WO2021098734A1 - 作为atm抑制剂的有取代的喹啉吡咯酮类合物及其应用 - Google Patents

作为atm抑制剂的有取代的喹啉吡咯酮类合物及其应用 Download PDF

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WO2021098734A1
WO2021098734A1 PCT/CN2020/129838 CN2020129838W WO2021098734A1 WO 2021098734 A1 WO2021098734 A1 WO 2021098734A1 CN 2020129838 W CN2020129838 W CN 2020129838W WO 2021098734 A1 WO2021098734 A1 WO 2021098734A1
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compound
pharmaceutically acceptable
acceptable salt
group
present
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PCT/CN2020/129838
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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 CN202080080572.9A priority Critical patent/CN114746421A/zh
Publication of WO2021098734A1 publication Critical patent/WO2021098734A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • 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
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • the present invention relates to a class of substituted quinoline pyrrolone compounds as ATM inhibitors, and their application in the preparation of drugs for diseases related to ATM inhibitors. Specifically, it relates to a compound represented by formula (I) or a pharmaceutically acceptable salt thereof.
  • Ataxia telangiectasia mutated gene is an autosomal recessive genetic gene, homozygous shows a progressive neurodegenerative disease, the patient is about 1 year old, showing the cerebellum Sexual ataxia, tumor-like small blood vessels dilated in the eyes, face and neck around 6 years old, often died of infection.
  • ATM gene is an important gene related to DNA damage repair, so patients generally show that they are particularly sensitive to X-rays and their DNA repair ability is significantly reduced.
  • Approximately 1% of humans are heterozygous for ATM mutant genes. Although they do not show disease, they also increase the risk of cancer.
  • the ATM gene is located on chromosome 11q22-q23, with a total length of 150kb, a coding sequence of 12kb, and a total of 66 exons. It is one of the human genes with the most exons found so far, and one of the most important genes. Kind of nursing gene.
  • ATM protein is a serine/threonine protein kinase containing 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 belongs to the phosphatidylinositol 3-kinase-related kinase family (PIKK). It is an autophosphorylated protein and usually exists in the form of an inactive dimer. When a double-strand break occurs in DNA, ATM protein kinase is phosphorylated and depolymerized within a few minutes at the earliest, and the phosphorylated ATM protein kinase reaches its maximum value in 2 to 3 hours.
  • PIKK phosphatidylinositol 3-kinase-related kinase family
  • the signaling pathways of ATM protein in DNA damage repair mainly include: 1ATM-CHK2-Cdc25A/B/C signaling pathway; 2ATM-CHK2-p53 signaling pathway; 3ATM-Nbs1-Smc1/3 signaling pathway; 4ATM-p38MAPK-MK2 signaling path.
  • M means MRE11 (meiotic recombinant protein) has nuclease activity and the 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 its normal assembly at the DNA break point.
  • the various proteins in the MRN complex must coordinate with each other to adjust the ATM protein to bind to the broken end of the DNA and help the broken DNA to complete the repair.
  • ATM plays a key role in the repair of DNA double-strand breaks. Since the probability of double-strand breaks in normal cells is relatively small, selective ATM inhibitors have little effect when used alone, but because ATM is the entire DNA damage repair pathway The key part of this link is that ATM inhibitors have many possible combinations. Preclinical and clinical studies have appeared in combination with radiotherapy, combination with chemotherapy, and other target inhibitors for DNA damage repair, such as PARP inhibitors. The combination and so on. AstraZeneca’s AZD0156 is the first compound to enter Phase I clinical studies. Another ATM inhibitor AZD1390 from AstraZeneca and M-3541 from Merck, Germany have also entered Phase I clinical studies.
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected C 1-3 alkyl group and a C 1-3 alkoxy, said C 1-3 alkyl and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy Optionally substituted by 1, 2 or 3 R b ;
  • R 3 is selected from H and N(R c )(R d );
  • R 4 is selected from F, CN and OH;
  • L 1 is selected from a single bond, -(CH 2 ) m -, -(CH 2 ) m -O- and -(CH 2 ) m -O-CH 2 -;
  • n is selected from 1, 2, 3 and 4;
  • Ring B is selected from a phenyl group and a 5-6 membered heteroaryl group, the phenyl group and a 5-6 membered heteroaryl group are optionally substituted with 1, 2 or 3 R e ;
  • R a and R b are each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c and R d are each independently selected from H and C 1-3 alkyl optionally substituted with 1, 2 or 3 R;
  • R c , R d and the N atom to which they are connected together form an optionally substituted with 1, 2 or 3 R
  • R e are each independently selected from H, F, Cl, Br, I and CH 3 ;
  • n is selected from 0, 1 and 2;
  • R is each independently selected from F, Cl, Br, I, OH, and NH 2 .
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected C 1-3 alkyl group and a C 1-3 alkoxy, said C 1-3 alkyl and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy Optionally substituted by 1, 2 or 3 R b ;
  • R 3 is selected from H and N(R c )(R d );
  • R 4 is selected from F, CN and OH;
  • 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 a phenyl group and a 5-6 membered heteroaryl group, the phenyl group and a 5-6 membered heteroaryl group are optionally substituted with 1, 2 or 3 R e ;
  • R a and R b are each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c and R d are each independently selected from H and C 1-3 alkyl optionally substituted with 1, 2 or 3 R;
  • R c , R d and the N atom to which they are connected together form an optionally substituted with 1, 2 or 3 R
  • R e are each independently selected from H, F, Cl, Br, I and CH 3 ;
  • n is selected from 0, 1 and 2;
  • R is each independently selected from F, Cl, Br, I, OH, and NH 2 .
  • the present invention provides a compound represented by formula (I) or a pharmaceutically acceptable salt thereof,
  • R 1 is selected C 1-3 alkyl group and a C 1-3 alkoxy, said C 1-3 alkyl and a C 1-3 alkoxy group optionally substituted with 1, 2 or 3 R a;
  • R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , C 1-3 alkyl and C 1-3 alkoxy, the C 1-3 alkyl and C 1-3 alkoxy Optionally substituted by 1, 2 or 3 R b ;
  • R 3 is selected from H and N(R c )(R d );
  • R 4 is selected from F, CN and OH;
  • 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 pyridyl, said phenyl and pyridyl optionally substituted with 1, 2, or 3 R e;
  • R a and R b are each independently selected from F, Cl, Br, I, OH and NH 2 ;
  • R c and R d are each independently selected from H and C 1-3 alkyl optionally substituted with 1, 2 or 3 R;
  • R c , R d and the N atom to which they are connected together form an optionally substituted with 1, 2 or 3 R
  • R e is selected from H, F, Cl, Br, I and CH 3 ;
  • n is selected from 0, 1 and 2;
  • R is selected from F, Cl, Br, I, OH, and NH 2 .
  • R 1 is selected from CH 3, CH 2 CH 3 and OCH 3, the CH 3, CH 2 CH 3 OCH 3, and optionally substituted with 1, 2 or 3 R a, the other variables As defined in the present invention.
  • R 1 is selected from CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 and OCH 3 , and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 CH 3 and OCH 3 , the CH 3 , CH 2 CH 3 and OCH 3 Optionally substituted by 1, 2 or 3 R b , and other variables are as defined in the present invention.
  • R 2 is selected from H, F, Cl, Br, I, OH, NH 2 , CH 3 , CH 2 F, CHF 2 , CF 3 , CH 2 CH 3 and OCH 3 , other variables As defined in the present invention.
  • R c and Rd are independently selected from H, CH 3 and CH 2 CH 3 , and other variables are as defined in the present invention.
  • R c and Rd are independently selected from H and CH 3 , and other variables are as defined in the present invention.
  • the above-mentioned R c , R d and the N atom to which they are connected together form a pyrrolidinyl group and a piperidinyl group, and the pyrrolidinyl group and piperidinyl group are optionally substituted with 1, 2 or 3 Rs.
  • Other variables are as defined in the present invention.
  • R 3 is selected from H, N(CH 3 ) 2 , N(CH 2 CH 3 ) 2 , Other variables are as defined in the present invention.
  • R 3 is selected from H, N(CH 3 ) 2 and Other variables are as defined in the present invention.
  • the above-mentioned L 1 is selected from a single bond, -CH 2 CH 2 CH 2 O-, -OCH 2 -and -CH 2 CH 2 OCH 2 -, and other variables are as defined in the present invention.
  • the aforementioned L 1 is selected from a single bond, -CH 2 CH 2 CH 2 O- and -OCH 2 -, and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from phenyl and pyridyl, and the phenyl and pyridyl are optionally substituted with 1, 2 or 3 R e , and other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from Said Optionally substituted with 1, 2, or 3 R e, the other variables are as defined in the present invention.
  • the above-mentioned ring B is selected from Other variables are as defined in the present invention.
  • R 3 -L 1 - is selected from H
  • Other variables are as defined in the present invention.
  • R 3 -L 1 - is selected from H
  • Other variables are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • R 1 , R 2 , R 3 and L 1 are as defined in the present invention.
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • R 1 , R 2 , R 4 , R c and R d are as defined in the present invention.
  • the present invention also provides a compound represented by the following formula or a pharmaceutically acceptable salt thereof,
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is selected from:
  • the above-mentioned compound or a pharmaceutically acceptable salt thereof is used in the preparation of drugs related to ATM inhibitors.
  • the above application is characterized in that the ATM inhibitor-related drugs are drugs for tumors.
  • the compound of the present invention has a significant ATM kinase inhibitory effect and excellent pharmacokinetic properties; the compound of the present invention has a weak degree of inhibition of the five CYP isoenzymes.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms that are within the scope of reliable medical judgment and are suitable for use in contact with human and animal tissues. , Without excessive toxicity, irritation, allergic reactions or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of the compound of the present invention, which is prepared from the compound with specific substituents discovered in the present invention and a relatively non-toxic acid or base.
  • a base addition salt can be obtained by contacting the compound with a sufficient amount of base in a pure solution or a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amine or magnesium salt or similar salts.
  • the acid addition salt can be obtained by contacting the compound with a sufficient amount of acid in a pure solution or a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, hydrogen carbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydroiodic acid, phosphorous acid, etc.; and organic acid salts, the organic acid includes, for example, acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , And salts of organic acids such as glucuronic acid. Certain specific compounds of the present invention contain basic and
  • the pharmaceutically acceptable salt of the present invention can be synthesized from the parent compound containing acid or base by conventional chemical methods. In general, such salts are prepared by reacting these compounds in free acid or base form with a stoichiometric amount of appropriate base or acid in water or organic solvent or a mixture of both.
  • the compounds of the present invention may exist in specific geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers Isomers, (D)-isomers, (L)-isomers, and their racemic mixtures and other mixtures, such as enantiomers or diastereomer-enriched mixtures, all of these mixtures belong to this Within the scope of the invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All these isomers and their mixtures are included in the scope of the present invention.
  • enantiomer or “optical isomer” refers to stereoisomers that are mirror images of each other.
  • cis-trans isomer or “geometric isomer” is caused by the inability to freely rotate the double bond or the single bond of the ring-forming carbon atom.
  • diastereomer refers to a stereoisomer in which the molecule has two or more chiral centers and the relationship between the molecules is non-mirror-image relationship.
  • wedge-shaped solid line keys And wedge-shaped dashed key Represents the absolute configuration of a solid center, with a straight solid line key And straight dashed key Indicates the relative configuration of the three-dimensional center, using wavy lines Represents a wedge-shaped solid line key Or wedge-shaped dashed key Or use wavy lines Represents a straight solid line key Or straight dashed key
  • the terms “enriched in one isomer”, “enriched in isomers”, “enriched in one enantiomer” or “enriched in enantiomers” refer to one of the isomers or pairs of
  • the content of the enantiomer is less than 100%, and the content of the isomer or enantiomer is greater than or equal to 60%, or greater than or equal to 70%, or greater than or equal to 80%, or greater than or equal to 90%, or greater than or equal to 95%, or 96% or greater, or 97% or greater, or 98% or greater, or 99% or greater, or 99.5% or greater, or 99.6% or greater, or 99.7% or greater, or 99.8% or greater, or greater than or equal 99.9%.
  • the term “isomer excess” or “enantiomeric excess” refers to the difference between the relative percentages of two isomers or two enantiomers. For example, if the content of one isomer or enantiomer is 90%, and the content of the other isomer or enantiomer is 10%, the isomer or enantiomer excess (ee value) is 80% .
  • optically active (R)- and (S)-isomers and D and L isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If you want to obtain an enantiomer of a compound of the present invention, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure The desired enantiomer.
  • the molecule when the molecule contains a basic functional group (such as an amino group) or an acidic functional group (such as a carboxyl group), it forms a diastereomeric salt with an appropriate optically active acid or base, and then passes through a conventional method known in the art The diastereoisomers are resolved, and then the pure enantiomers are recovered.
  • the separation of enantiomers and diastereomers is usually accomplished through the use of chromatography, which uses a chiral stationary phase and is optionally combined with chemical derivatization (for example, the formation of amino groups from amines). Formate).
  • the compound of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms constituting the compound.
  • compounds can be labeled with radioisotopes, such as tritium ( 3 H), iodine-125 ( 125 I), or C-14 ( 14 C).
  • deuterium can be substituted for hydrogen to form deuterated drugs.
  • the bond formed by deuterium and carbon is stronger than the bond formed by ordinary hydrogen and carbon.
  • deuterated drugs can reduce toxic side effects and increase drug stability. , Enhance the efficacy, prolong the biological half-life of drugs and other advantages. All changes in the isotopic composition of the compounds of the present invention, whether radioactive or not, are included in the scope of the present invention.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by substituents, and may include deuterium and hydrogen variants, as long as the valence of the specific atom is normal and the substituted compound is stable of.
  • oxygen it means that two hydrogen atoms are replaced. Oxygen substitution does not occur on aromatic groups.
  • optionally substituted means that it can be substituted or unsubstituted. Unless otherwise specified, the type and number of substituents can be arbitrary on the basis that they can be chemically realized.
  • any variable such as R
  • its definition in each case is independent.
  • the group can optionally be substituted with up to two Rs, and R has independent options in each case.
  • combinations of substituents and/or variants thereof are only permitted if such combinations result in stable compounds.
  • linking group When the number of a linking group is 0, such as -(CRR) 0 -, it means that the linking group is a single bond.
  • the substituent can be bonded to any atom on the ring, for example, a structural unit It means that the substituent R can be substituted at any position on the cyclohexyl or cyclohexadiene.
  • substituents do not indicate which atom is connected to the substituted group, such substituents can be bonded via any atom.
  • a pyridyl group can pass through any one of the pyridine ring as a substituent. The carbon atom is attached to the substituted group.
  • the middle linking group L is -MW-, at this time -MW- can be formed by connecting ring A and ring B in the same direction as the reading order from left to right It can also be formed by connecting ring A and ring B in the direction opposite to the reading order from left to right Combinations of the linking groups, substituents, and/or variants thereof are only permitted if such combinations result in stable compounds.
  • any one or more sites of the group can be connected to other groups through chemical bonds.
  • the connection method of the chemical bond is not positioned, and there is a H atom at the connectable site, when the chemical bond is connected, the number of H atoms at the site will correspondingly decrease with the number of chemical bonds connected to become the corresponding valence number ⁇ The group.
  • the chemical bond between the site and other groups can be a straight solid bond Straight dashed key Or wavy line Said.
  • the straight solid bond in -OCH 3 means that it is connected to other groups through the oxygen atom in the group;
  • the straight dashed bond in indicates that the two ends of the nitrogen atom in the group are connected to other groups;
  • the wavy line in represents the connection to other groups through the 1 and 2 carbon atoms in the phenyl group;
  • the number of atoms in a ring is generally defined as the number of ring members.
  • “5-7 membered ring” refers to a “ring” in which 5-7 atoms are arranged around.
  • C 1-3 alkyl is used to indicate a linear or branched saturated hydrocarbon group composed of 1 to 3 carbon atoms.
  • the C 1-3 alkyl group includes C 1-2 and C 2-3 alkyl groups, etc.; it can be monovalent (such as methyl), divalent (such as methylene) or multivalent (such as methine) .
  • Examples of C 1-3 alkyl include, but are not limited to, methyl (Me), ethyl (Et), propyl (including n-propyl and isopropyl), 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 an oxygen atom.
  • the C 1-3 alkoxy group includes C 1-2 , C 2-3 , C 3 and C 2 alkoxy groups and the like.
  • Examples of C 1-3 alkoxy include, but are not limited to, methoxy, ethoxy, propoxy (including n-propoxy and isopropoxy) and the like.
  • 5-6 membered heteroaryl ring and “5-6 membered heteroaryl group” can be used interchangeably in the present invention.
  • the term “5-6 membered heteroaryl group” means a ring consisting of 5 to 6 ring atoms. It is composed of a monocyclic group with a conjugated ⁇ -electron system, in which 1, 2, 3 or 4 ring atoms are heteroatoms independently selected from O, S and N, and the rest are carbon atoms. Where the nitrogen atom is optionally quaternized, the nitrogen and sulfur heteroatoms may optionally be oxidized (ie NO and S(O) p , p is 1 or 2).
  • the 5-6 membered heteroaryl group can be attached to the rest of the molecule through a heteroatom or a carbon atom.
  • the 5-6 membered heteroaryl group includes 5-membered and 6-membered heteroaryl groups.
  • Examples of the 5-6 membered heteroaryl include, but are not limited to, pyrrolyl (including N-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, etc.), pyrazolyl (including 2-pyrazolyl and 3-pyrrolyl, etc.) Azolyl, etc.), imidazolyl (including N-imidazolyl, 2-imidazolyl, 4-imidazolyl and 5-imidazolyl, etc.), oxazolyl (including 2-oxazolyl, 4-oxazolyl and 5- Oxazolyl, etc.), triazolyl (1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-triazolyl and 4H-1, 2,
  • protecting group includes, but is not limited to, "amino protecting group", “hydroxy protecting group” or “thiol protecting group”.
  • amino protecting group refers to a protecting group suitable for preventing side reactions at the amino nitrogen position.
  • Representative amino protecting groups include, but are not limited to: formyl; acyl, such as alkanoyl (such as acetyl, trichloroacetyl or trifluoroacetyl); alkoxycarbonyl, such as tert-butoxycarbonyl (Boc) ; Arylmethyloxycarbonyl, such as benzyloxycarbonyl (Cbz) and 9-fluorenylmethyloxycarbonyl (Fmoc); arylmethyl, such as benzyl (Bn), trityl (Tr), 1,1-di -(4'-Methoxyphenyl)methyl; silyl group, such as trimethylsilyl (TMS) and tert-butyldi
  • hydroxyl protecting group refers to a protecting group suitable for preventing side reactions of the hydroxyl group.
  • Representative hydroxy protecting groups include but are not limited to: alkyl groups, such as methyl, ethyl, and tert-butyl; acyl groups, such as alkanoyl groups (such as acetyl); arylmethyl groups, such as benzyl (Bn), p-methyl Oxybenzyl (PMB), 9-fluorenylmethyl (Fm) and diphenylmethyl (diphenylmethyl, DPM); silyl groups such as trimethylsilyl (TMS) and tert-butyl Dimethylsilyl (TBS) and so on.
  • alkyl groups such as methyl, ethyl, and tert-butyl
  • acyl groups such as alkanoyl groups (such as acetyl)
  • arylmethyl groups such as benzyl (Bn), p-methyl 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 well known to those skilled in the art Equivalent alternatives, preferred implementations include but are not limited to the embodiments of the present invention.
  • the structure of the compound of the present invention can be confirmed by conventional methods well known to those skilled in the art. If the present invention relates to the absolute configuration of the compound, the absolute configuration can be confirmed by conventional technical means in the art.
  • the single crystal X-ray diffraction method uses the Bruker D8 venture diffractometer to collect the diffraction intensity data of the cultured single crystal.
  • the light source is CuK ⁇ radiation
  • the scanning method After scanning and collecting relevant data, the direct method (Shelxs97) is further used to analyze the crystal structure to confirm the absolute configuration.
  • the solvent used in the present invention is commercially available.
  • the reactant 1-B (230mg, 761.27 ⁇ mol) was dissolved in dichloromethane (5mL), tetrabutylammonium bromide (12.27mg, 38.06 ⁇ mol), sodium hydroxide (60.90mg, 1.52mmol) in water ( 5mL) solution, slowly dropped into dichloromethane (5mL) solution of methyl iodide (324.16mg, 2.28mmol, 142.18 ⁇ L) under stirring at 35°C, and the mixed system was stirred at 35°C under nitrogen atmosphere for 12 hours.
  • reaction solution was dispersed in 100 mL of water, extracted with dichloromethane (50 mL*3), the organic phase was collected, and concentrated under reduced pressure at 45°C to obtain the crude product, which was subjected to column chromatography ( 40 g (0-20% THF/PE) was separated and purified to obtain compound 1-C.
  • the crude product was separated and purified by column chromatography (0-10% methanol/dichloromethane) After preparative high performance liquid chromatography (acidic, mobile phase: acetonitrile-water), the product was obtained.
  • the product was dissolved in ammonia (1.82g, 51.93mmol, 2mL), adjusted the pH to alkaline, and used dichloromethane (50mL *2) Extract, collect the organic phase, and concentrate under reduced pressure to obtain compound 1.
  • Acetic acid 52.50 g, 874.27 mmol, 50.00 mL was added to compound 4-A (5 g, 12.62 mmol), iron powder (4.23 g, 75.73 mmol) was slowly added in batches, and stirred at 40°C for 5 hours. Quench with 20mL concentrated hydrochloric acid, adjust the pH to 7 ⁇ 8 with 4M sodium hydroxide aqueous solution, filter to remove iron powder to obtain the crude product, and the crude product is passed through the automatic column machine ( 40g 0-50% tetrahydrofuran/dichloromethane) was separated and purified to obtain compound 4-B.
  • the automatic column machine 40g 0-50% tetrahydrofuran/dichloromethane
  • reaction solution was dispersed in 100 mL of water, extracted with dichloromethane (50 mL*3), the organic phase was collected, and concentrated under reduced pressure at 45°C to obtain the crude product. 40g (0-20% tetrahydrofuran/petroleum ether) was separated and purified to obtain compound 4-C.
  • AD_IPA_DEA_5_40_4ML_4MIN_5CM column: Chiralpak AD-3 ID, 3 ⁇ m, mobile phase: A: CO 2 B: isopropanol (0.05% diethylamine), gradient: B rises from 5% to 40% in 2 minutes, keeps 40% for 1.2 minutes, and then in 0.8 minutes Reduced to 5%, flow rate: 4mL/min, column temperature: 35°C, column pressure: 1500psi), retention time: 1.979 min, isomer excess: 96.48%.
  • AD_IPA_DEA_5_40_4ML_4MIN_5CM column: Chiralpak AD-3 ID, 3 ⁇ m, mobile phase: A: CO 2 B: isopropanol (0.05% diethylamine), gradient: B rises from 5% to 40% in 2 minutes, keeps 40% for 1.2 minutes, and then in 0.8 minutes Reduced to 5%, flow rate: 4mL/min, column temperature: 35°C, column pressure: 1500psi), retention time: 2.186min, isomer excess: 97.74%.
  • Compound 7 Analysis method: IC_IPA_DEA_50_28ML_10CM (column: Chiralpak IC-3 ID, 3 ⁇ m, mobile phase: A: CO 2 B: isopropanol (0.05% diethylamine), gradient: 50% B, flow rate: 2.8 mL/min, column temperature: 35°C, column pressure: 1500 psi), retention Time: 5.016 min, isomer excess: 97.84%.
  • Compound 8 Analysis method: IC_IPA_DEA_50_28ML_10CM (column: Chiralpak IC-3 ID, 3 ⁇ m, mobile phase: A: CO 2 B: isopropanol (0.05% diethylamine), gradient: 50% B, flow rate: 2.8 mL/min, column temperature: 35°C, column pressure: 1500 psi), retention Time: 8.986 min, isomer excess: 100%.
  • compound 10 was prepared in the same manner as compound 9 in Example 9.
  • the compound 12-B was prepared in the same manner as in Example 11 for preparing compound 11-B.
  • the compound 12-C was prepared by the same method as the compound 11-C in Example 11.
  • compound 12 was prepared in the same manner as compound 9 in Example 9.
  • the compound 14-C was prepared by the same method as the compound 1-A in Example 1, except that the corresponding raw materials were used.
  • the compound 14-D was prepared by the same method as the compound 1-B in Example 1.
  • the reactant 14-D (470mg, 1.42mmol) was dissolved in dichloromethane (5mL), tetrabutylammonium bromide (22.81mg, 70.75 ⁇ mol) and potassium carbonate (782.25mg, 5.66mmol) in water (5mL) were added ) Solution, slowly drop iodomethane (1.00 g, 7.08 mmol) with stirring, and the mixed system was stirred at 35° C. under a nitrogen atmosphere for 16 hours.
  • the reaction solution was dispersed in 20 mL of water, extracted with dichloromethane (10 mL*3), the organic phase was collected, and the organic phase was concentrated under reduced pressure to obtain 14-E, which was used directly in the next step.
  • Compound 14 was prepared in the same manner as compound 9 in Example 9 except for using the corresponding raw materials.
  • compound 15 was prepared in the same manner as in Example 9 for preparing compound 9.
  • the compounds of the present invention used for experiments are all self-made, and their chemical names and structural formulas are shown in the preparation examples of each compound.
  • the experimental test was carried out by Eurofins in the UK, and the experimental results were provided by the company. The following experimental procedures were also provided by the company.
  • Human-derived ATM kinase was incubated in a buffer solution containing 30 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 about 30 minutes of incubation at room temperature, add stop solution containing EDTA to terminate the reaction. Finally, for phosphorylated p53, a detection buffer containing d2-labeled anti-GST monoclonal antibody and europium-labeled phosphorylated Ser15 antibody was added.
  • HTRF homogeneous time-resolved fluorescence
  • the compound of the present invention has a significant inhibitory effect on ATM kinase.
  • the experimental test was carried out in Shanghai WuXi AppTec New Drug Development Co., Ltd.
  • the experimental results were provided by the company, and the following experimental procedures were also provided by the company.
  • the purpose of the research project is to use a 5-in-1 probe substrate of CYP isoenzymes to evaluate the inhibitory properties of the test product on human liver microsomal cytochrome P450 isoenzymes (CYP1A2, CYP2C9, CYP2C19, CYP2D6 and CYP3A4).
  • HMM human liver microsomes
  • the compound of the present invention has a weak degree of inhibition of the five CYP isozymes.
  • the compounds of the present invention for experiments are all self-made, and their chemical names and structural formulas are shown in the preparation examples of each compound.
  • the experimental tests were carried out in Shanghai WuXi AppTec New Drug Development Co., Ltd.
  • the experimental results were provided by the company.
  • the following experimental procedures were also provided by The company provides.
  • the aim was to investigate the plasma pharmacokinetics of the drug in female Balb/c-nude mice after a single intravenous bolus injection and intragastric administration of the compound of the present invention.
  • mice Female, 15-20g, 7-9 weeks old, fasting
  • the rodent pharmacokinetic characteristics of the compound after intravenous injection and oral administration were tested by standard protocols.
  • the candidate compound was prepared as a clear solution and given to mice by a single intravenous injection and oral administration.
  • the vehicle for intravenous injection and oral administration is 10% DMSO/90% (30% sulfobutyl cyclodextrin).
  • the compound of the present invention has excellent pharmacokinetic properties.

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Abstract

一类作为ATM抑制剂的有取代的喹啉吡咯酮类化合物，及其在制备ATM抑制剂相关疾病的药物中的应用。具体公开了式(I)所示化合物或其药学上可接受的盐。

Description

作为ATM抑制剂的有取代的喹啉吡咯酮类合物及其应用
本申请主张如下优先权
CN201911136079.X，申请日：2019-11-19；
CN202010633529.2，申请日：2020-07-01。
技术领域
本发明涉及一类作为ATM抑制剂的有取代的喹啉吡咯酮类化合物，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(I)所示化合物或其药学上可接受的盐。
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，临床前以及临床研究中均已出现与放疗联用，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，阿斯利康的另一个ATM抑制剂AZD1390和德国默克的M-3541也相继进入一期 临床的研究。
发明内容
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2020129838-appb-000001
其中，
R 1选自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 a取代；
R 2选自H、F、Cl、Br、I、OH、NH 2、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 3选自H和N(R c)(R d)；
R 4选自F、CN和OH；
L 1选自单键、-(CH 2) m-、-(CH 2) m-O-和-(CH 2) m-O-CH 2-；
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 e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和任选被1、2或3个R取代的C 1-3烷基；
或者，R c、R d和与它们连接的N原子共同构成任选被1、2或3个R取代的
Figure PCTCN2020129838-appb-000002
R e分别独立地选自H、F、Cl、Br、I和CH 3；
n选自0、1和2；
R分别独立地选自F、Cl、Br、I、OH和NH 2。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2020129838-appb-000003
其中，
R 1选自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 a取代；
R 2选自H、F、Cl、Br、I、OH、NH 2、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 3选自H和N(R c)(R d)；
R 4选自F、CN和OH；
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 e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和任选被1、2或3个R取代的C 1-3烷基；
或者，R c、R d和与它们连接的N原子共同构成任选被1、2或3个R取代的
Figure PCTCN2020129838-appb-000004
R e分别独立地选自H、F、Cl、Br、I和CH 3；
n选自0、1和2；
R分别独立地选自F、Cl、Br、I、OH和NH 2。
本发明提供了式(I)所示化合物或其药学上可接受的盐，
Figure PCTCN2020129838-appb-000005
其中，
R 1选自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 a取代；
R 2选自H、F、Cl、Br、I、OH、NH 2、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 3选自H和N(R c)(R d)；
R 4选自F、CN和OH；
L 1选自单键、-(CH 2) m-和-(CH 2) m-O-；
m选自1、2、3和4；
环B选自苯基和吡啶基，所述苯基和吡啶基任选被1、2或3个R e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和任选被1、2或3个R取代的C 1-3烷基；
或者，R c、R d和与它们连接的N原子共同构成任选被1、2或3个R取代的
Figure PCTCN2020129838-appb-000006
R e选自H、F、Cl、Br、I和CH 3；
n选自0、1和2；
R选自F、Cl、Br、I、OH和NH 2。
本发明的一些方案中，上述R 1选自CH 3、CH 2CH 3和OCH 3，所述CH 3、CH 2CH 3和OCH 3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OCH 3，其他变量如本发明所定义。
本发明的一些方案中，上述R 2选自H、F、Cl、Br、I、OH、NH 2、CH 3、CH 2CH 3和OCH 3，所述CH 3、CH 2CH 3和OCH 3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 2选自H、F、Cl、Br、I、OH、NH 2、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和OCH 3，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H、CH 3和CH 2CH 3，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H和CH 3，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被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 PCTCN2020129838-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 c、R d和与它们连接的N原子共同构成
Figure PCTCN2020129838-appb-000008
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、N(CH 3) 2、N(CH 2CH 3) 2、
Figure PCTCN2020129838-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 3选自H、N(CH 3) 2和
Figure PCTCN2020129838-appb-000010
其他变量如本发明所定义。
本发明的一些方案中，上述L 1选自单键、-CH 2CH 2CH 2O-、-OCH 2-和-CH 2CH 2OCH 2-，其他变量如本发明所定义。
本发明的一些方案中，上述L 1选自单键、-CH 2CH 2CH 2O-和-OCH 2-，其他变量如本发明所定义。
本发明的一些方案中，上述环B选自苯基和吡啶基，所述苯基和吡啶基任选被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，上述环B选自
Figure PCTCN2020129838-appb-000011
所述
Figure PCTCN2020129838-appb-000012
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，上述环B选自
Figure PCTCN2020129838-appb-000013
其他变量如本发明所定义。
本发明的一些方案中，上述R 3-L 1-选自H、
Figure PCTCN2020129838-appb-000014
Figure PCTCN2020129838-appb-000015
其他变量如本发明所定义。
本发明的一些方案中，上述R 3-L 1-选自H、
Figure PCTCN2020129838-appb-000016
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，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2020129838-appb-000017
其中，
R 1、R 2、R 3和L 1如本发明所定义。
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2020129838-appb-000018
其中，
R 1、R 2、R 4、R c和R d如本发明所定义。
本发明还提供了下式所示化合物或其药学上可接受的盐，
Figure PCTCN2020129838-appb-000019
Figure PCTCN2020129838-appb-000020
本发明的一些方案中，上述化合物或其药学上可接受的盐，其选自：
Figure PCTCN2020129838-appb-000021
本发明的一些方案中，上述化合物或其药学上可接受的盐在制备ATM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抑制剂相关药物是用于肿瘤的药物。
技术效果
本发明化合物具有显著的ATM激酶抑制作用和优异的药代动力学性质；本发明化合物对五个CYP同工酶抑制程度均较弱。
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接触的方式获得碱加成盐。药学上可接受的碱加成盐包括钠、钾、钙、铵、有机胺或镁盐或类似的盐。当本发明的化合物中含有相对碱性的官能团时，可以通过在纯的溶液或合适的惰性溶剂中用足够量的酸与这类化合物接触的方式获得酸加成盐。药学上可接受的酸加成盐的实例包括无机酸盐，所述无机酸包括例如盐酸、氢溴酸、硝酸、碳酸，碳酸氢根，磷酸、磷酸一氢根、磷酸二氢根、硫酸、硫酸氢根、氢碘酸、亚磷酸等；以及有机酸盐，所述有机酸包括如乙酸、丙酸、异丁酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、反丁烯二酸、乳酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸和甲磺酸等类似的酸；还包括氨基酸(如精氨酸等)的盐，以及如葡糖醛酸等有机酸的盐。本发明的某些特定的化合物含有碱性和酸性的官能团，从而可以被转换成任一碱或酸加成盐。
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。
除非另有说明，术语“异构体”意在包括几何异构体、顺反异构体、立体异构体、对映异构体、旋光异构体、非对映异构体和互变异构体。
本发明的化合物可以存在特定的几何或立体异构体形式。本发明设想所有的这类化合物，包括顺式和反式异构体、(-)-和(+)-对映体、(R)-和(S)-对映体、非对映异构体、(D)-异构体、(L)-异构体，及其外消旋混合物和其他混合物，例如对映异构体或非对映体富集的混合物，所有这些混合物都属于本发明的范围之内。烷基等取代基中可存在另外的不对称碳原子。所有这些异构体以及它们的混合物，均包括在本发明的范围之内。
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，“(+)”表示右旋，“(-)”表示左旋，“(±)”表示外消旋。
除非另有说明，用楔形实线键
Figure PCTCN2020129838-appb-000022
和楔形虚线键
Figure PCTCN2020129838-appb-000023
表示一个立体中心的绝对构型，用直形实线键
Figure PCTCN2020129838-appb-000024
和直形虚线键
Figure PCTCN2020129838-appb-000025
表示立体中心的相对构型，用波浪线
Figure PCTCN2020129838-appb-000026
表示楔形实线键
Figure PCTCN2020129838-appb-000027
或楔形虚线键
Figure PCTCN2020129838-appb-000028
或用波浪线
Figure PCTCN2020129838-appb-000029
表示直形实线键
Figure PCTCN2020129838-appb-000030
或直形虚线键
Figure PCTCN2020129838-appb-000031
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。
术语“任选”或“任选地”指的是随后描述的事件或状况可能但不是必需出现的，并且该描述包括其中所述事件或状况发生的情况以及所述事件或状况不发生的情况。
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。
当一个取代基数量为0时，表示该取代基是不存在的，比如-A-(R) 0表示该结构实际上是-A。
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。
当一个取代基的键可以交叉连接到一个环上的两一个以上原子时，这种取代基可以与这个环上的任意原子相键合，例如，结构单元
Figure PCTCN2020129838-appb-000032
表示其取代基R可在环己基或者环己二烯上的任意一个位置发生取代。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 PCTCN2020129838-appb-000033
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 PCTCN2020129838-appb-000034
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 PCTCN2020129838-appb-000035
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，当某一基团具有一个或多个可连接位点时，该基团的任意一个或多个位点可以通过化学键与其他基团相连。当该化学键的连接方式是不定位的，且可连接位点存在H原子时，则连接化学键时，该位点的H原子的个数会随所连接化学键的个数而对应减少变成相应价数的基团。所述位点与其他基团连接的化学键可以用直形实线键
Figure PCTCN2020129838-appb-000036
直形虚线键
Figure PCTCN2020129838-appb-000037
或波浪线
Figure PCTCN2020129838-appb-000038
表示。例如-OCH 3中的直形实线键表示通过该基团中的氧原子与其他基团相连；
Figure PCTCN2020129838-appb-000039
中的直形虚线键表示通过该基团中的氮原子的两端与其他基团相连；
Figure PCTCN2020129838-appb-000040
中的波浪线表示通过该苯基基团中的1和2位碳原子与其他基团相连；
Figure PCTCN2020129838-appb-000041
表示该哌啶基上的任意可连接位点可以通过1个化学键与其他 基团相连，至少包括
Figure PCTCN2020129838-appb-000042
这4种连接方式，即使-N-上画出了H原子，但是
Figure PCTCN2020129838-appb-000043
仍包括
Figure PCTCN2020129838-appb-000044
这种连接方式的基团，只是在连接1个化学键时，该位点的的H会对应减少1个变成相应的一价哌啶基。
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 1-3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 1-3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，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)。
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。
本发明的化合物可以通过本领域技术人员所熟知的常规方法来确认结构，如果本发明涉及化合物的绝对构型，则该绝对构型可以通过本领域常规技术手段予以确证。例如单晶X射线衍射法(SXRD)，把培养出的单晶用Bruker D8 venture衍射仪收集衍射强度数据，光源为CuKα辐射，扫描方式：
Figure PCTCN2020129838-appb-000045
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；DMF代表N,N-二甲基甲酰胺；THF代表四氢呋喃；eq代表当量、等量；DCM代表二氯甲烷；PE代表石油醚；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；r.t.代表室温；O/N代表过夜；THF代表四氢呋喃；Boc 2O代表二叔丁氧基二碳酸酯；TFA代表三氟乙酸；DIPEA代表二异丙基乙基胺；iPrOH代表2-丙醇；mp代表熔点；SOCl 2代表氯化亚砜；NBS代表N-溴代丁二酰亚胺；Pd(PPh 3) 4代表四三苯基膦钯；代表Pd(dppf)Cl 2代表[1,1'-双(二苯基膦基)二茂铁]二氯化钯；Xphos代表2-二环己基磷-2',4',6'-三异丙基联苯；Pd 2(dba) 3代表三(二亚苄基丙酮)二钯。
化合物依据本领域常规命名原则或者使用
Figure PCTCN2020129838-appb-000046
软件命名，市售化合物采用供应商目录名称。
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。
参考例1：中间体A的制备
Figure PCTCN2020129838-appb-000047
合成路线：
Figure PCTCN2020129838-appb-000048
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得到粗品中间体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)。
参考例2：中间体B的制备
Figure PCTCN2020129838-appb-000049
合成路线：
Figure PCTCN2020129838-appb-000050
步骤1：化合物B-3的合成
将B-1(500g,2.78mol,292.40mL)，B-2(447.62g,3.06mol,1.1eq)溶于DMSO(1500mL)中，向其中加入碳酸铯(1.81kg,5.57mol)，反应在65-75℃下搅拌64小时。将反应液分批、缓慢加入到水(6L)中，10-25℃下搅拌3小时。减压抽滤，滤饼中加入水(1.4L)和乙腈(130mL)搅拌，减压抽滤，收集滤饼并用水(400mL*3)洗涤，滤饼在40℃下真空干燥箱敞口烘干至恒重，得到化合物B-3。
MS m/z:298.7[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ8.25(d,J＝2.5Hz,1H),7.87(dd,J＝2.8,8.8Hz,1H),6.80(d,J＝8.8Hz,1H),4.23(t,J＝6.7Hz,2H),2.37-2.25(m,6H),1.83(quin,J＝6.9Hz,2H),1.47(quin,J＝5.5Hz,4H),1.40-1.30(m,2H)。
步骤2：化合物B的合成
将B-3加入到THF(2000mL)中，搅拌溶解，乙酸乙酯干冰浴降温至-65℃。氮气保护下，将正丁基锂(2.5M,641.70mL)缓慢滴加至反应液液中，滴加过程控制反应液温度-65℃至-55℃，滴加完毕搅拌1小时。之后在氮气保护下，将硼酸三异丙酯(307.87g,1.60mol,376.37mL)滴加至反应液中，滴加完毕，反应液自然升温至室温约15℃，反应16小时。向反应液中加入170mL浓度2M的HCl溶液进行淬灭，淬灭温度控制在10～15℃；将混合液减压旋蒸以除去THF(2300mL)。然后向剩余混合物加入1250mL浓度2M的HCl溶液调节pH至5.5～6，通过pH监测范围为5.5-9的精密pH试纸监测。15℃下搅拌0.5小时后，有固体析出，减压抽滤收集粗品。向粗品中加入1200mL乙腈，搅拌12小时后，减压抽滤收集滤饼，将滤饼减压旋蒸至恒重；再次加入1200mL乙腈，搅拌48小时后，减压抽滤收集滤饼，减压旋蒸至恒重，得到中间体B。
MS m/z:264.9[M+H] +；
1H NMR(400MHz,DMSO-d 6)δ9.91(br s,1H),8.51(d,J＝1.5Hz,1H),8.14(s,1H),8.02(dd,J＝2.0,8.3Hz,1H),6.76(d,J＝8.3Hz,1H),4.33(t,J＝6.1Hz,2H),3.44(br d,J＝11.5Hz,2H),3.19-3.11(m,2H),2.92-2.80(m,2H),2.21-2.12(m,2H),1.86-1.71(m,4H),1.68(br s,1H),1.46-1.29(m,1H)。
参考例3：中间体C的制备
Figure PCTCN2020129838-appb-000051
合成路线：
Figure PCTCN2020129838-appb-000052
步骤1：化合物C-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C-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，得到化合物C-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C-4的合成
在圆底烧瓶中，将硝基甲烷(18g,294.89mmol,15.93mL)(C-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，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C-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，得到残留固体，然后用乙腈(50mL)洗涤，得到化合物C-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3：化合物C-5的合成
在氮气保护下，将C-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C-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4：中间体C的合成
除了使用相应的原料外，以参考例1中制备中间体A相同的方法制备中间体C。
MS m/z:304.7[M+H] +。
实施例1
Figure PCTCN2020129838-appb-000053
合成路线：
Figure PCTCN2020129838-appb-000054
步骤1：化合物1-A的合成
将中间体A(2g,6.96mmol)溶于四氢呋喃(20mL)中，加入2-氰基丙酸乙酯(1.77g,13.91mmol)，碳酸钾(2.88g,20.87mmol)，混合体系在50℃氮气氛围下搅拌12小时。将反应液分散到200mL水中，用二氯甲烷萃取(300mL*3)，收集有机相，将有机相45℃减压浓缩得到粗产品，粗品经过柱层析(0～15％乙酸乙酯/石油醚)纯化，得到化合物1-A。
MS m/z:377.9[M+H] +。
步骤2：化合物1-B的合成
将化合物1-A(1.2g,3.17mmol)加入到四氢呋喃(20mL)中，加入氯化铵(1.02g,19.04mmol)的水(20mL)溶液，搅拌下分三批加入铁粉(1.06g,19.04mmol)，混合体系25℃室温搅拌12小时。反应液用硅藻土过滤，二氯甲烷(50mL)洗涤滤饼，滤饼中铁粉用2M盐酸淬灭后，用2M氢氧化钠水溶液调节pH＝7～8。滤液用二氯甲烷萃取(50mL*3)，收集有机相，45℃浓缩得到粗品，粗品经过柱层析(0～30％四氢呋喃/石油醚)纯化，得到化合物1-B。
MS m/z:301.8[M+H] +。
步骤3：化合物1-C的合成
将反应物1-B(230mg,761.27μmol)溶于二氯甲烷(5mL)中，加入四丁基溴化铵(12.27mg,38.06μmol)，氢氧化钠(60.90mg,1.52mmol)的水(5mL)溶液，35℃搅拌下缓慢滴入碘甲烷(324.16mg,2.28mmol,142.18μL)的二氯甲烷(5mL)溶液，混合体系在35℃氮气氛围下搅拌12小时。将反应液分散到100mL水中，用二氯甲烷(50mL*3)萃取，收集有机相，45℃减压浓缩得到粗品，经过柱层析(
Figure PCTCN2020129838-appb-000055
40g 0～20％THF/PE)分离纯化，得到化合物1-C。
MS m/z:315.9[M+H] +。
步骤4：化合物1的合成
将化合物1-C(100mg,316.30μmol)溶于二氧六环(10mL)和水(1mL)中，加入中间体B(125.32mg,474.45μmol)，碳酸钠(100.57mg,948.91μmol)，氮气氛围下加入四三苯基膦钯(36.55mg,31.63μmol)，混合体系在65℃氮气氛围下搅拌12小时。将反应液分散到100mL水中，用二氯甲烷(50mL*3)萃取，收集有机相，将有机相减压浓缩得到粗品，粗品经柱层析(0～10％甲醇/二氯甲烷)分离纯化，再经过制备高效液相色谱(酸性，流动相：乙腈-水)，得到产物，将产物溶于氨水(1.82g,51.93mmol,2mL)中，调节pH为碱性，用二氯甲烷(50mL*2)萃取，收集有机相，减压浓缩得到化合物1。
MS m/z:456.4[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.52(d,J＝2.3Hz,1H),8.23(d,J＝8.8Hz,1H),8.02(s,1H),7.95-7.84(m,2H),6.88(d,J＝8.5Hz,1H),4.41(t,J＝6.4Hz,2H),3.46(s,3H),2.59-2.50(m,2H),2.45(br s,4H),2.12-1.97(m,5H),1.69-1.53(m,4H),1.45(br s,2H)。
实施例2
Figure PCTCN2020129838-appb-000056
合成路线：
Figure PCTCN2020129838-appb-000057
步骤1：化合物2-A的合成
将化合物A(10g,34.78mmol)溶于四氢呋喃(100mL)中，加入2-甲基丙二酸二乙酯(6.66g,38.26mmol)，碳酸钾(9.61g,69.57mmol)，碘化钾(57.74mg,0.347mmol)，混合体系在60℃氮气氛围下搅拌12小时。将反应液分散到500mL水中，用二氯甲烷萃取(500mL*3)，收集有机相，将有机相45℃减压浓缩得到粗产品，粗品经过自动过柱机(
Figure PCTCN2020129838-appb-000058
80g，0～10％乙酸乙酯/石油醚)分离纯化，得到化合物2-A。
MS m/z:425.0[M+H] +。
步骤2：化合物2-B的合成
将化合物2-A(5g,11.76mmol)加入到四氢呋喃(50mL)中，加入氯化铵(3.77g,70.55mmol)的水(50mL)溶液，搅拌下分批加入锌粉(4.61g,70.55mmol)，混合体系70℃搅拌12小时。20℃下将反应液中加入水(300mL)溶液，用二氯甲烷(300mL)萃取，用水(300mL*3)洗涤有机相，收集有机相，45℃减压浓缩得到粗产品，经过自动过柱机(
Figure PCTCN2020129838-appb-000059
40g，0～20％四氢呋喃/二氯甲烷)分离纯化，得到化合物2-B。
MS m/z:348.9[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.83(s,1H),8.02-7.95(m,2H),7.68(dd,J＝2.0,9.0Hz,1H),4.26-4.13(m,2H),1.90(s,3H),1.14(t,J＝7.2Hz,3H)。
步骤3：化合物2-C的合成
将化合物2-B(1.6g,4.58mmol)溶于二甲亚砜(20mL)中，加入碳酸二甲酯(4.13g,45.82mmol)，碳酸钾(2.53g,18.33mmol)，混合体系在80℃搅拌16小时。将反应液自然冷却到室温后分散到200mL水中，二氯甲烷萃取(200mL*3)，收集有机相，再用水洗涤(500mL*3)，收集有机相，45℃减压浓缩得到粗产品，经过自动过柱机(
Figure PCTCN2020129838-appb-000060
40g，0～20％四氢呋喃/二氯甲烷)分离纯化，得到化合物2-C。
MS m/z:362.9[M+H] +。
步骤4：化合物2-D的合成
将化合物2-C(500mg,1.38mmol)溶于乙醇(10mL)中，加入氢氧化钠(550.65mg,13.77mmol)的H 2O(10mL)溶液，混合体系在25℃室温搅拌12小时，向反应液中加入1M盐酸调节pH＝7～8，乙酸乙酯(20mL*3)萃取，收集有机相，浓缩得到粗产品。粗品经过自动过柱机(
Figure PCTCN2020129838-appb-000061
12g，0～30％四氢呋喃/二氯甲烷)分离纯化，得到化合物2-D。
MS m/z:306.9[M+H] +。
步骤5：化合物2的合成
将化合物2-D(150mg,488.37μmol)溶于二氧六环(10mL)和水(1mL)中，加入中间体B(154.79mg,586.05μmol)，碳酸钠(155.29mg,1.47mmol)，氮气氛围下加入四三苯基膦钯(56.43mg,48.84μmol)，混合体系在80℃氮气氛围下搅拌32小时。将反应液分散到100mL水中，用二氯甲烷(50mL*3)萃取，收集有机相，将有机相45℃减压浓缩得到粗品，粗品经柱层析(0～10％甲醇/二氯甲烷)分离纯化， 再经过制备高效液相色谱(中性，流动相：乙腈-水)，得到化合物2。
MS m/z:447.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.68(d,J＝1.8Hz,1H),8.51(d,J＝2.0Hz,1H),8.25(s,1H),8.17(d,J＝8.8Hz,1H),7.92(dd,J＝2.3,8.5Hz,1H),7.81(br d,J＝8.8Hz,1H),6.84(d,J＝8.5Hz,1H),4.39(t,J＝6.1Hz,2H),3.38(s,3H),2.67-2.43(m,6H),2.10(br s,2H),1.85(s,3H),1.69(br s,4H),1.49(br s,2H)。
实施例3
Figure PCTCN2020129838-appb-000062
合成路线：
Figure PCTCN2020129838-appb-000063
步骤1：化合物3-A的合成
将化合物2-D(250mg,813.96μmol)溶于二氯甲烷(5mL)中，0℃氮气氛围下加入二乙氨基三氟化硫(656.01mg，4.07mmol，537.71μL)，混合体系在0℃搅拌1小时后，升高到20℃室温搅拌12小时。20℃下向反应液中加入水(10mL)，用二氯甲烷萃取(50mL*3)洗涤有机相，收集有机相，45℃减压浓缩得到粗产品，经过自动过柱机(
Figure PCTCN2020129838-appb-000064
24g，0～10％四氢呋喃/二氯甲烷)分离纯化，得到化合物3-A。
MS m/z:309.0[M+H] +。
步骤2：化合物3的合成
除了使用相应的原料外，以实施例2中制备化合物2相同的方法制备化合物3。
MS m/z:449.4[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.73(s,1H),8.49(d,J＝2.3Hz,1H),8.20(d,J＝8.8Hz,1H),8.05(s,1H),7.93(dd,J＝2.5,8.5Hz,1H),7.83(dd,J＝1.8,8.8Hz,1H),6.86(d,J＝8.5Hz,1H),4.46(t,J＝6.0Hz,2H),3.40(s,3H),3.08-2.86(m,6H),2.42-2.32(m,2H),2.04(d,J＝4.3Hz,2H),1.99(s,3H),1.62(br s,2H),1.28-1.21(m,2H)。
实施例4
Figure PCTCN2020129838-appb-000065
合成路线：
Figure PCTCN2020129838-appb-000066
步骤1：化合物4-A的合成
将中间体C(15g,49.10mmol)溶于THF(150mL)中，加入2-氰基丙酸乙酯(12.49g,98.20mmol)，碳酸钾(20.36g,147.31mmol)，混合体系在50℃氮气氛围下搅拌20小时。将反应液分散到500mL水中，用二氯甲烷萃取(500mL*3)，收集有机相，将有机相45℃减压浓缩得到粗产品，粗品经过自动过柱机(
Figure PCTCN2020129838-appb-000067
80g 0～15％乙酸乙酯/石油醚)分离纯化，得到化合物4-A。
MS m/z:395.9[M+H] +。
步骤2：化合物4-B的合成
向化合物4-A(5g,12.62mmol)中加入醋酸(52.50g,874.27mmol,50.00mL)，分批缓慢加入铁粉(4.23g,75.73mmol)，40℃搅拌5小时。用20mL浓盐酸淬灭，4M氢氧化钠水溶液调节pH到7～8，过滤除去铁粉得到粗品，粗品经过自动过柱机(
Figure PCTCN2020129838-appb-000068
40g 0～50％四氢呋喃/二氯甲烷)分离纯化，得到化合物4-B。
MS m/z:319.7[M+H] +。
步骤3：化合物4-C的合成
将化合物4-B(500mg,1.56mmol)溶于DCM(20mL)中，加入四丁基溴化铵(25.18mg,78.10μmol)，氢氧化钠(124.95mg,3.12mmol)的H 2O(20mL)溶液，40℃搅拌下缓慢滴入碘甲烷(1.11g,7.81mmol,)的DCM(10mL)溶液，混合体系在40℃氮气氛围下搅拌5小时。将反应液分散到100mL水中，用二氯甲烷(50mL*3)萃取，收集有机相，45℃减压浓缩得到粗品，经过自动过柱机(
Figure PCTCN2020129838-appb-000069
40g 0～20％四氢呋喃/石油醚)分离纯化，得到化合物4-C。
MS m/z:333.8[M+H] +。
步骤4：化合物4的合成
将化合物4-C溶于1,4-二氧六环(10mL)和H 2O(1mL)中，加入中间体B(177.85mg,673.36μmol)，碳酸钠(142.74mg,1.35mmol)，氮气氛围下加入四三苯基膦钯(51.87mg,44.89μmol)，混合体系在70℃氮气氛围下搅拌24小时。将反应液分散到100mL水中，用二氯甲烷(50mL*3)萃取,收集有机相，将有机相45℃减压浓缩得到粗品。粗品经过自动过柱机(
Figure PCTCN2020129838-appb-000070
20g 0～10％甲醇/二氯甲烷)分离纯化，再经过制备色谱(中性条件，乙腈-水)纯化，得到化合物4。
MS m/z:474.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.76(s,1H),8.44(s,1H),7.93(d,J＝3.8Hz,1H),7.91(d,J＝7.5Hz,1H),7.87(td,J＝2.2,8.7Hz,1H),6.88(d,J＝8.8Hz,1H),4.42(t,J＝6.4Hz,2H),3.46(s,3H),2.55-2.49(m,2H),2.44(br s,4H),2.08-2.04(m,1H),2.03(s,3H),2.00(br s,1H),1.61(quin,J＝5.5Hz,4H),1.45(br d,J＝4.8Hz,2H)。
实施例5
Figure PCTCN2020129838-appb-000071
合成路线：
Figure PCTCN2020129838-appb-000072
步骤1：化合物5和化合物6的合成
将化合物1(200mg,439.03μmol)通过SFC(色谱柱:DAICEL CHIRALPAK AD-H(250mm*30mm,5μm)；流动相:[0.1％NH 3H 2O IPA]；B(0.1％NH 3H 2O IPA)％:40％-40％)拆分得到化合物5和化合物6。
化合物5： 1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.53(d,J＝2.0Hz,1H),8.24(d,J＝8.8Hz,1H),8.02(d,J＝1.3Hz,1H),7.93(dd,J＝2.5,8.5Hz,1H),7.89(br d,J＝9.0Hz,1H),6.89(d,J＝8.5Hz,1H),4.42(t,J＝6.5Hz,2H),3.47(s,3H),2.56-2.49(m,2H),2.44(br s,4H),2.05(s,3H),1.82(br s,2H),1.66-1.58(m,4H),1.45(br s,2H)。
分析方法：AD_IPA_DEA_5_40_4ML_4MIN_5CM(色谱柱:Chiralpak AD-3
Figure PCTCN2020129838-appb-000073
I.D.,3μm，流动相:A:CO 2B:异丙醇(0.05％二乙胺)，梯度:B在2分钟内从5％升至40％，保持40％1.2分钟，然后在0.8分钟内降至5％，流速:4mL/min，柱温.:35℃，柱压:1500psi)，保留时间：1.979min，异构体过量：96.48％。
化合物6： 1H NMR(400MHz,CDCl 3)δ8.76(s,1H),8.52(d,J＝2.3Hz,1H),8.25(d,J＝8.8Hz,1H),8.02(d,J＝1.5Hz,1H),7.94(dd,J＝2.6,8.7Hz,1H),7.88(dd,J＝1.9,8.9Hz,1H),6.88(d,J＝8.3Hz,1H),4.45(t,J＝6.1Hz,2H),3.47(s,3H),2.83(br s,6H),2.26(br s,2H),2.06(s,3H),1.85(br s,4H),1.57(br s,2H)。
分析方法：AD_IPA_DEA_5_40_4ML_4MIN_5CM(色谱柱:Chiralpak AD-3
Figure PCTCN2020129838-appb-000074
I.D.,3μm，流动相:A:CO 2B:异丙醇(0.05％二乙胺)，梯度:B在2分钟内从5％升至40％，保持40％1.2分钟，然后在0.8分钟内降至5％，流速:4mL/min，柱温.:35℃，柱压:1500psi)，保留时间：2.186min，异构体过量：97.74％。
实施例7
Figure PCTCN2020129838-appb-000075
合成路线：
Figure PCTCN2020129838-appb-000076
步骤1：化合物7和化合物8的合成
将化合物4(44mg,92.92μmol)通过SFC(色谱柱:DAICEL CHIRALPAK IC(250mm*30mm,10μm)；流动相:[0.1％NH 3H 2O IPA]；B(0.1％NH 3H 2O IPA)％:55％-55％)拆分得到化合物7和化合物8。
化合物7：分析方法：IC_IPA_DEA_50_28ML_10CM(色谱柱:Chiralpak IC-3
Figure PCTCN2020129838-appb-000077
I.D.,3μm，流动相:A:CO 2B:异丙醇(0.05％二乙胺)，梯度:50％B，流速:2.8mL/min，柱温:35℃，柱压:1500psi)，保留时间：5.016min，异构体过量：97.84％。
化合物8：分析方法：IC_IPA_DEA_50_28ML_10CM(色谱柱:Chiralpak IC-3
Figure PCTCN2020129838-appb-000078
I.D.,3μm，流动相:A:CO 2B:异丙醇(0.05％二乙胺)，梯度:50％B，流速:2.8mL/min，柱温:35℃，柱压:1500psi)，保留时间：8.986min，异构体过量：100％。
实施例9
Figure PCTCN2020129838-appb-000079
合成路线：
Figure PCTCN2020129838-appb-000080
步骤1：化合物9-B的合成
在10℃条件下，将氢化钠(681.86mg,17.04mmol,60％纯度)加入到N,N-二甲基丙醇(9-A)(878.92 mg,8.52mmol,998.78μL)的DMF(15.00mL)溶液中，反应液在25℃下搅拌1小时。然后再在10℃下加入B-1(1.00g,5.68mmol,584.80μL)，反应体系升温至25℃并继续搅拌16小时。反应完毕，用水(5mL)淬灭，然后用二氯甲烷(10mL*3)萃取，再用水(10mL*2)洗涤，有机相无水硫酸钠干燥，过滤并浓缩，得到化合物9-B。
MS m/z:258.9[M+H] +。
步骤2：化合物9-C的合成
氮气保护下，将二氧六环(15.00mL)加入到9-B(530.00mg,2.05mmol)、双联频哪醇硼酸酯(780.87mg,3.08mmol)、Pd(dppf)Cl 2(150.00mg,205.00μmol)和KOAc(502.97mg,5.12mmol)的混合溶液中，反应体系在108℃下搅拌14小时。反应完毕后，加入水(5mL)淬灭，再用乙酸乙酯(30mL*3)萃取，用饱和氯化钠溶液(10mL)洗涤，有机相用无水硫酸钠干燥，过滤并浓缩，得到9-C。
MS m/z:307.2[M+H] +。
步骤3：化合物9的合成
向1-C(150mg,463.66μmol)的二氧六环(3mL)溶液中加入9-C(212.96mg,695.48μmol)，四三苯基膦钯(53.58mg,46.37μmol)，碳酸钠(147.43mg,1.39mmol,3eq)，水(1mL)，氮气置换三次，反应液在60℃搅拌2小时，将反应液直接减压浓缩得到粗品，经过柱层析(DCM：MeOH(滴加2mL氨水)＝40:1～10:1)纯化，再经过制备高效液相色谱(碱性条件，乙腈-水(0.05％氨水))纯化，得到化合物9。
MS m/z:416.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.52(d,J＝2.0Hz,1H),8.23(d,J＝9.0Hz,1H),8.01(d,J＝1.3Hz,1H),7.92(dd,J＝2.5,8.8Hz,1H),7.88(dd,J＝1.6,8.9Hz,1H),6.88(d,J＝8.8Hz,1H),4.42(t,J＝6.5Hz,2H),3.46(s,3H),2.48(t,J＝7.4Hz,2H),2.28(s,6H),2.05(s,3H),2.02-1.97(m,2H)。
实施例10
Figure PCTCN2020129838-appb-000081
合成路线：
Figure PCTCN2020129838-appb-000082
步骤1：化合物10的合成
除了使用相应的原料外，以实施例9中制备化合物9相同的方法制备化合物10。
MS m/z:434.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.76(s,1H),8.45(s,1H),7.94(d,J＝2.5Hz,1H),7.92(d,J＝6.3Hz,1H),7.88(td,J＝2.2,8.6Hz,1H),6.89(d,J＝8.5Hz,1H),4.44(t,J＝6.5Hz,2H),3.46(s,3H),2.52-2.46(m,2H),2.28(s,6H),2.03(s,3H),2.02-1.96(m,2H)。
实施例11
Figure PCTCN2020129838-appb-000083
合成路线：
Figure PCTCN2020129838-appb-000084
步骤1：化合物11-B的合成
于B-1(1g,5.68mmol)，11-A(807.56mg,6.25mmol)的二甲基亚砜(5mL)溶液中加入碳酸铯(3.70g,11.36mmol)，反应液在70℃搅拌16小时。室温下向反应液中加入50mL水，二氯甲烷(30mL*3)萃取，收集有机相，无水硫酸钠干燥，减压浓缩，得到褐色液体11-B直接用于下一步反应。
MS m/z:284.9[M+H] +。
步骤2：化合物11-C的合成
于11-B(1.8g,6.31mmol)的1,4-二氧六环(20mL)溶液中加入双联嚬哪醇硼酸酯(1.76g,6.94mmol)，醋酸钾(1.24g,12.62mmol)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(515.45mg,631.18μmol)，氮气保护下80℃搅拌6小时。得到11-C的反应液，直接用于下一步。
MS m/z:333.2[M+H] +。
步骤3：化合物11的合成
除了使用相应的原料外，以实施例9中制备化合物9相同的方法制备化合物11。
MS m/z:442.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.75(s,1H),8.52(d,J＝2.3Hz,1H),8.23(d,J＝9.0Hz,1H),8.01(d,J＝1.5Hz,1H),7.92(dd,J＝2.5,8.5Hz,1H),7.88(dd,J＝1.8,9.0Hz,1H),6.88(d,J＝8.8Hz,1H),4.44(t,J＝6.4Hz,2H),3.46(s,3H),2.70-2.62(m,2H),2.56(br s,4H),2.10-2.07(m,1H),2.05(s,3H),2.04-2.00(m,1H),1.80(br s,4H)。
实施例12
Figure PCTCN2020129838-appb-000085
合成路线：
Figure PCTCN2020129838-appb-000086
步骤1：化合物12-B的合成
除了使用相应的原料外，以实施例11中制备化合物11-B相同的方法制备化合物12-B。
MS m/z:286.9[M+H] +。
步骤2：化合物12-C的合成
除了使用相应的原料外，以实施例11中制备化合物11-C相同的方法制备化合物12-C。
MS m/z:335.1[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9中制备化合物9相同的方法制备化合物12。
MS m/z:444.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.74(s,1H),8.52(d,J＝1.8Hz,1H),8.23(d,J＝8.8Hz,1H),8.01(s,1H),7.92(dd,J＝2.3,8.8Hz,1H),7.88(br d,J＝9.0Hz,1H),6.88(d,J＝8.5Hz,1H),4.41(t,J＝6.3Hz,2H),3.46(s,3H),2.64(br t,J＝7.4Hz,2H),2.57(q,J＝7.2Hz,4H),2.05(s,3H),1.97(quin,J＝6.8Hz,2H),1.05(t,J＝7.2Hz,6H)。
实施例13
Figure PCTCN2020129838-appb-000087
合成路线：
Figure PCTCN2020129838-appb-000088
步骤1：化合物13-B的合成
-10℃于13-A(950mg,5.05mmol)的二氯甲烷(10mL)溶液中加入三乙胺(1.02g,10.11mmol)，然后缓慢加入甲磺酸酐(1.54g,8.84mmol)，反应液在-10℃搅拌1小时。向反应液中加入20mL水，二氯甲烷(10mL*3)萃取，收集有机相，无水硫酸钠干燥，减压浓缩，得到13-B，直接用于下一步。
MS m/z:265.7[M+H] +。
步骤2：化合物13-C的合成
0℃下于1－哌啶乙醇(364.13mg,2.82mmol)的四氢呋喃(10mL)溶液中加入钠氢(150.30mg,3.76mmol,60％纯度)，搅拌0.5小时，然后加入13-B(500.00mg,1.88mmol)，反应液在0℃搅拌1小时。向反应体系中加入20mL水淬灭反应，二氯甲烷(10mL*3)萃取，合并有机相，无水硫酸钠干燥，减压浓缩，得到13-C，直接用于下一步反应。
MS m/z:298.9[M+H] +。
步骤3：化合物13-D的合成
于13-C(0.67g,2.24mmol)的二氧六环(10mL)溶液中加入双联嚬哪醇硼酸酯(625.50mg,2.46mmol)，醋酸钾(439.52mg,4.48mmol)，[1,1-双(二苯基膦)二茂铁]二氯化钯二氯甲烷(182.87mg,223.93μmol)，氮气保护下80℃搅拌16小时，得到13-D的反应液，直接用于下一步。
MS m/z:265.1[M+H] +。
步骤4：化合物13的合成
除了使用相应的原料外，以实施例9中制备化合物9相同的方法制备化合物13。
MS m/z:456.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.90(d,J＝1.8Hz,1H),8.78(s,1H),8.27(d,J＝8.8Hz,1H),8.07(d,J＝1.5Hz,1H),8.02(dd,J＝2.3,8.0Hz,1H),7.91(dd,J＝1.8,8.8Hz,1H),7.62(d,J＝8.0Hz,1H),4.74(s,2H),3.75(t,J＝5.9Hz,2H),3.47(s,3H),2.66(t,J＝5.9Hz,2H),2.48(br s,4H),2.05(s,3H),1.61(quin,J＝5.6Hz,4H),1.49-1.39(m,2H)。
实施例14
Figure PCTCN2020129838-appb-000089
合成路线：
Figure PCTCN2020129838-appb-000090
步骤1：化合物14-A的合成
0℃下，于C-5(2g,6.97mmol)的N,N-二甲基甲酰胺(20mL)中加入甲醇(446.51mg,13.94mmol)，再缓慢加入钠氢(1.11g,27.87mmol,60％纯度)，反应液在0℃搅拌2小时。控制温度20℃，向反应液中加入10mL水，再使用1M的稀盐酸调节pH至中性，有固体析出，减压抽滤，10mL水淋洗，收集固体，减压浓缩，得到14-A，直接用于下一步。
MS m/z:298.8[M+H] +。
步骤2：化合物14-B的合成
将化合物14-A(2g,6.69mmol)溶于二氯甲烷(10mL)中，加入N,N-二甲基甲酰胺(24.44mg,334.36μmol)，缓慢加入草酰氯(1.70g,13.37mmol)，混合体系在25℃搅拌64小时。室温下缓慢滴加20mL水淬灭，二氯甲烷(20mL*3)萃取，水(20mL*3)洗涤，pH呈中性，有机相减压浓缩，得到14-B，直接用于下一步。
MS m/z:316.8[M+H] +。
步骤3：化合物14-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14-C。
MS m/z:407.9[M+H] +。
步骤4：化合物14-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-B相同的方法制备化合物14-D。
MS m/z:331.9[M+H] +。
步骤5：化合物14-E的合成
将反应物14-D(470mg,1.42mmol)溶于二氯甲烷(5mL)中，加入四丁基溴化铵(22.81mg,70.75μmol)和碳酸钾(782.25mg,5.66mmol)的水(5mL)溶液，搅拌下缓慢滴入碘甲烷(1.00g,7.08mmol)，混合体系在35℃氮气氛围下搅拌16小时。将反应液分散到20mL水中，用二氯甲烷(10mL*3)萃取，收集有机相，将有机相减压浓缩，得到14-E，直接用于下一步。
MS m/z:345.9[M+H] +。
步骤6：化合物14的合成
除了使用相应的原料外，以实施例9中制备化合物9相同的方法制备化合物14。
MS m/z:446.1[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.66(s,1H),8.39(br s,1H),7.86(br d,J＝7.0Hz,1H),7.80(s,1H),7.56(s,1H),6.84(br d,J＝8.5Hz,1H),4.42(br t,J＝6.1Hz,2H),3.98(s,3H),3.44(s,3H),2.53(br d,J＝6.5Hz,2H),2.33(s,6H),2.05(br d,J＝7.0Hz,2H),2.01(s,3H)。
实施例15
Figure PCTCN2020129838-appb-000091
合成路线：
Figure PCTCN2020129838-appb-000092
步骤1：化合物15的合成
除了使用相应的原料外，以实施例9中制备化合物9相同的方法制备化合物15。
MS m/z:486.2[M+H] +；
1H NMR(400MHz,CDCl 3)δ8.64(s,1H),8.37(d,J＝2.3Hz,1H),7.84(dd,J＝2.5,8.5Hz,1H),7.78(s,1H),7.55(s,1H),6.82(d,J＝8.5Hz,1H),4.39(t,J＝6.4Hz,2H),3.96(s,3H),3.42(s,3H),2.54-2.48(m,2H),2.43(br s,4H),2.07-2.00(m,2H),1.99(s,3H),1.60(quin,J＝5.5Hz,4H),1.43(br s,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。
ATM酶活性测试实验过程
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。
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。
表1：本发明化合物体外细胞活性测定结果(IC 50)
编号 ATM(IC 50nM)
化合物1 1
化合物2 6
化合物3 9
化合物4 2
化合物5 15
化合物6 1
化合物7 12
化合物8 2
结论：本发明化合物具有显著的ATM激酶抑制作用。
实验例2：人肝微粒体CYP抑制实验
实验测试在上海药明康德新药开发有限公司进行，实验结果由该公司提供，下面的实验过程也由该公司提供。
研究项目的目的是采用CYP同工酶的5合1探针底物来评价供试品对人肝微粒体细胞色素P450同工酶(CYP1A2、CYP2C9、CYP2C19、CYP2D6和CYP3A4)的抑制性。
混合人肝微粒体(HLM)购自Corning Inc.(Steuben,New York,USA)或者XenoTech,LLC.(Lenexa,KS,USA)或者其他的供应商，使用前都储存在低于-80℃条件下。
将稀释好的系列浓度的供试品工作液加入到含有人肝微粒体、探针底物和循环体系的辅助因子的孵育体系中，不含供试品而含有溶剂的对照作为酶活性对照(100％)。探针底物生成的代谢产物在样品中的浓度采用液相色谱-串联质谱(LC-MS/MS)方法进行测定。使用SigmaPlot(V.11)对供试品平均百分比活性对浓度作非线性回归分析。通过三参数或四参数反曲对数方程来计算IC 50值。测试结果如表2：
表2：
Figure PCTCN2020129838-appb-000093
结论：本发明化合物对五个CYP同工酶抑制程度均较弱。
实验例3：体内评价
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，实验测试在上海药明康德新药开发有限公司进行，实验结果由该公司提供，下面的实验过程也由该公司提供。
实验目的：
旨在考察本发明化合物单次静脉推注和灌胃给药后雌性Balb/c-nude小鼠体内药物血浆药代动力学。
实验材料：
Balb/c-nude小鼠(雌性,15-20g,7-9周龄，禁食)
实验操作：
以标准方案测试化合物静脉注射及口服给药后的啮齿类动物药代特征，实验中候选化合物配成澄清溶液，给予小鼠单次静脉注射及口服给药。静注及口服溶媒为10％DMSO/90％(30％磺丁基环糊精)。收集24小时内的全血样品，3000g离心15分钟，分离上清得血浆样品，加入6倍体积含内标的乙腈溶液沉淀蛋白，静脉注射剂量为1mpk，口服剂量为10mpk，离心取上清液加入等倍体积的水再离心取上清进样，以LC-MS/MS分析方法定量分析血药浓度，并计算药代参数，如清除率，半衰期，药时曲线下面积，生物利用度等。
实验结果：
表3：药代动力学测试结果
Figure PCTCN2020129838-appb-000094
结论：本发明化合物具有优异的药代动力学性质。

Claims (19)

  1. 式(I)所示化合物或其药学上可接受的盐，
    Figure PCTCN2020129838-appb-100001
    其中，
    R 1选自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 a取代；
    R 2选自H、F、Cl、Br、I、OH、NH 2、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 3选自H和N(R c)(R d)；
    R 4选自F、CN和OH；
    L 1选自单键、-(CH 2) m-、-(CH 2) m-O-和-(CH 2) m-O-CH 2-；
    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 e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和任选被1、2或3个R取代的C 1-3烷基；
    或者，R c、R d和与它们连接的N原子共同构成任选被1、2或3个R取代的
    Figure PCTCN2020129838-appb-100002
    R e分别独立地选自H、F、Cl、Br、I和CH 3；
    n选自0、1和2；
    R分别独立地选自F、Cl、Br、I、OH和NH 2。
  2. 根据权利要求1所述化合物或其药学上可接受的盐，其中，R 1选自CH 3、CH 2CH 3和OCH 3，所述CH 3、CH 2CH 3和OCH 3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OCH 3。
  4. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 2选自H、F、Cl、Br、I、OH、NH 2、CH 3、CH 2CH 3和OCH 3，所述CH 3、CH 2CH 3和OCH 3任选被1、2或3个R b取代。
  5. 根据权利要求4所述化合物或其药学上可接受的盐，其中，R 2选自H、F、Cl、Br、I、OH、NH 2、CH 3、CH 2F、CHF 2、CF 3、CH 2CH 3和OCH 3。
  6. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R c和R d分别独立地选自H、CH 3和CH 2CH 3。
  7. 根据权利要求1～3任意一项所述化合物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被1、2或3个R取代。
  8. 根据权利要求7所述化合物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 PCTCN2020129838-appb-100003
  9. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 3选自H、N(CH 3) 2、N(CH 2CH 3) 2、
    Figure PCTCN2020129838-appb-100004
  10. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，L 1选自单键、-CH 2CH 2CH 2O-、-OCH 2-和-CH 2CH 2OCH 2-。
  11. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，环B选自苯基和吡啶基，所述苯基和吡啶基任选被1、2或3个R e取代。
  12. 根据权利要求11所述化合物或其药学上可接受的盐，其中，环B选自
    Figure PCTCN2020129838-appb-100005
    所述
    Figure PCTCN2020129838-appb-100006
    任选被1、2或3个R e取代。
  13. 根据权利要求12所述化合物或其药学上可接受的盐，其中，环B选自
    Figure PCTCN2020129838-appb-100007
  14. 根据权利要求1～3任意一项所述化合物或其药学上可接受的盐，其中，R 3-L 1-选自H、
    Figure PCTCN2020129838-appb-100008
  15. 根据权利要求1～8任意一项所述化合物或其药学上可接受的盐，其选自：
    Figure PCTCN2020129838-appb-100009
    其中，
    R 1如权利要求1～3任意一项所定义；
    R 2如权利要求1、4或5任意一项所定义；
    R c和R d如权利要求1、6、7或8任意一项所定义；
    R 4如权利要求1所定义。
  16. 下式所示化合物或其药学上可接受的盐，
    Figure PCTCN2020129838-appb-100010
  17. 根据权利要求16所述化合物或其药学上可接受的盐，其选自
    Figure PCTCN2020129838-appb-100011
    Figure PCTCN2020129838-appb-100012
  18. 根据权利要求1～17任意一项所述的化合物或其药学上可接受的盐在制备ATM抑制剂相关药物上的应用。
  19. 根据权利要求18所述的应用，其特征在于，所述ATM抑制剂相关药物是用于肿瘤的药物。
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