C and stirred for 12 hours to complete the reaction. The reaction solution was added with water (80 ml) and extracted with ethyl acetate (80 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA = 50:1 to 10:1) to obtain compound 2B.
1H NMR(400MHz,CDCl3)δppm 5.81(s,1H),4.67(br,2H),4.00-3.84(m,4H),2.07-1.88(m,4H)。LCMS(ESI):m/z:249.3[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 5.81 (s, 1H), 4.67 (br, 2H), 4.00-3.84 (m, 4H), 2.07-1.88 (m, 4H). LCMS (ESI): m/z: 249.3 [M+1].
步骤2：化合物2C的合成Step 2: Synthesis of compound 2C
氮气保护下，向化合物2B(6.1克，24.53毫摩尔)的1,4-二氧六环(30毫升)和水(15毫升)溶液中加入溴乙醛缩二乙醇(14.50克，73.59毫摩尔)。加入完毕，升温至100℃，搅拌12小时。反应结束，反应液减压旋干，用四氢呋喃(200毫升)打浆1小时，过滤，干燥滤饼，得到化合物2C。Under nitrogen protection, bromoacetaldehyde diethyl acetal (14.50 g, 73.59 mmol) was added to a solution of compound 2B (6.1 g, 24.53 mmol) in 1,4-dioxane (30 ml) and water (15 ml). After the addition was completed, the temperature was raised to 100°C and stirred for 12 hours. After the reaction was completed, the reaction solution was dried under reduced pressure, slurried with tetrahydrofuran (200 ml) for 1 hour, filtered, and the filter cake was dried to obtain compound 2C.
1H NMR(400MHz,CDCl3)δppm 7.62(d,J＝0.86Hz,1H),7.39(s,1H),7.23(s,1H),3.73-3.61(m,4H),2.29-2.15(m,4H)。LCMS(ESI):m/z:273.0[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.62 (d, J = 0.86 Hz, 1H), 7.39 (s, 1H), 7.23 (s, 1H), 3.73-3.61 (m, 4H), 2.29-2.15 (m ,4H). LCMS (ESI): m/z: 273.0 [M+1].
步骤3：化合物2D的合成Step 3: Synthesis of compound 2D
氮气保护下，向化合物2C(1.39克，5.1毫摩尔)的DMF(10毫升)溶液中加入二苯甲酮亚胺(1.5克，7.65毫摩尔)、Xantphos(590.19毫克，1.02毫摩尔)、Pd(dba)2(586.51毫克，1.02毫摩尔)和碳酸铯(4.99克，15.3毫摩尔)。氮气置换3-4次，混合物于100℃搅拌4小时。反应液减压抽滤，滤液加入水(100毫升)，用乙酸乙酯萃取(160毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝30:1至2:1)得到化合物2D。Under nitrogen protection, benzophenone imine (1.5 g, 7.65 mmol), Xantphos (590.19 mg, 1.02 mmol), Pd(dba) 2 (586.51 mg, 1.02 mmol) and cesium carbonate (4.99 g, 15.3 mmol) were added to a DMF (10 ml) solution of compound 2C (1.39 g, 5.1 mmol) under nitrogen protection. The mixture was stirred at 100° C. for 4 hours after nitrogen replacement 3-4 times. The reaction solution was filtered under reduced pressure, water (100 ml) was added to the filtrate, and the mixture was extracted with ethyl acetate (160 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=30:1 to 2:1) to obtain compound 2D.
1H NMR(400MHz,CDCl3)δppm 7.82-7.76(m,2H),7.54-7.49(m,2H),7.46-7.40(m,2H),7.30-7.25(m,4H),7.22-7.17(m,2H),6.78(s,1H),3.37-3.28(m,4H),2.07-1.90(m,4H)。LCMS(ESI):m/z:418.3 [M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.82-7.76 (m, 2H), 7.54-7.49 (m, 2H), 7.46-7.40 (m, 2H), 7.30-7.25 (m, 4H), 7.22-7.17 ( m, 2H), 6.78(s, 1H), 3.37-3.28(m, 4H), 2.07-1.90(m, 4H). LCMS(ESI):m/z:418.3 [M+1].
步骤4：化合物2E的合成Step 4: Synthesis of compound 2E
氮气保护下，向化合物2D(950毫克，2.28毫摩尔)的四氢呋喃(10毫升)溶液中缓慢滴加稀盐酸(2M，3.0毫升)，混合物于20-30℃搅拌30分钟。反应液析出固体，减压抽滤，滤饼用四氢呋喃(20毫升)洗涤，干燥得到化合物2E。Under nitrogen protection, dilute hydrochloric acid (2M, 3.0 ml) was slowly added dropwise to a solution of compound 2D (950 mg, 2.28 mmol) in tetrahydrofuran (10 ml), and the mixture was stirred at 20-30°C for 30 minutes. Solids precipitated from the reaction solution, which were filtered under reduced pressure, and the filter cake was washed with tetrahydrofuran (20 ml) and dried to obtain compound 2E.
LCMS(ESI)m/z:254.0[M+1]。LCMS (ESI) m/z: 254.0 [M+1].
步骤5：化合物2F的合成Step 5: Synthesis of Compound 2F
氮气保护下，向化合物1-2(1.11克，3.11毫摩尔)的二氯甲烷(20毫升)中分别加入氯化亚砜(1.48克，12.44毫摩尔)和催化量DMF(1滴)，混合物于20-30℃搅拌0.5小时。减压浓缩，粗品加入二氯甲烷(20毫升)、磷酸钾(1.32克，6.21毫摩尔)，将化合物2E(1.17克，3.11毫摩尔)和N,N-二异丙基乙基胺(1.61克，12.43毫摩尔)缓慢加入上述溶液中，20-30℃搅拌12小时。反应液加入水(100毫升)淬灭，二氯甲烷(160毫升)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩所得粗品经柱层析(PE:EA＝10:1至20:1)分离得到化合物2F。Under nitrogen protection, thionyl chloride (1.48 g, 12.44 mmol) and catalytic amount of DMF (1 drop) were added to compound 1-2 (1.11 g, 3.11 mmol) in dichloromethane (20 ml), and the mixture was stirred at 20-30°C for 0.5 hours. After concentration under reduced pressure, dichloromethane (20 ml) and potassium phosphate (1.32 g, 6.21 mmol) were added to the crude product, and compound 2E (1.17 g, 3.11 mmol) and N,N-diisopropylethylamine (1.61 g, 12.43 mmol) were slowly added to the above solution, and stirred at 20-30°C for 12 hours. The reaction solution was quenched by adding water (100 ml), extracted with dichloromethane (160 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by column chromatography (PE:EA=10:1 to 20:1) to obtain compound 2F.
1H NMR(400MHz,CDCl3)δppm 13.12(s,1H),8.28(s,1H),8.04(d,J＝8.80Hz,1H),7.71-7.66(m,2H),7.59(d,J＝1.34Hz,1H),7.35(s,1H),3.69-3.58(m,4H),3.09(t,J＝5.01Hz,4H),2.18-2.35(m,4H),1.59(s,4H),0.44(s,4H)。LCMS(ESI)m/z:593.1[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 13.12 (s, 1H), 8.28 (s, 1H), 8.04 (d, J＝8.80 Hz, 1H), 7.71-7.66 (m, 2H), 7.59 (d, J =1.34Hz,1H),7.35(s,1H),3.69-3.58(m,4H),3.09(t,J＝5.01Hz,4H),2.18-2.35(m,4H),1.59(s,4H) ,0.44(s,4H). LCMS (ESI) m/z: 593.1 [M+1].
步骤6：化合物2的合成Step 6: Synthesis of Compound 2
氮气保护下，向化合物2F(270毫克，455.76微摩尔)的DMF(5毫升)溶液中加入化合物1-3(114.07毫克，911.51微摩尔)、磷酸钾(290.23毫克，1.37毫摩尔)、碘化亚铜(86.8毫克，455.76微摩尔)、反式N,N-二甲基环己基-1,2-二胺(32.41毫克，227.88微摩尔)。氮气置换3-4次，混合物于100℃搅拌12小时。反应液中加入纯化水(150毫升)，加入乙酸乙酯(100毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动相：水(0.225％FA)-乙腈，梯度：20％-50％乙腈；洗脱10分钟)纯化，干燥后得到化合物2。Under nitrogen protection, compound 1-3 (114.07 mg, 911.51 μmol), potassium phosphate (290.23 mg, 1.37 mmol), cuprous iodide (86.8 mg, 455.76 μmol), trans-N,N-dimethylcyclohexyl-1,2-diamine (32.41 mg, 227.88 μmol) were added to a DMF (5 ml) solution of compound 2F (270 mg, 455.76 μmol). Nitrogen was replaced 3-4 times, and the mixture was stirred at 100°C for 12 hours. Purified water (150 ml) was added to the reaction solution, and ethyl acetate (100 ml) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 20%-50% acetonitrile; elution within 10 minutes) and compound 2 was obtained after drying.
1H NMR(400MHz,CD3OD)δppm 13.56(s,1H),8.19-8.02(m,2H),7.83-7.65(m,1H),7.64-7.45(m,1H),7.32(d,J＝1.88Hz,1H),7.16(dd,J＝8.63,2.00Hz,1H),3.95(t,J＝6.19Hz,2H),3.69(s,4H),3.41-3.35(m,2H),3.13-3.00(m,4H),2.35-2.21(m,4H),3.16-1.37(m,4H),0.45(s,4H)；LCMS(ESI)m/z:590.2[M+1]。 1 H NMR (400 MHz, CD 3 OD) δ ppm 13.56 (s, 1H), 8.19-8.02 (m, 2H), 7.83-7.65 (m, 1H), 7.64-7.45 (m, 1H), 7.32 (d, J=1.88 Hz, 1H), 7.16 (dd, J=8.63, 2.00 Hz, 1H), 3.95 (t, J=6.19 Hz, 2H), 3.69 (s, 4H), 3.41-3.35 (m, 2H), 3.13-3.00 (m, 4H), 2.35-2.21 (m, 4H), 3.16-1.37 (m, 4H), 0.45 (s, 4H); LCMS (ESI) m/z: 590.2 [M+1].
实施例3
Example 3
步骤1：化合物3B的合成Step 1: Synthesis of compound 3B
向化合物3A(9克,60.41毫摩尔)的乙醇(50毫升)溶液中加入一水合肼(7.12克,120.82毫摩尔)。混合物于85℃搅拌12小时。反应液冷却，过滤，滤饼用冷的乙醇(50毫升)淋洗两次，滤饼干燥得到化合物3B。To a solution of compound 3A (9 g, 60.41 mmol) in ethanol (50 ml) was added hydrazine monohydrate (7.12 g, 120.82 mmol). The mixture was stirred at 85°C for 12 hours. The reaction solution was cooled and filtered, and the filter cake was rinsed twice with cold ethanol (50 ml), and the filter cake was dried to obtain compound 3B.
1H NMR(400MHz,DMSO-d6)δppm 8.28(br s,1H),8.06(d,J＝2.7Hz,1H),7.57(d,J＝2.7Hz,1H),4.33(br s,2H)。 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.28 (br s, 1H), 8.06 (d, J=2.7 Hz, 1H), 7.57 (d, J=2.7 Hz, 1H), 4.33 (br s, 2H).
步骤2：化合物3C的合成Step 2: Synthesis of compound 3C
-5℃下，向化合物3B(9.7克，67.10毫摩尔)的四氢呋喃(200毫升)的混合物中滴加三氟乙酸酐(15.50克，73.81毫摩尔)的四氢呋喃(100毫升)溶液。混合物于0℃搅拌2小时。向反应液中加入饱和食盐水(100毫升)，混合物用乙酸乙酯萃取(100毫升×2)，合并的有机相用无水硫酸钠干燥，过滤，滤液浓缩，所得粗品经制备HPLC(柱型：Phenomenex luna C18 250*80mm*10μm；流动相：水(0.225％FA)-乙腈，梯度： 25％-55％乙腈；洗脱20分钟)纯化，得到化合物3C。To a mixture of compound 3B (9.7 g, 67.10 mmol) in tetrahydrofuran (200 ml) was added a solution of trifluoroacetic anhydride (15.50 g, 73.81 mmol) in tetrahydrofuran (100 ml) at -5°C. The mixture was stirred at 0°C for 2 hours. Saturated brine (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml x 2). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by preparative HPLC (column type: Phenomenex luna C18 250*80mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: Purification by elution with 25%-55% acetonitrile; 20 minutes) gave compound 3C.
1H NMR(400MHz,DMSO-d6)δppm 11.59(br s,1H),9.46(s,1H),8.18(d,J＝2.7Hz,1H),7.88(d,J＝2.6Hz,1H)。LCMS(ESI):m/z:241.0[M+1]。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.59 (br s, 1H), 9.46 (s, 1H), 8.18 (d, J＝2.7 Hz, 1H), 7.88 (d, J＝2.6 Hz, 1H) . LCMS (ESI): m/z: 241.0 [M+1].
步骤3：化合物3D的合成Step 3: Synthesis of compound 3D
0℃下，向化合物3C(3.7克，15.38毫摩尔)的氯仿(40毫升)溶液中加入氯代丁二酰亚胺(3.08克，23.07毫摩尔)，混合物于70℃搅拌2小时。向反应液中加入饱和食盐水(100毫升)，混合物用乙酸乙酯萃取(100毫升×2)，合并的有机相用无水硫酸钠干燥，过滤，滤液浓缩，所得残留物通过柱层析分离(PE:EA＝30:1)得到化合物3D。To a solution of compound 3C (3.7 g, 15.38 mmol) in chloroform (40 ml) was added chlorosuccinimide (3.08 g, 23.07 mmol) at 0°C, and the mixture was stirred at 70°C for 2 hours. Saturated brine (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated, and the residue was separated by column chromatography (PE:EA=30:1) to give compound 3D.
1H NMR(400MHz,DMSO-d6)δppm 11.70(s,1H),9.66(s,1H),8.34(s,1H)。LCMS(ESI):m/z:274.9[M+1]。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 11.70 (s, 1H), 9.66 (s, 1H), 8.34 (s, 1H). LCMS (ESI): m/z: 274.9 [M+1].
步骤4：化合物3E的合成Step 4: Synthesis of compound 3E
向化合物3D(2.4克，9.73毫摩尔)的乙醇(25毫升)溶液中加入盐酸(12摩尔/升，7.27毫升)，混合物于80℃搅拌2小时。反应液用氢氧化钠水溶液(2摩尔/升)调pH至7-8，混合物用乙酸乙酯萃取(20毫升×2)，合并的有机相用无水硫酸钠干燥，过滤，滤液浓缩，所得残留物通过柱层析分离(PE:EA＝1:1)得到化合物3E。To a solution of compound 3D (2.4 g, 9.73 mmol) in ethanol (25 ml) was added hydrochloric acid (12 mol/L, 7.27 ml), and the mixture was stirred at 80°C for 2 hours. The reaction solution was adjusted to pH 7-8 with aqueous sodium hydroxide solution (2 mol/L), and the mixture was extracted with ethyl acetate (20 ml x 2), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by column chromatography (PE:EA=1:1) to give compound 3E.
1H NMR(400MHz,DMSO-d6)δppm 8.53(br s,1H),8.20(s,1H),4.40(br s,2H)。 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.53 (br s, 1H), 8.20 (s, 1H), 4.40 (br s, 2H).
步骤5：化合物3F的合成Step 5: Synthesis of compound 3F
化合物3E(1.83克，10.22毫摩尔)的原甲酸三甲酯(18毫升)溶液于100℃搅拌1.5小时。反应液减压浓缩，所得粗品经柱层析(PE:EA＝20:1至5:1)分离得到化合物3F。A solution of compound 3E (1.83 g, 10.22 mmol) in trimethyl orthoformate (18 ml) was stirred at 100° C. for 1.5 hours. The reaction solution was concentrated under reduced pressure, and the resulting crude product was separated by column chromatography (PE:EA=20:1 to 5:1) to obtain compound 3F.
1H NMR(400MHz,CDCl3)δppm 9.01(s,1H),8.17(s,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 9.01 (s, 1H), 8.17 (s, 1H).
步骤6：化合物3G的合成Step 6: Synthesis of Compound 3G
氮气保护下，向化合物3F(1.8克,9.52毫摩尔)的乙腈(15毫升)溶液中加入化合物1-1(2.25克,14.29毫摩尔)和N,N-二异丙基乙胺(3.69克,28.57毫摩尔)。混合物于85℃搅拌12小时。向反应液中加入饱和食盐水(100毫升)，混合物用乙酸乙酯萃取(100毫升×2)，合并的有机相用无水硫酸钠干燥，过滤，滤液浓缩，所得残留物通过柱层析分离(PE:EA＝20:1至5:1)得到化合物3G。Under nitrogen protection, compound 1-1 (2.25 g, 14.29 mmol) and N,N-diisopropylethylamine (3.69 g, 28.57 mmol) were added to a solution of compound 3F (1.8 g, 9.52 mmol) in acetonitrile (15 ml). The mixture was stirred at 85°C for 12 hours. Saturated brine (100 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (100 ml x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was separated by column chromatography (PE:EA = 20:1 to 5:1) to obtain compound 3G.
1H NMR(400MHz,CDCl3)δppm 8.71(s,1H),7.52(s,1H),5.08-3.95(m,4H),2.26-2.06(m,4H)。LCMS(ESI):m/z:274.1[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.71 (s, 1H), 7.52 (s, 1H), 5.08-3.95 (m, 4H), 2.26-2.06 (m, 4H). LCMS (ESI): m/z: 274.1 [M+1].
步骤7：化合物3H的合成Step 7: Synthesis of compound 3H
氮气保护下，向化合物3G(1.8克，6.58毫摩尔)的DMF(10毫升)溶液中加入二苯甲酮亚胺(1.79克，9.87毫摩尔)、Xantphos(761.15毫克，1.32毫摩尔)、Pd(dba)2(756.40毫克，1.32毫摩尔)和碳酸铯(6.43 克，19.73毫摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液减压抽滤，滤液加入水(100毫升)，用乙酸乙酯萃取(100毫升×2)，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝20:1至2:1)得到化合物3H。Benzophenone imine (1.79 g, 9.87 mmol), Xantphos (761.15 mg, 1.32 mmol), Pd(dba) 2 (756.40 mg, 1.32 mmol) and cesium carbonate (6.43 g, 1.32 mmol) were added to a solution of compound 3G ( 1.8 g, 6.58 mmol) in DMF (10 ml) under nitrogen protection. g, 19.73 mmol). The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100°C for 12 hours. The reaction solution was filtered under reduced pressure, water (100 ml) was added to the filtrate, and extracted with ethyl acetate (100 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=20:1 to 2:1) to obtain compound 3H.
1H NMR(400MHz,CDCl3)δppm 8.66(s,1H),8.02(s,1H),7.74(d,J＝7.3Hz,2H),7.53-7.49(m,1H),7.44-7.40(m,2H),7.37-7.31(m,3H),7.20(dd,J＝1.3,7.6Hz,2H),4.28-4.03(m,4H),1.98-1.84(m,4H)。LCMS(ESI):m/z:418.3[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.66 (s, 1H), 8.02 (s, 1H), 7.74 (d, J＝7.3 Hz, 2H), 7.53-7.49 (m, 1H), 7.44-7.40 (m , 2H), 7.37-7.31 (m, 3H), 7.20 (dd, J＝1.3, 7.6 Hz, 2H), 4.28-4.03 (m, 4H), 1.98-1.84 (m, 4H). LCMS (ESI): m/z: 418.3 [M+1].
步骤8：化合物3I的合成Step 8: Synthesis of compound 3I
氮气保护下，向化合物3H(1.3克，3.11毫摩尔)的四氢呋喃(14毫升)溶液中缓慢滴加稀盐酸(2M，7毫升)，混合物于20℃搅拌5分钟。反应液用氢氧化钠水溶液(2M，20毫升)淬灭，混合物用乙酸乙酯萃取(50毫升×2)，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1至1:2)得到化合物3I。Under nitrogen protection, dilute hydrochloric acid (2M, 7 mL) was slowly added dropwise to a solution of compound 3H (1.3 g, 3.11 mmol) in tetrahydrofuran (14 mL), and the mixture was stirred at 20° C. for 5 minutes. The reaction solution was quenched with aqueous sodium hydroxide solution (2M, 20 mL), and the mixture was extracted with ethyl acetate (50 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=10:1 to 1:2) to obtain compound 3I.
1H NMR(400MHz,CDCl3)δppm 8.56(s,1H),6.85(s,1H),4.49(br s,4H),4.01-3.66(m,2H),2.18-2.07(m,4H)。LCMS(ESI)m/z:255.2[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.56 (s, 1H), 6.85 (s, 1H), 4.49 (br s, 4H), 4.01-3.66 (m, 2H), 2.18-2.07 (m, 4H). LCMS (ESI) m/z: 255.2 [M+1].
步骤9：化合物3J的合成Step 9: Synthesis of compound 3J
氮气保护下，向化合物1-2(735.80毫克，2.06毫摩尔)的二氯甲烷(10毫升)中加入氯化亚砜(980.31毫克，8.24毫摩尔)，混合物于26℃搅拌0.5小时。减压浓缩，粗品加入二氯甲烷(10毫升)、磷酸钾(1.00克，4.72毫摩尔)，将化合物3I(400毫克，1.57毫摩尔)和N,N-二异丙基乙基胺(610.01毫克，4.72毫摩尔)的二氯甲烷(3毫升)溶液缓慢加入上述溶液中，于20℃搅拌12小时。反应液加入水(40毫升)淬灭，二氯甲烷(40毫升×2)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩所得粗品经柱层析(PE:EA＝30:1至1:2)分离得到化合物3J。Under nitrogen protection, thionyl chloride (980.31 mg, 8.24 mmol) was added to a solution of compound 1-2 (735.80 mg, 2.06 mmol) in dichloromethane (10 ml), and the mixture was stirred at 26°C for 0.5 hours. The mixture was concentrated under reduced pressure, dichloromethane (10 ml) and potassium phosphate (1.00 g, 4.72 mmol) were added to the crude product, and a solution of compound 3I (400 mg, 1.57 mmol) and N,N-diisopropylethylamine (610.01 mg, 4.72 mmol) in dichloromethane (3 ml) was slowly added to the above solution, and stirred at 20°C for 12 hours. The reaction solution was quenched by adding water (40 ml), extracted with dichloromethane (40 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by column chromatography (PE:EA=30:1 to 1:2) to obtain compound 3J.
1H NMR(400MHz,CDCl3)δppm 13.12(s,1H),8.76(d,J＝6.6Hz,2H),8.00(d,J＝8.8Hz,1H),7.73-7.66(m,2H),4.56(br s,4H),3.12-3.05(m,4H),2.22-2.11(m,4H),1.37-1.03(m,4H),0.45(s,4H)。LCMS(ESI)m/z:594.3[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 13.12 (s, 1H), 8.76 (d, J = 6.6 Hz, 2H), 8.00 (d, J = 8.8 Hz, 1H), 7.73-7.66 (m, 2H), 4.56 (br s, 4H), 3.12-3.05 (m, 4H), 2.22-2.11 (m, 4H), 1.37-1.03 (m, 4H), 0.45 (s, 4H). LCMS (ESI) m/z: 594.3 [M+1].
步骤10：化合物3的合成Step 10: Synthesis of compound 3
氮气保护下，向化合物3J(300毫克，505.55微摩尔)的DMF(4毫升)溶液中加入化合物1-3(126.54毫克，1.01毫摩尔)、磷酸钾(321.94毫克，1.52毫摩尔)、碘化亚铜(96.28毫克，505.55微摩尔)、反式N,N-二甲基环己基-1,2-二胺(35.95毫克，252.78微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。向反应液中加入饱和食盐水(30毫升)，混合物用乙酸乙酯萃取(30毫升×2)，合并的有机相用无水硫酸钠干燥，过滤，滤液浓缩后加入纯化水(150毫升)，加入乙酸乙酯(100毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动 相：水(0.225％FA)-乙腈，梯度：38％-68％乙腈；洗脱10分钟)纯化，干燥后得到化合物3。Under nitrogen protection, compound 1-3 (126.54 mg, 1.01 mmol), potassium phosphate (321.94 mg, 1.52 mmol), cuprous iodide (96.28 mg, 505.55 micromol), trans-N,N-dimethylcyclohexyl-1,2-diamine (35.95 mg, 252.78 micromol) were added to a DMF (4 ml) solution of compound 3J (300 mg, 505.55 micromol). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 100°C for 12 hours. Saturated brine (30 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml x 2). The combined organic phase was dried over anhydrous sodium sulfate and filtered. After the filtrate was concentrated, purified water (150 ml) was added, and ethyl acetate (100 ml) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The obtained crude product was subjected to preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase Phase: water (0.225% FA)-acetonitrile, gradient: 38%-68% acetonitrile; elution 10 minutes) and compound 3 was obtained after drying.
1H NMR(400MHz,DMSO-d6)δppm 13.10(s,1H),9.36(s,1H),8.78(s,1H),8.06(d,J＝8.6Hz,1H),7.26(s,1H),7.11(br d,J＝8.6Hz,1H),4.81-4.05(m,4H),3.75(t,J＝6.5Hz,2H),3.40-3.30(m,2H),2.98(br s,4H),2.24-2.09(m,4H),1.99-1.42(m,4H),0.41(s,4H)。LCMS(ESI)m/z:591.4[M+1]。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.10 (s, 1H), 9.36 (s, 1H), 8.78 (s, 1H), 8.06 (d, J＝8.6 Hz, 1H), 7.26 (s, 1H ),7.11(br d,J＝8.6Hz,1H),4.81-4.05(m,4H),3.75(t,J＝6.5Hz,2H),3.40-3.30(m,2H),2.98(br s, 4H), 2.24-2.09(m,4H), 1.99-1.42(m,4H), 0.41(s,4H). LCMS (ESI) m/z: 591.4 [M+1].
实施例4
Example 4
步骤1：化合物4B的合成Step 1: Synthesis of compound 4B
氮气保护下，向化合物4A(4.5克,16.19毫摩尔)的乙腈(25毫升)溶液中加入化合物1-1(3.83克,24.29毫摩尔)和N,N-二异丙基乙胺(6.28克,48.58毫摩尔)。混合物于85℃搅拌12小时。向反应液中加入水(100毫升)，混合物用乙酸乙酯萃取(100毫升)，合并的有机相用无水硫酸钠干燥，过滤，滤液浓缩，所得残留物通过柱层析分离(PE:EA＝100:1至10:1)得到化合物4B。Under nitrogen protection, compound 1-1 (3.83 g, 24.29 mmol) and N,N-diisopropylethylamine (6.28 g, 48.58 mmol) were added to a solution of compound 4A (4.5 g, 16.19 mmol) in acetonitrile (25 ml). The mixture was stirred at 85°C for 12 hours. Water (100 ml) was added to the reaction solution, the mixture was extracted with ethyl acetate (100 ml), the combined organic phase was dried over anhydrous sodium sulfate, filtered, the filtrate was concentrated, and the residue was separated by column chromatography (PE:EA=100:1 to 10:1) to obtain compound 4B.
1H NMR(400MHz,DMSO-d6)δppm 8.63(s,1H),8.53(s,1H),4.31(br s,4H),2.22-2.05(m,4H)。 1 H NMR (400 MHz, DMSO-d6) δ ppm 8.63 (s, 1H), 8.53 (s, 1H), 4.31 (br s, 4H), 2.22-2.05 (m, 4H).
步骤2：化合物4C的合成Step 2: Synthesis of compound 4C
氮气保护下,向化合物4B(4.5克，14.15毫摩尔)的DMF(40毫升)溶液中加入二苯甲酮亚胺(3.85克，21.22毫摩尔)、Xantphos(1.64克，2.83毫摩尔)、Pd(dba)2(1.63克，2.83毫摩尔)和碳酸铯(13.83克， 42.44毫摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液减压抽滤，滤液加入水(100毫升)，用乙酸乙酯萃取(100毫升×2)，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝30:1至3:1)得到化合物4C。Benzophenone imine (3.85 g, 21.22 mmol), Xantphos (1.64 g, 2.83 mmol), Pd(dba) 2 (1.63 g, 2.83 mmol) and cesium carbonate (13.83 g, 2.83 mmol) were added to a solution of compound 4B (4.5 g, 14.15 mmol) in DMF (40 ml) under nitrogen protection. 42.44 mmol). The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100°C for 12 hours. The reaction solution was filtered under reduced pressure, water (100 ml) was added to the filtrate, and the mixture was extracted with ethyl acetate (100 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=30:1 to 3:1) to obtain compound 4C.
LCMS(ESI):m/z:419.2[M+1]。LCMS (ESI): m/z: 419.2 [M+1].
步骤3：化合物4D的合成Step 3: Synthesis of compound 4D
氮气保护下，向化合物4C(4.8克，11.47毫摩尔)的四氢呋喃(40毫升)溶液中缓慢滴加稀盐酸(2M，20毫升)，混合物于25℃搅拌5分钟。反应液用氢氧化钠水溶液(2摩尔/升，30毫升)淬灭，混合物用乙酸乙酯萃取(50毫升×2)，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝30:1至3:1)得到化合物4D。Under nitrogen protection, dilute hydrochloric acid (2M, 20 mL) was slowly added dropwise to a solution of compound 4C (4.8 g, 11.47 mmol) in tetrahydrofuran (40 mL), and the mixture was stirred at 25° C. for 5 minutes. The reaction solution was quenched with aqueous sodium hydroxide solution (2 mol/L, 30 mL), and the mixture was extracted with ethyl acetate (50 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=30:1 to 3:1) to obtain compound 4D.
1H NMR(400MHz,CDCl3)δppm 8.14-8.06(m,1H),7.41-7.36(m,1H),4.42-4.31(m,4H),4.09-3.61(m,2H),2.17-2.03(m,4H)LCMS(ESI):m/z:255.2[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.14-8.06 (m, 1H), 7.41-7.36 (m, 1H), 4.42-4.31 (m, 4H), 4.09-3.61 (m, 2H), 2.17-2.03 (m, 4H) LCMS (ESI): m/z: 255.2 [M+1].
步骤4：化合物4E的合成Step 4: Synthesis of compound 4E
氮气保护下，向化合物1-2(1.84克，5.16毫摩尔)的二氯甲烷(30毫升)中加入氯化亚砜(2.46克，20.64毫摩尔)，混合物于26℃搅拌0.5小时。减压浓缩，粗品加入二氯甲烷(20毫升)、磷酸钾(2.19克，10.32毫摩尔)，将化合物4D(1克，3.44毫摩尔)和N,N-二异丙基乙基胺(2.67克，20.64毫摩尔)的二氯甲烷(5毫升)溶液缓慢加入上述溶液中，于26℃搅拌12小时。反应液加入水(40毫升)淬灭，二氯甲烷(40毫升×2)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩所得粗品经柱层析(PE:EA＝30:1至3:1)分离得到化合物4E。Under nitrogen protection, thionyl chloride (2.46 g, 20.64 mmol) was added to a solution of compound 1-2 (1.84 g, 5.16 mmol) in dichloromethane (30 ml), and the mixture was stirred at 26°C for 0.5 hours. After concentration under reduced pressure, dichloromethane (20 ml) and potassium phosphate (2.19 g, 10.32 mmol) were added to the crude product, and a solution of compound 4D (1 g, 3.44 mmol) and N,N-diisopropylethylamine (2.67 g, 20.64 mmol) in dichloromethane (5 ml) was slowly added to the above solution, and stirred at 26°C for 12 hours. The reaction solution was quenched by adding water (40 ml), extracted with dichloromethane (40 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by column chromatography (PE:EA=30:1 to 3:1) to obtain compound 4E.
1H NMR(400MHz,CDCl3)δppm 13.24-12.98(m,1H),9.25-9.17(m,1H),8.28-8.22(m,1H),8.06-7.97(m,1H),7.74-7.64(m,2H),4.45(br t,J＝5.6Hz,4H),3.09(br t,J＝5.1Hz,4H),2.22-2.07(m,4H),1.55-1.45(m,4H),0.50-0.40(m,4H)。LCMS(ESI)m/z:594.2[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 13.24-12.98 (m, 1H), 9.25-9.17 (m, 1H), 8.28-8.22 (m, 1H), 8.06-7.97 (m, 1H), 7.74-7.64 ( m, 2H), 4.45 (br t, J = 5.6 Hz, 4H), 3.09 (br t, J = 5.1 Hz, 4H), 2.22-2.07 (m, 4H), 1.55-1.45 (m, 4H), 0.50 -0.40(m,4H). LCMS (ESI) m/z: 594.2 [M+1].
步骤5：化合物4的合成Step 5: Synthesis of compound 4
氮气保护下，向化合物4E(300毫克，505.55微摩尔)的DMF(4毫升)溶液中加入化合物1-3(126.54毫克，1.01毫摩尔)、磷酸钾(321.94毫克，1.52毫摩尔)、碘化亚铜(96.28毫克，505.55微摩尔)、反式N,N-二甲基环己基-1,2-二胺(35.95毫克，252.78微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。向反应液中加入饱和食盐水(30毫升)，混合物用乙酸乙酯萃取(30毫升×2)，合并的有机相用无水硫酸钠干燥，过滤，滤液浓缩反应液中加入纯化水(150毫升)，加入乙酸乙酯(100毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动相：水(0.225％FA)-乙腈，梯度：51％-81％乙腈；洗脱10分钟)纯化，干燥后得到化合物4。Under nitrogen protection, compound 1-3 (126.54 mg, 1.01 mmol), potassium phosphate (321.94 mg, 1.52 mmol), cuprous iodide (96.28 mg, 505.55 mmol), trans-N,N-dimethylcyclohexyl-1,2-diamine (35.95 mg, 252.78 mmol) were added to a DMF (4 ml) solution of compound 4E (300 mg, 505.55 mmol). Nitrogen was replaced three times, and the mixture was stirred at 100°C for 12 hours. Saturated brine (30 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml x 2). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. Purified water (150 ml) was added to the reaction solution, and ethyl acetate (100 ml) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 51%-81% acetonitrile; elution within 10 minutes) and dried to obtain compound 4.
1H NMR(400MHz,DMSO-d6)δppm 13.28(s,1H),8.94(s,1H),8.47(s,1H),8.08(d,J＝8.6Hz,1H),7.33 -7.24(m,1H),7.17-7.10(m,1H),4.36(br s,4H),3.76(t,J＝6.4Hz,2H),3.40-3.30(m,2H),3.03-2.94(m,4H),2.23-2.08(m,4H),2.02-1.33(m,4H),0.41(s,4H).LCMS(ESI)m/z:591.4[M+1]。 1 H NMR (400 MHz, DMSO-d6) δ ppm 13.28 (s, 1H), 8.94 (s, 1H), 8.47 (s, 1H), 8.08 (d, J = 8.6 Hz, 1H), 7.33 -7.24 (m, 1H), 7.17-7.10 (m, 1H), 4.36 (br s, 4H), 3.76 (t, J=6.4 Hz, 2H), 3.40-3.30 (m, 2H), 3.03-2.94 (m, 4H), 2.23-2.08 (m, 4H), 2.02-1.33 (m, 4H), 0.41 (s, 4H). LCMS (ESI) m/z: 591.4 [M+1].
实施例5
Example 5
步骤1：化合物5A的合成Step 1: Synthesis of compound 5A
氮气保护下，向化合物1A(10克,39.54毫摩尔)的乙腈(30毫升)溶液中加入3,3-二氟氮杂环丁烷盐酸盐(5.63克,43.50毫摩尔)和N,N-二异丙基乙胺(22.26克,172.24毫摩尔)。加入完毕，升温至85℃，搅拌12小时，反应结束。将反应液加入水(100毫升)，乙酸乙酯(100毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩，将所得粗品悬浮于甲醇(50毫升)和水(50毫升)的混合溶剂中，于20℃搅拌1小时。混合物过滤，滤饼干燥得到化合物5A。Under nitrogen protection, 3,3-difluoroazetidine hydrochloride (5.63 g, 43.50 mmol) and N,N-diisopropylethylamine (22.26 g, 172.24 mmol) were added to a solution of compound 1A (10 g, 39.54 mmol) in acetonitrile (30 ml) . After the addition was completed, the temperature was raised to 85 ° C and stirred for 12 hours to complete the reaction. The reaction solution was added with water (100 ml) and extracted with ethyl acetate (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The obtained crude product was suspended in a mixed solvent of methanol (50 ml) and water (50 ml) and stirred at 20 ° C for 1 hour. The mixture was filtered and the filter cake was dried to obtain compound 5A.
1H NMR(400MHz,CDCl3)δppm 7.70(s,1H),4.43(t,J＝12.1Hz,6H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.70 (s, 1H), 4.43 (t, J=12.1 Hz, 6H).
步骤2：化合物5B的合成Step 2: Synthesis of compound 5B
氮气保护下，向化合物5A(10克，37.73毫摩尔)的乙醇(80毫升)和水(40毫升)溶液中加入溴乙醛缩二乙醇(39.30克，199.42毫摩尔)和48％HBr水溶液(59.60克，353.58毫摩尔)。加入完毕，升温至100℃，搅拌30分钟，反应结束。冰浴下，向反应液中加入饱和氢氧化钠水溶液(100毫升)淬灭，乙酸乙酯(200毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝50:1至10:1)得到 化合物5B。Under nitrogen protection, bromoacetaldehyde diethyl acetal (39.30 g, 199.42 mmol) and 48% HBr aqueous solution (59.60 g, 353.58 mmol) were added to a solution of compound 5A (10 g, 37.73 mmol) in ethanol (80 ml) and water (40 ml) . After the addition was completed, the temperature was raised to 100 ° C. and stirred for 30 minutes to complete the reaction. Under ice bath, saturated sodium hydroxide aqueous solution (100 ml) was added to the reaction solution to quench, and ethyl acetate (200 ml) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE: EA = 50: 1 to 10: 1) to obtain Compound 5B.
1H NMR(400MHz,DMSO-d6)δppm 8.25(s,1H),7.95(d,J＝0.9Hz,1H),7.62(d,J＝0.9Hz,1H),4.80(br t,J＝12.4Hz,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 8.25 (s, 1H), 7.95 (d, J=0.9 Hz, 1H), 7.62 (d, J=0.9 Hz, 1H), 4.80 (br t, J=12.4 Hz, 4H).
步骤3：化合物5C的合成Step 3: Synthesis of compound 5C
氮气保护下,向化合物5B(4克，13.84毫摩尔)的1,4-二氧六环(50毫升)溶液中加入氨基甲酸叔丁酯(2.43克，20.76毫摩尔)、XPhos(1.32克，2.77毫摩尔)、Pd(OAc)2(621.31毫克，2.77毫摩尔)和碳酸铯(11.27克，34.59毫摩尔)。氮气置换3-4次，混合物于110℃搅拌16小时。反应液减压抽滤，滤液加入饱和食盐水(100毫升)，用乙酸乙酯(200毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝50:1至20:1)得到化合物5C。Under nitrogen protection, tert-butyl carbamate (2.43 g, 20.76 mmol), XPhos (1.32 g, 2.77 mmol), Pd(OAc) 2 (621.31 mg, 2.77 mmol) and cesium carbonate (11.27 g, 34.59 mmol) were added to a solution of compound 5B (4 g, 13.84 mmol) in 1,4-dioxane (50 ml) . The nitrogen atmosphere was replaced 3-4 times, and the mixture was stirred at 110°C for 16 hours. The reaction solution was filtered under reduced pressure, and the filtrate was added with saturated brine (100 ml), extracted with ethyl acetate (200 ml x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=50:1 to 20:1) to obtain compound 5C.
1H NMR(400MHz,CDCl3)δppm 8.22(s,1H),7.51(dd,J＝0.7,14.9Hz,2H),6.75(br s,1H),4.77(t,J＝12.1Hz,4H),1.54(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.22 (s, 1H), 7.51 (dd, J=0.7, 14.9 Hz, 2H), 6.75 (br s, 1H), 4.77 (t, J=12.1 Hz, 4H), 1.54 (s, 9H).
步骤4：化合物5D的合成Step 4: Synthesis of compound 5D
氮气保护下，0℃向化合物5C(2.5克，7.68毫摩尔)的DMF(20毫升)溶液中缓慢加入钠氢(60％含量,768.49毫克，19.21毫摩尔)，混合物于0℃搅拌30分钟。向化合物1-2(5克，14.00毫摩尔)的二氯甲烷(40毫升)中加入氯化亚砜(3.66克，30.74毫摩尔)，混合物于25℃搅拌10分钟。减压浓缩，粗品溶于DMF(20毫升)缓慢加入上述化合物5C的反应溶液中，25℃搅拌12小时。反应液中加入水溶液(40毫升)，加入乙酸乙酯萃取(40毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1)得到化合物5D。Under nitrogen protection, sodium hydrogen (60% content, 768.49 mg, 19.21 mmol) was slowly added to a solution of compound 5C (2.5 g, 7.68 mmol) in DMF (20 ml) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Thionyl chloride (3.66 g, 30.74 mmol) was added to a solution of compound 1-2 (5 g, 14.00 mmol) in dichloromethane (40 ml), and the mixture was stirred at 25°C for 10 minutes. After concentration under reduced pressure, the crude product was dissolved in DMF (20 ml) and slowly added to the reaction solution of the above compound 5C, and stirred at 25°C for 12 hours. Aqueous solution (40 ml) was added to the reaction solution, and ethyl acetate was added for extraction (40 ml × 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA＝10:1) to obtain compound 5D.
步骤5：化合物5E的合成Step 5: Synthesis of compound 5E
氮气保护下，将化合物5D(0.4克，601.97微摩尔)的三氟乙酸(2.78毫升，37.41毫摩尔)溶液于20℃搅拌10分钟。反应液中加入水溶液(20毫升)，加入乙酸乙酯萃取(10毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝20:1)得到化合物5E。Under nitrogen protection, a solution of compound 5D (0.4 g, 601.97 μmol) in trifluoroacetic acid (2.78 ml, 37.41 mmol) was stirred at 20°C for 10 minutes. Aqueous solution (20 ml) was added to the reaction solution, and ethyl acetate (10 ml x 2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=20:1) to obtain compound 5E.
步骤6：化合物5的合成Step 6: Synthesis of compound 5
氮气保护下，向化合物5E(0.12克，212.63微摩尔)的DMF(3毫升)溶液中加入化合物1-3(53.22毫克，425.25微摩尔)、磷酸钾(135.40毫克，637.88微摩尔)、碘化亚铜(40.49毫克，212.63微摩尔)、反式N,N-二甲基环己基-1,2-二胺(15.12毫克，106.31微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液中加入水(20毫升)，加入乙酸乙酯(20毫升×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动相：水(0.225％FA)-乙腈，梯度：46％-73％乙腈；洗脱9分钟)分离得到化合物5。Under nitrogen protection, compound 1-3 (53.22 mg, 425.25 μmol), potassium phosphate (135.40 mg, 637.88 μmol), cuprous iodide (40.49 mg, 212.63 μmol), trans-N,N-dimethylcyclohexyl-1,2-diamine (15.12 mg, 106.31 μmol) were added to a DMF (3 ml) solution of compound 5E (0.12 g, 212.63 μmol). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 100°C for 12 hours. Water (20 ml) was added to the reaction solution, and ethyl acetate (20 ml x 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 46%-73% acetonitrile; elution within 9 minutes) to obtain compound 5.
1H NMR(400MHz,DMSO-d6)δppm 13.21(s,1H),8.82(s,1H),8.10(d,J＝0.9Hz,1H),8.07(d,J＝8.6 Hz,1H),7.58(d,J＝0.9Hz,1H),7.27(s,1H),7.13(br d,J＝8.0Hz,1H),4.79(br t,J＝12.3Hz,5H),3.76(t,J＝6.4Hz,2H),3.42-3.36(m,2H),2.98(br s,4H),1.81(br s,4H),0.42(s,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.21 (s, 1H), 8.82 (s, 1H), 8.10 (d, J＝0.9 Hz, 1H), 8.07 (d, J＝8.6 Hz, 1H), 7.58 (d, J = 0.9 Hz, 1H), 7.27 (s, 1H), 7.13 (br d, J = 8.0 Hz, 1H), 4.79 (br t, J = 12.3 Hz, 5H), 3.76 (t, J = 6.4 Hz, 2H), 3.42-3.36 (m, 2H), 2.98 (br s, 4H), 1.81 (br s, 4H), 0.42 (s, 4H).
实施例6
Example 6
步骤1：化合物6A的合成Step 1: Synthesis of compound 6A
氮气保护下，向化合物1A(2克,7.91毫摩尔)的乙腈(6毫升)溶液中加入2-甲基吗啡林(1克,9.89毫摩尔)和N,N-二异丙基乙胺(4.45克,34.45毫摩尔)。加入完毕，升温至85℃，搅拌12小时，反应结束。将反应液加入水(100毫升)，乙酸乙酯(100毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1至4:1)得到化合物6A。Under nitrogen protection, 2-methylmorphine (1 g, 9.89 mmol) and N,N-diisopropylethylamine (4.45 g, 34.45 mmol) were added to a solution of compound 1A (2 g, 7.91 mmol) in acetonitrile (6 ml) . After the addition was completed, the temperature was raised to 85°C and stirred for 12 hours to complete the reaction. The reaction solution was added with water (100 ml) and extracted with ethyl acetate (100 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=10:1 to 4:1) to obtain compound 6A.
1H NMR(400MHz,CDCl3)δppm 7.79(s,1H),4.59(br s,2H),4.00(dd,J＝1.7,11.6Hz,1H),3.83-3.72(m,2H),3.41(br dd,J＝1.7,12.5Hz,2H),2.95(dt,J＝3.2,12.2Hz,1H),2.67(dd,J＝10.3,12.7Hz,1H),1.24(d,J＝6.2Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.79 (s, 1H), 4.59 (br s, 2H), 4.00 (dd, J=1.7, 11.6 Hz, 1H), 3.83-3.72 (m, 2H), 3.41 (br dd, J=1.7, 12.5 Hz, 2H), 2.95 (dt, J=3.2, 12.2 Hz, 1H), 2.67 (dd, J=10.3, 12.7 Hz, 1H), 1.24 (d, J=6.2 Hz, 3H).
步骤2：化合物6B的合成Step 2: Synthesis of compound 6B
氮气保护下，向化合物6A(2.5克，9.15毫摩尔)的乙醇(40毫升)和水(20毫升)溶液中加入溴乙醛缩二乙醇(9.82克，49.86毫摩尔)和48％HBr水溶液(14.90克，88.39毫摩尔)。加入完毕，升温至100℃，搅拌30分钟，反应结束。冰浴下，向反应液中加入饱和氢氧化钠水溶液(100毫升)淬灭，乙酸乙酯(200毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝50:1至10:1)得到 化合物6B。Under nitrogen protection, bromoacetaldehyde diethyl acetal (9.82 g, 49.86 mmol) and 48% HBr aqueous solution (14.90 g, 88.39 mmol) were added to a solution of compound 6A (2.5 g, 9.15 mmol) in ethanol (40 ml) and water (20 ml) . After the addition was completed, the temperature was raised to 100 ° C. and stirred for 30 minutes to complete the reaction. Under ice bath, saturated sodium hydroxide aqueous solution (100 ml) was added to the reaction solution to quench, and ethyl acetate (200 ml) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA = 50:1 to 10:1) to obtain Compound 6B.
1H NMR(400MHz,CDCl3)δppm 7.63(s,1H),7.53(d,J＝1.0Hz,1H),7.46(d,J＝1.0Hz,1H),4.09-3.99(m,1H),3.88-3.43(m,3H),3.33-3.22(m,1H),2.92(dd,J＝10.5,13.3Hz,1H),1.30(d,J＝6.2Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.63 (s, 1H), 7.53 (d, J=1.0 Hz, 1H), 7.46 (d, J=1.0 Hz, 1H), 4.09-3.99 (m, 1H), 3.88-3.43 (m, 3H), 3.33-3.22 (m, 1H), 2.92 (dd, J=10.5, 13.3 Hz, 1H), 1.30 (d, J=6.2 Hz, 3H).
步骤3：化合物6C的合成Step 3: Synthesis of compound 6C
氮气保护下,向化合物6B(1.4克，4.71毫摩尔)的1,4-二氧六环(20毫升)溶液中加入氨基甲酸叔丁酯(827.91毫克，7.07毫摩尔)、XPhos(449.21毫克，942.28微摩尔)、Pd(OAc)2(211.55毫克，942.28微摩尔)和碳酸铯(3.84克，11.78毫摩尔)。氮气置换3次，混合物于110℃搅拌16小时。反应液减压抽滤，滤液加入饱和食盐水(100毫升)，用乙酸乙酯(200毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝50:1至20:1)得到化合物6C。Under nitrogen protection, tert-butyl carbamate (827.91 mg, 7.07 mmol), XPhos (449.21 mg, 942.28 μmol), Pd(OAc) 2 (211.55 mg, 942.28 μmol) and cesium carbonate (3.84 g, 11.78 mmol) were added to a solution of compound 6B (1.4 g, 4.71 mmol) in 1,4-dioxane (20 ml) . The nitrogen atmosphere was replaced three times, and the mixture was stirred at 110°C for 16 hours. The reaction solution was filtered under reduced pressure, saturated brine (100 ml) was added to the filtrate, and extracted with ethyl acetate (200 ml x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=50:1 to 20:1) to obtain compound 6C.
1H NMR(400MHz,CDCl3)δppm 8.17(s,1H),7.47(d,J＝14.6Hz,2H),6.66(br s,1H),5.37-5.19(m,2H),4.00(dd,J＝2.4,11.5Hz,1H),3.80-3.68(m,2H),3.25-3.16(m,1H),2.84(dd,J＝10.4,13.1Hz,1H),1.53(s,9H),1.27(d,J＝6.1Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.17 (s, 1H), 7.47 (d, J=14.6 Hz, 2H), 6.66 (br s, 1H), 5.37-5.19 (m, 2H), 4.00 (dd, J=2.4, 11.5 Hz, 1H), 3.80-3.68 (m, 2H), 3.25-3.16 (m, 1H), 2.84 (dd, J=10.4, 13.1 Hz, 1H), 1.53 (s, 9H), 1.27 (d, J=6.1 Hz, 3H).
步骤4：化合物6D的合成Step 4: Synthesis of compound 6D
氮气保护下，0℃向化合物5C(2克，6.00毫摩尔)的DMF(20毫升)溶液中缓慢加入钠氢(480毫克，12.00毫摩尔)，混合物于0℃搅拌30分钟。向化合物1-2(3.21克，9.00毫摩尔)的二氯甲烷(30毫升)中加入氯化亚砜(2.78克，23.41毫摩尔)，混合物于25℃搅拌10分钟。减压浓缩，粗品溶于DMF(30毫升)缓慢加入上述化合物5C的反应溶液中，25℃搅拌12小时。反应液中加入水溶液(80毫升)，加入乙酸乙酯萃取(80毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1)得到化合物6D。Under nitrogen protection, sodium hydrogen (480 mg, 12.00 mmol) was slowly added to a solution of compound 5C (2 g, 6.00 mmol) in DMF (20 ml) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Sulfonyl chloride (2.78 g, 23.41 mmol) was added to a solution of compound 1-2 (3.21 g, 9.00 mmol) in dichloromethane (30 ml), and the mixture was stirred at 25°C for 10 minutes. After concentration under reduced pressure, the crude product was dissolved in DMF (30 ml) and slowly added to the reaction solution of the above compound 5C, and stirred at 25°C for 12 hours. Aqueous solution (80 ml) was added to the reaction solution, and ethyl acetate was added for extraction (80 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA＝10:1) to obtain compound 6D.
步骤5：化合物6E的合成Step 5: Synthesis of compound 6E
氮气保护下，将化合物6D(1.6克，2.38毫摩尔)的三氟乙酸(16.47毫升，221.79毫摩尔)溶液于20℃搅拌10分钟。反应液中加入水溶液(20毫升)，加入乙酸乙酯萃取(10毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝20:1)得到化合物5E。Under nitrogen protection, a solution of compound 6D (1.6 g, 2.38 mmol) in trifluoroacetic acid (16.47 ml, 221.79 mmol) was stirred at 20°C for 10 minutes. Aqueous solution (20 ml) was added to the reaction solution, and ethyl acetate (10 ml x 2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=20:1) to obtain compound 5E.
步骤6：化合物5的合成Step 6: Synthesis of compound 5
氮气保护下，向化合物6E(140毫克，244.57微摩尔)的DMF(4毫升)溶液中加入化合物1-3(61.21毫克，489.13微摩尔)、磷酸钾(155.74毫克，733.70微摩尔)、碘化亚铜(46.58毫克，244.57微摩尔)、反式N,N-二甲基环己基-1,2-二胺(17.39毫克，122.28微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液中加入水(20毫升)，加入乙酸乙酯(20毫升×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC(柱型：Waters Xbridge 150*25mm*5μm；流动相：水(0.05％氨水)-乙腈，梯度：26％-56％乙腈；洗脱9分钟)分离得到化合物6。 Under nitrogen protection, compound 1-3 (61.21 mg, 489.13 μmol), potassium phosphate (155.74 mg, 733.70 μmol), cuprous iodide (46.58 mg, 244.57 μmol), trans-N,N-dimethylcyclohexyl-1,2-diamine (17.39 mg, 122.28 μmol) were added to a DMF (4 ml) solution of compound 6E (140 mg, 244.57 μmol). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 100°C for 12 hours. Water (20 ml) was added to the reaction solution, and ethyl acetate (20 ml × 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column type: Waters Xbridge 150*25mm*5μm; mobile phase: water (0.05% ammonia water)-acetonitrile, gradient: 26%-56% acetonitrile; elution time 9 minutes) to obtain compound 6.
1H NMR(400MHz,DMSO-d6)δppm 12.76(s,1H),11.07-9.79(m,1H),8.81(s,1H),8.09-8.06(m,2H),7.55(s,1H),7.27(s,1H),7.14(br d,J＝8.6Hz,1H),5.48-5.17(m,2H),3.95(br s,1H),3.80-3.60(m,4H),3.37-3.34(m,2H),3.23-3.12(m,1H),2.99(br s,4H),2.87(br s,1H),2.10-1.41(m,4H),1.19(d,J＝6.2Hz,4H),0.41(s,4H)。 1 H NMR (400 MHz, DMSO-d6) δ ppm 12.76 (s, 1H), 11.07-9.79 (m, 1H), 8.81 (s, 1H), 8.09-8.06 (m, 2H), 7.55 (s, 1H), 7.27 (s, 1H), 7.14 (br d, J=8.6 Hz, 1H), 5.48-5.17 (m, 2H), 3.95 (br s, 1H), 3.80-3.60 (m, 4H), 3.37-3.34 (m, 2H), 3.23-3.12 (m, 1H), 2.99 (br s, 4H), 2.87 (br s, 1H), 2.10-1.41 (m, 4H), 1.19 (d, J=6.2 Hz, 4H), 0.41 (s, 4H).
实施例7
Example 7
步骤1：化合物7A的合成Step 1: Synthesis of compound 7A
氮气保护下，向化合物1B(4.00克，13.65毫摩尔)的N,N-二甲基乙酰胺(20毫升)溶液中加入3-溴-1,1,1-三氟甲基-2-丙酮(6.51克，34.12毫摩尔)。混合物于90℃搅拌48小时，向反应液中加入水(100毫升)，乙酸乙酯(200毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝100:1至500:1)得到化合物7A。Under nitrogen protection, 3-bromo-1,1,1-trifluoromethyl-2-propanone (6.51 g, 34.12 mmol) was added to a solution of compound 1B (4.00 g, 13.65 mmol) in N,N-dimethylacetamide (20 ml) The mixture was stirred at 90°C for 48 hours, water (100 ml) was added to the reaction solution, and ethyl acetate (200 ml x 2) was used for extraction, the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=100:1 to 500:1) to obtain compound 7A.
1H NMR(400MHz,CDCl3)δppm 7.78-7.73(m,1H),7.67-7.59(m,1H),4.55-4.39(m,4H),2.20-2.08(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.78-7.73 (m, 1H), 7.67-7.59 (m, 1H), 4.55-4.39 (m, 4H), 2.20-2.08 (m, 4H).
步骤2：化合物7B的合成Step 2: Synthesis of compound 7B
氮气保护下，向化合物7A(2.60克，6.75毫摩尔)的DMF(25毫升)溶液中加入二苯甲酮亚胺(1.84 克，10.13毫摩尔)、Xantphos(781.25毫克，1.35毫摩尔)、Pd(dba)2(776.37毫克，1.35毫摩尔)和碳酸铯(6.60克，20.25毫摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液减压抽滤，滤液加入水(50毫升),用乙酸乙酯萃取(100毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝400:1至20:1)得到化合物7B。Under nitrogen protection, to a solution of compound 7A (2.60 g, 6.75 mmol) in DMF (25 ml) was added benzophenone imine (1.84 g, 10.13 mmol), Xantphos (781.25 mg, 1.35 mmol), Pd(dba) 2 (776.37 mg, 1.35 mmol) and cesium carbonate (6.60 g, 20.25 mmol). The atmosphere was replaced with nitrogen three times, and the mixture was stirred at 100°C for 12 hours. The reaction solution was filtered under reduced pressure, and water (50 ml) was added to the filtrate, and extracted with ethyl acetate (100 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=400:1 to 20:1) to obtain compound 7B.
步骤3：化合物7C的合成Step 3: Synthesis of compound 7C
氮气保护下，向化合物7B(3.60克，7.42毫摩尔)的四氢呋喃(25毫升)溶液中缓慢滴加稀盐酸(2M，13毫升)，混合物于20℃搅拌5分钟。反应液用饱和碳酸氢钠水溶液(30毫升)淬灭，用乙酸乙酯萃取(100毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝50:1至10:1)得到化合物7C。Under nitrogen protection, dilute hydrochloric acid (2M, 13 mL) was slowly added dropwise to a solution of compound 7B (3.60 g, 7.42 mmol) in tetrahydrofuran (25 mL), and the mixture was stirred at 20° C. for 5 minutes. The reaction solution was quenched with saturated aqueous sodium bicarbonate solution (30 mL), extracted with ethyl acetate (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=50:1 to 10:1) to obtain compound 7C.
1H NMR(400MHz,CDCl3)δppm 7.62(s,1H),6.91(s,1H),4.46-4.36(m,4H),3.96-3.63(m,2H),2.15-2.06(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.62 (s, 1H), 6.91 (s, 1H), 4.46-4.36 (m, 4H), 3.96-3.63 (m, 2H), 2.15-2.06 (m, 4H).
步骤4：化合物7D的合成Step 4: Synthesis of compound 7D
氮气保护下，向化合物1-2(1.67克，4.67毫摩尔)的二氯甲烷(20毫升)中加入氯化亚砜(2.22克，18.68毫摩尔)和催化量DMF(1滴)，混合物于26℃搅拌0.5小时。减压浓缩，粗品加入二氯甲烷(10毫升)、磷酸钾(1.98克，9.34毫摩尔)，将化合物7C(1.00克，3.11毫摩尔)和N,N-二异丙基乙基胺(2.41克，18.68毫摩尔)缓慢加入上述溶液中，混合物于26℃搅拌12小时。反应液加入水(40毫升)淬灭，二氯甲烷(40毫升×2)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩所得粗品经柱层析(PE:EA＝30:1)分离得到化合物7D。Under nitrogen protection, thionyl chloride (2.22 g, 18.68 mmol) and catalytic amount of DMF (1 drop) were added to compound 1-2 (1.67 g, 4.67 mmol) in dichloromethane (20 ml), and the mixture was stirred at 26°C for 0.5 hours. After concentration under reduced pressure, dichloromethane (10 ml) and potassium phosphate (1.98 g, 9.34 mmol) were added to the crude product, and compound 7C (1.00 g, 3.11 mmol) and N,N-diisopropylethylamine (2.41 g, 18.68 mmol) were slowly added to the above solution, and the mixture was stirred at 26°C for 12 hours. The reaction solution was quenched by adding water (40 ml), extracted with dichloromethane (40 ml×2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by column chromatography (PE:EA＝30:1) to obtain compound 7D.
1H NMR(400MHz,CDCl3)δppm 13.03-12.95(m,1H),8.81(s,1H),8.00(d,J＝8.8Hz,1H),7.82(s,1H),7.71-7.67(m,2H),4.53-4.44(m,4H),3.13-3.05(m,4H),2.18-2.11(m,4H),1.60-1.49(m,4H),0.49-0.41(m,4H)。LCMS(ESI)m/z:661.2[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 13.03-12.95 (m, 1H), 8.81 (s, 1H), 8.00 (d, J＝8.8 Hz, 1H), 7.82 (s, 1H), 7.71-7.67 (m , 2H), 4.53-4.44(m, 4H), 3.13-3.05(m, 4H), 2.18-2.11(m, 4H), 1.60-1.49(m, 4H), 0.49-0.41(m, 4H). LCMS (ESI) m/z: 661.2 [M+1].
步骤5：化合物7的合成Step 5: Synthesis of compound 7
氮气保护下，向化合物7D(200毫克，302.84微摩尔)的DMF(5毫升)溶液中加入化合物1-3(75.80毫克，605.68微摩尔)、磷酸钾(192.85毫克，908.51微摩尔)、碘化亚铜(57.68毫克，302.84微摩尔)、反式N,N-二甲基环己基-1,2-二胺(21.54毫克，151.42微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液中加入饱和食盐水(30毫升)，用乙酸乙酯(30毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动相：水(0.225％FA)-乙腈，梯度：66％-96％乙腈；洗脱10分钟)纯化，干燥后得到化合物7。Under nitrogen protection, compound 1-3 (75.80 mg, 605.68 μmol), potassium phosphate (192.85 mg, 908.51 μmol), cuprous iodide (57.68 mg, 302.84 μmol), trans-N,N-dimethylcyclohexyl-1,2-diamine (21.54 mg, 151.42 μmol) were added to a DMF (5 ml) solution of compound 7D (200 mg, 302.84 μmol). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 100°C for 12 hours. Saturated brine (30 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 66%-96% acetonitrile; elution within 10 minutes) and dried to obtain compound 7.
1H NMR(400MHz,DMSO-d6)δppm 13.01(br s,1H),10.37-10.03(m,1H),8.87(br s,1H),8.70(br s,1H),8.08(br d,J＝8.4Hz,1H),7.29(br s,1H),7.15(br d,J＝7.9Hz,1H),5.09-4.83(m,1H),4.45-4.30(m,4H), 3.76(br s,2H),3.40-3.30(m,2H),2.98(br s,4H),2.24-2.07(m,4H),1.96-1.45(m,4H),0.41(br s,4H)。LCMS(ESI)m/z:658.2[M+1]。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.01 (br s, 1H), 10.37-10.03 (m, 1H), 8.87 (br s, 1H), 8.70 (br s, 1H), 8.08 (br d, J=8.4 Hz, 1H), 7.29 (br s, 1H), 7.15 (br d, J=7.9 Hz, 1H), 5.09-4.83 (m, 1H), 4.45-4.30 (m, 4H), 3.76 (br s, 2H), 3.40-3.30 (m, 2H), 2.98 (br s, 4H), 2.24-2.07 (m, 4H), 1.96-1.45 (m, 4H), 0.41 (br s, 4H). LCMS (ESI) m/z: 658.2 [M+1].
实施例8
Example 8
步骤1：化合物8A的合成Step 1: Synthesis of compound 8A
氮气保护下，向化合物1B(5.00克，17.06毫摩尔)的异丙醇(50毫升)溶液中加入对甲苯磺酸吡啶盐(428.68毫克，1.71毫摩尔)和1-溴-2,2-甲氧基丙烷(4.68克，25.59毫摩尔)。混合物于85℃搅拌12小时，向反应液中加入饱和食盐水(50毫升)，用乙酸乙酯(200毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝100:1至50:1)得到化合物8A。Under nitrogen protection, pyridinium p-toluenesulfonate (428.68 mg, 1.71 mmol) and 1-bromo-2,2-methoxypropane (4.68 g, 25.59 mmol) were added to a solution of compound 1B (5.00 g, 17.06 mmol) in isopropanol (50 ml) . The mixture was stirred at 85°C for 12 hours, saturated brine (50 ml) was added to the reaction solution, extracted with ethyl acetate (200 ml x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=100:1 to 50:1) to obtain compound 8A.
1H NMR(400MHz,CDCl3)δppm 7.57(s,1H),7.22(d,J＝0.6Hz,1H),4.52-4.37(m,4H),2.41(d,J＝0.6Hz,3H),2.18-2.04(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.57 (s, 1H), 7.22 (d, J=0.6 Hz, 1H), 4.52-4.37 (m, 4H), 2.41 (d, J=0.6 Hz, 3H), 2.18-2.04 (m, 4H).
步骤2：化合物8B的合成Step 2: Synthesis of compound 8B
氮气保护下，向化合物8A(3.90克，11.78毫摩尔)的1,4-二氧六环(40毫升)溶液中加入氨基甲酸叔丁酯(2.07克，17.67毫摩尔)、XPhos(1.12克，2.36毫摩尔)、Pd(OAc)2(528.80毫克，2.36毫摩尔)和碳酸铯(9.59克，29.44毫摩尔)。氮气置换3次，混合物于110℃搅拌12小时。反应液减压抽滤，滤液加入饱 和食盐水(100毫升)，用乙酸乙酯(100毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝100:1至5:1)得到化合物8B。Under nitrogen protection, tert-butyl carbamate (2.07 g, 17.67 mmol), XPhos (1.12 g, 2.36 mmol), Pd(OAc) 2 (528.80 mg, 2.36 mmol) and cesium carbonate (9.59 g, 29.44 mmol) were added to a solution of compound 8A (3.90 g, 11.78 mmol) in 1,4-dioxane (40 ml) . The nitrogen atmosphere was replaced three times and the mixture was stirred at 110°C for 12 hours. The reaction solution was filtered under reduced pressure and the filtrate was added with saturated and brine (100 mL), extracted with ethyl acetate (100 mL×2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=100:1 to 5:1) to give compound 8B.
1H NMR(400MHz,CDCl3)δppm 8.11(s,1H),7.21(s,1H),6.63(s,1H),4.42-4.29(m,4H),2.39(s,3H),2.15-2.00(m,4H),1.53(s,9H)。LCMS(ESI):m/z:368.1[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.11 (s, 1H), 7.21 (s, 1H), 6.63 (s, 1H), 4.42-4.29 (m, 4H), 2.39 (s, 3H), 2.15-2.00 (m, 4H), 1.53 (s, 9H). LCMS (ESI): m/z: 368.1 [M+1].
步骤3：化合物8C的合成Step 3: Synthesis of compound 8C
氮气保护下，0℃向化合物8B(1.00克，2.72毫摩尔)的DMF(10毫升)溶液中缓慢加入钠氢(217.75毫克，5.44毫摩尔)，混合物于0℃搅拌30分钟。向化合物1-2(1.46克，4.08毫摩尔)的二氯甲烷(20毫升)中加入氯化亚砜(1.94克，16.32毫摩尔)，混合物于26℃搅拌30分钟。减压浓缩，粗品溶于DMF(8毫升)缓慢加入上述化合物8B的反应溶液中，25℃搅拌12小时。反应液中加入水溶液(100毫升)，用乙酸乙酯萃取(100毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝200:1至50:1)得到化合物8C。Under nitrogen protection, sodium hydrogen (217.75 mg, 5.44 mmol) was slowly added to a solution of compound 8B (1.00 g, 2.72 mmol) in DMF (10 ml) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Thionyl chloride (1.94 g, 16.32 mmol) was added to a solution of compound 1-2 (1.46 g, 4.08 mmol) in dichloromethane (20 ml), and the mixture was stirred at 26°C for 30 minutes. The mixture was concentrated under reduced pressure, and the crude product was dissolved in DMF (8 ml) and slowly added to the reaction solution of the above compound 8B, and stirred at 25°C for 12 hours. Aqueous solution (100 ml) was added to the reaction solution, and extracted with ethyl acetate (100 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=200:1 to 50:1) to obtain compound 8C.
1H NMR(400MHz,CDCl3)δppm 7.49(s,1H),7.46-7.31(m,3H),7.17(d,J＝8.1Hz,1H),4.40-4.32(m,4H),3.17-3.04(m,4H),2.47-2.42(m,3H),2.13-2.01(m,4H),1.57(br d,J＝5.1Hz,4H),1.28(s,9H),0.36(s,4H)。LCMS(ESI):m/z:707.0[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.49 (s, 1H), 7.46-7.31 (m, 3H), 7.17 (d, J＝8.1 Hz, 1H), 4.40-4.32 (m, 4H), 3.17-3.04 (m, 4H), 2.47-2.42 (m, 3H), 2.13-2.01 (m, 4H), 1.57 (br d, J = 5.1 Hz, 4H), 1.28 (s, 9H), 0.36 (s, 4H) . LCMS (ESI): m/z: 707.0 [M+1].
步骤4：化合物8D的合成Step 4: Synthesis of compound 8D
氮气保护下，将化合物8C(330毫克，467.05微摩尔)的三氟乙酸(3毫升)溶液于20℃搅拌2小时。反应液中加入饱和碳酸氢钠水溶液(20毫升)，用乙酸乙酯萃取(20毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过制备薄层硅胶层析分离(PE:EA＝3:1)得到化合物8D。Under nitrogen protection, a solution of compound 8C (330 mg, 467.05 μmol) in trifluoroacetic acid (3 ml) was stirred at 20°C for 2 hours. Saturated aqueous sodium bicarbonate solution (20 ml) was added to the reaction solution, and extracted with ethyl acetate (20 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by preparative thin layer silica gel chromatography (PE:EA=3:1) to obtain compound 8D.
1H NMR(400MHz,CDCl3)δppm 13.30(br d,J＝2.4Hz,1H),8.96-8.82(m,1H),8.07-7.95(m,1H),7.75-7.67(m,2H),7.44-7.36(m,1H),4.22-4.09(m,4H),3.09(br s,4H),2.63-2.47(m,7H),2.23-2.13(m,4H),0.45(s,4H)。LCMS(ESI):m/z:607.1[M+1]。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 13.30 (br d, J = 2.4 Hz, 1H), 8.96-8.82 (m, 1H), 8.07-7.95 (m, 1H), 7.75-7.67 (m, 2H), 7.44-7.36 (m, 1H), 4.22-4.09 (m, 4H), 3.09 (br s, 4H), 2.63-2.47 (m, 7H), 2.23-2.13 (m, 4H), 0.45 (s, 4H) . LCMS (ESI): m/z: 607.1 [M+1].
步骤5：化合物8的合成Step 5: Synthesis of compound 8
氮气保护下，向化合物8D(258毫克，425.23微摩尔)的DMF(4毫升)溶液中加入化合物1-3(106.48毫克，850.86微摩尔)、磷酸钾(270.92毫克，1.28毫摩尔)、碘化亚铜(81.02毫克，425.43微摩尔)、反式N,N-二甲基环己基-1,2-二胺(30.26毫克，2112.71微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液中加入饱和食盐水(30毫升)，用入乙酸乙酯(30毫升×2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动相：水(0.225％FA)-乙腈，梯度：55％-85％乙腈；洗脱10分钟)分离得到化合物8。Under nitrogen protection, compound 1-3 (106.48 mg, 850.86 μmol), potassium phosphate (270.92 mg, 1.28 mmol), cuprous iodide (81.02 mg, 425.43 μmol), trans-N,N-dimethylcyclohexyl-1,2-diamine (30.26 mg, 2112.71 μmol) were added to a DMF (4 ml) solution of compound 8D (258 mg, 425.23 μmol). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 100°C for 12 hours. Saturated brine (30 ml) was added to the reaction solution, and extracted with ethyl acetate (30 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 55%-85% acetonitrile; elution within 10 minutes) to obtain compound 8.
1H NMR(400MHz,DMSO-d6)δppm 12.86(br s,1H),8.74(s,1H),8.06(br d,J＝8.4Hz,1H),7.80(s,1H),7.26(br s,1H),7.12(br d,J＝8.6Hz,1H),4.38(br s,4H),3.76(br t,J＝6.1Hz,2H),3.40-3.30(m,2H),2.97(br  s,4H),2.32(br s,3H),2.08(br d,J＝10.0Hz,4H),1.99-1.32(m,4H),0.40(br s,4H)。LCMS(ESI)m/z:604.1[M+1]。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.86 (br s, 1H), 8.74 (s, 1H), 8.06 (br d, J=8.4 Hz, 1H), 7.80 (s, 1H), 7.26 (br s, 1H), 7.12 (br d, J=8.6 Hz, 1H), 4.38 (br s, 4H), 3.76 (br t, J=6.1 Hz, 2H), 3.40-3.30 (m, 2H), 2.97 (br s, 4H), 2.32 (br s, 3H), 2.08 (br d, J＝10.0 Hz, 4H), 1.99-1.32 (m, 4H), 0.40 (br s, 4H). LCMS (ESI) m/z: 604.1 [M+1].
实施例9
Example 9
步骤1：化合物9-3的合成Step 1: Synthesis of compound 9-3
向双(4-甲氧基苄基)胺(14.40克,55.96毫摩尔)的二氯甲烷(40毫升)溶液中加入N,N-二异丙基乙胺(8.48克,65.61毫摩尔)和化合物9-2(8克，46.35毫摩尔)。混合物于20℃搅拌16小时，向反应液中加稀盐酸(20毫升，2摩尔/升)，用乙酸乙酯(20毫升)萃取，有机相用10％碳酸钠水溶液(20毫升)洗涤，无水硫酸钠干燥，过滤浓缩，所得粗品经制备HPLC(柱型：Phenomenex luna C18(250*70mm,10μm)；流动相：水(0.225％FA)-乙腈，梯度：50％-80％乙腈；洗脱18分钟)分离得到化合物9-3。To a solution of bis(4-methoxybenzyl)amine (14.40 g, 55.96 mmol) in dichloromethane (40 ml) was added N,N-diisopropylethylamine (8.48 g, 65.61 mmol) and compound 9-2 (8 g, 46.35 mmol). The mixture was stirred at 20°C for 16 hours, diluted hydrochloric acid (20 ml, 2 mol/L) was added to the reaction solution, extracted with ethyl acetate (20 ml), the organic phase was washed with 10% sodium carbonate aqueous solution (20 ml), dried over anhydrous sodium sulfate, filtered and concentrated, and the crude product was separated by preparative HPLC (column type: Phenomenex luna C18 (250*70mm, 10μm); mobile phase: water (0.225% FA)-acetonitrile, gradient: 50%-80% acetonitrile; elution 18 minutes) to obtain compound 9-3.
1H NMR(400MHz,DMSO-d6)δppm 7.17-7.11(m,J＝8.6Hz,4H),6.88-6.83(m,J＝8.6Hz,4H),4.30-4.22(m,6H),4.15(q,J＝7.1Hz,2H),3.73(s,6H),1.21(t,J＝7.1Hz,3H)。 1 H NMR (400 MHz, DMSO-d6) δ ppm 7.17-7.11 (m, J=8.6 Hz, 4H), 6.88-6.83 (m, J=8.6 Hz, 4H), 4.30-4.22 (m, 6H), 4.15 (q, J=7.1 Hz, 2H), 3.73 (s, 6H), 1.21 (t, J=7.1 Hz, 3H).
步骤2：化合物9-4的合成Step 2: Synthesis of compound 9-4
氮气保护下，0℃向化合物9-3(13克，31.90毫摩尔)的DMF(100毫升)溶液中缓慢加入钠氢(60％含量,4.56克，113.90毫摩尔)，混合物于0℃搅拌30分钟。将碘甲烷(44.46克，313.24毫摩尔)缓慢加入上述反应溶液中，20℃搅拌2小时。反应液中加入水溶液(200毫升)，用乙酸乙酯萃取(300毫升)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1至1:1)得到化合物9-4。Under nitrogen protection, sodium hydrogen (60% content, 4.56 g, 113.90 mmol) was slowly added to a DMF (100 ml) solution of compound 9-3 (13 g, 31.90 mmol) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Iodomethane (44.46 g, 313.24 mmol) was slowly added to the above reaction solution and stirred at 20°C for 2 hours. Aqueous solution (200 ml) was added to the reaction solution and extracted with ethyl acetate (300 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=10:1 to 1:1) to obtain compound 9-4.
1H NMR(400MHz,CDCl3)δppm 7.10(d,J＝8.4Hz,4H),6.79(d,J＝8.6Hz,4H),4.33-4.23(m,6H),3.79(s,6H),1.74(s,6H),1.33(t,J＝7.1Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.10 (d, J=8.4 Hz, 4H), 6.79 (d, J=8.6 Hz, 4H), 4.33-4.23 (m, 6H), 3.79 (s, 6H), 1.74 (s, 6H), 1.33 (t, J=7.1 Hz, 3H).
步骤3：化合物9-1的合成 Step 3: Synthesis of compound 9-1
将化合物9-4(3克，6.89毫摩尔)的三氟乙酸(30毫升)和苯甲醚(5毫升)溶液于25℃搅拌16小时。反应液浓缩，向所得残留物中加入饱和碳酸氢钠水溶液(20毫升)，二氯甲烷(30毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1至1:1)得到化合物9-1。A solution of compound 9-4 (3 g, 6.89 mmol) in trifluoroacetic acid (30 ml) and anisole (5 ml) was stirred at 25° C. for 16 hours. The reaction solution was concentrated, and a saturated aqueous sodium bicarbonate solution (20 ml) was added to the resulting residue, and the mixture was extracted with dichloromethane (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=10:1 to 1:1) to obtain compound 9-1.
1H NMR(400MHz,CDCl3)δppm 4.95(br s,2H),4.27(q,J＝7.1Hz,2H),1.70(s,6H),1.33(t,J＝7.2Hz,3H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.95 (br s, 2H), 4.27 (q, J=7.1 Hz, 2H), 1.70 (s, 6H), 1.33 (t, J=7.2 Hz, 3H).
步骤4：化合物9A的合成Step 4: Synthesis of Compound 9A
氮气保护下，向化合物1F(0.30克，506.40微摩尔)的DMF(9毫升)溶液中加入化合物9-1(296.60毫克，1.52毫摩尔)、磷酸钾(322.48毫克，1.52毫摩尔)、碘化亚铜(96.44毫克，506.40微摩尔)、反式N,N-二甲基环己基-1,2-二胺(36.01毫克，253.20微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液中加入水(30毫升)，用乙酸乙酯(30毫升×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备薄层硅胶层析(二氯甲烷:甲醇＝20:1)分离得到化合物9A。Under nitrogen protection, compound 9-1 (296.60 mg, 1.52 mmol), potassium phosphate (322.48 mg, 1.52 mmol), cuprous iodide (96.44 mg, 506.40 micromol), trans-N,N-dimethylcyclohexyl-1,2-diamine (36.01 mg, 253.20 micromol) were added to a DMF (9 ml) solution of compound 1F (0.30 g, 506.40 micromol). Nitrogen was replaced 3 times, and the mixture was stirred at 100°C for 12 hours. Water (30 ml) was added to the reaction solution, extracted with ethyl acetate (30 ml × 3), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative thin layer silica gel chromatography (dichloromethane: methanol = 20:1) to obtain compound 9A.
1H NMR(400MHz,DMSO-d6)δppm 12.93(s,1H),10.61-10.33(m,1H),8.83(s,1H),8.15-7.97(m,2H),7.55(d,J＝0.8Hz,1H),7.38(d,J＝2.1Hz,1H),7.23-7.14(m,1H),4.43(br s,4H),4.19-4.08(m,2H),2.96(br s,4H),2.18-2.05(m,4H),1.97-1.60(m,4H),1.50(s,6H),1.03(t,J＝7.1Hz,3H),0.41(s,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.93 (s, 1H), 10.61-10.33 (m, 1H), 8.83 (s, 1H), 8.15-7.97 (m, 2H), 7.55 (d, J=0.8 Hz, 1H), 7.38 (d, J=2.1 Hz, 1H), 7.23-7.14 (m, 1H), 4.43 (br s, 4H), 4.19-4.08 (m, 2H), 2.96 (br s, 4H), 2.18-2.05 (m, 4H), 1.97-1.60 (m, 4H), 1.50 (s, 6H), 1.03 (t, J=7.1 Hz, 3H), 0.41 (s, 4H).
步骤5：化合物9的合成Step 5: Synthesis of compound 9
氮气保护下，于-70℃向化合物9A(180毫克，272.83微摩尔)的四氢呋喃(15毫升)溶液中滴加硼氢化锂的四氢呋喃溶液(0.55毫升，2摩尔/升)。混合物于20℃搅拌2小时。向反应液中加入饱和氯化铵水溶液(20毫升)，用乙酸乙酯(30毫升x2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动相：水(0.225％FA)-乙腈，梯度：57％-87％乙腈；洗脱10分钟)分离得到化合物9。Under nitrogen protection, a tetrahydrofuran solution of lithium borohydride (0.55 ml, 2 mol/L) was added dropwise to a tetrahydrofuran (15 ml) solution of compound 9A (180 mg, 272.83 μmol) at -70°C. The mixture was stirred at 20°C for 2 hours. A saturated aqueous solution of ammonium chloride (20 ml) was added to the reaction solution, extracted with ethyl acetate (30 ml x 2), and the organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 57%-87% acetonitrile; elution 10 minutes) to obtain compound 9.
1H NMR(400MHz,DMSO-d6)δppm 12.93(s,1H),9.98(s,1H),8.83(s,1H),8.08(d,J＝0.7Hz,1H),8.04(d,J＝8.6Hz,1H),7.55(s,1H),7.43(d,J＝2.0Hz,1H),7.19(dd,J＝2.0,8.7Hz,1H),4.43(br s,4H),3.55(s,2H),2.97(br s,4H),2.19-2.03(m,4H),1.75(br s,4H),1.25(s,6H),0.41(s,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 12.93 (s, 1H), 9.98 (s, 1H), 8.83 (s, 1H), 8.08 (d, J=0.7 Hz, 1H), 8.04 (d, J=8.6 Hz, 1H), 7.55 (s, 1H), 7.43 (d, J=2.0 Hz, 1H), 7.19 (dd, J=2.0, 8.7 Hz, 1H), 4.43 (br s, 4H), 3.55 (s, 2H), 2.97 (br s, 4H), 2.19-2.03 (m, 4H), 1.75 (br s, 4H), 1.25 (s, 6H), 0.41 (s, 4H).
实施例10

Example 10

步骤1：化合物10A的合成Step 1: Synthesis of compound 10A
氮气保护下，向化合物1A(5克,19.77毫摩尔)的乙腈(15毫升)溶液中加入吗啡林(2.18克,25.00毫摩尔)和N,N-二异丙基乙胺(11.13克,86.12毫摩尔)。加入完毕，升温至100℃，搅拌12小时，反应结束。向反应液加入水(100毫升)，乙酸乙酯(100毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1至1:1)得到化合物10A。Under nitrogen protection, add morphine (2.18 g, 25.00 mmol) and N,N-diisopropylethylamine (11.13 g, 86.12 mmol) to a solution of compound 1A (5 g, 19.77 mmol) in acetonitrile (15 ml). After the addition is complete, heat to 100°C and stir for 12 hours to terminate the reaction. Add water (100 ml) to the reaction solution, extract with ethyl acetate (100 ml), dry the organic phase with anhydrous sodium sulfate, filter and concentrate, and separate the residue by column chromatography (PE:EA=10:1 to 1:1) to obtain compound 10A.
1H NMR(400MHz,CDCl3)δppm 7.78(s,1H),4.60(br s,2H),3.91-3.78(m,4H),3.27-3.14(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.78 (s, 1H), 4.60 (br s, 2H), 3.91-3.78 (m, 4H), 3.27-3.14 (m, 4H).
步骤2：化合物10B的合成Step 2: Synthesis of compound 10B
氮气保护下，向化合物10A(4.8克，18.53毫摩尔)的乙醇(80毫升)和水(40毫升)溶液中加入溴乙醛缩二乙醇(19.65克，99.71毫摩尔)和48％HBr水溶液(29.80克，176.79毫摩尔)。加入完毕，升温至100℃，搅拌30分钟，反应结束。冰浴下，向反应液中加入饱和氢氧化钠水溶液(80毫升)淬灭，乙酸乙酯(100毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1至8:1)得到化合物10B。Under nitrogen protection, bromoacetaldehyde diethyl acetal (19.65 g, 99.71 mmol) and 48% HBr aqueous solution (29.80 g, 176.79 mmol) were added to a solution of compound 10A (4.8 g, 18.53 mmol) in ethanol (80 ml) and water (40 ml) . After the addition was completed, the temperature was raised to 100 ° C and stirred for 30 minutes to terminate the reaction. Under ice bath, saturated sodium hydroxide aqueous solution (80 ml) was added to the reaction solution to quench, and ethyl acetate (100 ml) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=10:1 to 8:1) to obtain compound 10B.
1H NMR(400MHz,CDCl3)δppm 7.63(s,1H),7.52(d,J＝1.0Hz,1H),7.46(d,J＝1.0Hz,1H),4.41-4.28(m,4H),3.90-3.81(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 7.63 (s, 1H), 7.52 (d, J=1.0 Hz, 1H), 7.46 (d, J=1.0 Hz, 1H), 4.41-4.28 (m, 4H), 3.90-3.81 (m, 4H).
步骤3：化合物10C的合成Step 3: Synthesis of compound 10C
氮气保护下,向化合物10B(3克，10.60毫摩尔)的1,4-二氧六环(40毫升)溶液中加入氨基甲酸叔丁酯(1.80克，15.36毫摩尔)、XPhos(1克，2.10毫摩尔)、Pd(OAc)2(0.5克，2.23毫摩尔)和碳酸铯(8.6克，26.39毫摩尔)。氮气置换3次，混合物于110℃搅拌16小时。反应液减压抽滤，滤液加入饱和食盐水(100毫升)，用二氯甲烷(80毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝6:1)得到化合物10C。Under nitrogen protection, tert-butyl carbamate (1.80 g, 15.36 mmol), XPhos (1 g, 2.10 mmol), Pd(OAc) 2 (0.5 g, 2.23 mmol) and cesium carbonate (8.6 g, 26.39 mmol) were added to a solution of compound 10B (3 g, 10.60 mmol) in 1,4-dioxane (40 ml) . The nitrogen atmosphere was replaced three times, and the mixture was stirred at 110°C for 16 hours. The reaction solution was filtered under reduced pressure, saturated brine (100 ml) was added to the filtrate, and extracted with dichloromethane (80 ml x 2), the organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=6:1) to obtain compound 10C.
1H NMR(400MHz,CDCl3)δppm 8.18(s,1H),7.49(s,1H),7.45(s,1H),6.68(br s,1H),4.31-4.19(m,4H),3.88-3.80(m,4H),1.53(s,9H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.18 (s, 1H), 7.49 (s, 1H), 7.45 (s, 1H), 6.68 (br s, 1H), 4.31-4.19 (m, 4H), 3.88-3.80 (m, 4H), 1.53 (s, 9H).
步骤4：化合物10D的合成Step 4: Synthesis of compound 10D
氮气保护下，0℃向化合物10C(1.8克，5.64毫摩尔)的DMF(20毫升)溶液中缓慢加入钠氢(60％含量，450毫克，11.25毫摩尔)，混合物于0℃搅拌30分钟。向化合物1-2(3克，8.40毫摩尔)的二氯甲烷(30毫升)中加入氯化亚砜(2.62克，21.99毫摩尔)，混合物于25℃搅拌10分钟。减压浓缩，粗品溶于DMF(30毫升)缓慢加入上述化合物10C的反应溶液中，25℃搅拌12小时。反应液中加入水溶液(80毫升)，加入乙酸乙酯萃取(80毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1)得到化合物10D。Under nitrogen protection, sodium hydrogen (60% content, 450 mg, 11.25 mmol) was slowly added to a solution of compound 10C (1.8 g, 5.64 mmol) in DMF (20 ml) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Thionyl chloride (2.62 g, 21.99 mmol) was added to a solution of compound 1-2 (3 g, 8.40 mmol) in dichloromethane (30 ml), and the mixture was stirred at 25°C for 10 minutes. The mixture was concentrated under reduced pressure, and the crude product was dissolved in DMF (30 ml) and slowly added to the reaction solution of the above compound 10C, and stirred at 25°C for 12 hours. Aqueous solution (80 ml) was added to the reaction solution, and ethyl acetate was added for extraction (80 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA＝10:1) to obtain compound 10D.
步骤5：化合物10E的合成Step 5: Synthesis of compound 10E
氮气保护下，将化合物10D(0.8克，1.21毫摩尔)的三氟乙酸(8毫升)溶液于20℃搅拌30分钟。反应液中加入水溶液(20毫升)，加入乙酸乙酯萃取(10毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝8:1)得到化合物10E。Under nitrogen protection, a solution of compound 10D (0.8 g, 1.21 mmol) in trifluoroacetic acid (8 ml) was stirred at 20°C for 30 minutes. Aqueous solution (20 ml) was added to the reaction solution, and ethyl acetate (10 ml x 2) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=8:1) to obtain compound 10E.
1H NMR(400MHz,CDCl3)δppm 12.97(s,1H),8.80(s,1H),8.01(d,J＝8.6Hz,1H),7.68(dt,J＝1.6,4.3Hz,2H),7.56-7.52(m,2H),4.38-4.28(m,4H),3.94-3.84(m,4H),3.08(br t,J＝4.9Hz,4H),1.93-1.39(m,4H),0.42(s,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 12.97 (s, 1H), 8.80 (s, 1H), 8.01 (d, J=8.6 Hz, 1H), 7.68 (dt, J=1.6, 4.3 Hz, 2H), 7.56-7.52 (m, 2H), 4.38-4.28 (m, 4H), 3.94-3.84 (m, 4H), 3.08 (br t, J=4.9 Hz, 4H), 1.93-1.39 (m, 4H), 0.42 (s, 4H).
步骤6：化合物10的合成Step 6: Synthesis of compound 10
氮气保护下，向化合物10E(0.2克，358.16微摩尔)的DMF(4毫升)溶液中加入化合物1-3(90毫克，719.16微摩尔)、磷酸钾(228毫克，1.07毫摩尔)、碘化亚铜(68毫克，357.05微摩尔)、反式N,N-二甲基环己基-1,2-二胺(26毫克，182.79微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液中加入水(20毫升)，加入乙酸乙酯(20毫升×3)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动相：水(0.225％FA)-乙腈，梯度：45％-69％乙腈；洗脱8分钟)分离得到化合物10。Under nitrogen protection, compound 1-3 (90 mg, 719.16 μmol), potassium phosphate (228 mg, 1.07 mmol), cuprous iodide (68 mg, 357.05 μmol), trans-N,N-dimethylcyclohexyl-1,2-diamine (26 mg, 182.79 μmol) were added to a DMF (4 ml) solution of compound 10E (0.2 g, 358.16 μmol). The nitrogen was replaced three times, and the mixture was stirred at 100°C for 12 hours. Water (20 ml) was added to the reaction solution, and ethyl acetate (20 ml × 3) was added for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 45%-69% acetonitrile; elution for 8 minutes) to obtain compound 10.
1H NMR(400MHz,DMSO-d6)δppm 13.03(s,1H),8.80(s,1H),8.07(d,J＝0.9Hz,1H),8.03(d,J＝8.6Hz,1H),7.54(d,J＝0.9Hz,1H),7.20(s,1H),7.06(br d,J＝8.6Hz,1H),4.27(br s,4H),3.82-3.71(m,7H),3.28(br s,2H),2.97(br s,4H),2.19-0.85(m,4H),0.40(s,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.03 (s, 1H), 8.80 (s, 1H), 8.07 (d, J=0.9 Hz, 1H), 8.03 (d, J=8.6 Hz, 1H), 7.54 (d, J=0.9 Hz, 1H), 7.20 (s, 1H), 7.06 (br d, J=8.6 Hz, 1H), 4.27 (br s, 4H), 3.82-3.71 (m, 7H), 3.28 (br s, 2H), 2.97 (br s, 4H), 2.19-0.85 (m, 4H), 0.40 (s, 4H).
实施例11

Embodiment 11

步骤1：化合物11B的合成Step 1: Synthesis of compound 11B
氮气保护下，向化合物11A(19.8克，71.50毫摩尔)和1,4-二氧杂-螺[4,5]癸-7-烯-8-硼酸嚬哪醇酯(19.80克，74.40毫摩尔)的水(20毫升)和1,4-二氧六环(200毫升)溶液中加入Pd(dppf)Cl2(5.15克，7.04毫摩尔)和碳酸铯(69.30毫克，212.69毫摩尔)。氮气置换3次，混合物于100℃搅拌16小时。反应液中加入水(400毫升)，用乙酸乙酯(400毫升×2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。残留物通过柱层析分离(PE:EA＝3:1)得到化合物11B。Under nitrogen protection, Pd(dppf)Cl 2 (5.15 g, 7.04 mmol) and cesium carbonate (69.30 mg, 212.69 mmol) were added to a solution of compound 11A (19.8 g, 71.50 mmol) and 1,4-dioxa-spiro[4,5]dec-7-ene- 8 -boronic acid naphthalene ester (19.80 g, 74.40 mmol) in water (20 ml) and 1,4-dioxane (200 ml). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 100° C. for 16 hours. Water (400 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (400 ml×2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EA＝3:1) to obtain compound 11B.
1H NMR(400MHz,CDCl3)δppm 8.03(s,1H),7.99-7.87(m,1H),7.67(d,J＝1.0Hz,1H),7.54(d,J＝1.0Hz,1H),3.95(s,4H),2.95-2.81(m,2H),2.66-2.54(m,2H),1.88(t,J＝6.6Hz,2H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.03 (s, 1H), 7.99-7.87 (m, 1H), 7.67 (d, J=1.0 Hz, 1H), 7.54 (d, J=1.0 Hz, 1H), 3.95 (s, 4H), 2.95-2.81 (m, 2H), 2.66-2.54 (m, 2H), 1.88 (t, J=6.6 Hz, 2H).
步骤2：化合物11C的合成Step 2: Synthesis of compound 11C
氮气保护下，于20℃向叔丁醇钾(4.57克，40.69毫摩尔)的二甲亚砜(80毫升)溶液中加入三甲基碘化亚砜(8.94克，40.61毫摩尔)。混合物升温至60℃，搅拌1小时。将11B(6.8克，20.23毫摩尔)的二甲亚砜(80毫升)溶液加入上述混合物中，反应液于60℃搅拌1小时。向反应液中加入水(200毫升)，乙酸乙酯(200毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝5:1)得到化合物11C。Under nitrogen protection, trimethylsulfoxide iodide (8.94 g, 40.61 mmol) was added to a solution of potassium tert-butoxide (4.57 g, 40.69 mmol) in dimethyl sulfoxide (80 ml) at 20°C. The mixture was heated to 60°C and stirred for 1 hour. A solution of 11B (6.8 g, 20.23 mmol) in dimethyl sulfoxide (80 ml) was added to the above mixture, and the reaction solution was stirred at 60°C for 1 hour. Water (200 ml) was added to the reaction solution, and ethyl acetate (200 ml x 2) was used for extraction. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=5:1) to obtain compound 11C.
1H NMR(400MHz,CDCl3)δppm 8.08(s,1H),7.70(s,1H),7.57(s,1H),3.99-3.89(m,4H),3.04(ddd,J＝5.7,8.7,14.2Hz,1H),2.44-2.33(m,2H),2.32-2.22(m,1H),2.02-1.81(m,3H),1.61(ddd,J＝5.0,8.6,13.4Hz,1H),1.28-1.16(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.08 (s, 1H), 7.70 (s, 1H), 7.57 (s, 1H), 3.99-3.89 (m, 4H), 3.04 (ddd, J=5.7, 8.7, 14.2 Hz, 1H), 2.44-2.33 (m, 2H), 2.32-2.22 (m, 1H), 2.02-1.81 (m, 3H), 1.61 (ddd, J=5.0, 8.6, 13.4 Hz, 1H), 1.28-1.16 (m, 1H).
步骤3：化合物11D的合成 Step 3: Synthesis of compound 11D
氮气保护下，向化合物11C(1.1克，3.14毫摩尔)的四氢呋喃(10毫升)溶液中加入稀盐酸(3毫升，2摩尔/升)，混合物于20℃搅拌16小时。向反应液中加入氢氧化钠水溶液(2摩尔/升)调pH至7，用乙酸乙酯(40毫升×2)萃取，有机相用无水硫酸钠干燥，过滤浓缩，得到化合物11D。Under nitrogen protection, dilute hydrochloric acid (3 ml, 2 mol/L) was added to a solution of compound 11C (1.1 g, 3.14 mmol) in tetrahydrofuran (10 ml), and the mixture was stirred at 20°C for 16 hours. Aqueous sodium hydroxide solution (2 mol/L) was added to the reaction solution to adjust the pH to 7, and the mixture was extracted with ethyl acetate (40 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 11D.
1H NMR(400MHz,CDCl3)δppm 8.15(s,1H),7.73(s,1H),7.63(d,J＝0.7Hz,1H),3.17-3.03(m,1H),2.94(dd,J＝5.3,18.3Hz,1H),2.71(dd,J＝2.8,18.3Hz,1H),2.64-2.51(m,2H),2.44(dtd,J＝2.9,5.8,8.8Hz,1H),2.38-2.22(m,1H),2.09(dd,J＝5.5,9.3Hz,1H),1.26(d,J＝3.3Hz,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.15 (s, 1H), 7.73 (s, 1H), 7.63 (d, J=0.7 Hz, 1H), 3.17-3.03 (m, 1H), 2.94 (dd, J=5.3, 18.3 Hz, 1H), 2.71 (dd, J=2.8, 18.3 Hz, 1H), 2.64-2.51 (m, 2H), 2.44 (dtd, J=2.9, 5.8, 8.8 Hz, 1H), 2.38-2.22 (m, 1H), 2.09 (dd, J=5.5, 9.3 Hz, 1H), 1.26 (d, J=3.3 Hz, 1H).
步骤4：化合物11E的合成Step 4: Synthesis of compound 11E
氮气保护下，向化合物11D(2.4克，7.84毫摩尔)的二氯甲烷(50毫升)溶液中缓慢加入二乙氨基三氟化硫(13.42克，83.26毫摩尔)，混合物于20℃搅拌16小时。向反应液中小心滴加冰水(50毫升)，用二氯甲烷萃取(50毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1)得到化合物11E。Under nitrogen protection, diethylaminosulfur trifluoride (13.42 g, 83.26 mmol) was slowly added to a solution of compound 11D (2.4 g, 7.84 mmol) in dichloromethane (50 ml), and the mixture was stirred at 20°C for 16 hours. Ice water (50 ml) was carefully added dropwise to the reaction solution, and extracted with dichloromethane (50 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=10:1) to obtain compound 11E.
1H NMR(400MHz,CDCl3)δppm 8.16-8.10(m,1H),7.79-7.71(m,1H),7.65-7.57(m,1H),3.41-2.73(m,2H),2.67-2.10(m,4H),2.01-1.69(m,2H),1.32-1.00(m,1H). 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.16-8.10 (m, 1H), 7.79-7.71 (m, 1H), 7.65-7.57 (m, 1H), 3.41-2.73 (m, 2H), 2.67-2.10 (m, 4H), 2.01-1.69 (m, 2H), 1.32-1.00 (m, 1H).
步骤5：化合物11F的合成Step 5: Synthesis of Compound 11F
氮气保护下，向化合物11E(1.7克，5.18毫摩尔)的1,4-二氧六环(20毫升)溶液中加入氨基甲酸叔丁酯(910.34毫克，7.77毫摩尔)、XPhos(493.92毫克，1.04毫摩尔)、Pd(OAc)2(232.61毫克，1.04毫摩尔)和碳酸铯(4.22克，12.95毫摩尔)。氮气置换3次，混合物于110℃搅拌16小时。反应液减压抽滤，滤液加入水(20毫升)，用乙酸乙酯(30毫升)萃取，有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝10:1)得到化合物11F。Under nitrogen protection, tert-butyl carbamate (910.34 mg, 7.77 mmol), XPhos (493.92 mg, 1.04 mmol), Pd(OAc) 2 (232.61 mg, 1.04 mmol) and cesium carbonate (4.22 g, 12.95 mmol) were added to a solution of compound 11E (1.7 g, 5.18 mmol) in 1,4-dioxane (20 ml) . The nitrogen atmosphere was replaced three times, and the mixture was stirred at 110°C for 16 hours. The reaction solution was filtered under reduced pressure, water (20 ml) was added to the filtrate, and the mixture was extracted with ethyl acetate (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=10:1) to obtain compound 11F.
1H NMR(400MHz,CDCl3)δppm 8.80-8.54(m,1H),7.79-7.55(m,2H),6.95(br d,J＝1.2Hz,1H),2.99(br s,1H),2.69-2.38(m,2H),2.26(br d,J＝13.0Hz,3H),2.00-1.82(m,2H),1.56(s,9H),1.38-1.22(m,1H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.80-8.54 (m, 1H), 7.79-7.55 (m, 2H), 6.95 (br d, J=1.2 Hz, 1H), 2.99 (br s, 1H), 2.69-2.38 (m, 2H), 2.26 (br d, J=13.0 Hz, 3H), 2.00-1.82 (m, 2H), 1.56 (s, 9H), 1.38-1.22 (m, 1H).
步骤6：化合物11G的合成Step 6: Synthesis of Compound 11G
氮气保护下，0℃向化合物11F(0.32克，817.18微摩尔)的DMF(5毫升)溶液中缓慢加入钠氢(112.00毫克，2.80毫摩尔)，混合物于0℃搅拌30分钟。向化合物1-2(480毫克，1.34毫摩尔)的二氯甲烷(8毫升)中加入氯化亚砜(524.16毫克，4.41毫摩尔)，混合物于20℃搅拌30分钟。减压浓缩，粗品溶于DMF(5毫升)缓慢加入上述化合物11F的反应溶液中，20℃搅拌16小时。反应液中加入水(40毫升)，用乙酸乙酯萃取(40毫升×2)。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝20:1至3:1)得到化合物11G。Under nitrogen protection, sodium hydrogen (112.00 mg, 2.80 mmol) was slowly added to a solution of compound 11F (0.32 g, 817.18 μmol) in DMF (5 ml) at 0°C, and the mixture was stirred at 0°C for 30 minutes. Thionyl chloride (524.16 mg, 4.41 mmol) was added to a solution of compound 1-2 (480 mg, 1.34 mmol) in dichloromethane (8 ml), and the mixture was stirred at 20°C for 30 minutes. After concentration under reduced pressure, the crude product was dissolved in DMF (5 ml) and slowly added to the reaction solution of the above compound 11F, and stirred at 20°C for 16 hours. Water (40 ml) was added to the reaction solution, and extracted with ethyl acetate (40 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=20:1 to 3:1) to obtain compound 11G.
步骤7：化合物11H的合成Step 7: Synthesis of compound 11H
氮气保护下，将化合物11G(0.5克，710.67微摩尔)的三氟乙酸(5毫升)溶液于20℃搅拌1小时。反 应液浓缩，向残留物中加入饱和碳酸氢钠水溶液调pH至7，用二氯甲烷(20毫升)萃取。有机相用无水硫酸钠干燥，过滤浓缩，残留物通过制备薄层硅胶层析分离(PE:EA＝1:1)得到化合物11H。Under nitrogen protection, a solution of compound 11G (0.5 g, 710.67 μmol) in trifluoroacetic acid (5 ml) was stirred at 20°C for 1 hour. The reaction mixture was concentrated, saturated aqueous sodium bicarbonate solution was added to the residue to adjust the pH to 7, and the mixture was extracted with dichloromethane (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by preparative thin layer silica gel chromatography (PE:EA=1:1) to obtain compound 11H.
步骤8：化合物11的合成Step 8: Synthesis of compound 11
氮气保护下，向化合物11H(40毫克，66.29微摩尔)的DMF(2毫升)溶液中加入化合物1-3(12.28毫克，102.30微摩尔)、磷酸钾(42.25毫克，199.04微摩尔)、碘化亚铜(12.80毫克，67.22微摩尔)、反式N,N-二甲基环己基-1,2-二胺(5.12毫克，36.00微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液中加入水(10毫升)，用乙酸乙酯(10毫升x2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*25mm*10μm；流动相：水(0.225％FA)-乙腈，梯度：63％-93％乙腈；洗脱10分钟)分离得到化合物11。Under nitrogen protection, compound 1-3 (12.28 mg, 102.30 μmol), potassium phosphate (42.25 mg, 199.04 μmol), cuprous iodide (12.80 mg, 67.22 μmol), trans-N,N-dimethylcyclohexyl-1,2-diamine (5.12 mg, 36.00 μmol) were added to a DMF (2 ml) solution of compound 11H (40 mg, 66.29 μmol). Nitrogen was replaced three times, and the mixture was stirred at 100°C for 12 hours. Water (10 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (10 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column type: Phenomenex luna C18 150*25mm*10μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 63%-93% acetonitrile; elution within 10 minutes) to obtain compound 11.
1H NMR(400MHz,DMSO-d6)δppm 13.25(s,1H),9.29(s,1H),8.21(s,1H),8.10(d,J＝8.6Hz,1H),7.69(s,1H),7.30(s,1H),7.15(br d,J＝8.6Hz,1H),3.77(br t,J＝6.4Hz,2H),3.19-3.08(m,2H),3.01(br s,4H),2.68(br s,2H),2.06(br dd,J＝3.9,8.9Hz,10H),1.15(br s,1H),0.43(s,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.25 (s, 1H), 9.29 (s, 1H), 8.21 (s, 1H), 8.10 (d, J=8.6 Hz, 1H), 7.69 (s, 1H), 7.30 (s, 1H), 7.15 (br d, J=8.6 Hz, 1H), 3.77 (br t, J=6.4 Hz, 2H), 3.19-3.08 (m, 2H), 3.01 (br s, 4H), 2.68 (br s, 2H), 2.06 (br dd, J=3.9, 8.9 Hz, 10H), 1.15 (br s, 1H), 0.43 (s, 4H).
实施例12
Example 12
步骤1：化合物12A的合成Step 1: Synthesis of compound 12A
氮气保护下，向化合物4E(900毫克，1.52毫摩尔)的DMF(4毫升)溶液中加入化合物9-1(592.21毫克，3.03毫摩尔)、磷酸钾(965.82毫克，4.55毫摩尔)、碘化亚铜(288.85毫克，1.52毫摩尔)、反 式N,N-二甲基环己基-1,2-二胺(107.86毫克，758.33微摩尔)。氮气置换3次，混合物于100℃搅拌12小时。反应液中加入水(30毫升)，用乙酸乙酯(30毫升×2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备薄层硅胶层析(PE:EA＝20:1至2:1)分离得到化合物12A。Under nitrogen protection, compound 9-1 (592.21 mg, 3.03 mmol), potassium phosphate (965.82 mg, 4.55 mmol), cuprous iodide (288.85 mg, 1.52 mmol), and the reaction mixture were added to a solution of compound 4E (900 mg, 1.52 mmol) in DMF (4 ml). Formula: N,N-dimethylcyclohexyl-1,2-diamine (107.86 mg, 758.33 μmol). The mixture was replaced with nitrogen three times and stirred at 100°C for 12 hours. Water (30 ml) was added to the reaction solution, and it was extracted with ethyl acetate (30 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative thin layer silica gel chromatography (PE:EA=20:1 to 2:1) to obtain compound 12A.
1H NMR(400MHz,CDCl3)δppm 13.17(br s,1H),9.20(s,1H),8.26(d,J＝8.6Hz,1H),7.51-7.32(m,2H),7.14(dd,J＝1.8,8.6Hz,1H),4.44(br t,J＝5.4Hz,4H),4.30-4.22(m,2H),3.09(br s,4H),2.22-2.07(m,4H),1.72-1.64(m,4H),1.61(s,6H),1.33-1.30(m,3H),0.44(s,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 13.17 (br s, 1H), 9.20 (s, 1H), 8.26 (d, J=8.6 Hz, 1H), 7.51-7.32 (m, 2H), 7.14 (dd, J=1.8, 8.6 Hz, 1H), 4.44 (br t, J=5.4 Hz, 4H), 4.30-4.22 (m, 2H), 3.09 (br s, 4H), 2.22-2.07 (m, 4H), 1.72-1.64 (m, 4H), 1.61 (s, 6H), 1.33-1.30 (m, 3H), 0.44 (s, 4H).
步骤2：化合物12的合成Step 2: Synthesis of compound 12
氮气保护下，于-70℃向化合物12A(670毫克，1.01毫摩尔)的四氢呋喃(8毫升)溶液中滴加硼氢化锂的四氢呋喃溶液(2.04毫升，2摩尔/升)。混合物于20℃搅拌2小时。向反应液中加入饱和氯化铵水溶液(20毫升)，用乙酸乙酯(30毫升×2)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC(柱型：Phenomenex luna C18 150*40mm*15μm；流动相：水(0.225％FA)-乙腈，梯度：53％-83％乙腈；洗脱15分钟)分离得到化合物12。Under nitrogen protection, a tetrahydrofuran solution of lithium borohydride (2.04 ml, 2 mol/L) was added dropwise to a tetrahydrofuran (8 ml) solution of compound 12A (670 mg, 1.01 mmol) at -70°C. The mixture was stirred at 20°C for 2 hours. A saturated aqueous solution of ammonium chloride (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (30 ml x 2). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column type: Phenomenex luna C18 150*40mm*15μm; mobile phase: water (0.225% FA)-acetonitrile, gradient: 53%-83% acetonitrile; elution 15 minutes) to obtain compound 12.
1H NMR(400MHz,DMSO-d6)δppm 13.32(s,1H),8.93(s,1H),8.47(s,1H),8.05(d,J＝8.6Hz,1H),7.44(d,J＝1.9Hz,1H),7.19(dd,J＝1.9,8.7Hz,1H),4.36(br s,4H),3.56(s,2H),2.96(br s,4H),2.21-2.08(m,4H),2.02-1.49(m,4H),1.25(s,6H),0.41(s,4H)。 1 H NMR (400 MHz, DMSO-d 6 ) δ ppm 13.32 (s, 1H), 8.93 (s, 1H), 8.47 (s, 1H), 8.05 (d, J=8.6 Hz, 1H), 7.44 (d, J=1.9 Hz, 1H), 7.19 (dd, J=1.9, 8.7 Hz, 1H), 4.36 (br s, 4H), 3.56 (s, 2H), 2.96 (br s, 4H), 2.21-2.08 (m, 4H), 2.02-1.49 (m, 4H), 1.25 (s, 6H), 0.41 (s, 4H).
实施例13

Example 13

步骤1：化合物13B的合成Step 1: Synthesis of compound 13B
向甲基三苯基碘化膦(116.47克,288.13毫摩尔)的二甲亚砜(450毫升)溶液中加入叔丁醇钾(32.33克,288.13毫摩尔)，混合物于25℃搅拌0.5小时。0℃下，将化合物13A(30克，192.09毫摩尔)的甲苯(75毫升)溶液滴加到上述混合物中，反应液于25℃搅拌4小时。反应液加入水(1500毫升)，过滤，滤液用石油醚(1000毫升x3)萃取，合并有机相用水(1000毫升x3)洗涤，有机相无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝1:0～10:1)得到化合物13B。Potassium tert-butoxide (32.33 g, 288.13 mmol) was added to a solution of methyltriphenylphosphine iodide (116.47 g, 288.13 mmol) in dimethyl sulfoxide (450 ml), and the mixture was stirred at 25°C for 0.5 hours. A solution of compound 13A (30 g, 192.09 mmol) in toluene (75 ml) was added dropwise to the above mixture at 0°C, and the reaction solution was stirred at 25°C for 4 hours. Water (1500 ml) was added to the reaction solution, filtered, and the filtrate was extracted with petroleum ether (1000 ml x 3), the combined organic phases were washed with water (1000 ml x 3), the organic phases were dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=1:0-10:1) to obtain compound 13B.
1H NMR(400MHz,CDCl3)δppm 4.68(s,2H),3.97(s,4H),2.31-2.27(m,4H),1.77-1.65(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 4.68 (s, 2H), 3.97 (s, 4H), 2.31-2.27 (m, 4H), 1.77-1.65 (m, 4H).
步骤2：化合物13C的合成Step 2: Synthesis of compound 13C
将13B(22.5克，145.91毫摩尔)溶于甲苯(50毫升)，-10℃氮气保护下，滴加二乙基锌甲苯溶液(364.77毫升，1摩尔/升)，混合物于-10℃搅拌30分钟。将二碘甲烷(195.40克，729.55毫摩尔)缓慢滴加到上述混合物中，反应液于25℃搅拌3小时30分钟。20℃下，向反应液中滴加饱和氯化铵水溶液和水(200毫升)，用乙酸乙酯(300毫升x3)萃取，合并有机相用食盐水(500毫升)洗涤，有机相无水硫 酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝200:1～10:1)得到化合物13C。13B (22.5 g, 145.91 mmol) was dissolved in toluene (50 ml), and diethylzinc toluene solution (364.77 ml, 1 mol/L) was added dropwise at -10°C under nitrogen protection, and the mixture was stirred at -10°C for 30 minutes. Diiodomethane (195.40 g, 729.55 mmol) was slowly added dropwise to the above mixture, and the reaction solution was stirred at 25°C for 3 hours and 30 minutes. At 20°C, saturated aqueous ammonium chloride solution and water (200 ml) were added dropwise to the reaction solution, and extracted with ethyl acetate (300 ml x 3), the combined organic phases were washed with brine (500 ml), and the organic phase was anhydrous sulfuric acid The residue was dried over sodium bicarbonate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=200:1-10:1) to obtain compound 13C.
1H NMR(400MHz,CDCl3)δppm 3.96(s,4H),1.74-1.66(m,4H),1.50-1.35(m,4H),0.28(s,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 3.96 (s, 4H), 1.74-1.66 (m, 4H), 1.50-1.35 (m, 4H), 0.28 (s, 4H).
步骤3：化合物13D的合成Step 3: Synthesis of compound 13D
向化合物13C(44克，261.54毫摩尔)的四氢呋喃(300毫升)溶液中加入稀盐酸(314.29毫升，2摩尔/升)，混合物于20℃搅拌12小时。用饱和碳酸氢钠溶液调pH至8～9，用乙酸乙酯萃取(300毫升x2)萃取，合并有机相用无水硫酸钠干燥，过滤浓缩，得到化合物13D。To a solution of compound 13C (44 g, 261.54 mmol) in tetrahydrofuran (300 ml) was added dilute hydrochloric acid (314.29 ml, 2 mol/L), and the mixture was stirred at 20°C for 12 hours. The pH was adjusted to 8-9 with saturated sodium bicarbonate solution, extracted with ethyl acetate (300 ml x 2), and the combined organic phases were dried over anhydrous sodium sulfate, filtered and concentrated to obtain compound 13D.
1H NMR(400MHz,CDCl3)δppm 2.42(t,J＝6.7Hz,4H),1.68(t,J＝6.7Hz,4H),0.49(s,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 2.42 (t, J=6.7 Hz, 4H), 1.68 (t, J=6.7 Hz, 4H), 0.49 (s, 4H).
步骤4：化合物13E的合成Step 4: Synthesis of compound 13E
氮气保护下，-70℃向化合物13D(17克，136.9毫摩尔)的四氢呋喃(170毫升)溶液中缓慢滴加六甲基二硅基胺基钾(191.66毫升，1摩尔/升)，混合物于-70℃搅拌30分钟。将N-苯基双(三氟甲烷磺酰)亚胺(63.58克，177.97毫摩尔)的四氢呋喃(170毫升)溶液滴加至上述混合物中，反应液于-78℃搅拌1小时后，缓慢升温至25℃，继续搅拌1小时。0℃下，向反应液中加入水(300毫升)，用乙酸乙酯萃取(400毫升x2)，合并有机相用无水硫酸钠干燥，过滤浓缩，残留物通过柱层析分离(PE:EA＝1:0)得到化合物13E。Under nitrogen protection, potassium hexamethyldisilazide (191.66 ml, 1 mol/L) was slowly added dropwise to a solution of compound 13D (17 g, 136.9 mmol) in tetrahydrofuran (170 ml) at -70°C, and the mixture was stirred at -70°C for 30 minutes. A solution of N-phenylbis(trifluoromethanesulfonyl)imide (63.58 g, 177.97 mmol) in tetrahydrofuran (170 ml) was added dropwise to the above mixture, and the reaction solution was stirred at -78°C for 1 hour, then slowly heated to 25°C and continued to stir for 1 hour. Water (300 ml) was added to the reaction solution at 0°C, and extracted with ethyl acetate (400 ml x 2), the organic phases were combined and dried over anhydrous sodium sulfate, filtered and concentrated, and the residue was separated by column chromatography (PE:EA=1:0) to obtain compound 13E.
步骤5：化合物13F的合成Step 5: Synthesis of Compound 13F
氮气保护下，将化合物13E(10克，39.03毫摩尔)、双联嚬哪醇硼酸酯(10.9克，42.93毫摩尔)、乙酸钾(11.49克，117.08毫摩尔)、Pd(dppf)Cl2(1.91克，2.34毫摩尔)和PDDF(649.05mg,1.17毫摩尔)的1,4-二氧六环(100毫升)溶液氮气置换三次后，加热至90℃搅拌12小时。向反应液中加入水(500毫升)，用乙酸乙酯(500毫升)萃取，有机相用食盐水(300毫升x2)，用无水硫酸钠干燥，过滤，浓缩。残留物通过柱层析分离(PE)得到化合物13F。Under nitrogen protection, a solution of compound 13E (10 g, 39.03 mmol), bis-naphthalene borate (10.9 g, 42.93 mmol), potassium acetate (11.49 g, 117.08 mmol), Pd(dppf)Cl 2 (1.91 g, 2.34 mmol) and PDDF (649.05 mg, 1.17 mmol) in 1,4-dioxane (100 ml) was replaced with nitrogen three times, and then heated to 90°C and stirred for 12 hours. Water (500 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (500 ml). The organic phase was washed with brine (300 ml x 2), dried over anhydrous sodium sulfate, filtered and concentrated. The residue was separated by column chromatography (PE) to obtain compound 13F.
1H NMR(400MHz,CDCl3)δppm 6.59-6.53(m,1H),2.23-2.20(m,2H),1.99-1.97(m,2H),1.36-1.35(m,2H),1.27(s,12H),0.28-0.27(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 6.59-6.53 (m, 1H), 2.23-2.20 (m, 2H), 1.99-1.97 (m, 2H), 1.36-1.35 (m, 2H), 1.27 (s, 12H), 0.28-0.27 (m, 4H).
步骤6：化合物13G的合成Step 6: Synthesis of Compound 13G
氮气保护下，向2-溴-4-硝基苯甲酸甲酯(6.66克，25.63毫摩尔)和化合物13F(12克，51.25毫摩尔)的水(50毫升)和1,4-二氧六环(100毫升)溶液中加入Pd(dppf)Cl2(1.88克，2.56毫摩尔)和碳酸铯(16.7克，51.25毫摩尔)。氮气置换3次，混合物于90℃搅拌12小时。反应液浓缩，向残留物中加入水(300毫升)，用乙酸乙酯(300毫升)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。残留物通过柱层析分离(PE:EA＝1:0～500:1)得到化合物13G。Under nitrogen protection, Pd(dppf)Cl 2 (1.88 g, 2.56 mmol) and cesium carbonate (16.7 g, 51.25 mmol) were added to a solution of methyl 2- bromo-4-nitrobenzoate (6.66 g, 25.63 mmol) and compound 13F (12 g, 51.25 mmol) in water (50 ml) and 1,4-dioxane (100 ml). The nitrogen atmosphere was replaced three times, and the mixture was stirred at 90°C for 12 hours. The reaction solution was concentrated, and water (300 ml) was added to the residue, which was extracted with ethyl acetate (300 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated by column chromatography (PE:EA=1:0-500:1) to obtain compound 13G.
1H NMR(400MHz,CDCl3)δppm 8.14-8.09(m,2H),7.87-7.85(m,1H),5.68-5.66(m,1H),3.90(s,3H),2.38-2.35(m,2H),2.07-2.05(m,2H),1.58-1.55(m,2H),0.42-0.37(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.14-8.09 (m, 2H), 7.87-7.85 (m, 1H), 5.68-5.66 (m, 1H), 3.90 (s, 3H), 2.38-2.35 (m, 2H), 2.07-2.05 (m, 2H), 1.58-1.55 (m, 2H), 0.42-0.37 (m, 4H).
步骤7：化合物13H的合成 Step 7: Synthesis of compound 13H
向化合物13G(9克，31.33毫摩尔)的甲醇(30毫升)和四氢呋喃(30毫升)的溶液中加入氢氧化钠(5.01克，125.3毫摩尔)，混合物于20℃搅拌4小时。用稀盐酸(2摩尔/升)调pH至3，混合物过滤，滤饼干燥，得到化合物13H。To a solution of compound 13G (9 g, 31.33 mmol) in methanol (30 ml) and tetrahydrofuran (30 ml) was added sodium hydroxide (5.01 g, 125.3 mmol), and the mixture was stirred for 4 hours at 20° C. The pH was adjusted to 3 with dilute hydrochloric acid (2 mol/L), the mixture was filtered, and the filter cake was dried to obtain compound 13H.
1H NMR(400MHz,CDCl3)δppm 8.18-8.14(m,2H),8.06-8.04(m,1H),5.72-5.71(m,1H),2.43-2.39(m,2H),2.08-2.07(m,2H),1.59-1.56(m,2H),0.41-0.40(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.18-8.14 (m, 2H), 8.06-8.04 (m, 1H), 5.72-5.71 (m, 1H), 2.43-2.39 (m, 2H), 2.08-2.07 (m, 2H), 1.59-1.56 (m, 2H), 0.41-0.40 (m, 4H).
步骤8：化合物13I的合成Step 8: Synthesis of compound 13I
向化合物13H(1.67克，6.12毫摩尔)的二氯甲烷(20毫升)溶液中加入氯化亚砜(2.91克，24.48毫摩尔)，混合物于20℃搅拌30分钟。加热至40℃继续反应30分钟。反应液减压浓缩，得到化合物13I。To a solution of compound 13H (1.67 g, 6.12 mmol) in dichloromethane (20 ml) was added thionyl chloride (2.91 g, 24.48 mmol), and the mixture was stirred at 20°C for 30 minutes. The mixture was heated to 40°C and the reaction was continued for 30 minutes. The reaction solution was concentrated under reduced pressure to obtain compound 13I.
步骤9：化合物13J的合成Step 9: Synthesis of compound 13J
0℃下，向化合物8B(1.5克，4.08毫摩尔)的N,N-二甲基甲酰胺(15毫升)悬浊液中依次加入钠氢(326.63毫克，8.17毫摩尔，纯度：60％)和化合物13I(1.79克，6.12毫摩尔)，反应液于20℃搅拌3小时。反应液加入水(30毫升)，用乙酸乙酯(30毫升)萃取，有机相用食盐水(20毫升)洗涤，无水硫酸钠干燥，过滤，滤液浓缩所得粗品经制备HPLC(柱型:Phenomenex Luna C8 250 x 50mm x 10um；流动相：水(0.225％甲酸)-乙腈，乙腈梯度：70％-92％；洗脱时间15分钟)分离得到化合物13J。At 0°C, sodium hydrogen sulfide (326.63 mg, 8.17 mmol, purity: 60%) and compound 13I (1.79 g, 6.12 mmol) were added to a suspension of compound 8B (1.5 g, 4.08 mmol) in N,N-dimethylformamide (15 ml) in sequence, and the reaction solution was stirred at 20°C for 3 hours. Water (30 ml) was added to the reaction solution, extracted with ethyl acetate (30 ml), the organic phase was washed with brine (20 ml), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by preparative HPLC (column type: Phenomenex Luna C8 250 x 50mm x 10um; mobile phase: water (0.225% formic acid)-acetonitrile, acetonitrile gradient: 70%-92%; elution time 15 minutes) to obtain compound 13J.
1H NMR(400MHz,CDCl3)δppm 8.18-8.16(m,2H),7.60-7.58(m,1H),7.46(s,1H),7.30(s,1H),5.95(s,1H),4.40-4.38(m,4H),2.50-2.44(m,5H),2.14-2.04(m,6H),1.60-1.59(m,2H),1.27(s,9H),0.44-0.39(m,4H)。 1 H NMR (400 MHz, CDCl3) δ ppm 8.18-8.16 (m, 2H), 7.60-7.58 (m, 1H), 7.46 (s, 1H), 7.30 (s, 1H), 5.95 (s, 1H), 4.40-4.38 (m, 4H), 2.50-2.44 (m, 5H), 2.14-2.04 (m, 6H), 1.60-1.59 (m, 2H), 1.27 (s, 9H), 0.44-0.39 (m, 4H).
步骤10：化合物13K的合成Step 10: Synthesis of compound 13K
将化合物13J(900毫克，1.45毫摩尔)和三氟乙酸(9毫升)的混合物在28℃搅拌0.5小时。向反应液滴加碳酸氢钠溶液(80毫升)，用二氯甲烷(30毫升)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩所得化合物13K。A mixture of compound 13J (900 mg, 1.45 mmol) and trifluoroacetic acid (9 ml) was stirred at 28°C for 0.5 hours. Sodium bicarbonate solution (80 ml) was added dropwise to the reaction solution, extracted with dichloromethane (30 ml), and the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain compound 13K.
1H NMR(400MHz,CDCl3)δppm 8.66(s,2H),8.49(s,1H),8.24-8.22(m,1H),8.15-8.14(m,1H),8.07-8.05(m,1H),7.33(s,1H),6.10(s,1H),4.41-4.39(m,4H),2.44(s,3H),2.38-2.37(m,2H),2.19-2.18(m,2H),2.12-2.10(m,4H),1.56-1.54(m,4H)。 1 H NMR (400 MHz, CDCl3) δ ppm 8.66 (s, 2H), 8.49 (s, 1H), 8.24-8.22 (m, 1H), 8.15-8.14 (m, 1H), 8.07-8.05 (m, 1H), 7.33 (s, 1H), 6.10 (s, 1H), 4.41-4.39 (m, 4H), 2.44 (s, 3H), 2.38-2.37 (m, 2H), 2.19-2.18 (m, 2H), 2.12-2.10 (m, 4H), 1.56-1.54 (m, 4H).
步骤11：化合物13L的合成Step 11: Synthesis of Compound 13L
向化合物13K(700毫克，1.34毫摩尔)的N,N-二甲基甲酰胺(7毫升)溶液中加入4,4-联吡啶(20.92毫克，133.96微摩尔)和四羟基二硼(600.47毫克，6.7毫摩尔)。反应液于20℃搅拌2小时。向反应液加入饱和碳酸氢钠溶液调节pH至8，用乙酸乙酯(30毫升)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩所得粗品经柱层析(PE:EA＝20:1～10:1，展开剂中含10％的二氯甲烷)分离得到化合物13L。 To a solution of compound 13K (700 mg, 1.34 mmol) in N,N-dimethylformamide (7 ml) were added 4,4-bipyridine (20.92 mg, 133.96 μmol) and tetrahydroxydiboron (600.47 mg, 6.7 mmol). The reaction solution was stirred at 20°C for 2 hours. Saturated sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8, and the mixture was extracted with ethyl acetate (30 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated to obtain a crude product, which was separated by column chromatography (PE:EA=20:1-10:1, the developing solvent contained 10% dichloromethane) to obtain compound 13L.
1H NMR(400MHz,CDCl3)δppm 8.71(s,1H),8.68(s,1H),7.86-7.84(m,1H),7.29-7.28(m,1H),6.67-6.64(m,1H),6.49-6.48(m,1H),5.96(s,1H),4.41-4.34(m,4H),3.99(br s,2H),2.41(s,3H),2.32-2.31(m,2H),2.17-2.06(m,6H),1.57-1.54(m,2H),0.39-0.33(m,4H)。 1 H NMR (400 MHz, CDCl3) δ ppm 8.71 (s, 1H), 8.68 (s, 1H), 7.86-7.84 (m, 1H), 7.29-7.28 (m, 1H), 6.67-6.64 (m, 1H), 6.49-6.48 (m, 1H), 5.96 (s, 1H), 4.41-4.34 (m, 4H), 3.99 (br s, 2H), 2.41 (s, 3H), 2.32-2.31 (m, 2H), 2.17-2.06 (m, 6H), 1.57-1.54 (m, 2H), 0.39-0.33 (m, 4H).
步骤12：化合物13M的合成Step 12: Synthesis of Compound 13M
氮气保护下，0℃向化合物13L(400毫克，812.08毫摩尔)和三乙胺(164.35毫克，1.62毫摩尔)的二氯甲烷(5毫升)溶液中滴加2-(氯磺酰基)乙酸甲酯(140.15毫克，1.35毫摩尔)的二氯甲烷(1毫升)溶液。反应液于20℃搅拌1小时。补加2-(氯磺酰基)乙酸甲酯(70.08毫克，406.04微摩尔)的二氯甲烷(1毫升)。反应液于20℃搅拌1小时。溶液反应液加入水(200毫升)，二氯甲烷(20毫升)萃取，有机相用无水硫酸钠干燥，过滤，滤液浓缩，所得粗品经薄层硅胶层析(PE:EA＝2:1)分离得到化合物13M。Under nitrogen protection, a solution of methyl 2-(chlorosulfonyl)acetate (140.15 mg, 1.35 mmol) in dichloromethane (1 ml) was added dropwise to a solution of compound 13L (400 mg, 812.08 mmol) and triethylamine (164.35 mg, 1.62 mmol) in dichloromethane (5 ml) at 0°C. The reaction solution was stirred at 20°C for 1 hour. Methyl 2-(chlorosulfonyl)acetate (70.08 mg, 406.04 μmol) in dichloromethane (1 ml) was added. The reaction solution was stirred at 20°C for 1 hour. Water (200 ml) was added to the reaction solution, and dichloromethane (20 ml) was extracted. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was separated by thin layer silica gel chromatography (PE:EA=2:1) to obtain compound 13M.
1H NMR(400MHz,CDCl3)δppm 8.71-8.65(m,2H),7.96-7.92(m,1H),7.33-7.31(m,2H),7.21-7.20(m,1H),7.07(s,1H),6.03-6.02(m,1H),4.34-4.31(m,4H),4.03(s,2H),3.84(s,3H),2.50(s,3H),2.33(br s,2H),2.15-2.11(m,6H),1.54-1.52(m,2H),0.38-0.34(m,4H)。 1 H NMR (400 MHz, CDCl 3 ) δ ppm 8.71-8.65 (m, 2H), 7.96-7.92 (m, 1H), 7.33-7.31 (m, 2H), 7.21-7.20 (m, 1H), 7.07 (s, 1H), 6.03-6.02 (m, 1H), 4.34-4.31 (m, 4H), 4.03 (s, 2H), 3.84 (s, 3H), 2.50 (s, 3H), 2.33 (br s, 2H), 2.15-2.11 (m, 6H), 1.54-1.52 (m, 2H), 0.38-0.34 (m, 4H).
步骤13：化合物13的合成Step 13: Synthesis of compound 13
-70℃向化合物13M(220毫克，349.93微摩尔)的四氢呋喃(5毫升)溶液中滴加硼氢化锂的四氢呋喃溶液(705.12微毫升，2摩尔/升)。混合物于20℃搅拌2小时。向反应液中加入饱和氯化铵水溶液(20毫升)，用乙酸乙酯(20毫升)萃取，有机相用无水硫酸钠干燥，过滤，浓缩。所得粗品经制备HPLC(柱型:Phenomenex luna C18 150x 25mm x 10μm；流动相：水(0.225％甲酸)-乙腈，乙腈梯度：51％-81％；洗脱时间10分钟)分离得到化合物13。To a solution of compound 13M (220 mg, 349.93 μmol) in tetrahydrofuran (5 ml) was added a solution of lithium borohydride in tetrahydrofuran (705.12 μml, 2 mol/L) at -70°C. The mixture was stirred at 20°C for 2 hours. A saturated aqueous solution of ammonium chloride (20 ml) was added to the reaction solution, and the mixture was extracted with ethyl acetate (20 ml). The organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated by preparative HPLC (column type: Phenomenex luna C18 150x 25mm x 10μm; mobile phase: water (0.225% formic acid)-acetonitrile, acetonitrile gradient: 51%-81%; elution time 10 minutes) to give compound 13.
1H NMR(400MHz,DMSO-d6)δppm 10.03(br s,1H),9.69(s,1H),8.62(s,1H),7.81(s,1H),7.54-7.52(m,1H),7.20-7.18(m,1H),7.02(s,1H),5.78(s,1H),5.08-4.95(m,1H),4.36-4.34(m,4H),3.77-3.74(m,2H),3.31-3.28(s,2H),2.31-2.29(m,5H),2.08-1.99(m,6H),1.44-1.41(m,2H),0.25-0.24(m,4H)。LCMS(ESI)m/z:601.2[M+1]。 1 H NMR (400 MHz, DMSO-d6) δ ppm 10.03 (br s, 1H), 9.69 (s, 1H), 8.62 (s, 1H), 7.81 (s, 1H), 7.54-7.52 (m, 1H), 7.20-7.18 (m, 1H), 7.02 (s, 1H), 5.78 (s, 1H), 5.08-4.95 (m, 1H), 4.36-4.34 (m, 4H), 3.77-3.74 (m, 2H), 3.31-3.28 (s, 2H), 2.31-2.29 (m, 5H), 2.08-1.99 (m, 6H), 1.44-1.41 (m, 2H), 0.25-0.24 (m, 4H). LCMS (ESI) m/z: 601.2 [M+1].
实验例1：NIH:OVCAR3细胞的抗增殖活性测试Experimental Example 1: Antiproliferative Activity Test of NIH:OVCAR3 Cells
实验材料：Experimental Materials:
RPMI 1640培养基购自VivaCell，胎牛血清购自ExCell，青霉素-链霉素溶液购自Giboco。Cell-Titer Glo reagent购自Promega(1kit，货号G7573)。读板仪器：Envision(PerkinElmer)。RPMI 1640 medium was purchased from VivaCell, fetal bovine serum was purchased from ExCell, and penicillin-streptomycin solution was purchased from Giboco. Cell-Titer Glo reagent was purchased from Promega (1 kit, catalog number G7573). Plate reader: Envision (PerkinElmer).
实验方法：experimental method:
收获处于对数生长期的细胞并采用血小板计数器进行细胞计数。用台盼蓝排斥法检测细胞活力，确保细胞活力在90％以上，调整细胞浓度；将96孔板中的细胞置于37℃、5％CO2、95％湿度条件下培养过夜， 配制药物溶液，在接种有细胞的96孔板中加入药物溶液，将已加药的96孔板中的细胞置于37℃、5％CO2、95％湿度条件下继续培养96小时，CellTiter-Glo发光法细胞活性检测，SpectraMax Paradigm读数得出对应的每孔荧光值RLU。细胞增殖抑制率数据采用下列公式来处理：Inhibition Rate(Inh％)＝100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100％。然后用GraphPad Prism软件作抑制率曲线图并计算IC50值。Cells in the logarithmic growth phase were harvested and counted using a platelet counter. Cell viability was detected using the trypan blue exclusion method to ensure that the cell viability was above 90%, and the cell concentration was adjusted; the cells in the 96-well plate were cultured overnight at 37°C, 5% CO 2 , and 95% humidity. Prepare drug solution, add drug solution to 96-well plate seeded with cells, place cells in 96-well plate with drug added at 37°C, 5% CO 2 , 95% humidity for 96 hours, detect cell activity by CellTiter-Glo luminescence method, and read SpectraMax Paradigm to obtain the corresponding fluorescence value RLU per well. The cell proliferation inhibition rate data are processed by the following formula: Inhibition Rate (Inh%) = 100-(RLUDrug-RLUMin)/(RLUMax-RLUMin)*100%. Then, use GraphPad Prism software to draw inhibition rate curve and calculate IC 50 value.
实验结果：本发明化合物NIH:OVCAR3细胞的抗增殖活性IC50的数据见表1。Experimental results: The data of IC 50 of the antiproliferative activity of the compounds of the present invention on NIH:OVCAR3 cells are shown in Table 1.
表1本发明化合物NIH:OVCAR3细胞的抗增殖活性IC50
Table 1 IC 50 of the antiproliferative activity of the compounds of the present invention in NIH:OVCAR3 cells
实验结论：本发明化合物对NIH:OVCAR3细胞具有较强的抗增殖活性。 Experimental conclusion: The compounds of the present invention have strong anti-proliferation activity against NIH:OVCAR3 cells.

Claims (13)

  1. 式(II)化合物、其立体异构体或其药学上可接受的盐，
    A compound of formula (II), a stereoisomer thereof or a pharmaceutically acceptable salt thereof,
    其中，in,
    环B选自5-6元杂环烷基、5-6元杂环烯基和5-6元杂环芳基，所述5-6元杂环烷基、5-6元杂环烯基和5-6元杂环芳基分别独立地任选被1或2个Ra取代；Ring B is selected from 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl, wherein the 5-6 membered heterocycloalkyl, 5-6 membered heterocycloalkenyl and 5-6 membered heterocycloaryl are each independently optionally substituted by 1 or 2 R a ;
    环A选自C3-8环烷基和3-8元杂环烷基，所述C3-8环烷基和3-8元杂环烷基分别独立地任选被1、2、3或4个Rb取代；Ring A is selected from C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl, and the C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are each independently optionally substituted by 1, 2, 3 or 4 R b ;
    T1和T2各自独立选自N、C和CH； T1 and T2 are each independently selected from N, C and CH;
    X1、X2和X3各自独立选自N和CRc；X 1 , X 2 and X 3 are each independently selected from N and CR c ;
    R1、R2、R3和R4分别独立地选自H、F、Cl、Br、OH、NH2、CN、C1-3烷基和OC1-3烷基，其中所述C1-3烷基和OC1-3烷基分别独立地任选被1、2和3个R取代；R 1 , R 2 , R 3 and R 4 are independently selected from H, F, Cl, Br, OH, NH 2 , CN, C 1-3 alkyl and OC 1-3 alkyl, wherein the C 1-3 alkyl and OC 1-3 alkyl are independently optionally substituted with 1, 2 and 3 R, respectively;
    R5选自5-8元杂环烷基和C5-8元环烯基，所述5-8元杂环烷基和C5-8元环烯基分别独立地任选被1、2、3或4个Rd取代；R 5 is selected from 5-8 membered heterocycloalkyl and C 5-8 membered cycloalkenyl, wherein the 5-8 membered heterocycloalkyl and C 5-8 membered cycloalkenyl are each independently optionally substituted by 1, 2, 3 or 4 R d ;
    Ra、Rb、Rc和Rd分别独立地选自H、F、Cl、Br、OH、NH2、CN、C1-3烷基和OC1-3烷基，其中所述C1-3烷基和OC1-3烷基分别独立地任选被1、2和3个R取代； Ra , Rb , Rc and Rd are independently selected from H, F, Cl, Br, OH, NH2, CN, C1-3 alkyl and OC1-3 alkyl, wherein the C1-3 alkyl and OC1-3 alkyl are independently optionally substituted with 1 , 2 and 3 Rs, respectively;
    R选自H、F、Cl、Br、OH、NH2和CN。R is selected from H, F, Cl, Br, OH, NH2 and CN.
  2. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中Ra、Rb、Rc和Rd分别独立地选自H、F和CH3。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein Ra , Rb , Rc and Rd are independently selected from H, F and CH3 .
  3. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中R1、R2、R3和R4分别独立地选自H和CH3。 The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 1 , R 2 , R 3 and R 4 are independently selected from H and CH 3 .
  4. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中R5选自 The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from
  5. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中环A选自 所述 分别独立地任选被1、2、3或4个Rb取代。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from Said Each independently is optionally substituted with 1, 2, 3 or 4 R b .
  6. 根据权利要求5所述的化合物、其立体异构体或其药学上可接受的盐，其中环A选自 所述 分别独立地任选被1、2、3或4个Rb取代。The compound according to claim 5, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from Said Each independently is optionally substituted with 1, 2, 3 or 4 R b .
  7. 根据权利要求6所述的化合物、其立体异构体或其药学上可接受的盐，其中环A选自 The compound according to claim 6, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein ring A is selected from
  8. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中结构单元选自 所述 分别独立地任选被1或2个Ra取代。The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from Said are each independently optionally substituted with 1 or 2 Ra .
  9. 根据权利要求8所述的化合物、其立体异构体或其药学上可接受的盐，其中结构单元选自 The compound according to claim 8, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from
  10. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中结构单元选自 The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the structural unit Selected from
  11. 根据权利要求1所述的化合物、其立体异构体或其药学上可接受的盐，其中化合物选自式(I-A)，(I- B)，(I-C)，(I-D)和(II-A)，
    The compound according to claim 1, its stereoisomer or a pharmaceutically acceptable salt thereof, wherein the compound is selected from formula (IA), (I- B), (IC), (ID) and (II-A),
    环A、环B、T1、T2、Rc、R1、R2、R3和R4如权利要求1所定义。Ring A, Ring B, T 1 , T 2 , R c , R 1 , R 2 , R 3 and R 4 are as defined in claim 1 .
  12. 如下化合物、其立体异构体或其药学上可接受的盐，

    The following compound, its stereoisomer or a pharmaceutically acceptable salt thereof,

  13. 根据权利要求1-12任意一项所述的化合物、其立体异构体或其药学上可接受的盐在制备治疗与KIF18A相关疾病的药物中的应用。 Use of the compound according to any one of claims 1 to 12, its stereoisomer or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating a disease related to KIF18A.
PCT/CN2023/130794 2022-11-10 2023-11-09 Class of sulfonamide compounds containing ortho-fused heterocycle and use thereof WO2024099398A1 (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020132653A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132651A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
CN114302880A (en) * 2019-08-02 2022-04-08 美国安进公司 KIF18A inhibitors
CN114391012A (en) * 2019-08-02 2022-04-22 美国安进公司 Pyridine derivatives as KIF18A inhibitors
CN114401953A (en) * 2019-08-02 2022-04-26 美国安进公司 KIF18A inhibitors

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2020132653A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Heteroaryl amides useful as kif18a inhibitors
WO2020132651A1 (en) * 2018-12-20 2020-06-25 Amgen Inc. Kif18a inhibitors
CN114302880A (en) * 2019-08-02 2022-04-08 美国安进公司 KIF18A inhibitors
CN114391012A (en) * 2019-08-02 2022-04-22 美国安进公司 Pyridine derivatives as KIF18A inhibitors
CN114401953A (en) * 2019-08-02 2022-04-26 美国安进公司 KIF18A inhibitors

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