WO2020063855A1 - 喹啉并吡咯烷-2-酮类衍生物及其应用 - Google Patents

喹啉并吡咯烷-2-酮类衍生物及其应用 Download PDF

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WO2020063855A1
WO2020063855A1 PCT/CN2019/108520 CN2019108520W WO2020063855A1 WO 2020063855 A1 WO2020063855 A1 WO 2020063855A1 CN 2019108520 W CN2019108520 W CN 2019108520W WO 2020063855 A1 WO2020063855 A1 WO 2020063855A1
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compound
isomer
pharmaceutically acceptable
acceptable salt
group
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PCT/CN2019/108520
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English (en)
French (fr)
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钱文远
杨纯道
代国强
黎健
陈曙辉
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南京明德新药研发有限公司
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Priority to RU2021110825A priority Critical patent/RU2771314C1/ru
Priority to CA3114646A priority patent/CA3114646C/en
Priority to EP19865180.4A priority patent/EP3845532B1/en
Priority to BR112021005989-0A priority patent/BR112021005989A2/pt
Priority to MX2021003739A priority patent/MX2021003739A/es
Priority to US17/280,538 priority patent/US11230549B2/en
Priority to JP2021517848A priority patent/JP6997358B2/ja
Priority to AU2019348132A priority patent/AU2019348132B2/en
Priority to KR1020217013030A priority patent/KR102345208B1/ko
Priority to CN201980064561.9A priority patent/CN112771045B/zh
Publication of WO2020063855A1 publication Critical patent/WO2020063855A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/472—Non-condensed isoquinolines, e.g. papaverine
    • A61K31/4725—Non-condensed isoquinolines, e.g. papaverine containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4747—Quinolines; Isoquinolines spiro-condensed
    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • 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
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/20—Spiro-condensed systems

Definitions

  • the present invention relates to a series of quinolinopyrrolidin-2-one compounds and their application in the preparation of drugs for ATM inhibitor-related diseases. Specifically, it relates to a derivative compound represented by formula (I), a tautomer thereof, or a pharmaceutically acceptable composition thereof.
  • Ataxia telangiectasia mutated gene is an autosomal recessive gene.
  • the homozygote shows a progressive neurodegenerative disease.
  • the patient is about 1 year old and shows cerebellum.
  • the ATM gene is an important gene related to DNA damage repair, so patients generally appear to be particularly sensitive to X-rays, and their DNA repair capacity is significantly reduced.
  • About 1% of humans are heterozygous for ATM mutant genes, and although they do not show disease, they also increase the risk of cancer.
  • the ATM gene is located on chromosomes 11q22-q23, with a total length of 150 kb and a coding sequence of 12 kb. It has 66 exons in total. It is one of the human genes with the most exons discovered so far and one of the most important genes. A care gene.
  • ATM protein which is a silk / threonine protein kinase. It contains 3056 amino acids and a relative molecular weight of 370 000. It is mainly located in the nucleus and microsomes. It is involved in the progress of the cell cycle and the cell cycle checkpoint for DNA damage Reaction.
  • ATM protein kinase is a member of the phosphatidylinositol 3-kinase-related kinase family (PIKK). It is an autophosphorylated protein, usually in the form of an inactive dimer. When double-strand breaks occur in DNA, ATM protein kinase appears to be phosphorylated and disaggregated as early as a few minutes, and the phosphorylated ATM protein kinase reaches its maximum in 2 to 3 hours.
  • the signal pathways of ATM protein in DNA damage repair are: 1ATM-CHK2-Cdc25A / B / C signal pathway; 2ATM-CHK2-p53 signal pathway; 3ATM-Nbs1-Smc1 / 3 signal pathway; 4ATM-p38MAPK-MK2 signal path.
  • M MRE11 (meiotic recombinant protein) has nuclease activity and ability to bind DNA; R is Rad50 has ATPase activity; N It means that NBS1 is involved in the localization of the complex in the nucleus and helps it to assemble normally at the DNA breakpoint.
  • the various proteins in the MRN complex must coordinate with each other in order to regulate the ATM protein binding to the breakpoint of the DNA and help the broken DNA complete repair.
  • ATM plays a key role in the repair of DNA double-strand breaks. Due to the low probability of double-strand breaks in normal cells, selective ATM inhibitors have little effect when used alone, but because ATM is in the entire DNA damage repair pathway A key part of this is that there are many possible combinations of ATM inhibitors. At present, pre-clinical and clinical studies have appeared in combination with radiation therapy, combined with chemotherapy, and other target inhibitors such as PARP inhibitors for DNA damage repair. Combination. AstraZeneca's AZD0156 is the earliest compound that has entered phase I clinical trials. At present, AZD1390 and Merck M-3541 have also entered phase I clinical research.
  • ATM kinase inhibitors are used to treat related diseases as solid tumors, wherein the solid tumors include but are not limited to: lung cancer, breast cancer, head and neck cancer, prostate cancer, lymphoma, ovarian cancer, renal cell cancer, esophageal cancer, leukemia, Bladder cancer, gastric cancer, melanoma, urothelial cancer, brain tumor, colorectal cancer, liver cancer, mesothelioma, intrahepatic bile duct cancer, etc.
  • the present invention provides a compound represented by formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof,
  • E is selected from -N (R 5 )-, -O-, and -C (R 6 ) (R 7 )-;
  • R 1 is selected from C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkyl, said C 1-3 alkyl, C 1-3 alkoxy and C 3-6 cycloalkane Is optionally substituted with 1, 2 or 3 R a ;
  • R 2 is selected from H, F, Cl, Br, I, OH and NH 2 ;
  • R 3 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-3 alkyl and C 1-3 alkoxy, said C 1-3 alkyl and C 1-3 alkoxy
  • the oxy group is optionally substituted with 1, 2 or 3 R b ;
  • R 4 is selected from C 1-6 alkyl and N (R c ) (R d );
  • R 6 and R 7 are each independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, C 1-6 alkyl and C 1-6 alkoxy, said C 1-6 alkyl or C 1- 6 alkoxy is optionally substituted with 1, 2 or 3 R f;
  • L 1 is selected from a single bond,-(CH 2 ) m -and-(CH 2 ) m -O-;
  • n is selected from 1, 2, 3 and 4;
  • Ring B is selected from phenyl and 5- to 6-membered heteroaryl, which is optionally substituted with 1, 2 or 3 R g ;
  • R a and R b are independently selected from F, Cl, Br, I, OH, and NH 2 ;
  • R c and R d are independently selected from H, C 1-3 alkyl and C 3-6 cycloalkyl, respectively, said C 1-3 alkyl and C 3-6 cycloalkyl optionally being 1, 2 or 3 R substitutions;
  • R c , Rd and the N atom to which they are attached together form an optionally substituted 4-6 membered heterocycloalkyl group
  • R e , R f and R g are each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R is independently selected from F, Cl, Br, I, OH, and NH 2 ;
  • the 5- to 6-membered heteroaryl group and the 4- to 6-membered heterocycloalkyl group respectively include 1, 2, 3, or 4 heteroatoms or heteroatom groups independently selected from -NH-, -O-, -S-, and N .
  • R 1 is selected from CH 3 , CH 2 CH 3 and cyclopropanyl, and CH 3 , CH 2 CH 3 and cyclopropanyl are optionally substituted with 1, 2 or 3 R a , Other variables are as defined in the present invention.
  • R 1 is selected from the group consisting of CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 and cyclopropanyl, and other variables are as defined in the present invention.
  • the R 3 is selected from the group consisting of H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 CH 3 and , The CH 3 , CH 2 CH 3 and It is optionally substituted by 1, 2 or 3 Rb , other variables are as defined in the present invention.
  • the R 3 is selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 and Other variables are as defined in the present invention.
  • R c and Rd are independently selected from CH 3 , CH 2 CH 3 and cyclopropanyl, and other variables are as defined in the present invention.
  • the aforementioned R c , Rd and the N atom connected to them together form a pyrrolidinyl group and a piperidinyl group, and the pyrrolidinyl group and the piperidinyl group are optionally substituted by 1, 2 or 3 R, Other variables are as defined in the present invention.
  • the R 4 is selected from CH 3 , CH 2 CH 3 , Other variables are as defined in the present invention.
  • the aforementioned R 6 and R 7 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 and The CH 3 , CH 3 CH 2 , CH (CH 3 ) 2 and It is optionally substituted by 1, 2 or 3 R f and other variables are as defined in the present invention.
  • R 6 and R 7 are independently selected from H, F, Cl, Br, I, OH, NH 2 , CN, CH 3 , CH 2 F, CHF 2 , CF 3 , and CH 3 CH 2 , CH (CH 3 ) 2 and Other variables are as defined in the present invention.
  • the E is selected from the group consisting of -O-, -CF 2- , -N (CH 3 )-, -NH-,
  • the above-mentioned L 1 is selected from a single bond,-(CH 2 ) -O-, and-(CH 2 ) 3 -O-, and other variables are as defined in the present invention.
  • the ring B is selected from phenyl, pyridyl, pyrazolyl, indazolyl, and imidazolyl, and the phenyl, pyridyl, pyrazolyl, indazolyl, and imidazolyl is optionally 1, 2 or 3 R g substitutions, other variables are as defined in the present invention.
  • the ring B is selected from Said It is optionally substituted by 1, 2 or 3 Rg , other variables are as defined in the present invention.
  • the ring B is selected from Other variables are as defined in the present invention.
  • R 4 -L 1 - is selected from CH 3 , CH 3 OCH 2- ,
  • Other variables are as defined in the present invention.
  • the present invention also has some solutions from any combination of the above variables.
  • the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 and L 1 are as defined in the present invention.
  • the invention also provides the following compounds, isomers thereof or pharmaceutically acceptable salts thereof, said compounds being selected from
  • the aforementioned compound, an isomer thereof, or a pharmaceutically acceptable salt thereof is selected from the group consisting of
  • the use of the above compound, an isomer thereof, or a pharmaceutically acceptable salt thereof in the preparation of an ATM kinase inhibitor-related drug is not limited.
  • the aforementioned application is characterized in that the ATM kinase inhibitor-related drug is a drug for solid tumors.
  • pharmaceutically acceptable refers to those compounds, materials, compositions, and / or dosage forms that are within the scope of sound medical judgment and are suitable for use in contact with human and animal tissues Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit / risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, prepared from a compound having a specific substituent and a relatively non-toxic acid or base found in the present invention.
  • base addition salts can be obtained by contacting a sufficient amount of a base with a neutral form of such compounds in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc .; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and acidic functional groups
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing an acid group or a base by a conventional chemical method. Generally, such salts are prepared by reacting these compounds in the form of a free acid or base with a stoichiometric appropriate base or acid in water or an organic solvent or a mixture of the two.
  • the structure of the compound 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 compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • the single crystal X-ray diffraction method uses a Bruker D8venture diffractometer to collect diffraction intensity data.
  • the light source is CuK ⁇ radiation.
  • the scanning method is ⁇ / ⁇ scanning. After collecting relevant data, the direct method is further used (Shelxs97) Analysis of the crystal structure can confirm the absolute configuration.
  • the compounds of the invention may exist in specific geometric or stereoisomeric forms.
  • This invention contemplates all such compounds, including cis and trans isomers, (-)-and (+)-enantiomers, (R)-and (S) -enantiomers, diastereomers Isomers, (D) -isomers, (L) -isomers, and racemic and other mixtures thereof, such as enantiomers or diastereomerically enriched mixtures, all of which belong to Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomers or “optical isomers” refer to stereoisomers in mirror image relationship to each other.
  • cis-trans isomer or “geometric isomer” are caused by the inability of a double bond or a single bond of a ring-forming carbon atom to rotate freely.
  • diastereomer refers to a stereoisomer in which a molecule has two or more centers of chirality and is in a non-mirror relationship between molecules.
  • wedge solid line key And wedge dashed keys Represents the absolute configuration of a solid center, using straight solid line keys And straight dashed keys Represents the relative configuration of the solid center, with wavy lines Represents a wedge solid line key Or wedge-shaped dotted key Or with wavy lines Represents a straight solid line key And straight dashed keys
  • the following formula (A) indicates that the compound exists as a single isomer of formula (A-1) or formula (A-2) or as two isomers of formula (A-1) and formula (A-2) Exists in the form of a mixture;
  • the following formula (B) represents that the compound exists as a single isomer of the formula (B-1) or (B-2) or in the form of both (B-1) and (B-2) The isomers exist as a mixture.
  • the following formula (C) represents that the compound exists as a single isomer of the formula (C-1) or (C-2) or in the form of the two isomers of the formula (C-1) and the formula (C-2) It exists as a mixture.
  • tautomer or “tautomeric form” means that at room temperature, the isomers of different functional groups are in dynamic equilibrium and can be quickly converted to each other. If tautomers are possible (eg in solution), the chemical equilibrium of the tautomers can be reached.
  • proton tautomers also known as prototropic tautomers
  • proton migration such as keto-enol isomerization and imine-ene Amine isomerization.
  • Valence tautomers include recombination of some bonding electrons for mutual conversion.
  • a specific example of the keto-enol tautomerization is the interconversion between two tautomers of pentane-2,4-dione and 4-hydroxypent-3-en-2-one.
  • the terms “rich in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enantiomerically enriched” refer to one of the isomers or the The enantiomeric content is less than 100%, and the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, or 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98% or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or more 99.9%.
  • the terms “isomer excess” or “enantiomeric excess” refer to the difference between the two isomers or the relative percentages of the 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 an enantiomer of a compound of the present invention is desired, it can be prepared by asymmetric synthesis or derivatization with a chiral auxiliary, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • a diastereomeric salt is formed with a suitable optically active acid or base, and then a conventional method known in the art Diastereomeric resolution is performed and the pure enantiomer is recovered.
  • the separation of enantiomers and diastereoisomers is usually accomplished by using chromatography that employs a chiral stationary phase and optionally is combined with chemical derivatization (such as the generation of amino groups from amines) Formate).
  • the compounds of the invention may contain atomic isotopes in unnatural proportions on one or more of the atoms constituting the compound.
  • compounds such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C) can be labeled with radioisotopes.
  • deuterated drugs can be replaced by heavy hydrogen. The bond between deuterium and carbon is stronger than the bond between ordinary hydrogen and carbon. Compared with non-deuterated drugs, deuterated drugs have reduced side effects and increased drug stability. , Enhance efficacy, extend the biological half-life of drugs and other advantages. Transformations of all isotopic compositions of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • “Optional” or “optionally” refers to events or conditions described later that may, but need not, occur, and that the description includes situations in which the events or conditions occur and situations in which the events or conditions do not occur.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specific atom with a substituent, and can include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • O oxygen
  • Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the kind and number of substituents may be arbitrary on the basis of chemically achievable.
  • any variable such as R
  • its definition in each case is independent.
  • the group may be optionally substituted with at most two R, and R in each case has independent options.
  • combinations of substituents and / or variants are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as-(CRR) 0- , the linking group is a single bond.
  • substituents When a substituent is vacant, it means that the substituent does not exist.
  • X in A-X indicates that the structure is actually A.
  • substituents may be bonded through any of its atoms, for example, pyridyl as a substituent may be passed through any of the pyridine rings. The carbon atom is attached to a substituted group.
  • the intermediate linking group L is -MW-.
  • -MW- can be connected to ring A and ring B in the same direction as the reading order from left to right. You can also connect ring A and ring B in the opposite direction from the reading order from left to right.
  • the number of atoms on a ring is generally defined as the number of rings, for example, a "5-7 member ring” refers to a “ring” arranged around 5-7 atoms.
  • C 1-6 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 6 carbon atoms.
  • the C 1-6 alkyl includes C 1-5 , C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 and C 5 alkyl, etc .; it may Is monovalent (such as methyl), divalent (such as methylene) or polyvalent (such as methine).
  • C 1-6 alkyl examples include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), butyl (including n-butyl, isobutyl , S-butyl and t-butyl), pentyl (including n-pentyl, isopentyl and neopentyl), hexyl and the like.
  • C 1-3 alkyl is used to indicate a straight or branched chain saturated hydrocarbon group consisting of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, and the like; it may be monovalent (such as methyl), divalent (such as methylene), or polyvalent (such as methine).
  • Example C 1- 3 alkyl groups include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n- propyl and isopropyl) and the like.
  • C 1-6 alkoxy refers to those alkyl groups containing 1 to 6 carbon atoms that are attached to the rest of the molecule through one oxygen atom.
  • the C 1-6 alkoxy group includes C 1-4 , C 1-3 , C 1-2 , C 2-6 , C 2-4 , C 6 , C 5 , C 4 and C 3 alkoxy, etc. .
  • C 1-6 alkoxy examples include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), butoxy (including n-butoxy, isobutyl (Oxy, s-butoxy and t-butoxy), pentyloxy (including n-pentyloxy, isopentyloxy and neopentyloxy), hexyloxy, and the like.
  • C 1-3 alkoxy refers to those alkyl groups containing 1 to 3 carbon atoms that are attached to the rest of the molecule through one oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy, and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy), and the like.
  • C 3-6 cycloalkyl means a saturated cyclic hydrocarbon group consisting of 3 to 6 carbon atoms, which is a monocyclic and bicyclic system.
  • the C 3-6 cycloalkyl includes C 3-5 , C 4-5 and C 5-6 cycloalkyl and the like; it may be monovalent, divalent or polyvalent.
  • Examples of C 3-6 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • the term "4- to 6-membered heterocycloalkyl" itself or in combination with other terms means a saturated cyclic group consisting of 4 to 6 ring atoms, which has 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, and the nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p , p Is 1 or 2). It includes single ring and double ring systems, where the double ring system includes a spiro ring, a parallel ring and a bridge ring.
  • a heteroatom may occupy a connection position between the heterocycloalkyl group and the rest of the molecule.
  • the 4- to 6-membered heterocycloalkyl includes 5- to 6, 4-, 5-, and 6-membered heterocycloalkyl.
  • 4- to 6-membered heterocycloalkyl examples include, but are not limited to, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl ( Including tetrahydrothiophen-2-yl and tetrahydrothiophen-3-yl, etc.), tetrahydrofuryl (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, dithiazyl, isoxazolidinyl, isothiazolyl,
  • the terms “5-6 membered heteroaryl ring” and “5-6 membered heteroaryl group” in the present invention are used interchangeably, and the term “5-6 membered heteroaryl group” means from 5 to 6 ring atoms A single-ring group consisting of a conjugated ⁇ -electron system.
  • One, two, three, or four ring atoms are heteroatoms independently selected from O, S, and N, and the rest are carbon atoms.
  • the nitrogen and sulfur heteroatoms can be optionally oxidized (ie NO and S (O) p , p is 1 or 2).
  • the 5- to 6-membered heteroaryl can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5- to 6-membered heteroaryl includes 5- and 6-membered heteroaryl.
  • Examples of the 5- to 6-membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl and 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrrolyl and 3-pyryl) Oxazolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl, and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl, and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, and 4H-1, 2,4-triazo
  • C n-n + m or C n -C n + m includes any specific case of n to n + m carbons, for example, C 1-12 includes C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , and C 12 , and also include any range from n to n + m, for example, C 1-12 includes C 1- 3 , C 1-6 , C 1-9 , C 3-6 , C 3-9 , C 3-12 , C 6-9 , C 6-12 , and C 9-12, etc.
  • n yuan to n + m means that the number of atoms on the ring is n to n + m.
  • a 3-12-membered ring includes a 3-membered ring, a 4-membered ring, a 5-membered ring, a 6-membered ring, a 7-membered ring, an 8-membered ring, and a 9-membered ring.
  • 3-membered ring includes 3-6-membered ring, 3-9-membered ring, 5-6-membered ring Ring, 5-7 member ring, 6-7 member ring, 6-8 member ring, and 6-10 member 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 (eg, an affinity substitution reaction).
  • representative leaving groups include triflate; chlorine, bromine, and iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, and p-toluenesulfonic acid. Esters, etc .; acyloxy, such as acetoxy, trifluoroacetoxy and the like.
  • protecting group includes but is not limited to "amino protecting group", “hydroxy protecting group” or “mercapto 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-butoxycarbonyl (Boc) ; Arylmethoxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethoxycarbonyl (Fmoc); Arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-methoxyphenyl) methyl; silyl, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxy protecting group refers to a protecting group suitable for preventing side reactions of a 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 (such as acetyl); aryl methyl groups such as benzyl (Bn), p-formyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and more.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl (such as acetyl)
  • aryl methyl groups such as benzyl (Bn), p-formyl Oxybenzyl
  • the compounds of the present invention can be prepared by a variety of synthetic methods well known to those skilled in the art, including the specific embodiments listed below, the embodiments formed by combining them with other chemical synthesis methods, and those familiar to those skilled in the art. Equivalent alternatives, preferred embodiments include, but are not limited to, the embodiments of the present invention.
  • the solvent used in the present invention is commercially available.
  • the present invention uses the following abbreviations: aq stands for water; HATU stands for O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tetramethylurea hexafluorophosphate ; EDC stands for N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride; m-CPBA stands for 3-chloroperoxybenzoic acid; eq stands for equivalent, equivalent; CDI stands for Carbonyl diimidazole; DCM stands for dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N, N-dimethylformamide; DMSO stands for dimethyl sulfoxide; EtOAc stands for ethyl acetate EtOH for ethanol; MeOH for methanol; CBz for benzy
  • the compound of the invention has significant ATM kinase inhibitory effect and very good kinase selectivity, has good solubility and permeability, can penetrate the brain, and has the potential to be developed into a drug for treating brain tumors.
  • the compound of the present invention and etoposide show a good synergistic effect, which is better than the drug effect of AZD0156 and etoposide.
  • Figure 2 Tumor growth curve.
  • nitromethane (18 g, 294.89 mmol, 15.93 mL) (B-3) was slowly added to a solution of NaOH (17.69 g, 442.33 mmol) in H 2 O (100 mL), keeping the internal temperature at 30 °C, then heated to 40 ° C and stirred for 30 minutes, cooled, and then slowly added another part of nitromethane (18.00g, 294.89mmol, 15.93mL), the reaction system was heated to 45 ° C and stirred for 30 minutes, then raised to 50 ° C After stirring at 55 ° C for 5 minutes, a mixed solution of B-6 was obtained and used directly in the next reaction.
  • N-BuLi (2M, 765.23 ⁇ L) was slowly added dropwise to a solution of DIPA (193.58 mg, 1.91 mmol, 270.37 ⁇ L) in THF (1 mL) at -60 ° C, stirred for 0.5 hours, and then tetrahydrogen was added dropwise at -60 ° C.
  • Methylpyran-4-carboxylic acid 300.88 mg, 2.09 mmol, 278.59 ⁇ L was stirred for 1 hour, and a solution of intermediate A (500 mg, 1.74 mmol) in THF (4 mL) was added, followed by stirring at -60 ° C for 2 hours.
  • 1,4-dioxane (3 mL) and H 2 O (3 mL) were added to compound 1-C (70 mg, 201.61 ⁇ mol), 2-fluoropyridine-5-boronic acid (42.61 mg, 302.41). ⁇ mol), Pd (PPh 3 ) 4 (23.30 mg, 20.16 ⁇ mol) and Na 2 CO 3 (64.11 mg, 604.83 ⁇ mol) in a reaction system, and stirred at 80 ° C. for 3 hours. After the reaction was completed, H 2 O (20 mL) and EtOAc (30 mL) were added to the reaction system, and then filtered through celite.
  • Compound 3 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 4-C was prepared in the same manner as in Example 3 except that the corresponding raw materials were used.
  • Compound 4 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 5-C was prepared in the same manner as in Example 3 except that the corresponding raw materials were used.
  • Compound 5 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 6-C was prepared in the same manner as in Example 3 except that the corresponding raw materials were used.
  • Compound 6 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 7-A was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 7-B was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 7-C was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 7-D was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 7 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 8-A was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 8-B was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 8-C was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 8-D was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 8-E was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Trifluoroacetic acid (1mL) was added to 8-E (100mg, 183.26 ⁇ mol), and the reaction solution was stirred at 20 ° C for 1 hour.
  • compound 10-B 400 mg, 1.07 mmol
  • 2-fluoropyridine-5-boronic acid 301.19 mg, 2.14 mmol
  • Na 2 CO 3 226.55 mg, 2.14 mmol
  • Pd (PPh 3 ) 4 123.50 mg, 106.87 ⁇ mol
  • aqueous solution of dioxane 18 mL
  • H 2 O 2 mL
  • the reaction solvent was removed by concentration, and the crude product was subjected to column chromatography (0 to 5% MeOH / DCM) to obtain compound 10-C.
  • Compound 11-C was prepared in the same manner as in Example 3 except that the corresponding raw materials were used.
  • Compound 11 was prepared in the same manner as in Example 10 except that the corresponding starting materials were used.
  • Compound 12-A was prepared in the same manner as in Compound 10-B except that the corresponding starting materials were used.
  • Compound 12-B was prepared in the same manner as in Compound 10-C except that the corresponding starting materials were used.
  • Compound 12 was prepared in the same manner as in Example 10 except that the corresponding starting materials were used.
  • Compound 13-A was prepared in the same manner as in Compound 10-B except that the corresponding starting materials were used.
  • Compound 13-B was prepared in the same manner as in Example 10 except for using the corresponding starting materials.
  • Compound 13 was prepared in the same manner as in Example 10 except that the corresponding starting materials were used.
  • Compound 14 was prepared in the same manner as in Example 10 except that the corresponding starting materials were used.
  • Compound 15-A was prepared in the same manner as in Compound 10-B except that the corresponding starting materials were used.
  • Compound 15-B was prepared in the same manner as in Compound 10-C except that the corresponding starting materials were used.
  • Compound 15 was prepared in the same manner as in Example 10 except that the corresponding starting materials were used.
  • Compound 16 was prepared in the same manner as in Example 10 except that the corresponding starting materials were used.
  • Compound 18-A was prepared in the same manner as in Example 17 except for using the corresponding starting materials.
  • Compound 18-B was prepared in the same manner as in Example 17 except for using the corresponding starting materials.
  • Compound 18 was prepared in the same manner as in Example 17 except that the corresponding starting materials were used.
  • Compound 19-A was prepared in the same manner as in Compound 17-A except that the corresponding starting materials were used.
  • Compound 19-B was prepared in the same manner as in Example 17 except for using the corresponding starting materials.
  • Compound 19 was prepared in the same manner as in Example 17 except that the corresponding starting materials were used.
  • Compound 20 was prepared in the same manner as in Example 17 except that the corresponding starting materials were used.
  • Compound 21-A was prepared in the same manner as in Example 17 except that the corresponding raw materials were used.
  • Compound 21-B was prepared in the same manner as in Example 17 except for using the corresponding starting materials.
  • Compound 21 was prepared in the same manner as in Example 17 except that the corresponding starting materials were used.
  • 1,2-Dichloroethane 100 mL was added to methyl 4-piperidinecarboxylic acid (10 g, 69.84 mmol), cyclopropylboronic acid (12.00 g, 139.68 mmol), pyridine (5.52 g, 69.84 mmol, 5.64 mL ) And sodium carbonate (14.80 g, 139.68 mmol, 2 eq), replaced with oxygen 3 times, and stirred at 70 ° C. for 16 hours in an oxygen atmosphere. After the reaction was completed, the temperature was lowered to 0 ° C and 200 mL of water was added to quench the reaction.
  • Compound 22-C was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • 1,4-dioxane (20 mL) and H 2 O (20 mL) were added to compound 22-E (1 g, 2.53 mmol), 2-fluoropyridine-5-boronic acid (534.71 mg, 3.79 mmol), tetratriphenylphosphine palladium (292.34 mg, 252.98 ⁇ mol) and sodium carbonate (804.41 mg, 7.59 mmol) in a reaction system, and stirred at 80 ° C. for 16 hours. After completion of the reaction, the solvent was removed under reduced pressure to obtain a crude compound 22-F, which was directly used in the next reaction.
  • Compound 22 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 23 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 25-A was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 25-B was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 25-D was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Sodium hydride (106.29 mg, 2.66 mmol, purity: 60%) was dissolved in tetrahydrofuran (10 mL), and a solution of 25-E (320 mg, 885.86 ⁇ mol) in tetrahydrofuran (10 mL) was added under a nitrogen atmosphere at 0 ° C, and stirred at 0 ° C for 0.5
  • methyl iodide (502.95mg, 3.54mmol, 220.59 ⁇ L) was added under a nitrogen atmosphere, the mixed system was raised to 25 ° C room temperature, and after stirring for 2 hours under a nitrogen atmosphere, the mixed solution was dispersed into 50mL of water and quenched.
  • Compound 25-G was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 25 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Chloromethane (100mL, 50mL * 2) was extracted, the organic phase was collected, and the organic phase was concentrated to obtain a crude product.
  • Compound 26-D was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 26 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 27-C was prepared in the same manner as in Example 1 except for using the corresponding starting materials.
  • Compound 27-D was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 28-A was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 28 was prepared in the same manner as in Example 27 except that the corresponding starting materials were used.
  • Compound 29-B was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 29 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 30 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 31 was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • n-BuLi (2M, 3.93mL) was slowly added to a solution of DIPA (993.72mg, 9.82mmol, 1.39mL) in THF (10mL). The reaction system was stirred at -30 ° C for 30 minutes. , And then slowly added tetrahydropyran-4-carboxylic acid methyl ester (1.49 g, 10.31 mmol, 1.38 mL) in a THF (10 mL) solution, and the reaction system was stirred at -65 ° C for 1 hour, and finally compound B (1.5 g , 4.91 mmol) in THF (10 mL), and the reaction was stirred at -65 ° C for 2 hours.
  • Compound 33 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 34-A was prepared in the same manner as in Compound 29-A except that the corresponding starting materials were used.
  • Compound 34-B was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 34 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 35 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 36-A was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 36-B was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 36-C was prepared in the same manner as in Example 1 except that the corresponding raw materials were used.
  • Compound 36-D was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • Compound 36 was prepared in the same manner as in Example 1 except that the corresponding starting materials were used.
  • the compounds of the present invention used for the experiments are all self-made.
  • the chemical names and structural formulas are shown in the preparation examples of the compounds.
  • the experimental tests were performed by the British company Eurofins, and the experimental results were provided by the company.
  • Human ATM kinase was incubated in a buffer solution containing 30nM GST-cMyc-p53 and Mg / ATP. The concentration of Mg / ATP was determined according to different needs. The reaction was initiated by adding a Mg / ATP complex. After approximately 30 minutes of incubation at room temperature, the reaction was stopped by adding a stop solution containing EDTA. Finally, a detection buffer containing d2-labeled anti-GST monoclonal antibody and tritium-labeled phosphorylated Ser15 antibody was added to phosphorylated p53.
  • HTRF 10000x (Em665nm / Em620nm).
  • Human-derived DNA-PK kinase was incubated in a buffer solution containing 50 nM GST-cMyc-p53 and Mg / ATP. The concentration of Mg / ATP was determined according to different needs. The reaction was initiated by adding a Mg / ATP complex. After approximately 30 minutes of incubation at room temperature, the reaction was stopped by adding a stop solution containing EDTA. Finally, a detection buffer containing d2-labeled anti-GST monoclonal antibody and tritium-labeled phosphorylated Ser15 antibody was added to phosphorylated p53.
  • HTRF 10000x (Em665nm / Em620nm).
  • Example 10 2 80 Example 11 2 243 Example 12 2 26 Example 13 4 27 Example 14 3 46 Example 15 2 41 Example 16 4 204 Example 17 3 352 Example 18 2 343 Example 19 0.8 77 Example 20 2 129 Example 21 7 509 Example 22 1 14 Example 23 0.8 30 Example 24 2 80 Example 25 1 92 Example 26 1 76 Example 27 1 99 Example 28 2 334 Example 29 2 269 Example 30 2 475 Example 31 63 88 Example 32 2 561 Example 33 1 593 Example 34 5 > 1000 Example 35 3 > 1000 Example 36 12 > 1000
  • the compounds of the present invention have significant ATM kinase inhibition and good selectivity for DNA-PK kinase.
  • IP intraperitoneal injection
  • PO oral
  • QD once daily
  • BIW twice a week
  • QD PG-D0, 3Don, 4D off from PG-D1
  • BIW BIW + QD (PG-D0, 3D, 4D off from PG-D1) ⁇ 4W: Etoposide on Monday, ATM inhibitor on Tuesday to Thursday, once a day, Circulate once a week for four weeks.
  • Human lung cancer cell H446 (ATCC, Manassas, VA, HTB-171) was cultured in vitro in a monolayer, the culture conditions were RPMI-1640, and 10% fetal calf serum, 100 U / mL penicillin and 100 ⁇ g / mL streptomycin were added to the medium, 37 C. 5% CO 2 culture. Passage with trypsin-EDTA for routine digestion treatment twice a week. When the cell saturation is 80% -90%, the cells are collected, counted, and seeded.
  • the experimental index is to investigate whether tumor growth is inhibited, delayed or cured.
  • Tumor diameter was measured twice a week with vernier calipers.
  • T Tumor proliferation rate T / C (%): where T is the average tumor volume obtained from the last measurement (PG-D26) in the treatment group, and C is the average tumor volume obtained from the last measurement (PG-D26) in the control group.
  • the body weight of experimental animals was used as a reference indicator for indirect determination of drug toxicity. In this model, all the administration groups showed no significant weight loss (Figure 1). The number 42161 mice were found dead on the 15th day after administration in the etoposide, 15 mg / kg and AZD0156, 5 mg / kg combination group. In the treatment groups in which etoposide was used in combination with Example 32 and AZD0156, some animals lost more than 10% but not less than 15% in weight.
  • the effect of the test drugs ATM inhibitor and etoposide on the body weight of a female BALB / c nude mouse model of a subcutaneous xenograft tumor of H446 cells is shown in FIG. 1. The relative weight change was calculated based on the animal's weight at the beginning of the dose. Data points represent the percentage change in average body weight within the group, and error bars represent standard error (SEM).
  • Table 4 shows the changes in tumor volume in each female BALB / c nude mouse model given H446 cells subcutaneous xenograft tumors after treatment with the test drug ATM inhibitor and etoposide.
  • Tumor growth curve of H446 xenograft tumor model tumor-bearing mice after administration of the test drug ATM inhibitor and etoposide The tumor growth curve is shown in FIG. 2. Data points represent the average tumor volume within the group, and error bars represent standard error (SEM).
  • Antitumor efficacy evaluation index (calculated based on tumor volume on day 26 after administration)
  • c. p value is calculated based on tumor volume.
  • Example 32 in combination with etoposide showed a good synergistic effect, which was superior to the pharmacodynamic effect of AZD0156 and etoposide in combination.

Abstract

公开了一系列喹啉并吡咯烷-2-酮类的化合物，及其在制备ATM抑制剂相关疾病的药物中的应用。具体涉及了式(Ι)所示衍生化合物、其互变异构体或其药学上可接受的组合物。（I）

Description

喹啉并吡咯烷-2-酮类衍生物及其应用
本申请主张如下优先权：
CN201811157825.9，申请日2018.09.30。
技术领域
本发明涉及一系列喹啉并吡咯烷-2-酮类的化合物，及其在制备ATM抑制剂相关疾病的药物中的应用。具体涉及式(Ι)所示衍生化合物、其互变异构体或其药学上可接受的组合物。
背景技术
毛细血管扩张性共济失调突变基因(ATM，Ataxia telangiectasia mutated gene)是一种常染色体隐性遗传基因，纯合子表现出一种进行性神经变性性疾病，患者1岁左右患病，表现为小脑性共济失调，6岁左右眼和面颈部出现瘤样小血管扩张，常死于感染。ATM基因是与DNA损伤修复相关的一种重要基因，因此患者一般表现为对X射线特别敏感，DNA修复能力明显下降。人类中大约有1％的人是ATM突变基因的杂合子，虽然不表现出疾病，但也增加了患癌的风险。ATM基因位于染色体11q22-q23，全长150kb，编码序列12kb，共有66个外显子，是到目前为止所发现的外显子最多的人类基因之一，也是最重要的基因之一，是一种看护基因。
ATM基因编码产物为ATM蛋白，是一种丝/苏氨酸蛋白激酶，包含3056个氨基酸，相对分子量370 000，主要位于细胞核和微粒体内，参与细胞周期的进行及对DNA损伤的细胞周期检查点的反应。ATM蛋白激酶属于磷脂酰肌醇3-激酶相关激酶家族(PIKK)中的一员，是一种自动磷酸化蛋白，通常以无活性的二聚体的形式存在，当DNA发生双链断裂时，ATM蛋白激酶最早在数分钟就出现磷酸化而解聚，在2到3小时磷酸化的ATM蛋白激酶达到最大值。
ATM蛋白在DNA的损伤修复中的信号通路主要有：①ATM-CHK2-Cdc25A/B/C信号通路；②ATM-CHK2-p53信号通路；③ATM-Nbs1-Smc1/3信号通路；④ATM-p38MAPK-MK2信号通路。ATM蛋白识别DNA双链断裂并发生自动磷酸化的过程涉及MRN复合物的参与，M即MRE11(减数分裂重组蛋白)具有核酸酶活性及结合DNA的能力；R为Rad50具有ATP酶活性；N指NBS1涉及该复合物在细胞核内的定位及帮助其在DNA断裂点正常装配。MRN复合物中各种蛋白必须相互协调才能调节ATM蛋白结合到DNA的断端点，帮助断裂的DNA完成修复。
ATM在DNA双链断裂的修复中起关键作用，由于正常细胞发生双链断裂的几率较小，因此选择性的ATM抑制剂单用时几乎没有什么作用，但由于ATM是整个DNA损伤修复的通路中的关键一环，ATM抑制剂存在多种联用的可能，目前临床前以及临床研究中已出现与放疗联用，与化疗联用，以及与DNA损伤修复的其它靶点抑制剂如PARP抑制剂的联用等。阿斯利康的AZD0156是最早进入一期临床的化合物，目前AZD1390和德国默克的M-3541也相继进入一期临床的研究。
ATM激酶抑制剂用于治疗相关的疾病为实体瘤，其中所述实体瘤包括但不限于：肺癌、乳腺癌、头颈 癌、前列腺癌、淋巴瘤、卵巢癌、肾细胞癌、食管癌，白血病、膀胱癌、胃癌、黑色素瘤、尿路上皮癌、脑肿瘤、结直肠癌、肝癌、间皮瘤、肝内胆管癌等。
Figure PCTCN2019108520-appb-000001
发明内容
本发明提供了式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
Figure PCTCN2019108520-appb-000002
其中，
E选自-N(R 5)-、-O-和-C(R 6)(R 7)-；
R 1选自C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基任选被1、2或3个R a取代；
R 2选自H、F、Cl、Br、I、OH和NH 2；
R 3选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R b取代；
R 4选自C 1-6烷基和N(R c)(R d)；
R 5选自H、C 1-6烷基、C 3-6环烷基、C 1-6烷基-C＝O-、C 1-6烷基-O-C＝O-和C 3-6环烷基-C＝O-，所述C 1-6烷基、C 3-6环烷基、C 1-6烷基-C＝O-、C 1-6烷基-O-C＝O-和C 3-6环烷基-C＝O-任选被1、2或3个R e取代；
R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基或C 1- 6烷氧基任选被1、2或3个R f取代；
L 1选自单键、-(CH 2) m-和-(CH 2) m-O-；
m选自1、2、3和4；
环B选自苯基和5～6元杂芳基，所述苯基和5～6元杂芳基任选被1、2或3个R g取代；
R a和R b分别独立地选自F、Cl、Br、I、OH和NH 2；
R c和R d分别独立地选自H、C 1-3烷基和C 3-6环烷基，所述C 1-3烷基和C 3-6环烷基任选被1、2或3个R取代；
或者，R c、R d和与它们连接的N原子共同构成任选1、2或3个R取代的4-6元杂环烷基；
R e、R f和R g分别独立地选自F、Cl、Br、I、OH和NH 2；
R分别独立地选自F、Cl、Br、I、OH和NH 2；
所述5～6元杂芳基和4-6元杂环烷基分别包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
本发明的一些方案中，上述R 1选自CH 3、CH 2CH 3和环丙烷基，所述CH 3、CH 2CH 3和环丙烷基任选被1、2或3个R a取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 1选自CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和环丙烷基，其他变量如本发明所定义。
本发明的一些方案中，上述R 3选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3和
Figure PCTCN2019108520-appb-000003
，所述CH 3、CH 2CH 3和
Figure PCTCN2019108520-appb-000004
任选被1、2或3个R b取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 3选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和
Figure PCTCN2019108520-appb-000005
其他变量如本发明所定义。
本发明的一些方案中，上述R c和R d分别独立地选自CH 3、CH 2CH 3和环丙烷基，其他变量如本发明所定义。
本发明的一些方案中，上述R c、R d和与它们连接的N原子共同构成吡咯烷基和哌啶基，所述吡咯烷基和哌啶基任选1、2或3个R取代，其他变量如本发明所定义。
本发明的一些方案中，上述R c、R d和与它们连接的N原子共同构成
Figure PCTCN2019108520-appb-000006
Figure PCTCN2019108520-appb-000007
其他变量如本发明所定义。
本发明的一些方案中，上述R 4选自CH 3、CH 2CH 3、
Figure PCTCN2019108520-appb-000008
Figure PCTCN2019108520-appb-000009
其他变量如本发明所定义。
本发明的一些方案中，上述R 5选自H、CH 3、CH 3CH 2、CH(CH 3) 2、环丙烷基、CH 3OC＝O-、CH(CH 3) 2OC＝O-、CH 3C＝O-和环丙烷基-C＝O-，所述CH 3、CH 3CH 2、CH(CH 3) 2、环丙烷基、CH 3OC＝O-、CH(CH 3) 2OC＝O-、CH 3C＝O-和环丙烷基-C＝O-任选被1、2或3个R e取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 5选自H、CH 3、CH 2F、CHF 2、CF 3、CH 3CH 2、CH 2FCH 2、CHF 2CH 2、CF 3CH 2、CH(CH 3) 2、环丙烷基、CH 3OC＝O-、CH(CH 3) 2OC＝O-、CH 3C＝O-和环丙烷基-C＝O-，其他变量如本发明所定义。
本发明的一些方案中，上述R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 3CH 2、CH(CH 3) 2和
Figure PCTCN2019108520-appb-000010
所述CH 3、CH 3CH 2、CH(CH 3) 2和
Figure PCTCN2019108520-appb-000011
任选被1、2或3个R f取代，其他变量如本发明所定义。
本发明的一些方案中，上述R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 3CH 2、CH(CH 3) 2和
Figure PCTCN2019108520-appb-000012
其他变量如本发明所定义。
本发明的一些方案中，上述E选自-O-、-CF 2-、-N(CH 3)-、-NH-、
Figure PCTCN2019108520-appb-000013
Figure PCTCN2019108520-appb-000014
本发明的一些方案中，上述L 1选自单键、-(CH 2)-O-和-(CH 2) 3-O-，其他变量如本发明所定义。
本发明的一些方案中，上述环B选自苯基、吡啶基、吡唑基、吲唑基和咪唑基，所述苯基、吡啶基、吡唑基、吲唑基和咪唑基任选被1、2或3个R g取代，其他变量如本发明所定义。
本发明的一些方案中，上述环B选自
Figure PCTCN2019108520-appb-000015
所述
Figure PCTCN2019108520-appb-000016
Figure PCTCN2019108520-appb-000017
任选被1、2或3个R g取代，其他变量如本发明所定义。
本发明的一些方案中，上述环B选自
Figure PCTCN2019108520-appb-000018
其他变量如本发明所定义。
本发明的一些方案中，上述R 4-L 1-选自CH 3、CH 3OCH 2-、
Figure PCTCN2019108520-appb-000019
Figure PCTCN2019108520-appb-000020
其他变量如本发明所定义。
本发明还有一些方案由上述变量任意组合而来。
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2019108520-appb-000021
其中，
R 1、R 2、R 3、R 4、R 5、R 6、R 7和L 1如本发明所定义。
本发明还提供了下列化合物、其异构体或其药学上可接受的盐，所述化合物选自
Figure PCTCN2019108520-appb-000022
Figure PCTCN2019108520-appb-000023
Figure PCTCN2019108520-appb-000024
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐，其选自
Figure PCTCN2019108520-appb-000025
本发明的一些方案中，上述化合物、其异构体或其药学上可接受的盐在制备ATM激酶抑制剂相关药物上的应用。
本发明的一些方案中，上述的应用，其特征在于，所述ATM激酶抑制剂相关药物是用于实体瘤的药物。
定义和说明
除非另有说明，本文所用的下列术语和短语旨在具有下列含义。一个特定的术语或短语在没有特别定义的情况下不应该被认为是不确定的或不清楚的，而应该按照普通的含义去理解。当本文中出现商品名时，意在指代其对应的商品或其活性成分。
这里所采用的术语“药学上可接受的”，是针对那些化合物、材料、组合物和/或剂型而言，它们在可靠的医学判断的范围之内，适用于与人类和动物的组织接触使用，而没有过多的毒性、刺激性、过敏性反应或其它问题或并发症，与合理的利益/风险比相称。
术语“药学上可接受的盐”是指本发明化合物的盐，由本发明发现的具有特定取代基的化合物与相对无毒的酸或碱制备。当本发明的化合物中含有相对酸性的功能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的碱与这类化合物的中性形式接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机氨或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物的中性形式接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、 对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
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。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：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。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
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。
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。
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。
除非另有说明，“(D)”或者“(+)”表示右旋，“(L)”或者“(-)”表示左旋，“(DL)”或者“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2019108520-appb-000026
和楔形虚线键
Figure PCTCN2019108520-appb-000027
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2019108520-appb-000028
和直形虚线键
Figure PCTCN2019108520-appb-000029
表示立体中心的相对构型，用波浪线
Figure PCTCN2019108520-appb-000030
表示楔形实线键
Figure PCTCN2019108520-appb-000031
或楔形虚线键
Figure PCTCN2019108520-appb-000032
或用波浪线
Figure PCTCN2019108520-appb-000033
表示直形实线键
Figure PCTCN2019108520-appb-000034
和直形虚线键
Figure PCTCN2019108520-appb-000035
除非另有说明，当化合物中存在双键结构，如碳碳双键、碳氮双键和氮氮双键，且双键上的各个原子均连接有两个不同的取代基时(包含氮原子的双键中，氮原子上的一对孤对电子视为其连接的一个取代基)，如果该化合物中双键上的原子与其取代基之间用波浪线
Figure PCTCN2019108520-appb-000036
连接，则表示该化合物的(Z)型异构体、(E)型异构体或两种异构体的混合物。例如下式(A)表示该化合物以式(A-1)或式(A-2)的单一异构体形式存在或以式(A-1)和式(A-2)两种异构体的混合物形式存在；下式(B)表示该化合物以式(B-1)或式(B-2)的单一异构体形式存在或以式(B-1)和式(B-2)两种异构体的混合物形式存在。下式(C)表示该化合物以式(C-1)或式(C-2)的单一异构体形式存在或以式(C-1)和式(C-2)两种异构体的混合物形 式存在。
Figure PCTCN2019108520-appb-000037
本发明的化合物可以存在特定的。除非另有说明，术语“互变异构体”或“互变异构体形式”是指在室温下，不同官能团异构体处于动态平衡，并能很快的相互转化。若互变异构体是可能的(如在溶液中)，则可以达到互变异构体的化学平衡。例如，质子互变异构体(proton tautomer)(也称质子转移互变异构体(prototropic tautomer))包括通过质子迁移来进行的互相转化，如酮-烯醇异构化和亚胺-烯胺异构化。价键异构体(valence tautomer)包括一些成键电子的重组来进行的相互转化。其中酮-烯醇互变异构化的具体实例是戊烷-2,4-二酮与4-羟基戊-3-烯-2-酮两个互变异构体之间的互变。
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％。
除非另有说明，术语“异构体过量”或“对映体过量”指两种异构体或两种对映体相对百分数之间的差值。例如，其中一种异构体或对映体的含量为90％，另一种异构体或对映体的含量为10％，则异构体或对映体过量(ee值)为80％。
可以通过的手性合成或手性试剂或者其他常规技术制备光学活性的(R)-和(S)-异构体以及D和L异构体。如果想得到本发明某化合物的一种对映体，可以通过不对称合成或者具有手性助剂的衍生作用来制备，其中将所得非对映体混合物分离，并且辅助基团裂开以提供纯的所需对映异构体。或者，当分子中含有碱性官能团(如氨基)或酸性官能团(如羧基)时，与适当的光学活性的酸或碱形成非对映异构体的盐，然后通过本领域所公知的常规方法进行非对映异构体拆分，然后回收得到纯的对映体。此外，对映异构体和非对映异构体的分离通常是通过使用色谱法完成的，所述色谱法采用手性固定相，并任选地与化学衍生法相结合(例如由胺生成氨基甲酸盐)。本发明的化合物可以在一个或多个构成该化合物的原子上包含非天然比例的原子同位素。例如，可用放射性同位素标记化合物，比如氚( 3H)，碘-125( 125I)或C-14( 14C)。又例如，可用重氢取代氢形成氘代药物，氘与碳构成的键比普通氢与碳构成的键更坚固，相比于未氘化药 物，氘代药物有降低毒副作用、增加药物稳定性、增强疗效、延长药物生物半衰期等优势。本发明的化合物的所有同位素组成的变换，无论放射性与否，都包括在本发明的范围之内。“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
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，可以包括重氢和氢的变体，只要特定原子的价态是正常的并且取代后的化合物是稳定的。当取代基为氧(即＝O)时，意味着两个氢原子被取代。氧取代不会发生在芳香基上。术语“任选被取代的”是指可以被取代，也可以不被取代，除非另有规定，取代基的种类和数目在化学上可以实现的基础上可以是任意的。
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。
当一个连接基团的数量为0时，比如-(CRR) 0-，表示该连接基团为单键。
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。
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。
当所列举的连接基团没有指明其连接方向，其连接方向是任意的，例如，
Figure PCTCN2019108520-appb-000038
中连接基团L为-M-W-，此时-M-W-既可以按与从左往右的读取顺序相同的方向连接环A和环B构成
Figure PCTCN2019108520-appb-000039
也可以按照与从左往右的读取顺序相反的方向连接环A和环B构成
Figure PCTCN2019108520-appb-000040
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。
除非另有规定，环上原子的数目通常被定义为环的元数，例如，“5-7元环”是指环绕排列5-7个原子的“环”。
除非另有规定，术语“C 1-6烷基”用于表示直链或支链的由1至6个碳原子组成的饱和碳氢基团。所述C 1-6烷基包括C 1-5、C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6和C 5烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1-6烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异 丙基)、丁基(包括n-丁基，异丁基，s-丁基和t-丁基)、戊基(包括n-戊基，异戊基和新戊基)、己基等。
除非另有规定，术语“C 1-3烷基”用于表示直链或支链的由1至3个碳原子组成的饱和碳氢基团。所述C 1-3烷基包括C 1-2和C 2-3烷基等；其可以是一价(如甲基)、二价(如亚甲基)或者多价(如次甲基)。C 1- 3烷基的实例包括但不限于甲基(Me)、乙基(Et)、丙基(包括n-丙基和异丙基)等。
除非另有规定，术语“C 1-6烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至6个碳原子的烷基基团。所述C 1-6烷氧基包括C 1-4、C 1-3、C 1-2、C 2-6、C 2-4、C 6、C 5、C 4和C 3烷氧基等。C 1-6烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)、丁氧基(包括n-丁氧基、异丁氧基、s-丁氧基和t-丁氧基)、戊氧基(包括n-戊氧基、异戊氧基和新戊氧基)、己氧基等。
除非另有规定，术语“C 1-3烷氧基”表示通过一个氧原子连接到分子的其余部分的那些包含1至3个碳原子的烷基基团。所述C 1-3烷氧基包括C 1-2、C 2-3、C 3和C 2烷氧基等。C 1-3烷氧基的实例包括但不限于甲氧基、乙氧基、丙氧基(包括正丙氧基和异丙氧基)等。
除非另有规定，“C 3-6环烷基”表示由3至6个碳原子组成的饱和环状碳氢基团，其为单环和双环体系，所述C 3-6环烷基包括C 3-5、C 4-5和C 5-6环烷基等；其可以是一价、二价或者多价。C 3-6环烷基的实例包括，但不限于，环丙基、环丁基、环戊基、环己基等。
除非另有规定，术语“4-6元杂环烷基”本身或者与其他术语联合分别表示由4至6个环原子组成的饱和环状基团，其1、2、3或4个环原子为独立选自O、S和N的杂原子，其余为碳原子，其中氮原子任选地被季铵化，氮和硫杂原子可任选被氧化(即NO和S(O) p，p是1或2)。其包括单环和双环体系，其中双环体系包括螺环、并环和桥环。此外，就该“4-6元杂环烷基”而言，杂原子可以占据杂环烷基与分子其余部分的连接位置。所述4-6元杂环烷基包括5-6元、4元、5元和6元杂环烷基等。4-6元杂环烷基的实例包括但不限于氮杂环丁基、氧杂环丁基、硫杂环丁基、吡咯烷基、吡唑烷基、咪唑烷基、四氢噻吩基(包括四氢噻吩-2-基和四氢噻吩-3-基等)、四氢呋喃基(包括四氢呋喃-2-基等)、四氢吡喃基、哌啶基(包括1-哌啶基、2-哌啶基和3-哌啶基等)、哌嗪基(包括1-哌嗪基和2-哌嗪基等)、吗啉基(包括3-吗啉基和4-吗啉基等)、二噁烷基、二噻烷基、异噁唑烷基、异噻唑烷基、1,2-噁嗪基、1,2-噻嗪基、六氢哒嗪基、高哌嗪基或高哌啶基等。
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)。
除非另有规定，C n-n+m或C n-C n+m包括n至n+m个碳的任何一种具体情况，例如C 1-12包括C 1、C 2、C 3、C 4、C 5、C 6、C 7、C 8、C 9、C 10、C 11、和C 12，也包括n至n+m中的任何一个范围，例如C 1-12包括C 1- 3、C 1-6、C 1-9、C 3-6、C 3-9、C 3-12、C 6-9、C 6-12、和C 9-12等；同理，n元至n+m元表示环上原子数为n至n+m个，例如3-12元环包括3元环、4元环、5元环、6元环、7元环、8元环、9元环、10元环、11元环、和12元环，也包括n至n+m中的任何一个范围，例如3-12元环包括3-6元环、3-9元环、5-6元环、5-7元环、6-7元环、6-8元环、和6-10元环等。
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(例如亲和取代反应)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。
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。
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。
本发明所使用的溶剂可经市售获得。本发明采用下述缩略词：aq代表水；HATU代表O-(7-氮杂苯并三唑-1-基)-N,N,N',N'-四甲基脲六氟磷酸盐；EDC代表N-(3-二甲基氨基丙基)-N'-乙基碳二亚胺盐酸盐；m-CPBA代表3-氯过氧苯甲酸；eq代表当量、等量；CDI代表羰基二咪唑；DCM代表二氯甲烷；PE代表石油醚；DIAD代表偶氮二羧酸二异丙酯；DMF代表N,N-二甲基甲酰胺；DMSO代表二甲亚砜；EtOAc代表乙酸乙酯；EtOH代表乙醇；MeOH代表甲醇；CBz代表苄氧羰基，是一种胺保护基团；BOC代表叔丁氧羰基是一种胺保护基团；HOAc代表乙酸；NaCNBH 3代表氰基硼氢化钠；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二叔丁基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；SOCl 2代表氯化亚砜；CS 2代表二硫化碳；TsOH代表对甲苯磺酸；NFSI代表N-氟-N-(苯磺酰基)苯磺酰胺； NCS代表1-氯吡咯烷-2,5-二酮；n-Bu 4NF代表氟化四丁基铵；iPrOH代表2-丙醇；mp代表熔点；LDA代表二异丙基胺基锂；LiHMDS代表六甲基二硅基胺基锂；Xantphos代表4,5-双二苯基膦-9,9-二甲基氧杂蒽；LiAlH 4代表四氢铝锂；Pd(dba) 2代表三(二亚苄基丙酮)二钯；mCPBA代表间氯过氧苯甲酸；pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；DBU代表1,8-二氮杂双环[5.4.0]十一碳-7-烯；DIPA代表二异丙胺；n-BuLi代表正丁基锂；NBS代表N-溴代丁二酰亚胺；MeI代表碘甲烷；TBAB代表四丁基溴化铵；Pd(PPh 3) 4代表四三苯基膦钯；MeCN代表乙腈；NaH代表氢化钠；TBSOTf代表(叔丁基二甲基硅基)三氟甲基磺酸酯。
化合物经手工或者
Figure PCTCN2019108520-appb-000041
软件命名，市售化合物采用供应商目录名称。
技术效果：
本发明化合物具有显著的ATM激酶抑制作用和非常好的激酶的选择性，有良好溶解性和渗透性，能够透脑，具备开发成治疗脑部肿瘤药物的潜力。本发明化合物与etoposide联用表现出很好的协同效应，优于AZD0156与etoposide联用的药效
附图说明：
图1：相对体重变化；
图2：肿瘤生长曲线。
具体实施方式
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。
中间体A
Figure PCTCN2019108520-appb-000042
合成路线：
Figure PCTCN2019108520-appb-000043
步骤1：中间体A的合成
于化合物A-1(34g,126.37mmol)的SOCl 2(200mL)溶液中加入DMF(95.00mg,1.30mmol,0.1mL)，反应液在80℃搅拌16小时。反应结束后减压除去SOCl 2得到粗品A，直接用于下一步反应。
MS m/z:286.7[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.20(s,1H),8.29(d,J＝2.3Hz,1H),7.94(dd,J＝2.3,8.8Hz,1H),7.72(d,J＝8.8Hz,1H)
中间体B
Figure PCTCN2019108520-appb-000044
合成路线：
Figure PCTCN2019108520-appb-000045
步骤1：化合物B-2的合成
在0℃氮气保护下，将NBS(30.12g,169.22mmol)的DMF(100mL)溶液加入到B-1(25g,161.16mmol)的DMF(100mL)溶液中，反应体系在30℃搅拌2小时。反应完毕后，减压浓缩除去反应溶剂，然后用水(100mL)打浆30分钟，再用乙腈(10mL)洗涤，得到B-2。
MS m/z:233.8[M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.88(br d,J＝7.88Hz,1H),6.69(br d,J＝11.38Hz,1H)
步骤2：化合物B-6的合成
在圆底烧瓶中，将硝基甲烷(18g,294.89mmol,15.93mL)(B-3)缓慢加入到NaOH(17.69g,442.33mmol)的H 2O(100mL)溶液中，保持内部温度在30℃，然后加热到40℃搅拌30分钟，冷却，再缓慢加入另一部分硝基甲烷(18.00g,294.89mmol,15.93mL)，反应体系被加热到45℃搅拌30分钟，然后升高到50℃-55℃搅拌5分钟，得到B-6的混合液，直接用于下一步反应。
步骤3：化合物B-4的合成
将B-6的混合溶液冷却到30℃，加入冰(80g)和浓盐酸(15mL)。将上述混合液加入到B-2(34.3g,146.57mmol)的HCl(12M,90mL)和H 2O(200mL)溶液中，30℃搅拌12小时。有固体析出，过滤，收集滤饼，然后用乙腈(50mL)洗涤，得到化合物B-4。
MS m/z:304.7[M+H] +
1H NMR(400MHz,DMSO-d 6)δ12.99(br d,J＝12.5Hz,1H),8.23-8.13(m,1H),8.08-7.96(m,1H),7.88(br d,J＝10.5Hz,1H),6.80(br s,1H)
步骤4：化合物B-5的合成
在氮气保护下，将B-4(44g,111.06mmol)的乙酸酐(397.79g,3.90mol,364.94mL)溶液在100℃加热1小时，然后停止加热，加入乙酸钠(9.38g,114.39mmol)，在150℃回流15分钟，最后加入另一部分乙酸钠(9.38g,114.39mmol)，反应体系在150℃回流1小时。反应完毕后，浓缩除去溶剂，残留固体用水(200mL)打浆1小时，然后再用EtOAc和甲醇混合液(55mL,EtOAc:MeOH＝10:1)打浆1小时，过滤得到化合物B-5。
MS m/z:287.0[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.25(s,1H),8.44(d,J＝7.5Hz,1H),7.63(br d,J＝9.3Hz,1H)
步骤5：中间体B的合成
除了使用相应的原料外，以中间体A中制备化合物A相同的方法制备中间体B。
MS m/z:304.7[M+H] +
中间体C
Figure PCTCN2019108520-appb-000046
合成路线：
Figure PCTCN2019108520-appb-000047
步骤1：化合物C-2的合成
除了使用相应的原料外，以中间体B中制备化合物B-2相同的方法制备化合物C-2。
MS m/z:249.8[M+H] +
1H NMR(400MHz,DMSO-d 6)δ7.90(br s,1H),7.01(br s,1H)
步骤2：化合物C-3的合成
除了使用相应的原料外，以中间体B中制备化合物B-4相同的方法制备化合物C-3。
MS m/z:320.8[M+H] +
1H NMR(400MHz,DMSO-d 6)δ14.71-13.60(m,1H),12.91(br s,1H),8.26-8.01(m,3H),6.80(br s,1H)
步骤3：化合物C-4的合成
除了使用相应的原料外，以中间体B中制备化合物B-5相同的方法制备化合物C-4。
MS m/z:302.7[M+H] +
1H NMR(400MHz,DMSO-d 6)δ9.29(br s,1H),8.46(s,1H),7.94(s,1H)
步骤4：中间体C的合成
除了使用相应的原料外，以中间体A中制备化合物A相同的方法制备中间体C。
MS m/z:320.7[M+H] +
实施例1：化合物1
Figure PCTCN2019108520-appb-000048
合成路线：
Figure PCTCN2019108520-appb-000049
步骤1：化合物1-A的合成
-60℃下于DIPA(193.58mg,1.91mmol,270.37μL)的THF(1mL)溶液中缓慢滴加n-BuLi(2.5M,765.23μL)，搅拌0.5小时，然后-60℃下滴加四氢吡喃-4-甲酸甲酯(300.88mg,2.09mmol,278.59μL)搅拌1小时，加入中间体A(500mg,1.74mmol)的THF(4mL)溶液，在-60℃下搅拌2小时。反应结束后，0℃下加入20mL饱和NH 4Cl溶液淬灭反应，EtOAc(30mL,10mL*3)萃取，合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品经柱层析(0～10％THF/PE)纯化得到化合物1-A。
MS m/z:394.9[M+H] +
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.52(d,J＝1.8Hz,1H),8.05(d,J＝9.0Hz,1H),7.88(dd,J＝2.0,9.0Hz,1H),4.00-3.89(m,4H),3.69(s,3H),2.52-2.46(m,2H),2.43-2.31(m,2H)
步骤2：化合物1-B的合成
于化合物1-A(200mg,506.07μmol)的H 2O(10mL)和THF(10mL)溶液加入Zn(330.92mg,5.06mmol)和NH 4Cl(270.70mg,5.06mmol)。反应液于70℃搅拌0.5小时。反应结束后，反应液通过硅藻土过滤， EtOAc(90mL,30mL*3)萃取滤液，合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品，粗品经柱层析(0～10％THF/DCM)纯化得到化合物1-B。
MS m/z:332.8[M+H] +
1H NMR(400MHz,CDCl 3)δ8.74(s,1H),8.23(d,J＝1.8Hz,1H),8.01(d,J＝9.0Hz,1H),7.69(dd,J＝2.0,9.0Hz,1H),4.48-4.40(m,2H),4.01(dd,J＝5.1,11.7Hz,2H),2.68(dt,J＝5.1,13.5Hz,2H),1.75(br d,J＝14.3Hz,2H)
步骤3：化合物1-C的合成
于化合物1-B(100mg,300.14μmol)的DCM(5mL)和H 2O(5mL)混合液中加入MeI(1.350g,9.51mmol,592.11μL),TBAB(9.68mg,30.01μmol)和NaOH(24.01mg,600.28μmol)，25℃搅拌21小时。反应结束后，室温下向反应体系中加入10mL水淬灭反应，DCM(30mL,10mL*3)萃取，合并有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品，粗品经柱层析(0～10％THF/DCM)纯化得到化合物1-C。
MS m/z:346.9[M+H] +
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.24(d,J＝2.0Hz,1H),8.01(d,J＝9.1Hz,1H),7.68(dd,J＝2.1,9.1Hz,1H),4.48(dt,J＝2.1,12.2Hz,2H),4.00(dd,J＝5.1,11.6Hz,2H),3.38(s,3H),2.67(dt,J＝5.3,13.4Hz,2H),1.66(br d,J＝14.3Hz,2H)
步骤4：化合物1-D的合成
在氮气保护下，将1,4-二氧六环(3mL)和H 2O(3mL)加入到化合物1-C(70mg,201.61μmol),2-氟吡啶-5-硼酸(42.61mg,302.41μmol),Pd(PPh 3) 4(23.30mg,20.16μmol)和Na 2CO 3(64.11mg,604.83μmol)的反应体系中，80℃搅拌3小时。反应结束后，向反应体系中加入H 2O(20mL)和EtOAc(30mL)，硅藻土过滤，收集有机相，饱和食盐水(50mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品，粗品经柱层析(0～30％THF/DCM)纯化得到化合物1-D。
MS m/z:364.0[M+H] +
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.56(d,J＝2.1Hz,1H),8.26(d,J＝8.9Hz,1H),8.18(d,J＝1.5Hz,1H),8.11(dt,J＝2.5,8.0Hz,1H),7.79(dd,J＝1.8,8.8Hz,1H),7.12(dd,J＝3.0,8.4Hz,1H),4.50(br t,J＝11.3Hz,2H),4.00(dd,J＝4.9,11.7Hz,2H),3.41(s,3H),2.74(dt,J＝5.3,13.4Hz,2H),1.72(br d,J＝14.1Hz,2H)
步骤5：化合物1的合成
0℃氮气保护下，于化合物3-二甲氨基-1-丙醇(34.39mg,333.34μmol,38.99μL)的DMF(2mL)溶液中加入NaH(26.67mg,666.68μmol,60％纯度)，然后加入化合物1-D(61.45mg,166.67μmol)的DMF(2mL)溶液，27℃搅拌2.5小时。0℃下向反应体系中加入50mL水淬灭反应，DCM/i-prOH(5/1)(10mL*3)萃取，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品，粗品经柱层析(0～10％MeOH/DCM(加入氨水))得到化合物1。
MS m/z:447.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.66(s,1H),8.47(d,J＝2.5Hz,1H),8.16(d,J＝8.9Hz,1H),8.12(d,J＝1.5Hz,1H),7.88(dd,J＝2.5,8.6Hz,1H),7.75(dd,J＝1.7,8.8Hz,1H),6.85(d,J＝8.5Hz,1H),4.49-4.34(m,4H),3.94(dd,J＝4.9,11.6Hz,2H),3.35(s,3H),2.71(dt,J＝5.1,13.4Hz,2H),2.50-2.43(m,2H),2.25(s,6H),2.02-1.94(m,2H),1.65(br d,J＝14.0Hz,2H)
实施例2：化合物2
Figure PCTCN2019108520-appb-000050
合成路线：
Figure PCTCN2019108520-appb-000051
步骤1：化合物2的合成
在氮气保护下，将1,4-二氧六环(3mL)加入到化合物1-C(200mg,576.03μmol),(1-甲基-1H-吡唑)-4-硼酸(179.78mg,864.04μmol),[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物(47.04mg,57.60μmol)和醋酸钾(169.59mg,1.73mmol)的反应体系中，80℃搅拌18小时。反应结束后，减压除去溶剂得到粗品，粗品经柱层析(0～10％THF/DCM)纯化得到化合物2。
MS m/z:349.1[M+H] +
1H NMR(400MHz,CDCl 3)δ8.64(s,1H),8.13(d,J＝8.9Hz,1H),8.08(d,J＝1.8Hz,1H),7.91(s,1H),7.83(s,1H),7.75(dd,J＝1.8,8.8Hz,1H),4.51(dt,J＝2.1,12.2Hz,2H),4.04-3.98(m,5H),3.38(s,3H),2.81-2.70(m,2H),1.69(br d,J＝14.3Hz,2H)
实施例3：化合物3
Figure PCTCN2019108520-appb-000052
合成路线：
Figure PCTCN2019108520-appb-000053
步骤1：化合物3-C的合成
将乙腈(10mL)加入到3-A(200mg,1.59mmol)、3-B(225.80mg,1.62mmol,146.62μL)和K 2CO 3(660.37mg,4.78mmol)的烧瓶中，80℃搅拌12小时。体系加入甲醇(50mL)过滤，滤液然后减压除去溶剂，残留固体加入二氯甲烷(50mL)，过滤，减压浓缩得到3-C。
MS m/z:147.9[M+H] +
1H NMR(400MHz,CD 3OD)δ5.28-5.07(m,1H),3.72-3.57(m,2H),3.04-2.87(m,2H),2.73-2.56(m,3H),2.47-2.39(m,1H),2.28-1.90(m,2H),1.82-1.69(m,2H)
步骤2：化合物3的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物3。
MS m/z:491.2[M+H] +
ee:100％,RT＝1.955min(柱型:Chiralpak AD-3 50×3mm I.D.,3μm流动相:A:CO 2B:乙醇(0.05％二乙胺梯度:流动相2.5分钟内B的比例从5％上升至40％并且40％保留0.35分钟，然后在0.15分钟内流动相的比例从40％降至5％，流速:2.5mL/min柱温:40℃)
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.51(d,J＝2.5Hz,1H),8.21(d,J＝8.8Hz,1H),8.16(d,J＝1.8Hz,1H),7.93(dd,J＝2.5,8.5Hz,1H),7.80(dd,J＝1.9,8.9Hz,1H),6.89(d,J＝8.5Hz,1H),5.28-5.09(m,1H),4.53-4.42(m,4H),3.99(dd,J＝4.8,11.5Hz,2H),3.40(s,3H),2.98-2.85(m,2H),2.84-2.77(m,1H),2.75(br d,J＝5.0Hz,1H),2.74-2.66(m,3H),2.52-2.44(m,1H),2.25-1.98(m,4H),1.70(br d,J＝14.3Hz,2H)
实施例4：化合物4
Figure PCTCN2019108520-appb-000054
合成路线：
Figure PCTCN2019108520-appb-000055
步骤1：化合物4-C的合成
除了使用相应的原料外，以实施例3中制备化合物3-C相同的方法制备化合物4-C。
MS m/z:147.9[M+H] +
1H NMR(400MHz,CD 3OD)δ5.30-5.08(m,1H),3.64(t,J＝6.28Hz,2H),3.04-2.89(m,2H),2.62(ddd,J＝9.66,5.52,2.38Hz,3H),2.42(td,J＝8.16,7.03Hz,1H),2.29-1.94(m,2H),1.83-1.70(m,2H)
步骤2：化合物4的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物4。
MS m/z:491.3[M+H] +
ee:100％,保留时间＝1.952min(柱型:Chiralpak AD-3 50×3mm I.D.,3μm流动相:A:CO 2B:乙醇(0.05％二乙胺)梯度:5％-40％B,2.5分钟40％-40％B,0.35分钟；40％-5％B,0.15分钟；流速:2.5mL/min柱温:40℃)
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.51(d,J＝2.3Hz,1H),8.21(d,J＝8.8Hz,1H),8.16(s,1H),7.93(dd,J＝2.4,8.7Hz,1H),7.83-7.77(m,1H),6.89(d,J＝8.8Hz,1H),5.28-5.08(m,1H),4.54-4.42(m,4H),3.99(br dd,J＝4.6,11.7Hz,2H),3.40(s,3H),2.98-2.85(m,2H),2.84-2.66(m,5H),2.53-2.43(m,1H),2.26-1.97(m,4H),1.71(br s,2H)
实施例5：化合物5
Figure PCTCN2019108520-appb-000056
合成路线：
Figure PCTCN2019108520-appb-000057
步骤1：化合物5-C的合成
除了使用相应的原料外，以实施例3中制备化合物3-C相同的方法制备化合物5-C。
1H NMR(400MHz,CDCl 3)δ4.84-4.56(m,1H),3.83-3.70(m,3H),3.52(t,J＝6.5Hz,1H),2.64-2.57(m,3H),2.10-04(m,1H),1.93-1.87(m,2H),1.87-1.81(m,2H),1.74-1.68(m,2H)
步骤2：化合物5的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物5。
MS m/z:505.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.51(d,J＝2.3Hz,1H),8.22(d,J＝9.0Hz,1H),8.16(d,J＝1.5Hz,1H),7.93(dd,J＝2.5,8.8Hz,1H),7.80(dd,J＝1.8,8.8Hz,1H),6.89(d,J＝8.5Hz,1H),4.80-4.59(m,1H),4.49(br t,J＝11.4Hz,2H),4.43(t,J＝6.5Hz,2H),3.99(dd,J＝4.9,11.7Hz,2H),3.40(s,3H),2.76(dt,J＝5.1,13.5Hz,2H),2.63(br s,2H),2.56(br t,J＝7.4Hz,2H),2.42(br s,2H),2.08-1.99(m,2H),1.88(br d,J＝4.5Hz,4H),1.70(br d,J＝14.1Hz,2H)
实施例6：化合物6
Figure PCTCN2019108520-appb-000058
合成路线：
Figure PCTCN2019108520-appb-000059
步骤1：化合物6-C的合成
除了使用相应的原料外，以实施例3中制备化合物3-C相同的方法制备化合物6-C。
MS m/z:155.9[M+H] +
步骤2：化合物6的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物6。
MS m/z:499.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.52(d,J＝2.0Hz,1H),8.22(d,J＝8.8Hz,1H),8.17(d,J＝1.8Hz,1H),7.93(dd,J＝2.5,8.5Hz,1H),7.80(dd,J＝1.9,8.9Hz,1H),6.90(d,J＝8.5Hz,1H),4.49(br t,J＝11.2Hz,2H),4.39(t,J＝6.5Hz,2H),3.99(dd,J＝4.8,11.5Hz,2H),3.40(s,3H),2.94-2.88(m,2H),2.76(dt,J＝5.0,13.4Hz,2H),2.18-2.10(m,2H),1.94-1.87(m,2H),1.70(br d,J＝14.3Hz,2H),0.50-0.39(m,8H)
实施例7：化合物7
Figure PCTCN2019108520-appb-000060
合成路线：
Figure PCTCN2019108520-appb-000061
步骤1：化合物7-A的合成
除了使用相应的原料外，以实施例1中制备化合物1-A相同的方法制备化合物7-A。
MS m/z:443.0[M+H] +
1H NMR(400MHz,CDCl 3)δ8.79(s,1H),8.52(d,J＝1.8Hz,1H),8.05(d,J＝9.0Hz,1H),7.88(dd,J＝1.9,8.9Hz,1H),4.14(q,J＝7.2Hz,2H),2.66-2.57(m,2H),2.53-2.39(m,3H),2.38-2.27(m,1H),2.21-2.09(m,2H),1.08(t,J＝7.2Hz,3H)
步骤2：化合物7-B的合成
除了使用相应的原料外，以实施例1中制备化合物1-B相同的方法制备化合物7-B。
MS m/z:366.8[M+H] +
1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.05-8.02(m,2H),7.70(dd,J＝2.0,9.0Hz,1H),2.92-2.80(m,1H),2.78-2.65(m,3H),2.17(br s,2H),1.94(br d,J＝12.3Hz,2H)
步骤3：化合物7-C的合成
除了使用相应的原料外，以实施例1中制备化合物1-C相同的方法制备化合物7-C。
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.04(d,J＝1.8Hz,1H),8.01(d,J＝9.0Hz,1H),7.68(dd,J＝1.8,9.0Hz,1H),3.38(s,3H),2.94-2.75(m,2H),2.74-2.63(m,2H),2.15(br s,2H),1.89-1.79(m,2H)
步骤4：化合物7-D的合成
除了使用相应的原料外，以实施例1中制备化合物1-D相同的方法制备化合物7-D。
MS m/z:398.0[M+H] +
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.56(d,J＝2.5Hz,1H),8.26(d,J＝8.8Hz,1H),8.10(dt,J＝2.5,8.0Hz,1H),8.06(d,J＝1.8Hz,1H),7.82(dd,J＝2.0,8.8Hz,1H),7.11(dd,J＝2.9,8.4Hz,1H),3.41(s,3H),2.95-2.73(m,4H),2.15(br d,J＝5.3Hz,2H),1.90(br d,J＝11.5Hz,2H)
步骤5：化合物7的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物7。
MS m/z:481.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.70(s,1H),8.50(d,J＝2.3Hz,1H),8.21(d,J＝9.0Hz,1H),8.02(d,J＝1.8Hz,1H),7.91(dd,J＝2.6,8.7Hz,1H),7.81(dd,J＝1.9,8.9Hz,1H),6.88(d,J＝8.5Hz,1H),4.43(t,J＝6.4Hz,2H),3.40(s,3H),2.96-2.74(m,4H),2.58(br t,J＝7.5Hz,2H),2.35(s,6H),2.20-2.11(m,2H),2.10-2.01(m,2H),1.88(br d,J＝9.8Hz,2H)
实施例8：化合物8
Figure PCTCN2019108520-appb-000062
合成路线：
Figure PCTCN2019108520-appb-000063
步骤1：化合物8-A的合成
除了使用相应的原料外，以实施例1中制备化合物1-A相同的方法制备化合物8-A。
1H NMR(400MHz,CDCl 3)δ8.74(s,1H),8.46(d,J＝1.8Hz,1H),8.05(d,J＝8.8Hz,1H),7.88(dd,J＝2.0,9.0Hz,1H),4.02(br s,2H),3.66(s,3H),3.36-3.22(m,2H),2.53(br s,2H),2.28-2.18(m,2H),1.48(s,9H)
步骤2：化合物8-B的合成
除了使用相应的原料外，以实施例1中制备化合物1-B相同的方法制备化合物8-B。
MS:m/z:432.0[M+H] +
1H NMR(400MHz,CDCl 3)δ8.73(s,1H),8.07(s,1H),8.02-7.98(m,2H),7.68(dd,J＝2.0,9.0Hz,1H),4.30- 4.01(m,2H),3.78-3.72(m,2H),2.49(br s,2H),1.78(br d,J＝13.8Hz,2H),1.62(s,9H)
步骤3：化合物8-C的合成
除了使用相应的原料外，以实施例1中制备化合物1-C相同的方法制备化合物8-C。
MS m/z:446.0[M+H] +
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.03-7.99(m,2H),7.67(dd,J＝2.1,9.2Hz,1H),4.30-4.02(m,2H),3.75(br d,J＝6.8Hz,2H),3.38(s,3H),2.48(br s,2H),1.69(br d,J＝13.1Hz,2H),1.57(s,9H)
步骤4：化合物8-D的合成
除了使用相应的原料外，以实施例1中制备化合物1-D相同的方法制备化合物8-D。
MS m/z:463.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.51(d,J＝2.5Hz,1H),8.25(d,J＝8.8Hz,1H),8.06(dt,J＝2.6,8.0Hz,1H),7.97(d,J＝1.8Hz,1H),7.78(dd,J＝1.8,8.8Hz,1H),7.06(dd,J＝3.0,8.5Hz,1H),4.29-4.02(m,2H),3.90-3.72(m,2H),3.41(s,3H),2.55(br s,2H),1.76(br d,J＝14.1Hz,2H),1.50(s,9H)
步骤5：化合物8-E的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物8-E。
1H NMR(400MHz,CDCl 3)δ8.70(s,1H),8.45(d,J＝2.3Hz,1H),8.20(d,J＝8.8Hz,1H),7.96(d,J＝1.5Hz,1H),7.86(dd,J＝2.5,8.5Hz,1H),7.78(dd,J＝1.9,8.9Hz,1H),6.84(d,J＝8.5Hz,1H),4.41(t,J＝6.5Hz,2H),3.81-3.77(m,2H),3.39(s,3H),2.57-2.52(m,2H),2.50-2.45(m,2H),2.28(s,6H),2.03-1.96(m,2H),1.74(br d,J＝13.6Hz,2H),1.71-1.65(m,2H),1.51(s,9H)
步骤6：化合物8的合成
于8-E(100mg,183.26μmol)中加入三氟乙酸(1mL)，反应液在20℃搅拌1小时，减压除去三氟乙酸得到粗品，经制备色谱(酸性，流动相：乙腈-水)分离，再加入氨水调pH＝8，减压浓缩得粗品，经柱层析(0～10％MeOH/DCM)纯化得到化合物8。
MS m/z:446.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.51(d,J＝2.5Hz,1H),8.22(d,J＝1.5Hz,1H),8.20(d,J＝8.9Hz,1H),7.93(dd,J＝2.6,8.6Hz,1H),7.77(dd,J＝1.7,8.8Hz,1H),6.88(d,J＝8.6Hz,1H),4.42(t,J＝6.5Hz,2H),3.74-3.65(m,2H),3.38(s,3H),3.04(br dd,J＝3.4,12.3Hz,2H),2.59(dt,J＝4.6,13.3Hz,2H),2.50-2.45(m,2H),2.27(s,6H),2.04-1.96(m,2H),1.75(br d,J＝14.0Hz,2H)
实施例9：化合物9
Figure PCTCN2019108520-appb-000064
合成路线：
Figure PCTCN2019108520-appb-000065
步骤1：化合物9的合成
于化合物8(70mg,157.11μmol)的甲酸(3mL)溶液中加入甲醛水溶液(127.51mg,1.57mmol,116.98μL,37％纯度)，反应液在60℃搅拌23小时。反应结束后，减压浓缩得到粗品，加入20毫升氨水，减压浓缩得到粗品，经柱层析(0～6％MeOH/DCM)纯化再经过制备色谱(中性，流动相：乙腈-水)纯化，得到化合物9。
MS m/z:460.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.52(br s,1H),8.26(br s,1H),8.19(br d,J＝8.8Hz,1H),7.96(br d,J＝7.8Hz,1H),7.76(br d,J＝8.5Hz,1H),6.87(br d,J＝8.5Hz,1H),4.41(br t,J＝6.1Hz,2H),3.37(s,3H),3.10-2.98(m,2H),2.79(br d,J＝8.8Hz,4H),2.51-2.45(m,2H),2.27(s,9H),2.05-1.94(m,2H),1.76(br d,J＝12.8Hz,2H)
实施例10：化合物10
Figure PCTCN2019108520-appb-000066
合成路线：
Figure PCTCN2019108520-appb-000067
步骤1：化合物10-A的合成
于化合物8-C(900mg,2.02mmol)中加入三氟乙酸(3mL)，反应液在20℃搅拌0.5小时。反应结束后，减压浓缩得到粗品，加入氨水调节pH＝9，二氯甲烷(90mL,30mL*3)萃取，有机相减压浓缩得到粗品10-A，直接用于下一步反应。
MS m/z:346.1[M+H] +
1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.41(d,J＝2.0Hz,1H),7.99(d,J＝9.0Hz,1H),7.69(dd,J＝2.0,9.0Hz,1H),3.97-3.88(m,2H),3.39(s,3H),3.35(br d,J＝3.0Hz,2H),2.94-2.86(m,2H),1.84(br d,J＝14.6Hz,2H)
步骤2：化合物10-B的合成
在20℃氮气保护下，将K 2CO 3(1.20g,8.67mmol)加入到化合物10-A(1g,2.89mmol)和溴乙烷(629.82mg,5.78mmol,431.38μL)的乙腈(20mL)溶液中，反应液在60℃搅拌1小时，在20℃加入水(5mL)淬灭反应，再加入水(20mL)稀释，用EtOAc(90mL,30mL*3)萃取，合并有机相用饱和氯化钠洗涤(90mL,30mL*3)，无水硫酸钠干燥，过滤，浓缩，粗品经过过柱层析(0～5％MeOH/DCM)得到化合物10-B。
MS m/z:373.9[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.94(s,1H),8.15(d,J＝1.8Hz,1H),8.03(d,J＝9.0Hz,1H),7.76(dd,J＝2.3,9.0Hz,1H),3.30(s,3H),2.92-2.75(m,4H),2.56-2.53(m,1H),2.48-2.39(m,3H),1.80-1.64(m,2H),1.14-1.08(m,3H)
步骤3：化合物10-C的合成
在氮气保护下，将化合物10-B(400mg,1.07mmol)、2-氟吡啶-5-硼酸(301.19mg,2.14mmol)、Na 2CO 3(226.55mg,2.14mmol)、Pd(PPh 3) 4(123.50mg,106.87μmol)的二氧六环(18mL)和H 2O(2mL)水溶液在100℃搅拌4小时。浓缩除去反应溶剂，粗品经过柱层析(0～5％MeOH/DCM)得到化合物10-C。
MS m/z:391.1[M+H] +
步骤8：化合物10的合成
在20℃氮气保护下，将化合物10-C(200mg,512.23μmol)加入到3-二甲氨基-1-丙醇(105.69mg,1.02mmol,119.82μL)和NaH(81.96mg,2.05mmol,60％纯度)的DMF(10mL)溶液中，反应液在70℃搅拌2小时。20℃条件用水(2mL)淬灭，加水(10mL)稀释，用EtOAc萃取(10mL*3)，合并有机相用饱和氯化钠洗涤(10mL*3)，无水硫酸钠干燥，过滤，浓缩，粗品经过柱层析(0～5％MeOH/DCM)得到化合物10。
MS m/z:474.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.51(d,J＝2.3Hz,1H),8.26-8.23(m,1H),8.19(d,J＝9.0Hz,1H),7.98-7.89(m,1H),7.80-7.71(m,1H),6.88(d,J＝8.8Hz,1H),4.42(t,J＝6.5Hz,2H),3.37(s,3H),3.03(br s,2H),2.87(br d,J＝11.5Hz,2H),2.76(br s,2H),2.62(q,J＝7.1Hz,2H),2.47(s,2H),2.27(s,6H),2.04-1.96(m,2H),1.78(br d,J＝13.8Hz,2H),1.17(t,J＝7.3Hz,3H)
实施例11：化合物11
Figure PCTCN2019108520-appb-000068
合成路线：
Figure PCTCN2019108520-appb-000069
步骤1：化合物11-C的合成
除了使用相应的原料外，以实施例3中制备化合物3-C相同的方法制备化合物11-C。
1H NMR(400MHz,CDCl 3)δ5.96-5.45(m,1H),3.78-3.70(m,2H),2.51(t,J＝5.6Hz,2H),2.47-2.05(m,4H),1.65(quin,J＝5.5Hz,2H),1.52(quin,J＝5.5Hz,4H),1.39(br s,2H)
步骤2：化合物11的合成
除了使用相应的原料外，以实施例10中制备化合物10相同的方法制备化合物11。
MS m/z:514.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.67(s,1H),8.53(d,J＝2.5Hz,1H),8.30(d,J＝1.3Hz,1H),8.19(d,J＝8.8Hz,1H),7.97(dd,J＝2.5,8.8Hz,1H),7.77(dd,J＝1.8,8.8Hz,1H),6.87(d,J＝8.5Hz,1H),4.40(t,J＝6.5Hz,2H),3.37(s,3H),3.11-2.98(m,2H),2.92-2.84(m,2H),2.78(br s,2H),2.62(q,J＝7.1Hz,2H),2.54-2.33(m,8H),2.08-1.95(m,2H),1.77(br d,J＝13.8Hz,2H),1.64-1.60(m,2H),1.44(br d,J＝4.8Hz,2H),1.17(t,J＝7.2Hz,3H)
实施例12：化合物12
Figure PCTCN2019108520-appb-000070
合成路线：
Figure PCTCN2019108520-appb-000071
步骤1：化合物12-A的合成
除了使用相应的原料外，以实施例10中制备化合物10-B相同的方法制备化合物12-A。
MS m/z:410.4[M+H] +
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.25(d,J＝1.8Hz,1H),8.00(d,J＝9.0Hz,1H),7.67(dd,J＝2.0,9.0Hz,1H),6.21-5.85(m,1H),3.36(s,3H),3.33-3.25(m,2H),3.00-2.87(m,4H),2.65(dt,J＝4.6,13.4Hz,2H),1.73(br d,J＝14.6Hz,2H)
步骤2：化合物12-B的合成
除了使用相应的原料外，以实施例10中制备化合物10-C相同的方法制备化合物12-B。
MS m/z:427.2[M+H] +
步骤3：化合物12的合成
除了使用相应的原料外，以实施例10中制备化合物10相同的方法制备化合物12。
MS m/z:510.4[M+H] +
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.53(d,J＝2.3Hz,1H),8.24-8.16(m,2H),7.93(dd,J＝2.5,8.5Hz,1H),7.78(dd,J＝2.0,8.8Hz,1H),6.90(d,J＝8.5Hz,1H),6.20-5.81(m,1H),4.43(t,J＝6.5Hz,2H),3.38(s,3H),3.31(br t,J＝11.0Hz,2H),3.00-2.93(m,1H),2.92-2.81(m,3H),2.75(dt,J＝4.8,13.3Hz,2H),2.52-2.46(m,2H),2.29(s,6H),2.07-1.96(m,2H),1.77(br d,J＝14.3Hz,2H)。
实施例13：化合物13
Figure PCTCN2019108520-appb-000072
合成路线：
Figure PCTCN2019108520-appb-000073
步骤1：化合物13-A的合成
除了使用相应的原料外，以实施例10中制备化合物10-B相同的方法制备化合物13-A。
MS m/z:428.1[M+H] +
步骤2：化合物13-B的合成
除了使用相应的原料外，以实施例10中制备化合物10-C相同的方法制备化合物13-B。
MS m/z:445.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.73(s,1H),8.58(d,J＝2.3Hz,1H),8.27-8.22(m,2H),8.13(dt,J＝2.6,8.0Hz,1H),7.79(dd,J＝1.8,9.0Hz,1H),7.11(dd,J＝2.9,8.4Hz,1H),3.50-3.41(m,2H),3.39(s,3H),3.17(q,J＝9.5Hz,2H),2.94(br dd,J＝3.9,10.9Hz,2H),2.76(dt,J＝4.8,13.3Hz,2H),1.80(br s,2H)。
步骤3：化合物13的合成
除了使用相应的原料外，以实施例10中制备化合物10相同的方法制备化合物13。
MS m/z:528.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.53(d,J＝2.3Hz,1H),8.23-8.18(m,2H),7.94(dd,J＝2.5,8.8Hz,1H),7.79(dd,J＝1.6,8.9Hz,1H),6.90(d,J＝8.5Hz,1H),4.43(t,J＝6.4Hz,2H),3.46(br t,J＝11.2Hz,2H),3.38(s,3H),3.17(q,J＝9.7Hz,2H),2.92(br d,J＝11.0Hz,2H),2.78(dt,J＝4.5,13.3Hz,2H),2.53-2.46(m,2H),2.28(s,6H),2.06-1.96(m,2H),1.77(br s,2H)
实施例14：化合物14
Figure PCTCN2019108520-appb-000074
合成路线：
Figure PCTCN2019108520-appb-000075
步骤1：化合物14的合成
除了使用相应的原料外，以实施例10中制备化合物10相同的方法制备化合物14。
MS m/z:568.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.53(d,J＝2.5Hz,1H),8.24-8.18(m,2H),7.94(dd,J＝2.5,8.5Hz,1H),7.79(dd,J＝1.6,8.9Hz,1H),6.89(d,J＝8.5Hz,1H),4.42(t,J＝6.4Hz,2H),3.46(br t,J＝11.2Hz,2H),3.38(s,3H),3.17(q,J＝9.5Hz,2H),2.92(br d,J＝11.3Hz,2H),2.77(dt,J＝4.6,13.4Hz,2H),2.58-2.51(m,2H),2.46(br s,2H),2.10-2.00(m,2H),1.77(br d,J＝14.1Hz,2H),1.63(br s,6H),1.46(br s,2H)。
实施例15：化合物15
Figure PCTCN2019108520-appb-000076
合成路线：
Figure PCTCN2019108520-appb-000077
步骤1：化合物15-A的合成
除了使用相应的原料外，以实施例10中制备化合物10-B相同的方法制备化合物15-A。
MS m/z:388.1[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.94(s,1H),8.22-8.14(m,1H),8.03(d,J＝9.0Hz,1H),7.76(dd,J＝2.0,9.0Hz,1H),3.30(s,3H),3.19-3.04(m,2H),2.92(br d,J＝8.3Hz,1H),2.83-2.66(m,2H),2.43(br s,2H),1.82-1.68(m,2H),1.11(br d,J＝4.8Hz,6H)
步骤2：化合物15-B的合成
除了使用相应的原料外，以实施例10中制备化合物10-C相同的方法制备化合物15-B。
MS m/z:405.0[M+H] +
1H NMR(400MHz,CDCl 3)δ8.64(s,1H),8.53(d,J＝2.0Hz,1H),8.39(s,1H),8.15(d,J＝8.8Hz,2H),7.70(dd,J＝1.8,8.8Hz,1H),6.98(dd,J＝2.8,8.5Hz,1H),3.31(s,3H),3.28-3.17(m,2H),2.87(br s,1H),2.83-2.67(m,4H),1.81-1.67(m,2H),1.09(br d,J＝6.0Hz,6H)
步骤3：化合物15的合成
除了使用相应的原料外，以实施例10中制备化合物10相同的方法制备化合物15。
MS m/z:488.4[M+H] +
1H NMR(400MHz,CDCl 3)δ8.70(s,1H),8.56(d,J＝2.3Hz,1H),8.37(s,1H),8.21(d,J＝8.8Hz,1H),8.03(br d,J＝6.8Hz,1H),7.85-7.76(m,1H),6.91(d,J＝8.5Hz,1H),4.44(s,2H),3.39(s,3H),3.37-3.26(m,2H),2.97(br s,1H),2.81(br s,4H),2.49(s,2H),2.29(s,6H),2.07-1.98(m,2H),1.87-1.75(m,2H),1.19(br d,J＝6.5Hz,6H)
实施例16：化合物16
Figure PCTCN2019108520-appb-000078
合成路线：
Figure PCTCN2019108520-appb-000079
步骤1：化合物16的合成
除了使用相应的原料外，以实施例10中制备化合物10相同的方法制备化合物16。
MS m/z:528.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.61(s,1H),8.48(d,J＝2.4Hz,1H),8.29(br s,1H),8.13(d,J＝8.9Hz,1H),7.94(br s,1H),7.71(br d,J＝8.8Hz,1H),6.81(d,J＝8.6Hz,1H),4.33(s,2H),3.31(s,3H),3.28-3.16(m,2H),2.89(br s,1H),2.73(br s,4H),2.43(br d,J＝7.9Hz,2H),2.36(br s,4H),2.05(br s,2H),1.99-1.93(m,2H),1.72(br d,J＝12.8Hz,2H),1.58-1.54(m,2H),1.38(br d,J＝3.8Hz,2H),1.11(br d,J＝6.1Hz,6H)
实施例17：化合物17
Figure PCTCN2019108520-appb-000080
合成路线：
Figure PCTCN2019108520-appb-000081
步骤1：化合物17-A的合成
将化合物10-A(150mg,433.25μmol)溶于二氯甲烷(10mL)中，加入N,N-二异丙基乙胺(111.99mg,866.50μmol,150.93μL)，在0℃氮气氛围下加入乙酰氯(51.01mg,649.87μmol,46.38μL)，混合体系升温到30℃搅拌2小时后，浓缩得到粗产品，经过层析柱(DCM/THF＝1/0～4/1)分离纯化，得到化合物17-A。
MS m/z:388.1[M+H] +
1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.01(d,J＝9.3Hz,1H),7.98(d,J＝2.0Hz,1H),7.68(dd,J＝2.0,9.0Hz,1H),4.74(br dd,J＝4.9,13.7Hz,1H),4.18(dt,J＝2.8,13.3Hz,1H),3.84(br dd,J＝4.6,13.7Hz,1H),3.60(dt,J＝2.9,13.2Hz,1H),3.39(s,3H),2.56-2.40(m,2H),2.26(s,3H),1.87-1.74(m,2H)
步骤2：化合物17-B的合成
将化合物17-A(85mg,218.93μmol)溶于无水二氧六环(10mL)和水(2mL)中，加入2-氟吡啶-5-硼酸(46.27mg,328.39μmol)，碳酸钠(69.61mg,656.78μmol)，在氮气氛围下加入四三苯基膦钯(37.95mg,32.84μmol)，混合体系在80℃下搅拌4小时后，用二氯甲烷(150mL,50mL*3)萃取，收集有机相，用饱和食盐水(50mL洗涤)，无水硫酸钠干燥，浓缩得到粗产品，经过层析柱(DCM:THF＝1/0～4/1)分离纯化，得到化合物17-B。
MS m/z:405.6[M+H] +
1H NMR(400MHz,CDCl 3)δ8.76(s,1H),8.49(d,J＝2.5Hz,1H),8.26(d,J＝8.8Hz,1H),8.09-8.01(m,1H),7.92(d,J＝1.8Hz,1H),7.78(dd,J＝2.0,8.8Hz,1H),7.12(dd,J＝2.9,8.4Hz,1H),4.71(br d,J＝8.5Hz,1H),4.20(dt,J＝2.9,13.2Hz,1H),3.84(br d,J＝9.3Hz,1H),3.68-3.54(m,1H),3.42(s,3H),2.65-2.49(m,2H),2.22(s,3H),1.86(br dd,J＝14.9,18.9Hz,2H)
步骤3：化合物17的合成
将氢化钠(24.07mg,601.71μmol,纯度：60％)溶于N，N二甲基甲酰胺(10mL)中，0℃氮气氛围下加入3-二甲氨基-1-丙醇(23.28mg,225.64μmol,26.39μL)搅拌0.5小时后，加入17-B(70mg,150.43μmol)的N，N二甲基甲酰胺(5mL)溶液，混合体系升高到25℃室温下搅拌4小时后，加水(20mL)淬灭，将混合体系分散到100mL水中，用二氯甲烷(150mL,50mL*3)萃取，收集有机相，用饱和食盐水(50mL)洗涤，无水硫酸钠干燥，浓缩得到粗产品，经过制备高效液相色谱(中性，流动相：乙腈-水)分离纯化，得到化合物17。
MS m/z:488.4[M+H] +
1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.44(d,J＝2.0Hz,1H),8.22(d,J＝8.8Hz,1H),7.90(d,J＝1.5Hz,1H),7.85(dd,J＝2.5,8.5Hz,1H),7.79(dd,J＝1.9,8.9Hz,1H),6.90(d,J＝8.8Hz,1H),4.71(br d,J＝10.0Hz,1H),4.43(t,J＝6.4Hz,2H),4.24-4.13(m,1H),3.83(br d,J＝13.8Hz,1H),3.68-3.57(m,1H),3.41(s,3H),2.65-2.52(m,2H),2.52-2.43(m,2H),2.28(s,6H),2.23(s,3H),2.05-1.96(m,2H),1.85(br t,J＝14.2Hz,2H)
实施例18：化合物18
Figure PCTCN2019108520-appb-000082
合成路线：
Figure PCTCN2019108520-appb-000083
步骤1：化合物18-A的合成
除了使用相应的原料外，以实施例17中制备化合物17-A相同的方法制备化合物18-A。
MS m/z:414.1[M+H] +
步骤2：化合物18-B的合成
除了使用相应的原料外，以实施例17中制备化合物17-B相同的方法制备化合物18-B。
MS m/z:431.2[M+H ]+
1H NMR(400MHz,CDCl 3)δ8.76(s,1H),8.50(d,J＝2.5Hz,1H),8.26(d,J＝9.0Hz,1H),8.05(dt,J＝2.6,8.0Hz,1H),7.93(d,J＝1.5Hz,1H),7.79(dd,J＝1.9,8.9Hz,1H),7.11(dd,J＝2.8,8.5Hz,1H),4.67(br d,J＝12.5Hz,1H),4.26(br d,J＝7.5Hz,2H),3.67(br t,J＝12.8Hz,1H),3.42(s,3H),2.59(br d,J＝12.3Hz,2H),1.95-1.85(m,2H),1.79(br d,J＝13.1Hz,1H),1.12(br s,1H),1.00(br s,1H),0.83(dd,J＝3.6,7.9Hz,2H)
步骤3：化合物18的合成
除了使用相应的原料外，以实施例17中制备化合物17相同的方法制备化合物18。
MS m/z:514.4[M+H] +
1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.45(d,J＝2.3Hz,1H),8.21(d,J＝8.8Hz,1H),7.91(d,J＝1.8Hz,1H),7.86(dd,J＝2.5,8.5Hz,1H),7.80(dd,J＝1.8,8.8Hz,1H),6.88(d,J＝8.3Hz,1H),4.67(br d,J＝11.0Hz,1H),4.43(t,J＝6.4Hz,2H),4.25(br d,J＝8.3Hz,2H),3.67(br t,J＝12.3Hz,1H),3.41(s,3H),2.71-2.52(m,4H),2.34(s,6H),2.09-2.05(m,1H),2.04-2.00(m,1H),1.95-1.83(m,3H),1.16-1.01(m,2H),0.89-0.79(m,2H)
实施例19：化合物19
Figure PCTCN2019108520-appb-000084
合成路线：
Figure PCTCN2019108520-appb-000085
步骤1：化合物19-A的合成
除了使用相应的原料外，以实施例17中制备化合物17-A相同的方法制备化合物19-A。
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.03-7.99(m,2H),7.67(dd,J＝2.0,9.0Hz,1H),4.35-4.09(m,2H),3.82(s,3H),3.38(s,3H),2.57-2.44(m,2H),1.74(br d,J＝14.1Hz,2H),1.04(br s,2H)
步骤2：化合物19-B的合成
除了使用相应的原料外，以实施例17中制备化合物17-B相同的方法制备化合物19-B。
MS m/z:421.1[M+H] +
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.51(d,J＝2.0Hz,1H),8.25(d,J＝9.0Hz,1H),8.07(dt,J＝2.5,7.9Hz,1H),7.97(s,1H),7.78(dd,J＝1.8,8.8Hz,1H),7.11(dd,J＝2.9,8.4Hz,1H),4.24(br s,2H),3.83(br s,2H),3.79(s,3H),3.41(s,3H),2.64-2.51(m,2H),1.79(br d,J＝14.1Hz,2H)
步骤3：化合物19的合成
除了使用相应的原料外，以实施例17中制备化合物17相同的方法制备化合物19。
MS m/z:504.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.46(d,J＝2.3Hz,1H),8.21(d,J＝8.8Hz,1H),7.94(d,J＝1.5Hz,1H),7.88(dd,J＝2.5,8.5Hz,1H),7.78(dd,J＝1.9,8.9Hz,1H),6.89(d,J＝8.8Hz,1H),4.42(t,J＝6.4Hz,2H),4.32- 4.08(m,2H),3.92-3.81(m,2H),3.79(s,3H),3.40(s,3H),2.65-2.55(m,2H),2.53-2.47(m,2H),2.29(s,6H),2.06-1.97(m,2H),1.76(br s,2H)
实施例20：化合物20
Figure PCTCN2019108520-appb-000086
合成路线：
Figure PCTCN2019108520-appb-000087
步骤1：化合物20的合成
除了使用相应的原料外，以实施例17中制备化合物17相同的方法制备化合物20。
MS m/z:544.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.46(s,1H),8.21(d,J＝8.8Hz,1H),7.94(s,1H),7.87(dd,J＝2.1,8.7Hz,1H),7.78(br d,J＝9.0Hz,1H),6.88(d,J＝8.5Hz,1H),4.41(br t,J＝6.4Hz,2H),4.33-4.07(m,2H),3.94-3.81(m,2H),3.79(s,3H),3.40(s,3H),2.66-2.37(m,8H),2.10-1.98(m,2H),1.78(br d,J＝12.8Hz,6H),1.45(br s,2H)
实施例21：化合物21
Figure PCTCN2019108520-appb-000088
合成路线：
Figure PCTCN2019108520-appb-000089
步骤1：化合物21-A的合成
除了使用相应的原料外，以实施例17中制备化合物17-A相同的方法制备化合物21-A。
MS m/z:432.2[M+H] +
步骤2：化合物21-B的合成
除了使用相应的原料外，以实施例17中制备化合物17-B相同的方法制备化合物21-B。
MS m/z:449.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.51(d,J＝2.5Hz,1H),8.25(d,J＝8.8Hz,1H),8.09-8.02(m,1H),7.96(d,J＝1.8Hz,1H),7.78(dd,J＝2.0,8.8Hz,1H),7.08(dd,J＝2.9,8.4Hz,1H),5.02(td,J＝6.3,12.4Hz,1H),4.15(br s,2H),3.83(br s,2H),3.41(s,3H),2.57(br s,2H),1.77(br d,J＝14.1Hz,2H),1.28(d,J＝6.3Hz,6H)
步骤3：化合物21的合成
除了使用相应的原料外，以实施例17中制备化合物17相同的方法制备化合物21。
MS m/z:532.3[M+H] +
1H NMR(400MHz,CD 3OD)δ8.77(s,1H),8.45(d,J＝2.3Hz,1H),8.12(d,J＝8.8Hz,1H),8.02(dd,J＝2.5,8.8Hz,1H),7.96(d,J＝1.5Hz,1H),7.85(dd,J＝1.8,9.0Hz,1H),6.92(d,J＝8.8Hz,1H),4.97(td,J＝6.2,12.5Hz,1H),4.44(t,J＝6.0Hz,2H),4.12(br dd,J＝3.5,13.3Hz,2H),3.84-3.71(m,2H),3.38(s,3H),3.13-3.06(m,2H),2.74(s,6H),2.60-2.49(m,2H),2.23-2.13(m,2H),1.73(br d,J＝14.1Hz,2H),1.27(d,J＝6.3Hz,6H)
实施例22：化合物22
Figure PCTCN2019108520-appb-000090
合成路线：
Figure PCTCN2019108520-appb-000091
步骤1：化合物22-B的合成
将1,2-二氯乙烷(100mL)加入到4-哌啶甲酸甲酯(10g,69.84mmol)，环丙基硼酸(12.00g,139.68mmol)，吡啶(5.52g,69.84mmol,5.64mL)和碳酸钠(14.80g,139.68mmol,2eq)中，氧气置换3次，在氧气氛围下70℃搅拌16小时。反应结束后，降至0℃加入200mL水淬灭反应，再加入氨水100mL，二氯甲烷萃取(150mL,50mL*3)，合并有机相，饱和食盐水(200mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品。粗品经柱层析(0～10％EtOAc/PE)纯化得到化合物22-B。
1H NMR(400MHz,CDCl 3)δ3.66(s,3H),3.03-2.95(m,2H),2.29(tt,J＝4.0,11.2Hz,1H),2.20(dt,J＝2.5,11.5Hz,2H),1.91-1.83(m,2H),1.73-1.62(m,2H),1.59-1.52(m,1H),0.46-0.40(m,2H),0.40-0.36(m,2H)
步骤2：化合物22-C的合成
除了使用相应的原料外，以实施例1中制备化合物1-A相同的方法制备化合物22-C。
MS m/z:434.0[M+H] +
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.68(d,J＝1.8Hz,1H),8.03(d,J＝8.8Hz,1H),7.86(dd,J＝1.9,8.9Hz,1H),3.67(s,3H),2.95(br d,J＝12.3Hz,2H),2.81-2.70(m,2H),2.55(br d,J＝13.1Hz,2H),2.32-2.22(m,2H),1.77-1.66(m,1H),0.45(br d,J＝7.0Hz,2H),0.42(br d,J＝4.3Hz,2H)
步骤3：化合物22-D的合成
将化合物22-C(1.7g,3.91mmol)溶于THF(70mL)中，加入NH 4Cl(2.09g,39.14mmol)的水(70mL)溶液，再加入锌粉(2.56g,39.14mmol)，反应液在70℃搅拌24小时。反应结束后除去锌粉，浓缩混合液，得到的粗品直接用于下一步反应。
MS m/z:371.9[M+H] +
步骤4：化合物22-E的合成
于22-D(1.5g,4.03mmol)的二氯甲烷(40mL)溶液中加入氢氧化钠(322.36mg,8.06mmol)和四丁基溴化铵(64.95mg,201.47μmol)的水(20mL)溶液，然后滴加碘甲烷(3.660g,25.79mmol,1.61mL)，反应液于20℃下搅拌48小时。反应结束后，室温下向反应体系中加入50mL水淬灭反应，二氯甲烷(90mL,30mL*3)萃取，合并有机相，饱和食盐水(100mL)洗涤，无水硫酸钠干燥。滤去干燥剂后，减压除去溶剂得到粗品化合物22-E，直接用于下一步反应。
MS m/z:386.1[M+H] +
步骤5：化合物22-F的合成
在氮气保护下，将1,4-二氧六环(20mL)和H 2O(20mL)加入到化合物22-E(1g,2.53mmol)、2-氟吡啶-5-硼酸(534.71mg,3.79mmol),四三苯基膦钯(292.34mg,252.98μmol)和碳酸钠(804.41mg,7.59mmol)的反应体系中，80℃搅拌16小时。反应结束后，减压除去溶剂得到粗品化合物22-F，直接用于下一步反应。
MS m/z:403.1[M+H] +
步骤6：化合物22的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物22。
MS m/z:486.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.51(d,J＝2.0Hz,1H),8.24(s,1H),8.19(d,J＝8.8Hz,1H),7.94(dd,J＝2.0,8.5Hz,1H),7.76(br d,J＝8.8Hz,1H),6.87(d,J＝8.5Hz,1H),4.41(t,J＝6.4Hz,2H),3.38(s,3H),3.27(br t,J＝11.4Hz,2H),2.97(br d,J＝9.5Hz,2H),2.68(dt,J＝4.4,13.2Hz,2H),2.47(br t,J＝7.4Hz,2H),2.27(s,6H),1.98(br s,2H),1.88(br d,J＝4.3Hz,1H),1.75(br d,J＝13.8Hz,2H),0.52(br s,4H)
实施例23：化合物23
Figure PCTCN2019108520-appb-000092
合成路线：
Figure PCTCN2019108520-appb-000093
步骤1：化合物23的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物23。
MS m/z:526.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.51(d,J＝2.3Hz,1H),8.24(d,J＝1.5Hz,1H),8.19(d,J＝9.0Hz,1H),7.94(dd,J＝2.5,8.5Hz,1H),7.76(dd,J＝1.8,8.8Hz,1H),6.87(d,J＝8.5Hz,1H),4.40(t,J＝6.5Hz,2H),3.38(s,3H),3.32-3.22(m,2H),3.01-2.93(m,2H),2.68(dt,J＝4.5,13.3Hz,2H),2.55-2.49(m,2H),2.44(br s,2H),2.08-1.97(m,6H),1.91-1.86(m,1H),1.75(br d,J＝13.8Hz,2H),1.65-1.62(m,1H),1.60-1.58(m,1H),1.45(br s,2H),0.55-0.49(m,4H)
实施例24：化合物24
Figure PCTCN2019108520-appb-000094
合成路线：
Figure PCTCN2019108520-appb-000095
步骤1：化合物24的合成
将氢化钠(101.26mg,2.53mmol，纯度：60％)溶于N,N-二甲基甲酰胺(10mL)中，在0℃氮气氛围下加入化合物11-C(181.31mg,1.27mmol)的N,N-二甲基甲酰胺(5mL)溶液，搅拌0.5小时后，加入1-D(230mg,632.94μmol)的N,N-二甲基甲酰胺(5mL)溶液，混合体系升高到25℃室温，氮气氛围下继续搅拌2小时后，加水(10mL)淬灭，用二氯甲烷(150mL,50mL*3)萃取，收集有机相，将有机相浓缩得到粗产品，经过制备级高效液相色谱([水(10mM碳酸氢铵)-乙腈]；乙腈B％:28％-58％,7min)分离纯化，得到化合物24。
MS m/z:487.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.50(d,J＝2.0Hz,1H),8.20(d,J＝8.8Hz,1H),8.15(s,1H),7.91(dd,J＝2.3,8.5Hz,1H),7.78(br d,J＝8.0Hz,1H),6.87(d,J＝8.5Hz,1H),4.54-4.34(m,4H),3.97(br dd,J＝4.8,11.5Hz,2H),3.38(s,3H),2.74(dt,J＝4.9,13.2Hz,2H),2.54-2.46(m,2H),2.42(br s,2H),2.12(br s,2H),2.02(td,J＝6.9,14.3Hz,2H),1.68(br d,J＝13.8Hz,2H),1.62-1.53(m,4H),1.43(br s,2H)
实施例25：化合物25
Figure PCTCN2019108520-appb-000096
合成路线：
Figure PCTCN2019108520-appb-000097
步骤1：化合物25-A的合成
除了使用相应的原料外，以实施例1中制备化合物1-A相同的方法制备化合物25-A。
MS m/z:465.0[M+H] +
步骤2：化合物25-B的合成
除了使用相应的原料外，以实施例1中制备化合物1-B相同的方法制备化合物25-B。
MS m/z:389.4[M+H] +
步骤3：化合物25-C的合成
将化合物25-B(3.2g,8.22mmol)溶于四氢呋喃(10mL)中，加入三氟乙酸(15.40g,135.06mmol,10.00mL)和水(10.00g,555.08mmol,10mL)，混合体系在25℃室温下搅拌12小时后，用氢氧化钠(1M)调节pH＝7～8,用EtOAc(200mL,100mL*2)萃取，收集有机相，浓缩得到粗品，经过层析柱(二氯甲烷/四氢呋喃＝1/0～4/1)分离纯化，得到化合物25-C。
MS m/z:345.1[M+H] +
步骤4：化合物25-D的合成
除了使用相应的原料外，以实施例1中制备化合物1-C相同的方法制备化合物25-D。
MS m/z:359.1[M+H] +
步骤5：化合物25-E的合成
将化合物25-D(0.367g,1.02mmol)溶于甲醇(20mL)中，在0℃氮气氛围下加入硼氢化钠(77.30mg,2.04mmol)，混合体系升高温度到20℃室温，继续搅拌3小时后，加水(20mL)淬灭，用二氯甲烷/甲醇＝10/1(50mL)萃取，收集有机相，浓缩得到粗品，经过层析柱(DCM/THF＝1/0～4/1)分离纯化，得到化合物25-E。
MS m/z:360.9[M+H] +
步骤6：化合物25-F的合成
将氢化钠(106.29mg,2.66mmol,纯度：60％)溶于四氢呋喃(10mL)中，0℃氮气氛围下加入25-E(320mg,885.86μmol)的四氢呋喃(10mL)溶液，0℃下搅拌0.5小时后，氮气氛围下加入碘甲烷(502.95mg,3.54mmol,220.59μL)，混合体系升高到25℃室温，并在氮气氛围下搅拌2小时后，将混合液分散到50mL水中淬灭，用二氯甲烷(150mL,50mL*3)萃取，饱和食盐水(50mL)洗涤，收集有机相，有机相用无水硫酸钠干燥，经过层析柱(二氯甲烷/四氢呋喃＝1/0～10/1)分离纯化，得到化合物25-F。
MS m/z 375.1[M+H] +
步骤6：化合物25-G的合成
除了使用相应的原料外，以实施例1中制备化合物1-D相同的方法制备化合物25-G。
MS m/z:392.6[M+H] +
步骤7：化合物25的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物25。
MS m/z:475.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.50(d,J＝2.5Hz,1H),8.20(d,J＝8.8Hz,1H),8.01(s,1H),7.90(dd,J＝2.5,8.5Hz,1H),7.76(dd,J＝1.5,8.8Hz,1H),6.91(d,J＝8.5Hz,1H),4.43(t,J＝6.4Hz,2H),3.48(s,3H),3.38(s,3H),2.53-2.44(m,4H),2.41-2.35(m,2H),2.28(s,6H),2.10-1.97(m,4H),1.91(br d,J＝13.8Hz,2H)，1.78(br s,2H)
实施例26：化合物26
Figure PCTCN2019108520-appb-000098
合成路线：
Figure PCTCN2019108520-appb-000099
步骤1：化合物26-A的合成
将化合物25-C(1.05g,3.04mmol)溶于甲醇(20mL)中，在0℃氮气氛围下加入硼氢化钠(172.62mg,4.56mmol)，混合体系升高温度到20℃室温，继续搅拌3小时后，加水(20mL)淬灭，用二氯甲烷(100mL,50mL*2)萃取，收集有机相，浓缩得到粗品，经过层析柱(二氯甲烷/四氢呋喃＝1/0～4/1)分离纯化，得到化合物26-A。
MS m/z:347.0[M+H] +
步骤2：化合物26-B的合成
将化合物26-A(840mg,2.42mmol)溶于二氯甲烷(5mL)中，加入氢氧化钠(387.09mg,9.68mmol)的水(5mL)溶液，四丁基溴化铵(39.00mg,120.97μmol)，0℃氮气氛围下加入碘甲烷(1.37g,9.68mmol,602.44μL)，混合体系升高到25℃室温并在氮气氛围下搅拌3小时后，将混合液分散到50mL水中，用二氯甲烷(100mL,50mL*2)萃取，收集有机相，将有机相浓缩得到粗产品，粗品经过层析柱(二氯甲烷/四氢呋喃＝1/0～5/1)分离纯化，得到26-B。
MS m/z:361.1[M+H] +
步骤3：化合物26-C的合成
将化合物26-B(260mg,719.76μmol)溶于N,N二甲基甲酰胺(10mL)中，加入吡啶(56.93mg,719.76μmol,58.09μL)和TBSOTf(190.26mg,719.76μmol,165.44μL)，25℃室温下搅拌3小时后，加水300mL(100mL*3)洗涤，用二氯甲烷150mL(50mL*3)萃取，收集有机相，浓缩得到粗产品，经过柱层析(二氯甲烷/四氢呋喃＝1/0～10/1)分离纯化，得到26-C。
MS m/z:474.6[M+H] +
步骤4：化合物26-D的合成
除了使用相应的原料外，以实施例1中制备化合物1-D相同的方法制备化合物26-D。
MS m/z:492.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.72(s,1H),8.55(d,J＝2.3Hz,1H),8.24(d,J＝9.0Hz,1H),8.12-8.05(m,1H), 8.03(d,J＝1.8Hz,1H),7.75(dd,J＝2.0,8.8Hz,1H),7.12(dd,J＝2.8,8.5Hz,1H),3.39(s,3H),2.55-2.40(m,4H),1.94-1.78(m,4H),0.97-0.88(m,9H),0.13(s,6H)
步骤5：化合物26的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物26。
MS m/z:461.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.49(d,J＝2.3Hz,1H),8.21(d,J＝8.8Hz,1H),8.00(d,J＝1.5Hz,1H),7.89(dd,J＝2.6,8.7Hz,1H),7.77(dd,J＝1.8,8.8Hz,1H),6.90(d,J＝8.5Hz,1H),4.43(t,J＝6.5Hz,2H),3.99-3.89(m,1H),3.39(s,3H),2.58-2.36(m,6H),2.28(s,6H),2.06-1.96(m,4H),1.89(br d,J＝13.8Hz,2H)
实施例27：化合物27
Figure PCTCN2019108520-appb-000100
合成路线：
Figure PCTCN2019108520-appb-000101
步骤1：化合物27-A的合成
将化合物25-D(900mg,2.51mmol)在0℃下溶于四氢呋喃(20mL)中，在氮气氛围下滴入甲基溴化镁(4M,1.88mL)，混合体系升高温度到25℃，并在氮气氛围下搅拌2小时后，将反应体系用水(50mL)淬灭，二氯甲烷/异丙醇＝10/1(50mL*3)萃取，收集有机相，经过层析柱(DCM/四氢呋喃＝1/0～3/1)分离纯化，得到化合物27-A。
MS m/z:375.0[M+H] +
步骤2：化合物27-B的合成
将化合物27-A(380mg,1.01mmol)溶于二氯甲烷(10mL)，加入TBSOTf(401.52mg,1.52mmol,349.14μL)和三乙胺(204.94mg,2.03mmol,281.89μL)，混合体系在25℃室温下搅拌12小时后，加水300mL(100 mL*3)洗涤，用二氯甲烷(150mL,50mL*3)萃取，收集有机相，浓缩得到粗产品，经过柱层析(二氯甲烷/四氢呋喃＝1/0～10/1)分离纯化，得到27-B。
MS m/z:489.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.68(s,1H),8.10(d,J＝2.0Hz,1H),8.00(d,J＝9.0Hz,1H),7.66(dd,J＝2.3,9.0Hz,1H),3.36(s,3H),2.71-2.54(m,2H),2.41(dt,J＝3.8,14.2Hz,2H),1.80-1.65(m,4H),1.56(s,3H),0.91(s,9H),0.22-0.13(m,6H)
步骤3：化合物27-C的合成
除了使用相应的原料外，以实施例1中制备化合物1-D相同的方法制备化合物27-C。
MS m/z:506.8[M+H] +
步骤4：化合物27-D的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物27-D。
MS m/z:589.6[M+H] +
步骤5：化合物27的合成
将化合物27-D(110mg,186.80μmol)溶于三氟乙酸(21.30mg,186.80μmol,13.83μL)中，在60℃下搅拌1小时后，用1M的氢氧化钠溶液调节pH＝7～8，二氯甲烷(150mL,50mL*3)萃取，饱和食盐水(50mL)洗涤，收集有机相，并用无水硫酸钠干燥，浓缩得到粗产品，经过制备高效液相色谱(中性，流动相：乙腈-水)分离纯化，得到化合物27。
MS m/z:475.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.49(d,J＝2.5Hz,1H),8.22(d,J＝8.8Hz,1H),8.06(d,J＝1.8Hz,1H),7.89(dd,J＝2.5,8.5Hz,1H),7.79(dd,J＝2.0,8.8Hz,1H),6.89(d,J＝8.5Hz,1H),4.42(t,J＝6.5Hz,2H),3.39(s,3H),2.57(d,J＝9.0Hz,4H),2.51-2.45(m,2H),2.28(s,6H),2.04-1.96(m,2H),1.87-1.75(m,4H),1.58(s,3H)
实施例28：化合物28
Figure PCTCN2019108520-appb-000102
合成路线：
Figure PCTCN2019108520-appb-000103
步骤1：化合物28-A的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物28-A。
MS m/z:629.6[M+H] +
步骤2：化合物28的合成
除了使用相应的原料外，以实施例27中制备化合物27相同的方法制备化合物28。
MS m/z:515.4[M+H] +
1H NMR(400MHz,CDCl 3)δ8.69(s,1H),8.49(d,J＝2.8Hz,1H),8.22(d,J＝8.8Hz,1H),8.05(d,J＝1.5Hz,1H),7.89(dd,J＝2.5,8.5Hz,1H),7.79(dd,J＝2.0,8.8Hz,1H),6.89(d,J＝8.5Hz,1H),4.41(t,J＝6.5Hz,2H),3.39(s,3H),2.57(d,J＝9.3Hz,2H),2.50(br d,J＝8.0Hz,2H),2.43(br s,2H),2.09-1.97(m,2H),1.84(br d,J＝8.5Hz,2H),1.78(br d,J＝7.8Hz,2H),1.59(br s,8H),1.57(br s,3H),1.45(br s,2H)
实施例29：化合物29
Figure PCTCN2019108520-appb-000104
合成路线：
Figure PCTCN2019108520-appb-000105
步骤1：化合物29-A的合成
将化合物1-B(200mg,600.28μmol)溶于无水甲苯(15mL)中，加入环丙基硼酸(103.12mg,1.20mmol)，碳酸钠(127.25mg,1.20mmol)，醋酸铜(109.03mg,600.28μmol)和吡啶(94.96mg,1.20mmol,96.90μL)，混合体系在70℃下搅拌12小时后，过滤，收集滤液，浓缩得到粗产品，经过层析柱(二氯甲烷/四氢呋喃＝1/0～10/1)分离纯化，得到化合物29-A。
MS m/z:373.0[M+H] +
1H NMR(400MHz,CDCl 3)δ8.95(s,1H),8.22(d,J＝1.5Hz,1H),8.01(d,J＝9.0Hz,1H),7.67(dd,J＝2.0,9.0Hz,1H),4.50-4.35(m,2H),4.03-3.91(m,2H),2.80(tt,J＝3.6,7.0Hz,1H),2.64(dt,J＝5.4,13.5Hz,2H),1.64(s, 2H),1.23-1.15(m,2H),1.01-0.93(m,2H)
步骤2：化合物29-B的合成
除了使用相应的原料外，以实施例1中制备化合物1-D相同的方法制备化合物29-B。
MS m/z:390.1[M+H] +
1H NMR(400MHz,CDCl 3)δ8.99(s,1H),8.55(d,J＝1.8Hz,1H),8.26(d,J＝8.8Hz,1H),8.17(d,J＝1.0Hz,1H),8.11(dt,J＝2.5,7.9Hz,1H),7.85-7.75(m,1H),7.11(dd,J＝2.9,8.4Hz,1H),4.47(br t,J＝11.3Hz,2H),3.98(dd,J＝5.0,11.8Hz,2H),2.83(tt,J＝3.7,6.9Hz,1H),2.71(dt,J＝5.3,13.4Hz,2H),1.70(br s,2H),1.28-1.16(m,2H),1.05-0.90(m,2H)
步骤3：化合物29的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物29。
MS m/z:473.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.95(s,1H),8.50(d,J＝2.5Hz,1H),8.21(d,J＝8.8Hz,1H),8.15(d,J＝1.8Hz,1H),7.92(dd,J＝2.5,8.5Hz,1H),7.79(dd,J＝1.8,8.8Hz,1H),6.89(d,J＝8.5Hz,1H),4.51-4.42(m,4H),3.97(dd,J＝4.9,11.7Hz,2H),2.82(td,J＝3.3,6.9Hz,1H),2.73(dt,J＝5.3,13.7Hz,2H),2.64(br s,2H),2.40(s,6H),2.14-2.05(m,2H),1.67(br d,J＝14.1Hz,2H),1.21(q,J＝6.8Hz,2H),1.02-0.96(m,2H)
实施例30：化合物30
Figure PCTCN2019108520-appb-000106
合成路线：
Figure PCTCN2019108520-appb-000107
步骤1：化合物30的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物30。
MS m/z:513.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.95(s,1H),8.50(d,J＝2.5Hz,1H),8.21(d,J＝9.0Hz,1H),8.15(d,J＝1.5Hz,1H),7.92(dd,J＝2.6,8.7Hz,1H),7.79(dd,J＝1.9,8.9Hz,1H),6.88(d,J＝8.5Hz,1H),4.51-4.39(m,4H),3.97(dd,J＝4.9,11.7Hz,2H),2.82(tt,J＝3.5,7.0Hz,1H),2.73(dt,J＝5.3,13.4Hz,2H),2.55-2.48(m,2H),2.43(br s,2H), 2.12-1.98(m,2H),1.68(br s,4H),1.63-1.56(m,4H),1.45(br d,J＝5.3Hz,2H),1.26-1.14(m,2H),1.08-0.90(m,2H)
实施例31：化合物31
Figure PCTCN2019108520-appb-000108
合成路线：
Figure PCTCN2019108520-appb-000109
步骤1：化合物31-B的合成
在0℃氮气保护条件下，将化合物31-A(5g,26.59mmol)缓慢加入到氢化钠(1.60g,39.89mmol,60％纯度)的THF(20mL)溶液中，反应液在25℃搅拌0.5小时，然后在0℃缓慢加入碘甲烷(5.66g,39.89mmol,2.48mL)的THF(10mL)溶液，反应液在20℃搅拌12小时。20℃条件下用水(20mL)淬灭，加水(10mL)稀释，用EtOAc萃取(150mL,50mL*3)，合并有机相用饱和氯化钠洗涤(150mL,50mL*3)，无水硫酸钠干燥，过滤，浓缩得到粗品，残留物经柱层析(0～10％EtOAc/PE)纯化得到31-B。
MS m/z:201.8[M+H] +
1H NMR(400MHz,CDCl 3)δ8.61(d,J＝2.0Hz,1H),7.82(dd,J＝2.3,8.5Hz,1H),7.33(d,J＝8.3Hz,1H),4.53(s,2H),3.47(s,3H)
步骤2：化合物31-C的合成
在氮气保护下，将31-B(4.8g,23.76mmol)，双联嚬哪醇硼酸酯(6.64g,26.13mmol)，醋酸钾(6.99g,71.27mmol)和Pd(dppf)Cl 2(1.74g,2.38mmol)的二氧六环(40mL)和水(8mL)混合液在100℃搅拌12小时。反应液过滤，滤液浓缩得到残留物，经过制备薄层色谱硅胶板分离纯化得到化合物31-C。
MS m/z:167.9[M+H] +
1H NMR(400MHz,DMSO-d 6)δ8.88(s,1H),8.49(d,J＝7.8Hz,1H),7.73(d,J＝7.8Hz,1H),4.69(s,2H),3.42(s,3H).
步骤3：化合物31的合成
除了使用相应的原料外，以实施例1中制备化合物1-D相同的方法制备化合物31。
MS m/z:390.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.92(d,J＝2.0Hz,1H),8.74(s,1H),8.28-8.19(m,2H),8.03(dd,J＝2.3,8.0Hz,1H),7.84(dd,J＝2.0,8.8Hz,1H),7.59(d,J＝8.0Hz,1H),4.69(s,2H),4.56-4.41(m,2H),3.99(dd,J＝4.9,11.7Hz,2H),3.54(s,3H),3.40(s,3H),2.75(dt,J＝5.3,13.4Hz,2H),1.71(br d,J＝14.1Hz,2H)
实施例32：化合物32
Figure PCTCN2019108520-appb-000110
合成路线：
Figure PCTCN2019108520-appb-000111
步骤1：化合物32-A的合成
在-60℃氮气保护下，将n-BuLi(2.5M,3.93mL)缓慢加入到DIPA(993.72mg,9.82mmol,1.39mL)的THF(10mL)溶液中，反应体系在-30℃搅拌30分钟，然后缓慢加入四氢吡喃-4-甲酸甲酯(1.49g,10.31mmol,1.38mL)的THF(10mL)溶液中，反应体系在-65℃搅拌1小时，最后缓慢加入化合物B(1.5g,4.91mmol)的THF(10mL)溶液，反应体系在-65℃搅拌2小时。反应完毕后，加入水(5mL)淬灭反应，再加入饱和食盐水(10mL)稀释，用EtOAc萃取(30mL,10mL*3)，合并有机相用饱和食盐水洗涤(30mL,10mL*3)，无水硫酸钠干燥，浓缩得到残留固体，经过柱层析(0～5％THF/PE)得到32-A。
MS m/z:412.8[M+H] +
步骤2：化合物32-B的合成
在氮气保护下，将锌粉(1.14g,17.43mmol)加入到32-A(720mg,1.74mmol)和NH 4Cl(932.10mg,17.43mmol,609.22μL)的THF(10mL)和H 2O(10mL)溶液中，反应体系在70℃搅拌3小时。反应完毕后过滤，滤液浓缩得到残留固体，固体用水(20mL)打浆30分钟，得到32-B。
MS m/z:350.9[M+H] +
步骤3：化合物32-C的合成
在氮气保护下，将碘甲烷(347.68mg,2.45mmol,152.49μL)的二氯甲烷(10mL)溶液加入到32-B(500mg,1.07mmol)，TBAB(34.33mg,106.50μmol)和NaOH(63.90mg,1.60mmol)的DCM(10mL)和H 2O(10mL)溶液中，反应体系在30℃搅拌1小时。反应完毕后，过滤，滤液浓缩得到残留固体，残留固体用水(20mL)打浆30分钟得到32-C。
MS m/z:364.9[M+H] +
步骤4：化合物32-D的合成
在氮气保护条件下，将32-C(200mg,547.65μmol)，2-氟吡啶-5-硼酸(154.34mg,1.10mmol)，Na 2CO 3(116.09mg,1.10mmol)，Pd 2(dba) 3(50.15mg,54.77μmol)和Xphos(50.15mg,54.77μmol)的二氧六环(18mL)和水(2mL)溶液100℃搅拌2小时。反应混合液浓缩得到残留固体，固体经过柱层析(0～50％EtOAc/PE)得到化合物32-D。
MS m/z:382.0[M+H] +
步骤5：化合物32的合成
在20℃氮气保护条件下，将32-D(100mg,262.21μmol)加入到1-哌啶丙醇(75.11mg,524.42μmol,28.71μL)和NaH(41.95mg,1.05mmol,60％纯度)的DMF(10mL)溶液中，反应体系70℃搅拌2小时。反应结束加入水(2mL)淬灭，浓缩得到残留固体，固体经过柱层析(0～10％MeOH/DCM)和制备HPLC(column:Boston Prime C18 150×30mm 5μm；mobile流动相:[水(0.05％氢氧化铵v/v)-乙腈]；乙腈B％:50％-80％,8min)分离得到化合物32。
MS m/z:505.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.71(s,1H),8.42(s,1H),8.07(d,J＝8.0Hz,1H),7.93-7.84(m,2H),6.89(d,J＝8.8Hz,1H),4.56-4.34(m,4H),3.97(dd,J＝4.8,11.5Hz,2H),3.39(s,3H),2.78-2.60(m,2H),2.52(br s,2H),2.50-2.33(m,4H),2.10-1.99(m,2H),1.69(br d,J＝14.3Hz,2H),1.60(br s,4H),1.50-1.40(m,2H)
实施例33：化合物33
Figure PCTCN2019108520-appb-000112
合成路线：
Figure PCTCN2019108520-appb-000113
步骤1：化合物33的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物33。
MS m/z:465.2[M+H] +
1H NMR(400MHz,CDCl 3)δ8.64(s,1H),8.37-8.32(m,1H),7.99(d,J＝8.0Hz,1H),7.85-7.77(m,2H),6.82(d,J＝8.5Hz,1H),4.45-4.35(m,4H),3.90(dd,J＝4.9,11.7Hz,2H),3.32(s,3H),2.69-2.54(m,4H),2.34(s,6H),2.11-1.97(m,2H),1.63(br d,J＝14.1Hz,2H)
实施例34：化合物34
Figure PCTCN2019108520-appb-000114
合成路线：
Figure PCTCN2019108520-appb-000115
步骤1：化合物34-A的合成
除了使用相应的原料外，以实施例29中制备化合物29-A相同的方法制备化合物34-A。
1H NMR(400MHz,CDCl 3)δ8.95(s,1H),8.31(d,J＝7.3Hz,1H),7.84(d,J＝9.5Hz,1H),4.50-4.37(m,2H),3.98(dd,J＝5.0,11.8Hz,2H),2.84-2.72(m,1H),2.66-2.52(m,2H),1.62(s,2H),0.98-0.94(m,2H),0.90-0.86(m,2H)
步骤2：化合物34-B的合成
除了使用相应的原料外，以实施例1中制备化合物1-D相同的方法制备化合物34-B。
MS m/z:408.1[M+H] +
1H NMR(400MHz,CDCl 3)δ8.92(s,1H),8.42(s,1H),8.01(d,J＝8.0Hz,2H),7.86(d,J＝11.4Hz,1H),7.05(dd,J＝2.9,8.4Hz,1H),4.38(dt,J＝1.9,12.1Hz,2H),3.89(dd,J＝5.1,11.7Hz,2H),2.75(s,1H),2.56(br d,J＝4.6Hz,2H),1.63(s,1H),1.61-1.59(m,1H),1.17-1.11(m,2H),0.96-0.89(m,2H)
步骤3：化合物34的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物34。
MS m/z:491.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.97(s,1H),8.43(s,1H),8.07(d,J＝8.0Hz,1H),7.96-7.85(m,2H),6.91(d,J＝8.5Hz,1H),4.46(br t,J＝6.4Hz,4H),4.03-3.92(m,2H),2.90-2.79(m,1H),2.72-2.62(m,2H),2.56-2.49(m,2H),2.31(s,6H),2.07-2.01(m,2H),1.71-1.66(m,2H),1.26-1.20(m,2H),1.05-0.97(m,2H)
实施例35：化合物35
Figure PCTCN2019108520-appb-000116
合成路线：
Figure PCTCN2019108520-appb-000117
步骤1：化合物35的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物35。
MS m/z:531.4[M+H] +
1H NMR(400MHz,CDCl 3)δ8.97(s,1H),8.43(s,1H),8.07(d,J＝8.1Hz,1H),7.95-7.85(m,2H),6.91(d,J＝8.6Hz,1H),4.45(br d,J＝6.8Hz,4H),4.04-3.94(m,2H),2.88-2.80(m,1H),2.72-2.61(m,2H),2.57-2.51(m,2H),2.50-2.33(m,4H),2.11-2.03(m,2H),1.72-1.66(m,6H),1.47(br s,2H),1.26-1.20(m,2H),1.05-0.98(m,2H)
实施例36：化合物36
Figure PCTCN2019108520-appb-000118
合成路线：
Figure PCTCN2019108520-appb-000119
步骤1：化合物36-A的合成
除了使用相应的原料外，以实施例1中制备化合物1-A相同的方法制备化合物36-A。
MS m/z:429.0[M+H] +
步骤2：化合物36-B的合成
除了使用相应的原料外，以实施例1中制备化合物1-B相同的方法制备化合物36-B。
MS m/z:366.9[M+H] +
步骤3：化合物36-C的合成
除了使用相应的原料外，以实施例1中制备化合物1-C相同的方法制备化合物36-C。
MS m/z:381.0[M+H] +
步骤4：化合物36-D的合成
除了使用相应的原料外，以实施例1中制备化合物1-D相同的方法制备化合物36-D。
MS m/z:398.0[M+H] +
1H NMR(400MHz,CDCl 3)δ8.76(s,1H),8.36(d,J＝2.3Hz,1H),8.32(s,1H),8.01(s,1H),8.00-7.94(m,1H),7.10(dd,J＝2.8,8.3Hz,1H),4.50-4.39(m,2H),3.95(dd,J＝5.0,11.8Hz,2H),3.40(s,3H),2.61(dt,J＝5.3,13.4Hz,2H),1.68(br d,J＝14.6Hz,2H)
步骤5：化合物36的合成
除了使用相应的原料外，以实施例1中制备化合物1相同的方法制备化合物36。
MS m/z:481.3[M+H] +
1H NMR(400MHz,CDCl 3)δ8.66(s,1H),8.27-8.17(m,2H),7.93(s,1H),7.73(dd,J＝2.5,8.5Hz,1H),6.80(d,J＝8.5Hz,1H),4.45-4.33(m,4H),3.88(dd,J＝4.9,11.7Hz,2H),3.33(s,3H),2.75-2.65(m,2H),2.57(dt,J＝5.3, 13.3Hz,2H),2.43(s,6H),2.16-2.06(m,2H),1.61(br d,J＝13.8Hz,2H)
生物学评价
实验例1：体外评价
供实验用的本发明化合物均为自制，其化学名称和结构式见各化合物的制备实施例，实验测试在英国Eurofins公司进行，实验结果由该公司提供，下面的实验过程也由该公司提供。
ATM酶活性测试实验过程
将人源的ATM激酶置于包含30nM的GST-cMyc-p53和Mg/ATP的缓冲溶液中孵化，Mg/ATP的浓度根据不同需要确定，反应通过加入Mg/ATP的复合物引发。大约在室温下孵化30分钟后，加入含有EDTA的停止液终止反应。最后，针对磷酸化的p53加入包含d2标记的抗GST单克隆抗体和铕标记的磷酸化Ser15抗体的检测缓冲液。然后用时间分辨荧光模式读取检测盘，均相时间分辨荧光(HTRF)信号通过公式HTRF＝10000x(Em665nm/Em620nm)计算得到。
DNA-PK酶活性测试实验过程
将人源的DNA-PK激酶置于包含50nM的GST-cMyc-p53和Mg/ATP的缓冲溶液中孵化，Mg/ATP的浓度根据不同需要确定，反应通过加入Mg/ATP的复合物引发。大约在室温下孵化30分钟后，加入含有EDTA的停止液终止反应。最后，针对磷酸化的p53加入包含d2标记的抗GST单克隆抗体和铕标记的磷酸化Ser15抗体的检测缓冲液。然后用时间分辨荧光模式读取检测盘，均相时间分辨荧光(HTRF)信号通过公式HTRF＝10000x(Em665nm/Em620nm)计算得到。
表1：本发明化合物体外细胞活性测定结果(IC 50)
化合物编号 ATM(IC50nM) DNA-PK(IC50nM)
AZD0156 1 58
实施例1 0.9 78
实施例2 288 73
实施例3 1 48
实施例4 1 62
实施例5 2 92
实施例6 2 800
实施例7 1 153
实施例8 3 99
实施例9 1 83
实施例10 2 80
实施例11 2 243
实施例12 2 26
实施例13 4 27
实施例14 3 46
实施例15 2 41
实施例16 4 204
实施例17 3 352
实施例18 2 343
实施例19 0.8 77
实施例20 2 129
实施例21 7 509
实施例22 1 14
实施例23 0.8 30
实施例24 2 80
实施例25 1 92
实施例26 1 76
实施例27 1 99
实施例28 2 334
实施例29 2 269
实施例30 2 475
实施例31 63 88
实施例32 2 561
实施例33 1 593
实施例34 5 >1000
实施例35 3 >1000
实施例36 12 >1000
结论：本发明化合物具有显著的ATM激酶抑制作用，并且对DNA-PK激酶具有良好的选择性。
实验例2：ATM抑制剂与etoposide协同作用于人肺癌H446细胞皮下异种移植肿瘤雌性BALB/c裸小鼠模型的体内药效学研究
实验目的：
对受试药ATM抑制剂和etoposide经腹腔或口服在人肺癌H446细胞皮下异种移植瘤BALB/c裸小鼠模型体内药效进行评估。
实验设计：
表2.ATM抑制剂和etoposide体内药效实验动物分组及给药方案
Figure PCTCN2019108520-appb-000120
注：IP：腹腔注射；PO：口服；QD：每日一次；BIW：每周两次；QD(PG-D0,3D on,4D off from PG-D1)×4W：周二至周四给药，每日一次，一周一循环，给药四周；BIW+QD(PG-D0,3D on,4D off from PG-D1)×4W：周一给etoposide，周二至周四给ATM抑制剂，每日一次，一周一循环，给药四周。
实验方法与步骤：
1.细胞培养
人肺癌细胞H446(ATCC,Manassas,VA,HTB-171)体外单层培养，培养条件为RPMI-1640，培养基中加10％胎牛血清，100U/mL青霉素和100μg/mL链霉素，37℃ 5％CO 2培养。一周两次用胰酶-EDTA进行常规消化处理传代。当细胞饱和度为80％-90％时，收取细胞，计数，接种。
2.肿瘤细胞接种
将0.2mL 5×10 6个H446细胞(1:1加基质胶)皮下接种于每只裸小鼠的右后背。肿瘤平均体积达到125mm 3时开始分组给药(表)。
3.受试物的配制
表3.受试物配制方法
Figure PCTCN2019108520-appb-000121
Figure PCTCN2019108520-appb-000122
注：在给动物给药前需要轻轻将药物充分混匀。
肿瘤测量和实验指标：
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。每周两次用游标卡尺测量肿瘤直径。肿瘤体积的计算公式为：V＝0.5a×b 2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)。TGI(％)，反映肿瘤生长抑制率。TGI(％)的计算：TGI(％)＝【1-(某处理组给药结束时平均瘤体积－该处理组开始给药时平均瘤体积)/(溶剂对照组治疗结束时平均瘤体积－溶剂对照组开始治疗时平均瘤体积)】×100％。
肿瘤增殖率T/C(％)：其中T是治疗组最后一次测量(PG-D26)所得平均肿瘤体积，C是对照组最后一次测量(PG-D26)所得平均肿瘤体积。
统计分析：
包括每个组的每个时间点的肿瘤体积的平均值和标准误(SEM)(具体数据见表)。治疗组在试验结束时给药后第26天表现出最好的治疗效果，因此基于此数据进行统计学分析评估组间差异。两组间比较用T-test进行分析，三组或多组间比较用one-way ANOVA进行分析，如果方差不齐，应用Games-Howell法进行检验。如果方差齐性，应用Dunnet(2-sided)法进行分析。用SPSS 17.0进行所有数据分析。p<0.05认为有显著性差异。
实验结果：
死亡率、发病率及体重变化情况
实验动物的体重作为间接测定药物毒性的参考指标。在此模型中所有给药组均未显示有显著性体重下降(附图1)编号42161小鼠在etoposide,15mg/kg和AZD0156,5mg/kg联合组给药后第15天发现死亡。etoposide分别与实施例32和AZD0156联用的治疗组中，有部分动物体重下降超过10％但未低于15％。受试药ATM抑制剂和etoposide，对H446细胞皮下异种移植肿瘤雌性BALB/c裸小鼠模型的体重影响附图1所示。相对体重变化基于开始给药时动物体重计算得出。数据点代表组内平均体重变化百分比，误差线代表标准误(SEM)。
肿瘤体积
给予H446细胞皮下异种移植肿瘤雌性BALB/c裸小鼠模型在受试药ATM抑制剂与etoposide治疗后各组肿瘤体积变化如表4所示。
表4.各组不同时间点的瘤体积
Figure PCTCN2019108520-appb-000123
Figure PCTCN2019108520-appb-000124
注：a.平均值±SEM。
肿瘤生长曲线
H446异种移植瘤模型荷瘤鼠在给予受试药ATM抑制剂与etoposide后的肿瘤生长曲线。肿瘤生长曲线如附图2所示。数据点代表组内平均肿瘤体积，误差线代表标准误(SEM)。
抗肿瘤药效评价指标(基于给药后第26天肿瘤体积计算得出)
表5.受试药ATM抑制剂与etoposide对H446异种移植瘤模型的抑瘤药效评价
Figure PCTCN2019108520-appb-000125
注：a.平均值±SEM。第5组动物#42161在PG-D15发现死亡，其数据不计入统计。
b.肿瘤生长抑制由T/C和TGI(TGI(％)＝[1-(T 26-T 0)/(V 26-V 0)]×100)计算。
c.p值根据肿瘤体积计算。
实验讨论：
在本实验中，我们评价了受试药ATM抑制剂和etoposide在人肺癌H446异种移植瘤模型中的体内药效。各组在不同时间点的瘤体积如表4，表5及附图2所示。开始给药后26天，溶剂对照组荷瘤鼠的瘤体积达到2,782mm 3，Etoposide+实施例32(15mg/kg+5mg/kg)和Etoposide+AZD0156(15mg/kg+5mg/kg)组的平均瘤体积分别为930mm 3、和1,344mm 3，T/C分别为33.42％和48.30％，TGI分别为69.70％和54.11％，与溶剂对照相比p值分别为0.006和0.028。
实验结论：
在该ATM抑制剂和etoposide在人肺癌H446异种移植瘤模型中的体内药效实验中，实施例32与etoposide联用表现出很好的协同效应，优于AZD0156与etoposide联用的药效。

Claims (24)

  1. 式(Ⅰ)所示化合物、其异构体或其药学上可接受的盐，
    Figure PCTCN2019108520-appb-100001
    其中，
    E选自-N(R 5)-、-O-和-C(R 6)(R 7)-；
    R 1选自C 1-3烷基、C 1-3烷氧基和C 3-6环烷基，所述C 1-3烷基、C 1-3烷氧基和C 3-6环烷基任选被1、2或3个R a取代；
    R 2选自H、F、Cl、Br、I、OH和NH 2；
    R 3选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-3烷基和C 1-3烷氧基，所述C 1-3烷基和C 1-3烷氧基任选被1、2或3个R b取代；
    R 4选自C 1-6烷基和N(R c)(R d)；
    R 5选自H、C 1-6烷基、C 3-6环烷基、C 1-6烷基-C＝O-、C 1-6烷基-O-C＝O-和C 3-6环烷基-C＝O-，所述C 1-6烷基、C 3-6环烷基、C 1-6烷基-C＝O-、C 1-6烷基-O-C＝O-和C 3-6环烷基-C＝O-任选被1、2或3个R e取代；
    R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、C 1-6烷基和C 1-6烷氧基，所述C 1-6烷基或C 1- 6烷氧基任选被1、2或3个R f取代；
    L 1选自单键、-(CH 2) m-和-(CH 2) m-O-；
    m选自1、2、3和4；
    环B选自苯基和5～6元杂芳基，所述苯基和5～6元杂芳基任选被1、2或3个R g取代；
    R a和R b分别独立地选自F、Cl、Br、I、OH和NH 2；
    R c和R d分别独立地选自H、C 1-3烷基和C 3-6环烷基，所述C 1-3烷基和C 3-6环烷基任选被1、2或3个R取代；
    或者，R c、R d和与它们连接的N原子共同构成任选1、2或3个R取代的4-6元杂环烷基；
    R e、R f和R g分别独立地选自F、Cl、Br、I、OH和NH 2；
    R分别独立地选自F、Cl、Br、I、OH和NH 2；
    所述5～6元杂芳基和4-6元杂环烷基分别独立包含1、2、3或4个独立选自-NH-、-O-、-S-和N的杂原子或杂原子团。
  2. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自CH 3、CH 2CH 3和环丙烷基，所述CH 3、CH 2CH 3和环丙烷基任选被1、2或3个R a取代。
  3. 根据权利要求2所述化合物、其异构体或其药学上可接受的盐，其中，R 1选自CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和环丙烷基。
  4. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 3选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2CH 3和
    Figure PCTCN2019108520-appb-100002
    所述CH 3、CH 2CH 3和
    Figure PCTCN2019108520-appb-100003
    任选被1、2或3个R b取代。
  5. 根据权利要求4所述化合物、其异构体或其药学上可接受的盐，其中，R 3选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和
    Figure PCTCN2019108520-appb-100004
  6. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，R c和R d分别独立地选自CH 3、CH 2CH 3和环丙烷基。
  7. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R c、R d和与它们连接的N原子共同构成吡咯烷基和哌啶基，所述吡咯烷基和哌啶基任选1、2或3个R取代。
  8. 根据权利要求7所述化合物、其异构体或其药学上可接受的盐，其中，R c、R d和与它们连接的N原子共同构成
    Figure PCTCN2019108520-appb-100005
  9. 根据权利要求6或8所述化合物、其异构体或其药学上可接受的盐，其中，R 4选自CH 3、CH 2CH 3、
    Figure PCTCN2019108520-appb-100006
    Figure PCTCN2019108520-appb-100007
  10. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 5选自H、CH 3、CH 3CH 2、CH(CH 3) 2、环丙烷基、CH 3OC＝O-、CH(CH 3) 2OC＝O-、CH 3C＝O-、和环丙烷基-C＝O-，所述CH 3、CH 3CH 2、CH(CH 3) 2、环丙烷基、CH 3OC＝O-、CH(CH 3) 2OC＝O-、CH 3C＝O-、和环丙烷基-C＝O-任选被1、2或3个R e取代。
  11. 根据权利要求10所述化合物、其异构体或其药学上可接受的盐，其中，R 5选自H、CH 3、CH 2F、CHF 2、CF 3、CH 3CH 2、CH 2FCH 2、CHF 2CH 2、CF 3CH 2、CH(CH 3) 2、环丙烷基、CH 3OC＝O-、CH(CH 3) 2OC＝O-、CH 3C＝O-、和环丙烷基-C＝O-。
  12. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 3CH 2、CH(CH 3) 2和
    Figure PCTCN2019108520-appb-100008
    所述CH 3、CH 3CH 2、CH(CH 3) 2和
    Figure PCTCN2019108520-appb-100009
    任选被1、2或3个R f取代。
  13. 根据权利要求12所述化合物、其异构体或其药学上可接受的盐，其中，R 6和R 7分别独立地选自H、F、Cl、Br、I、OH、NH 2、CN、CH 3、CH 2F、CHF 2、CF 3、CH 3CH 2、CH(CH 3) 2和
    Figure PCTCN2019108520-appb-100010
  14. 根据权利要求11或13所述化合物、其异构体或其药学上可接受的盐，其中，E选自-O-、-CF 2-、-N(CH 3)-、-NH-、
    Figure PCTCN2019108520-appb-100011
    Figure PCTCN2019108520-appb-100012
  15. 根据权利要求1所述化合物、其异构体或其药学上可接受的盐，其中，L 1选自单键、-(CH 2)-O-和-(CH 2) 3-O-。
  16. 根据权利要求1～3任意一项所述化合物、其异构体或其药学上可接受的盐，其中，环B选自苯基、吡啶基、吡唑基、吲唑基和咪唑基，所述苯基、吡啶基、吡唑基、吲唑基和咪唑基任选被1、2或3个R g取代。
  17. 根据权利要求16所述化合物、其异构体或其药学上可接受的盐，其中，环B选自
    Figure PCTCN2019108520-appb-100013
    Figure PCTCN2019108520-appb-100014
    所述
    Figure PCTCN2019108520-appb-100015
    任选被1、2或3个R g取代。
  18. 根据权利要求17所述化合物、其异构体或其药学上可接受的盐，其中，环B选自
    Figure PCTCN2019108520-appb-100016
    Figure PCTCN2019108520-appb-100017
  19. 根据权利要求15所述化合物、其异构体或其药学上可接受的盐，其中R 4-L 1-选自CH 3、CH 3OCH 2-、
    Figure PCTCN2019108520-appb-100018
  20. 根据权利要求1～15任意一项所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2019108520-appb-100019
    其中，
    R 1、R 2、R 3、R 4、R 5、R 6、R 7和L 1如权利要求1～15任意一项所定义。
  21. 下式所示化合物、其异构体或其药学上可接受的盐，所述化合物选自
    Figure PCTCN2019108520-appb-100020
    Figure PCTCN2019108520-appb-100021
  22. 根据权利要求21所述化合物、其异构体或其药学上可接受的盐，其选自
    Figure PCTCN2019108520-appb-100022
  23. 根据权利要求1～22任意一项所述的化合物、其异构体或其药学上可接受的盐在制备ATM激酶抑制剂相关药物上的应用。
  24. 根据权利要求23所述的应用，其特征在于，所述ATM激酶抑制剂相关药物是用于实体瘤的药物。
PCT/CN2019/108520 2018-09-30 2019-09-27 喹啉并吡咯烷-2-酮类衍生物及其应用 WO2020063855A1 (zh)

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JP2021517848A JP6997358B2 (ja) 2018-09-30 2019-09-27 キノリノピロリジン－２－オン系誘導化合物及びその使用
AU2019348132A AU2019348132B2 (en) 2018-09-30 2019-09-27 Quinolino-pyrrolidin-2-one derivative and application thereof
KR1020217013030A KR102345208B1 (ko) 2018-09-30 2019-09-27 퀴놀리노-피롤리딘-2-온 유도체 및 이의 응용
CN201980064561.9A CN112771045B (zh) 2018-09-30 2019-09-27 喹啉并吡咯烷-2-酮类衍生物及其应用

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