WO2020103897A1 - 杂环稠合嘧啶衍生物、其药物组合物及应用 - Google Patents

杂环稠合嘧啶衍生物、其药物组合物及应用

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Publication number
WO2020103897A1
WO2020103897A1 PCT/CN2019/119899 CN2019119899W WO2020103897A1 WO 2020103897 A1 WO2020103897 A1 WO 2020103897A1 CN 2019119899 W CN2019119899 W CN 2019119899W WO 2020103897 A1 WO2020103897 A1 WO 2020103897A1
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alkyl
compound
mmol
substituted
alkoxy
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PCT/CN2019/119899
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English (en)
French (fr)
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赵志明
杨伟
武志恒
仝朝龙
高大新
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上海迪诺医药科技有限公司
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • 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
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
    • A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D419/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms
    • C07D419/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen, oxygen, and sulfur atoms as the only ring hetero atoms containing three or more hetero rings
    • 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
    • C07D491/02—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 two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/044—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring
    • C07D491/052—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being six-membered
    • 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
    • C07D491/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/20—Spiro-condensed systems

Definitions

  • the invention relates to a heterocyclic fused pyrimidine derivative, a pharmaceutical composition thereof and its application as a therapeutic agent, especially as a cancer therapeutic agent.
  • DNA damage Human cells suffer from hundreds of DNA damages every day.
  • the causes of DNA damage include normal cell functions (such as oxidative metabolites), DNA metabolites (such as spontaneous errors in DNA during transcription and replication), and environmental factors (Such as ultraviolet rays, ionizing radiation, genotoxins, etc.), etc. If the damage cannot be repaired properly, it will lead to the loss of activity of the cell or organism.
  • the accumulation of DNA damage can also affect the stability and integrity of the genome and promote the formation of cancer. DNA damage may occur through oxidation or alkylation of DNA bases, DNA base mismatches and dimers, breaks and discontinuities in the DNA backbone, intra- and inter-strand DNA cross-linking, and overall changes in DNA structure.
  • DDR DNA damage response
  • the ataxia telangiectasia mutant gene and Rad 3 related kinase ATR (ataxia telangiectasia mutated and Rad3-related, ATR, also known as FRAP-Related Protein 1; FRP1; MEC1; SCK1; SECKL1) is phosphatidylinositol-3
  • a member of the kinase-associated kinase (PIKK) protein family is an important kinase (Cimprich KA) that can activate cellular responses after DNA damage, thereby blocking cell cycle progression and stably replicating forks and repairing DNA, thereby avoiding apoptosis , Nature Rev. Mol. Cell Biol., 2008, 9: 616-627).
  • ATR works by stabilizing the stagnant replication fork, regulating cell cycle checkpoint activation and DNA damage repair. After ATR is activated, it will activate three signal transduction pathways by regulating its downstream regulatory factors (mainly including Chk1, WRN and FANCI) to block the cell cycle process, promote DNA repair, and stabilize the replication fork.
  • regulatory factors mainly including Chk1, WRN and FANCI
  • ATR can also be activated without DNA helicase polymerase uncoupling, such as by UV radiation, platinum chemotherapy Or alkylating agent.
  • DNA repair in tumor cells may be defective due to the presence of multiple mutations, it shows greater dependence on the undamaged DNA repair pathway. Therefore, the synthetic lethal theory can be used to kill specific tumor cells while retaining healthy cells.
  • Current cancer treatments including chemotherapy and ionizing radiation, can induce DNA damage and replication fork arrest, thereby activating cell cycle checkpoints and causing cell cycle arrest. This response mechanism is an important mechanism to help cancer cells survive treatment.
  • Broken double-stranded DNA or replication stress can quickly activate ATR, and the corresponding ATR can initiate a series of downstream targets such as Chk1 (ATR substrate), p53, DNA topoisomerase 2 binding protein (TopBP1), etc., which leads to DNA repair. And cell cycle stagnation.
  • the ATR gene is seldom mutated, so it is easily activated during cancer chemotherapy.
  • several synthetic lethal interactions can be produced by inhibiting ATR, especially interacting with the ATM / p53 pathway.
  • p53 is the most common tumor suppressor gene mutation, and DNA repair of cells with ATM / p53 gene defects or mutations is more dependent on ATR activation (Reaper, P.M., Nat. Chem. Biol., 2011, 7, 428-430).
  • ATR pathway plays an important role in the survival of tumor cells. Inhibition of its key factor ATR can induce the death of ATR pathway-dependent malignant tumor cells and has little effect on normal cells. It is an ideal target for the development of low-toxic and highly effective targeted drugs.
  • the technical problem to be solved by the present invention is to provide a novel heterocyclic fused pyrimidine derivative, its preparation method, pharmaceutical composition and application.
  • the heterocyclic fused pyrimidine derivative of the present invention has a good ATR inhibitory effect, and can effectively treat and / or alleviate various related diseases mediated by ATR, such as malignant tumors.
  • the present invention provides a heterocyclic fused pyrimidine derivative (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt;
  • X is -CR 8 R 9- , -O-, -C (O)-or -NR 10- ;
  • Y is O or NR 10 ;
  • L is-(CR 8 'R 9 ') n- ;
  • R 1 is optionally H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or halogenated C 1-6 alkyl;
  • R 2 is optionally H, R 11 , -OR 11 or -NR 11 R 11a ;
  • R 1 and R 2 are independent substituents, or R 1 and R 2 are connected to each other to form a 3-8 membered heterocycloalkyl; the 3-8 membered heterocycloalkyl is unsubstituted or optionally selected by one or more Substituent substituents from halogen and C 1-6 alkyl are substituted at any position;
  • R 3 is optionally Cy, -O-Cy, -NR 10 ' -Cy or -NR 10' -CH 2 -Cy;
  • Cy is optionally aryl or heteroaryl, and Cy is unsubstituted or optionally selected by one or more selected from R 12 , halogen, hydroxyl, amino, cyano, carboxy, -OR 12a , -NR 12 R 12a , -N (CN) R 12a , -N (OR 12 ) R 12a , -S (O) 0-2 R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -C (NH) NR 12 R 12a , -NR 12 C (O) R 12a , -NR 12 C (O) NR 12 R 12a , -NR 12 S (O) 2 R 12a, and -OC (O)
  • the substituent of R 12a is substituted at any position;
  • R 4 and R 5 are independently independently H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • R 6 is H, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl ;
  • the C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylamino group, C 3-8 cycloalkyl group or 3-8 membered heterocycloalkyl group is unsubstituted or optionally substituted by one or Multiple selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 3-
  • the substituents of 8 cycloalkyl, 3-8 membered heterocycloalkyl, hydroxyl, cyano and amino are substituted at any position;
  • R 7 is H, halogen or C 1-6 alkyl
  • R 6 and R 7 are independent substituents, or R 6 and R 7 together with the C atom to which they are connected together form a carbonyl group;
  • R 1 and R 6 are independent substituents, or R 1 and R 6 are connected to each other through -L'- to form a bridge ring group;
  • R 8 , R 8 ′ and R 8 are independently H, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 ring Alkyl or 3-8 membered heterocycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocyclic
  • the alkyl group is unsubstituted or optionally selected by one or more of halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy , C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, hydroxyl, cyano and amino substituents are substituted at any position;
  • R 9 , R 9 ′ and R 9 are independently H, halogen or C 1-6 alkyl
  • R 10 and R 10 ' are independently H or C 1-6 alkyl
  • Each R 11 and each R 11a are independently H, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-6 membered heteroaryl C 1-6 alkyl Group; the R 11 or R 11a is unsubstituted, or is optionally selected by one or more selected from halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C The substituents of 1-6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino are substituted at any position;
  • Each R 12 and each R 12a are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycle Alkyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl Group or 5-6 membered heteroaryl C 1-6 alkyl; the R 12 or R 12a is unsubstituted, or is optionally selected by one or more selected from deuterium, oxo, halogen, hydroxyl, amino, cyan Group, halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycle Alkyl, -NHC (O) -C 2-6 alken
  • n, and t are independently 0, 1, 2, or 3, respectively.
  • the definition of certain groups in the compound of formula I, its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, without The described group can be as described in any of the above schemes:
  • X is -CR 8 R 9- , -O-, -C (O)-or -NR 10- ;
  • Y is O or NR 10 ;
  • L is-(CR 8 'R 9 ') n- ;
  • R 1 is optionally H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or halogenated C 1-6 alkyl;
  • R 2 is optionally H, R 11 , -OR 11 or -NR 11 R 11a ;
  • R 1 and R 2 are independent substituents, or R 1 and R 2 are connected to each other to form a 3-8 membered heterocycloalkyl; the 3-8 membered heterocycloalkyl is unsubstituted or optionally selected by one or more Substituent substituents from halogen and C 1-6 alkyl are substituted at any position;
  • R 3 is optionally Cy, -O-Cy, -NR 10 ' -Cy or -NR 10' -CH 2 -Cy;
  • Cy is optionally aryl or heteroaryl, and Cy is unsubstituted or optionally selected by one or more selected from R 12 , halogen, hydroxyl, amino, cyano, carboxy, -OR 12a , -NR 12 R 12a , -S (O) 0-2 R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -C (NH) NR 12 R 12a , -NR
  • the substituents of 12 C (O) R 12a , -NR 12 C (O) NR 12 R 12a , -NR 12 S (O) 2 R 12a and -OC (O) R 12a are substituted in any position;
  • R 4 and R 5 are independently independently H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • R 6 is H, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl ;
  • the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, cycloalkyl or heterocycloalkyl is unsubstituted or optionally one or more selected from halogen, C 1 -6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8
  • the substituents of the member heterocyclic alkyl, hydroxyl, cyano and amino are substituted at any position;
  • R 7 is H, halogen or C 1-6 alkyl
  • R 6 and R 7 are independent substituents, or R 6 and R 7 together with the C atom to which they are connected together form a carbonyl group;
  • R 1 and R 6 are independent substituents, or R 1 and R 6 are connected to each other through -L'- to form a bridge ring group;
  • R 8 , R 8 ′ and R 8 are independently H, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 ring Alkyl or 3-8 membered heterocycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, cycloalkyl or heterocycloalkyl is unsubstituted or selective It is selected from one or more of halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkylamino, The substituents of C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, hydroxyl, cyano and amino are substituted at any position;
  • R 9 , R 9 ′ and R 9 are independently H, halogen or C 1-6 alkyl
  • R 10 and R 10 ' are independently H or C 1-6 alkyl
  • Each R 11 and each R 11a are independently C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3 -8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-6 membered heteroaryl C 1-6 alkyl;
  • the R 11 or R 11a is unsubstituted, or is optionally selected from one or more selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, and halogenated C 1- 6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino substituents are substituted at any position;
  • Each R 12 and each R 12a are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycle Alkyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl Group or 5-6 membered heteroaryl C 1-6 alkyl; the R 12 or R 12a is unsubstituted, or is optionally selected by one or more selected from oxo, halogen, hydroxyl, amino, cyano, Halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl , -NHC (O) -C 2-6 alkenyl,
  • n, and t are independently 0, 1, 2, or 3, respectively.
  • the definition of certain groups in the compound of formula I, its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, without The described group can be as described in any of the above schemes:
  • X is -CR 8 R 9- , -O-, -C (O)-or -NR 10- ;
  • Y is O or NR 10 ;
  • L is-(CR 8 'R 9 ') n- ;
  • R 1 is optionally H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl or halogenated C 1-6 alkyl;
  • R 2 is optionally H, R 11 , -OR 11 or -NR 11 R 11a ;
  • R 1 and R 2 are independent substituents, or R 1 and R 2 are connected to each other to form a 3-8 membered heterocycloalkyl; the 3-8 membered heterocycloalkyl is unsubstituted or optionally selected by one or more Substituent substituents from halogen and C 1-6 alkyl are substituted at any position;
  • R 3 is optionally Cy, -O-Cy, -NR 10 ' -Cy or -NR 10' -CH 2 -Cy;
  • Cy is optionally aryl or heteroaryl, and Cy is unsubstituted or optionally selected by one or more selected from R 12 , halogen, hydroxyl, amino, cyano, carboxy, -OR 12a , -NR 12 R 12a , -S (O) 0-2 R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -NR 12 C (O) R 12a , -NR
  • the substituents of 12 C (O) NR 12 R 12a , -NR 12 S (O) 2 R 12a and -OC (O) R 12a are substituted in any position;
  • R 4 and R 5 are independently independently H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy or halogenated C 1-6 alkoxy;
  • R 6 is H, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl or 3-8 membered heterocycloalkyl ;
  • the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, cycloalkyl or heterocycloalkyl is unsubstituted or optionally one or more selected from halogen, C 1 -6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8
  • the substituents of the member heterocyclic alkyl, hydroxyl, cyano and amino are substituted at any position;
  • R 7 is H, halogen or C 1-6 alkyl
  • R 6 and R 7 are independent substituents, or R 6 and R 7 together with the C atom to which they are connected together form a carbonyl group;
  • R 1 and R 6 are independent substituents, or R 1 and R 6 are connected to each other through -L'- to form a bridge ring group;
  • R 8 , R 8 ′ and R 8 are independently H, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 ring Alkyl or 3-8 membered heterocycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, cycloalkyl or heterocycloalkyl is unsubstituted or selective It is selected from one or more of halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkylamino, The substituents of C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, hydroxyl, cyano and amino are substituted at any position;
  • R 9 , R 9 ′ and R 9 are independently H, halogen or C 1-6 alkyl
  • R 10 and R 10 ' are independently H or C 1-6 alkyl
  • Each R 11 and each R 11a are independently C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3 -8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-6 membered heteroaryl C 1-6 alkyl;
  • the R 11 or R 11a is unsubstituted, or is optionally selected from one or more selected from halogen, hydroxyl, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, and halogenated C 1- 6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino substituents are substituted at any position;
  • Each R 12 and each R 12a are independently H, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocycle Alkyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl Group or 5-6 membered heteroaryl C 1-6 alkyl; the R 12 or R 12a is unsubstituted, or is optionally selected by one or more selected from oxo, halogen, hydroxyl, amino, cyano, Halogenated C 1-6 alkyl, halogenated C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl And -NHC (O) -C 2-6 alkenyl substituent
  • n, and t are independently 0, 1, 2, or 3, respectively.
  • the definition of certain groups in the compound of formula I, its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts may be as follows, without The described group can be as described in any of the above schemes:
  • X is -CR 8 R 9- , -O-, -C (O)-, or -NR 10- ;
  • Y is O, or NR 10 ;
  • L is-(CR 8 'R 9 ') n- ;
  • R 1 is optionally H, halogen, C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, or halogenated C 1-6 alkyl;
  • R 2 is optionally H, R 11 , -OR 11 , or -NR 11 R 11a ;
  • R 1 and R 2 are independent substituents, or R 1 and R 2 are connected to each other to form a 3-8 membered heterocycloalkyl; the 3-8 membered heterocycloalkyl is unsubstituted or optionally selected by one or more Substituent substituents from halogen and C 1-6 alkyl are substituted at any position;
  • R 3 is optionally Cy, -O-Cy, -NR 10 ' -Cy, or -NR 10' -CH 2 -Cy;
  • Cy is optionally aryl or heteroaryl, where Cy is unsubstituted, or is optionally selected by one or more selected from R 12 , halogen, hydroxyl, amino, cyano, carboxy, -OR 12 , -NR 12 R 12a , -S (O) 0-2 R 12 , -C (O) R 12 , -C (O) OR 12 , -C (O) NR 12 R 12a , -NR 12a C (O) R 12 and- The substituent of OC (O) R 12 is substituted at any position;
  • R 4 and R 5 are each independently optionally H, halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, or halogenated C 1-6 alkoxy;
  • R 6 is H, halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, or 3-8 membered heterocycloalkane Group; the C 1-6 alkyl group, C 1-6 alkoxy group, C 1-6 alkylamino group, cycloalkyl group, or heterocycloalkyl group is unsubstituted, or optionally one or more selected from halogen , C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocyclic alkyl, hydroxy, cyano and amino substituents are substituted at any position;
  • R 7 is H, halogen, or C 1-6 alkyl
  • R 6 and R 7 are independent substituents, or R 6 and R 7 together with the C atom to which they are connected together form a carbonyl group;
  • R 1 and R 6 are independent substituents, or R 1 and R 6 are connected to each other through -L'- to form a bridge ring group;
  • R 8 , R 8 ′ and R 8 are independently H, halogen, cyano, hydroxyl, C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 ring Alkyl, or 3-8 membered heterocycloalkyl; the C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkylamino, cycloalkyl, or heterocycloalkyl is unsubstituted, Alternatively, one or more are selected from halogen, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 1-6 The substituents of alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, hydroxyl, cyano and amino are substituted at any position;
  • R 9 , R 9 'and R 9 are independently H, halogen, or C 1-6 alkyl;
  • R 10 and R 10 ' are each independently H or C 1-6 alkyl
  • Each R 11 and each R 11a are independently C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3 -8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl, or 5-6 membered heteroaryl C 1-6 alkyl ;
  • the R 11 or R 11a is unsubstituted, or is optionally selected from one or more of halogen, hydroxy, amino, cyano, C 1-6 alkyl, C 1-6 alkoxy, halo C 1 -6 alkyl, halogenated C 1-6 alkoxy and C 1-6 alkylamino substituents are substituted at any position;
  • Each R 12 and each R 12a are independently H, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl, or 5-6 membered heteroaryl C 1-6 Alkyl; the R 12 or R 12a is unsubstituted, or is optionally selected from one or more of halogen, hydroxy, amino, cyano, halo C 1-6 alkyl, halo C 1-6 alkoxy The substituents of the group, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl and 3-8 membered heterocycloalkyl are substituted at any position;
  • n, and t are independently 0, 1, 2, or 3, respectively.
  • X is O.
  • X is NR 10 , wherein R 10 is as defined above.
  • R 10 is H, methyl, ethyl, propyl, isopropyl, or cyclopropyl.
  • Y is O.
  • Y is NH
  • R 1 is C 1-6 alkyl; more preferably C 1-4 alkyl (for example: methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl base).
  • R 2 is R 11 ;
  • R 11 is as defined above;
  • the R 11 is C 1-6 alkyl, phenyl, 5-6 membered heteroaryl, 3-6 membered heterocycloalkyl, or C 3-6 cycloalkyl; the R 11 It is unsubstituted, or is optionally selected from 1-3, 1-2 or 1 selected from fluorine, chlorine, hydroxyl, amino, cyano, methoxy, ethoxy, trifluoromethoxy, difluoromethyl The substituents of oxy, dimethylamino, and methylamino are substituted at any positions.
  • R 2 is C 1-6 alkyl or C 3-6 cycloalkyl.
  • R 2 is methyl, ethyl, n-propyl, isopropyl, t-butyl, cyclopropyl, or cyclobutyl.
  • R 1 and R 2 are independent substituents.
  • R 1 and R 2 are interconnected to form a 5-8 membered heterocycloalkyl.
  • the Cy is optionally aryl or heteroaryl, and the Cy is unsubstituted or optionally substituted by one or more selected from R 12 , halogen, hydroxyl, amino, cyano, carboxy,- OR 12 , -NR 12 R 12a , -S (O) 0-2 R 12 , -C (O) R 12 , -C (O) OR 12 , -C (O) NR 12 R 12a , -NR 12a C
  • the substituents of (O) R 12 and -OC (O) R 12 are substituted at arbitrary positions.
  • R 3 is Cy
  • the Cy is a substituted or unsubstituted 6-10 membered aryl group.
  • the Cy is a substituted or unsubstituted 5-10 membered heteroaryl.
  • the substituted or unsubstituted 6-10 membered aryl group is substituted or unsubstituted phenyl, naphthyl, indolinyl, or 2-oxo Generation-2,3-dihydro-1H-benzo [d] imidazolyl.
  • the substituted or unsubstituted 6-10 membered aryl group is a substituted or unsubstituted phenyl group.
  • the substituted or unsubstituted 5-10 membered heteroaryl group is a substituted or unsubstituted one of the following groups: pyridyl, pyrimidinyl, pyridine Azinyl, imidazolyl, pyrazolyl, 1H-1,2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, quin Porphyrinyl, isoquinolinyl, quinazolinyl, 1H-indazolyl, 1H-indolyl, 1H-pyrrolo [2,3-b] pyridyl, 1H-pyrrolo [2,3-c] Pyridyl, 1H-pyrrolo [3,2-c] pyridyl, 1H-pyrrolo [3,2-b] pyridyl, 7H-pyrrolo [2,3-c] pyridazinyl
  • the substituted or unsubstituted 5-10 membered heteroaryl group is a substituted or unsubstituted one of the following groups: 1H-indolyl, 1H -Pyrrolo [2,3-b] pyridyl, 1H-pyrrolo [2,3-c] pyridyl, 1H-pyrrolo [3,2-c] pyridyl, 1H-benzimidazolyl, 1H- Indazolyl, 1H-benzo [d] [1,2,3] triazolyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, imidazolyl, pyrazolyl, 1H-1 , 2,3-triazolyl, 1H-1,2,4-triazolyl, 4H-1,2,4-triazolyl, 7H-pyrrolo [2,3-c] pyridazinyl ,
  • the substituted or unsubstituted 5-10 membered heteroaryl group is a substituted or unsubstituted one of the following groups: 1H-indolyl, 1H -Pyrrolo [2,3-b] pyridyl, 1H-pyrrolo [2,3-c] pyridyl, 1H-pyrrolo [3,2-c] pyridyl, 1H-benzimidazolyl, 1H- Indazolyl, 1H-benzo [d] [1,2,3] triazolyl, quinolinyl, isoquinolinyl, quinazolinyl, pyridyl, imidazolyl, pyrazolyl, 1H-1 , 2,3-triazolyl, 1H-1,2,4-triazolyl or 4H-1,2,4-triazolyl.
  • the Cy is any of the following structures, substituted or unsubstituted:
  • the substituted or unsubstituted 5-10 membered heteroaryl group is a substituted or unsubstituted one of the following structures:
  • the substituted or unsubstituted 5-10 membered heteroaryl group is a substituted or unsubstituted one of the following structures:
  • R 3 when Cy is substituted, it is optionally substituted with 1 to 3, 1 to 2 or 1 selected from R 12 , halogen, hydroxyl, amino, cyano, carboxyl, -OR 12a , -NR 12 R 12a , -N (CN) R 12a , -N (OH) R 12a , -S (O) 0-2 R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -NHC (O) R 12a , -NHC (O) NR 12 R 12a , and -OC (O) R 12a are substituted at any position;
  • the definitions of 12 and R 12a are as described above.
  • R 3 when Cy is substituted, it is optionally substituted with 1 to 3, 1 to 2 or 1 selected from R 12 , halogen, hydroxyl, amino, cyano, carboxyl, -OR 12a , -NR 12 R 12a , -S (O) 0-2 R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -NHC ( O)
  • the substituents of R 12a and -OC (O) R 12a are substituted at arbitrary positions; the definitions of R 12 and R 12a are as described above.
  • the selectivity is 1 to 3, 1 to 2, or 1 selected from F, Cl, Br, -OH, -NH 2 ,- CN, -COOH, R 12 , -OR 12a , -NR 12 R 12a , -N (CN) R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R
  • the substituents of 12a , -NHC (O) R 12a , -NHC (O) NR 12 R 12a and -C (NH) NR 12 R 12a are substituted at any position; the definitions of R 12 and R 12a are as described above .
  • the selectivity is 1 to 3, 1 to 2, or 1 selected from F, Cl, Br, -OH, -NH 2 ,- CN, -COOH, R 12 , -OR 12a , -NR 12 R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -NHC (O) R
  • the substituent of 12a or -C (NH) NR 12 R 12a is substituted at any position; the definitions of R 12 and R 12a are as described above.
  • R 3 when Cy is substituted, 1 to 2 or 1 is selected from F, Cl, Br, -OH, -NH 2 , -CN, -COOH, R 12 , -OR 12a , -NR 12 R 12a , -N (CN) R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -NHC (O )
  • the substituents of NR 12 R 12a and -NHC (O) R 12a are substituted at any position; the definitions of R 12 and R 12a are as described above.
  • R 3 when Cy is substituted, 1 to 2 or 1 is selected from F, Cl, Br, -OH, -NH 2 , -CN, -COOH, R 12 , -OR 12a , -NR 12 R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a or -NHC (O) R 12a Any position; the definitions of R 12 and R 12a are as described above.
  • each R 12 and each R 12a are independently H, C 1-6 alkyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, 5-6 membered heteroaryl, C 3-8 cycloalkyl C 1-6 alkyl, 3-8 membered heterocycloalkyl C 1-6 alkyl, phenyl C 1-6 alkyl or 5-6 membered Heteroaryl C 1-6 alkyl; said R 12 or R 12a is unsubstituted, or is optionally selected by one or more selected from halogen, hydroxy, amino, cyano, halogenated C 1-6 alkyl, halogen Substitute substituents for C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, and 3-8 membered heterocycloalkyl at any position;
  • R 12 is H, C 1-6 alkyl, C 2-6 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, phenyl, or 5-6 Yuan heteroaryl.
  • R 12 is H, C 1-4 alkyl, C 2-6 alkenyl, C 3-6 cycloalkyl, 5-6 membered heteroaryl, or 3-6 membered heterocycloalkane base.
  • R 12 is unsubstituted.
  • the R 12 is optionally selected from 1-5, 1-4, or 1-3 selected from deuterium, oxo, halogen, hydroxy, amino, cyano, halo C 1-6 alkyl , Halogenated C 1-6 alkoxy, C 1-6 alkoxy, C 1-6 alkylamino, C 3-8 cycloalkyl, 3-8 membered heterocycloalkyl, -NHC (O) -C 2-6 alkenyl, -NHC (O) -C 1-6 alkyl, -NHC (O) NH-C 1-6 alkyl, -NHC (O) OC 1-6 alkyl, and -NHS (O) 2 -C 1-6 alkyl substituent is substituted at any position;
  • the substituent of C 1-4 alkyl, C 1-4 alkoxy or C 1-4 alkylamino is substituted at any position.
  • the substituents of 4 alkoxy and C 1-4 alkylamino are substituted at arbitrary positions.
  • R 12 is H, C 1-4 alkyl, C 3-6 cycloalkyl, or 3-6 membered heterocycloalkyl, and R 12 is unsubstituted, or optionally substituted by 1 ⁇ 3 substituents selected from F, Cl, —OH, —NH 2 , C 1-4 alkyl, C 1-4 alkoxy, and C 1-4 alkylamino are substituted at arbitrary positions.
  • R 12a is H, C 2-6 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocycloalkyl, or C 1-4 alkyl.
  • R 12a is H or C 1-4 alkyl.
  • the selectivity is 1 to 3, 1 to 2, or 1 selected from F, Cl, Br, -OH, -NH 2 ,- NH (CH 3 ), -N (CH 3 ) 2 , -NH (CH 2 CH 3 ), -NH (CN), -NH (OH), -NHC (O) H, -NH-n-propyl,- NH-isopropyl, -NH-cyclopropyl, -NHC (O) CH 3 , -NHC (O) NH 2 , -CN, -COOH, -CH 3 , -CF 3 , -CHF 2 , -CH 2 CHF 2 , -CH 2 OH, -CH 2 NH 2 , -CH 2 NH (CH 3 ), -OCH 3 , -OCF 3 , -OCH 2 CF 3 , -OCH 2 CHF 2 , -O-cyclo
  • the 6-10 membered aryl group is The 5-10 membered heteroaryl group is: R 'is H, F, Cl, -CH 3 , -CF 3 or -OCH 3 ; R is H, F, Cl, Br, -OH, -NH 2 , -CN, -COOH, R 12 , -OR 12a , -NR 12 R 12a , -N (CN) R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -NHC (O) NR 12 R 12a Or -NHC (O) R 12a ; the definitions of R 12 and R 12a are as described above.
  • the 5-10 membered heteroaryl is: R 'is H, F, Cl, -CH 3 , -CF 3 or -OCH 3 ;
  • R is H, F, Cl, Br, -OH, -NH 2 , -CN, -COOH, R 12 , -OR 12a , -NR 12 R 12a , -N (CN) R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -NHC (O) NR 12 R 12a Or -NHC (O) R 12a ; the definitions of R 12 and R 12a are as described above.
  • R is H, F, Cl, Br, -OH, -NH 2 , -NH (CH 3 ), -N (CH 3 ) 2 , -NH (CH 2 CH 3 ), -NH (CN), -NHC ( O) NH 2 , -NHC (O) H, -NH-propyl, -NH-isopropyl, -NH-cyclopropyl, -NHC (O) CH 3 , -CN, -COOH, -CH 3 , -CF 3 , -CHF 2 , -CH 2 CHF 2 , -CH 2 OH, -CH 2 NH 2 , -CH 2 NH (CH 3 ), -OCH 3 , -OCF 3 , -OCH 2 CF 3 or -OCH 2 CHF 2 .
  • R 4 is methyl
  • R 5 is H, F, methyl, methoxy, ethoxy, or trifluoromethoxy.
  • R 5 is H.
  • t is 1 or 2.
  • n 0, 1, or 2.
  • n 1 or 2.
  • the R 8 , R 8 ′, and R 8 ′′ are each independently H, F, or C 1-4 alkyl.
  • each of R 9 , R 9 ′, and R 9 ′′ is independently H, F, or C 1-4 alkyl.
  • R 1 and R 6 are connected to each other through -L'- to form a bridged ring group; wherein, L 'is -CH 2- , -CH 2 CH 2- , -CH 2 O-, or -O -;
  • R 1 and R 6 are connected to each other through -L'- to form a bridged ring group; wherein, L 'is -CH 2- .
  • L is -CH 2 -or -CH 2 CH 2- .
  • L is -CH 2- .
  • the compound of formula I, its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt is the compound of formula II, its isomer, pro Medicine, stable isotope derivative or pharmaceutically acceptable salt:
  • R 2 , R 3 , R 7 , L, L ′, X and Y are as described above.
  • X is O
  • L is -CH 2- ;
  • L ' is -CH 2- ;
  • R 2 is -CH 3 , -CH 2 CH 3 , -CH (CH 3 ) 2 or cyclopropyl;
  • R 3 is Cy
  • Cy is R 'is H, F, Cl, -CH 3 , -CF 3 or -OCH 3 ;
  • R is H, F, Cl, Br, -OH, -NH 2 , -CN, -COOH, R 12 , -OR 12a , -NR 12 R 12a , -N (CN) R 12a , -C (O) R 12a , -C (O) OR 12a , -C (O) NR 12 R 12a , -NHC (O) NR 12 R 12a Or -NHC (O) R 12a ; the definitions of R 12 and R 12a are as described above.
  • the compound represented by formula (I) and / or the pharmaceutically acceptable salt are optionally the following compounds:
  • the compound represented by formula (I) and / or the pharmaceutically acceptable salt are optionally the following compounds:
  • the compound represented by formula (I) and / or the pharmaceutically acceptable salt are optionally the following compounds:
  • the compound represented by formula (I) and / or the pharmaceutically acceptable salt are optionally the following compounds:
  • the compound represented by formula (I) and / or the pharmaceutically acceptable salt are optionally the following compounds:
  • the compound represented by formula (I) and / or the pharmaceutically acceptable salt are optionally the following compounds:
  • the present invention also provides a method for preparing the compound represented by formula (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, which is any of the following methods:
  • Lev is a leaving group, preferably Cl, Br, I or OTf; M is a borate group or a boric acid group; R 3 is Cy; R 1 , R 2 , R 4 , R 5 , R 6 , R 7.
  • the definitions of X, Y, L and t are as described above.
  • the IA and R 3 -H are subjected to nucleophilic substitution reaction or Buchwald-Hartwig coupling reaction to obtain the compound represented by formula I;
  • Lev is a leaving group, preferably Cl, Br, I or OTf;
  • R 3 is heteroaryl, -NR 10 ' -Cy or -NR 10' -CH 2 -Cy; in R 3 , the hetero The aryl group is connected to the parent molecule through a ring N atom; the definitions of R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , X, Y, L, and t are as described above.
  • Lev is a leaving group, preferably Cl, Br, I or OTf;
  • R 3 is Cy;
  • R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , X, Y, L and t The definition is as described above.
  • ring A is a benzene ring or a 5-6 membered heteroaromatic ring, the ring A is unsubstituted or optionally substituted by one or more R ′ and / or R at any position; R, R ′, R 1 , R 2 , R 4 , R 5 , R 6 , R 7 , X, Y, L and t are as defined above.
  • ring A is a benzene ring or a 5-6 membered heteroaryl ring, the ring A is unsubstituted or optionally substituted with one or more R 'and / or R substituted at any position; R, R', R. 1, R 2 , R 4 , R 5 , R 6 , R 7 , X, Y, L and t are as defined above.
  • NH or NH 2 when there is NH or NH 2 that does not participate in the reaction in IA, IB, IC, ID, R 3 -H or R 3 -Lev, it is preferably protected by a protecting group to avoid any side reactions. If the above protecting group is present, it is necessary to go through the subsequent deprotection step to obtain the compound represented by formula I.
  • Any suitable protecting group such as tert-butoxycarbonyl (Boc), trifluoromethanesulfonyl (Tf) or benzenesulfonyl, can be used for the protection of NH or NH 2 .
  • the subsequent deprotection reaction can be performed under standard conditions, for example, p-toluenesulfonic acid / methanol system, methylene chloride / trifluoroacetic acid system, saturated hydrogen chloride ether solution, or trifluoromethanesulfonic acid trimethyl Carboxymethyl ester / 2,6-lutidine / dichloromethane system; if using trifluoromethanesulfonyl or benzenesulfonyl as the protecting group, the subsequent deprotection reaction can be under standard conditions, for example, sodium hydroxide 3.
  • the pharmaceutically acceptable salt of the heterocyclic fused pyrimidine derivative (I) can be synthesized by a general chemical method.
  • the salt can be prepared by reacting a free base or acid with an equivalent stoichiometric amount or an excess of acid (inorganic acid or organic acid) or base (inorganic base or organic base) in a suitable solvent or solvent composition.
  • the present invention also provides a pharmaceutical composition, which includes a therapeutically effective amount of an active component and a pharmaceutically acceptable excipient;
  • the active component includes a heterocyclic fused pyrimidine derivative (I), its isomer, One or more of a prodrug, a stable isotope derivative, or a pharmaceutically acceptable salt.
  • the active component may further include other therapeutic agents for related diseases caused by abnormal ATR levels.
  • the pharmaceutically acceptable excipient may include a pharmaceutically acceptable carrier, diluent and / or excipient.
  • the pharmaceutical composition can be made into various types of unit dosage forms, such as tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories and injections (solutions and suspensions), etc. , Liquids, suspensions, emulsions, suppositories and injections (solutions and suspensions) are preferred.
  • any excipient known and widely used in the art may be used.
  • carriers such as lactose, white sugar, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, crystalline cellulose, silicic acid, etc .
  • binders such as water, ethanol, propanol, ordinary syrup, glucose solution, starch Solution, gelatin solution, carboxymethyl cellulose, shellac, methyl cellulose and potassium phosphate, polyvinylpyrrolidone, etc .
  • disintegrants such as dry starch, sodium alginate, agar powder and kelp powder, sodium bicarbonate, carbonic acid Calcium, fatty acid esters of polyethylene sorbitan, dodecyl Na 2 SO 4 , monoglyceryl stearate, starch and lactose, etc .
  • disintegration inhibitors such as white sugar, glycerol tristearate, coconut oil Hydrogenated oil
  • Adsorption accelerators such as quaternary am
  • any known and widely used excipients in the art can be used, for example, carriers such as lactose, starch, coconut oil, hardened vegetable oil, kaolin and talc, etc .; , Such as gum arabic powder, tragacanth powder, gelatin and ethanol; disintegrants, such as agar and kelp powder.
  • any excipient known and widely used in the art may be used, for example, polyethylene glycol, coconut oil, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides .
  • the solution or suspension can be sterilized (preferably with an appropriate amount of sodium chloride, glucose or glycerin, etc.) to make an injection that is isotonic with blood.
  • any carrier commonly used in the art may also be used.
  • common dissolving agents, buffering agents and analgesics can also be added.
  • the content of the composition in the pharmaceutical composition is not particularly limited, and can be selected within a wide range, usually 5 to 95% by mass, preferably 30 to 80 by mass %.
  • the administration method of the pharmaceutical composition is not particularly limited. According to the patient's age, sex and other conditions and symptoms, various formulations can be selected for administration. For example, tablets, pills, solutions, suspensions, emulsions, granules, or capsules are administered orally; injections can be administered alone or mixed with injection delivery fluids (such as glucose solution and amino acid solution) for intravenous injection; Medicine to the rectum.
  • various formulations can be selected for administration.
  • injections can be administered alone or mixed with injection delivery fluids (such as glucose solution and amino acid solution) for intravenous injection
  • Medicine to the rectum Medicine to the rectum.
  • the present invention also provides the heterocyclic fused pyrimidine derivative (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of an ATR inhibitor Application.
  • the ATR inhibitor means that it can inhibit ATR activity or expression (including abnormal activity or overexpression of ATR).
  • the present invention also provides the heterocyclic fused pyrimidine derivative (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition has resistance to tumor cell proliferation , Promote the apoptosis of tumor cells and / or resist the invasion of tumor cells. The effect of promoting apoptosis of tumor cells is achieved by inhibiting ATR activity.
  • the present invention also provides the heterocyclic fused pyrimidine derivative (I), its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts, or the pharmaceutical composition in the preparation of treatment, remission And / or the use of drugs to prevent related diseases mediated by ATR.
  • the present invention also provides the heterocyclic fused pyrimidine derivative (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition in the preparation of treatment and / or Or the application of cancer relief drugs.
  • the present invention also provides the heterocyclic fused pyrimidine derivative (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition is prepared in a mammal Application in medicine with anti-proliferative effect in vivo.
  • the present invention also provides the heterocyclic fused pyrimidine derivative (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition is prepared in a mammal Application in medicine with pro-apoptotic effect in vivo.
  • the present invention also provides the heterocyclic fused pyrimidine derivative (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition is prepared in a mammal The application of medicines with anti-cancer cell invasion effect in vivo.
  • the present invention also provides the heterocyclic fused pyrimidine derivative (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition in the treatment and / or Use in cancer relief, which includes administering to a mammal a therapeutically effective dose of a compound represented by formula (I), its isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts, or containing thereof Pharmaceutical composition.
  • the present invention also provides the heterocyclic fused pyrimidine derivative (I), its isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt, or the pharmaceutical composition and one or more Other kinds of therapeutic agents and / or methods for treating cancer are used in combination to treat, alleviate, and / or prevent related diseases mediated by ATR.
  • the related diseases mediated by ATR are related diseases caused by abnormal ATR levels, preferably value-added diseases, and more preferably cancer.
  • the other therapeutic agent for the related diseases mediated by ATR is preferably another kind of therapeutic agent for treating cancer.
  • the other kinds of therapeutic agents for treating cancer can be made into a single-dose therapeutic dosage form with the heterocyclic fused pyrimidine derivative (I), or a single-dose therapeutic dosage form.
  • the other kinds of therapeutic agents for treating cancer may include, but are not limited to: alkylating agents, topozyme I / II inhibitors, anti-mitotic agents, antimetabolites, hormones and hormone analogs, anti- Tumor antibiotics, small molecule kinase inhibitors, small molecule immunomodulators, interferons, aromatase inhibitors, PARP inhibitors, anti-tumor vaccines, cytokines, chimeric antigen receptor T cells (CAR-T), monoclonal antibodies And one or more of radiotherapy.
  • the alkylating agent may be selected from but not limited to: cisplatin, carboplatin, oxaliplatin, nedaplatin, nitrogen mustard, N-oxide-nitrogen mustard hydrochloride, chlorambucil, uracil Nitrogen mustard, cyclophosphamide, ifosfamide, thiotepa, carboquinone, triiminoquinone, inprosulfan tosylate, mannosulfan, trioxifan, busulan, nimustine hydrochloride , Dibromomannitol, melphalan, dacarbazine, ramustine, carmustine, lomustine, streptozotocin, temozolomide, procarbazine, ethyleneimine derivatives, methanesulfonate One or more of the class, nitrosourea, triazene.
  • the topozyme I / II inhibitor may be selected from but not limited to: doxorubicin, daunorubicin, epirubicin, idarubicin, irinotecan, topotecan, lubi One or more of tecan, belotecan, etoposide, teniposide, doxorubicin and dexrazoxane, camptothecin.
  • the anti-mitotic agents include but are not limited to: paclitaxel, docetaxel, polyglutamic acid paclitaxel, isovinblastine, vincristine, vinblastine, vindesine, vinpodine, etoposide, and One or more of nipatoside, ixabepilone, raloxatose, ortataxel, tesetaxel, tocosal, and ispins.
  • the antimetabolite drugs may be selected from but not limited to: folic acid antagonists, pyrimidine analogs, purine analogs, adenosine deaminase inhibitors, such as: methotrexate, 5-fluorouracil, fluorourea One or more of glycosides, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatin and gemcitabine.
  • the hormone therapeutic agent may be selected from, but not limited to: phosphoestrol, diethylstilbestrol, chlorostilbestrol, medroxyprogesterone acetate, megestrol acetate, chlorgesterone acetate, cyproterone acetate , Danazol, dienogest, allyl estradiol, gestrinone, nomegestrol, tonazepam, mepatricin, raloxifene, omemexifen, zomeloxifen, an Lumit, testosterone, anti-estrogen, LH-RH derivatives, aromatase inhibitors, anti-androgens, adrenocortical hormones, androgen synthesis inhibitors, retinoic acid and drugs that delay retinoic acid metabolism One or more.
  • the anti-tumor antibiotics include but are not limited to: actinomycin D, doxorubicin, daunorubicin, bleomycin, pelopromycin, mitomycin C, arubicin , One or more of pirarubicin, epirubicin, netastatin, idarubicin, sirolimus and penrorubicin.
  • the small molecule kinase inhibitors include but are not limited to: erlotinib, imatinib, apatinib, nilotinib, crizotinib, dasatinib, pazopanib , Regefenib, rusolitinib, sorafenib, sunitinib, vandetanib, verofenib, bosutinib, gefitinib, afatinib, axitinib Nigra, dalapini, dacomitinib, nidanib, lovastinib, marcetinib, middoturin, lenatinib, panatinib, redotinib, trametinib , Alanine brinibub, sildenibu, carbotinib malate, ibrutinib, icotinib, cipatinib, cobin
  • the anti-tumor vaccine includes but is not limited to: synthetic peptides, DNA vaccines and recombinant viruses.
  • the cytokine therapy includes but is not limited to: IL2 and GM-CSF.
  • the monoclonal antibodies include but are not limited to: alemtuzumab, bentuximab, cetuximab, rituximab, denosumab, epilimumab, ofatumumab , Monoclonal antibody, panitumumab, tositumomab, trastuzumab, bevacizumab, pertuzumab, catumaxomab, elotuzumab, epalizumab , Rituximab, nimotuzumab, tocilizumab, mattozumab, zalutumumab, atuzumab, ramucirumab, nivolumab, mogamulizumab, One or more of ocaratuzumab, oregovomab, dalotuzumab, onartuzumab.
  • the small molecule immunomodulator includes but is not limited to one or more of TLR7 agonist, TLR8 agonist, TLR9 agonist, IDO inhibitor, CD73 inhibitor, STING inhibitor, A2AR antagonist .
  • the interferon used for cancer treatment includes but is not limited to: interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a or interferon gamma-n1, etc. .
  • the aromatase inhibitors include but are not limited to: one or more of anatozole, aminoglutamide, exemestane, fadrozole, and letrozole.
  • the PARP inhibitors include but are not limited to one or more of Olaparib, Niraparib, Rucaparib, Veliparib, SC10914.
  • the cancer includes metastatic and non-metastatic cancers, and also includes family inherited and sporadic cancers, and may also include solid tumors and non-solid tumors.
  • specific examples of the solid tumor may include but are not limited to: eye, bone, lung, stomach, pancreas, breast, prostate, brain (including glioblastoma and medulloblastoma), ovary (including those Stromal cells, germ cells and stromal cells produced from epithelial cells), bladder, testis, spinal cord, kidney (including adenocarcinoma, nephroblastoma), mouth, lips, throat, oral cavity (including squamous cell carcinoma), nasal cavity , Small intestine, colon, rectum, parathyroid gland, gallbladder, bile duct, cervix, heart, hypopharyngeal gland, bronchus, liver, ureter, vagina, anus, laryngeal gland, thyroid (including thyroid cancer and medullary cancer), esophagus, nose Pharyngeal pituitary, salivary glands, adrenal glands, head and neck intraepithelial neoplasia (including Bow
  • the solid tumor is preferably human eye cancer, bone cancer, lung cancer, gastric cancer, pancreatic cancer, breast cancer, prostate cancer, brain cancer (including but not limited to malignant glioma, medulloblastoma), Ovarian cancer, bladder cancer, cervical cancer, testicular cancer, kidney cancer (including but not limited to adenocarcinoma, renal cell carcinoma), oral cancer (including squamous cell carcinoma), tongue cancer, laryngeal cancer, nasopharyngeal cancer, head and neck Cancer, colon cancer, small intestine cancer, rectal cancer, parathyroid cancer, thyroid cancer, esophageal cancer, gallbladder cancer, cholangiocarcinoma, cervical cancer, liver cancer, lung cancer (including but not limited to small cell lung cancer, non-small cell lung cancer), villi One or more of epithelial cancer, osteosarcoma, Ewing's tumor, soft tissue sarcoma, and skin cancer.
  • brain cancer including but not limited to malignant glioma
  • non-solid tumors may include, but are not limited to: lymphocytic leukemia (including lymphoblastic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia (T-cell chronic lymphoid Leukemia, B-cell chronic lymphocytic leukemia), Hodgkin lymphoma, non-Hodgkin lymphoma), myeloid-associated leukemia (including acute myeloid leukemia, chronic myelogenous leukemia) and AIDs-related leukemia Or more.
  • lymphocytic leukemia including lymphoblastic leukemia, lymphoma, myeloma, chronic lymphocytic leukemia (T-cell chronic lymphoid Leukemia, B-cell chronic lymphocytic leukemia), Hodgkin lymphoma, non-Hodgkin lymphoma), myeloid-associated leukemia (including acute myeloid leukemia, chronic myelogenous leukemia) and
  • the cancer is preferably one or more of the following: non-small cell lung cancer, small cell lung cancer, gastric cancer, esophageal cancer, melanoma, colon cancer, pancreatic cancer, breast cancer, uterine cancer, ovarian cancer, prostate cancer , Brain cancer, bladder cancer, kidney cancer, myeloma, liver cancer, acute myeloid leukemia, chronic myeloid leukemia, lymphoblastic leukemia, chronic lymphocytic leukemia, and lymphoma.
  • the mammal is preferably a human.
  • substitution by one or more groups at any position refers to any one or more hydrogen atoms of one or more atoms specified on the group Substitution, provided that the normal valence of the specified atom is not exceeded, and the substitutions are all reasonable substitutions common in the art. For example, substitution by 1 to 3 groups at arbitrary positions means that they can be reasonably substituted at any position by 1, 2 or 3 identical or different substituents.
  • alkyl refers to a saturated linear or branched hydrocarbon group containing 1-20 carbon atoms, preferably 1-10 carbon atoms, more preferably 1-8, 1-6 or 1-4 carbon atoms, alkyl Representative examples include, but are not limited to: methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, isobutyl, n-pentyl, n-hexyl, n-heptyl, Octyl, nonyl, decyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methyl Butyl, 3-methylbutyl, 1-ethyl-2-methylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethyl Butylbutyl, 2,2-dimethylbutyl, 2,2-d
  • cycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) monocyclic or fused ring group containing 3-20 carbon atoms.
  • the "monocyclic cycloalkyl group” is preferably a 3-10 membered monocyclic alkyl group, more preferably a 3-8 or 3-6 membered monocyclic alkyl group.
  • cycloalkyl examples include but are not limited to: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclododecyl, cyclohexenyl, 2 , 3-dihydro-1-H-indene, decalin, etc.
  • the cycloalkyl group may be linked to the parent molecule through any carbon atom on the ring.
  • heterocycloalkyl refers to a saturated or partially unsaturated (containing 1 or 2 double bonds) 3-20 membered non-aromatic cyclic group composed of carbon atoms and heteroatoms selected from nitrogen, oxygen, or sulfur ,
  • the cyclic group may be a monocyclic ring or a condensed ring group.
  • the number of hetero atoms in the heterocycloalkyl group is preferably 1, 2, 3 or 4, and the nitrogen, carbon or Sulfur atoms can be optionally oxidized.
  • the nitrogen atom may optionally be further substituted with other groups to form a tertiary amine or quaternary ammonium salt.
  • the heterocycloalkyl group is preferably a 3-10 membered monocyclic heterocycloalkyl group, more preferably a 3-6 membered monocyclic heterocycloalkyl group.
  • the heterocyclic alkyl include but are not limited to: aziridinyl, tetrahydrofuran-2-yl, morpholin-4-yl, thiomorpholin-4-yl, thiomorpholin-S-oxide-4 -Yl, piperidin-1-yl, N-alkylpiperidin-4-yl, pyrrolidin-1-yl, N-alkylpyrrolidin-2-yl, piperazin-1-yl, 4-alkyl Piperazin-1-yl and so on.
  • the heterocycloalkyl group can be linked to the parent molecule through any ring atom on the ring.
  • the above ring atom refers specifically to a carbon atom and / or a nitrogen atom constituting a ring skeleton.
  • bridged ring group refers to a group formed by connecting any two unlinked ring atoms of a cycloalkyl group or a heterocycloalkyl group with a linear group formed by one or more additional carbon atoms or hetero atoms.
  • the linear group is selected from but not limited to: -CH 2- , -O-, -NH-, -S-, -CH 2 CH 2- , -CH 2 O-, -CH 2 S-, -CH 2 NH-, -CH 2 CH 2 CH 2- , -CH 2 OCH 2- , -CH 2 CH 2 O-, -CH 2 CH 2 NH-.
  • cycloalkylalkyl refers to the connection between the cycloalkyl group and the parent core structure through an alkyl group.
  • cycloalkylalkyl includes the above definitions of alkyl and cycloalkyl.
  • heterocycloalkylalkyl refers to the connection between the heterocycloalkyl group and the parent core structure through an alkyl group.
  • heterocycloalkylalkyl includes the above definitions of alkyl and heterocycloalkyl.
  • alkoxy refers to a cyclic or acyclic alkyl group having the number of carbon atoms connected through an oxygen bridge, and includes alkyloxy, cycloalkyloxy, and heterocycloalkyloxy groups. Thus, “alkoxy” includes the above definitions of alkyl, heterocycloalkyl, and cycloalkyl.
  • alkenyl refers to a linear, branched or cyclic non-aromatic hydrocarbon group containing at least one carbon-carbon double bond. There may be 1-3 carbon-carbon double bonds, preferably one carbon-carbon double bond.
  • C 2-4 alkenyl refers to an alkenyl group having 2-4 carbon atoms
  • C 2-6 alkenyl refers to an alkenyl group having 2-6 carbon atoms, including vinyl, propenyl , Butenyl, 2-methylbutenyl and cyclohexenyl.
  • alkynyl refers to a linear, branched, or cyclic hydrocarbon group containing at least one carbon-carbon triple bond. There may be 1-3 carbon-carbon triple bonds, preferably one carbon-carbon triple bond.
  • C 2-6 alkynyl refers to an alkynyl group having 2 to 6 carbon atoms, including ethynyl, propynyl, butynyl, and 3-methylbutynyl.
  • aryl refers to any stable 6-10 membered monocyclic or fused aromatic group, wherein at least one ring of the fused aromatic group is a benzene ring, and the remaining rings may be benzene rings, Monocyclic cycloalkyl or monocyclic heterocycloalkyl.
  • the aryl group includes but is not limited to: phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, biphenyl, benzo [d] [1,3] dioxolyl, ind Indoline Isoindolinyl 2,3-dihydrobenzofuranyl 2,3-dihydrobenzo [b] thienyl Benzopyranyl 1,2,3,4-tetrahydroquinolinyl 1,2,3,4-tetrahydroisoquinolinyl 2,2-Dioxide-1,3-dihydrobenzo [c] isothiazolyl 1,1-dihydrobenzothiopyranyl 1,1-Dioxide-2,3-dihydrobenzo [b] thienyl 1-imino-1-oxy-2,3-dihydrobenzo [b] thienyl 2-oxo-2,3-dihydro-1H-benzo [d
  • heteroaryl refers to an aromatic ring group formed by replacing at least one ring carbon atom with a heteroatom selected from nitrogen, oxygen, or sulfur, which may be a 5-7 membered monocyclic structure or 7-12 A member-fused ring structure, wherein at least one ring in the fused ring structure is a heteroaryl group, and the remaining rings may be optionally an aromatic ring, a heteroaromatic ring, a cycloalkyl group, or a heterocycloalkyl group.
  • the number of hetero atoms is preferably 1, 2, 3, or 4, and the nitrogen atom in the heteroaryl group may be optionally oxidized.
  • the heteroaryl group is preferably a 5-10 membered heteroaryl group, including but not limited to: pyridyl, pyrimidinyl, pyrazinyl, pyridazin-3 (2H) -keto, furanyl, thienyl, thiazolyl, Pyrrolyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, 1,2,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1H-1,2,4-triazole Azazolyl 4H-1,2,4-triazolyl 1H-1,2,3-triazolyl 1H-Tetrazolyl 1H-indazolyl 1H-pyrazolo [3,4-b] pyridyl 1H-pyrazolo [3,4-c] pyridyl 1H-pyrazolo [4,3-c] pyridyl 1H-pyrazolo [4,3-c
  • arylalkyl refers to the connection between the aryl group and the parent core structure through an alkyl group.
  • arylalkyl includes the above definitions of alkyl and aryl.
  • heteroarylalkyl refers to the connection between the heterocycloalkyl group and the parent core structure through an alkyl group.
  • heteroarylalkyl includes the above definitions of alkyl and heteroaryl.
  • halogen means fluorine, chlorine, bromine or iodine.
  • haloalkyl refers to an alkyl group optionally substituted with halogen.
  • haloalkyl includes the above definitions of halogen and alkyl.
  • haloalkoxy refers to an alkoxy group optionally substituted with halogen.
  • haloalkoxy includes the above definitions of halogen and alkoxy.
  • amino refers to -NH 2
  • alkylamino refers to the substitution of at least one hydrogen atom on the amino group by an alkyl group, including but not limited to: -NHCH 3 , -N (CH 3 ) 2 , -NHCH 2 CH 3 , -N (CH 2 CH 3 ) 2 , -N (CH 3 ) (CH 2 CH 3 ).
  • alkylamino includes the above definitions of alkyl and amino.
  • room temperature in the present invention refers to 15-30 ° C.
  • the isotopically substituted derivatives include: isotope-substituted derivatives obtained by replacing any hydrogen atom in formula I with 1-5 deuterium atoms, and isotopes in which any carbon atom in formula I is substituted with 1-3 carbon 14 atoms Substituted derivatives or isotope substituted derivatives obtained by replacing any oxygen atom in formula I with 1-3 oxygen 18 atoms.
  • prodrug refers to the conversion of the compound into the original active compound after metabolism in the body.
  • the prodrug is an inactive substance, or less active than the active parent compound, but can provide convenient handling, administration, or improved metabolic properties.
  • the “pharmaceutically acceptable salts” of the present invention are discussed in Berge, et al., “Pharmaceutically Acceptable Salts", J. Pharm. Sci., 66, 1-19 (1977), It is obvious that the salts are essentially non-toxic and can provide the required pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion.
  • the compound of the present invention may have an acidic group, a basic group or an amphoteric group.
  • Typical pharmaceutically acceptable salts include salts prepared by reacting the compound of the present invention with an acid, for example: hydrochloride, hydrobromic acid Salt, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogen phosphate, dihydrogen phosphate, metaphosphate, pyrophosphate, nitrate, acetate, Propionate, caprate, caprylate, formate, acrylate, isobutyrate, caproate, enanthate, oxalate, malonate, succinate, suberate, Benzoate, methylbenzoate, phthalate, maleate, mesylate, p-toluenesulfonate, (D, L) -tartaric acid, citric acid, maleic acid, (D, L) -malic acid, fumaric acid, succinic acid, succinate, lactate, triflate, naphthalene-1-sul
  • its pharmaceutically acceptable salts may also include: alkali metal salts, such as sodium or potassium salts; alkaline earth metal salts, such as calcium or magnesium salts; organic alkali salts, such as ammonia and alkyl Salts formed by base aminos, hydroxyalkyl aminos, amino acids (lysine, arginine), N-methylglucamine, etc.
  • alkali metal salts such as sodium or potassium salts
  • alkaline earth metal salts such as calcium or magnesium salts
  • organic alkali salts such as ammonia and alkyl Salts formed by base aminos, hydroxyalkyl aminos, amino acids (lysine, arginine), N-methylglucamine, etc.
  • the “isomer” in the present invention means that the compound of formula (I) of the present invention may have an asymmetric center and a racemate, a racemic mixture, and a single diastereomer, all of these isomers, including Stereoisomers, geometric isomers, and atropisomers are all included in the present invention.
  • the compound of formula I or its salt exists in stereoisomeric form (for example, it contains one or more asymmetric carbon atoms)
  • the individual stereoisomers (enantiomers and diastereomers) Isomers) and mixtures thereof are included within the scope of the present invention.
  • the invention also includes individual isomers of compounds or salts represented by formula I, and mixtures of isomers in which one or more chiral centers are inverted.
  • the scope of the present invention includes mixtures of stereoisomers, as well as purified enantiomers or enantiomer / diastereomer-enriched mixtures.
  • the present invention includes all enantiomers and mixtures of stereoisomers of all possible different combinations of diastereomers.
  • the present invention includes all combinations and subsets of the stereoisomers of all specific groups defined above.
  • the invention also includes geometric isomers of compounds of formula I or salts thereof, said geometric isomers including cis-trans isomers.
  • the reagents and raw materials used in the present invention are commercially available.
  • the structures of all compounds of the present invention can be identified by nuclear magnetic resonance ( 1 H NMR) and / or mass spectrometry (MS).
  • MS Low resolution mass spectrometry
  • the purification of the compounds and intermediates of the present invention can be carried out by conventional preparation of silica gel plates or by use of a rapid separator.
  • the elution system can be an EtOAc / PE system or a DCM / MeOH system.
  • Preparative HPLC can also be used for separation.
  • a high performance liquid chromatograph uses SHIMADZU LC-20 to prepare liquid chromatography.
  • the column is: waters xbridge Pre C18, 10um, 19 ⁇ 260mm.
  • Purification conditions 1-1 Elution gradient, mobile phase B: 15-70% (v / v%), elution time 20 minutes, mobile phase A: 10 mM NH 4 HCO 3 (aq), mobile phase B: acetonitrile;
  • Purification conditions 1-2 gradient elution: mobile phase B from 20% to 35%, elution time 5 minutes, mobile phase B from 35% to 60%, elution time 15 minutes, mobile phase A: 10 mM NH 4 HCO 3 (aq), mobile phase B: acetonitrile;
  • purification conditions 1-3 gradient elution: mobile phase B from 20% to 50%, elution time 8 minutes, mobile phase B from 50% to 80%, elution time 12 minutes, mobile phase A: 10 mM NH 4 HCO 3 (aq), mobile phase B
  • the thin-layer silicone board is Yantai Huanghai HSGF254 or Qingdao GF254 silicone board.
  • Flash column chromatography flash system / Cheetah TM
  • Agela Technologies MP200 Flash columm Silica-CS (80g), Cat No. CS140080-0.
  • All compounds of the present invention can be analyzed by an ultra-high performance liquid chromatograph (UPLC) using the Waters ACQUITY Hclass platform, the chromatography column is: Waters ACQUITY UPLC BEH Shield RP18 2.1mm * 100mm, 1.7um, mobile phase A: acetonitrile, mobile phase B: 5mm potassium dihydrogen phosphate aqueous solution (adjust pH to 2.5 with phosphoric acid). Gradient elution time 15 minutes, flow rate: 0.4mL / min, detection wavelength: 214nm &254nm; column temperature: 40 ° C; injection volume 1uL; gradient elution conditions are as follows:
  • Step 2 To a mixed solution of intermediate 1-2 (10g, 48.7mmol) in acetone / water (160mL / 80mL) was added K 2 OsO 4 ⁇ 2H 2 O (500mg, 13.6mmol) and N-methyl-N -Oxidized morpholine (11.4 g, 97.3 mmol). The resulting mixture was stirred at room temperature for 2 hours, and NaIO 4 (31.2 mg, 13.6 mmol) was added to the reaction system. After the mixture was stirred at room temperature overnight, water (80 mL) was added to quench the reaction, filtered, and the filtrate was extracted with EtOAc (150 mL ⁇ 3).
  • Step 3 To a solution of intermediate 1-3 (17.5 g, 84.5 mmol) and (R) -3-methylmorpholine (8.6 g, 84.5 mmol) in EtOH (160 mL) was added DIPEA (21.5 mL, 127 mmol). The resulting mixture was stirred at 80 ° C for 8 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was extracted with EtOAc (100 mL ⁇ 3).
  • Step 4 Under ice bath conditions, to a solution of Intermediate 1-4 (15 g, 55.5 mmol) in MeOH (120 mL) was added NaBH 4 (2.57 g, 71.8 mmol) in portions, and the resulting mixture was stirred at room temperature for 2 hours. Then, the reaction liquid was cooled to 0 ° C, and the pH of the reaction liquid was adjusted to 7-8 with hydrochloric acid (1M). The reaction solution was concentrated under reduced pressure, and the residue was extracted with EtOAc (100 mL ⁇ 3). The organic phase was dried over anhydrous Na 2 SO 4 and filtered.
  • Step 5 To a solution of intermediate 1-5 (3 g, 11 mmol) in 1,2-dichloroethane (200 mL) was added anhydrous AlCl 3 (7.3 g, 55 mmol). The resulting mixture was stirred at 65 ° C for 2 hours. After the mixture was cooled to 0 ° C, hydrochloric acid (1M, 30 mL) was slowly added, and the reaction solution was extracted with DCM / MeOH (10/1) (100 mL ⁇ 3).
  • Step 6 To a solution of intermediate 1-6 (500 mg, 1.93 mmol) in MeOH (15 mL) was added MeONa (104 mg, 1.93 mmol). The reaction system was stirred at room temperature for 2 hours. After concentration under reduced pressure, 1,2-dibromoethane (1.8 g, 9.65 mmol) and DMF (10 mL) were added to the residue. The reaction solution was stirred at room temperature overnight and then extracted with EtOAc (30 mL ⁇ 3).
  • Step 7 Under ice bath conditions, add MsCl (191 mg, 1.67 mmol) to a solution of Intermediate 1-7 (406 mg, 1.11 mmol), TEA (337 mg, 3.33 mmol) in DCM (10 mL). After the resulting mixture was stirred at 0 ° C for 1 hour, the reaction was quenched with water (5 mL), and extracted with EtOAc (30 mL ⁇ 2). The organic phase was washed with saturated NaCl (aq), dried over anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to give Intermediate 1-8 (480 mg) as a yellow oil. m / z: [M + H] + 443.8.
  • Step 10 Under ice bath conditions, add t-BuONa (78 mg, 0.81 mmol) to a solution of Intermediate 1-10 (290 mg, 0.68 mmol) in DMF (60 mL). After the resulting mixture was stirred at 0 ° C for 15 minutes, add it again t-BuONa (78 mg, 0.81 mmol) and CH 3 I (97 mg, 0.68 mmol). Stirring was continued for 20 minutes at 0 ° C, water (30 mL) was added to quench the reaction, and then EtOAc was extracted (50 mL ⁇ 3).
  • Step 1 To the mixed solution of intermediate 1-11 (100 mg, 0.28 mmol) in 1,4-dioxane / water (8 mL / 1.5 mL) was added intermediate 1-12 (143 mg, 0.42 mmol), Pd ( PPh 3 ) 4 (35 mg, 0.03 mmol) and K 2 CO 3 (116 mg, 0.84 mmol). The reaction system was replaced with nitrogen and stirred at 100 ° C. for 3 hours. After the reaction system was cooled to room temperature, it was extracted with a mixed solvent of DCM / MeOH (10/1) (30 mL ⁇ 2). The organic phase was dried over anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain compound X-1 (280 mg, crude product) as a brown oil. m / z: [M + H] + 544.0.
  • Step 3 Under ice bath conditions, t-BuONa (25 mg, 0.26 mmol) was added to a solution of Intermediate 2-2 (120 mg, 0.24 mmol) in DMF (30 mL), and the resulting mixture was stirred at 0 ° C for 30 minutes, and then again Add t-BuONa (34 mg, 0.35 mmol). The reaction system was further stirred at room temperature for 1 hour, water (15 mL) was added to quench the reaction, and the aqueous phase was extracted with EtOAc (30 mL ⁇ 3).
  • Step 1 To a solution of intermediate 1-6 (1.15 g, 4.44 mmol) in MeOH (50 mL) was added MeONa (240 mg, 4.44 mmol). The reaction solution was stirred at room temperature for 2 hours. It was then concentrated under reduced pressure, and diethyl bromomalonate (3.18 g, 13.3 mmol) and DMF (30 mL) were added to the residue. The resulting mixture was stirred at room temperature overnight and extracted with EtOAc (50 mL ⁇ 3).
  • Step 3 Under ice bath conditions, to a mixture solution of intermediate 3-2 (260 mg, 0.78 mmol) and TEA (467 mg, 4.62 mmol) in DCM (20 mL) and THF (4 mL) was added MsCl (446 mg, 3.89 mmol). The reaction system was stirred at 0 ° C for 1 hour, quenched with water (5 mL), and extracted with EtOAc (30 mL ⁇ 3). The organic phase was washed with saturated NaCl (aq), dried over anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain Intermediate 3-3 (400 mg) as a yellow oil. m / z: [M + H] + 567.8.
  • Step 6 Under ice bath conditions, add t-BuONa (25 mg, 0.26 mmol) to the intermediate 3-5 (160 mg, 0.26 mmol) in DMF (30 mL) solution, and after the reaction system was stirred at 0 ° C for 20 minutes, again Add t-BuONa (25 mg, 0.26 mmol). The reaction system was further stirred at 0 ° C. for 20 minutes, water (15 mL) was added, and then extracted with EtOAc (50 mL ⁇ 3).
  • the compound 5-1 was obtained by reacting with the intermediate 4-2 (purification method: prep-HPLC, condition 2-2).
  • Example 7 4-((R) -3-methylmorpholinyl) -8- (S-methylsulfinimido) -2- (1H-pyrrolo [2,3-b] pyridine -4-yl) -7,8-dihydro-6H-6,8-methylenepyrano [3,2-d] pyrimidine hydrochloride (compound 7)
  • m / z [M + H] + 599.6.
  • Step 4 Under ice bath conditions, t-BuONa (144 mg, 1.5 mmol) was added to the intermediate 5-3 (900 mg, 1.5 mmol) in DMF (55 mL), the reaction system was stirred at 0 ° C. for 20 minutes, and t was added again -BuONa (144 mg, 1.5 mmol). The reaction system was further stirred at 0 ° C for 20 minutes, water (50 mL) was added, and then extracted with EtOAc (80 mL ⁇ 3).
  • Step 5 To a DCM solution of intermediate 5-4 (375 mg, 1.09 mmol) and trifluoroacetamide (247 mg, 2.19 mmol), add MgO (174 mg, 4.36 mmol), iodobenzene diacetic acid (364 mg, 1.09 mmol) and Rhodium acetate (145 mg, 0.33 mmol). The reaction solution was refluxed and stirred for 2 days (during which additional 2 eq of MgO, 0.5 eq of iodophthalic acid and 0.15 eq of rhodium acetate were added, a total of 8 additional times).
  • Step 1 To the mixed solution of intermediate 5-5 (56 mg, 0.12 mmol) in 1,4-dioxane / water (8 mL / 1.6 mL) was added intermediate 1-12 (76 mg, 0.22 mmol), Pd ( PPh 3 ) 4 (28 mg, 0.02 mmol) and K 2 CO 3 (50 mg, 0.36 mmol). The reaction system was replaced with nitrogen and stirred at 96 ° C. for 1.5 hours. After the reaction system was cooled to room temperature, it was extracted with a mixed solvent of DCM / MeOH (10/1) (30 mL ⁇ 2).
  • Step 2 Compound Y-1 (53 mg, 0.10 mmol) and TFA (1 mL) in DCM (5 mL) were stirred at room temperature for 1 hour. The organic solvent was concentrated under reduced pressure, and the residue was adjusted to pH 7-8 with saturated NaHCO 3 (aq) and extracted with EtOAc (30 mL ⁇ 3). The organic phases were combined and dried with anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Condition: 2-3) to obtain compound 7 (18 mg, yield: 42%) as a pale yellow solid.
  • Step 1 Under ice bath conditions, m-CPBA (3.09g, 15.2mmol) was slowly added to a solution of 4-bromo-1H-pyrrolo [2,3-b] pyridine (2g, 10.2mmol) in DCM (60mL). . After the addition is complete, stir at room temperature overnight. DCM (40 mL) was added to the reaction system, the organic phase was washed with saturated NaHCO 3 (aq) and saturated NaCl (aq), dried over anhydrous Na 2 SO 4 , and filtered, and the filtrate was concentrated under reduced pressure to obtain intermediate 7-1 (1.1 g ) Is a brown oil. m / z: [M + H] + 213.0.
  • Step 2 Intermediate 7-1 (300 mg, 1.41 mmol) was dissolved in DMF (2.5 mL), and MsCl (403 mg, 3.52 mmol) was slowly added at 50 ° C. After the reaction system was stirred at 75 ° C for 2 hours, it was cooled to room temperature, and water (5 mL) was added to the reaction system. The pH was adjusted to 7 with NaOH (aq) (6N) at 0 ° C. The mixture was stirred at room temperature for 3 hours, and the aqueous phase was extracted with EtOAc.
  • Step 3 To a solution of intermediate 7-2 (140 mg, 0.60 mmol) in DCM (10 mL) was added TEA (0.25 mL, 1.80 mmol), (Boc) 2 O (198 mg, 0.91 mmol) and DMAP (8 mg, 0.06 mmol) ). The reaction system was stirred at room temperature for 2 hours. The reaction solution was washed with hydrochloric acid (1N) and saturated NaCl (aq), dried over anhydrous Na 2 SO 4 , and filtered. The filtrate was concentrated under reduced pressure to obtain Intermediate 7-3 (214 mg) as a yellow oil. m / z: [M + H] + 330.9.
  • Step 1 A solution of 2-fluoro-4-methyl-5-nitropyridine (1 g, 6.41 mmol) and DMFDMA (1.7 g, 14.1 mmol) in DMF (6 mL) was stirred at 90 ° C for 3 hours. After the reaction solution was cooled to room temperature, it was directly poured into ice water, filtered, and the filter cake was dried in vacuum to obtain Intermediate 11-1 (1.2 g) as a red solid.
  • m / z [M + H] + 212.2.
  • Step 2 To a mixed solution of intermediate 11-1 (600 mg, 2.84 mmol) in MeOH (50 mL) and DCM (10 mL), acetic acid (3.5 mL) and palladium carbon (300 mg, 10%) were added, and the resulting mixture was hydrogenated Replace 3 times and then stir under hydrogen atmosphere at room temperature overnight. The reaction solution was filtered, and the filtrate was concentrated to obtain Intermediate 11-2 (322 mg) as an off-white solid. m / z: [M + H] + 137.0.
  • Example 18 (R) -5-fluoro-N-methyl-1- (4- (3-methylmorpholinyl) -8- (methylsulfonyl) -7,8-dihydro-6H- 6,8-methylenepyrano [3,2-d] pyrimidin-2-yl) -1H-benzo [d] imidazol-2-amine (Compound 18) and Example 19: (R) -6 -Fluoro-N-methyl-1- (4- (3-methylmorpholinyl) -8- (methylsulfonyl) -7,8-dihydro-6H-6,8-methylenepyran Synthesis of benzo [3,2-d] pyrimidin-2-yl) -1H-benzo [d] imidazol-2-amine (Compound 19)
  • Step 2 A mixture of compound U-1 (80 mg, crude product) and palladium carbon (50 mg) in MeOH (30 mL) was replaced with hydrogen three times, and then the reaction system was stirred at room temperature overnight under a hydrogen atmosphere. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure to obtain compound U-2 (70 mg, crude product) as a red-brown solid.
  • m / z [M + H] +450.0.
  • Step 3 A solution of compound U-2 (70 mg, 0.16 mmol) and BrCN (83 mg, 0.78 mmol) in MeOH (5 mL) was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Condition 1-2) to obtain compound 20 (2.68 mg, three-step yield: 2%) as a white solid.
  • Step 1 CuI (3mg, 0.014mmol) was added to the intermediate 9-1 (87mg, 0.14mmol), 12-1 (81mg, 0.21mmol), pd (pph 3 ) 4 (16mg, 0.014mmol) of 1,
  • m / z [M + H] + 627.0.
  • Step 3 Raney nickel (30 mg) was added to a solution of compound V-1 (60 mg, 0.09 mmol) in THF (20 mL), the reaction system was replaced with hydrogen three times, and the mixture was stirred overnight at room temperature under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure to obtain compound V-2 (54 mg, yield: 90%) as a white solid.
  • m / z [M + H] + 597.0.
  • Step 4 Cs 2 CO 3 (118 mg, 0.36 mmol) was added to a solution of compound V-2 (54 mg, 0.09 mmol) in THF (3 mL) and trifluoroethanol (3 mL), the reaction system was replaced with nitrogen three times, and then refluxed Stir for 2 days. Filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Condition 1-3) to obtain compound 22 (14 mg, yield: 34%) as a yellow solid.
  • Step 1 Under ice bath conditions, to a solution of compound 14 (28 mg, 0.06 mmol) in THF (12 mL) was added NaH (60%, 10 mg, 0.24 mmol). After the reaction system was stirred at 0 ° C for 0.5 hours, benzenesulfonyl chloride was added (44 mg, 0.24 mmol), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was poured into saturated NH 4 Cl (aq) and extracted with EtOAc, the organic phase was separated and concentrated under reduced pressure to obtain compound W-1 (30 mg, crude product) as a white solid. m / z: [M + H] + 600.0.
  • Step 2 A methylamine ethanol solution (30%, 9 mL) of compound W-1 (30 mg, crude product) was stirred at 120 ° C. in a sealed tube overnight. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Condition 3-2) to obtain compound 27 (14.8 mg, two-step yield: 42%) as a yellow solid.
  • Example 29 (R) -N-methyl-1- (4- (3-methylmorpholinyl) -8- (methylsulfonyl) -7,8-dihydro-6H-6,8- Methylenepyrano [3,2-d] pyrimidin-2-yl) -1H-imidazo [4,5-c] pyridin-2-amine (Compound 29),
  • Example 30 (R) -N -Methyl-3- (4- (3-methylmorpholinyl) -8- (methylsulfonyl) -7,8-dihydro-6H-6,8-methylenepyrano [3, 2-d] pyrimidin-2-yl) -1H-imidazo [4,5-c] pyridin-2-amine (Compound 30) and Example 31: (R) -N- (3H-imidazo [4, 5-c] pyridin-2-yl) -N-methyl-4- (3-methylmorpholinyl) -8- (methylsulfonyl) -7,8-d
  • Step 1 A mixed solution of compound V-2 (10 mg, 0.017 mmol) in formic acid (0.5 mL) and acetic anhydride (0.5 mL) was stirred at 100 ° C. for 1 hour. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, the residue was dissolved in EtOAc, the organic phase was washed with saturated NaHCO 3 (aq) and saturated NaCl (aq), dried over anhydrous Na 2 SO 4 and filtered, and the filtrate was concentrated under reduced pressure to obtain the compound V-3 (15 mg, crude product) is a yellow solid.
  • m / z [M + H] + 625.0.
  • Step 3 Under nitrogen protection, NaOH (20 mg, 0.03 mmol) was added to the compound V-4 (5 mg, 7.6 ⁇ mol) in MeOH (2 mL) solution, and the reaction solution was stirred under reflux for 16 hours. After cooling to room temperature, the reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Method 1-4) to obtain compound 32 (0.34 mg, yield: 10%) as a yellow solid.
  • UPLCRT 4.179min; m / z: [M + H] + 471.2.
  • Step 1 To a solution of ethyl 2-methylpyrrole-3-carboxylate (500 mg, 3.26 mmol) in MeOH (20 mL) was added cerium ammonium nitrate (7.35 g, 13.4 mmol) and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by flash column chromatography (100% EtOAc) to obtain intermediate 18-1 (60 mg) as a yellow solid. m / z: [M + H] + 168.0.
  • m / z [M + H] + 136.0.
  • Step 2 To a solution of compound A-1 (20 mg) in MeOH (5 mL) was added NaOH (aq) (3 drops, 2N), and the resulting mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by prep-HPLC (Condition 3-3) to obtain compound 40 (1.54 mg, yield: 10%) as a yellow solid.
  • Step 1 Dissolve thiophene-3,4-diamine (300mg, 1.6mmol), TEA (324mg, 3.2mmol) and methyl isothiocyanate (117mg, 1.6mmol) in THF (10mL) solution, the reaction solution Stir at reflux for 3 hours. After cooling to room temperature, it was concentrated under reduced pressure to obtain Intermediate 19-1 (300 mg) as an oily liquid.
  • m / z [M + H] + 188.0.
  • Step 1 Compound B-1 (using the synthesis method of U-2, using 3-6 and 2-fluoro-6-nitroaniline to obtain compound B-1) (60mg, 0.133mmol), TEA (14mg, 0.133 mmol) and methyl isothiocyanate (29 mg, 0.4 mmol) in THF (5 mL) were stirred at reflux for 16 hours. The reaction system was cooled to room temperature and concentrated under reduced pressure to obtain compound B-2 (69 mg, yield: 100%) as a brown solid. m / z: [M + H] +522.6.
  • Step 2 A solution of compound B-2 (69 mg, 0.13 mmol) and CH 3 I (38 mg, 0.27 mmol) in EtOH (5 mL) was stirred at reflux overnight. The reaction solution was cooled to room temperature and concentrated under reduced pressure. The residue was purified by prep-HPLC (Condition 1-2) to obtain 57 (3.5 mg, yield: 5%) as a white solid.
  • Step 1 To a solution of intermediate 25-1 (47.8 mg, 0.16 mmol) and 9-1 (100 mg, 0.16 mmol) in 1,4-dioxane (2 mL) was added Pd (PPh 3 ) 4 (18.8 mg , 0.01 mmol) and CuI (3.1 mg, 0.01 mmol), the reaction system was replaced with nitrogen and stirred at 120 ° C. for 16 hours. Concentrate under reduced pressure to obtain compound D-1 (crude product).
  • Step 2 To a mixed solution of compound D-1 (crude product) in THF / MeOH / H 2 O (3mL / 3mL / 3mL) was added t-BuOK (143mg, 1.28mmol), and the reaction system was stirred at 55 ° C overnight . The reaction solution was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by prep-HPLC (Condition 3-2) to obtain compound 59 (6.12 mg, two-step yield: 7%) as a yellow solid.
  • Step 1 EtOH solution of intermediate 12-1 (2g, 5.25mmol) is / H 2 O (60mL / 6mL ) was added a mixed solution of iron powder (2.94g, 52.5mmol) and ammonium chloride (2.81g, 52.5mmol) .
  • the reaction solution was stirred at 80 ° C for 1 hour. After cooling to room temperature, the solid was filtered off. The filtrate was concentrated under reduced pressure and diluted with EtOAc (100 mL). The organic phase was washed with saturated NaCl (aq). The organic phase was separated and concentrated under reduced pressure to obtain Intermediate 12-2 (1.65 g) as a brown solid.
  • Step 1 To compound C-1 (according to the synthesis method of compound V-2, using intermediates 9-1 and 12-4 to give C-1) (58 mg, 0.04 mmol) in THF / MeOH / H 2 O (2.0 mL / 2.0mL / 0.5mL) was added t-BuOK (36mg, 0.32mmol) to the mixed solution, and the reaction solution was stirred at 50 ° C for 12 hours. It was then concentrated under reduced pressure to obtain compound C-2 (crude product). m / z: [M + H-56] + 525.7.
  • Step 2 To a solution of compound C-2 (crude product) in DCM (5 mL) was added TFA (1 mL), and the reaction solution was stirred at room temperature for 1 hour. It was then concentrated under reduced pressure, and the residue was purified by prep-HPLC (Condition 3-6) to obtain Compound 60 (3.6 mg, two-step yield: 18%) as a yellow solid.
  • Step 3 At 0 ° C, m-CPBA (197 mg, 0.97 mmol) was added to a solution of intermediate 12-6 (210 mg, 0.65 mmol) in DCM (20 mL), and stirred at room temperature for 4 hours. DCM (40 mL) was added, the organic phase was washed with saturated NaHCO 3 (aq) and saturated NaCl (aq), and concentrated under reduced pressure, and the residue was purified with prep-TLC (EtOAc) to obtain intermediate 12-7 (160 mg) as a yellow solid. . m / z: [M + H] + 341.8.
  • Step 4 To a solution of intermediate 12-7 (130 mg, 0.38 mmol) in acetonitrile (3.0 mL) was added TMSCN (565 mg, 5.70 mmol), and the reaction solution was stirred at 100 ° C. for 16 hours in a sealed tube. The reaction solution was concentrated under reduced pressure and purified by prep-HPLC to obtain intermediate 12-8 (15 mg) as a yellow solid. m / z: [M + H] + 250.9.
  • intermediate 84-1 was reacted with 1-methyl-1H-benzo [d] imidazol-2 (3H) -one to obtain compound 84;
  • ATR protein phosphorylates P53 substrate, and the level of phosphorylated P53 was detected by HTRF method of Cisbio Bioassays.
  • the components of the reaction buffer used in the experiment were: 25 mM HEPES pH 8.0, 0.01% Brij-35, 1% Glycerol.
  • the composition of the dilution buffer is: 25 mM HEPES pH 8.0, 0.01% Brij-35, 1% Glycerol, 5 mM DTT, 1 mg / ml BSA.
  • the components of the stop solution are: 12.5 mM HEPES pH 8.0, 0.005% Brij-35, 0.5% Glycerol, 250 mM EDTA.
  • the components of the detection solution are: 50 mM HEPES pH 7.0, 150 mM NaCl, 267 mM KF, 0.1% sodium cholate, 0.01% Tween 20, 0.42 ng / well anti-phospho-p53 (Ser15) -K (CisBio, 61P08KAE), and 25 ng / Well anti-GST-d2 (CisBio, 61GSTDLA).
  • the 10ul ATR reaction system includes 5ng ATR (Eurofins, 14-953), 10nM P53 substrate (Eurofins, 14-952), 1uM ATP and different concentrations of the test compound. The reaction system was incubated at room temperature for 30 minutes, and then 5ul of stop solution was added.
  • ATR is activated and phosphorylates its downstream kinase Chk1, and Chk1 plays a vital role in DNA damage checkpoint control.
  • the CHK1 p-Ser345 kit was used to determine endogenous Chk1 phosphorylation in HT29 colon cancer cells. The experiment was conducted according to the manufacturer's experimental protocol. In short, HT29 cells were plated on 96-well cell culture plates with 100ul of 5x105 cells / ml RPMI-1640 medium and 10% serum, and cultured at 37 ° C overnight. The next day, cells were added with new serum-free RPMI-1640 medium and cultured at 37 ° C for 2h. The concentration range of the test compound is created by diluting 100% DMSO and then further diluting it with serum-free medium. Cells were added with diluted compounds and incubated at 37 ° C for 1 h.
  • the cells were added with 4-NQO at a final concentration of 10 ⁇ M and the incubation was continued for 30 min at 37 ° C. Finally, the cells were added with 1X lysis buffer and shaken on a plate shaker (about 350 rpm) for 10 min at room temperature. 4 ⁇ l of cell lysate was transferred 384-well plate. Add 5 ⁇ l of Acceptor Mix reagent, seal with Topseal membrane, and incubate at room temperature for 2h. Finally add 2 ⁇ l Donor Mix reagent, seal with membrane and cover foil. The reaction was incubated at room temperature for 2h, and then tested on the TECAN M1000 Pro plate reader using standard AlphaScreen settings. The test results are as follows:
  • the cell test method is used to evaluate the biological activity of the compound.
  • LOVO Nelol
  • a human colon cancer cell line cultured in Dulbecco's Modified Eagle's medium 96-well plate, supplemented with 10% fetal bovine serum and 1% P / S, cultured at 37 ° C and 5% CO 2 .
  • the compound concentration ranges from 4.5nM to 30 ⁇ M.
  • the test compound stock solution was dissolved in DMSO and added to the medium of the indicated concentration, and incubated for 72 hours. Negative control cells were treated with vehicles only. In some experiments, known ATR inhibitors were added as positive controls.
  • CCG Cell titer glo kit
  • Use Graphpad software to analyze the data, and get IC50 value and compound fitting curve.
  • Compound number IC 50 (nM) Compound number IC 50 (nM) 1 485.1 27 15.26 2 327.5 28 119.4 3 290.8 32 66.71 4 133.1 34 116.4 6 123.5 35 213.6 7 477.8 37 240.3 8 25.78 41 65.23 9 47.99 45 227.9 11 202.8 46 24.81 14 155.7 49 64.05 18 157.8 62 368.9 19 203.4 67 415.4 20 232.6 70 187.4 twenty two 62.27 72 110.9 twenty three 169.3 74 67.55 26 63.16 76 246.4

Abstract

一种杂环稠合嘧啶衍生物、其药物组合物及应用。杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐具有如下结构。杂环稠合嘧啶衍生物在体内和体外均具有良好的抑制ATR水平的作用，进一步的杂环稠合嘧啶衍生物还可以有效治疗由于ATR水平失常引起的疾病，例如：癌症。

Description

杂环稠合嘧啶衍生物、其药物组合物及应用
本申请要求申请日为2018年11月22日的中国专利申请CN201811401357.5、申请日为2019年2月1日的中国专利申请CN201910102883.X、申请日为2019年4月30日的中国专利申请CN201910359013.0、申请日为2019年8月15日的中国专利申请CN201910753694.9的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种杂环稠合嘧啶衍生物、其药物组合物及其作为治疗剂，特别是作为癌症治疗剂的应用。
背景技术
人类细胞每天都要遭受成千上百的DNA损伤，造成DNA损伤的原因包括正常细胞功能(例如氧化代谢产物)、DNA代谢产物(例如DNA在转录、复制过程中自发的错误)、以及环境因素(例如紫外线、电离辐射、基因毒素等)等。如果上诉损伤不能正确得到修复则会导致细胞或生物体丧失活性，DNA损伤的积累还可以影响基因组的稳定性和完整性，并会促进癌症的形成。DNA损伤可能通过DNA碱基的氧化或烷基化、DNA碱基错配和二聚体、DNA骨架中的断裂和不连续、链内/链间DNA交联和DNA结构的总体变化而产生。为保证细胞基因组的稳定性和完整性，细胞有一套复杂的DNA损伤应答(DDR)机制，能够识别和处理细胞周期特定部分中的这些特定类型的DNA损伤，以维持基因组完整性和细胞活力。研究发现，健康细胞存在多种DDR机制，并且这些修复机制可以在DNA修复过程中彼此补偿。(Jackson SP,Nature,2009,461(7267),1071-1078)。而许多癌细胞中多种DNA修复通路存在缺陷，因此对未受损的DNA修复通路表现出更大的依赖性。
共济失调毛细血管扩张突变基因和Rad 3相关激酶ATR(ataxia telangiectasia mutated and Rad3-related,ATR,又被称作FRAP-Related Protein 1；FRP1；MEC1；SCK1；SECKL1)是磷脂酰肌醇-3激酶相关激酶(PIKK)蛋白家族中的一员，是一种在DNA损伤后能够激活细胞应答，进而阻滞细胞周期进程并稳定复制叉及修复DNA，从而回避细胞凋亡的重要激酶(Cimprich K.A.,Nature Rev.Mol.Cell Biol.,2008,9:616-627)。ATR通过稳定停滞的复制叉起作用，调节细胞周期检查点的激活以及DNA损伤修复。ATR被激活后将通过调节其下游调节因子(主要包括Chk1、WRN以及FANCI)激活三条信号转导路径阻滞细胞周期进程，促进DNA修复，稳定复制叉。虽然RPA包被的单链DNA的存在是 ATR活化的共同特征，但是在某些情况下ATR也可以在没有DNA解旋酶聚合酶解偶联的情况下被激活，例如通过UV辐射、铂化疗或烷化剂等。
由于肿瘤细胞中DNA修复可能由于存在多种突变而存在缺陷，导致其对未受损的DNA修复通路表现出更大的依赖性。因此可以利用合成致死理论杀死特定肿瘤细胞而保留健康细胞。目前的癌症治疗中，包括化疗和电离辐射都可以诱导DNA损伤和复制叉停滞，从而激活细胞周期检查点并导致细胞周期停滞。这种反应机制是帮助癌细胞在治疗中存活的重要机制。断裂的双链DNA或者复制应激可以快速激活ATR，相应的ATR可以启动一系列诸如Chk1(ATR底物)、p53、DNA拓扑异构酶2结合蛋白(TopBP1)等下游靶标进而导致DNA的修复和细胞周期停滞。ATR基因由于很少出现突变，因而在癌症化疗过程中极易被激活。此外，通过抑制ATR可以产生几种合成致死相互作用(synthetic lethal interactions)，尤其和ATM/p53通路产生相互作用。p53是最常见的肿瘤抑制基因突变，具有ATM/p53基因缺陷或突变的细胞DNA修复更依赖于ATR的激活(Reaper,P.M.,Nat.Chem.Biol.,2011,7,428-430)。
研究表明，特异性DNA修复蛋白缺失，如X线交错互补修复基因1、错配切除交叉互补修复基因1等也可以导致肿瘤细胞对ATR抑制作用更敏感(Sultana R,PLoS One,2013,8(2):e57098)。另外，低氧肿瘤细胞可能会造成复制应激，导致其对ATR抑制作用更加敏感，通过抑制ATR可以选择性增加肿瘤细胞对电离辐射和化疗的敏感性，增加肿瘤细胞对复制应激的敏感性，其增加的水平要比正常细胞高出很多倍(Lecona E,Exp Cell Res,2014,329(1):26-34)。除此以外，由于ATR对于维持端粒的同源重组至关重要，因此依赖于端粒替代延伸通路进行DNA损伤修复的肿瘤细胞对于ATR抑制作用也更加的敏感。
ATR通路作为一种DNA损伤应答机制，对于肿瘤细胞的存活起到重要作用。对其关键因子ATR的抑制可以诱导ATR通路依赖型恶性肿瘤细胞的死亡而对正常细胞影响较小，是一种开发低毒高效靶向药物的理想靶标，目前已有VX970和AZD6738两个小分子实体进入临床II期实验，也有多篇针对ATR通路的专利公开：WO2015/084384、WO2017/180723、WO2016/061097、WO2014/140644、WO2007/015632、WO2017/123588、WO2007/046426，但还未有对应的药物上市，本发明的杂环稠合嘧啶衍生物对ATR抑制剂的开发提供了新的思路。
发明内容
本发明所要解决的技术问题在于，提供了一种新型杂环稠合嘧啶衍生物、其制备方法、药物组合物及应用。本发明的杂环稠合嘧啶衍生物具有良好的ATR抑制作用，可以 有效治疗和/或缓解由ATR介导的各种相关疾病，例如恶性肿瘤。
本发明提供了一种杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐；
Figure PCTCN2019119899-appb-000001
其中，X为-CR 8R 9-、-O-、-C(O)-或-NR 10-；
Y为O或NR 10；
L为-(CR 8’R 9’) n-；
R 1任选为H、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基或卤代C 1-6烷基；
R 2任选为H、R 11、-OR 11或-NR 11R 11a；
R 1和R 2为独立取代基，或者R 1和R 2相互连接形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者选择性被一个或多个选自卤素和C 1-6烷基的取代基取代在任意位置；
R 3任选为Cy、-O-Cy、-NR 10’-Cy或-NR 10’-CH 2-Cy；
Cy任选为芳基或杂芳基，所述Cy为未取代或者选择性被一个或多个选自R 12、卤素、羟基、氨基、氰基、羧基、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-N(OR 12)R 12a、-S(O) 0-2R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-C(NH)NR 12R 12a、-NR 12C(O)R 12a、-NR 12C(O)NR 12R 12a、-NR 12S(O) 2R 12a和-OC(O)R 12a的取代基取代在任意位置；
R 4和R 5分别独立地任选为H、卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；
R 6为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基为未取代或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨基的取代基取代在任意位置；
R 7为H、卤素或C 1-6烷基；
R 6和R 7分别为独立取代基，或者R 6和R 7与它们共同连接的C原子一起形成羰基；
R 1和R 6分别为独立取代基，或者R 1和R 6通过-L’-相互连接形成桥环基；
L’为-(CR 8”R 9”) m-、-(CR 8”R 9”) mO-或-(CR 8”R 9”) mNR 10’-；
R 8、R 8’和R 8”分别独立地为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基为未取代或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨基的取代基取代在任意位置；
R 9、R 9’和R 9”分别独立地为H、卤素或C 1-6烷基；
R 10和R 10’分别独立地为H或C 1-6烷基；
每个R 11和每个R 11a分别独立地为H、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；所述R 11或R 11a为未取代，或者选择性被一个或多个选自卤素、羟基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置；
每个R 12和每个R 12a分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；所述R 12或R 12a为未取代，或者选择性被一个或多个选自氘、氧代基、卤素、羟基、氨基、氰基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、-NHC(O)-C 2-6烯基、-NHC(O)-C 1-6烷基、-NHC(O)NH-C 1-6烷基、-NHC(O)O-C 1-6烷基和-NHS(O) 2-C 1-6烷基的取代基取代在任意位置；
m、n和t分别独立地为0、1、2或3。
以下所述的如式I所述的所有实施方案、及任意实施方案的组合均包含在本发明如式I所示的结构式的范围中。
在一些实施方案中，所述的如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐里某些基团的定义可如下所述，未描述的基团可如上任一方案所述：
其中，X为-CR 8R 9-、-O-、-C(O)-或-NR 10-；
Y为O或NR 10；
L为-(CR 8’R 9’) n-；
R 1任选为H、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基或卤代C 1-6烷基；
R 2任选为H、R 11、-OR 11或-NR 11R 11a；
R 1和R 2为独立取代基，或者R 1和R 2相互连接形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者选择性被一个或多个选自卤素和C 1-6烷基的取代基取代在任意位置；
R 3任选为Cy、-O-Cy、-NR 10’-Cy或-NR 10’-CH 2-Cy；
Cy任选为芳基或杂芳基，所述Cy为未取代或者选择性被一个或多个选自R 12、卤素、羟基、氨基、氰基、羧基、-OR 12a、-NR 12R 12a、-S(O) 0-2R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-C(NH)NR 12R 12a、-NR 12C(O)R 12a、-NR 12C(O)NR 12R 12a、-NR 12S(O) 2R 12a和-OC(O)R 12a的取代基取代在任意位置；
R 4和R 5分别独立地任选为H、卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；
R 6为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、环烷基或杂环烷基为未取代或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨基的取代基取代在任意位置；
R 7为H、卤素或C 1-6烷基；
R 6和R 7分别为独立取代基，或者R 6和R 7与它们共同连接的C原子一起形成羰基；
R 1和R 6分别为独立取代基，或者R 1和R 6通过-L’-相互连接形成桥环基；
L’为-(CR 8”R 9”) m-、-(CR 8”R 9”) mO-或-(CR 8”R 9”) mNR 10’-；
R 8、R 8’和R 8”分别独立地为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、环烷基或杂环烷基为未取代或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨基的取代基取代在任意位置；
R 9、R 9’和R 9”分别独立地为H、卤素或C 1-6烷基；
R 10和R 10’分别独立地为H或C 1-6烷基；
每个R 11和每个R 11a分别独立地为C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；所述R 11或R 11a为未取代，或者选择性被一个或多个选自卤素、羟基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置；
每个R 12和每个R 12a分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；所述R 12或R 12a为未取代，或者选择性被一个或多个选自氧代基、卤素、羟基、氨基、氰基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、-NHC(O)-C 2-6烯基、-NHC(O)-C 1-6烷基、 -NHC(O)NH-C 1-6烷基、-NHC(O)O-C 1-6烷基和-NHS(O) 2-C 1-6烷基的取代基取代在任意位置；
m、n和t分别独立地为0、1、2或3。
在一些实施方案中，所述的如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐里某些基团的定义可如下所述，未描述的基团可如上任一方案所述：
其中，X为-CR 8R 9-、-O-、-C(O)-或-NR 10-；
Y为O或NR 10；
L为-(CR 8’R 9’) n-；
R 1任选为H、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基或卤代C 1-6烷基；
R 2任选为H、R 11、-OR 11或-NR 11R 11a；
R 1和R 2为独立取代基，或者R 1和R 2相互连接形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者选择性被一个或多个选自卤素和C 1-6烷基的取代基取代在任意位置；
R 3任选为Cy、-O-Cy、-NR 10’-Cy或-NR 10’-CH 2-Cy；
Cy任选为芳基或杂芳基，所述Cy为未取代或者选择性被一个或多个选自R 12、卤素、羟基、氨基、氰基、羧基、-OR 12a、-NR 12R 12a、-S(O) 0-2R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NR 12C(O)R 12a、-NR 12C(O)NR 12R 12a、-NR 12S(O) 2R 12a和-OC(O)R 12a的取代基取代在任意位置；
R 4和R 5分别独立地任选为H、卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；
R 6为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、环烷基或杂环烷基为未取代或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨基的取代基取代在任意位置；
R 7为H、卤素或C 1-6烷基；
R 6和R 7分别为独立取代基，或者R 6和R 7与它们共同连接的C原子一起形成羰基；
R 1和R 6分别为独立取代基，或者R 1和R 6通过-L’-相互连接形成桥环基；
L’为-(CR 8”R 9”) m-、-(CR 8”R 9”) mO-或-(CR 8”R 9”) mNR 10’-；
R 8、R 8’和R 8”分别独立地为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、环烷基或杂环烷基为未取代或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨 基的取代基取代在任意位置；
R 9、R 9’和R 9”分别独立地为H、卤素或C 1-6烷基；
R 10和R 10’分别独立地为H或C 1-6烷基；
每个R 11和每个R 11a分别独立地为C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；所述R 11或R 11a为未取代，或者选择性被一个或多个选自卤素、羟基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置；
每个R 12和每个R 12a分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；所述R 12或R 12a为未取代，或者选择性被一个或多个选自氧代基、卤素、羟基、氨基、氰基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基和-NHC(O)-C 2-6烯基的取代基取代在任意位置；
m、n和t分别独立地为0、1、2或3。
在一些实施方案中，所述的如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐里某些基团的定义可如下所述，未描述的基团可如上任一方案所述：
其中，X为-CR 8R 9-、-O-、-C(O)-、或-NR 10-；
Y为O、或NR 10；
L为-(CR 8’R 9’) n-；
R 1任选为H、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基、或卤代C 1-6烷基；
R 2任选为H、R 11、-OR 11、或-NR 11R 11a；
R 1和R 2为独立取代基，或者R 1和R 2相互连接形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者选择性被一个或多个选自卤素和C 1-6烷基的取代基取代在任意位置；
R 3任选为Cy、-O-Cy、-NR 10’-Cy、或-NR 10’-CH 2-Cy；
Cy任选为芳基或杂芳基，所述Cy为未取代、或者选择性被一个或多个选自R 12、卤素、羟基、氨基、氰基、羧基、-OR 12、-NR 12R 12a、-S(O) 0-2R 12、-C(O)R 12、-C(O)OR 12、-C(O)NR 12R 12a、-NR 12aC(O)R 12和-OC(O)R 12的取代基取代在任意位置；
R 4和R 5分别独立地任选为H、卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、或卤代C 1-6烷氧基；
R 6为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、或 3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、环烷基、或杂环烷基为未取代、或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨基的取代基取代在任意位置；
R 7为H、卤素、或C 1-6烷基；
R 6和R 7分别为独立取代基，或者R 6和R 7与它们共同连接的C原子一起形成羰基；
R 1和R 6分别为独立取代基，或者R 1和R 6通过-L’-相互连接形成桥环基；
L’为-(CR 8”R 9”) m-、-(CR 8”R 9”) mO-、或-(CR 8”R 9”) mNR 10’-；
R 8、R 8’和R 8”分别独立地为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、或3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、环烷基、或杂环烷基为未取代、或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨基的取代基取代在任意位置；
R 9、R 9’和R 9”分别独立地为H、卤素、或C 1-6烷基；
R 10和R 10’分别独立地为H、或C 1-6烷基；
每个R 11和每个R 11a分别独立地为C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述R 11或R 11a为未取代，或者选择性被一个或多个选自卤素、羟基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置；
每个R 12和每个R 12a分别独立地为H、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基、或5-6元杂芳基C 1-6烷基；所述R 12或R 12a为未取代，或者选择性被一个或多个选自卤素、羟基、氨基、氰基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基和3-8元杂环烷基的取代基取代在任意位置；
m、n和t分别独立地为0、1、2、或3。
在一些实施方案中，所述X为O。
在一些实施方案中，所述X为NR 10，其中，R 10的定义如前所述。
在一些实施方案中，所述R 10为H、甲基、乙基、丙基、异丙基或环丙基。
在一些实施方案中，所述Y为O。
在一些实施方案中，所述Y为NH。
在一些实施方案中，所述R 1为C 1-6烷基；更优选为C 1-4烷基(例如：甲基、乙基、 正丙基、异丙基、正丁基、叔丁基)。
在一些实施方案中，所述R 2为R 11；所述R 11的定义如前所述；
在一些实施方案中，所述R 11为C 1-6烷基、苯基、5-6元杂芳基、3-6元杂环烷基或C 3-6环烷基；所述R 11为未取代，或者选择性被1～3个、1～2个或1个选自氟、氯、羟基、氨基、氰基、甲氧基、乙氧基、三氟甲氧基、二氟甲氧基、二甲氨基、甲氨基的取代基取代在任意位置。
在一些实施方案中，所述R 2为C 1-6烷基或C 3-6环烷基。
在一些实施方案中，所述R 2为甲基、乙基、正丙基、异丙基、叔丁基、环丙基或环丁基。
在一些实施方案中，所述R 1、R 2为独立取代基。
在一些实施方案中，所述R 1、R 2为相互连接形成5-8元杂环烷基。
在一些实施方案中，所述Cy任选为芳基或杂芳基，所述Cy为未取代或者选择性被一个或多个选自R 12、卤素、羟基、氨基、氰基、羧基、-OR 12、-NR 12R 12a、-S(O) 0-2R 12、-C(O)R 12、-C(O)OR 12、-C(O)NR 12R 12a、-NR 12aC(O)R 12和-OC(O)R 12的取代基取代在任意位置。
在一些实施方案中，所述R 3为Cy。
在一些实施方案中，所述R 3中，所述Cy为取代或未取代的6-10元芳基。
在一些实施方案中，所述R 3中，所述Cy为取代或未取代的5-10元杂芳基。
在一些实施方案中，所述R 3中，所述Cy中，所述取代或未取代的6-10元芳基为取代或未取代的苯基、萘基、吲哚啉基或2-氧代-2,3-二氢-1H-苯并[d]咪唑基。
在一些实施方案中，所述R 3中，所述Cy中，所述取代或未取代的6-10元芳基为取代或未取代的苯基。
在一些实施方案中，所述R 3中，所述Cy中，所述取代或未取代的5-10元杂芳基为取代或未取代的以下任一基团：吡啶基、嘧啶基、吡嗪基、咪唑基、吡唑基、1H-1,2,3-三氮唑基、1H-1,2,4-三氮唑基、4H-1,2,4-三氮唑基、喹啉基、异喹啉基、喹唑啉基、1H-吲唑基、1H-吲哚基、1H-吡咯并[2,3-b]吡啶基、1H-吡咯并[2,3-c]吡啶基、1H-吡咯并[3,2-c]吡啶基、1H-吡咯并[3,2-b]吡啶基、7H-吡咯并[2,3-c]哒嗪基、1H-吡咯并[2,3-d]哒嗪基、1H-苯并咪唑基、1H-苯并[d][1,2,3]三氮唑基、3H-噻吩并[2,3-d]咪唑基、1H-噻吩并[2,3-d]咪唑基、1H-噻吩并[3,4-d]咪唑基、1H-吡唑并[3,4-b]吡啶基、1H-吡唑并[3,4-c]吡啶基、1H-吡唑并[4,3-c]吡啶基、1H-吡唑并[4,3-b]吡啶基、4H-咪唑并[4,5-d]异噻唑基、6H-咪唑并[4,5-d]异噻唑基、1H-咪唑并[4,5-b]吡啶基、3H-咪唑并[4,5-b]吡啶基、3H-咪唑并[4,5-c]吡啶基、1H-咪唑并[4,5-c]吡啶基、1H-咪唑并[4,5-b]吡啶基、7H-吡咯并[2,3-d]嘧啶基或 7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶基。
在一些实施方案中，所述R 3中，所述Cy中，所述取代或未取代的5-10元杂芳基为取代或未取代的以下任一基团：1H-吲哚基、1H-吡咯并[2,3-b]吡啶基、1H-吡咯并[2,3-c]吡啶基、1H-吡咯并[3,2-c]吡啶基、1H-苯并咪唑基、1H-吲唑基、1H-苯并[d][1,2,3]三氮唑基、喹啉基、异喹啉基、喹唑啉基、吡啶基、咪唑基、吡唑基、1H-1,2,3-三氮唑基、1H-1,2,4-三氮唑基、4H-1,2,4-三氮唑基、7H-吡咯并[2,3-c]哒嗪基、1H-吡咯并[2,3-d]哒嗪基、3H-噻吩并[2,3-d]咪唑基、1H-噻吩并[2,3-d]咪唑基、4H-咪唑并[4,5-d]异噻唑基、6H-咪唑并[4,5-d]异噻唑基或1H-咪唑并[4,5-b]吡啶基。
在一些实施方案中，所述R 3中，所述Cy中，所述取代或未取代的5-10元杂芳基为取代或未取代的以下任一基团：1H-吲哚基、1H-吡咯并[2,3-b]吡啶基、1H-吡咯并[2,3-c]吡啶基、1H-吡咯并[3,2-c]吡啶基、1H-苯并咪唑基、1H-吲唑基、1H-苯并[d][1,2,3]三氮唑基、喹啉基、异喹啉基、喹唑啉基、吡啶基、咪唑基、吡唑基、1H-1,2,3-三氮唑基、1H-1,2,4-三氮唑基或4H-1,2,4-三氮唑基。
在一些实施方案中，所述R 3中，所述Cy为取代或未取代的以下任一结构：
Figure PCTCN2019119899-appb-000002
Figure PCTCN2019119899-appb-000003
在一些实施方案中，所述R 3中，所述Cy中，所述取代或未取代的5-10元杂芳基为 取代或未取代的以下任一结构：
Figure PCTCN2019119899-appb-000004
Figure PCTCN2019119899-appb-000005
在一些实施方案中，所述R 3中，所述Cy中，所述取代或未取代的5-10元杂芳基为取代或未取代的以下任一结构：
Figure PCTCN2019119899-appb-000006
Figure PCTCN2019119899-appb-000007
在一些实施方案中，所述R 3中，所述Cy被取代时，选择性被1～3个、1～2个或1个选自R 12、卤素、羟基、氨基、氰基、羧基、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-N(OH)R 12a、-S(O) 0-2R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)R 12a、-NHC(O)NR 12R 12a、和-OC(O)R 12a的取代基取代在任意位置；所述R 12和R 12a的定义如前所述。
在一些实施方案中，所述R 3中，所述Cy被取代时，选择性被1～3个、1～2个或1个选自R 12、卤素、羟基、氨基、氰基、羧基、-OR 12a、-NR 12R 12a、-S(O) 0-2R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)R 12a和-OC(O)R 12a的取代基取代在任意位置；所述R 12和R 12a的定义如前所述。
在一些实施方案中，所述R 3中，所述Cy被取代时，选择性被1～3个、1～2个或1个选自F、Cl、Br、-OH、-NH 2、-CN、-COOH、R 12、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)R 12a、-NHC(O)NR 12R 12a和-C(NH)NR 12R 12a的取代基取代在任意位置；所述R 12和R 12a的定义如前所述。
在一些实施方案中，所述R 3中，所述Cy被取代时，选择性被1～3个、1～2个或1个选自F、Cl、Br、-OH、-NH 2、-CN、-COOH、R 12、-OR 12a、-NR 12R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)R 12a或-C(NH)NR 12R 12a的取代基取代在任意位置；所述R 12和 R 12a的定义如前所述。
在一些实施方案中，所述R 3中，所述Cy被取代时选择性被1～2个或1个选自F、Cl、Br、-OH、-NH 2、-CN、-COOH、R 12、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)NR 12R 12a和-NHC(O)R 12a的取代基取代在任意位置；所述R 12和R 12a的定义如前所述。
在一些实施方案中，所述R 3中，所述Cy被取代时选择性被1～2个或1个选自F、Cl、Br、-OH、-NH 2、-CN、-COOH、R 12、-OR 12a、-NR 12R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a或-NHC(O)R 12a的取代基取代在任意位置；所述R 12和R 12a的定义如前所述。
在一些实施方案中，所述每个R 12和每个R 12a分别独立地为H、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；所述R 12或R 12a为未取代，或者选择性被一个或多个选自卤素、羟基、氨基、氰基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基和3-8元杂环烷基的取代基取代在任意位置；
在一些实施方案中，所述R 12为H、C 1-6烷基、C 2-6烯基、C 3-8环烷基、3-8元杂环烷基、苯基或5-6元杂芳基。
在一些实施方案中，所述R 12为H、C 1-4烷基、C 2-6烯基、C 3-6环烷基、5-6元杂芳基或3-6元杂环烷基。
在一些实施方案中，所述R 12为未取代。
在一些实施方案中，所述R 12选择性被1～5、1～4或1～3个选自氘、氧代基、卤素、羟基、氨基、氰基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、-NHC(O)-C 2-6烯基、-NHC(O)-C 1-6烷基、-NHC(O)NH-C 1-6烷基、-NHC(O)O-C 1-6烷基和-NHS(O) 2-C 1-6烷基的取代基取代在任意位置；
在一些实施方案中，所述R 12选择性被1～3个选自D、F、Cl、-OH、-NH 2、-NHC(O)CH＝CH 2、-NHC(O)CH 3、C 1-4烷基、C 1-4烷氧基或C 1-4烷氨基的取代基取代在任意位置。
在一些实施方案中，所述R 12选择性被1～3个选自F、Cl、-OH、-NH 2、-NHC(O)CH＝CH 2、C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基的取代基取代在任意位置。
在一些实施方案中，所述R 12为H、C 1-4烷基、C 3-6环烷基或3-6元杂环烷基，所述R 12为未取代，或者选择性被1～3个选自F、Cl、-OH、-NH 2、C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基的取代基取代在任意位置。
在一些实施方案中，所述R 12a为H、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基或C 1-4烷基。
在一些实施方案中，所述R 12a为H或C 1-4烷基。
在一些实施方案中，所述R 3中，所述Cy被取代时，选择性被1～3个、1～2个或1个选自F、Cl、Br、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-NH(CH 2CH 3)、-NH(CN)、-NH(OH)、-NHC(O)H、-NH-正丙基、-NH-异丙基、-NH-环丙基、-NHC(O)CH 3、-NHC(O)NH 2、-CN、-COOH、-CH 3、-CF 3、-CHF 2、-CH 2CHF 2、-CH 2OH、-CH 2NH 2、-CH 2NH(CH 3)、-OCH 3、-OCF 3、-OCH 2CF 3、-OCH 2CHF 2、-O-环丙基、-CH 2F、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、-C(NH)NH 2、-NH(CD 3)、-NHCH 2CF 3、-NHCF 3、-NHCH 2F、-NHCH 2CH 2F、-NHCH 2CHF 2、
Figure PCTCN2019119899-appb-000008
Figure PCTCN2019119899-appb-000009
的取代基取代在任意位置。
在一些实施方案中，所述R 3中，所述Cy中，所述6-10元芳基为
Figure PCTCN2019119899-appb-000010
所述5-10元杂芳基为：
Figure PCTCN2019119899-appb-000011
R’为H、F、Cl、-CH 3、-CF 3或-OCH 3；R为H、F、Cl、Br、-OH、-NH 2、-CN、-COOH、R 12、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)NR 12R 12a或-NHC(O)R 12a；所述R 12和R 12a的定义如前所述。
在一些实施方案中，所述R 3中，所述Cy中，所述5-10元杂芳基为：
Figure PCTCN2019119899-appb-000012
Figure PCTCN2019119899-appb-000013
R’为H、F、Cl、-CH 3、-CF 3或-OCH 3；R为H、F、Cl、Br、-OH、-NH 2、-CN、-COOH、R 12、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)NR 12R 12a或-NHC(O)R 12a；所述R 12和R 12a的定义如前所述。
在一些实施方案中，所述R 3中，所述Cy中，所述5-10元杂芳基为：
Figure PCTCN2019119899-appb-000014
Figure PCTCN2019119899-appb-000015
R为H、F、Cl、Br、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-NH(CH 2CH 3)、-NH(CN)、-NHC(O)NH 2、-NHC(O)H、-NH-丙基、-NH-异丙基、-NH-环丙基、-NHC(O)CH 3、-CN、-COOH、-CH 3、-CF 3、-CHF 2、-CH 2CHF 2、-CH 2OH、-CH 2NH 2、-CH 2NH(CH 3)、-OCH 3、-OCF 3、-OCH 2CF 3或-OCH 2CHF 2。
在一些实施方案中，所述R 4为甲基。
在一些实施方案中，所述R 5为H、F、甲基、甲氧基、乙氧基或三氟甲氧基。
在一些实施方案中，所述R 5为H。
在一些实施方案中，所述t为1或2。
在一些实施方案中，所述m为0、1或2。
在一些实施方案中，所述n为1或2。
在一些实施方案中，所述R 8、R 8’和R 8”分别独立地为H、F或C 1-4烷基。
在一些实施方案中，所述R 9、R 9’和R 9”分别独立地为H、F或C 1-4烷基。
在一些实施方案中，所述R 1和R 6通过-L’-相互连接形成桥环基；其中，L’为-CH 2-、-CH 2CH 2-、-CH 2O-或-O-；
在一些实施方案中，所述R 1和R 6通过-L’-相互连接形成桥环基；其中，L’为-CH 2-。
在一些实施方案中，所述L为-CH 2-或-CH 2CH 2-。
在一些实施方案中，所述L为-CH 2-。
在一些实施方案中，所述如式I所述的化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐为如式II所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐：
Figure PCTCN2019119899-appb-000016
其中，R 2、R 3、R 7、L、L’、X和Y的定义均如前所述。
以下各种情况均包括在结构式(II)的定义中：
在其中一种优选实施方案中，X为O；
在其中一种优选实施方案中，L为-CH 2-；
在其中一种优选实施方案中，L’为-CH 2-；
在其中一种优选实施方案中，R 2为-CH 3、-CH 2CH 3、-CH(CH 3) 2或环丙基；
在其中一种优选实施方案中，R 3为Cy；
在其中一种优选实施方案中，Cy为
Figure PCTCN2019119899-appb-000017
Figure PCTCN2019119899-appb-000018
R’为H、F、Cl、-CH 3、-CF 3或-OCH 3；R为H、F、Cl、Br、-OH、-NH 2、-CN、-COOH、R 12、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)NR 12R 12a或-NHC(O)R 12a；所述R 12和R 12a的定义如前所述。
在一些实施方案中，如式(I)所示的化合物和/或药学上可接受的盐任选为以下化合物：
Figure PCTCN2019119899-appb-000019
Figure PCTCN2019119899-appb-000020
在一些实施方案中，如式(I)所示的化合物和/或药学上可接受的盐任选为以下化合物：
Figure PCTCN2019119899-appb-000021
在一些实施方案中，如式(I)所示的化合物和/或药学上可接受的盐任选为以下化合物：
Figure PCTCN2019119899-appb-000022
Figure PCTCN2019119899-appb-000023
Figure PCTCN2019119899-appb-000024
在一些实施方案中，如式(I)所示的化合物和/或药学上可接受的盐任选为以下化合物：
Figure PCTCN2019119899-appb-000025
Figure PCTCN2019119899-appb-000026
在一些实施方案中，如式(I)所示的化合物和/或药学上可接受的盐任选为以下化合物：
Figure PCTCN2019119899-appb-000027
在一些实施方案中，如式(I)所示的化合物和/或药学上可接受的盐任选为以下化合物：
Figure PCTCN2019119899-appb-000028
Figure PCTCN2019119899-appb-000029
本发明还提供了所述如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐的制备方法，其为如下任一方法：
方法1：
Figure PCTCN2019119899-appb-000030
将I-A和R 3-M通过Suzuki交叉偶联反应得到式I所示化合物；
其中，Lev为离去基团，优选为Cl、Br、I或OTf；M为硼酸酯基或硼酸基；R 3为Cy；R 1、R 2、R 4、R 5、R 6、R 7、X、Y、L和t的定义如前所述。
方法2：
Figure PCTCN2019119899-appb-000031
将I-A和R 3-H通过亲核取代反应或Buchwald-Hartwig偶联反应得到式I所示化合物；
其中，Lev为离去基团，优选为Cl、Br、I或OTf；R 3为杂芳基、-NR 10’-Cy或-NR 10’-CH 2-Cy；R 3中，所述杂芳基通过环N原子与母体分子连接；R 1、R 2、R 4、R 5、R 6、R 7、X、Y、L和t的定义如前所述。
方法3：
Figure PCTCN2019119899-appb-000032
将I-B和R 3-Lev通过Stille偶联反应得到式I所示化合物；
其中，Lev为离去基团，优选为Cl、Br、I或OTf；R 3为Cy；R 1、R 2、R 4、R 5、R 6、R 7、X、Y、L和t的定义如前所述。
方法4：
Figure PCTCN2019119899-appb-000033
将I-C在碘甲烷和乙醇体系下回流搅拌1-24小时关环得到式III所示化合物；
其中，A环为苯环或5-6元杂芳环，所述A环为未取代或者选择性被一个或多个R’和/或R取代在任意位置；R、R’、R 1、R 2、R 4、R 5、R 6、R 7、X、Y、L和t的定义如前所述。
方法5：
Figure PCTCN2019119899-appb-000034
将I-D在BrCN和甲醇体系下室温搅拌1-24小时关环得到式IV所示化合物；
其中，A环为苯环或5-6元杂芳环，所述A环为未取代或者选择性被一个或多个R’和/或R取代在任意位置；R、R’、R 1、R 2、R 4、R 5、R 6、R 7、X、Y、L和t的定义如前 所述。
在上述方法中，在I-A、I-B、I-C、I-D、R 3-H或R 3-Lev中存在不参与反应的NH或NH 2时，优选通过保护基保护，避免有任何副反应发生。如果存在上述保护基则需要经过后续的脱保护步骤后，得到如式I所示化合物。任何合适的保护基团，例如：叔丁氧羰基(Boc)、三氟甲磺酰基(Tf)或苯磺酰基，均可以用于NH或NH 2的保护。如果使用Boc作为保护基，后续的脱保护反应可以在标准条件，例如，对甲苯磺酸/甲醇体系，二氯甲烷/三氟乙酸体系、饱和的氯化氢乙醚溶液、或三氟甲磺酸三甲基硅酯/2,6-二甲基吡啶/二氯甲烷体系中进行；如果使用三氟甲磺酰基或苯磺酰基作为保护基，后续的脱保护反应可以在标准条件，例如，氢氧化钠、叔丁醇钾在四氢呋喃、水和/或甲醇溶剂中脱保护或使用甲胺醇溶液(例如甲胺甲醇溶液，甲胺乙醇溶液)进行脱保护。上述脱保护反应优选在最后一步进行。
所述杂环稠合嘧啶衍生物(I)的药学上可接受的盐可通过一般的化学方法合成。
一般情况下，盐的制备可以通过游离碱或酸与等化学当量或者过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。
本发明还提供了一种药物组合物，其包括治疗有效量的活性组分以及药学上可接受的辅料；所述活性组分包括杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐中的一种或多种。
所述药物组合物中，所述活性组分还可包括由ATR水平失常引起的相关疾病的其它治疗剂。
所述药物组合物中，所述药学上可接受的辅料可包括药学上可接受的载体、稀释剂和/或赋形剂。
根据治疗目的，可将药物组合物制成各种类型的给药单位剂型，如片剂、丸剂、粉剂、液体、悬浮液、乳液、颗粒剂、胶囊、栓剂和针剂(溶液及悬浮液)等，优选液体、悬浮液、乳液、栓剂和针剂(溶液及悬浮液)等。
为了使片剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋形剂。例如，载体，如乳糖、白糖、氯化钠、葡萄糖、尿素、淀粉、碳酸钙、高岭土、结晶纤维素和硅酸等；粘合剂，如水、乙醇、丙醇、普通糖浆、葡萄糖溶液、淀粉溶液、明胶溶液，羧甲基纤维素、紫胶、甲基纤维素和磷酸钾、聚乙烯吡咯烷酮等；崩解剂，如干淀粉、藻酸钠、琼脂粉和海带粉，碳酸氢钠、碳酸钙、聚乙烯脱水山梨醇的脂肪酸酯、十二烷基Na 2SO 4、硬脂酸单甘酯、淀粉和乳糖等；崩解抑制剂，如白糖、甘油三硬脂酸酯、椰子油和氢化油；吸附促进剂，如季胺碱和十二烷基Na 2SO 4等；润湿剂，如甘油、淀粉等；吸附剂，如淀粉、乳糖、高岭土、膨润土和胶体硅酸等；以及润滑剂，如纯净 的滑石，硬脂酸盐、硼酸粉和聚乙二醇等。还可以根据需要选用通常的涂渍材料制成糖衣片剂、涂明胶膜片剂、肠衣片剂、涂膜片剂、双层膜片剂及多层片剂。
为了使丸剂形式的药物组合物成形，可使用本领域任何已知的并广泛使用的赋形剂，例如，载体，如乳糖，淀粉，椰子油，硬化植物油，高岭土和滑石粉等；粘合剂，如阿拉伯树胶粉，黄蓍胶粉，明胶和乙醇等；崩解剂，如琼脂和海带粉等。
为了使栓剂形式的药物组合物成形，可使用本领域任何已知并广泛使用的赋性剂，例如，聚乙二醇，椰子油，高级醇，高级醇的酯，明胶和半合成的甘油酯等。
为了制备针剂形式的药物组合物，可将溶液或悬浮液消毒后(最好加入适量的氯化钠，葡萄糖或甘油等)，制成与血液等渗压的针剂。在制备针剂时，也可使用本领域内任何常用的载体。例如，水，乙醇，丙二醇，乙氧基化的异硬脂醇，聚氧基化的异硬脂醇和聚乙烯脱水山梨醇的脂肪酸酯等。此外，还可加入通常的溶解剂、缓冲剂和止痛剂等。
本发明中，所述的组合物在药物组合物中的含量无特殊限制，可在很宽的范围内进行选择，通常可为质量百分比的5～95％，较佳的为质量百分比30～80％。
本发明中，所述药物组合物的给药方法没有特殊限制。可根据病人年龄、性别和其它条件及症状，选择各种剂型的制剂给药。例如，片剂、丸剂、溶液、悬浮液、乳液、颗粒剂或胶囊口服给药；针剂可以单独给药，或者和注射用输送液(如葡萄糖溶液及氨基酸溶液)混合进行静脉注射；栓剂为给药到直肠。
本发明还提供了所述杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备ATR抑制剂中的应用。所述的ATR抑制剂是指可以抑制ATR活性或表达(包括ATR的异常活动或过表达)。
本发明还提供了所述杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物具有抵抗肿瘤细胞增殖、促进肿瘤细胞凋亡和/或抵抗肿瘤细胞侵袭的作用。所述促进肿瘤细胞凋亡的作用是通过抑制ATR活性实现的。
本发明还提供了所述杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备治疗、缓解和/或预防由ATR介导的相关疾病的药物中的应用。
本发明还提供了所述杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备治疗和/或缓解癌症药物中的应用。
本发明还提供了所述杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备在哺乳动物体内具有抗增殖作用的药物中的应用。
本发明还提供了所述杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备在哺乳动物体内具有促凋亡作用的药物中的应用。
本发明还提供了所述杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在制备在哺乳动物体内具有抵抗癌细胞侵袭作用的药物中的应用。
本发明还提供了所述杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物在治疗和/或缓解癌症中的应用，其包括给与哺乳动物治疗有效剂量的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或包含其的药物组合物。
本发明还提供了所述杂环稠合嘧啶衍生物(I)、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或所述药物组合物和一种或多种其它种类的用于治疗癌症的治疗剂和/或治疗方法联合用于治疗、缓解和/或预防由ATR介导的相关疾病。
本发明中，所述ATR介导的相关疾病为由ATR水平失常引起的相关疾病，优选增值性疾病，更优选为癌症。
本发明中，所述的ATR介导的相关疾病的其它治疗剂优选为其它种类的用于治疗癌症的治疗剂。
本发明中，所述其它种类的用于治疗癌症的治疗剂可以和所述的杂环稠合嘧啶衍生物(I)做成单一给药的治疗剂型，或者分别先后给药的治疗剂型。
本发明中，所述其它种类的用于治疗癌症的治疗剂可包括但不限于：烷化剂、拓扑酶I/II抑制剂、抗有丝分裂剂、抗代谢类药物、激素和激素类似物、抗肿瘤抗生素、小分子激酶抑制剂、小分子免疫调节剂、干扰素、芳香酶抑制剂、PARP抑制剂、抗肿瘤疫苗、细胞因子、嵌合抗原受体T细胞(CAR-T)、单克隆抗体和放疗中的一种或多种。
本发明中，所述烷化剂可选自但不限于：顺铂、卡铂、奥沙利铂、奈达铂、氮芥、盐酸N-氧化-氮芥、环丁酸氮芥、尿嘧啶氮芥、环磷酰胺、异环磷酰胺、噻替派、卡波醌、三亚胺醌、甲苯磺酸英丙舒凡、甘露舒凡、曲奥舒凡、白消安、盐酸尼莫司汀、二溴甘露醇、美法仑、达卡巴嗪、雷莫司汀、卡莫司汀、洛莫司汀、链脲霉素、替莫唑胺、丙卡巴肼、乙烯亚胺衍生物、甲烷磺酸酯类、亚硝脲类、三氮烯类中的一种或多种。
本发明中，所述拓扑酶I/II抑制剂可选自但不限于：多柔比星、柔红霉素、表柔比星、依达比星、伊立替康、拓扑替康、鲁比替康、贝洛替康、依托泊苷、提尼泊苷、阿霉素和右雷佐生、喜树碱中的一种或多种。
本发明中，所述抗有丝分裂剂包括但不限于：紫杉醇、多西紫杉醇、聚谷氨酸紫杉 醇、异长春碱、长春新碱、长春碱、长春地辛、长春利定、依托泊苷、替尼泊苷、伊沙匹隆、拉洛他塞、ortataxel、tesetaxel、tocosal和伊斯平斯中的一种或多种。
本发明中，所述抗代谢类药物可选自但不限于：叶酸拮抗剂、嘧啶类似物、嘌呤类似物、腺苷脱氨酶抑制剂，例如：甲氨蝶呤、5-氟尿嘧啶、氟脲苷、阿糖胞苷、6-巯基嘌呤、6-硫鸟嘌呤、磷酸氟达拉滨、喷司他丁和吉西他滨中的一种或多种。
本发明中，所述激素治疗剂可选自但不限于：磷雌酚、己烯雌酚、氯烯雌酚、醋酸甲羟孕酮、醋酸甲地孕酮、醋酸氯地孕酮、醋酸环丙孕酮、达那唑、地诺孕素、烯丙雌醇、孕三烯酮、诺美孕酮、通尿灵、美帕曲星、雷洛昔芬、奥美昔芬、佐美洛昔芬、安鲁米特、睾内酯、抗雌激素类、LH-RH衍生物、芳香酶抑制剂、抗雄激素类、肾上腺皮质激素类、雄激素合成抑制剂、维甲酸和延迟维甲酸代谢的药物中的一种或多种。
本发明中，所述抗肿瘤抗生素包括但不限于：放线菌素D、多柔比星、柔红霉素、博来霉素、培洛霉素、丝裂霉素C、阿柔比星、吡柔比星、表柔比星、净司他丁斯酯、伊达比星、西罗莫司和戊柔比星中的一种或多种。
本发明中，所述小分子激酶抑制剂包括但不限于：厄洛替尼、伊马替尼、阿帕替尼、尼洛替尼、克唑替尼、达沙替尼、帕唑帕尼、瑞格菲尼、鲁索利替尼、索拉菲尼、苏尼替尼、凡德他尼、维罗非尼、博舒替尼、吉非替尼、阿法替尼、阿昔替尼、达拉菲尼、达克替尼、尼达尼布、乐伐替尼、马赛替尼、米哚妥林、来那替尼、帕纳替尼、雷多替尼、曲美替尼、丙氨酸布立尼布、西地尼布、苹果酸卡博替尼、依鲁替尼、埃克替尼、西帕替尼、考比替尼、艾代拉利司、普纳替尼、alisertib、dinaciclib、linsitinib、orantinib、rigosertib、tipifarnib、tivozanib、pimasertib、buparlisib和fedratinib中的一种或多种。
本发明中，所述抗肿瘤疫苗包括但不限于：合成肽、DNA疫苗和重组病毒。
本发明中，所述细胞因子治疗包括但不限于：IL2和GM-CSF。
本发明中，所述单克隆抗体包括但不限于：阿伦单抗、本妥昔单抗、西妥昔单抗、利妥昔单抗、地诺单抗、依匹单抗、奥法木、单抗、帕尼单抗、托西莫单抗、曲妥单抗、贝伐珠单抗、帕妥珠单抗、卡妥索单抗、埃洛妥珠单抗、依帕珠单抗、耐昔妥珠单抗、尼妥珠单抗、托珠单抗、马托珠单抗、扎鲁木单抗、阿托珠单抗、雷莫芦单抗、纳武单抗、mogamulizumab、ocaratuzumab、oregovomab、dalotuzumab、onartuzumab中的一种或多种。
本发明中，所述小分子免疫调节剂包括但不限于：TLR7激动剂、TLR8激动剂、TLR9激动剂、IDO抑制剂、CD73抑制剂、STING抑制剂、A2AR拮抗剂中的一种或多种。
本发明中，所述用于癌症治疗的干扰素包括但不限于：干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a或干扰素γ-n1等。
本发明中，所述芳香酶抑制剂包括但不限于：阿纳托唑、氨格鲁米特、依西美坦、法倔唑、来曲唑中的一种或多种。
本发明中，所述PARP抑制剂包括但不限于：Olaparib、Niraparib、Rucaparib、Veliparib、SC10914中的一种或多种。
本发明中，所述癌症包括转移性的和非转移性的癌症，也包括家族遗传性的和偶发性的癌症，还可包括固体肿瘤和非固体肿瘤。
本发明中，所述固体肿瘤的具体例子可包括但不限于：眼、骨、肺、胃、胰腺、乳腺、前列腺、脑(包括胶质母细胞瘤和髓母细胞瘤)、卵巢(包括那些从上皮细胞产生的基质细胞，生殖细胞和间质细胞)、膀胱、睾丸、脊髓、肾脏(包括腺癌、肾母细胞瘤)、口、唇、咽喉、口腔(包括鳞状细胞癌)、鼻腔、小肠、结肠、直肠、甲状旁腺、胆囊、胆管、宫颈、心、咽下腺、支气管、肝、输尿管、阴道、肛门、喉腺、甲状腺(包括甲状腺癌和髓样癌)，食道、鼻咽腺垂体、唾液腺、肾上腺、头颈部上皮内瘤样病变(包括Bowen病和Paget氏病)，肉瘤(包括平滑肌肉瘤、横纹肌肉瘤、脂肪肉瘤、纤维肉瘤、骨肉瘤)、皮肤(包括黑色素瘤、卡波氏肉瘤、basocellular癌和鳞状细胞癌)等相关的肿瘤。
本发明中，所述固体肿瘤优选为人的眼癌、骨癌、肺癌、胃癌、胰腺癌、乳腺癌、前列腺癌、脑癌(包括但不限于噁性胶质瘤、成神经管细胞瘤)、卵巢癌、膀胱癌、子宫颈癌、睾丸癌、肾癌(包括但不限于腺癌、肾母细胞癌)、口腔癌(包括鳞状细胞癌)、舌癌、喉癌、鼻咽癌、头颈癌、结肠癌、小肠癌、直肠癌、甲状旁腺癌、甲状腺癌、食管癌、胆囊癌、胆管癌、宫颈癌、肝癌、肺癌(包括但不限于小细胞肺癌、非小细胞肺癌)、绒毛上皮癌、骨肉瘤、尤文瘤、软组织肉瘤和皮肤癌中的一种或多种。
本发明中，所述非固体肿瘤(包括血液学肿瘤)的具体例子可包括但不限于：淋巴性白血病(包括成淋巴细胞白血病、淋巴瘤、骨髓瘤、慢性淋巴性白血病(T细胞慢性淋巴性白血病、B细胞慢性淋巴性白血病)、霍奇金淋巴瘤、非霍奇金淋巴瘤)、髓性相关的白血病(包括急性髓性白血病、慢性髓性白血病)和AIDs相关的白血病中的一种或多种。
本发明中，所述癌症优选为以下一种或多种：非小细胞肺癌、小细胞肺癌、胃癌、食道癌、黑色素瘤、结肠癌、胰腺癌、乳腺癌、子宫癌、卵巢癌、前列腺癌、脑癌、膀胱癌、肾癌、骨髓瘤、肝癌、急性髓性白血病、慢性髓性白血病、成淋巴细胞白血病、慢性淋巴性白血病和淋巴瘤。
本发明中，所述哺乳动物优选为人。
本发明中，除非另有说明，术语“被一个或多个基团取代在任意位置”是指基团上所 指定的一个或多个原子的任何一个或者多个氢原子用所指定的基团取代，条件是不超过指定原子的正常化合价，所述取代均为本领域常见的合理取代。例如：被1～3个基团取代在任意位置，是指可以被1个、2个或3个相同或者不同的取代基合理取代在任意位置。
本发明中，当与取代基的键合显示与连接环中两个原子的键合相交时，那么这样的取代基可键合在环上的任何可键合的环原子；例如，
Figure PCTCN2019119899-appb-000035
为以下任一结构：
Figure PCTCN2019119899-appb-000036
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
术语“烷基”是指包含1-20个碳原子的饱和直链或支链烃基，优选1～10个碳原子，更优选1～8、1～6或1～4个碳原子，烷基的代表性例子包括但不限于：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、叔丁基、异丁基、正戊基、正己基、正庚基、辛基、壬基、癸基、1,1-二甲基丙基、1,2-二甲基丙基、2,2-二甲基丙基、1-乙基丙基、2-甲基丁基、3-甲基丁基、1-乙基-2-甲基丙基、1,1,2-三甲基丙基、1,1-二甲基丁基、1,2-二甲基丁基、2,2-二甲基丁基、1,3-二甲基丁基、2,3-二甲基丁基、2-乙基丁基、2-甲基戊基、3-甲基戊基、4-甲基戊基、4,4-二甲基戊基、2-甲基己基、3-甲基己基、4-甲基己基、5-甲基己基、2,3-二甲基戊基、2,4-二甲基戊基、2,2-二甲基戊基、3,3-二甲基戊基、2-乙基戊基、3-乙基戊基、2,2,4-三甲基戊基、十一烷基、十二烷基，及它们的各种异构体等。
术语“环烷基”是指包含3-20个碳原子的饱和或部分不饱和(包含1或2个双键)的单环或稠合环基团。“单环环烷基”优选3-10元单环烷基，更优选3-8或3-6元单环烷基。所述环烷基例子包括但不限于：环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环癸基、环十二烷基、环己烯基、2,3-二氢-1-H-茚、十氢萘等。所述环烷基可以通过环上任意的碳原子链接到母体分子上。
术语“杂环烷基”指由碳原子以及选自氮、氧或硫等杂原子组成的饱和或部分不饱和(包含1或2个双键)的3-20元的非芳香环状基团，此环状基团可为单环或稠合环基团，在本发明中，杂环烷基中杂原子个数优选1、2、3或4，杂环烷基中的氮、碳或硫原子可任选地被氧化。氮原子可任选进一步被其他基团取代而形成叔胺或季铵盐。所述杂环烷基优选3-10元单环杂环烷基，更优选3-6元单环杂环烷基。所述杂环烷基例子包括但不限于：氮丙啶基、四氢呋喃-2-基、吗啉-4-基、硫代吗啉-4-基、硫代吗啉-S-氧化物-4-基、哌啶-1-基、N-烷基哌啶-4-基、吡咯烷-1-基、N-烷基吡咯烷-2-基、哌嗪-1-基、4-烷基哌嗪-1-基等。所述杂环烷基可以通过环上任意的环原子链接到母体分子上。上述环原子特 指组成环骨架的碳原子和/或氮原子。
术语“桥环基”指环烷基或杂环烷基任意两个不相链接的环原子被1个或多个额外的碳原子或杂原子形成的直链基团连接所形成的基团，所述的直链基团选自但不限于：-CH 2-、-O-、-NH-、-S-、-CH 2CH 2-、-CH 2O-、-CH 2S-、-CH 2NH-、-CH 2CH 2CH 2-、-CH 2OCH 2-、-CH 2CH 2O-、-CH 2CH 2NH-。
术语“环烷基烷基”是指环烷基与母核结构之间通过烷基连接。由此，“环烷基烷基”包含上述烷基和环烷基的定义。
术语“杂环烷基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂环烷基烷基”包含上述烷基和杂环烷基的定义。
术语“烷氧基”指通过氧桥连接的具有所述碳原子数目的环状或者非环状烷基，包含烷基氧基、环烷基氧基和杂环烷基氧基。由此，“烷氧基”包含上述烷基、杂环烷基和环烷基的定义。
术语“烯基”指含有至少1个碳碳双键的直链、支链或者环状非芳香烃基。其中可以存在1-3个碳碳双键，优选存在1个碳碳双键。术语“C 2-4烯基”是指具有2-4个碳原子的烯基，术语“C 2-6烯基”是指具有2-6个碳原子的烯基，包括乙烯基、丙烯基、丁烯基、2-甲基丁烯基和环己烯基。
术语“炔基”是指含有至少1个碳碳三键的直链、支链或者环状烃基。其中可以存在1-3个碳碳三键，优选存在1个碳碳三键。术语“C 2-6炔基”是指具有2-6个碳原子的炔基，包括乙炔基、丙炔基、丁炔基和3-甲基丁炔基。
术语“芳基”是指任何稳定的6-10元单环或稠合芳香族基团，其中，所述稠合芳香族基团中至少有一个环为苯环、其余环可以为苯环、单环环烷基或单环杂环烷基。所述芳基包括但不限于：苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、苯并[d][1,3]二氧戊环基、吲哚啉基
Figure PCTCN2019119899-appb-000037
异吲哚啉基
Figure PCTCN2019119899-appb-000038
2,3-二氢苯并呋喃基
Figure PCTCN2019119899-appb-000039
2,3-二氢苯并[b]噻吩基
Figure PCTCN2019119899-appb-000040
苯并吡喃基
Figure PCTCN2019119899-appb-000041
1,2,3,4-四氢喹啉基
Figure PCTCN2019119899-appb-000042
1,2,3,4-四氢异喹啉基
Figure PCTCN2019119899-appb-000043
2,2-二氧化-1,3-二氢苯并[c]异噻唑基
Figure PCTCN2019119899-appb-000044
1,1-二氧化二氢苯并噻喃基
Figure PCTCN2019119899-appb-000045
1,1-二氧化-2,3- 二氢苯并[b]噻吩基
Figure PCTCN2019119899-appb-000046
1-亚氨基-1-氧化-2,3-二氢苯并[b]噻吩基
Figure PCTCN2019119899-appb-000047
2-氧代-2,3-二氢-1H-苯并[d]咪唑基
Figure PCTCN2019119899-appb-000048
术语“杂芳基”是指至少1个环上的碳原子被选自氮、氧或硫的杂原子置换所形成的芳香环基团，其可为5-7元单环结构或7-12元稠环结构，其中，所述稠环结构中至少有一个环为杂芳基、其余环可以任选为芳环、杂芳环、环烷基或杂环烷基。在本发明中，杂原子个数优选1、2、3或4，杂芳基中的氮原子可任选地被氧化。所述杂芳基优选为5-10元杂芳基，包括但不限于：吡啶基、嘧啶基、吡嗪基、哒嗪-3(2H)-酮基、呋喃基、噻吩基、噻唑基、吡咯基、咪唑基、吡唑基、恶唑基、异恶唑基、1,2,5-恶二唑基、1,2,4-恶二唑基、1H-1,2,4-三氮唑基
Figure PCTCN2019119899-appb-000049
4H-1,2,4-三氮唑基
Figure PCTCN2019119899-appb-000050
1H-1,2,3-三氮唑基
Figure PCTCN2019119899-appb-000051
1H-四氮唑基
Figure PCTCN2019119899-appb-000052
1H-吲唑基
Figure PCTCN2019119899-appb-000053
1H-吡唑并[3,4-b]吡啶基
Figure PCTCN2019119899-appb-000054
1H-吡唑并[3,4-c]吡啶基
Figure PCTCN2019119899-appb-000055
1H-吡唑并[4,3-c]吡啶基
Figure PCTCN2019119899-appb-000056
1H-吡唑并[4,3-b]吡啶基
Figure PCTCN2019119899-appb-000057
1H-吡唑并[4,3-d]嘧啶基
Figure PCTCN2019119899-appb-000058
1H-吡唑并[3,4-d]嘧啶基
Figure PCTCN2019119899-appb-000059
1H-吲哚基
Figure PCTCN2019119899-appb-000060
1H-异吲哚基
Figure PCTCN2019119899-appb-000061
1H-苯并咪唑基
Figure PCTCN2019119899-appb-000062
1H-苯并[d][1,2,3]三氮唑基
Figure PCTCN2019119899-appb-000063
苯并呋喃基
Figure PCTCN2019119899-appb-000064
苯并噻吩基
Figure PCTCN2019119899-appb-000065
苯并噻唑基
Figure PCTCN2019119899-appb-000066
苯并噁唑基
Figure PCTCN2019119899-appb-000067
喹啉基
Figure PCTCN2019119899-appb-000068
异喹啉基
Figure PCTCN2019119899-appb-000069
喹唑啉基
Figure PCTCN2019119899-appb-000070
1H-吡咯并[3,2-c]吡啶基
Figure PCTCN2019119899-appb-000071
1H-吡咯并[2,3-c]吡啶基
Figure PCTCN2019119899-appb-000072
1H-吡咯并[2,3-b]吡啶基
Figure PCTCN2019119899-appb-000073
1H-吡咯并[3,2-b]吡啶基
Figure PCTCN2019119899-appb-000074
3H-咪唑并[4,5-b]吡啶基
Figure PCTCN2019119899-appb-000075
3H-咪唑并[4,5-c]吡啶基
Figure PCTCN2019119899-appb-000076
1H-咪唑并[4,5-c]吡啶基
Figure PCTCN2019119899-appb-000077
1H-咪唑并[4,5-b]吡啶基
Figure PCTCN2019119899-appb-000078
7H-嘌呤基
Figure PCTCN2019119899-appb-000079
9H-嘌呤基
Figure PCTCN2019119899-appb-000080
7H-吡咯并[2,3-c]哒嗪基
Figure PCTCN2019119899-appb-000081
1H-吡咯并[2,3-d]哒嗪基
Figure PCTCN2019119899-appb-000082
5H-吡咯并[3,2-c]哒嗪基
Figure PCTCN2019119899-appb-000083
3H-噻吩并[2,3-d]咪唑基
Figure PCTCN2019119899-appb-000084
1H-噻吩并[2,3-d]咪唑基
Figure PCTCN2019119899-appb-000085
4H-咪唑并[4,5-d]异噻唑基
Figure PCTCN2019119899-appb-000086
6H-咪唑并[4,5-d]异噻唑基
Figure PCTCN2019119899-appb-000087
1H-噻吩并[3,4-d]咪唑基
Figure PCTCN2019119899-appb-000088
咪唑并[1,2-a]吡啶-5(1H)-酮基
Figure PCTCN2019119899-appb-000089
[1,2,4]三氮唑并[4,3-a]吡啶-5(1H)-酮基
Figure PCTCN2019119899-appb-000090
2,3-二氢-1H-吡咯并[2,3-c]吡啶基
Figure PCTCN2019119899-appb-000091
2,3-二氢-1H-吡咯并[2,3-b]吡啶基
Figure PCTCN2019119899-appb-000092
7H-吡咯并[2,3-d]嘧啶基
Figure PCTCN2019119899-appb-000093
7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶基
Figure PCTCN2019119899-appb-000094
术语“芳基烷基”是指芳基与母核结构之间通过烷基连接。由此，“芳基烷基”包含上 述烷基和芳基的定义。
术语“杂芳基烷基”是指杂环烷基与母核结构之间通过烷基连接。由此，“杂芳基烷基”包含上述烷基和杂芳基的定义。
术语“卤素”表示氟、氯、溴或碘。
术语“卤代烷基”是指被卤素任意取代的烷基。由此，“卤代烷基”包含以上卤素和烷基的定义。
术语“卤代烷氧基”是指被卤素任意取代的烷氧基。由此，“卤代烷氧基”包含以上卤素和烷氧基的定义。
术语“氨基”是指-NH 2，术语“烷氨基”是指氨基上至少一个氢原子被烷基所取代，包括但不限于：-NHCH 3、-N(CH 3) 2、-NHCH 2CH 3、-N(CH 2CH 3) 2、-N(CH 3)(CH 2CH 3)。由此，“烷氨基”包含上述烷基和氨基的定义。
术语“羧基”是指-C(O)OH。
术语“氧代基”是指＝O。
符号“＝”表示双键。
本发明所述“室温”是指15-30℃。
所述的同位素取代衍生物包括：式I中任意的氢原子被1-5个氘原子取代得到的同位素取代衍生物、式I中任意的碳原子被1-3个碳14原子取代得到的同位素取代衍生物或式I中任意的氧原子被1-3个氧18原子取代得到的同位素取代衍生物。
所述的“前药”是指化合物在体内代谢后转换成原始活性化合物。代表性地讲，前药为非活性物质，或者比活性母体化合物活性小，但可以提供方便的操作、给药或者改善代谢特性。
本发明所述的“药学上可接受的盐”在Berge，et al.，“Pharmaceutically acceptable salts”，J.Pharm.Sci.,66,1-19(1977)中有讨论，并对药物化学家来说是显而易见，所述的盐是基本上无毒性的，并能提供所需的药代动力学性质、适口性、吸收、分布、代谢或排泄等。本发明所述化合物可以具有酸性基团、碱性基团或两性基团，典型的药学上可接受的盐包括通过本发明化合物和酸反应制备得到的盐，例如：盐酸盐、氢溴酸盐、硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、硝酸盐、乙酸盐、丙酸盐、癸酸盐、辛酸盐、甲酸盐、丙烯酸盐、异丁酸盐、己酸盐、庚酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、苯甲酸盐、甲基苯甲酸盐、邻苯二甲酸盐、马来酸盐、甲磺酸盐、对甲苯磺酸盐、(D，L)-酒石酸，柠檬酸，马来酸，(D，L)-苹果酸，富马酸，丁二酸、琥珀酸盐、乳酸盐、三氟甲磺酸盐、萘-1-磺酸盐、扁桃酸盐、丙酮酸盐、硬脂酸盐、抗坏血酸盐、水杨酸盐。当本发明化合 物含有酸性基团时，其药学上可接受的盐还可以包括：碱金属盐，例如钠或钾盐；碱土金属盐，例如钙或镁盐；有机碱盐，例如和氨、烷基氨类、羟基烷基氨类、氨基酸(赖氨酸、精氨酸)、N-甲基葡糖胺等形成的盐。
本发明所述“异构体”是指本发明的式(I)化合物可以有不对称中心和外消旋体、外消旋混合物和单个非对映异构体，所有这些异构体，包括立体异构体、几何异构体、阻转异构体均包含在本发明中。在本发明中，式I化合物或其盐以立体异构的形式(例如，其含有一个或多个不对称碳原子)存在时，单独的立体异构体(对映异构体和非对映异构体)以及它们的混合物包括在本发明的范围内。本发明还包括式I表示的化合物或盐的单独异构体，以及与其中一个或多个手性中心反转的异构体的混合物。本发明的范围包括：立体异构体的混合物，以及纯化的对映异构体或对映异构体/非对映异构体富集的混合物。本发明包括所有对映异构体及非对应异构体所有可能的不同组合的立体异构体的混合物。本发明包括上文定义的所有具体基团的立体异构体的全部组合和子集。本发明还包括式I化合物或其盐的几何异构体，所述几何异构体包括顺反异构体。
在不违背本领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明实施例中使用的缩写含义如下：
(aq)：水溶液；AlCl 3：三氯化铝；(Boc) 2O：二碳酸二叔丁酯；Cs 2CO 3：碳酸铯；CuI：碘化亚铜；CH 3I：碘甲烷；DCM：二氯甲烷；DDQ：2,3-二氯-5,6-二氰基-1,4-苯醌；DIPEA：N,N-二异丙基乙胺；DMAC：N,N-二甲基乙酰胺；DMAP：4-二甲氨基吡啶；DMF：N,N-二甲基甲酰胺；DMFDMA：N,N-二甲基甲酰胺二甲基缩醛；EtOAc：乙酸乙酯；EtOH：乙醇；K 2CO 3：碳酸钾；K 2OsO 4·2H 2O：二水合锇酸钾；KOAc：醋酸钾；LDA：二异丙基氨基锂；LiBH 4：硼氢化锂；LiI：碘化锂；KI：碘化钾；MeOH：甲醇；MeONa：甲醇钠；MgO：氧化镁；MsCl：甲基磺酰氯；m-CPBA：间氯过氧苯甲酸；NaBH 4：硼氢化钠；LiBH 4：硼氢化锂；NaHCO 3：碳酸氢钠；NaH：钠氢；NaOH：氢氧化钠；NH 4HCO 3：碳酸氢铵；Na 2SO 4：硫酸钠；NaIO 4：高碘酸钠；n-BuOH：正丁醇；Pd(OAc) 2：醋酸钯；Pd(PPh 3) 4：四(三苯基膦)钯；Pd 2(dba) 3：三(二亚苄基丙酮)二钯；PE：石油醚； PdCl 2(dppf)CH 2Cl 2：[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物；TsCl：对甲苯磺酰氯；Tf 2O：三氟甲磺酸酐；TEA：三乙胺；t-BuONa：叔丁醇钠；TFA：三氟乙酸；TIPSCl：三异丙基氯硅烷；THF：四氢呋喃；Xantphos：4,5‐双二苯基膦‐9,9‐二甲基氧杂蒽；X-Phos：2‐二环己基磷‐2,4,6‐三异丙基联苯；NCS：N-氯代丁二酰亚胺；TMSCN：三甲基氰硅烷；BrCN：溴氰。
本发明所有化合物的结构可通过核磁共振( 1H NMR)和/或质谱检测(MS)鉴定。
1H NMR化学位移(δ)以PPM记录(10 -6)。NMR通过Bruker AVANCE-400光谱仪进行。合适的溶剂是氘代氯仿(CDCl 3)，氘代甲醇(CD 3OD)，氘代二甲亚砜(DMSO-d 6)，四甲基硅烷作为内标(TMS)。
低分辨率质谱(MS)由Utimate 3000 HPLC-MSQ Plus MS质谱仪测定，使用Kinetex 2.6u C18 100A(50×4.6mm)LCMS-02-001，ESI源，梯度洗脱条件：95％溶剂A和5％溶剂B(小于1.5分钟或大于3分钟)，然后5％溶剂A和95％溶剂B(1.5分钟到3分钟)，百分数为某一溶剂占总溶剂体积的体积百分数。溶剂A：10mM NH 4HCO 3(aq)；溶剂B：乙腈；
本发明化合物及中间体的纯化可以使用常规的制备硅胶板或使用快速分离机进行分离纯化，洗脱体系可以是EtOAc/PE体系或DCM/MeOH体系。还可以使用制备HPLC进行分离。
高效液相色谱仪(prep-HPLC)使用SHIMADZU LC-20制备液相色谱，色谱柱为：waters xbridge Pre C18，10um，19×260mm。纯化条件1-1：洗脱梯度，流动相B：15～70％(v/v％)，洗脱时间20分钟，流动相A：10mM NH 4HCO 3(aq)，流动相B：乙腈；纯化条件1-2：梯度洗脱：流动相B从20％到35％，洗脱时间5分钟，流动相B从35％到60％，洗脱时间15分钟，流动相A：10mM NH 4HCO 3(aq)，流动相B：乙腈；纯化条件1-3：梯度洗脱：流动相B从20％到50％，洗脱时间8分钟，流动相B从50％到80％，洗脱时间12分钟，流动相A：10mM NH 4HCO 3(aq)，流动相B：乙腈；纯化条件1-4：梯度洗脱：流动相B从15％到20％，洗脱时间5分钟，流动相B从20％到40％，洗脱时间15分钟，流动相A：10mM NH 4HCO 3(aq)，流动相B：乙腈；纯化条件2-1：洗脱梯度，流动相B：90～35％(v/v％)，洗脱时间20分钟，流动相A：0.05％的盐酸水溶液，流动相B：乙腈；纯化条件2-2：洗脱梯度，流动相B：90～45％(v/v％)，洗脱时间20分钟，流动相A：0.05％的盐酸水溶液，流动相B：乙腈；纯化条件2-3：流动相B从10％到20％，洗脱时间5分钟，流动相B从20％到45％，洗脱时间15分钟，流动相A：0.05％盐酸水溶液，流动相B：乙腈；纯化条件2-4：洗脱梯度，流动相B：25～75％(v/v％)，洗脱时间20分钟，流动相A：0.05％的盐酸水溶液，流动相B：乙腈；纯化条件2-5：流动相B从 15％到35％，洗脱时间5分钟，流动相B从35％到65％，洗脱时间15分钟，流动相A：0.05％盐酸水溶液，流动相B：乙腈；纯化条件3-1：梯度洗脱：流动相B从0％到10％，洗脱时间7分钟，流动相B从10％到55％，洗脱时间18分钟，流动相A：0.1％TFA(aq)，流动相B：乙腈；纯化条件3-2：梯度洗脱：流动相B从10％到30％，洗脱时间5分钟，流动相B从30％到65％，洗脱时间15分钟，流动相A：0.1％TFA(aq)，流动相B：乙腈；纯化条件3-3：梯度洗脱：流动相B从15％到20％，洗脱时间5分钟，流动相B从20％到45％，洗脱时间15分钟，流动相A：0.1％TFA(aq)，流动相B：乙腈；纯化条件3-4：梯度洗脱：流动相B从20％到50％，洗脱时间5分钟，流动相B从50％到80％，洗脱时间15分钟，流动相A：0.1％TFA(aq)，流动相B：乙腈；纯化条件3-5：梯度洗脱：流动相B从15％到35％，洗脱时间15分钟，流动相B从35％到80％，洗脱时间5分钟，流动相A：0.1％TFA(aq)，流动相B：乙腈；纯化条件3-6：梯度洗脱：流动相B从15％到25％，洗脱时间5分钟，流动相B从25％到55％，洗脱时间15分钟，流动相A：0.1％TFA(aq)，流动相B：乙腈。检测波长：214nm、和/或254nm、和/或262nm；流速：10.0mL/分钟。
薄层硅胶板(prep-TLC)是烟台黄海HSGF254或青岛GF254硅胶板。
快速分离机(flash柱层析)(flash system/Cheetah TM)使用的是Agela Technologies MP200，配套使用的分离柱为Flash columm Silica-CS(80g)，Cat No.CS140080-0。
本发明所有化合物可通过超高效液相色谱仪进行分析，超高效液相色谱仪(UPLC)使用Waters ACQUITY Hclass平台，色谱柱为：Waters ACQUITY UPLC BEH Shield RP18 2.1mm*100mm，1.7um，流动相A：乙腈，流动相B：5mm磷酸二氢钾水溶液(用磷酸调pH值至2.5)。梯度洗脱时间15分钟，流速：0.4mL/min，检测波长：214nm&254nm；柱温：40℃；进样量1uL；梯度洗脱条件如下表：
表1：
时间(分钟) 流速相A(％) 流速相B(％)
0.00 10 90
5.00 40 60
7.00 90 10
13.00 90 10
13.10 10 90
15.00 10 90
本发明无特殊注明外，所有实施例中的反应均在氮气或氩气保护下进行。
实施例1：8-甲基-4-((R)-3-甲基吗啉基)-8-(甲基磺酰基)-2-(1H-吡咯[2,3-b]吡啶-4-基)-7,8-二氢-6H-吡喃[3,2-d]嘧啶(化合物1)的合成
中间体1-11的合成：
Figure PCTCN2019119899-appb-000095
步骤1：2,4-二氯-5-甲氧基嘧啶(20g，118mmol)溶解在THF(150mL)中，内温保持在30℃以下缓慢滴加烯丙基溴化镁的THF溶液(1M，167mL)。得到的混合物在室温下搅拌2小时。向反应体系中缓慢滴加丙酮(40mL)，内温控制在20℃以下。得到的混合物继续搅拌1小时后，缓慢加入DDQ(30.4g，134mmol)。得到的混合物在室温下搅拌过夜后，过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝100/1～10/1)纯化得到中间体1-2(17g)为棕色固体。m/z:[M+H] +205.0.
步骤2：向中间体1-2(10g，48.7mmol)的丙酮/水(160mL/80mL)混合溶液中依次加入K 2OsO 4·2H 2O(500mg，13.6mmol)和N-甲基-N-氧化吗啉(11.4g，97.3mmol)。得到的混合物在室温下搅拌2小时，向反应体系加入NaIO 4(31.2mg，13.6mmol)。混合物室温搅拌过夜后，加入水(80mL)淬灭反应，过滤，滤液用EtOAc(150mL×3)萃取。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～1/1)纯化得到中间体1-3(9g)为黄色油状物。m/z:[M+H] +206.9.
步骤3：向中间体1-3(17.5g，84.5mmol)和(R)-3-甲基吗啉(8.6g，84.5mmol)的EtOH(160mL)溶液中加入DIPEA(21.5mL，127mmol)。得到的混合物80℃下搅拌8小时。冷却至室温后，反应液减压浓缩，残留物用EtOAc萃取(100mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～2/1)纯化得到中间体1-4(15g)为黄色油状物。
步骤4：冰浴条件下，向中间体1-4(15g，55.5mmol)的MeOH(120mL)溶液中 分批加入NaBH 4(2.57g，71.8mmol)，得到的混合物在室温下搅拌2小时。然后将反应液冷却至0℃，用盐酸(1M)调节反应液的pH＝7～8。反应液减压浓缩，残留物用EtOAc萃取(100mL×3)。有机相用无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～1/1)纯化得到中间体1-5(10.3g)为黄色油状物。m/z:[M+H] +273.7.
步骤5：向中间体1-5(3g，11mmol)的1,2-二氯乙烷(200mL)溶液中加入无水AlCl 3(7.3g，55mmol)。得到的混合物在65℃下搅拌2小时。混合物冷却至0℃后，缓慢加入盐酸(1M，30mL)，反应液用DCM/MeOH(10/1)萃取(100mL×3)。合并的有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～1/1)纯化得到中间体1-6(1.2g)为黄色固体。m/z:[M+H] +260.0.
步骤6：向中间体1-6(500mg，1.93mmol)的MeOH(15mL)溶液中加入MeONa(104mg，1.93mmol)。反应体系在室温下搅拌2小时。减压浓缩后，向残留物中加入1,2-二溴乙烷(1.8g，9.65mmol)和DMF(10mL)。反应液室温搅拌过夜后用EtOAc萃取(30mL×3)。合并的有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～3/1)纯化得到中间体1-7(406mg)为黄色固体。m/z:[M+H] +365.9.
步骤7：冰浴条件下，向中间体1-7(406mg，1.11mmol)，TEA(337mg，3.33mmol)的DCM(10mL)溶液中加入MsCl(191mg，1.67mmol)。得到的混合物在0℃下搅拌1小时后，用水(5mL)淬灭反应，EtOAc萃取(30mL×2)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩得到中间体1-8(480mg)为黄色油状物。m/z:[M+H] +443.8.
步骤8：将中间体1-8(480mg，1.11mmol)和LiI(149mg，1.11mmol)的1,4-二氧六环(10mL)混合物在90℃搅拌1小时。然后将反应体系冷却至室温，加水(10mL)淬灭反应，EtOAc萃取(30mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～2/1)纯化得到中间体1-9(400mg)为黄色油状物。m/z:[M+H] +475.8.
步骤9：将中间体1-9(400mg，0.84mmol)和甲烷亚磺酸钠(86mg，0.84mmol)的DMF(8mL)溶液在室温下搅拌2小时。加入水(10mL)淬灭反应，然后EtOAc萃取(30mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～2/1)纯化得到中间体1-10(340mg)为黄色油状物。m/z:[M+H] +427.8.
步骤10：冰浴条件下，向中间体1-10(290mg，0.68mmol)的DMF(60mL)溶液 中加入t-BuONa(78mg，0.81mmol)，得到的混合物0℃搅拌15分钟后，再次加入t-BuONa(78mg，0.81mmol)和CH 3I(97mg，0.68mmol)。0℃下继续搅拌20分钟，加入水(30mL)淬灭反应，然后EtOAc萃取(50mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～2/1)纯化得到中间体1-11(180mg)为黄色固体。m/z:[M+H] +362.0.
中间体1-12的合成：
Figure PCTCN2019119899-appb-000096
向4-溴-1H-吡咯并[2,3-b]吡啶-1-羧酸叔丁酯(3.1g，10.2mmol)的1,4-二氧六环(60mL)溶液中加入联硼酸频那醇酯(2.72g，10.7mmol)，PdCl 2(dppf)CH 2Cl 2(373mg，0.51mmol)和KOAc(3g，30.6mmol)，反应体系氮气置换后90℃搅拌6小时。然后将反应液冷却至室温，过滤，滤液减压浓缩，残留物用flash柱层析(PE/EtOAc＝20/1～10/1)纯化得到中间体1-12(2.4g)为绿色油状物。 1H-NMR(400MHz,CDCl 3):δ8.52-8.53(d,J＝4.8Hz,1H),7.66-7.67(d,J＝4.0Hz,1H),7.55-7.57(d,J＝4.4Hz,1H),6.94-6.95(d,J＝4.0Hz,1H),1.69(s,9H),1.41(s,12H).
化合物1的合成：
Figure PCTCN2019119899-appb-000097
步骤1：向中间体1-11(100mg，0.28mmol)的1,4-二氧六环/水(8mL/1.5mL)混合溶液中加入中间体1-12(143mg，0.42mmol)，Pd(PPh 3) 4(35mg，0.03mmol)和K 2CO 3(116mg，0.84mmol)，反应体系用氮气置换后在100℃下搅拌3小时。反应体系冷却至室温后，用DCM/MeOH(10/1)混合溶剂萃取(30mL×2)。有机相用无水Na 2SO 4干燥、过滤，滤液减压浓缩得到化合物X-1(280mg，粗品)为棕色油状物。m/z:[M+H] +544.0.
步骤2：化合物X-1(280mg，粗品)和TFA(1mL)的DCM(4mL)溶液在室温下搅拌1小时。减压浓缩除去有机溶剂，残留物用饱和NaHCO 3(aq)调pH至7～8，EtOAc萃取(30mL×3)。合并有机相并用无水Na 2SO 4干燥、过滤，滤液减压浓缩。残留物用 prep-TLC(DCM/MeOH＝10/1)纯化得到化合物1(86mg，两步产率：59％)为淡黄色固体。UPLCRT:5.692min；m/z:[M+H] +444.1； 1H-NMR(400MHz,DMSO-d 6):δ11.8(s,1H),8.32(d,J＝5.2Hz,1H),7.89(t,J＝4.4Hz,1H),7.57(d,J＝2.4Hz,1H),7.22(d,J＝1.2Hz,1H),4.72-4.77(m,1H),4.47-4.52(m,1H),4.25-4.34(m,2H),3.96(d,J＝10.0Hz,1H),3.73(d,J＝4.0Hz,2H),3.56-3.62(m,1H),3.42-3.45(m,1H),3.31(d,J＝3.2Hz,3H),2.73-2.78(m,1H),2.15-2.21(m,1H),1.91(s,3H),1.29-1.36(m,3H).
实施例2：N-甲基-1-(8-甲基-4-((R)-3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-吡喃[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物2)的合成
Figure PCTCN2019119899-appb-000098
向中间体1-11(40mg，0.12mmol)，N-甲基-1H-苯并咪唑-2-胺(32mg，0.22mmol)的DMF(1mL)溶液中依次加入2,6-二甲基吡啶(19mg，0.19mmol)和Cs 2CO 3(118mg，0.32mmol)。反应液在封管中130℃搅拌2天。冷却至室温后，加入水(1mL)淬灭反应，混合物用DCM/MeOH(10/1)混合溶剂萃取(20mL×2)。合并有机相并用无水Na 2SO 4干燥、过滤，滤液减压浓缩。残留物用prep-HPLC(条件1-1)纯化得到化合物2(4mg，产率：7％)为类白色固体。UPLCRT:5.353min；m/z:[M+H] +473.0； 1H-NMR(400MHz,DMSO-d 6):δ8.54-8.56(m,1H),8.06(d,J＝8.8Hz,1H),7.25(d,J＝8.0Hz,1H),7.08(t,J＝7.6Hz,1H),6.98(t,J＝7.6Hz,1H),4.70-4.76(m,1H),4.47-4.51(m,1H),4.22-4.33(m,2H),3.95-3.99(m,1H),3.73(s,2H),3.35-3.60(m,2H),3.09(s,3H),3.02(d,J＝4.8Hz,3H),2.68-2.75(m,1H),2.18-2.23(m,1H),1.82(s,3H),1.36(t,J＝6.4Hz,3H).
实施例3：4-((R)-3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-4',5',6,7-四氢-3'H-螺[吡喃[3,2-d]嘧啶-8,2'-噻吩]1',1'-二氧化物(化合物3)的合成
中间体2-3的合成：
Figure PCTCN2019119899-appb-000099
步骤1：将中间体1-9(450mg，0.94mmol)、3-氯-1-丙硫醇(157mg，1.42mmol)和DIPEA(243mg，1.88mmol)的DCM(18mL)溶液在封管中50℃搅拌16小时。反应液减压浓缩，残留物溶于EtOAc(30mL)中。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液浓缩，残留物通过flash柱层析(PE/EtOAc＝10/1～5/1)纯化得到中间体2-1(280mg)为无色油状物。m/z:[M+H] +457.8.
步骤2：冰浴条件下，向中间体2-1(200mg，0.44mmol)的DCM(20mL)溶液中加入m-CPBA(188mg，1.09mmol)，得到的混合物在室温下搅拌2小时，然后用DCM萃取(30mL×2)。有机相用饱和NaHCO 3(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物用prep-TLC(PE/EtOAc＝2/1)纯化得到中间体2-2(150mg)为无色油状物。m/z:[M+H] +489.8.
步骤3：冰浴条件下，向中间体2-2(120mg，0.24mmol)的DMF(30mL)溶液中加入t-BuONa(25mg，0.26mmol)，得到的混合物0℃下搅拌30分钟后，再次加入t-BuONa(34mg，0.35mmol)。反应体系室温下继续搅拌1小时，加入水(15mL)淬灭反应，水相用EtOAc萃取(30mL×3)。合并有机相并用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物用prep-TLC(PE/EtOAc＝2/1)纯化得到中间体2-3(100mg)为无色油状物。m/z:[M+H] +374.0.
化合物3的合成：
Figure PCTCN2019119899-appb-000100
利用化合物1的合成方法，用中间体2-3反应得到化合物3(纯化方法：prep-HPLC，条件2-1)。UPLCRT:5.745,5.780min；m/z:[M+H] +456.0； 1H-NMR(400MHz,DMSO-d 6+D 2O):δ8.43(d,J＝5.6Hz,1H),8.01(d,J＝5.2Hz,1H),7.72(d,J＝3.2Hz,1H),7.31(d,J＝3.2Hz,1H),4.71-4.76(m,1H),4.52-4.56(m,1H),4.17-4.31(m,2H),3.95(d,J＝11.2Hz,1H),3.72(s,2H),3.56-3.62(m,1H),3.41-3.49(m,3H),2.92-2.95(m,1H),2.51-2.67(m,2H),2.13-2.33(m,3H),1.31-1.34(m,3H).
实施例4：(R)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-4-基-4-基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物4)的合成
中间体3-6的合成：
Figure PCTCN2019119899-appb-000101
步骤1：向中间体1-6(1.15g，4.44mmol)的MeOH(50mL)溶液中加入MeONa(240mg，4.44mmol)。反应液室温搅拌2小时。然后减压浓缩，向残留物中加入溴代丙二酸二乙酯(3.18g，13.3mmol)和DMF(30mL)。得到的混合物在室温搅拌过夜后用EtOAc萃取(50mL×3)。合并的有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～2/1)纯化得到中间体3-1(810mg)为黄色油状物。m/z:[M+H] +418.0.
步骤2：冰浴条件下，向中间体3-1(400mg，0.96mmol)的THF(15mL)溶液中加入LiBH 4(84mg，3.84mmol)，反应液室温下搅拌2小时，加入MeOH(10mL)，反应液减压浓缩后通过flash柱层析(DCM/MeOH＝8/1)纯化得到中间体3-2(260mg)为粉色固体。m/z:[M+H] +334.0.
步骤3：冰浴条件下，向中间体3-2(260mg，0.78mmol)和TEA(467mg，4.62mmol)的DCM(20mL)和THF(4mL)混合物溶液中加入MsCl(446mg，3.89mmol)。反应体系在0℃下搅拌1小时，用水(5mL)淬灭反应，EtOAc萃取(30mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩得到中间体3-3(400mg)为黄色油状物。m/z:[M+H] +567.8.
步骤4：向中间体3-3(400mg，粗品)的1,4-二氧六环(50mL)溶液中加入LiI(521mg，3.9mmol)，反应体系在93℃下搅拌28小时。然后将反应体系冷却至室温，减压浓缩，残留物用flash柱层析(PE/EtOAc＝8/1～2/1)纯化得到中间体3-4(400mg)为黄色固体。m/z:[M+H] +663.6.
步骤5：将中间体3-4(400mg，0.60mmol)和甲烷亚磺酸钠(68mg，0.66mmol)的DMF(9mL)溶液在室温下搅拌过夜。加入水(10mL)淬灭反应，然后用EtOAc萃取(30mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩后通过flash柱层析(PE/EtOAc＝10/1～2/1)纯化得到中间体3-5(323mg)为无色油状物。 m/z:[M+H] +615.6.
步骤6：冰浴条件下，向中间体3-5(160mg，0.26mmol)的DMF(30mL)溶液中加入t-BuONa(25mg，0.26mmol)，反应体系在0℃下搅拌20分钟后，再次加入t-BuONa(25mg，0.26mmol)。反应体系在0℃下继续搅拌20分钟，加入水(15mL)，然后用EtOAc萃取(50mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过prep-TLC(PE/EtOAc＝1/2)纯化得到中间体3-6(53mg)为黄色固体。m/z:[M+H] +360.0； 1H-NMR(400MHz,CDCl 3):δ5.27-5.29(m,1H),4.76-4.83(m,1H),4.37-4.40(d,J＝9.6Hz,1H),3.95-3.99(m,1H),3.72-3.76(m,2H),3.59-3.65(m,1H),3.39-3.46(m,1H),3.29(s,3H),2.98-3.04(m,2H),1.97-2.02(m,2H),1.36-1.38(d,J＝4.8Hz,3H).
化合物4的合成：
Figure PCTCN2019119899-appb-000102
利用化合物1的合成方法，用中间体3-6反应得到化合物4(纯化方法：prep-HPLC，条件2-2)。UPLCRT:5.083min；m/z:[M+H] +442.0； 1H-NMR(400MHz,DMSO-d 6):δ11.76(s,1H),8.32(d,J＝4.8Hz,1H),7.87(d,J＝5.2Hz,1H),7.56-7.58(m,1H),7.45(s,1H),5.40-5.42(m,1H),4.81-4.82(m,1H),4.36(d,J＝12.0Hz,1H),3.95-3.98(m,1H),3.74(s,2H),3.57-3.62(m,1H),3.40-3.47(m,1H),3.32(s,3H),2.87-2.88(m,2H),2.08-2.10(m,2H),1.32-1.34(d,J＝6.8Hz,3H).
实施例5：6,8-二甲基-4-((R)-3-甲基吗啉基)-8-(甲基磺酰基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-7,8-二氢-6H-吡喃并[3,2-d]嘧啶(化合物5-1、5-2)的合成
中间体4-2/4-3的合成：
Figure PCTCN2019119899-appb-000103
利用中间体3-5的合成方法，将溴代丙二酸二乙酯替换为2-溴丙酸乙酯得到中间体4-1。
冰浴条件下，向中间体4-1(153mg，0.31mmol)的DMF(30mL)溶液中加入t-BuONa (30mg，0.31mmol)，反应液搅拌20分钟后，再次加入t-BuONa(25mg，0.26mmol)和CH 3I(44mg,0.31mmol)。0℃下继续搅拌30分钟，加入水(10mL)淬灭反应，然后用EtOAc萃取(30mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过prep-TLC(PE/EtOAc＝1/1)纯化得到中间体4-2(63mg，极性较小)和4-3(53mg，极性较大)，均为黄色固体。m/z:[M+H] +376.0.
化合物5-1/5-2的合成：
Figure PCTCN2019119899-appb-000104
利用化合物1的合成方法，用中间体4-2反应得到化合物5-1(纯化方法：prep-HPLC，条件2-2)。UPLCRT:6.659,6.685min；m/z:[M+H] +458.0； 1H-NMR(400MHz,DMSO-d 6+D 2O):δ8.45(d,J＝5.6Hz,1H),8.13-8.15(m,1H),7.74(d,J＝3.2Hz,1H),7.41(d,J＝3.2Hz,1H),4.68-4.79(m,2H),4.29-4.38(m,1H),3.95-3.98(m,1H),3.71-3.73(m,2H),3.59-3.62(m,1H),3.45-3.48(m,1H),3.26(s,3H),2.82(d,J＝15.2Hz,1H),1.99-2.05(m,1H),1.86(s,3H),1.44(d,J＝6.4Hz,3H),1.33-1.37(m,3H).
利用化合物1的合成方法，用中间体4-3反应得到化合物5-2(纯化方法：prep-HPLC，条件2-2)。UPLCRT:6.243,6.321min；m/z:[M+H] +458.0； 1H-NMR(400MHz,DMSO-d 6+D 2O):δ8.46(d,J＝5.6Hz,1H),8.09-8.11(m,1H),7.74(d,J＝3.2Hz,1H),7.43-7.45(m,1H),4.67-4.82(m,1H),4.21-4.46(m,2H),3.97(d,J＝11.8Hz,1H),3.65-3.74(m,2H),3.39-3.54(m,2H),3.28(d,J＝4.4Hz,3H),2.39-2.45(m,1H),2.16(d,J＝13.6Hz,1H),1.96(s,3H),1.50(d,J＝6.0Hz,3H),1.23-1.35(m,3H).
实施例6：(R)-8-(环丙基磺酰基)-4-(3-甲基吗啉基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物6)的合成
Figure PCTCN2019119899-appb-000105
利用化合物4的合成方法，将甲烷亚磺酸钠替换为环丙烷亚磺酸钠反应得到化合物6(纯化方法：prep-HPLC，条件2-2)。UPLCRT:5.863min；m/z:[M+H] +468.0； 1H-NMR(400 MHz,DMSO-d 6):δ11.75(s,1H),8.32(d,J＝4.8Hz,1H),7.87(d,J＝5.2Hz,1H),7.53-7.60(m,2H),5.39-5.40(m,1H),4.78-4.86(m,1H),4.38(d,J＝13.2Hz,1H),3.97(d,J＝10.8Hz,1H),3.74(s,2H),3.54-3.64(m,1H),3.35-3.46(m,2H),2.85-2.89(m,2H),2.05-2.12(m,2H),1.34(d,J＝7.2Hz,3H),1.06-1.09(m,2H),0.94-1.01(m,2H).
实施例7：4-((R)-3-甲基吗啉基)-8-(S-甲基亚磺酰亚胺基)-2-(1H-吡咯并[2,3-b]吡啶-4-基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶盐酸盐(化合物7)的合成
中间体5-5的合成：
Figure PCTCN2019119899-appb-000106
步骤1：冰浴条件下，向中间体3-3(2.53g，4.72mmol)的DMF(15mL)溶液中加入甲硫醇钠(1.57mL，4.48mmol，20％水溶液)。反应体系在0℃下搅拌1小时后，EtOAc萃取(50mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物用flash柱层析(PE/EtOAc＝2/1～1/3)纯化得到中间体5-1(1.9g)为黄色油状物。m/z:[M+H] +519.8.
步骤2：冰浴条件下，向中间体5-1(1.9g，3.66mmol)的DCM(50mL)溶液中加入m-CPBA(569mg，3.29mmol)。反应体系室温下搅拌2小时后，加入DCM(50mL)。有机相分别用饱和NaHCO 3(aq)和饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物用flash柱层析(DCM/MeOH＝80/1～20/1)纯化得到中间体5-2(1.03g)为白色固体。m/z:[M+H] +535.8.
步骤3：向中间体5-2(1.03g，1.87mmol)的1,4-二氧六环(50mL)溶液中加入LiI(1g，7.84mmol)，反应体系在93℃搅拌1小时。冷却至室温后，反应液减压浓缩，残留物用flash柱层析(PE/EtOAc＝1/1～1/5)纯化得到中间体5-3(1.02g)为黄色固体。m/z:[M+H] +599.6.
步骤4：冰浴条件下，向中间体5-3(900mg，1.5mmol)的DMF(55mL)溶液中加入t-BuONa(144mg，1.5mmol)，反应体系0℃下搅拌20分钟，再次加入t-BuONa (144mg，1.5mmol)。反应体系0℃下继续搅拌20分钟，加入水(50mL)，然后用EtOAc萃取(80mL×3)。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物用flash柱层析(PE/EtOAc＝1/1～1/5)纯化得到中间体5-4(375mg)为黄色固体。m/z:[M+H] +344.0.
步骤5：向中间体5-4(375mg，1.09mmol)和三氟乙酰胺(247mg，2.19mmol)的DCM溶液中加入MgO(174mg，4.36mmol)，碘苯二乙酸(364mg，1.09mmol)和醋酸铑(145mg，0.33mmol)。反应液回流搅拌2天(期间补加MgO 2eq，碘苯二乙酸0.5eq和醋酸铑0.15eq，一共补加8次)。反应液冷却至室温后，滤除固体，滤液减压浓缩，残留物用flash柱层析(PE/EtOAc＝4/1～1/1)纯化得到中间体5-5(56mg)为黄色固体。m/z:[M+H] +455.0.
化合物7的合成：
Figure PCTCN2019119899-appb-000107
步骤1：向中间体5-5(56mg，0.12mmol)的1,4-二氧六环/水(8mL/1.6mL)混合溶液中加入中间体1-12(76mg，0.22mmol)，Pd(PPh 3) 4(28mg，0.02mmol)和K 2CO 3(50mg，0.36mmol)，反应体系用氮气置换后在96℃下搅拌1.5小时。反应体系冷却至室温后，用DCM/MeOH(10/1)混合溶剂萃取(30mL×2)。有机相用无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物用prep-TLC(DCM/MeOH＝20/1)纯化得到化合物Y-1(280mg，产率：80％)为棕色油状物。m/z:[M+H] +541.0.
步骤2：化合物Y-1(53mg，0.10mmol)和TFA(1mL)的DCM(5mL)溶液在室温下搅拌1小时。减压浓缩除去有机溶剂，残留物用饱和NaHCO 3(aq)调pH至7～8，EtOAc萃取(30mL×3)。合并有机相并用无水Na 2SO 4干燥、过滤，滤液减压浓缩。残留物用prep-HPLC(条件：2-3)纯化得到化合物7(18mg，产率：42％)为淡黄色固体。UPLCRT:3.970min；m/z:[M+H] +441.0； 1H-NMR(400MHz,DMSO-d 6+D 2O):δ8.42-8.44(d,J＝5.2Hz,1H),8.02-8.03(d,J＝5.2Hz,1H),7.72(d,J＝3.2Hz,1H),7.42(d,J＝3.2Hz,1H),5.52-5.56(m,1H),4.80-4.88(m,1H),4.37-4.44(m,1H),3.99(d,J＝10.8Hz,1H),3.90(s,3H),3.71-3.78(m,2H),3.42-3.50(m,2H),3.26-3.32(m,1H),3.04-3.06(m,1H),2.28-2.33(m,2H),1.35(d,J＝6.4Hz,3H).
实施例8：(R)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-2-(1H-吡咯并[2,3-c]吡啶-4-基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物8)的合成
中间体6-1的合成：
Figure PCTCN2019119899-appb-000108
向4-溴-1H-吡咯并[2,3-c]吡啶(300g，1.52mmol)的1,4-二氧六环(5mL)和水(0.5mL)的混合溶液中加入联硼酸频那醇酯(1.3g，5.06mmol)，PdCl 2(dppf)CH 2Cl 2(222mg，0.30mmol)和KOAc(696mg，7.09mmol)，反应体系用氮气置换后在110℃搅拌4天。然后将反应液冷却至室温，过滤，滤液减压浓缩得到中间体6-1(370mg)为黑色固体。
化合物8的合成：
Figure PCTCN2019119899-appb-000109
向中间体3-6(50mg，0.14mmol)的1,4-二氧六环(10mL)溶液中加入化合物6-1(102mg，0.41mmol)，Pd(PPh 3) 4(31mg，0.026mmol)和K 2CO 3(aq)(2N，0.54mL，1.1mmol)，反应体系用氮气置换后在100℃下搅拌16小时。反应体系冷却至室温后，过滤，滤液减压浓缩。残留物用prep-HPLC(条件1-1)纯化得到化合物8(35.3mg，产率：58％)为白色固体。UPLCRT:4.217min；m/z:[M+H] +442.1； 1H-NMR(400MHz,DMSO-d 6):δ11.75(s,1H),8.98(s,1H),8.79(s,1H),7.70(s,1H),7.50(s,1H),5.40(t,J＝4.0Hz,1H),4.81-4.78(m,1H),4.35(d,J＝14.0Hz,1H),3.96(d,J＝11.6Hz,1H),3.74(s,2H),3.59(dd,J＝12.0,6.0Hz,1H),3.45(dd,J＝13.2,6.0Hz,1H),3.32(s,3H),2.85(br.s,2H),2.08(dd,J＝16.0,6.8Hz,2H),1.33(d,J＝6.4Hz,3H).
实施例9：(R)-N-甲基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物9)的合成
Figure PCTCN2019119899-appb-000110
向中间体3-6(60mg，0.16mmol)，N-甲基-1H-苯并咪唑-2-胺(42mg，0.29mmol) 的DMF(10mL)溶液中依次加入2,6-二甲基吡啶(27mg，0.25mmol)和Cs 2CO 3(108mg，0.33mmol)。反应液在110℃下搅拌16小时。冷却至室温后，加入EtOAc，有机相分别用水和饱和NaCl(aq)洗涤。有机相减压浓缩。残留物用prep-HPLC(条件1-1)纯化得到化合物9(24mg，产率：31％)为白色固体。UPLCRT:5.221min；m/z:[M+H] +471.0； 1H-NMR(400MHz,DMSO-d 6):δ8.42-8.45(m,1H),8.10(d,J＝8.0Hz,1H),7.26(d,J＝7.6Hz,1H),7.08(t,J＝7.6Hz,1H),6.98(t,J＝7.6Hz,1H),5.40(t,J＝4.0Hz,1H),4.80-4.78(m,1H),4.36-4.33(m,1H),3.98(d,J＝10.0Hz,1H),3.78-3.71(m,2H),3.59(dd,J＝11.6,10.8Hz,1H),3.48(ddd,J＝15.2,8.8,2.4Hz,1H),3.22(s,3H),3.02(d,J＝4.8Hz,3H),2.88-2.84(m,2H),2.07(dd,J＝15.6,7.2Hz,2H),1.36(d,J＝6.8Hz,3H).
实施例10：(R)-2-(6-氯-1H-吡咯并[2,3-b]吡啶-4-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物10)的合成
中间体7-4的合成：
Figure PCTCN2019119899-appb-000111
步骤1：冰浴条件下，向4-溴-1H-吡咯并[2,3-b]吡啶(2g，10.2mmol)的DCM(60mL)溶液中缓慢加入m-CPBA(3.09g，15.2mmol)。加毕，室温下搅拌过夜。向反应体系中加入DCM(40mL)，有机相用饱和NaHCO 3(aq)和饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩得到中间体7-1(1.1g)为棕色油状物。m/z:[M+H] +213.0.
步骤2：中间体7-1(300mg，1.41mmol)溶解在DMF(2.5mL)中，50℃下缓慢加入MsCl(403mg，3.52mmol)。反应体系75℃搅拌2小时后，冷却至室温，向反应体系加入水(5mL)。0℃下用NaOH(aq)(6N)调节pH＝7。混合物室温下搅拌3小时，用EtOAc萃取水相。有机相用饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物用flash柱层析(PE/EtOA＝40/1～10/1)纯化得到中间体7-2(140mg)为白色固体。
步骤3：向中间体7-2(140mg，0.60mmol)的DCM(10mL)溶液中加入TEA(0.25mL，1.80mmol)，(Boc) 2O(198mg，0.91mmol)和DMAP(8mg，0.06mmol)。反应体系室温搅拌2小时。反应液用盐酸(1N)和饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩得到中间体7-3(214mg)为黄色油状物。m/z:[M+H] +330.9.
步骤4：向中间体7-3(214mg，0.6mmol)的1,4-二氧六环(8mL)溶液中加入联硼酸频那醇酯(152g，0.6mmol)，PdCl 2(dppf)CH 2Cl 2(22mg，0.06mmol)和KOAc(177 g，1.8mmol)，反应体系氮气置换后在100℃搅拌4小时。冷却至室温后，过滤，滤液减压浓缩，残留物用flash柱层析(PE/EtOAc＝10/1～3/1)纯化得到中间体7-4(86mg)为黄色油状物。m/z:[M+H] +379.1.
化合物10的合成：
Figure PCTCN2019119899-appb-000112
用化合物1的合成方法，用中间体3-6和7-4反应得到化合物10(纯化方法：prep-HPLC，条件2-4)。UPLCRT:7.301min；m/z:[M+H] +476.2； 1H-NMR(400MHz,CDCl 3):δ9.51(s,1H),7.95(s,1H),7.64(s,1H),7.46(s,1H),5.35-5.38(m,1H),4.87-4.94(m,1H),4.47(d,J＝13.6Hz,1H),4.07(d,J＝10.8Hz,1H),3.81-3.89(m,2H),3.70-3.76(m,1H),3.55-3.58(m,1H),3.31(s,3H),3.08-3.16(m,2H),2.08-2.14(m,2H),1.44(d,J＝6.8Hz,3H).
实施例11：(R)-2-(6-甲氧基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物11)的合成
中间体8-1的合成：利用中间体6-1的合成方法，用4-溴-6-甲氧基-1H-吡咯并[2,3-b]吡啶反应得到6-甲氧基-4-(4,4,5,5-四甲基-1,3,2-二氧硼戊烷-2-基)-1H-吡咯并[2,3-b]吡啶(中间体8-1)。
化合物11的合成：
Figure PCTCN2019119899-appb-000113
用化合物1的合成方法，用中间体3-6和8-1反应得到化合物11(纯化方法：prep-HPLC，条件2-4)。UPLCRT:7.135min；m/z:[M+H] +472.0； 1H-NMR(400MHz,CDCl 3):δ9.76(s,1H),7.95(d,J＝8.4Hz,2H),7.25(s,1H),5.35-5.39(m,1H),4.84-4.92(m,1H),4.46(d,J＝13.2Hz,1H),4.16(s,3H),4.04(d,J＝8.8Hz,1H),3.79-3.85(m,2H),3.69-3.71(m,1H),3.50-3.57(m,1H),3.31(s,3H),3.07-3.16(m,2H),2.06-2.13(m,2H),1.43(d,J＝6.8Hz,3H).
实施例12：(R)-2-(5-氟-1H-吡咯并[2,3-b]吡啶-4-基)-4-(3-甲基吗啉基)-8-(甲基磺酰 基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物12)的合成
中间体9-1的合成：
Figure PCTCN2019119899-appb-000114
向中间体3-6(30mg，0.08mmol)的1,4-二氧六环(5mL)溶液中加入三正丁基氢锡(48mg，0.166mmol)和Pd(PPh 3) 4(4.8mg，4μmol)，反应体系在封管中用氮气置换后在160℃下搅拌3小时。反应体系冷却至室温得到含有中间体9-1的1,4-二氧六环溶液，可直接用于下一步反应。
化合物12的合成：
Figure PCTCN2019119899-appb-000115
向中间体9-1的1,4-二氧六环溶液(0.08mmol，5mL)中加入4-溴-5-氟-1H-吡咯并[2,3-b]吡啶(18mg，0.08mmol)，Pd(PPh 3) 4(4.82mg，4μmol)和催化量的CuI，反应体系在封管中用氮气置换后在160℃下搅拌2小时或微波反应1小时。反应体系冷却至室温后，过滤，滤液减压浓缩。残留物用prep-HPLC(条件2-1)纯化得到化合物12(3mg，产率：8％)为黄色固体。UPLCRT:6.801min；m/z:[M+H] +460.2； 1H-NMR(400MHz,CDCl 3):δ12.84(s,1H),8.19(s,1H),7.61(s,1H),7.50(s,1H),5.38(s,1H),4.86-4.87(m,1H),4.50(d,J＝13.2Hz,1H),4.02(d,J＝11.6Hz,1H),3.76-3.83(m,2H),3.70(t,J＝11.6Hz,1H),3.53(t,J＝12.4Hz,1H),3.25(s,3H),3.11(s,2H),2.09-2.11(m,2H),1.42(d,J＝6.4Hz,3H).
实施例13：(R)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-N-(1H-吡唑-5-基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-胺(化合物13)的合成
中间体10-1的合成：
Figure PCTCN2019119899-appb-000116
向1H-吡唑-5-胺(292mg，3.51mmol)、NaHCO 3(445mg，5.26mmol)的乙腈(10 mL)溶液中加入TsCl(603mg，3.16mmol)，反应体系室温搅拌4小时。然后将反应液浓缩，残留物通过flash柱层析(PE/EtOAc＝3/1)纯化得到中间体10-1(312mg)为白色固体。m/z:[M+H] +238.2.
化合物13的合成：
Figure PCTCN2019119899-appb-000117
步骤1：中间体10-1(30mg，0.13mmol)、3-6(41mg，0.12mmol)、Pd 2(dba) 3(21mg，0.02mmol)、Xantphos(20mg，0.03mmol)、t-BuONa(22mg，0.2mmol)悬浮在1,4-二氧六环(5mL)中，得到的混合物用氮气置换后在130℃搅拌5小时。反应体系冷却至室温后直接减压浓缩，残留物通过prep-TLC(DCM/MeOH＝20/1)纯化得到化合物Z-1(54mg，产率：84％)为黄色固体。m/z:[M+H] +561.0.
步骤2：向化合物Z-1(54mg，0.12mmol)的MeOH(2mL)与水(0.1mL)混合溶液中加入NaOH(10mg，0.23mmol)，反应液60℃搅拌1小时。冷却至室温后直接减压浓缩，残留物通过prep-TLC(DCM/MeOH＝20/1)纯化得到化合物13(10mg，产率：21％)为黄色固体。UPLCRT:4.339min；m/z:[M+H] +407.0； 1H NMR(400MHz,CDCl 3):δ10.88(s,1H),7.46(s,1H),7.26(s,1H),5.21(s,1H),4.75(s,1H),4.27-4.30(m,1H),4.00-3.94(m,1H),3.82(d,J＝11.6Hz,1H),3.78(d,J＝11.2Hz,1H),3.70-3.63(m,1H),3.43-3.39(m,1H),3.25(s,3H),3.01-2.93(m,2H),2.08-2.00(m,2H),135(s,3H).
实施例14：(R)-2-(5-氟-1H-吡咯并[2,3-c]吡啶-4-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物14)的合成
中间体11-4的合成：
Figure PCTCN2019119899-appb-000118
步骤1：将2-氟-4-甲基-5-硝基吡啶(1g，6.41mmol)和DMFDMA(1.7g，14.1mmol)的DMF(6mL)溶液在90℃下搅拌3小时。反应液冷却至室温后直接倒入冰水中，过滤、滤饼真空干燥得到中间体11-1(1.2g)为红色固体。m/z:[M+H] +212.2.
步骤2：向中间体11-1(600mg，2.84mmol)的MeOH(50mL)和DCM(10mL)的混合溶液中加入醋酸(3.5mL)和钯碳(300mg，10％)，得到的混合物用氢气置换3次然后在氢气氛下室温搅拌过夜。反应液过滤，滤液浓缩得到中间体11-2(322mg)为 类白色固体。m/z:[M+H] +137.0.
步骤3：冰浴条件下，向中间体11-2(2.2g，16.2mmol)的THF(200mL)溶液中加入NaH(60％，1.5g，37.2mmol)，反应体系0℃下搅拌1小时后，加入TIPSCl(6.5g，34mmol)，室温搅拌3小时。反应液倒入饱和NH 4Cl(aq)并用EtOAc萃取，有机相浓缩，残留物用flash柱层析(PE/EtOAc＝4/1)纯化得到中间体11-3(1.35g)为白色固体。m/z:[M+H] +293.1.
步骤4：-78℃下，向中间体11-3(876mg，3mmol)的THF(50mL)溶液中滴加入LDA的THF溶液(1M，9mL)，反应体系在此温度下搅拌0.5小时后，滴加硼酸三甲酯(935mg，9mmol)，得到的混合物在室温下搅拌1小时。然后将反应液倒入冰水中并用盐酸(1N)调节pH＝6，水相用EtOAc萃取，分离有机相并减压浓缩得到中间体11-4(1.1g)为类白色固体。m/z:[M+H] +337.2.
化合物14的合成：
Figure PCTCN2019119899-appb-000119
将中间体11-4(111mg，0.33mmol)、3-6(54mg，0.15mmol)、Pd(PPh 3) 4(18mg，15μmol)、K 2CO 3(63mg，0.45mmol)的1,4-二氧六环(3mL)和水(0.5mL)的混合物用氮气置换3次，然后110℃微波反应2小时。冷却至室温，反应液减压浓缩，残留物用prep-HPLC(条件3-1)纯化得到化合物14(18.8mg，产率：27％)为白色固体。UPLCRT:6.414min；m/z:[M+H] +460.0； 1H NMR(400MHz,CDCl 3):δ11.76(s,1H),9.00(s,1H),7.95(s,1H),7.66(s,1H),5.38(s,1H),4.94-4.79(m,1H),4.50(d,J＝13.2Hz,1H),4.01(d,J＝11.2Hz,1H),3.87-3.75(m,2H),3.76-3.62(m,1H),3.56-3.45(m,1H),3.28(s,3H),3.11(s,2H),2.19-2.06(m,2H),1.42(d,J＝6.4Hz,3H).
实施例15：(R)-2-(2-甲基-1H-苯并[d]咪唑-1-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶盐酸盐(化合物15)的合成
Figure PCTCN2019119899-appb-000120
用化合物9的合成方法，用中间体3-6和2-甲基-1H-苯并[d]咪唑反应得到化合物15(纯化方法：prep-HPLC，条件2-3)。UPLCRT:4.635min；m/z:[M+H] +456.0； 1H-NMR(400MHz,CD 3OD):δ8.54-8.56(m,1H),7.81(d,J＝5.2Hz,1H),7.66(d,J＝8.0Hz,2H),5.46(s,1H),5.09(s,1H),4.53(d,J＝9.2Hz,1H),4.01(d,J＝10.8Hz,1H),3.82(s,2H),3.50-3.82(m,3H),3.07-3.20(m,7H),2.12(d,J＝8.4Hz,2H),1.46(d,J＝6.4Hz,3H).
实施例16：(R)-N-环丙基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺盐酸盐(化合物16)的合成
Figure PCTCN2019119899-appb-000121
用化合物9的合成方法，用中间体3-6和N-环丙基-1H-苯并[d]咪唑-2-胺反应得到化合物16(纯化方法：prep-HPLC，条件2-3)。UPLCRT:5.535min；m/z:[M+H] +497.0； 1H-NMR(400MHz,CD 3OD):δ8.42-8.46(m,1H),7.54-7.58(m,1H),7.42-7.50(m,2H),5.45(s,1H),4.94-4.98(m,1H),4.55(d,J＝12.8Hz,1H),4.05(d,J＝9.2Hz,1H),3.84(s,2H),3.60-3.74(m,2H),3.20(s,3H),3.06-3.08(m,2H),2.93-2.98(m,1H),2.07-2.14(m,2H),1.50(d,J＝6.8Hz,3H),1.03-1.11(m,4H).
实施例17：(R)-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3，2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物17)的合成
Figure PCTCN2019119899-appb-000122
用化合物9的合成方法，用中间体3-6和1H-苯并[d]咪唑-2-胺反应得到化合物17(纯化方法：prep-TLC，DCM/MeOH＝10/1)。UPLCRT:4.795min；m/z:[M+H] +457.0； 1H-NMR(400MHz,DMSO-d 6):δ9.42(s,2H),8.25(s,1H),7.47(d,J＝6.0Hz,1H),7.34(s,2H),5.44(s,1H),4.79(s,1H),4.33(d,J＝11.6Hz,1H),3.98(d,J＝10.0Hz,1H),3.75(s,2H),3.60-3.51(m,2H),3.24(s,3H),2.91(s,2H),2.09(d,J＝6.4Hz,2H),1.36(s,3H).
实施例18：(R)-5-氟-N-甲基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物18)和实施例19：(R)-6-氟-N- 甲基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物19)的合成
Figure PCTCN2019119899-appb-000123
用化合物9的合成方法，用中间体3-6和6-氟-N-甲基-1H-苯并[d]咪唑-2-胺反应得到化合物18和19(纯化方法：prep-HPLC，条件1-2)。化合物18：UPLCRT:5.397min；m/z:[M+H] +489.1； 1H-NMR(400MHz,DMSO-d 6):δ8.58(d,J＝4.0Hz,1H),8.04-8.07(m,1H),7.07(d,J＝9.6Hz,1H),6.82(t,J＝8.8Hz,1H),5.40(s,1H),4.76-4.77(m,1H),4.33(d,J＝12.4Hz,1H),3.99(d,J＝10.8Hz,1H),3.71-3.77(m,2H),3.62(t,J＝11.6Hz,1H),3.50(t,J＝12.8Hz,1H),3.22(s,3H),3.03(d,J＝3.6Hz,3H),2.88(s,2H),2.08-2.10(m,2H),1.36(d,J＝6.4Hz,3H)；化合物19：UPLCRT:5.276min；m/z:[M+H] +489.0； 1H-NMR(400MHz,DMSO-d 6):δ8.40(s,1H),7.91(d,J＝10.0Hz,1H),7.21-7.24(m,1H),6.90-6.95(m,1H),5.40(s,1H),4.75(d,J＝6.4Hz,1H),4.32-4.36(m,1H),3.98(d,J＝9.6Hz,1H),3.71-3.78(m,2H),3.46-3.62(m,2H),3.21(s,3H),3.00(s,3H),2.88(s,2H),2.06-2.10(m,2H),1.35-1.39(m,3H).
实施例20：(R)-5-氟-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺三氟乙酸盐(化合物20)的合成
Figure PCTCN2019119899-appb-000124
步骤1：将中间体3-6(72mg，0.20mmol)、4-氟-2-硝基苯腈(47mg，0.30mmol)、Pd 2(dba) 3(19mg，0.02mmol)、Xantphos(18mg，0.03mmol)、Cs 2CO 3(196mg，0.60mmol)的1,4-二氧六环(6mL)溶液用氮气置换3次，然后在120℃微波反应4小时。反应体系冷却至室温后直接减压浓缩，残留物经flash柱层析(PE/EtOAc＝1/1)纯化得到化合物U-1(92mg，粗品)为黄色固体。m/z:[M+H] +480.0.
步骤2：将化合物U-1(80mg，粗品)和钯碳(50mg)的MeOH(30mL)混合物用氢气置换3次，然后反应体系在氢气氛下室温搅拌过夜。反应液过滤，滤液减压浓缩 得到化合物U-2(70mg，粗品)为红棕色固体。m/z:[M+H]+450.0.
步骤3：将化合物U-2(70mg，0.16mmol)和BrCN(83mg，0.78mmol)的MeOH(5mL)溶液在室温下搅拌过夜。反应液减压浓缩，残留物经prep-HPLC(条件1-2)纯化得到化合物20(2.68mg，三步产率：2％)为白色固体。UPLCRT:5.101min；m/z:[M+H] +475.0； 1H NMR(400MHz,CD 3OD):δ8.46-8.37(m,1H),7.28-7.13(m,2H),5.45(s,1H),4.91(s,1H),4.52(d,J＝12.8Hz,1H),4.05(d,J＝11.2Hz,1H),3.84(s,2H),3.77-3.61(m,2H),3.21(s,3H),3.12-3.02(m2H),2.15-2.07(m,2H),1.49(d,J＝6.8Hz,3H).
实施例21：(R)-N-(1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-基)乙酰胺(化合物21)的合成
Figure PCTCN2019119899-appb-000125
用化合物9的合成方法，用中间体3-6和N-(1H-苯并[d]咪唑-2-基)乙酰胺反应得到化合物21(纯化方法：prep-HPLC，条件1-2)。UPLCRT:5.206min；m/z:[M+H] +499.0； 1H-NMR(400MHz,CDCl 3):δ10.66(s,1H),8.07-8.08(m,1H),7.66(d,J＝8.8Hz,1H),7.22(s,2H),5.30(s,1H),4.83(d,J＝7.6Hz,1H),4.44(s,1H),3.96-3.99(m,1H),3.74(s,2H),3.50-3.61(m,2H),3.01-3.09(m,2H),2.99(s,2H),2.42(s,2H),3.42(s,3H),1.42(s,3H).
实施例22：(R)-4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-5-胺(化合物22)的合成
中间体12-1的合成：
Figure PCTCN2019119899-appb-000126
-10℃下，将Tf 2O(1.20g，3.57mmol)加入到4-溴-1-(苯磺酰基)-1H-吡咯并[2,3-b]吡啶(1.2g，3.57mmol)、四甲基硝酸铵(729mg，5.36mmol)的DCM(20mL)溶液中，反应体系室温搅拌过夜。然后有机相分别用饱和NaHCO 3(aq)和饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩，残留物通过flash柱层析(PE/EtOAc＝8/1～2/1)纯化得到中间体12-1(600mg)为黄色固体。m/z:[M+H] +381.8.
化合物22的合成：
Figure PCTCN2019119899-appb-000127
步骤1：将CuI(3mg，0.014mmol)加入到中间体9-1(87mg，0.14mmol)、12-1(81mg，0.21mmol)、pd(pph 3) 4(16mg，0.014mmol)的1,4-二氧六环(2mL)溶液中，反应体系用氮气置换3次，在150℃搅拌1小时。冷却至室温后，过滤，滤液浓缩，残留物用prep-TLC(PE/EtOAc＝1/2)纯化得到化合物V-1(60mg，产率：68％)为黄色固体。m/z:[M+H] +627.0.
步骤3：将兰尼镍(30mg)加入到化合物V-1(60mg，0.09mmol)的THF(20mL)溶液中，反应体系用氢气置换三次，在氢气氛下室温搅拌过夜。过滤，滤液减压浓缩得到化合物V-2(54mg，产率：90％)为白色固体。m/z:[M+H] +597.0.
步骤4：将Cs 2CO 3(118mg，0.36mmol)加入到化合物V-2(54mg，0.09mmol)的THF(3mL)和三氟乙醇(3mL)溶液中，反应体系用氮气置换三次，然后回流搅拌2天。过滤，滤液减压浓缩，残留物通过prep-HPLC(条件1-3)纯化得到化合物22(14mg，产率：34％)为黄色固体。UPLCRT:4.238min；m/z:[M+H] +457.0； 1H-NMR(400MHz,CDCl 3):δ8.96(s,1H),7.98(s,1H),7.30(s,1H),7.21(s,1H),5.69(s,2H),5.36(s,1H),4.91(d,J＝6.8Hz,1H),4.42(d,J＝12.8Hz,1H),3.86(d,J＝11.6Hz,1H),3.69-3.88(m,3H),3.54-3.60(m,1H),3.25(s,3H),3.07-3.10(m,2H),2.08-2.12(m,2H),1.43(d,J＝6.8Hz,3H).
实施例23：(R)-N-异丙基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺三氟乙酸盐(化合物23)的合成
Figure PCTCN2019119899-appb-000128
将Pd 2(dba) 3(13mg，0.014mmol)加入到中间体3-6(50mg，0.14mmol)、N-异丙基-1H-苯并[d]咪唑-2-胺(29mg，0.17mmol)、X-phos(13mg，0.028mmol)和Cs 2CO 3(91mg，0.28mmol)的1,4-二氧六环(2.5mL)溶液中，反应体系用氮气置换3次，然后150℃微波反应1小时。冷却至室温后，过滤，滤液减压浓缩，残留物通过prep-HPLC(条件1-1)纯化得到化合物23(39.5mg，产率：57％)为白色固体。UPLCRT:5.716min；m/z:[M+H] +499.0； 1H-NMR(400MHz,DMSO-d 6):δ9.38(s,1H),8.25(d,J＝7.6Hz,1H),7.31-7.48(m,3H),5.44(s,1H),4.80(s,1H),4.34-4.37(m,1H),4.16(s,1H),3.93-4.00(m,1H),3.71-3.79(m,2H),3.48-3.62(m,2H),3.26(s,3H),2.92(s,2H),2.09(d,J＝8.4Hz,2H),1.36-1.38(m,9H).
实施例24：(R)-2-(2-异丙基-1H-苯并[d]咪唑-1-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶三氟乙酸盐(化合物24)的合成
Figure PCTCN2019119899-appb-000129
用化合物23的合成方法，用中间体3-6和2-异丙基-1H-苯并[d]咪唑反应得到化合物24(纯化方法：prep-HPLC，条件3-2)。UPLCRT:5.407min；m/z:[M+H] +484.0； 1H-NMR(400MHz,CD 3OD):δ8.28(d,J＝7.6Hz,1H),7.81(d,J＝7.2Hz,1H),7.66-7.57(m,2H),5.47(s,1H),4.91(s,1H),4.53(d,J＝13.2Hz,1H),4.39-4.27(m,1H),4.00(d,J＝10.4Hz,1H),3.85-3.76(m,2H),3.73-3.53(m,2H),3.19(s,3H),3.12-3.03(m,2H),2.17-2.08(m,2H),1.54(d,J＝6.8Hz,6H),1.46(d,J＝6.8Hz,3H).
实施例25：(R)-2-(1H-苯并[d]咪唑-1-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物25)的合成
Figure PCTCN2019119899-appb-000130
用化合物23的合成方法，用中间体3-6和1H-苯并[d]咪唑反应得到化合物25(纯化方法：prep-HPLC，条件2-5)。UPLCRT:6.257min；m/z:[M+H] +442.0； 1H-NMR(400MHz,DMSO-d 6):δ9.75(s,1H),8.75(d,J＝8.0Hz,1H),7.86(d,J＝8.0Hz,1H),7.49-7.55(m,2H),5.42(s,1H),4.95-4.90(m,1H),4.54(d,J＝13.6Hz,1H),3.97(d,J＝10.8Hz,1H),3.68(s,2H),3.61-3.53(m,1H),3.47-3.39(m,1H),3.27(s,3H),2.94-2.86(m,2H),2.05(s,2H),1.35(s,3H).
实施例26：(R)-N-乙基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物26)的合成
Figure PCTCN2019119899-appb-000131
用化合物23的合成方法，用中间体3-6和N-乙基-1H-苯并[d]咪唑-2-胺反应得到化合物26(纯化方法：prep-HPLC，条件3-2)。UPLCRT:5.347min；m/z:[M+H] +485.0； 1H-NMR(400MHz,DMSO-d 6):δ8.41(s,1H),8.09(d,J＝11.6Hz,1H),7.25(d,J＝7.6Hz,1H),7.08(d,J＝7.6Hz,1H),7.00-6.95(m,1H),5.39(s,1H),4.86(d,J＝6.0Hz,1H),4.50(s,1H),3.98(d,J＝10.8Hz,1H),3.78-3.70(m,2H),3.62-3.56(m,1H),3.53-3.47(m,3H),3.23(s,3H),2.90-2.86(s,2H),2.12-2.07(m,2H),1.35(s,3H),1.27-1.22(m,3H).
实施例27：(R)-N-甲基-4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-c]吡啶-5-胺(化合物27)的合成
Figure PCTCN2019119899-appb-000132
步骤1：冰浴条件下，向化合物14(28mg，0.06mmol)的THF(12mL)溶液中加入NaH(60％，10mg，0.24mmol)，反应体系在0℃下搅拌0.5小时后加入苯磺酰氯(44mg，0.24mmol)，得到的混合物室温搅拌2小时。将反应液倒入到饱和NH 4Cl(aq)中并用EtOAc萃取，分离有机相并减压浓缩得到化合物W-1(30mg，粗品)为白色固体。m/z:[M+H] +600.0.
步骤2：将化合物W-1(30mg，粗品)的甲胺乙醇溶液(30％，9mL)于封管中120℃搅拌过夜。反应液减压浓缩，残留物经过prep-HPLC(条件3-2)纯化得到化合物27(14.8mg，两步产率：42％)为黄色固体。UPLCRT:4.797min；m/z:[M+H] +471.0； 1H NMR(400MHz,CD 3OD):δ8.18(s,1H),7.89(s,1H),7.39(s,1H),5.32(s,1H),4.87-4.84(m,1H),4.35(d,J＝13.2Hz,1H),3.92(d,J＝11.2Hz,1H),3.77-3.67(m,2H),3.64-3.44(m,2H),3.08(d,J＝10.0Hz,6H),2.98-2.91(m,2H),2.04-1.93(m,2H),1.33(d,J＝6.4Hz,3H).
实施例28：(R)-N-(2-氟乙基)-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物28)的合成
中间体13-1的合成：
Figure PCTCN2019119899-appb-000133
将2-氯-1H-苯并[d]咪唑(300mg，1.97mmol)、2-氟乙基胺盐酸盐(580mg，5.9mmol)、TEA(790mg，7.88mmol)的n-BuOH溶液(2mL)120℃微波反应3小时。冷却至室温，反应液减压浓缩，残留物经fash柱层析纯化(100％EtOAc)得到中间体13-1(78mg)为粉色固体。m/z:[M+H] +180.0.
化合物28的合成：
Figure PCTCN2019119899-appb-000134
用化合物23的合成方法，用中间体3-6和13-1反应得到化合物28(纯化方法：prep-HPLC，条件3-2)。UPLCRT:5.217min；m/z:[M+H] +503.0； 1H-NMR(400MHz,DMSO-d 6):δ9.71(s,1H),8.26(d,J＝7.8Hz,1H),7.45(d,J＝7.6Hz,1H),7.34-7.25(m,2H),5.47-5.43(m,1H),4.81-4.76(m,2H),4.69-4.64(m,1H),4.40-4.32(m,1H),4.02-3.96(m,1H),3.91-3.88(m,1H),3.84-3.81(m,1H),3.76-3.74(m,2H),3.62-3.58(m,2H),3.22(s,3H), 2.94-2.87(m,2H),2.11-2.08(m,2H),1.38(d,J＝6.6Hz,3H).
实施例29：(R)-N-甲基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-咪唑并[4,5-c]吡啶-2-胺(化合物29)、实施例30：(R)-N-甲基-3-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-咪唑并[4,5-c]吡啶-2-胺(化合物30)和实施例31：(R)-N-(3H-咪唑并[4,5-c]吡啶-2-基)-N-甲基-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-胺(化合物31)的合成
中间体14-2的合成：
Figure PCTCN2019119899-appb-000135
步骤1：向3,4-二氨基吡啶(2.26g，0.02mol)的EtOAc(30mL)溶液中加入异硫氰酸甲酯(1.51g，0.02mol)，反应体系回流搅拌3小时。冷却至室温后过滤，滤液减压浓缩，残留物用flash柱层析(PE/EtOAc＝1/2)纯化得到1-(3-氨基吡啶-4-基)-3-甲硫脲(1.88g)为白色固体。
步骤2：向1-(3-氨基吡啶-4-基)-3-甲硫脲(1g，5.48mmol)的EtOH(15mL)溶液中加入CH 3I(3.1g，219mmol)，反应体系回流搅拌16小时。冷却至室温后过滤，滤液减压浓缩，残留物用flash柱层析(DCM/MeOH＝10/1)纯化得到中间体14-2(650mg)为紫色固体。
化合物29、30和31的合成
Figure PCTCN2019119899-appb-000136
向中间体14-2(81mg，0.54mmol)和3-6(130mg，0.36mmol)的DMAC(6mL)溶液中分别加入2,6-二甲基吡啶(57.8mg，0.54mmol)和Cs 2CO 3(235mg，0.72mmol)，反应体系在120℃下搅拌16小时。然后将反应体系减压浓缩，残留物用EtOAc和水稀释。分离有机相，有机相减压浓缩。残留物用prep-HPLC(条件1-4)纯化得到化合物29(3.1mg，类白色固体)、30(2.63mg，类白色固体)和31(20.3mg，黄色固体)。化合物29：UPLCRT:3.854min；m/z:[M+H] +472.1； 1H-NMR(400MHz,DMSO-d 6):δ9.19(s,1H),8.89(d,J＝4.4Hz,1H),8.20(s,1H),7.25-7.27(m,1H),5.42(s,1H),4.79-4.81(m,1H),4.38(d,J＝12.4Hz,1H),4.02(d,J＝10.8Hz,1H),3.72-3.80(m,2H),3.57-3.63(m,1H), 3.47-3.54(m,1H),3.23(s,3H),3.07(d,J＝4.0Hz,3H),2.89(s,2H),2.09-2.11(m,2H),1.38(d,J＝6.8Hz,3H)；化合物30：UPLCRT:3.859min；m/z:[M+H] +472.1；化合物31：UPLCRT:3.860min；m/z:[M+H] +472.1.
实施例32：(R)-N-甲基-4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-5-胺(化合物32)的合成
Figure PCTCN2019119899-appb-000137
步骤1：将化合物V-2(10mg，0.017mmol)的甲酸(0.5mL)和乙酸酐(0.5mL)混合溶液在100℃搅拌1小时。冷却至室温后，反应液减压浓缩，残留物溶于EtOAc，有机相用饱和NaHCO 3(aq)和饱和NaCl(aq)洗涤，无水Na 2SO 4干燥、过滤，滤液减压浓缩得到化合物V-3(15mg，粗品)为黄色固体。m/z:[M+H] +625.0.
步骤2：氮气保护下，将硼烷的THF溶液(1M，0.18mL)加入到化合物V-3(15mg，粗品)的THF(4mL)溶液中，反应液回流搅拌6小时。冷却至室温后，加入MeOH淬灭反应。反应液减压浓缩，残留物用perp-TLC(DCM/MeOH＝10/1)纯化得到化合物V-4(5mg，两步产率：49％)为黄色固体。m/z:[M+H] +611.0.
步骤3：氮气保护下，将NaOH(20mg，0.03mmol)加入到化合物V-4(5mg，7.6μmol)的MeOH(2mL)溶液中，反应液回流搅拌16小时。冷却至室温后，反应液减压浓缩，残留物用prep-HPLC(方法1-4)纯化得到化合物32(0.34mg，产率：10％)为黄色固体。UPLCRT:4.179min；m/z:[M+H] +471.2.
实施例33：(R)-(1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-基)氨基甲酸乙酯(化合物33)的合成
Figure PCTCN2019119899-appb-000138
冰浴条件下，将氯甲酸乙酯(30mg，0.28mmol)加入到化合物17(70mg，0.15mmol)的无水吡啶(5mL)中，室温搅拌1小时。反应液用水淬灭，EtOAc萃取，有机相合并，减压浓缩，残留物用prep-HPLC(条件3-2)纯化得到化合物33(35.5mg，产率：44％)为白色固体。UPLCRT:5.917min；m/z:[M+H] +529.0； 1H-NMR(400MHz,DMSO-d 6):δ10.10(s,1H),7.81-7.83(d,J＝8.0Hz,1H),7.47-7.48(m,1H),7.26-7.35(m,1H),5.33(s,1H),4.73-4.75(d,J＝5.6Hz,1H),4.52-4.57(m,2H),4.24-4.27(d,J＝10.8Hz,1H),3.89-3.92(d,J＝11.6Hz,1H),3.64-3.71(m,5H),3.34-3.51(m,1H),3.27-3.37(m,1H),2.80(s,2H),1.98-2.00(d,J＝7.6Hz,2H),1.42-1.35(m,3H),1.23-1.33(m,3H).
实施例34：(R)-4-氟-N-甲基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物34)的合成
Figure PCTCN2019119899-appb-000139
用化合物29的合成方法，用中间体3-6和7-氟-N-甲基-1H-苯并[d]咪唑-2-胺反应得到化合物34(纯化方法：prep-TLC，PE/EtOAc＝1/2)。UPLCRT:5.448min；m/z:[M+H] +489.0； 1H-NMR(400MHz,DMSO-d 6):δ8.54(s,1H),7.92(d,J＝6.0Hz,1H),6.95(d,J＝8.0Hz,2H),5.40(s,1H),4.90(s,1H),4.50(d,J＝13.2Hz,1H),4.03-4.06(m,1H),3.74(s,2H),3.55-3.58(m,1H),3.47-3.50(m,1H),3.22(s,3H),3.03(s,3H),2.88(s,2H),2.09(d,J＝7.6Hz,2H),1.35-1.36(m,3H).
实施例35：(R)-(3-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)苯基)甲醇(化合物35)的合成
Figure PCTCN2019119899-appb-000140
向化合物3-6(50mg，0.14mmol)的1,4-二氧六环/水(5mL/1.0mL)混合溶液中加入3-羟甲基苯基硼酸频哪醇酯(49mg，0.21mmol)，Pd(PPh 3) 4(16mg，0.014mmol)和K 2CO 3(58mg，0.42mmol)，反应体系用氮气置换后在100℃搅拌2～4小时。然后冷却至室温，反应液用DCM/MeOH混合溶剂(10/1，30mL×2)萃取。有机相用无水Na 2SO 4干燥、过滤，滤液减压浓缩。残留物用prep-HPLC(条件3-2)纯化得到化合物35(20.5mg，产率：33％)为白色固体。UPLCRT:6.498min；m/z:[M+H] +432.0； 1H-NMR(400MHz,CDCl 3):δ8.22-8.29(m,2H),7.45(d,J＝3.6Hz,2H),5.32(s,1H),4.85-4.91(m,1H),4.80(s,2H),4.45(d,J＝13.2Hz,1H),4.04(d,J＝10.4Hz,1H),3.72-3.85(m,3H),3.46-3.55(m,1H),3.40(s,3H),3.22(s,1H),3.07(s,2H),2.04-2.11(m,2H),1.40(d,J＝6.4Hz,3H).
实施例36：(R)-4-(3-甲基吗啉基)-2-(2-(4-甲基哌嗪-1-基)-1H-苯并[d]咪唑-1-基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物36)的合成
中间体15-1的合成：
Figure PCTCN2019119899-appb-000141
将2-氯-1H-苯并[d]咪唑(500mg，3.28mmol)与1-甲基哌嗪(984mg，9.83mmol)混合后于130℃搅拌4小时，冷却后减压浓缩，残留物通过flash柱层析(DCM/MeOH＝10/1)纯化得到化合物15-1(390mg)为白色固体。m/z:[M+H] +238.2.
Figure PCTCN2019119899-appb-000142
用化合物23的合成方法，用中间体3-6和15-1反应得到化合物36(纯化方法：prep-TLC，MeOH/DCM＝1/10)。UPLCRT:3.990min；m/z:[M+H] +540.0； 1H-NMR(400MHz,DMSO-d 6):δ7.63(d,J＝7.8Hz,1H),7.37(d,J＝7.8Hz,1H),7.11(t,J＝7.6Hz,1H),7.01(t,J＝7.6Hz,1H),5.41-5.38(m,1H),4.83-4.78(m,1H),4.10-4.32(m,1H),3.93(d,J＝10.6Hz, 1H),3.72-3.68(m,2H),3.55(t,J＝11.6Hz,1H),3.48-3.43(m,1H),3.31(s,3H),3.22-3.18(m,4H),2.87-2.81(m,2H),2.37-2.31(m,4H),2.17(s,3H),2.09-2.05(m,2H),1.32(d,J＝6.8Hz,3H).
实施例37：(R)-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-N-(2,2,2-三氟乙基)-1H-苯并[d]咪唑-2-胺(化合物37)的合成
中间体16-1的合成：
Figure PCTCN2019119899-appb-000143
将2-氯-1H-苯并[d]咪唑(300mg，1.97mmol)、2,2,2-三氟乙胺盐酸盐(800mg，5.9mmol)、TEA(790mg，7.88mmol)的n-BuOH(2mL)溶液于120℃下微波反应3小时。然后将反应液冷却至室温，减压浓缩，残留物经flash柱层析(DCM/MeOH＝10/1)纯化得到化合物16-1(20mg)为黄色固体。m/z:[M+H] +216.0.
Figure PCTCN2019119899-appb-000144
用化合物23的合成方法，用中间体3-6和16-1反应得到化合物37(纯化方法：prep-TLC，MeOH/DCM＝1/10)。UPLCRT:6.682min；m/z:[M+H] +539.0； 1H-NMR(400MHz,DMSO-d 6):δ8.93(t,J＝6.5Hz,1H),8.16(d,J＝7.9Hz,1H),7.33(d,J＝7.7Hz,1H),7.14(t,J＝7.5Hz,1H),7.07(t,J＝7.6Hz,1H),5.43-5.39(m,1H),4.83-4.76(m,1H),4.35-4.29(m,2H),3.97(d,J＝10.8Hz,1H),3.74(t,J＝12.0Hz,2H),3.60(t,J＝12.0Hz,1H),3.49(t,J＝12.4Hz,2H),3.18(s,3H),2.91-2.85(m,2H),2.13-2.07(m,2H),1.37(d,J＝6.6Hz,3H).
实施例38：(R)-N-甲基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-咪唑并[4,5-b]吡啶-2-胺(化合物38)的合成
中间体17-1的合成：利用中间体14-2的合成方法，用2,3-二氨基吡啶反应得到N-甲基-3H-咪唑并[4,5-b]吡啶-2-胺(17-1)。
化合物38的合成：
Figure PCTCN2019119899-appb-000145
用化合物29的合成方法，用中间体3-6和17-1反应得到化合物38(纯化方法：prep-HPLC，条件3-2)。UPLCRT:4.294min；m/z:[M+H] +472.2； 1H-NMR(400MHz,DMSO-d 6):δ8.79-8.83(m,1H),8.25-8.27(m,1H),8.08-8.09(m,1H),6.95-6.98(m,1H),5.42(t,J＝4.0Hz,1H),4.75-4.76(m,1H),4.32(d,J＝12.8Hz,1H),3.97-4.00(m,1H),3.71-3.78(m,2H),3.56-3.62(m,1H),3.44-3.51(m,1H),3.24(s,3H),3.07(d,J＝4.8Hz,3H),2.88-2.90(m,2H),2.07-2.13(m,2H),1.36(d,J＝6.8Hz,3H).
实施例39：(R)-(4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)苯基)甲胺(化合物39)的合成
Figure PCTCN2019119899-appb-000146
用化合物35的合成方法，用中间体3-6和4-氨甲基苯基硼酸频哪醇酯反应得到化合物39(纯化方法：flash柱层析，DCM/MeOH＝10/1)。UPLCRT:3.928min；m/z:[M+H] +431.0； 1H-NMR(400MHz,DMSO-d 6):δ8.26(d,J＝8.4Hz,2H),8.22(br.s,2H),7.57(d,J＝8.4Hz,2H),5.39(t,J＝4.0Hz,1H),4.77-4.82(m,1H),4.38(d,J＝13.6Hz,1H),4.10-4.12(m,2H),3.93-3.96(m,1H),3.69-3.75(m,2H),3.53-3.60(m,1H),3.40-3.41(m,1H),3.36(s,3H),2.82-2.87(m,2H),1.99-2.05(m,2H),1.31(d,J＝6.8Hz,3H).
实施例40：(R)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-2-(1H-吡咯并[2,3-d]吡嗪-4-基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物40)的合成
中间体18-4的合成：
Figure PCTCN2019119899-appb-000147
步骤1：向2-甲基吡咯-3-甲酸乙酯(500mg，3.26mmol)的MeOH(20mL)溶液中加入硝酸铈铵(7.35g，13.4mmol)，室温下搅拌1小时。反应液减压浓缩，残留物经 flash柱层析(100％EtOAc)纯化得到中间体18-1(60mg)为黄色固体。m/z:[M+H] +168.0.
步骤2：中间体18-1(60mg，0.36mmol)、水合肼(40mg，0.9mmol)的EtOH(5mL)溶液在室温下搅拌2小时，反应液减压浓缩，残留物经prep-TLC(DCM/MeOH＝10/1)纯化得到中间体18-2(50mg)为黄色固体。m/z:[M+H] +182.0.
步骤3：将中间体18-2(50mg)、乙酸(0.5mL)的MeOH(5mL)溶液在80℃搅拌3小时。冷却至室温，反应液减压浓缩，残留物经prep-TLC(DCM/MeOH＝10/1)纯化得到中间体18-3(28mg)为黄色固体。m/z:[M+H] +136.0.
步骤4：向中间体18-3(28mg，0.21mmol)、吡啶(35mg，0.41mmol)的DCM(5mL)溶液加入Tf 2O(88mg，0.31mmol)，得到的混合物在室温下搅拌2小时。反应液减压浓缩，残留物经prep-TLC(PE/EtOAc＝2/1)纯化得到中间体18-4(20mg)为黄色固体。m/z:[M+H] +399.8.
Figure PCTCN2019119899-appb-000148
步骤1：将中间体9-1(20mg，0.05mmol)、18-4(60mg，0.10mmol)、Pd(PPh 3) 4(6mg，0.005mmol)、CuI(20mg，0.10mmol)的1,4-二氧六环(3mL)溶液用氮气置换后在150℃下搅拌1小时，然后将反应体系冷却至室温。减压浓缩，残留物经prep-TLC(DCM/MeOH＝20/1)纯化得到化合物A-1(22mg，产率：77％)为黄色固体。m/z:[M+H] +575.0.
步骤2：向化合物A-1(20mg)的MeOH(5mL)溶液中加入NaOH(aq)(3滴，2N)，得到的混合物在室温下搅拌1小时。反应液减压浓缩，残留物经prep-HPLC(条件3-3)纯化得到化合物40(1.54mg，产率：10％)为黄色固体。UPLCRT:3.622min；m/z:[M+H] +443.0； 1H-NMR(400MHz,CDCl 3):δ14.70(s,1H),9.90(s,1H),8.08-7.98(m,2H),5.44-5.41(m,1H),5.10-5.03(m,1H),4.74-4.66(m,1H),4.09-4.02(m,1H),3.88-3.83(m,2H),3.74-3.68(m,1H),3.62-3.55(m,1H),3.27-3.10(m,5H),2.13-2.08(m,2H),1.49-1.45(m,3H).
实施例41：(R)-N-甲基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-噻吩并[3,4-d]咪唑-2-胺(化合物41)的合成
中间体19-2的合成：
Figure PCTCN2019119899-appb-000149
步骤1：将噻吩-3,4-二胺(300mg，1.6mmol)、TEA(324mg，3.2mmol)和异硫氰酸甲酯(117mg，1.6mmol)溶于THF(10mL)溶液中，反应液回流搅拌3小时。冷却至室温后，减压浓缩得到中间体19-1(300mg)为油状液体。m/z:[M+H] +188.0.
步骤2：将中间体19-1(360mg，1.93mmol)和CH 3I(546mg，3.85mmol)的EtOH(10mL)溶液在封管中回流搅拌过夜。冷却至室温后，减压浓缩，残留物经prep-TLC(DCM/MeOH＝10/1)纯化得到中间体19-2(13mg)为黑色固体。m/z:[M+H] +154.0.
化合物41的合成：
Figure PCTCN2019119899-appb-000150
用化合物23的合成方法，用中间体3-6和19-2反应得到化合物41(纯化方法：prep-HPLC，条件3-2)。UPLCRT:4.912min；m/z:[M+H] +477.0； 1H-NMR(400MHz,CD 3OD):δ7.51(s,1H),7.03(s,1H),5.42-5.44(m,1H),4.52-4.55(b,1H),4.03-4.06(m,1H),3.83(s,2H),3.57-3.73(m,2H),3.15-3.27(m,7H),3.01-3.07(m,2H),2.07-2.11(m,2H),1.47-1.48(m,3H).
实施例42：(R)-2-(1H-吲唑-7-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物42)的合成
Figure PCTCN2019119899-appb-000151
用化合物12的合成方法，用中间体9-1和7-溴-1H-吲唑反应得到化合物42(纯化方法：prep-HPLC，条件3-4)。UPLCRT:7.325min；m/z:[M+H] +442.0； 1H-NMR(400MHz,DMSO-d 6):δ12.72(s,1H),8.27(dd,J＝7.6,0.8Hz,1H),8.22-8.19(m,1H),7.93(d,J＝8.0Hz,1H),7.29(t,J＝7.6Hz,1H),5.46-5.41(m,1H),4.90-4.82(m,1H),4.44(d,J＝13.2Hz, 1H),4.00-3.93(m,1H),3.74(s,2H),3.63-3.54(m,1H),3.48-3.38(m,1H),3.26(s,3H),2.99-2.90(m,2H),2.19-2.10(m,2H),1.34(d,J＝6.8Hz,3H).
实施例43：(R)-2-(1H-吲哚-7-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物43)的合成
Figure PCTCN2019119899-appb-000152
用化合物12的合成方法，用中间体9-1和7-溴-1H-吲哚反应得到化合物43(纯化方法：prep-HPLC，条件3-4)。UPLCRT:7.746min；m/z:[M+H] +441.0； 1H-NMR(400MHz,DMSO-d 6):δ11.37(s,1H),8.08-8.05(m,1H),7.70(d,J＝7.7Hz,1H),7.45(t,J＝2.8Hz,1H),7.15(t,J＝7.6Hz,1H),6.55(t,J＝2.8Hz,1H),5.42(t,J＝4.1Hz,1H),4.88(q,J＝6.6Hz,1H),4.46(d,J＝13.3Hz,1H),3.96(dd,J＝11.3,2.6Hz,1H),3.73(s,2H),3.61-3.55(m,1H),3.44(d,J＝3.4Hz,1H),3.25(s,3H),2.95-2.89(m,2H),2.15-2.10(m,2H),1.34(d,J＝6.8Hz,3H).
实施例44：(R)-2-(2-甲氧基吡啶-4-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物44)的合成
Figure PCTCN2019119899-appb-000153
用化合物35的合成方法，用中间体3-6和2-甲氧基吡啶-4-硼酸频哪醇酯反应得到化合物44(纯化方法：prep-HPLC，条件3-2)。UPLCRT:6.925min；m/z:[M+H] +433.0； 1H-NMR(400MHz,DMSO-d 6):δ8.29(d,J＝5.2Hz,1H),7.71(dd,J＝5.2,1.2Hz,1H),7.49(s,1H),5.38(t,J＝4.0Hz,1H),4.80-4.74(m,1H),4.35(d,J＝13.6Hz,1H),3.95-3.92(m,1H),3.90(s,3H),3.55-3.53(m,2H),3.41-3.37(m,2H),3.34(s,3H),2.87-2.80(m,2H),2.06-2.01(m,2H),1.29(d,J＝6.8Hz,3H).
实施例45：(R)-2-(1H-吲哚-4-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物45)的合成
Figure PCTCN2019119899-appb-000154
用化合物35的合成方法，用中间体3-6和4-吲哚硼酸频那醇酯反应得到化合物45(纯化方法：prep-HPLC，条件3-1)。UPLCRT:7.185min；m/z:[M+H] +441.0； 1H-NMR(400MHz,CDCl 3):δ8.37(s,1H),8.06(d,J＝7.2Hz,1H),7.64(s,1H)7.53(d,J＝8.0Hz,1H),7.36-7.39(m,1H),7.28-7.32(m,1H),5.34-5.36(m,1H),4.92-4.99(m,1H),4.53(d,J＝13.2Hz,1H),4.05-4.08(m,1H),3.70-3.91(m,3H),3.54-3.61(m,1H),3.36(s,3H),3.06-3.12(m,2H),2.13-2.16(m,2H),1.44-1.45(d,J＝6.8Hz,3H).
实施例46：(R)-4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-c]吡啶-5-胺三氟乙酸盐(化合物46)的合成
Figure PCTCN2019119899-appb-000155
用化合物27的合成方法，将步骤2中的甲胺乙醇溶液替换为氨乙醇溶液(2M)反应得到化合物46(纯化方法：prep-HPLC，条件3-2)。UPLCRT:4.369min；m/z:[M+H] +457.2； 1H-NMR(400MHz,CD 3OD):δ8.36(s,1H),8.01(d,J＝3.2Hz,1H),7.56(d,J＝2.8Hz,1H),5.51(s,1H),5.43(t,J＝4.0Hz,1H),4.44(d,J＝13.6Hz,1H),4.07-4.00(m,1H),3.90-3.78(m,2H),3.77-3.67(m,1H),3.65-3.55(m,1H),3.23(s,3H),3.10-3.02(m,2H),2.15-2.06(m,2H),1.45(d,J＝6.8Hz,3H).
实施例47：(R)-5-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)吡啶-2-胺三氟乙酸盐(化合物47)的合成
Figure PCTCN2019119899-appb-000156
用化合物35的合成方法，用中间体3-6和2-氨基吡啶-5-硼酸频哪醇酯反应得到化合物47(纯化方法：prep-HPLC，条件3-5)。UPLCRT:3.595min；m/z:[M+H] +418.0； 1H-NMR(400MHz,CD 3OD):δ8.63(dd,J＝9.2Hz,2.0Hz,1H),8.55-8.51(m,1H),6.98(d,J＝9.6Hz,1H),5.26(t,J＝4.4Hz,1H),4.37(d,J＝14.0Hz,1H),3.91-3.87(m,1H),3.72-3.63(m,2H),3.61-3.50(m,1H),3.42-3.32(m,1H),3.23-3.21(m,4H),2.95-2.85(m,2H),1.96-1.86(m,2H),1.28(d,J＝6.8Hz,3H).
实施例48：(R)-2-甲氧基-5-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)吡啶-3-胺三氟乙酸盐(化合物48)的合成
Figure PCTCN2019119899-appb-000157
用化合物35的合成方法，用中间体3-6和2-甲氧基-3-氨基吡啶-5-硼酸频哪醇酯反应得到化合物48(纯化方法：prep-HPLC，条件3-2)。UPLCRT:6.336min；m/z:[M+H] +448.0； 1H-NMR(400MHz,CD 3OD):δ8.30(d,J＝2.4Hz,1H),7.71(d,J＝2.4Hz,1H),5.36(t,J＝4.4Hz,1H),4.73-4.78(m,1H),4.34(d,J＝13.2Hz,1H),3.91-3.95(m,4H),3.71-3.71(m,2H),3.53-3.60(m,1H),3.33-3.40(m,4H),2.79-2.84(m,2H),2.00-2.03(m,2H),1.30(d,J＝6.8Hz,3H).
实施例49：N-( 2H 3)甲基-1-(8-甲基-4-((R)-3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物49)的合成
中间体20-1的合成：
Figure PCTCN2019119899-appb-000158
将2-氯-1H-苯并[d]咪唑(217mg，1.42mmol)和氘代甲胺盐酸盐(100mg，1.42mmol)的无水EtOH(10mL)溶液在封管中140℃搅拌过夜。冷却至室温后，减压浓缩，残留物用prep-TLC(DCM/MeOH＝10/1)纯化得到中间体20-1(200mg)为棕色固体。m/z:[M+H] +151.2.
化合物49的合成：
Figure PCTCN2019119899-appb-000159
用化合物29的合成方法，用中间体3-6和20-1反应得到化合物49(纯化方法：prep-HPLC，条件1-1)。UPLCRT:5.117min；m/z:[M+H] +474.0； 1H-NMR(400MHz,CDCl 3):δ8.40(s,1H),8.07(d,J＝8.0Hz,1H),7.51(d,J＝8.0Hz,1H),7.20(t,J＝7.6Hz,1H),7.04-7.08(t,J＝7.6Hz,1H),5.35-4.37(m,1H),4.88-4.92(b,1H),4.52(d,J＝13.6Hz,1H),4.05(d,J＝11.2Hz,1H),3.86(s,2H),3.67-3.74(m,1H),3.53-3.60(m,1H),3.17(s,3H),3.05-3.08(m,2H),2.09-2.12(m,2H),1.27-1.49(m,3H).
实施例50：(R)-2-(4-(1H-咪唑-2-基)苯基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物50)的合成
中间体21-1的合成：利用中间体6-1的合成方法，用2-(4-溴苯基)-1H-咪唑-1-羧酸叔丁酯反应得到2-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)-1H-咪唑(21-1)。m/z:[M-55] +271.0.
Figure PCTCN2019119899-appb-000160
用化合物35的合成方法，用中间体3-6和21-1反应得到化合物50(纯化方法：prep-HPLC，条件1-1)。UPLCRT:4.394min；m/z:[M+H] +467.8； 1H-NMR(400MHz,DMSO-d 6):δ12.62(s,1H),8.28(d,J＝8.8Hz,2H),8.02(d,J＝8.4Hz,2H),7.31(s,1H),7.07(s,1H),5.38(t,J＝4.0Hz,1H),4.85-4.75(m,1H),4.36(d,J＝13.2Hz,1H),3.99-3.92(m,1H),3.77-3.69(m,2H),3.64-3.53(m,1H),3.45-3.37(m,4H),2.91-2.79(m,2H),2.08-1.99(m,2H),1.31(d,J＝6.8Hz,3H).
实施例51：(R)-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-醇(化合物51)的合成
Figure PCTCN2019119899-appb-000161
用化合物29的合成方法，用中间体3-6和1H-苯并[d]咪唑-2-醇反应得到化合物51(纯化方法：prep-HPLC，条件3-2)。UPLCRT:6.352min；m/z:[M+H] +457.8； 1H-NMR(400MHz,CDCl 3):δ8.70(s,1H),7.84-7.87(m,1H),7.15-7.18(m,2H),7.08-7.10(m,1H),5.32-5.36(m,1H),4.84-4.92(m,1H),4.49(d,J＝14.0Hz,1H),3.97-4.04(m,1H),3.65-3.84(m,3H),3.38-3.53(m,1H),3.41(s,3H),3.03-3.08(m,2H),2.03-2.07(m,2H),1.43(d,J＝6.8Hz,3H).
实施例52：(R)-N-甲基-2-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)苯胺(化合物52)的合成
中间体22-1的合成：
Figure PCTCN2019119899-appb-000162
-78℃下，向2-氨基苯硼酸频哪醇酯(1g，4.56mmol)的THF(10mL)溶液中加入n-BuLi(0.9mL，2.28mmol，2.5M正己烷溶液)，反应体系-78℃下搅拌0.5小时后加入CH 3I(323mg，2.28mmol)，得到的混合物在室温下搅拌3小时。用水淬灭反应，EtOAc萃取。有机相干燥后减压浓缩，残留物用flash柱层析纯化(EtOAc/PE＝1/4)得到中间体22-1(250mg)为白色固体。m/z:[M+H] +234.0.
化合物52的合成：
Figure PCTCN2019119899-appb-000163
用化合物35的合成方法，用中间体3-6和22-1反应得到化合物52(纯化方法：prep-HPLC，条件3-2)。UPLCRT:6.952min；m/z:[M+H] +430.8； 1H-NMR(400MHz, DMSO-d 6):δ8.18(dd,J＝8.0,1.6Hz,1H),7.27-7.23(m,1H),6.68(d,J＝8.0Hz,1H),6.63(t,J＝7.2Hz,1H),5.38(t,J＝4.0Hz,1H),4.78-4.71(m,1H),4.30(d,J＝13.2Hz,1H),3.96-3.91(m,2H),3.59-3.52(m,2H),3.41-3.31(m,1H),3.22(s,3H),2.89-2.81(m,5H),2.06-2.03(m,2H),1.29(d,J＝6.8Hz,3H).
实施例53：(R)-N-甲基-1-(4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)苯基)甲胺三氟乙酸盐(化合物53)的合成
中间体23-1的合成：利用中间体6-1的合成方法，用(4-溴苄基)-甲基氨基甲酸叔丁酯反应得到(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苄基)-甲基氨基甲酸叔丁酯(23-1)。m/z:[M-55] +371.0.
化合物53的合成：
Figure PCTCN2019119899-appb-000164
用化合物1的合成方法，用中间体3-6和23-1反应得到化合物53(纯化方法：prep-HPLC，条件3-3)。UPLCRT:4.079min；m/z:[M+H] +444.8； 1H-NMR(400MHz,DMSO-d 6):δ9.05(s,2H),8.25(d,J＝8.4Hz,2H),7.57(d,J＝8.4Hz,2H),5.38-5.35(t,J＝4.0Hz,1H),4.83-4.76(m,1H),4.35(d,J＝13.2Hz,1H),4.19(s,2H),3.97-3.90(m,1H),3.71(s,2H),3.60-3.53(m,1H),3.42-3.39(m,1H),3.36(s,3H),2.87-2.80(m,2H),2.59(s,3H),2.06-1.98(m,2H),1.29(d,J＝6.8Hz,3H).
实施例54：(R)-2-(1-吲哚啉-4-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物54)的合成
Figure PCTCN2019119899-appb-000165
用化合物12的合成方法，用中间体9-1和4-溴-1-甲基吲哚啉反应得到化合物54(纯化方法：prep-HPLC，条件1-1)。UPLCRT:6.969min；m/z:[M+H] +457.2； 1H-NMR(400MHz,DMSO-d 6):δ7.45(d,J＝7.6Hz,1H),7.15(t,J＝7.6Hz,1H),6.59(d,J＝7.6Hz,1H),5.35-5.37(m,1H),4.70-4.75(m,1H),4.26(d,J＝13.6Hz,1H),3.92-3.95(m,1H), 3.70-3.71(m,2H),3.52-3.59(m,2H),3.31-3.33(m,5H),3.26-3.28(m,2H),2.81-2.86(m,2H),2.73(s,3H),2.01-2.05(m,2H),1.28(d,J＝6.8Hz,3H).
实施例55：(R)-1-(4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)苯基)环丙胺(化合物55)的合成
中间体24-1的合成：利用中间体6-1的合成方法，用(1-(4-溴苯基)环丙基)氨基甲酸叔丁酯反应得到(1-(4-(4,4,5,5-四甲基-1,3,2-二氧杂硼烷-2-基)苯基)环丙基)氨基甲酸叔丁酯(24-1)。m/z:[M-55] +304.1.
化合物55的合成：
Figure PCTCN2019119899-appb-000166
用化合物1的合成方法，用中间体3-6和24-1反应得到化合物55(纯化方法：prep-HPLC，条件1-1)。UPLCRT:4.633min；m/z:[M+H] +457.2； 1H-NMR(400MHz,DMSO-d 6):δ8.11(d,J＝8.4Hz,2H),7.39(d,J＝8.8Hz,2H),5.36(t,J＝4.0Hz,1H),4.80-4.73(m,1H),4.33(d,J＝13.2Hz,1H),3.94(dd,J＝11.6,2.8Hz,1H),3.73-3.69(m,2H),3.61-3.52(m,1H),3.49-3.38(m,4H),2.87-2.78(m,2H),2.06-1.98(m,2H),1.29(d,J＝6.4Hz,3H),1.05-0.94(m,4H).
实施例56：(R)-3-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)苯胺(化合物56)的合成
Figure PCTCN2019119899-appb-000167
用化合物35的合成方法，用中间体3-6和3-氨基苯硼酸频哪醇酯反应得到化合物56(纯化方法：prep-HPLC，条件1-4)。UPLCRT:4.771min；m/z:[M+H] +416.8； 1H-NMR(400MHz,DMSO-d 6):δ7.46(t,J＝2.0Hz,1H),7.41(d,J＝7.6Hz,1H),7.10(t,J＝8.0Hz,1H),6.63(dd,J＝8.0,1.6Hz,1H),5.35(t,J＝4.4Hz,1H),5.19(s,2H),4.81-4.72(m,1H),4.31(d,J＝13.6Hz,1H),3.94(dd,J＝10.8,2.4Hz,1H),3.75-3.68(m,2H),3.61-3.52(m,1H),3.41-3.38(m,4H),2.87-2.77(m,2H),2.05-1.96(m,2H),1.29(d,J＝6.8Hz,3H).
实施例57：(R)-7-氟-N-甲基-1-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-苯并[d]咪唑-2-胺(化合物57)的合成
Figure PCTCN2019119899-appb-000168
步骤1：将化合物B-1(利用U-2的合成方法，用3-6和2-氟-6-硝基苯胺反应得到化合物B-1)(60mg，0.133mmol)、TEA(14mg，0.133mmol)和异硫氰酸甲酯(29mg，0.4mmol)的THF(5mL)溶液回流搅拌16小时。反应体系冷却至室温后减压浓缩得到化合物B-2(69mg，产率：100％)为棕色固体。m/z:[M+H]+522.6.
步骤2：将化合物B-2(69mg，0.13mmol)和CH 3I(38mg，0.27mmol)的EtOH(5mL)溶液回流搅拌过夜。反应液冷却至室温后减压浓缩，残留物经prep-HPLC(条件1-2)纯化得到57(3.5mg，产率：5％)为白色固体。UPLCRT:5.241min；m/z:[M+H] +488.8； 1H-NMR(400MHz,CDCl 3):δ8.15-8.25(b,1H),7.36(d,J＝7.2Hz,1H),7.13-7.17(m,1H),6.80-6.85(m,1H),5.35-5.37(m,1H),4.95(d,J＝6.4Hz,1H),4.56(d,J＝13.6Hz,1H),3.96-3.99(m,1H),3.82(s,2H),3.58-3.65(m,1H),3.42-3.45(m,1H),3.20(s,6H),3.03-3.08(m,2H),2.03-2.11(m,2H),1.41-1.44(m,3H).
实施例58：(R)-(3-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)苯基)甲胺(化合物58)的合成
Figure PCTCN2019119899-appb-000169
用化合物1的合成方法，用中间体3-6和3-((N-Boc-氨基)甲基)苯硼酸频哪醇酯(CAS No:832114-05-3)反应得到化合物58(纯化方法：prep-HPLC，条件1-4)。UPLCRT:4.093min；m/z:[M+H] +431.2； 1H-NMR(400MHz,CDCl 3):δ8.19-8.23(m,2H),7.37-7.46(m,2H),5.29-5.33(m,1H),4.82-4.90(m,1H),4.40-4.46(m,1H),4.00-4.05(m,1H),3.96(s,2H),3.68-3.87(m,3H),3.46-3.52(m,1H),3.40(s,3H),3.03-3.09(m,2H),2.05-2.09(m,2H),1.39-1.41(d,J＝6.8Hz,3H).
实施例59：(R)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-2-(7H-吡咯并[2,3-c]哒嗪-4-基)-7,8- 二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶三氟乙酸盐(化合物59)的合成
中间体25-1的合成：
Figure PCTCN2019119899-appb-000170
向4-氯-7H-吡咯并[2,3-c]哒嗪(40mg，0.26mmol)的DCM溶液中加入苯磺酰氯(68mg，0.38mmol)，DMAP(3.2mg，0.02mmol)和TEA(80mg，0.78mmol)。反应体系在室温下搅拌过夜。将反应液减压浓缩，残留物用prep-TLC(PE/EA＝4/1)纯化得到中间体25-1(60mg)为黄色固体。
化合物59的合成：
Figure PCTCN2019119899-appb-000171
步骤1：向中间体25-1(47.8mg，0.16mmol)和9-1(100mg，0.16mmol)的1,4-二氧六环(2mL)溶液中加入Pd(PPh 3) 4(18.8mg，0.01mmol)和CuI(3.1mg，0.01mmol)，反应体系用氮气置换后在120℃下搅拌16小时。减压浓缩得到化合物D-1(粗品)。
步骤2：向化合物D-1(粗品)的THF/MeOH/H 2O(3mL/3mL/3mL)的混合溶液中加入t-BuOK(143mg，1.28mmol)，该反应体系在55℃下搅拌过夜。反应液过滤，滤液减压浓缩。残留物用prep-HPLC(条件3-2)纯化得到化合物59(6.12mg，两步产率：7％)为黄色固体。UPLCRT:3.991min；m/z:[M+H] +442.8；1H-NMR(400MHz,DMSO-d 6):δ13.35(s,1H),9.74(s,1H),8.46-8.47(m,1H),7.73(d,J＝3.2Hz,1H),7.22(s,0.5H),7.09(s,0.5H),5.51(t,J＝3.6Hz,1H),4.90-4.95(m,1H),4.51(d,J＝13.6Hz,1H),4.03-4.06(m,1H),3.81(m,2H),3.62-3.69(m,1H),3.45-3.55(m,1H),3.37(s,3H),2.94-2.99(m,2H),2.13-2.19(m,2H),1.42(d,J＝6.8Hz,3H).
实施例60：(R)-1-(4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-5-基)脲(化合物60)的合成
中间体12-4的合成：
Figure PCTCN2019119899-appb-000172
步骤1：向中间体12-1(2g，5.25mmol)的EtOH/H 2O(60mL/6mL)混合溶液中加入铁粉(2.94g，52.5mmol)和氯化铵(2.81g，52.5mmol)。反应液在80℃下搅拌1小时。冷却至室温后，滤除固体。滤液减压浓缩后用EtOAc(100mL)稀释，有机相用饱和NaCl(aq)洗涤，分离有机相减压浓缩后得到中间体12-2(1.65g)为棕色固体。m/z:[M+H] +351.6.
步骤2：将中间体12-2(500mg，1.42mmol)和Boc 2O(6mL)的混合物在100℃下搅拌4小时。冷却至室温后，反应液减压浓缩，残留物经flash柱层析(PE/EtOAc＝40/1～8/1)纯化得到中间体12-3(320mg)为白色固体。m/z:[M+H] +451.6.
步骤3：冰浴条件下，向中间体12-3(100mg，0.22mmol)的THF(2mL)溶液中加入NaH(18mg，0.44mmol，60％)。反应液搅拌5分钟后，加入BrCN(24mg，0.22mmol)，反应液在室温下搅拌2小时。加水(3滴)淬灭反应后，减压浓缩，残留物用prep-TLC(PE/EtOAc＝4/1)纯化得到中间体12-4(70mg)为白色固体。m/z:[M+H] +476.6.
化合物60的合成：
Figure PCTCN2019119899-appb-000173
步骤1：向化合物C-1(按化合物V-2的合成方法，用中间体9-1和12-4反应得到C-1)(58mg，0.04mmol)的THF/MeOH/H 2O(2.0mL/2.0mL/0.5mL)混合溶液中加入t-BuOK(36mg，0.32mmol)，反应液在50℃搅拌12小时。然后减压浓缩得到化合物C-2(粗品)。m/z:[M+H-56] +525.7.
步骤2：向化合物C-2(粗品)的DCM(5mL)溶液中加入TFA(1mL)，反应液室温搅拌1小时。然后减压浓缩，残留物经prep-HPLC(条件3-6)纯化得到化合物60(3.6mg，两步产率：18％)为黄色固体。UPLCRT:5.421min；m/z:[M+H] +500.1； 1H-NMR(400MHz,CD 3OD):δ9.00(s,1H),7.56-7.57(d,J＝3.6Hz,1H),7.12-7.13(d,J＝3.2Hz,1H),5.44-5.47(m,1H),5.00-5.04(m,1H),4.56-4.60(d,J＝13.6Hz,1H),3.98-4.02(m,1H),3.78-3.87(m,2H),3.67-3.73(m,1H),3.55-3.62(m,1H),3.26(s,3H),3.07-3.11(m,2H), 2.13-2.18(m,2H),1.45-1.46(d,J＝6.8Hz,3H).
实施例61：(R)-N-(4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-5-基)甲酰胺(化合物61)的合成
Figure PCTCN2019119899-appb-000174
向化合物V-3(38mg，0.06mmol)的THF/MeOH/H 2O(2.5mL/2.5mL/1mL)混合溶液中加入t-BuOK(54mg，0.49mmol)，反应液在50℃搅拌1小时。然后将反应液减压浓缩，残留物经prep-HPLC(条件3-6)纯化得到化合物61(12.0mg，产率：41％)为黄色固体。UPLCRT:6.074min；m/z:[M+H] +484.7； 1H-NMR(400MHz,CD 3OD):δ9.46(s,1H),8.45(s,1H),7.60-7.61(d,J＝3.2Hz,1H),7.30-7.31(d,J＝3.6Hz,1H),5.45-5.47(m,1H),5.00-5.04(m,1H),4.54-4.57(d,J＝13.2Hz,1H),4.00-4.03(m,1H),3.81-3.87(m,2H),3.67-3.71(m,1H),3.60-3.63(m,1H),3.22(s,3H),3.06-3.09(m,2H),2.13-2.18(m,2H),1.45-1.47(d,J＝6.8Hz,3H).
实施例62：(R)-N-(4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-5-基)氰胺(化合物62)的合成
中间体26-1的合成：
Figure PCTCN2019119899-appb-000175
冰浴条件下，向NCS(550mg，1.65mmol)的乙腈/水(20mL/2mL)混合溶液中加入氰化锌(184mg，1.57mmol)。搅拌5分钟后，加入中间体12-2(550mg，1.57mmol)，反应液在室温下搅拌24小时。滤除固体后，反应液减压浓缩，残留物经flash柱层析(PE/EtOAc＝10/1～2/1)纯化得到中间体26-1(59mg)为黄色固体。m/z:[M+H] +376.6.
化合物62的合成：
Figure PCTCN2019119899-appb-000176
向化合物D-1(利用V-1的合成方法，用中间体9-1和26-1反应得到化合物D-1)(50mg，0.08mmol)的THF/MeOH/H 2O(2mL/2mL/0.5mL)混合溶液中加入t-BuOK(72mg，0.64mmol)，反应液在50℃搅拌16小时。然后将反应液减压浓缩，残留物经prep-HPLC(条件3-6)纯化得到化合物62(6.0mg，产率：16％)为黄色固体。UPLCRT:6.882min；m/z:[M+H] +481.8； 1H-NMR(400MHz,CD 3OD):δ8.32(s,1H),7.54-7.55(d,J＝3.6Hz,1H),7.31-7.32(d,J＝3.6Hz,1H),5.44-5.46(m,1H),5.98-5.04(m,1H),4.55-4.59(d,J＝13.6Hz,1H),4.02-4.05(m,1H),3.81-3.89(m,2H),3.70-3.76(m,1H),3.59-3.66(m,1H),3.21(s,3H),3.05-3.10(m,2H),2.12-2.16(m,2H),1.45-1.46(d,J＝6.8Hz,3H).
实施例63：(R)-N-(4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-c]吡啶-5-基)氰胺(化合物63)的合成
Figure PCTCN2019119899-appb-000177
冰浴条件下，向化合物46(90mg，0.20mmol)的乙腈(19mL)和水(1.9mL)的混合溶液中加入NCS(29.1mg，0.22mmol)和氰化锌(24.5mg，0.21mmol)。反应体系在室温下搅拌48小时。将反应液减压浓缩。残留物用prep-HPLC(条件1-1)纯化得到化合物63(1.28mg，产率：1％)为橙色固体。UPLCRT:6.665min；m/z:[M+H] +481.8； 1H NMR(400MHz,DMSO-d 6):δ11.79(s,1H),11.74(s,1H),8.58(s,1H),7.74(t,J＝2.8Hz,1H),7.25(s,1H),5.44(t,J＝4.0Hz,1H),4.82-4.87(m,1H),4.37(d,J＝12.8Hz,1H),3.97-4.00(m,1H),3.75-3.75(m,2H),3.57-3.63(m,2H),3.22(s,3H),2.90-2.94(m,2H),2.10-2.17(m,2H),1.36(d,J＝6.8Hz,3H).
实施例64：(R)-4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-7H-吡咯并[2,3-d]嘧啶-2-胺(化合物64)的合成
中间体27-1的合成：
Figure PCTCN2019119899-appb-000178
冰浴条件下，将Tf 2O(1.32g，4.67mmol)滴加入2-氨基-7H-吡咯并[2,3-d]嘧啶-4-醇(700mg，4.67mmol)的无水吡啶(20mL)溶液中。反应体系在此温度搅拌1小时，然后继续滴加Tf 2O(1.32g，4.67mmol)，再继续搅拌1小时，加入EtOAc淬灭反应，有机相依次用水和饱和NaCl(aq)洗涤，分离有机相并减压浓缩，残留物经flash柱层析(DCM/MeOH＝20/1)纯化得到中间体27-1(410mg)为棕色固体。m/z:[M+H] +282.8.
化合物64的合成：
Figure PCTCN2019119899-appb-000179
用化合物12的合成方法，用中间体9-1和中间体27-1反应得到化合物64(纯化方法：prep-HPLC，条件1-2)。UPLCRT:3.915min；m/z:[M+H] +458.2； 1H-NMR(400MHz,CDCl 3):δ7.35(b,1H),7.02(s,1H),5.25(s,1H),4.80-5.00(b,3H),5.35-5.37(m,1H),4.07-4.06(m,1H),3.68-3.88(m,3H),3.32-3.57(m,1H),3.31(s,3H),3.08-3.12(m,2H),2.06-2.11(m,2H),1.44-1.49(m,3H).
实施例65：(R)-5-(甲基氨基)-4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-6-腈(化合物65)的合成
中间体12-8的合成：
Figure PCTCN2019119899-appb-000180
步骤1：向中间体12-3(1.8g，2.21mmol)和Cs 2CO 3(2.15g，6.63mmol)的DMF(15mL)溶液中缓慢加入CH 3I(628mg，4.42mmol)，反应液室温搅拌1小时。反应液 加入水(20mL)后用EtOAc(100mL)萃取，有机相用饱和NaCl(aq)洗涤，减压浓缩后经flash柱层析(PE/EtOAc＝50/1～2/1)纯化得到中间体12-5(1.10g)为白色固体。
步骤2：向中间体12-5(400mg，0.86mmol)的THF/MeOH/H 2O(10mL/10mL/3mL)混合溶液中加入t-BuOK(797mg，6.85mmol)，50℃搅拌2小时。反应液减压浓缩，水相用EtOAc(60mL)萃取。有机相用饱和NaCl(aq)洗涤，过滤、浓缩，残留物经flash柱层析(PE/EtOAc＝10/1～1/1)纯化后得到中间体12-6(230mg)为白色固体。m/z:[M+H] +325.8.
步骤3：0℃下，向中间体12-6(210mg，0.65mmol)的DCM(20mL)溶液中加入m-CPBA(197mg，0.97mmol)，室温下搅拌4小时。加入DCM(40mL)，有机相用饱和NaHCO 3(aq)和饱和NaCl(aq)洗涤后，减压浓缩，残留物用prep-TLC(EtOAc)纯化得到中间体12-7(160mg)为黄色固体。m/z:[M+H] +341.8.
步骤4：向中间体12-7(130mg，0.38mmol)的乙腈(3.0mL)溶液中加入TMSCN(565mg，5.70mmol)，反应液在封管中100℃下搅拌16小时。反应液减压浓缩后经过prep-HPLC纯化得到中间体12-8(15mg)的黄色固体。m/z:[M+H] +250.9.
化合物65的合成：
Figure PCTCN2019119899-appb-000181
用化合物12的合成方法，用中间体9-1和中间体12-8反应得到化合物65(纯化方法：prep-HPLC，条件3-6)。UPLCRT:6.987min；m/z:[M+H] +496.2； 1H-NMR(400MHz,CD 3OD):δ7.82(s,1H),7.36(s,1H),5.44-5.47(m,1H),4.97-5.01(m,1H),4.54-4.57(d,J＝12.8Hz,1H),4.02-4.05(m,1H),3.80-3.85(m,2H),3.62-3.72(m,2H),3.23(s,3H),3.15(s,3H),3.07-3.11(m,2H),2.10-2.16(m,2H),1.47-1.49(d,J＝6.8Hz,3H).
实施例66：(R)-(4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-b]吡啶-6-基)甲醇(化合物66)的合成
中间体28-1的合成：
Figure PCTCN2019119899-appb-000182
向4-溴-1H-吡咯并[2,3-b]吡啶-6-腈(200mg，0.91mmol)的甲醇(5mL)溶液中加入浓硫酸(2mL)，反应液90℃搅拌5小时，减压浓缩后加入EtOAc和水，用饱和NaHCO 3(aq)调节体系pH＝7～8，有机相用水和饱和NaCl(aq)洗，分离有机相并用无水Na 2SO 4干燥，过滤、浓缩，残留物用flash柱层析(PE/EtOAc＝6/1)纯化得到中间体28-1(180mg)为白色固体。m/z:[M+H] +255.0.
化合物66的合成：
Figure PCTCN2019119899-appb-000183
用化合物12的合成方法，用中间体9-1和中间体28-1反应得到化合物E-1。m/z:[M+H] +500.0.
向化合物E-1(40mg，0.08mmol)的THF(5mL)溶液中加入LiBH 4(6mg，0.24mmol)。反应体系在室温下搅拌2小时。用饱和NH 4Cl(aq)淬灭反应，加入EtOAc和水，有机相用水和饱和NaCl(aq)洗，分离有机相并用无水Na 2SO 4干燥，过滤、浓缩。残留物用prep-HPLC(条件1-1)纯化得到化合物66(1.9mg，产率：5％)为黄色固体。UPLCRT:5.072min；m/z:[M+H] +472.2； 1H NMR(400MHz,DMSO-d 6):δ8.00(s,1H),7.48(d,J＝3.6Hz,1H),7.39(d,J＝3.2Hz,1H),5.39(t,J＝4.0Hz,1H),4.84-4.78(m,1H),4.64(s,2H),4.34(d,J＝13.2Hz,1H),3.98-3.95(m,1H),3.75-3.72(m,2H),3.63-3.58(m,2H),3.32(s,3H),2.89-2.83(m,2H),2.09-2.02(m,2H),1.31(d,J＝6.8Hz,3H).
实施例67：(R)-(4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-c]吡啶-7-基)甲醇(化合物67)的合成
Figure PCTCN2019119899-appb-000184
用化合物66的合成方法，用中间体9-1和4-溴-1H-吡咯并[2,3-c]吡啶-7-羧酸甲酯反应得到化合物67(纯化方法：prep-HPLC，条件3-6)。UPLCRT:4.134min；m/z:[M+H] +472.2； 1H-NMR(400MHz,DMSO-d 6):δ8.82(s,1H),8.34(d,J＝2.8Hz,1H),7.89(d,J＝3.2Hz,1H),5.42(t,J＝4.0Hz,1H),5.23(s,2H),4.83-4.76(m,1H),4.35(d,J＝13.2Hz,1H),3.96 (dd,J＝11.2,3.2Hz,1H),3.77-3.72(m,2H),3.64-3.55(m,2H),3.27(s,3H),2.95-2.85(m,2H),2.09-2.02(m,2H),1.33(d,J＝6.8Hz,3H).
实施例68：(R)-2-(6-甲基-1H-吡咯并[2,3-b]吡啶-4-基)-4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶(化合物68)的合成
Figure PCTCN2019119899-appb-000185
将4-氯-6-甲基-1H-吡咯并[2,3-b]吡啶(22mg，0.13mmol)、中间体9-1(80mg，0.13mmol)、Pd(OAc) 2(3mg，0.013mmol)、X-phos(6mg，0.013mmol)和Xantphos(8mg，0.013mmol)的1,4-二氧六环(3mL)溶液加入到微波管中并用氮气置换3次，在微波条件下120℃反应8小时。反应液减压浓缩经prep-HPLC(条件3-6)纯化得到化合物68(13.8mg，产率：23％)为黄色固体。UPLCRT:5.351min；m/z:[M+H] +456.2； 1H NMR(400MHz,CDCl 3)δ13.71(s,1H),7.97(s,1H),7.74-7.73(m,1H),7.52(s,1H),5.40(s,1H),4.91(d,J＝6.4Hz,1H),4.49(d,J＝13.2Hz,1H),4.09-4.05(m,1H),3.86-3.84(m,2H),3.73-3.72(m,1H),3.70-3.56(m,1H),3.27(s,3H),3.15-3.12(m,2H),2.91(s,3H),2.11-2.07(m,2H),1.49(s,3H).
实施例69-84：化合物69-84的合成
利用化合物12的合成方法，用中间体9-1和相应的溴化物反应得到化合物69-76，80-83；
利用化合物9的合成方法，用中间体9-1和1-甲基-1H-苯并[d]咪唑-2(3H)-酮反应得到化合物84；
利用化合物68的合成方法，用中间体9-1和相应的溴化物反应得到化合物77-79：
表2：
Figure PCTCN2019119899-appb-000186
Figure PCTCN2019119899-appb-000187
Figure PCTCN2019119899-appb-000188
Figure PCTCN2019119899-appb-000189
Figure PCTCN2019119899-appb-000190
实施例85：(R)-4-(4-(3-甲基吗啉基)-8-(甲基磺酰基)-7,8-二氢-6H-6,8-亚甲基吡喃并[3,2-d]嘧啶-2-基)-1H-吡咯并[2,3-c]吡啶-7-醇(化合物85)的合成
Figure PCTCN2019119899-appb-000191
将KI(15mg，0.09mmol)加入到化合物75(50mg，0.11mmol)的乙腈和水(2mL，1/1)的混合溶液中，室温搅拌15分钟后，向反应体系中加入三甲基氯硅烷(17mg，0.16mmol)得到的混合物在85℃下搅拌过夜。浓缩，残留物经prep-HPLC(条件3-6)纯化得到化合物85(10mg，产率：20％)为白色固体。m/z:[M+H] +458.2； 1H NMR(400MHz,CDCl 3):δ11.53(s,1H),10.35(b,1H),8.09(s,1H),7.62(s,1H),7.47(s,1H),5.36-5.34(m,1H),4.82(d,J＝6.0Hz,1H),4.39-4.36(m,1H),4.03-4.00(m,1H),3.86-3.82(m,2H),3.77-3.70(m,1H),3.69-3.66(m,1H),3.31(s,3H),3.07-3.06(m,2H),2.11-2.07(m,2H),1.43-1.40(m,3H).
生物实施例
实施例1：ATR酶学测试
本实验中，ATR蛋白磷酸化P53底物，磷酸化的P53水平用Cisbio Bioassays的HTRF方法进行检测。实验使用的反应缓冲液成分为：25mM HEPES pH8.0，0.01％Brij-35，1％Glycerol。稀释缓冲液成分为：25mM HEPES pH8.0，0.01％Brij-35，1％Glycerol，5mM DTT，1mg/ml BSA。终止液成分为：12.5mM HEPES pH8.0，0.005％Brij-35，0.5％Glycerol，250mM EDTA。检测液成分为：50mM HEPES pH7.0，150mM NaCl，267mM KF，0.1％胆酸钠，0.01％Tween 20，0.42ng/孔anti-phospho-p53(Ser15)-K(CisBio，61P08KAE),和25ng/孔anti-GST-d2(CisBio，61GSTDLA)。10ul的ATR反应体系包括5ng ATR(Eurofins，14-953)，10nM P53底物(Eurofins，14-952)，1uM ATP和不同浓度的待测化合物。反应体系在室温条件下孵育30分钟，然后加入5ul终止液，1000rmp离心30秒后再加入5ul检测液，然后再1000rmp离心30秒。封板室温孵育过夜，用TECAN M1000-pro检测。实验数据通过GraphPad Prism 5软件进行分析处理得到IC 50值。
表3：
化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
1 18.7 33 357
2 15.0 34 1.59
3 4.44 35 2.70
4 1.10 36 469
5-1 17.6 37 9.58
5-2 25.6 38 17.6
6 2.37 39 1.87
7 7.31 40 20.3
8 1.33 41 2.96
9 1.84 42 29.8
10 41.8 43 34.2
11 5.52 44 370
12 34.9 45 1.75
13 62.3 46 0.90
14 5.24 47 83.9
15 6.04 48 348
16 7.37 49 2.72
17 1.77 50 22.5
18 3.64 51 533
19 4.29 52 119
20 2.29 53 ＞1000
21 32.7 54 970
22 1.36 55 ＞1000
23 4.54 56 79.5
24 52.2 59 40.9
25 3.43 60 36.2
26 3.01 61 14.1
27 1.75 62 2.25
28 6.20 63 1.29
29 167 64 20.7
32 6.69 65 61.5
实施例2：pCHK1细胞水平检测
DNA损伤后，ATR被激活并磷酸化其下游激酶Chk1，而Chk1在DNA损伤检查点控制中起着至关重要的作用。
Figure PCTCN2019119899-appb-000192
CHK1 p-Ser345试剂盒(PE)用于测定HT29结肠癌细胞中内源性Chk1的磷酸化。该实验是根据制造商的实验方案进行的。简单来说,HT29细胞用100ul的5x105细胞/ml的RPMI-1640培养基和10％血清铺在96孔细胞培养板上，并在37℃培养过夜。第二天，细胞中加入新的无血清RPMI-1640培养基并在37℃下培养2h。待测化合物的浓度范围是通过稀释100％DMSO,然后进一步用无血清培养基稀释来创建的。细胞加入稀释的化合物并在37℃培养1h。然后细胞加入终浓度为10μM的4-NQO并在37℃继续培养30min.最后细胞中加入1X裂解缓冲液，并室温在平板振动器(约350rpm)上震动10min.4μl的细胞裂解液被转移到384孔板。加入5μl的Acceptor Mix试剂，用Topseal膜密封,并在室温下孵育2h。最后加入2μl Donor Mix试剂，用膜密封并覆盖箔纸。反应在室温下孵育2h,然后在TECAN M1000 Pro读板仪上使用标准AlphaScreen设置进行测试。测试结果如下：
表4：
Figure PCTCN2019119899-appb-000193
实施例3：细胞增殖试验
本发明中，运用细胞试验法来评价化合物的生物活性。LOVO(南京科佰)，人类结 肠癌细胞系，将细胞种于Dulbecco’s Modified Eagle’s介质96孔板中培养，补给10％胎牛血清和1％的P/S，培养环境为37℃及5％CO 2。化合物浓度范围为4.5nM～30μM。将待测化合物储备液溶入DMSO并加入至指示浓度的介质中，孵化72小时。阴性对照细胞仅用vehicle进行处理。在部分试验中，加入已知的ATR抑制剂作为阳性对照。在产品说明书的指示下运用Cell titer glo试剂盒(CTG，Promega)来评价细胞活性。运用Graphpad软件对数据进行分析，并得到IC50值及化合物拟合曲线。
表5：
化合物编号 IC 50(nM) 化合物编号 IC 50(nM)
1 485.1 27 15.26
2 327.5 28 119.4
3 290.8 32 66.71
4 133.1 34 116.4
6 123.5 35 213.6
7 477.8 37 240.3
8 25.78 41 65.23
9 47.99 45 227.9
11 202.8 46 24.81
14 155.7 49 64.05
18 157.8 62 368.9
19 203.4 67 415.4
20 232.6 70 187.4
22 62.27 72 110.9
23 169.3 74 67.55
26 63.16 76 246.4

Claims (16)

  1. 一种如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐；
    Figure PCTCN2019119899-appb-100001
    其中，X为-CR 8R 9-、-O-、-C(O)-或-NR 10-；
    Y为O或NR 10；
    L为-(CR 8’R 9’) n-；
    R 1任选为H、卤素、C 1-6烷基、C 2-6烯基、C 2-6炔基或卤代C 1-6烷基；
    R 2任选为H、R 11、-OR 11或-NR 11R 11a；
    R 1和R 2为独立取代基，或者R 1和R 2相互连接形成3-8元杂环烷基；所述3-8元杂环烷基为未取代或者选择性被一个或多个选自卤素和C 1-6烷基的取代基取代在任意位置；
    R 3任选为Cy、-O-Cy、-NR 10’-Cy或-NR 10’-CH 2-Cy；
    Cy任选为芳基或杂芳基，所述Cy为未取代或者选择性被一个或多个选自R 12、卤素、羟基、氨基、氰基、羧基、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-N(OR 12)R 12a、-S(O) 0-2R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-C(NH)NR 12R 12a、-NR 12C(O)R 12a、-NR 12C(O)NR 12R 12a、-NR 12S(O) 2R 12a和-OC(O)R 12a的取代基取代在任意位置；
    R 4和R 5分别独立地任选为H、卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基或卤代C 1-6烷氧基；
    R 6为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基为未取代或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨基的取代基取代在任意位置；
    R 7为H、卤素或C 1-6烷基；
    R 6和R 7分别为独立取代基，或者R 6和R 7与它们共同连接的C原子一起形成羰基；
    R 1和R 6分别为独立取代基，或者R 1和R 6通过-L’-相互连接形成桥环基；
    L’为-(CR 8”R 9”) m-、-(CR 8”R 9”) mO-或-(CR 8”R 9”) mNR 10’-；
    R 8、R 8’和R 8”分别独立地为H、卤素、氰基、羟基、C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基；所述C 1-6烷基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基或3-8元杂环烷基为未取代或者选择性被一个或多个选自卤素、C 1-6烷基、卤代C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、羟基、氰基和氨基的取代基取代在任意位置；
    R 9、R 9’和R 9”分别独立地为H、卤素或C 1-6烷基；
    R 10和R 10’分别独立地为H或C 1-6烷基；
    每个R 11和每个R 11a分别独立地为H、C 1-6烷基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；所述R 11或R 11a为未取代，或者选择性被一个或多个选自卤素、羟基、氨基、氰基、C 1-6烷基、C 1-6烷氧基、卤代C 1-6烷基、卤代C 1-6烷氧基和C 1-6烷氨基的取代基取代在任意位置；
    每个R 12和每个R 12a分别独立地为H、C 1-6烷基、C 2-6烯基、C 2-6炔基、C 3-8环烷基、3-8元杂环烷基、苯基、5-6元杂芳基、C 3-8环烷基C 1-6烷基、3-8元杂环烷基C 1-6烷基、苯基C 1-6烷基或5-6元杂芳基C 1-6烷基；所述R 12或R 12a为未取代，或者选择性被一个或多个选自氘、氧代基、卤素、羟基、氨基、氰基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、-NHC(O)-C 2-6烯基、-NHC(O)-C 1-6烷基、-NHC(O)NH-C 1-6烷基、-NHC(O)O-C 1-6烷基和-NHS(O) 2-C 1-6烷基的取代基取代在任意位置；
    m、n和t分别独立地为0、1、2或3。
  2. 如权利要求1所述的如式(I)所示的化合物，其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于，R 4为甲基；
    和/或，R 5为H、F、甲基、甲氧基、乙氧基或三氟甲氧基；
    和/或，R 8、R 8’和R 8”分别独立地为H、F或C 1-4烷基；
    和/或，R 9、R 9’和R 9”分别独立地为H、F或C 1-4烷基；
    和/或，L’为-CH 2-、-CH 2CH 2-、-CH 2O-或-O-；
    和/或，L为-CH 2-或-CH 2CH 2-。
  3. 如权利要求1所述的如式(I)所示的化合物，其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于，X为-O-或-NR 10-；R 10为H、甲基、乙基、丙基、异丙基或环丙基；
    和/或，Y为O或NH；
    和/或，R 3为Cy；
    和/或，Cy为取代或未取代的6-10元芳基或取代或未取代的5-10元杂芳环；
    和/或，R 1为C 1-6烷基；
    和/或，R 2为R 11；
    和/或，R 11为C 1-6烷基、苯基、5-6元杂芳基、3-6元杂化烷基、或C 3-6环烷基；所述R 11为未取代，或者选择性被1～3个、1～2个或1个选自氟、氯、羟基、氨基、氰基、甲氧基、乙氧基、三氟甲氧基、二氟甲氧基、二甲氨基和甲氨基的取代基取代在任意位置；
    和/或，R 12为H、C 1-6烷基、C 2-6烯基、C 3-8环烷基、3-8元杂环烷基、苯基或5-6元杂芳基，所述R 12为未取代，或者选择性被1～5个选自氘、氧代基、卤素、羟基、氨基、氰基、卤代C 1-6烷基、卤代C 1-6烷氧基、C 1-6烷氧基、C 1-6烷氨基、C 3-8环烷基、3-8元杂环烷基、-NHC(O)-C 2-6烯基、-NHC(O)-C 1-6烷基、-NHC(O)NH-C 1-6烷基、-NHC(O)O-C 1-6烷基和-NHS(O) 2-C 1-6烷基的取代基取代在任意位置；
    和/或，R 12a为H、C 2-6烯基、C 3-6环烷基、3-6元杂环烷基或C 1-4烷基。
  4. 如权利要求1～3任一项所述的如式(I)所示的化合物，其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于，Cy为取代或未取代的以下任一基团：苯基、萘基、吲哚啉基、2-氧代-2,3-二氢-1H-苯并[d]咪唑基、吡啶基、嘧啶基、吡嗪基、咪唑基、吡唑基、1H-1,2,3-三氮唑基、1H-1,2,4-三氮唑基、4H-1,2,4-三氮唑基、喹啉基、异喹啉基、喹唑啉基、1H-吲唑基、1H-吲哚基、1H-吡咯并[2,3-b]吡啶基、1H-吡咯并[2,3-c]吡啶基、1H-吡咯并[3,2-c]吡啶基、1H-吡咯并[3,2-b]吡啶基、7H-吡咯并[2,3-c]哒嗪基、1H-吡咯并[2,3-d]哒嗪基、1H-苯并咪唑基、1H-苯并[d][1,2,3]三氮唑基、3H-噻吩并[2,3-d]咪唑基、1H-噻吩并[2,3-d]咪唑基、1H-噻吩并[3,4-d]咪唑基、1H-吡唑并[3,4-b]吡啶基、1H-吡唑并[3,4-c]吡啶基、1H-吡唑并[4,3-c]吡啶基、1H-吡唑并[4,3-b]吡啶基、4H-咪唑并[4,5-d]异噻唑基、6H-咪唑并[4,5-d]异噻唑基、1H-咪唑并[4,5-b]吡啶基、3H-咪唑并[4,5-b]吡啶基、3H-咪唑并[4,5-c]吡啶基、1H-咪唑并[4,5-c]吡啶基、1H-咪唑并[4,5-b]吡啶基、7H-吡咯并[2,3-d]嘧啶基或7-氧代-6,7-二氢-1H-吡咯并[2,3-c]吡啶基；所述Cy为未取代，或者选择性被1～3个、1～2个、或1个选自R 12、卤素、羟基、氨基、氰基、羧基、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-N(OH)R 12a、-S(O) 0-2R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)R 12a、-NHC(O)NR 12R 12a和-OC(O)R 12a的取代基取代在任意位置。
  5. 如权利要求4所述的如式(I)所示的化合物，其异构体、前药、稳定的同位素 衍生物或药学上可接受的盐，其特征在于，Cy为
    Figure PCTCN2019119899-appb-100002
    Figure PCTCN2019119899-appb-100003
    R’为H、F、Cl、-CH 3、-CF 3或-OCH 3；R为H、F、Cl、Br、-OH、-NH 2、-CN、-COOH、R 12、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)NR 12R 12a或-NHC(O)R 12a。
  6. 如权利要求5所述的如式(I)所示的化合物，其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于，R 12为H、C 1-4烷基、C 2-6烯基、C 3-6环烷基、5-6元杂芳基或3-6元杂环烷基；所述R 12为未取代或者选择性被1～3个选自D、F、Cl、-OH、-NH 2、-NHC(O)CH＝CH 2、-NHC(O)CH 3、C 1-4烷基、C 1-4烷氧基和C 1-4烷氨基的取代基取代在任意位置；
    和/或，R 12a为H或C 1-4烷基。
  7. 如权利要求1所述的如式(I)所示的化合物，其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于，所述R 3中，所述Cy被取代时，选择性被1～3个选自F、Cl、Br、-OH、-NH 2、-NH(CH 3)、-N(CH 3) 2、-NH(CH 2CH 3)、-NH(CN)、-NH(OH)、-NHC(O)H、-NH-正丙基、-NH-异丙基、-NH-环丙基、-NHC(O)CH 3、-NHC(O)NH 2、-CN、-COOH、-CH 3、-CF 3、-CHF 2、-CH 2CHF 2、-CH 2OH、-CH 2NH 2、-CH 2NH(CH 3)、-OCH 3、-OCF 3、-OCH 2CF 3、-OCH 2CHF 2、-O-环丙基、-CH 2F、甲基、乙基、正丙基、异丙基、叔丁基、环丙基、环丁基、-C(NH)NH 2、-NH(CD 3)、-NHCH 2CF 3、-NHCF 3、-NHCH 2F、-NHCH 2CH 2F、-NHCH 2CHF 2、
    Figure PCTCN2019119899-appb-100004
    Figure PCTCN2019119899-appb-100005
    的取代基取代在任意位置。
  8. 如权利要求1～7任一项所述的如式(I)所示的化合物，其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于，所述如式(I)所示的化合物为式(II)所示的化合物，其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，
    Figure PCTCN2019119899-appb-100006
    其中，R 2、R 3、R 7、L、L’、X和Y的定义如权利要求1所述。
  9. 如权利要求8所述的如式(I)所示的化合物，其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，其特征在于，X为O；
    和/或，L为-CH 2-；
    和/或，L’为-CH 2-；
    和/或，R 2为-CH 3、-CH 2CH 3、-CH(CH 3) 2或环丙基；
    和/或，R 3为Cy；
    和/或，Cy为
    Figure PCTCN2019119899-appb-100007
    R’为H、F、Cl、-CH 3、-CF 3或-OCH 3；R为H、F、Cl、Br、-OH、-NH 2、-CN、-COOH、R 12、-OR 12a、-NR 12R 12a、-N(CN)R 12a、-C(O)R 12a、-C(O)OR 12a、-C(O)NR 12R 12a、-NHC(O)NR 12R 12a或-NHC(O)R 12a。
  10. 如权利要求1所述的如式(I)所示的化合物，其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，为以下化合物：
    Figure PCTCN2019119899-appb-100008
    Figure PCTCN2019119899-appb-100009
    Figure PCTCN2019119899-appb-100010
    Figure PCTCN2019119899-appb-100011
    Figure PCTCN2019119899-appb-100012
    Figure PCTCN2019119899-appb-100013
  11. 一种药物组合物，其包括治疗有效量的活性组分以及药学上可接受的辅料；所 述活性组分包括如权利要求1～10任一项所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐。
  12. 如权利要求11所述的药物组合物，其特征在于，所述的药物组合物进一步含有其它种类的用于治疗由ATR水平失常引起的相关疾病的治疗剂；所述的药学上可接受的辅料为药学上可接受的载体、稀释剂和/或赋形剂。
  13. 如权利要求12所述的药物组合物，其特征在于，所述的用于治疗由ATR水平失常引起的相关疾病的治疗剂为癌症治疗剂。
  14. 如权利要求1～10任一项所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或如权利要求11或12所述药物组合物在制备ATR抑制剂药物中的应用。
  15. 如权利要求1～10任一项所述的如式(I)所示化合物、其异构体、前药、稳定的同位素衍生物或药学上可接受的盐，或如权利要求11或12所述药物组合物在制备治疗和/或缓解由ATR水平失常引起的相关疾病的药物中的应用。
  16. 如权利要求15所述的应用，其特征在于，所述的由ATR水平失常引起的相关疾病为癌症。
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