WO2019120276A1 - Pyrimidone compound and application thereof - Google Patents

Pyrimidone compound and application thereof Download PDF

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Publication number
WO2019120276A1
WO2019120276A1 PCT/CN2018/122557 CN2018122557W WO2019120276A1 WO 2019120276 A1 WO2019120276 A1 WO 2019120276A1 CN 2018122557 W CN2018122557 W CN 2018122557W WO 2019120276 A1 WO2019120276 A1 WO 2019120276A1
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group
substituted
compound
unsubstituted
alkyl
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PCT/CN2018/122557
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French (fr)
Chinese (zh)
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邹斌
马世超
付贤磊
董宏平
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上海青煜医药科技有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
    • 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
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    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the hetero ring
    • C07D307/83—Oxygen atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
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    • C07D313/02—Seven-membered rings
    • C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
    • C07D313/08—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with one six-membered ring
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/44—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D317/46—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 ortho- or peri-condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
    • C07D317/62—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to atoms of the carbocyclic ring
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    • C07D319/04—1,3-Dioxanes; Hydrogenated 1,3-dioxanes
    • C07D319/08—1,3-Dioxanes; Hydrogenated 1,3-dioxanes condensed with carbocyclic rings or ring systems
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    • C07D319/00—Heterocyclic compounds containing six-membered rings having two oxygen atoms as the only ring hetero atoms
    • C07D319/10—1,4-Dioxanes; Hydrogenated 1,4-dioxanes
    • C07D319/14—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems
    • C07D319/16—1,4-Dioxanes; Hydrogenated 1,4-dioxanes condensed with carbocyclic rings or ring systems condensed with one six-membered ring
    • C07D319/18—Ethylenedioxybenzenes, not substituted on the hetero ring
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D417/14—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 containing three or more hetero rings
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    • 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
    • C07D491/048—Ortho-condensed systems with only one oxygen atom as ring hetero atom in the oxygen-containing ring the oxygen-containing ring being five-membered
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a pyrimidinone compound, a pharmaceutically acceptable salt thereof, and a solvate thereof.
  • the invention also relates to a process for the preparation of such compounds, compositions containing such compounds, and pharmaceutical use as a medicament for treating a mechanism of action with EED proteins and/or PRC2 protein complexes.
  • the PcG (Polycomb Group) protein is an important class of chromatin-modifying enzymes. It regulates the transcription of genes by modifying the chromatin, which plays an important role in stem cell growth, differentiation and long-term cellular memory.
  • PcG proteins are mainly divided into two types of transcriptional repression complexes, namely, PRC1 (Polycomb Repressive Complex 1) and PRC2 (Polycomb Repressive Complex 2).
  • PRC2 inhibits the expression of related genes by methylation modification of the 27th lysine (H3K27) of histone 3 in chromatin.
  • the PRC2 protein complex consists mainly of core proteins such as EZH2 (Enhancer of Zeste Homolog 2) (or its very similar homologous protein EZH1), EED (Embryonic ectoderm Development), and SUZ12 (Suppressor of Zeste 12).
  • EZH2 has enzymatic activity, and the methyl group of the substrate SAM (S-adenosyl-L-methionine) can be transferred to H3K27 through the SET (Su(var), E(Z), and Trithorax) protein domain. A one to three methylation modification of H3K27 is achieved.
  • the enzymatic activity of EZH2 is also dependent on other components of PRC2, such as the EED protein belonging to the WD40 repeat structural protein family.
  • PRC2 such as the EED protein belonging to the WD40 repeat structural protein family.
  • the binding of EED to trimethylated H3K27Me3 exerts a great allosteric effect on the enzymatic function of EZH2 on the one hand, and the PCR2 complex on the chromatin to be modified on the other hand.
  • Abnormal function of PRC2, such as EZH2 overexpression or functional acquisition mutation is associated with many clinical oncological diseases, including lung cancer, breast cancer, rectal cancer, prostate cancer, bladder cancer, pancreatic cancer, sarcoma and lymphoma.
  • PRC2 is also associated with a variety of cellular immune functions, such as EZH2 involved in the regulation of lymphocyte activation, and together with glycolysis to promote T cell response to tumor cells. Therefore, the development of PRC2 small molecule inhibitors has important and broad drug development value.
  • EZH2 inhibitors currently in clinical practice include EPZ-6438 (Epizyme, clinical phase II), GSK2816126 (GSK, clinical phase I), and CPI-1205 (Constellation, clinical phase I) and the like.
  • EPZ-6438 Epizyme, clinical phase II
  • GSK2816126 GSK2816126
  • CPI-1205 Constellation, clinical phase I
  • EED inhibitors have an allosteric inhibition of EZH2 enzyme function and can achieve the same or similar biological functions as EZH2.
  • EED inhibitors have well overcome the problem of drug resistance of EZH2.
  • EED inhibitors can be combined with EZH2 inhibitors to achieve better synergistic effects.
  • Novartis see Nature Chemical Biology 2017, 13, 381-388
  • Abbott see Nature Chemical Biology 2017, 13, 389-395 have reported two classes of EED inhibitors with better biological activity.
  • the present invention provides a pyrimidinone compound, a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, which is a novel class of EED inhibitors which exhibits excellent inhibitory activity against tumor cells, and has Broad prospects for drug development.
  • the present invention provides a pyrimidinone compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt;
  • n is independently 0 or 1;
  • n is independently 0 or 1;
  • o is independently 0 or 1;
  • p is independently 0 or 1;
  • X is independently C, O or CH 2 O (C and O in CH 2 O are both atoms on the ring);
  • Y is independently C or O
  • Z is independently C or N
  • R 0 is independently hydrogen, hydroxy, halogen (such as fluorine), substituted or unsubstituted alkoxy or carbonyl;
  • R 1 is independently hydrogen, halogen (such as fluorine) or C 1-4 alkyl (such as methyl);
  • R 2 and R 3 are each independently hydrogen, halogen (such as fluorine) or C 1-4 alkyl (such as methyl);
  • R 4 is independently hydrogen, R 4a substituted or unsubstituted C 1-4 alkyl (the C 1-4 alkyl group such as methyl, ethyl, n-propyl or isopropyl), R 4a substituted or not Substituted C 1-4 haloalkyl (the C 1-4 haloalkyl group such as C 1-4 fluoroalkyl, as for 2,2-difluoroethyl), C 3-8 cycloalkyl or C 2 - 6 alkenyl (such as allyl);
  • Each R 4a is independently hydrazine, halogen (such as fluorine) or C 1-4 alkyl;
  • R 5 is independently hydrogen, C 1-4 alkyl (such as methyl) or amino;
  • R 6 is independently hydrogen, halogen (such as fluorine, bromine or iodine), cyano, R 6a substituted or unsubstituted C 1-8 alkyl (the C 1-8 alkyl group such as C 1-4 alkyl, Another example is methyl, ethyl, n-propyl or isopropyl), C 1-8 alkoxy (such as C 1-4 alkoxy, or methoxy, ethoxy, n-propoxy or iso) a propoxy group), a C 1-8 haloalkyl group (such as a C 1-4 haloalkyl group), a R 6a substituted or unsubstituted C 3-8 cycloalkyl group (the C 3-8 cycloalkyl group such as a cyclohexyl group), R 6b substituted or unsubstituted C 3-8 cycloalkyl (the C 3-8 cycloalkyl group such as cyclohexyl), R 6b
  • Each R 6c is independently a C 1-4 alkyl or ester group (eg Wherein R 7c is C 1-4 alkyl);
  • Each R 6d is independently C 1-20 alkyl (such as C 1-8 alkyl, as for C 1-6 alkyl), benzyl, R 7d substituted or unsubstituted C 6-10 aryl, R 7d substituted or unsubstituted "heteroaryl having a C 1-20 carbon atom and 1-4 heteroatoms independently selected from N, NR 6e1 , O and S(O) 0-2 " (the "having C” a heteroaryl group of 1 to 20 carbon atoms and 1 to 4 hetero atoms independently selected from N, NR 6e1 , O and S(O) 0-2 may be "having a C 1-10 carbon atom and 1-4 a heteroaryl group independently selected from the heteroatoms of N, NR 6e1 , O and S(O) 0-2 , for example "having a C 1-10 carbon atom and 1-4 independently selected from N, NR 6e1 , O and a 5-12 membered heteroaryl of a hetero
  • R 8d is C 1-4 alkyl
  • Each R 6e1 is independently hydrogen or C 1-4 alkyl; each R 6e2 is independently hydrogen or C 1-4 alkyl; and R 6e3 is C 1-4 alkyl.
  • 2, 3 or 4 of m, n, o and p are 1.
  • Y is O and X is C.
  • m is 0, p is 1, and n is 0 or 1.
  • Y is O
  • X is C
  • o and p are 1
  • m is 0 or 1
  • n is 0 or 1.
  • Y is O and X is O, Is a single bond; m and o are 1; p is 0 and n is 1, or p is 1 and is 0.
  • X is O and Y is C. Is a single bond; m and p are 1; n and o are 0.
  • R 0 is independently hydrogen, halogen, substituted or unsubstituted alkoxy or carbonyl.
  • R 0 when X is O, R 0 is absent.
  • R 1 is H, F or Me.
  • R 1 is absent when Z is N, R 1 is absent.
  • R 2 is H or F.
  • R 3 is H or F.
  • R 4 is hydrogen, methyl, deuterated methyl (eg, -CD 3 ), ethyl, allyl, isopropyl or difluoroethyl (eg, 2,2-difluoroethyl) base).
  • R 5 is hydrogen, methyl or amino.
  • R 6 is hydrogen, halogen, cyano, R 6a substituted or unsubstituted C 1-4 alkyl or any of the following structures:
  • the ring A' is a six-membered heteroaryl group having from 1 to 3 hetero atoms.
  • the ring B' is a five-membered heterocyclic group having from 1 to 4 hetero atoms.
  • R 6 is hydrogen, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyclopropyl, cyano, methoxy,
  • the pyrimidinone compound represented by the formula (I) is selected from any one of the following structures:
  • n R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and The definition is as described above.
  • the invention also provides the following scheme:
  • the present invention also provides a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt:
  • n is independently 0 or 1;
  • n is independently 0 or 1;
  • o is independently 0 or 1;
  • p is independently 0 or 1;
  • X is independently C, O or CH 2 O;
  • Y is independently C or O
  • Z is independently C or N
  • R 0 is independently hydrogen, halogen, substituted or unsubstituted alkoxy or carbonyl
  • R 1 is independently hydrogen, halogen or C 1-4 alkyl
  • R 2 and R 3 are independently hydrogen, halogen or C 1-4 alkyl
  • R 4 is independently hydrogen, R 4a substituted or unsubstituted C 1-4 alkyl, R 4a substituted or unsubstituted C 1-4 haloalkyl, C 3-8 cycloalkyl or C 2-6 alkenyl;
  • R 4a is independently halogen or C 1-4 alkyl
  • R 5 is independently hydrogen, C 1-4 alkyl or amino
  • R 6 is independently hydrogen, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, R 6a substituted or unsubstituted C 3-8 cycloalkyl, R 6b substituted or unsubstituted C 3 -8 heterocyclyl, R 6c substituted or unsubstituted alkenyl group, R 6b a substituted or unsubstituted C 5- 8 cycloalkenyl, R 6b a substituted or unsubstituted C 5-8 heterocycloalkenyl group, R 6d substituted substituted Or unsubstituted amino, R 6d substituted or unsubstituted oxy, R 6d substituted or unsubstituted amide, 0-3 R 6e substituted C 6-10 aryl or 0-3 R 6e substituted C a heteroaryl ring of 1-20 carbon atoms and 1-4 hetero atoms such as N, NR 6e1 , O or S(O) 0-2
  • R 6a and R 6b are independently amino, protecting group protected amino, monofluoro or polyfluoro;
  • R 6c is independently C 1-4 alkyl, ester group
  • R 6d is independently a C 1-20 alkyl group, a benzyl group, a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted C 1- 20 containing 1-4 carbon atoms and N, NR 6e1, O Or a heteroaromatic ring of a hetero atom such as S(O) 0-2 ;
  • R 6e1 is independently hydrogen or C 1-4 alkyl
  • R 6e2 is independently hydrogen or C 1-4 alkyl
  • R 6e3 is C 1-4 alkyl.
  • Y is O and X is C.
  • m is 0, p is 1, and n is 0 or 1.
  • Y is O and X is O, Is a single bond; m, o is 1; p is 0 and n is 1 or p is 1 and is 0.
  • X is O and Y is C. Is a single bond; m, p is 1; n, o is 0.
  • Y is O and X is CH 2 O
  • p is 0, m, o is 1; n is independently 1 or 2.
  • R 0 is independently hydrogen, halogen, substituted or unsubstituted alkoxy or carbonyl.
  • R 0 when X is O, R 0 is absent.
  • R 1 is H, F or Me.
  • R 1 is absent when Z is N, R 1 is absent.
  • R 2 is H or F.
  • R 3 is H or F.
  • R 4 is hydrogen, methyl, deuterated methyl, ethyl, allyl, isopropyl or difluoroethyl.
  • R 5 is hydrogen, methyl or amino.
  • R 6 is hydrogen, halogen, cyano, R 6a substituted or unsubstituted C 1-4 alkyl or has any of the following structures:
  • the ring A is a six-membered heteroaryl group having from 1 to 3 hetero atoms.
  • the ring B is a five-membered heterocyclic group having from 1 to 4 hetero atoms.
  • the compound is selected from any of the following compounds:
  • n R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and The definition is as described above.
  • the pyrimidinone compound represented by the formula (I) is selected from any one of the following compounds:
  • the present invention provides a pyrimidone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt as described above.
  • the atoms which can be labeled with isotopes include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine and the like. They may be replaced by the isotopes 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, respectively.
  • the isotope-labeled compound is preferably a deuterated substance.
  • the present invention provides a process for the preparation of a pyrimidinone compound represented by formula (I) as described above, which comprises the steps of:
  • W is halogen, preferably Br or I; R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
  • the definitions of m, n, o, p, R 0 and R 6 are as described above.
  • the method for producing the pyrimidinone compound represented by the formula (I) may include the step of reacting the compound A and R 6 -W in a solvent to obtain a pyrimidinone compound represented by the formula (I). can.
  • the preparation method of the compound I-A includes the following steps: the compound A and the corresponding boric acid under the conditions of coupling, to obtain the compound I-A;
  • the method for preparing the compound IC comprises the steps of: subjecting the compound A to zinc cyanide under coupling conditions to obtain a cyano compound IB; and subjecting the cyano compound IB to hydrogen peroxide and basic conditions. The reaction is carried out to obtain an amide compound IC;
  • the preparation method of the compound I-D includes the following steps: the compound A is combined with a substituted amine or a thiol to obtain the compound I-D;
  • W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, m, n, o, p, R 0 and R 6d are as defined above, and Q is N or S.
  • the preparation method of the compound I-E comprises the steps of: hydrogenating the double bond of the compound I-A (1) to obtain the corresponding saturated substituted compound I-E;
  • R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, V, j, m, n, o, p, R 0 , R 6b and R 6c are as defined above.
  • the preparation method of the compound I-F includes the following steps: the compound E is substituted with the compound C under basic conditions to obtain the compound I-F;
  • R 1 , R 2 , R 3 , R 4 , X, Y, Z The definitions of m, n, o, p, R 0 and R 6d are as described above.
  • the invention also provides a compound A,
  • the present invention also provides a preparation method of Compound A as described above, which comprises the steps of: Compound B is substituted with Compound C under basic conditions to obtain Compound A;
  • the present invention also provides another preparation method of Compound A, which comprises the steps of: Compound D is substituted with Compound C after activation of active agent (such as BOP-Cl) to obtain Compound A;
  • active agent such as BOP-Cl
  • the invention also provides a compound B,
  • W, R 4 and R 5 are as defined above.
  • the present invention also provides a method for preparing the compound B as described above, which comprises the steps of: converting compound B-a to compound B-b under basic conditions; and compound B-b by nitrogen alkylation to obtain compound B;
  • W, R 4 and R 5 are as defined above.
  • the present invention also provides another preparation method of Compound B, which comprises the steps of: Compound Bc is protected by a suitable protecting group (such as Boc, diphenylmethyl, etc.) to obtain Compound Bd; Compound Bd is alkyl under basic conditions. Compound Be is obtained; then, compound Be is deprotected to obtain compound Bf and then converted into compound B;
  • a suitable protecting group such as Boc, diphenylmethyl, etc.
  • W, R 4 and R 5 are as defined above.
  • the invention also provides a compound D,
  • W, R 4 and R 5 are as defined above.
  • the present invention also provides a process for the preparation of the compound D as described above, which comprises the steps of: preparing a compound D-a by halogenation;
  • W, R 4 and R 5 are as defined above.
  • the invention also provides a compound E,
  • R 4 and R 6d are as defined above.
  • the invention also provides a preparation method of the compound E, which comprises the steps of: compound Ea is added with methanol ammonia to obtain compound Eb, and then condensed with acetal to obtain compound Ec; compound Ec is methylated to obtain compound Ed; Condensation with the compound Ee under basic conditions to obtain the compound Ef; finally, oxidizing the thioether of the compound Ef to obtain the compound E;
  • R 4 and R 6d are as defined above.
  • the invention also provides a compound C1 or C2,
  • R 1 , R 2 and R 3 are as defined above.
  • the present invention also provides a process for the preparation of the compound C1 or C2 as described above, which comprises the steps of: the compound C1-a is substituted with a phenolic hydroxyl group to obtain the compound C1-b and then intramolecularly condensed to obtain a compound C1-c.
  • R 3 is hydrogen
  • the by-product compound C1-d formed by the condensation process can be separated and removed by column chromatography after the next step
  • the compound C1-c is cyanated to obtain the compound C1-e
  • Compound C1-e is obtained by reducing cyano group to obtain compound C2;
  • Compound C2 is hydrogenated and reduced to give compound C1.
  • the compound C1-e can also be obtained by hydrogenating the furan and the cyano group while Boc protecting the resulting amino group to obtain C1-f; finally, the compound C1-f is de Boc-protected to obtain the compound C1;
  • R 1 , R 2 and R 3 are as defined above.
  • the invention also provides a compound C3,
  • R 1 , R 2 and R 3 are as defined above.
  • the invention also provides a preparation method of the compound C3 as described above, which comprises the steps of: substituting a compound C1-a with a substituted phenolic hydroxyl group by a propargyl group to obtain a compound C3-a; the condition of the compound C3-a at a high temperature The rearrangement occurs to obtain the compound C3-b.
  • R 3 is hydrogen
  • the compound C3-c is formed; after the compound C3-b is obtained, the compound C3 can be obtained by a similar method to the synthesis of C1;
  • the invention also provides a compound C4,
  • R 1 , R 2 and R 3 are as defined above.
  • the present invention also provides a process for the preparation of the compound C4 as described above, which comprises the steps of: ally-substituted compound C4-a to obtain compound C4-b; compound C4-b after heat rearrangement to obtain compound C4-c Further allylation gives compound C4-d; compound C4-d is cyclized by RCM to give compound C4-e, then hydrogenation of cyano and double bond and simultaneous Boc protection affords compound C4-f; After the protection, the compound C4 is obtained;
  • the invention also provides a compound C5,
  • R 1 , R 2 and R 3 are as defined above.
  • the invention also provides a preparation method of the compound C5 as described above, which comprises the steps of: the compound C5-a is substituted by a phenolic hydroxyl group to obtain the compound C5-b and then intramolecularly condensed to obtain a compound C5-c; the compound C5-c is cyanide After compounding, the compound C5-d is obtained; the compound C5-d is simultaneously Boc-protected to form the compound C5-e by reducing the furan and the cyano group; the compound C5-e is de Boc-protected to obtain the compound C5;
  • the invention also provides a compound C6,
  • R 1 , R 2 and R 3 are as defined above.
  • the present invention also provides a process for the preparation of the compound C6 as described above, which comprises the steps of: decarboxylating the compound C6-a to obtain the compound C6-b; and ring-alkylating the compound C6-b to obtain the compound C6-c. Substituting aldehyde group to obtain compound C6-d; compound C6-d is condensed with hydroxylamine to obtain compound C6-e; while reducing formaldehyde oxime, Boc protection gives compound C6-f; finally, deprotection to obtain compound C6;
  • the invention also provides a compound C7,
  • R 1 , R 2 and R 3 are as defined above.
  • the present invention also provides a process for the preparation of the compound C7 as described above, which comprises the steps of: the compound C7-a is introduced into the aldehyde group by the action of LDA/DMF to obtain the compound C7-b; the methoxy substituted compound C7-b After the fluorine, the compound C7-c is obtained; the compound C7-c is removed by a Lewis acid to obtain the compound C7-d; and the compound C7-d is condensed with trimethylsulfoxonium under basic conditions. Obtaining the compound C7-e; the compound C7-e is cyanated to obtain the compound C7-f, and then the cyano group is reduced to obtain the compound C7;
  • the invention also provides a compound C8,
  • R 1 , R 2 and R 3 are as defined above.
  • the present invention also provides a process for the preparation of the compound C8 as described above, which comprises the steps of: reducing the compound C7-d aldehyde group to obtain the compound C8-a, and then cyclizing the dihydroxy group to obtain the compound C8-b; the compound C8-b After cyanation, the compound C8-c is obtained and the cyano group is reduced to obtain the compound C8;
  • the invention also provides a compound C9,
  • R 2 and R 3 are as defined above.
  • the present invention also provides a preparation method of the compound C9 as described above, which comprises the steps of: c9-b after compounding C9-a to give a compound C9-b, and then reducing the cyano group and the furan ring by hydrogenation to obtain Boc protection Compound C9-c; finally deprotected to give compound C9;
  • the preparation method of the compound I-A includes the following steps: the compound A and the corresponding boric acid are coupled to form the compound I-A;
  • the inert solvent to which the present invention relates is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP, THF or a combination thereof.
  • the base to which the present invention relates includes an organic base and/or an inorganic base.
  • the organic base to which the present invention relates is selected from the group consisting of TEA, DIPEA, or a combination thereof.
  • the inorganic base to which the present invention relates is selected from the group consisting of sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium t-butoxide, sodium t-butoxide, LiHMDS, LDA, butyl lithium or a combination thereof.
  • the isotopically labeled compound of the compound of the formula (I) according to the present invention can be prepared by a synthetic method similar to the unlabeled compound, except that the unlabeled starting material and/or reagent is replaced with an isotope-labeled Starting materials and/or reagents.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt as described above , or an isotopically labeled compound as described above, and a pharmaceutically acceptable excipient.
  • the pharmaceutically acceptable excipient may be one or more of a diluent, an absorbent, a wetting agent, a binder, a disintegrant, and a lubricant.
  • the present invention provides the pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate thereof, as described above, or as described above Use of the isotopically labeled compound, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a cancer associated with the mechanism of action of an EED protein and/or PRC2 protein complex.
  • the cancer includes, but is not limited to, lymphoma including diffuse large B cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer , breast cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nose Throat cancer, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma, and the like.
  • lymphoma including diffuse large B cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate
  • the present invention also provides a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, or an isotopically-labeled compound as described above, as described above Or the use of a pharmaceutical composition as described above for the preparation of a medicament for treating cancer.
  • the cancer includes, but is not limited to, lymphoma including diffuse large B-cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer , breast cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nose Throat cancer, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma, and the like.
  • lymphoma including diffuse large B-cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer
  • the present invention provides a pharmaceutical preparation comprising a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, as described above, Or an isotopically-labeled compound as described above, or a pharmaceutical composition as described above, may be administered in a suitable manner, such as as a tablet, a capsule (such as a sustained release or timed release capsule), a pill, a powder, a granule (such as a small granule). In the form of suspensions, syrups, emulsions, solutions, etc.
  • a suitable manner such as as a tablet, a capsule (such as a sustained release or timed release capsule), a pill, a powder, a granule (such as a small granule).
  • elixirs in the form of elixirs, elixirs, elixirs, suspensions (such as nanosuspensions, microsuspensions), spray-dried dispersions, etc., for oral, sublingual, including Injections in the form of subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, injections, nasal administration (such as nasal inhalation), topical surfaces (such as creams and ointments), rectal administration (such as suppositories), and the like.
  • the compounds disclosed herein may be administered alone or together with a suitable pharmaceutical carrier.
  • the present invention provides the pharmaceutical preparation of the sixth aspect which can be formulated into an appropriate pharmaceutical dosage to facilitate and control the dosage of the medicament.
  • the dosage regimen of the compounds disclosed herein varies according to specific factors, such as pharmacodynamics and manner of administration, subject, sex, age, health status, weight of the subject, condition, other concurrent medication, medication Frequency, liver and kidney function, and the effect you want to achieve.
  • the compounds disclosed herein may be administered in a single dose per day or in multiple doses (e.g., two to four times per day).
  • the present invention provides a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, or an isotopic label as described above, as described above a compound, or a pharmaceutical composition as described above, for use in combination with other drugs selected from the group consisting of: anticancer drugs, tumor immunopharmaceuticals, antiallergic agents, antiemetics, analgesics, cytoprotective drugs, etc., together The combination has a better effect.
  • the present invention provides a method of treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a pyrimidinone compound as shown in formula (I) as described above, which is pharmaceutically acceptable a salt or a solvate thereof, or a solvate of the salt, or an isotopically-labeled compound as described above, or a pharmaceutical composition as described above.
  • the cancer includes, but is not limited to, lymphoma including diffuse large B cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast.
  • brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma , ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma.
  • the term “about” means that the value can vary by no more than 1% from the recited value.
  • the expression “about 100” includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
  • the terms "containing” or “including” may be open, semi-closed, and closed. In other words, the terms also include “consisting essentially of,” or “consisting of.”
  • reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention.
  • the above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification.
  • group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
  • substituent When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left.
  • substituent -CH 2 O- is equivalent to -OCH 2 -.
  • C1-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6) carbon atoms.
  • the total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
  • halogen means fluoro, chloro, bromo or iodo.
  • Haldroxy means an -OH group.
  • Hydroalkyl means an alkyl group as defined below which is substituted by a hydroxy group (-OH).
  • Amino means -NH 2 .
  • Ester group means R may be an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a cycloalkenyl group, an arylalkyl group or a heteroarylalkyl group.
  • Amide means Each R may independently be hydrogen, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl or heteroarylalkyl, and the like.
  • Substituted amino means an amino group substituted with one or two independent alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino , alkyl amido, aralkylamino, heteroarylalkylamino.
  • Carboxyl means -COOH.
  • alkyl means a fully saturated straight or branched hydrocarbon chain group, It consists only of carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4) carbon atoms, and passes through a single bond with the rest of the molecule Partial linkages, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.
  • haloalkyl as a group or part of another group means that one or more hydrogen atoms in the alkyl group (as defined in the present invention) are halogen (as defined in the present invention)
  • the number of halogens may be one or more; when the number of halogens is plural, the halogens are the same or different.
  • fluoroalkyl means that the alkyl group is substituted by one or more fluorines.
  • haloalkyl groups include, but are not limited to, trifluoromethyl and difluoromethyl.
  • alkenyl as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) More preferably, from 2 to 6, more preferably from 2 to 4, carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propylene Alkyl group, allyl group, but-1-enyl group, but-2-enyl group, penten-1-alkenyl group, pentane-1,4-dienyl group and the like.
  • cycloalkyl as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include a fused ring. a system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be via any suitable
  • the carbon atom is attached to the rest of the molecule by a single bond. Unless otherwise specifically indicated in the specification, a carbon atom in a cyclic hydrocarbon group may be optionally oxidized.
  • cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indole Base, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzo Cycloheptene-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Indenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bi
  • cycloalkyl as a group or part of another group means a saturated cyclic hydrocarbon group.
  • cycloalkenyl as a group or part of another group means a cyclic hydrocarbon group having at least one double bond (such as a carbon-carbon double bond).
  • the cycloalkenyl group may be attached to the remainder of the molecule through the atoms of the double bond therein.
  • heterocyclyl as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur.
  • a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system;
  • the nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated.
  • the heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond.
  • one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom.
  • the heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur.
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene.
  • Alkan-7-yl 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.
  • heterocyclenyl as a group or part of another group means a heterocyclic group having at least one double bond (such as a carbon-carbon double bond).
  • the heterocyclenyl group may be attached to the remainder of the molecule through the atoms of the double bond therein.
  • aryl as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms.
  • an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond.
  • aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
  • arylalkyl refers to an alkyl group as defined above substituted with an aryl group as defined above.
  • heteroaryl as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring.
  • the nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized.
  • the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected
  • heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, diaza naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl
  • heteroarylalkyl refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
  • “optionally” or “optionally” means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition.
  • “optionally substituted aryl” means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group.
  • substituents described in the claims and the specification of the present invention are selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro
  • substituted or “substituent” means that one or more hydrogen atoms are replaced by a designated group.
  • the substituent may be one or more; when no substitution position is indicated, the substitution may be at any position, but only a stable or chemically feasible chemical is formed. Allowed.
  • any variable eg, R
  • its definition in each case is independent.
  • the group may optionally be substituted with at most two R, and each case has an independent option.
  • n 2 R
  • each R has an independent option, that is, 2 Rs may be the same or different.
  • substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
  • a chemical moiety refers to a particular fragment or functional group in a molecule.
  • a chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
  • the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.
  • Tautomer refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
  • the compounds of the invention may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms.
  • Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry.
  • the invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof.
  • the preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates.
  • Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
  • pharmaceutically acceptable salt includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
  • “Pharmaceutically acceptable acid addition salt” means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects.
  • Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, me
  • “Pharmaceutically acceptable base addition salt” refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects.
  • Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like.
  • Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts.
  • Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins.
  • ammonia isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like.
  • Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine.
  • pharmaceutical composition refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human.
  • the medium includes a pharmaceutically acceptable carrier.
  • the purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
  • pharmaceutically acceptable refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
  • pharmaceutically acceptable excipients include, but are not limited to, any adjuvants, carriers, excipients, glidants, supplements approved by the relevant government authorities for acceptable use by humans or domestic animals.
  • the "tumor” of the present invention includes, but is not limited to, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, sarcoma, melanoma, articular chondrocarcinoma, cholangiocarcinoma, leukemia, gastrointestinal Lymphoma, disseminated large B-cell lymphoma, follicular lymphoma and other lymphoma, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate Cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, colon cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, multiple myeloma, mesothelioma ,
  • preventing include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
  • treatment and other similar synonyms as used herein includes the following meanings:
  • an "effective amount,” “therapeutically effective amount,” or “pharmaceutically effective amount,” as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system.
  • an "effective amount” for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic.
  • An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
  • administering refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration.
  • parenteral injections including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion
  • topical administration and rectal administration.
  • the techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa.
  • the compounds and compositions discussed herein are administered orally.
  • pharmaceutical combination means a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients.
  • fixed combination refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form.
  • unfixed combination refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
  • the intermediate compound functional groups may need to be protected by a suitable protecting group.
  • suitable protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like.
  • Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like.
  • Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like.
  • Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
  • Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley.
  • the protecting group can also be a polymeric resin.
  • the starting materials used in the following examples can be purchased from chemical distributors such as Aldrich, TCI, Alfa Aesar, Bied, Angie, etc., or can be synthesized by known methods.
  • the ice bath means -5 degrees Celsius to 0 degrees Celsius
  • the room temperature means 10 degrees Celsius to 30 degrees Celsius.
  • the reflux temperature generally means the solvent reflux temperature under normal pressure of the solvent.
  • the reaction overnight means that the time is 8-15 hours.
  • the specific operating temperatures were not limited and were carried out at room temperature.
  • the separation and purification of the intermediate and final product is carried out by normal phase or reverse phase chromatography column or other suitable method.
  • the normal phase flash column uses ethyl acetate and n-hexane or methanol and dichloromethane as the mobile phase.
  • Reversed phase preparative high pressure liquid chromatography (HPLC) was performed on a C18 column with UV 214 nm and 254 nm.
  • the mobile phase was A (water and 0.1% formic acid), B (acetonitrile) or mobile phase A (water and 0.1% carbonic acid). Ammonium hydroxide), B (acetonitrile).
  • the intermediates B1-b were respectively reacted with ethyl iodide, allyl bromide and deuterated methyl iodide to obtain B2, B3 and B5, respectively; using 5-bromo-2,4-dichloro- Intermediate B4 can be obtained by using 6-methylpyrimidine as a starting material; intermediate B6 can be obtained by using 5-iodo-2,4-dichloropyrimidine and 5-fluoro-2,4-dichloropyrimidine as starting materials. And B7.
  • Step 4 Intermediate ((6-fluorochroman-5-yl)methyl)carbamic acid tert-butyl ester (C3-1f)
  • Step 5 ((7-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxa-6-yl)methyl)carbamic acid tert-butyl ester (C4-1f)
  • Step 6 (7-Fluoro-2,3,4,5-tetrahydro-benzo[b]oxa-6-yl)methylamine (C4-1)
  • Step 5 Intermediate ((5-fluorobenzo[d][1,3]dioxol-4-yl)methyl)carbamic acid tert-butyl ester (C6-1f)
  • Trimethyl iodide (9.73 g, 44.2 mmol) and DMSO (50 ml) were added to a dry three-neck flask.
  • Sodium tert-butoxide (4.25 g, 44.2 mmol) was added under ice water bath.
  • the reaction solution was stirred at room temperature for 2 hr, and then 2-bromo-3-fluoro-6-hydroxybenzaldehyde (C7-1d) (8.8 g, 40.2 mmol).
  • ethyl acetate 250 ml
  • water 250 ml
  • the organic phase was washed once with water and brine, dried over anhydrous sodium sulfate.
  • the residue was purified on silica gel (EtOAc:EtOAc:EtOAc:EtOAc: 66.2% yield) as a white solid.
  • Step 2 ((2,3-Dihydrofuro[3,2-c]pyridin-4-yl)methyl)carbamic acid tert-butyl ester (C9-1c)
  • Furano[3,2-c]pyridine-4-carbonitrile C9-1b (150 mg, 1.04 mmol), BOC anhydride (227 mg, 1.04 mmol), methanol (20 mL) and 10% palladium carbon were sequentially added to a 100 mL vial. (15 mg, containing 50% water).
  • the reaction mixture was purged with hydrogen for 5 minutes, ventilated three times with a hydrogen balloon, and stirred at 60 ° C for 18 hours under a hydrogen balloon.
  • the mixture was filtered over EtOAc (EtOAc)EtOAc.
  • the concentrate was purified by silica gel column chromatography eluting with EtOAc EtOAc (EtOAc:EtOAc 4-yl)methyl)amino)-3-methylpyrimidin-4(3H)-one A-1 (80 mg, yield 52.9%), pale yellow solid.
  • Example 12 Compound 2-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-(methylsulfonyl)phenyl)pyrimidine- 4(3H)-ketone
  • Example 28 2 - ((2,3-dihydrofuro[3,2-c]pyridin-4-yl)methyl)amino)-3-methyl-5-(4-(trifluoromethyl) Phenyl)pyrimidine-4(3H)-one
  • Example 54 4-(2-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl-1,6-di Hydropyrimidin-5-yl)benzamide
  • Example 72 tert-Butyl 4-(2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl-1 ,6-dihydropyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate
  • Example 77 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(6-(4-methylpiperazine) -1-yl)pyridin-3-yl)pyrimidine-4(3H)-one
  • Example 80 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-methylpyridin-3-yl) Pyrimidine-4(3H)-one
  • Example 100 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-ethyl-2-(((5-fluoro-2,3-dihydrobenzofuran-4) -yl)methyl)amino)pyrimidine-4(3H)-one
  • Example 104 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(6-morpholinopyridine-3- Pyrimidine-4(3H)-one
  • Example 109 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(6-(4-methylpiperazine) -1-yl)pyridin-3-yl)pyrimidine-4(3H)-one
  • Example 110 3-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(5-methylpyridin-3-yl) Pyrimidine-4(3H)-one
  • Example 120 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(4-methylpyridin-3-yl)pyrimidine-4(3H)- ketone
  • Example 127 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(6-(4-methylpiperazin-1-yl)pyridine-3 -yl)pyrimidine-4(3H)-one
  • Example 130 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(6-(4-methylpiperazin-1-yl)pyridine-3 -yl)pyrimidine-4(3H)-one
  • Example 135 4-(1-Ethyl-2-((6-fluorochroman-5-yl)methyl)amino)-6-carbonyl-1,6-dihydropyrimidin-5-yl)benzene Amide
  • Example 138 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(2-methylpyridin-3-yl)pyrimidine-4(3H)- ketone
  • Example 142 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(1,2,3,6-tetra Hydropyridin-4-yl)pyrimidine-4(3H)-one
  • reaction liquid was distilled under reduced pressure, and the obtained crude product was purified by reverse-phase high-purity liquid chromatography to give the product 2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3- Methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4(3H)-one (5 mg, 32.7% yield)
  • Example 150 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyrimidine- 5-carbonitrile
  • Methyl isothiocyanate E1-a (6 g, 82.1 mmol) was added to a solution of ammonia in methanol (7M, 58 mL). The reaction solution was stirred at 50 ° C for 6 hours. The reaction mixture was cooled to room temperature and then filtered to give a crystallite crystallite.
  • N-methylthiourea E1-b (6.5 g, 72.1 mmol) was dissolved in 50 mL of dichloromethane, and N,N-dimethylformamide dimethyl acetal (10.31 g, 86.5 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into 100 mL of water and extracted with dichloromethane (100 mL X 2).
  • Step 3 Intermediate iodide (Z,E)-1-((dimethylamino)methylene)-2,3-dimethylisothiosaccharide cation (E1-d)
  • Step 5 Synthesis of intermediate 5-methoxy-3-methyl-2-(methylsulfinyl ⁇ sulfinyl)pyrimidine-4(3H)-one (E1)
  • E1-f 500 mg, 2.68 mmol was dissolved in 15 mL dichloromethane and 3-chloroperoxybenzoic acid (463.31 mg, 2.68 mmol). The reaction solution was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic phases were washed with EtOAc EtOAc EtOAc EtOAc. Synthesis of methyl-2-(methylsulfinyl ⁇ sulfinyl)pyrimidine-4(3H)-one (E1) (300 mg, 55% yield) as white solid.
  • Step 6 Compound 2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-methoxy-3-methylpyrimidine-4(3H)- ketone
  • Example 154 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(pyridin-3-ylamino)pyrimidine- 4(3H)-ketone
  • Example 156 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-((2-(trifluoromethyl)) Pyridin-3-yl)thio)pyrimidine-4(3H)-one

Abstract

Disclosed in the present invention are a pyrimidone compound represented by formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof. Also provided in the present invention are a preparation method for the pyrimidone compound, a composition comprising the pyrimidone compound, and a use of the pyrimidone compound in the preparation of a drug for treating diseases or disorders associated with the mechanism of action of an EED protein and/or a PRC2 protein complex.

Description

嘧啶酮化合物及其应用Pyrimidinone compounds and their applications
本申请要求申请日为2017年12月21日的中国专利申请CN201711392421.3的优先权。本申请引用上述中国专利申请的全文。The present application claims priority from Chinese Patent Application No. CN201711392421.3, filed on Dec. 21, 2017. This application cites the entire text of the above-mentioned Chinese patent application.
技术领域Technical field
本发明涉及一种嘧啶酮化合物、其药学上可接受的盐及其溶剂化物。本发明也涉及该类化合物的制备方法、含有该类化合物的组合物和作为治疗与EED蛋白和/或PRC2蛋白复合物作用机理相关疾病的药物用途。The present invention relates to a pyrimidinone compound, a pharmaceutically acceptable salt thereof, and a solvate thereof. The invention also relates to a process for the preparation of such compounds, compositions containing such compounds, and pharmaceutical use as a medicament for treating a mechanism of action with EED proteins and/or PRC2 protein complexes.
背景技术Background technique
PcG(Polycomb Group)蛋白是一类重要的染色质修饰酶。它通过对染色质的修饰调控基因的转录，从而对干细胞的生长、分化及长期的细胞记忆有重要作用。在哺乳动物细胞中，PcG蛋白主要分为两类转录抑制复合物，分别是PRC1(Polycomb Repressive Complex 1)和PRC2(Polycomb Repressive Complex 2)。其中，PRC2通过对染色质中组蛋白3的27位赖氨酸(H3K27)的甲基化修饰来抑制相关基因的表达。PRC2蛋白复合物主要由EZH2(Enhancer of Zeste Homolog 2)(或其非常类似的同源蛋白EZH1)，EED(Embryonic ectoderm Development)以及SUZ12(Suppressor of Zeste 12)等核心蛋白组成。其中，EZH2具有酶催化活性，通过SET(Su(var),E(Z)，and Trithorax)蛋白结构域能够把底物SAM(S-adenosyl-L-methionine)的甲基转移到H3K27上，从而达到H3K27的一到三甲基化修饰。EZH2的酶催化活性也依赖于PRC2其他组成部分，比如属于WD40重复结构蛋白家族的EED蛋白。EED与三甲基化的H3K27Me3的结合作用一方面对EZH2的酶催化功能有很大的变构促进作用，另一方面也能把PCR2复合物定位在需要修饰的染色质上。PRC2的功能异常，比如EZH2的过表达或功能获得性突变，与临床上许多肿瘤疾病相关，包括肺癌，乳腺癌，直肠癌，***癌，膀胱癌，胰腺癌，肉瘤以及淋巴癌等等。PRC2也与多种细胞免疫功能相关，比如EZH2参与调节淋巴细胞活化，也能与糖酵解共同促进T细胞对肿瘤细胞的应答。因此，研发PRC2小分子抑制剂有重要且广阔的药物开发价值。The PcG (Polycomb Group) protein is an important class of chromatin-modifying enzymes. It regulates the transcription of genes by modifying the chromatin, which plays an important role in stem cell growth, differentiation and long-term cellular memory. In mammalian cells, PcG proteins are mainly divided into two types of transcriptional repression complexes, namely, PRC1 (Polycomb Repressive Complex 1) and PRC2 (Polycomb Repressive Complex 2). Among them, PRC2 inhibits the expression of related genes by methylation modification of the 27th lysine (H3K27) of histone 3 in chromatin. The PRC2 protein complex consists mainly of core proteins such as EZH2 (Enhancer of Zeste Homolog 2) (or its very similar homologous protein EZH1), EED (Embryonic ectoderm Development), and SUZ12 (Suppressor of Zeste 12). Among them, EZH2 has enzymatic activity, and the methyl group of the substrate SAM (S-adenosyl-L-methionine) can be transferred to H3K27 through the SET (Su(var), E(Z), and Trithorax) protein domain. A one to three methylation modification of H3K27 is achieved. The enzymatic activity of EZH2 is also dependent on other components of PRC2, such as the EED protein belonging to the WD40 repeat structural protein family. The binding of EED to trimethylated H3K27Me3 exerts a great allosteric effect on the enzymatic function of EZH2 on the one hand, and the PCR2 complex on the chromatin to be modified on the other hand. Abnormal function of PRC2, such as EZH2 overexpression or functional acquisition mutation, is associated with many clinical oncological diseases, including lung cancer, breast cancer, rectal cancer, prostate cancer, bladder cancer, pancreatic cancer, sarcoma and lymphoma. PRC2 is also associated with a variety of cellular immune functions, such as EZH2 involved in the regulation of lymphocyte activation, and together with glycolysis to promote T cell response to tumor cells. Therefore, the development of PRC2 small molecule inhibitors has important and broad drug development value.
围绕PRC2抑制剂的研发主要是开发EZH2抑制剂以及EED抑制剂两个策略。目前进入临床的EZH2抑制剂有EPZ-6438(Epizyme，临床二期)，GSK2816126(GSK，临床一期)，以及CPI-1205(Constellation,临床一期)等等。尽管EZH2抑制剂研发有多个进入临 床研究阶段，但这些抑制剂都含有一个共同的2-吡啶酮的药效团。并且，在将已有EZH2抑制剂用于临床治疗中，已经开始出现二次突变。EED抑制剂对EZH2酶功能有变构抑制的作用，可以达到与EZH2相同或类似的生物功能。而且一方面EED抑制剂很好的克服了EZH2的耐药性问题，另一方面EED抑制剂可以与EZH2抑制剂联用达到更好的协同作用效果。近期，诺华(参见Nature Chemical Biology 2017,13,381-388)和雅培(参见Nature Chemical Biology 2017,13,389-395)同时报道了两类具有较好生物活性的EED抑制剂。The development of PR2 inhibitors is mainly to develop two strategies for EZH2 inhibitors and EED inhibitors. EZH2 inhibitors currently in clinical practice include EPZ-6438 (Epizyme, clinical phase II), GSK2816126 (GSK, clinical phase I), and CPI-1205 (Constellation, clinical phase I) and the like. Although EZH2 inhibitor development has multiple entry into the clinical research phase, these inhibitors all contain a common 2-pyridone pharmacophore. Moreover, in the use of existing EZH2 inhibitors for clinical treatment, secondary mutations have begun to appear. EED inhibitors have an allosteric inhibition of EZH2 enzyme function and can achieve the same or similar biological functions as EZH2. On the one hand, EED inhibitors have well overcome the problem of drug resistance of EZH2. On the other hand, EED inhibitors can be combined with EZH2 inhibitors to achieve better synergistic effects. Recently, Novartis (see Nature Chemical Biology 2017, 13, 381-388) and Abbott (see Nature Chemical Biology 2017, 13, 389-395) have reported two classes of EED inhibitors with better biological activity.
发明内容Summary of the invention
本发明提供了一种嘧啶酮化合物、其药学上可接受的盐或其溶剂化物，或该盐的溶剂化物，是一类全新的EED抑制剂，表现出对肿瘤细胞很好的抑制活性，具有广阔的药物开发前景。The present invention provides a pyrimidinone compound, a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, which is a novel class of EED inhibitors which exhibits excellent inhibitory activity against tumor cells, and has Broad prospects for drug development.
第一方面，本发明提供了一种如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物；In a first aspect, the present invention provides a pyrimidinone compound represented by formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt;
Figure PCTCN2018122557-appb-000001
Figure PCTCN2018122557-appb-000001
其中，among them,
Figure PCTCN2018122557-appb-000002
为单键或双键；
Figure PCTCN2018122557-appb-000002
For single or double keys;
m独立地为0或1；m is independently 0 or 1;
n独立地为0或1；n is independently 0 or 1;
o独立地为0或1；o is independently 0 or 1;
p独立地为0或1；p is independently 0 or 1;
X独立地为C、O或CH 2O(CH 2O中的C和O均为环上的原子)； X is independently C, O or CH 2 O (C and O in CH 2 O are both atoms on the ring);
Y独立地为C或O；Y is independently C or O;
Z独立地为C或N；Z is independently C or N;
当X为C时，R 0独立地为氢、羟基、卤素(如氟)、取代或未取代的烷氧基或羰基； When X is C, R 0 is independently hydrogen, hydroxy, halogen (such as fluorine), substituted or unsubstituted alkoxy or carbonyl;
当X为O时，R 0不存在； When X is O, R 0 does not exist;
当Z为C时，R 1独立地为氢、卤素(如氟)或C 1-4烷基(如甲基)； When Z is C, R 1 is independently hydrogen, halogen (such as fluorine) or C 1-4 alkyl (such as methyl);
当Z为N时，R 1不存在； When Z is N, R 1 does not exist;
R 2和R 3各自独立地为氢、卤素(如氟)或C 1-4烷基(如甲基)； R 2 and R 3 are each independently hydrogen, halogen (such as fluorine) or C 1-4 alkyl (such as methyl);
R 4独立地为氢、R 4a取代或未取代的C 1-4烷基(所述C 1-4烷基例如甲基、乙基、正丙基或异丙基)、R 4a取代或未取代的C 1-4卤代烷基(所述C 1-4卤代烷基例如C 1-4氟代烷基，又如2,2-二氟乙基)、C 3-8环烷基或C 2-6烯基(如烯丙基)； R 4 is independently hydrogen, R 4a substituted or unsubstituted C 1-4 alkyl (the C 1-4 alkyl group such as methyl, ethyl, n-propyl or isopropyl), R 4a substituted or not Substituted C 1-4 haloalkyl (the C 1-4 haloalkyl group such as C 1-4 fluoroalkyl, as for 2,2-difluoroethyl), C 3-8 cycloalkyl or C 2 - 6 alkenyl (such as allyl);
每个R 4a独立地为氘、卤素(如氟)或C 1-4烷基； Each R 4a is independently hydrazine, halogen (such as fluorine) or C 1-4 alkyl;
R 5独立地为氢、C 1-4烷基(如甲基)或氨基； R 5 is independently hydrogen, C 1-4 alkyl (such as methyl) or amino;
R 6独立地为氢、卤素(如氟、溴或碘)、氰基、R 6a取代或未取代的C 1-8烷基(所述C 1-8烷基例如C 1-4烷基，又如甲基、乙基、正丙基或异丙基)、C 1-8烷氧基(如C 1-4烷氧基，又如甲氧基、乙氧基、正丙氧基或异丙氧基)、C 1-8卤代烷基(如C 1-4卤代烷基)、R 6a取代或未取代的C 3-8环烷基(所述C 3-8环烷基例如环己基)、R 6b取代或未取代的C 3-8环烷基(所述C 3-8环烷基例如环己基)、R 6b取代或未取代的C 3-8杂环基(所述的C 3-8杂环基优选为具有1至3个独立选自氮、氧和硫的杂原子的C 3-8杂环基，例如
Figure PCTCN2018122557-appb-000003
R 6c取代或未取代的烯基(所述烯基例如C 2-10烯基，又如C 2-6烯基，又如乙烯基)、R 6b取代或未取代的C 5-8环烯基(所述C 5-8环烯基例如
Figure PCTCN2018122557-appb-000004
R 6b取代或未取代的C 5-8杂环烯基(所述C 5-8杂环烯基优选为具有1至3个独立选自氮、氧和硫的杂原子的C 5-8杂环烯基，例如
Figure PCTCN2018122557-appb-000005
R 6d取代或未取代的氨基、R 6d取代或未取代的氧基、R 6d取代或未取代的巯基、R 6d取代或未取代的酰胺、0-3个R 6e取代的C 6-10芳基(所述C 6-10芳基例如苯基)或0-3个R 6e取代的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”(所述“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”可以为“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”，例如“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的5-12元杂芳基”，又如
Figure PCTCN2018122557-appb-000006
Figure PCTCN2018122557-appb-000007
R 6 is independently hydrogen, halogen (such as fluorine, bromine or iodine), cyano, R 6a substituted or unsubstituted C 1-8 alkyl (the C 1-8 alkyl group such as C 1-4 alkyl, Another example is methyl, ethyl, n-propyl or isopropyl), C 1-8 alkoxy (such as C 1-4 alkoxy, or methoxy, ethoxy, n-propoxy or iso) a propoxy group), a C 1-8 haloalkyl group (such as a C 1-4 haloalkyl group), a R 6a substituted or unsubstituted C 3-8 cycloalkyl group (the C 3-8 cycloalkyl group such as a cyclohexyl group), R 6b substituted or unsubstituted C 3-8 cycloalkyl (the C 3-8 cycloalkyl group such as cyclohexyl), R 6b substituted or unsubstituted C 3-8 heterocyclic group (described C 3 The 8- heterocyclic group is preferably a C 3-8 heterocyclic group having 1 to 3 hetero atoms independently selected from nitrogen, oxygen and sulfur, for example
Figure PCTCN2018122557-appb-000003
R 6c substituted or unsubstituted alkenyl group (the alkenyl group such as C 2-10 alkenyl group, such as C 2-6 alkenyl group, and also like vinyl group), R 6b substituted or unsubstituted C 5-8 cycloolefin Base (the C 5-8 cycloalkenyl group, for example
Figure PCTCN2018122557-appb-000004
R 6b a substituted or unsubstituted heterocyclyl C 5-8 alkenyl group (said C 5-8 heterocycloalkenyl group having preferably C 1 to 3 hetero atoms independently selected from nitrogen, oxygen and sulfur heteroatoms 5-8 Cycloalkenyl, for example
Figure PCTCN2018122557-appb-000005
R 6d substituted or unsubstituted amino group, R 6d substituted or unsubstituted oxy group, R 6d substituted or unsubstituted fluorenyl group, R 6d substituted or unsubstituted amide, 0-3 R 6e substituted C 6-10 aryl Substituents (the C 6-10 aryl group such as phenyl) or 0-3 R 6e substituted "having a C 1-20 carbon atom and 1-4 independently selected from N, NR 6e1 , O and S(O) Heteroaryl heteroatoms of 0-2 " (the "heteroaryl" having a C 1-20 carbon atom and 1-4 heteroatoms independently selected from N, NR 6e1 , O and S(O) 0-2 The group "may be a heteroaryl group having a C 1-10 carbon atom and 1-4 hetero atoms independently selected from N, NR 6e1 , O and S(O) 0-2 ", for example, "having C 1-10" a carbon atom and 1-4 5-12 membered heteroaryl groups independently selected from N, NR 6e1 , O and S(O) 0-2 hetero atoms,
Figure PCTCN2018122557-appb-000006
Figure PCTCN2018122557-appb-000007
每个R 6a和R 6b各自独立地为C 1-4烷氧基、-C(＝O)NR 6e1R 6e2、C 1-4烷基(如甲基)、C 1- 4卤代烷基(如三氟甲基)、氨基、保护基团保护的氨基(所述的保护基团可以为
Figure PCTCN2018122557-appb-000008
R 7b为C 1-4烷基或C 1-4烷氧基；例如
Figure PCTCN2018122557-appb-000009
可以为叔丁氧羰基)、单氟或多氟； Each of R 6a and R 6b is independently C 1-4 alkoxy, -C(=O)NR 6e1 R 6e2 , C 1-4 alkyl (such as methyl), C 1 -4 haloalkyl (such as Trifluoromethyl), amino, protecting group protected amino group (the protecting group can be
Figure PCTCN2018122557-appb-000008
R 7b is C 1-4 alkyl or C 1-4 alkoxy; for example
Figure PCTCN2018122557-appb-000009
Can be tert-butoxycarbonyl), monofluoro or polyfluoro;
每个R 6c独立地为C 1-4烷基或酯基(如
Figure PCTCN2018122557-appb-000010
其中R 7c为C 1-4烷基)； Each R 6c is independently a C 1-4 alkyl or ester group (eg
Figure PCTCN2018122557-appb-000010
Wherein R 7c is C 1-4 alkyl);
每个R 6d独立地为C 1-20烷基(如C 1-8烷基，又如C 1-6烷基)、苄基、R 7d取代或未取代的C 6-10芳基、R 7d取代或未取代的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”(所述“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”可以为“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”，例如“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的5-12元杂芳基”)； Each R 6d is independently C 1-20 alkyl (such as C 1-8 alkyl, as for C 1-6 alkyl), benzyl, R 7d substituted or unsubstituted C 6-10 aryl, R 7d substituted or unsubstituted "heteroaryl having a C 1-20 carbon atom and 1-4 heteroatoms independently selected from N, NR 6e1 , O and S(O) 0-2 " (the "having C" a heteroaryl group of 1 to 20 carbon atoms and 1 to 4 hetero atoms independently selected from N, NR 6e1 , O and S(O) 0-2 may be "having a C 1-10 carbon atom and 1-4 a heteroaryl group independently selected from the heteroatoms of N, NR 6e1 , O and S(O) 0-2 , for example "having a C 1-10 carbon atom and 1-4 independently selected from N, NR 6e1 , O and a 5-12 membered heteroaryl of a hetero atom of S(O) 0-2 ");
每个R 7d独立地为卤素(例如氟或氯)、C 1-4烷基、C 1-4烷氧基、-C(＝O)NR 6e1R 6e2、C 1- 4卤代烷基(如三氟甲基)、氨基或
Figure PCTCN2018122557-appb-000011
Each R 7d is independently halogen (for example, fluorine or chlorine), C 1-4 alkyl, C 1-4 alkoxy, -C(=O)NR 6e1 R 6e2 , C 1- 4 haloalkyl (such as three Fluoromethyl), amino or
Figure PCTCN2018122557-appb-000011
R 8d为C 1-4烷基； R 8d is C 1-4 alkyl;
R 6e独立地为卤素(例如氟或氯)、R 4a取代或未取代的C 1-4烷氧基(如甲氧基)、R 4a取代或未取代的C 1-4烷基(所述C 1-4烷基例如甲基、乙基、正丙基或异丙基)、-C(＝O)NR 6e1R 6e2(所述-C(＝O)NR 6e1R 6e2例如-C(＝O)NH 2)、-S(＝O) 2R 6e3(所述-S(＝O) 2R 6e3为-S(＝O) 2Me)、NR 6e1R 6e2(所述NR 6e1R 6e2例如-NH 2)、R 7e取代或未取代的C 3-10环烷基(如C 3-8环烷基)、R 7e取代或未取代的“具有C 1-20碳原子及1-4个独立选自NR 6e1、O和S(O) 0- 2的杂原子的杂环基”(所述“具有C 1-20碳原子及1-4个独立选自NR 6e1、O和S(O) 0-2的杂原子的杂环基”可以为“具有C 1-10碳原子及1-4个独立选自NR 6e1、O和S(O) 0-2的杂原子的杂环基”，例如“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的5-12元杂环基”，又如
Figure PCTCN2018122557-appb-000012
R 6e is independently halogen (for example, fluorine or chlorine), R 4a substituted or unsubstituted C 1-4 alkoxy (such as methoxy), R 4a substituted or unsubstituted C 1-4 alkyl (described C 1-4 alkyl such as methyl, ethyl, n-propyl or isopropyl), -C(=O)NR 6e1 R 6e2 (the -C(=O)NR 6e1 R 6e2 such as -C(= O) NH 2 ), -S(=O) 2 R 6e3 (the -S(=O) 2 R 6e3 is -S(=O) 2 Me), NR 6e1 R 6e2 (the NR 6e1 R 6e2 -NH 2 ), R 7e substituted or unsubstituted C 3-10 cycloalkyl (such as C 3-8 cycloalkyl), R 7e substituted or unsubstituted "having C 1-20 carbon atoms and 1-4 is independently selected from NR 6e1, O, and S (O) heterocyclic group of 0-2 hetero atoms "(the" C 1-20 carbon atoms and having 1-4 substituents independently selected from NR 6e1, O and S (O The heterocyclic group of the hetero atom of 0-2 " may be "heterocyclic group having a C 1-10 carbon atom and 1-4 hetero atoms independently selected from NR 6e1 , O and S(O) 0-2 " For example, a "5-12 membered heterocyclic group having a C 1-10 carbon atom and 1-4 hetero atoms independently selected from N, NR 6e1 , O and S(O) 0-2 ",
Figure PCTCN2018122557-appb-000012
每个R 7e独立地为卤素、C 1-4烷基、C 1-4烷氧基、-C(＝O)NR 6e1R 6e2或C 1-4卤代烷基； Each R 7e is independently halogen, C 1-4 alkyl, C 1-4 alkoxy, -C(=O)NR 6e1 R 6e2 or C 1-4 haloalkyl;
每个R 6e1独立地为氢或C 1-4烷基；每个R 6e2独立地为氢或C 1-4烷基；R 6e3为C 1-4烷基。 Each R 6e1 is independently hydrogen or C 1-4 alkyl; each R 6e2 is independently hydrogen or C 1-4 alkyl; and R 6e3 is C 1-4 alkyl.
在一个优选例中，m、n、o和p中有2、3或4个为1。In a preferred embodiment, 2, 3 or 4 of m, n, o and p are 1.
在另一优选例中，Y为O，X为C，
Figure PCTCN2018122557-appb-000013
为单键或双键，m为0，p为1，n为0或1。 In another preferred embodiment, Y is O and X is C.
Figure PCTCN2018122557-appb-000013
For single or double bonds, m is 0, p is 1, and n is 0 or 1.
在另一优选例中，Y为O，X为C，o和p为1；
Figure PCTCN2018122557-appb-000014
为单键或双键；m为0或1；n为0或1。 In another preferred embodiment, Y is O, X is C, and o and p are 1;
Figure PCTCN2018122557-appb-000014
Is a single bond or a double bond; m is 0 or 1; n is 0 or 1.
在另一优选例中，Y为O，X为O，
Figure PCTCN2018122557-appb-000015
为单键；m和o为1；p为0且n为1，或p为1且为0。 In another preferred embodiment, Y is O and X is O,
Figure PCTCN2018122557-appb-000015
Is a single bond; m and o are 1; p is 0 and n is 1, or p is 1 and is 0.
在另一优选例中，X为O，Y为C，
Figure PCTCN2018122557-appb-000016
为单键；m和p为1；n和o为0。 In another preferred embodiment, X is O and Y is C.
Figure PCTCN2018122557-appb-000016
Is a single bond; m and p are 1; n and o are 0.
在另一优选例中，当Y为O，X为CH 2O时，p为0，m和o为1；n为1或2。 In another preferred embodiment, when Y is O and X is CH 2 O, p is 0, m and o are 1; and n is 1 or 2.
在另一优选例中，当X为C，R 0独立地为氢、卤素、取代或未取代的烷氧基或羰基。 In another preferred embodiment, when X is C, R 0 is independently hydrogen, halogen, substituted or unsubstituted alkoxy or carbonyl.
在另一优选例中，当X为O，R 0不存在。 In another preferred embodiment, when X is O, R 0 is absent.
在另一优选例中，当Z为C，R 1为H、F或Me。 In another preferred embodiment, when Z is C, R 1 is H, F or Me.
在另一优选例中，当Z为N，R 1不存在。 In another preferred embodiment, when Z is N, R 1 is absent.
在另一优选例中，R 2为H或F。 In another preferred embodiment, R 2 is H or F.
在另一优选例中，R 3为H或F。 In another preferred embodiment, R 3 is H or F.
在另一优选例中，R 4为氢、甲基、氘代甲基(如-CD 3)、乙基、烯丙基、异丙基或二氟乙基(如2,2-二氟乙基)。 In another preferred embodiment, R 4 is hydrogen, methyl, deuterated methyl (eg, -CD 3 ), ethyl, allyl, isopropyl or difluoroethyl (eg, 2,2-difluoroethyl) base).
在另一优选例中，R 5为氢、甲基或氨基。 In another preferred embodiment, R 5 is hydrogen, methyl or amino.
在另一优选例中，R 6为氢、卤素、氰基、R 6a取代或未取代的C 1-4烷基或以下任一结构： In another preferred embodiment, R 6 is hydrogen, halogen, cyano, R 6a substituted or unsubstituted C 1-4 alkyl or any of the following structures:
Figure PCTCN2018122557-appb-000017
Figure PCTCN2018122557-appb-000017
其中，每个j独立地为0、1、2或3；k为0、1、2、3或4；每个l独立地为0、1或2；每个V独立地为C、N或O，且在同一环中最多同时有两个N或O；环A’为具有1-3个杂原子的取代或未取代的C 5-10杂芳基；每个环B’独立地为具有1-4个杂原子的取代或未取代的C 5-10杂芳基，其中所述杂原子独立地为N、O或S；Q为N、O或S。 Wherein each j is independently 0, 1, 2 or 3; k is 0, 1, 2, 3 or 4; each l is independently 0, 1 or 2; each V is independently C, N or O, and at most two N or O at the same time in the same ring; ring A' is a substituted or unsubstituted C 5-10 heteroaryl group having 1-3 heteroatoms; each ring B' is independently a substituted or unsubstituted C 5-10 heteroaryl group of from 1 to 4 heteroatoms wherein the hetero atom is independently N, O or S; and Q is N, O or S.
在另一优选例中，所述环A’为具有1-3个杂原子的六元杂芳基。In another preferred embodiment, the ring A' is a six-membered heteroaryl group having from 1 to 3 hetero atoms.
在另一优选例中，所述环B’为具有1-4个杂原子的五元杂环基。In another preferred embodiment, the ring B' is a five-membered heterocyclic group having from 1 to 4 hetero atoms.
在本发明的一些方案中，R 6为氢、氟、溴、碘、甲基、乙基、异丙基、环丙基、氰基、甲氧基、
Figure PCTCN2018122557-appb-000018
Figure PCTCN2018122557-appb-000019
In some embodiments of the invention, R 6 is hydrogen, fluoro, bromo, iodo, methyl, ethyl, isopropyl, cyclopropyl, cyano, methoxy,
Figure PCTCN2018122557-appb-000018
Figure PCTCN2018122557-appb-000019
在另一优选例中，所述的式(I)所示的嘧啶酮化合物选自下列任一结构：In another preferred embodiment, the pyrimidinone compound represented by the formula (I) is selected from any one of the following structures:
Figure PCTCN2018122557-appb-000020
Figure PCTCN2018122557-appb-000020
Figure PCTCN2018122557-appb-000021
Figure PCTCN2018122557-appb-000021
其中，n、R 0、R 1、R 2、R 3、R 4、R 5、R 6和
Figure PCTCN2018122557-appb-000022
的定义如上所述。 Wherein n, R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and
Figure PCTCN2018122557-appb-000022
The definition is as described above.
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000023
为
Figure PCTCN2018122557-appb-000024
Figure PCTCN2018122557-appb-000025
Figure PCTCN2018122557-appb-000026
其中R 1、R 2、R 3和Z的定义如本发明中所述。 In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000023
for
Figure PCTCN2018122557-appb-000024
Figure PCTCN2018122557-appb-000025
Figure PCTCN2018122557-appb-000026
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention.
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000027
为
Figure PCTCN2018122557-appb-000028
其中R 1、R 2、R 3和Z的定义如本发明中所述。在本发明的一些方案中，
Figure PCTCN2018122557-appb-000029
为
Figure PCTCN2018122557-appb-000030
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000027
for
Figure PCTCN2018122557-appb-000028
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention. In some aspects of the invention,
Figure PCTCN2018122557-appb-000029
for
Figure PCTCN2018122557-appb-000030
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000031
为
Figure PCTCN2018122557-appb-000032
其中R 1、R 2、R 3和Z的定义如本发明中所述。在本发明的一些方案中，
Figure PCTCN2018122557-appb-000033
为
Figure PCTCN2018122557-appb-000034
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000031
for
Figure PCTCN2018122557-appb-000032
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention. In some aspects of the invention,
Figure PCTCN2018122557-appb-000033
for
Figure PCTCN2018122557-appb-000034
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000035
为
Figure PCTCN2018122557-appb-000036
其中R 1、R 2、R 3和Z的定义如本发明中所述。在本发明的一些方案中，
Figure PCTCN2018122557-appb-000037
为
Figure PCTCN2018122557-appb-000038
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000035
for
Figure PCTCN2018122557-appb-000036
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention. In some aspects of the invention,
Figure PCTCN2018122557-appb-000037
for
Figure PCTCN2018122557-appb-000038
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000039
为
Figure PCTCN2018122557-appb-000040
其中R 1、R 2、R 3和Z的定义如本发明中所述。在本发明的一些方案中，
Figure PCTCN2018122557-appb-000041
为
Figure PCTCN2018122557-appb-000042
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000039
for
Figure PCTCN2018122557-appb-000040
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention. In some aspects of the invention,
Figure PCTCN2018122557-appb-000041
for
Figure PCTCN2018122557-appb-000042
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000043
为
Figure PCTCN2018122557-appb-000044
其中R 1、R 2、R 3和Z的定义如本发明中所述。在本发明的一些方案中，
Figure PCTCN2018122557-appb-000045
为
Figure PCTCN2018122557-appb-000046
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000043
for
Figure PCTCN2018122557-appb-000044
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention. In some aspects of the invention,
Figure PCTCN2018122557-appb-000045
for
Figure PCTCN2018122557-appb-000046
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000047
为
Figure PCTCN2018122557-appb-000048
其中R 1、R 2、R 3和Z的定义如本发明中所述。在本发明的一些方案中，
Figure PCTCN2018122557-appb-000049
为
Figure PCTCN2018122557-appb-000050
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000047
for
Figure PCTCN2018122557-appb-000048
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention. In some aspects of the invention,
Figure PCTCN2018122557-appb-000049
for
Figure PCTCN2018122557-appb-000050
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000051
为
Figure PCTCN2018122557-appb-000052
在本发明的一些方案中，
Figure PCTCN2018122557-appb-000053
为
Figure PCTCN2018122557-appb-000054
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000051
for
Figure PCTCN2018122557-appb-000052
In some aspects of the invention,
Figure PCTCN2018122557-appb-000053
for
Figure PCTCN2018122557-appb-000054
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000055
为
Figure PCTCN2018122557-appb-000056
其中R 1、R 2、R 3和Z的定义如本发明中所述。在本发明的一些方案中，
Figure PCTCN2018122557-appb-000057
为
Figure PCTCN2018122557-appb-000058
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000055
for
Figure PCTCN2018122557-appb-000056
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention. In some aspects of the invention,
Figure PCTCN2018122557-appb-000057
for
Figure PCTCN2018122557-appb-000058
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000059
为
Figure PCTCN2018122557-appb-000060
其中R 1、R 2、R 3和Z的定义如本发明中所述。在本发明的一些方案中，
Figure PCTCN2018122557-appb-000061
为
Figure PCTCN2018122557-appb-000062
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000059
for
Figure PCTCN2018122557-appb-000060
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention. In some aspects of the invention,
Figure PCTCN2018122557-appb-000061
for
Figure PCTCN2018122557-appb-000062
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000063
为
Figure PCTCN2018122557-appb-000064
其中R 1、R 2、R 3和Z的定义如本发明中所述。在本发明的一些方案中，
Figure PCTCN2018122557-appb-000065
为
Figure PCTCN2018122557-appb-000066
在本发明的一些方案中，式(I)所示的嘧啶酮化合物中的
Figure PCTCN2018122557-appb-000067
为
Figure PCTCN2018122557-appb-000068
Figure PCTCN2018122557-appb-000069
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000063
for
Figure PCTCN2018122557-appb-000064
Wherein R 1 , R 2 , R 3 and Z are as defined in the present invention. In some aspects of the invention,
Figure PCTCN2018122557-appb-000065
for
Figure PCTCN2018122557-appb-000066
In some embodiments of the invention, in the pyrimidinone compound of formula (I)
Figure PCTCN2018122557-appb-000067
for
Figure PCTCN2018122557-appb-000068
Figure PCTCN2018122557-appb-000069
本发明还提供了如下方案：The invention also provides the following scheme:
本发明还提供一种如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物：The present invention also provides a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt:
Figure PCTCN2018122557-appb-000070
Figure PCTCN2018122557-appb-000070
其中，among them,
Figure PCTCN2018122557-appb-000071
是单键或双键；
Figure PCTCN2018122557-appb-000071
Is a single or double button;
m独立地为0或1；m is independently 0 or 1;
n独立地为0或1；n is independently 0 or 1;
o独立地为0或1；o is independently 0 or 1;
p独立地为0或1；p is independently 0 or 1;
X独立地为C、O或CH 2O； X is independently C, O or CH 2 O;
Y独立地为C或O；Y is independently C or O;
Z独立地为C或N；Z is independently C or N;
当X为C时，R 0独立地为氢、卤素、取代或未取代的烷氧基或羰基； When X is C, R 0 is independently hydrogen, halogen, substituted or unsubstituted alkoxy or carbonyl;
当X为O时，R 0不存在； When X is O, R 0 does not exist;
当Z为C时，R 1独立地为氢、卤素或C 1-4烷基； When Z is C, R 1 is independently hydrogen, halogen or C 1-4 alkyl;
当Z为N时，R 1不存在； When Z is N, R 1 does not exist;
R 2和R 3独立地为氢、卤素或C 1-4烷基； R 2 and R 3 are independently hydrogen, halogen or C 1-4 alkyl;
R 4独立地为氢、R 4a取代或未取代的C 1-4烷基、R 4a取代或未取代的C 1-4卤代烷基、C 3-8环烷基或C 2-6烯基； R 4 is independently hydrogen, R 4a substituted or unsubstituted C 1-4 alkyl, R 4a substituted or unsubstituted C 1-4 haloalkyl, C 3-8 cycloalkyl or C 2-6 alkenyl;
R 4a独立地为卤素或C 1-4烷基； R 4a is independently halogen or C 1-4 alkyl;
R 5独立地为氢、C 1-4烷基或氨基； R 5 is independently hydrogen, C 1-4 alkyl or amino;
R 6独立地为氢、卤素、氰基、C 1-8烷基、C 1-8卤代烷基、R 6a取代或未取代的C 3-8环烷基、R 6b取代或未取代的C 3-8杂环基、R 6c取代或未取代的烯基、R 6b取代或未取代的C 5- 8环烯基、R 6b取代或未取代的C 5-8杂环烯基、R 6d取代或未取代的氨基、R 6d取代或未取代的氧基、R 6d取代或未取代的酰胺、0-3个R 6e取代的C 6-10芳基或0-3个R 6e取代的含有C 1-20碳原子及1-4个N、NR 6e1、O或S(O) 0-2等杂原子的杂芳环； R 6 is independently hydrogen, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, R 6a substituted or unsubstituted C 3-8 cycloalkyl, R 6b substituted or unsubstituted C 3 -8 heterocyclyl, R 6c substituted or unsubstituted alkenyl group, R 6b a substituted or unsubstituted C 5- 8 cycloalkenyl, R 6b a substituted or unsubstituted C 5-8 heterocycloalkenyl group, R 6d substituted Or unsubstituted amino, R 6d substituted or unsubstituted oxy, R 6d substituted or unsubstituted amide, 0-3 R 6e substituted C 6-10 aryl or 0-3 R 6e substituted C a heteroaryl ring of 1-20 carbon atoms and 1-4 hetero atoms such as N, NR 6e1 , O or S(O) 0-2 ;
R 6a和R 6b独立地为氨基、保护基团保护的氨基、单氟或多氟； R 6a and R 6b are independently amino, protecting group protected amino, monofluoro or polyfluoro;
R 6c独立地为C 1-4烷基、酯基； R 6c is independently C 1-4 alkyl, ester group;
R 6d独立地为C 1-20烷基、苄基、取代或未取代的C 6-10芳基、取代或未取代的含有C 1- 20碳原子及1-4个N、NR 6e1、O或S(O) 0-2等杂原子的杂芳环； R 6d is independently a C 1-20 alkyl group, a benzyl group, a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted C 1- 20 containing 1-4 carbon atoms and N, NR 6e1, O Or a heteroaromatic ring of a hetero atom such as S(O) 0-2 ;
R 6e独立地为卤素、R 4a取代或未取代的C 1-4烷氧基、R 4a取代或未取代的C 1-4烷基、-C(＝O)NR 6e1R 6e2、-S(＝O) 2R 6e3、NR 6e1R 6e2、含有C 1-20碳原子及1-4个NR 6e1、O或S(O) 0- 2等杂原子的杂环； R 6e is independently halogen, R 4a substituted or unsubstituted C 1-4 alkoxy, R 4a substituted or unsubstituted C 1-4 alkyl, -C(=O)NR 6e1 R 6e2 , -S( = O) 2 R 6e3, NR 6e1 R 6e2, C 1-20 carbon atoms and containing 1-4 NR 6e1, O, or S (O) 0- 2 other hetero atom;
其中，R 6e1独立地为氢或C 1-4烷基；R 6e2独立地为氢或C 1-4烷基；R 6e3为C 1-4烷基。 Wherein R 6e1 is independently hydrogen or C 1-4 alkyl; R 6e2 is independently hydrogen or C 1-4 alkyl; and R 6e3 is C 1-4 alkyl.
在另一优选例中，Y为O，X为C，
Figure PCTCN2018122557-appb-000072
为单键或双键，m为0，p为1，n为0或1。 In another preferred embodiment, Y is O and X is C.
Figure PCTCN2018122557-appb-000072
For single or double bonds, m is 0, p is 1, and n is 0 or 1.
在另一优选例中，Y为O，X为O，
Figure PCTCN2018122557-appb-000073
为单键；m，o为1；p为0且n为1或p为1且为0。 In another preferred embodiment, Y is O and X is O,
Figure PCTCN2018122557-appb-000073
Is a single bond; m, o is 1; p is 0 and n is 1 or p is 1 and is 0.
在另一优选例中，X为O，Y为C，
Figure PCTCN2018122557-appb-000074
为单键；m，p为1；n，o为0。 In another preferred embodiment, X is O and Y is C.
Figure PCTCN2018122557-appb-000074
Is a single bond; m, p is 1; n, o is 0.
在另一优选例中，当Y为O，X为CH 2O时，p为0，m，o为1；n独立地为1或2。 In another preferred embodiment, when Y is O and X is CH 2 O, p is 0, m, o is 1; n is independently 1 or 2.
在另一优选例中，当X为C，R 0独立地为氢、卤素、取代或未取代的烷氧基或羰 基。 In another preferred embodiment, when X is C, R 0 is independently hydrogen, halogen, substituted or unsubstituted alkoxy or carbonyl.
在另一优选例中，当X为O，R 0不存在。 In another preferred embodiment, when X is O, R 0 is absent.
在另一优选例中，当Z为C，R 1为H、F或Me。 In another preferred embodiment, when Z is C, R 1 is H, F or Me.
在另一优选例中，当Z为N，R 1不存在。 In another preferred embodiment, when Z is N, R 1 is absent.
在另一优选例中，R 2为H或F。 In another preferred embodiment, R 2 is H or F.
在另一优选例中，R 3为H或F。 In another preferred embodiment, R 3 is H or F.
在另一优选例中，R 4为氢、甲基、氘代甲基、乙基、烯丙基、异丙基或二氟乙基。 In another preferred embodiment, R 4 is hydrogen, methyl, deuterated methyl, ethyl, allyl, isopropyl or difluoroethyl.
在另一优选例中，R 5为氢、甲基或氨基。 In another preferred embodiment, R 5 is hydrogen, methyl or amino.
在另一优选例中，R 6为氢、卤素、氰基、R 6a取代或未取代的C 1-4烷基或具有以下任一结构： In another preferred embodiment, R 6 is hydrogen, halogen, cyano, R 6a substituted or unsubstituted C 1-4 alkyl or has any of the following structures:
Figure PCTCN2018122557-appb-000075
Figure PCTCN2018122557-appb-000075
其中，j为0、1、2或3；k为0、1、2、3或4；l为0、1或2；V为C、N或O，且在同一环中最多同时有两个N或O；环A含有1-3个杂原子的取代或未取代的C 5-10杂芳基；环B选自含有1-4个杂原子的取代或未取代的C 5-10杂芳基，其中所述杂原子选自N、O或S；Q为N、O或S。 Where j is 0, 1, 2 or 3; k is 0, 1, 2, 3 or 4; l is 0, 1 or 2; V is C, N or O, and there are at most two in the same ring N or O; ring A contains 1-3 heteroatoms of substituted or unsubstituted C 5-10 heteroaryl; ring B is selected from substituted or unsubstituted C 5-10 heteroaryl containing 1-4 heteroatoms a group wherein the hetero atom is selected from N, O or S; and Q is N, O or S.
在另一优选例中，所述环A为含有1-3个杂原子的六元杂芳基。In another preferred embodiment, the ring A is a six-membered heteroaryl group having from 1 to 3 hetero atoms.
在另一优选例中，所述环B为含有1-4个杂原子的五元杂环基。In another preferred embodiment, the ring B is a five-membered heterocyclic group having from 1 to 4 hetero atoms.
在另一优选例中，所述的化合物选自下列任一化合物：In another preferred embodiment, the compound is selected from any of the following compounds:
Figure PCTCN2018122557-appb-000076
Figure PCTCN2018122557-appb-000076
Figure PCTCN2018122557-appb-000077
Figure PCTCN2018122557-appb-000077
其中，n、R 0、R 1、R 2、R 3、R 4、R 5、R 6和
Figure PCTCN2018122557-appb-000078
的定义如上所述。 Wherein n, R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and
Figure PCTCN2018122557-appb-000078
The definition is as described above.
在另一优选例中，所述的式(I)所示的嘧啶酮化合物选自以下任一化合物：In another preferred embodiment, the pyrimidinone compound represented by the formula (I) is selected from any one of the following compounds:
Figure PCTCN2018122557-appb-000079
Figure PCTCN2018122557-appb-000079
Figure PCTCN2018122557-appb-000080
Figure PCTCN2018122557-appb-000080
Figure PCTCN2018122557-appb-000081
Figure PCTCN2018122557-appb-000081
Figure PCTCN2018122557-appb-000082
Figure PCTCN2018122557-appb-000082
Figure PCTCN2018122557-appb-000083
Figure PCTCN2018122557-appb-000083
Figure PCTCN2018122557-appb-000084
Figure PCTCN2018122557-appb-000084
Figure PCTCN2018122557-appb-000085
Figure PCTCN2018122557-appb-000085
Figure PCTCN2018122557-appb-000086
Figure PCTCN2018122557-appb-000086
Figure PCTCN2018122557-appb-000087
Figure PCTCN2018122557-appb-000087
Figure PCTCN2018122557-appb-000088
Figure PCTCN2018122557-appb-000088
Figure PCTCN2018122557-appb-000089
Figure PCTCN2018122557-appb-000089
Figure PCTCN2018122557-appb-000090
Figure PCTCN2018122557-appb-000090
Figure PCTCN2018122557-appb-000091
Figure PCTCN2018122557-appb-000091
第二方面，本发明提供了如上所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物的同位素标记化合物。如式(I)所示的嘧啶酮化合物中能够被同位素标记的原子包括但不局限于氢、碳、氮、氧、磷、氟、氯和碘等。它们可分别被同位素 2H、 3H、 11C、 13C、 14C、 15N、 18F、 31P、 32P、 35S、 36Cl和 125I等代替。氘代物通常可以保留与未氘代的化合物相当的活性，并且当氘代在某些特定位点时可以取得更好的代谢稳定性，从而获得某些治疗优势(如体内半衰期增加或剂量需求减少)。因此，在本发明中，所述的同位素标记化合物优选为氘代物。 In a second aspect, the present invention provides a pyrimidone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt as described above. Among the pyrimidinone compounds represented by the formula (I), the atoms which can be labeled with isotopes include, but are not limited to, hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, iodine and the like. They may be replaced by the isotopes 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I, respectively. Deuterated products generally retain activity comparable to that of non-deuterated compounds, and achieve better metabolic stability when deuterated at certain sites, resulting in certain therapeutic advantages (eg, increased in vivo half-life or reduced dosage requirements) ). Therefore, in the present invention, the isotope-labeled compound is preferably a deuterated substance.
第三方面，本发明提供如上所述的如式(I)所示的嘧啶酮化合物的制备方法，其包括如下步骤：In a third aspect, the present invention provides a process for the preparation of a pyrimidinone compound represented by formula (I) as described above, which comprises the steps of:
Figure PCTCN2018122557-appb-000092
Figure PCTCN2018122557-appb-000092
其中，W为卤素，优选Br或I；R 1、R 2、R 3、R 4、R 5、X、Y、Z、
Figure PCTCN2018122557-appb-000093
m、n、o、 p、R 0和R 6的定义如上所述。所述的如式(I)所示的嘧啶酮化合物的制备方法可以包括如下步骤：在溶剂中，将化合物A和R 6-W进行反应，得到如式(I)所示的嘧啶酮化合物即可。 Wherein W is halogen, preferably Br or I; R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
Figure PCTCN2018122557-appb-000093
The definitions of m, n, o, p, R 0 and R 6 are as described above. The method for producing the pyrimidinone compound represented by the formula (I) may include the step of reacting the compound A and R 6 -W in a solvent to obtain a pyrimidinone compound represented by the formula (I). can.
在另一优选例中，化合物I-A的制备方法包括如下步骤：将化合物A与相应的硼酸在偶联的条件下，得到化合物I-A；In another preferred embodiment, the preparation method of the compound I-A includes the following steps: the compound A and the corresponding boric acid under the conditions of coupling, to obtain the compound I-A;
Figure PCTCN2018122557-appb-000094
Figure PCTCN2018122557-appb-000094
其中，W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、、V、j、m、n、o、p、k、R 0、R 6b、R 6c、R 6e、
Figure PCTCN2018122557-appb-000095
环A’和环B’的定义如上所述。 Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, V, j, m, n, o, p, k, R 0 , R 6b , R 6c , R 6e ,
Figure PCTCN2018122557-appb-000095
The definitions of ring A' and ring B' are as described above.
在另一优选例中，化合物I-C的制备方法包括如下步骤：将化合物A与氰化锌在偶联的条件下，得到氰基化合物I-B；将氰基化合物I-B在过氧化氢和碱性的条件下进行反应得到酰胺化合物I-C；In another preferred embodiment, the method for preparing the compound IC comprises the steps of: subjecting the compound A to zinc cyanide under coupling conditions to obtain a cyano compound IB; and subjecting the cyano compound IB to hydrogen peroxide and basic conditions. The reaction is carried out to obtain an amide compound IC;
Figure PCTCN2018122557-appb-000096
Figure PCTCN2018122557-appb-000096
其中，W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、
Figure PCTCN2018122557-appb-000097
m、n、o、p和R 0的定义如上所述。 Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
Figure PCTCN2018122557-appb-000097
The definitions of m, n, o, p and R 0 are as described above.
在另一优选例中，化合物I-D的制备方法包括如下步骤：将化合物A与取代胺或硫醇在偶联的条件下，得到化合物I-D；In another preferred embodiment, the preparation method of the compound I-D includes the following steps: the compound A is combined with a substituted amine or a thiol to obtain the compound I-D;
Figure PCTCN2018122557-appb-000098
Figure PCTCN2018122557-appb-000098
其中，W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、
Figure PCTCN2018122557-appb-000099
m、n、o、p、R 0和R 6d的定义如上所述，Q为N或S。 Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
Figure PCTCN2018122557-appb-000099
m, n, o, p, R 0 and R 6d are as defined above, and Q is N or S.
在另一优选例中，化合物I-E的制备方法包含如下步骤：氢化化合物I-A(1)的双键得到相应的饱和取代化合物I-E；In another preferred embodiment, the preparation method of the compound I-E comprises the steps of: hydrogenating the double bond of the compound I-A (1) to obtain the corresponding saturated substituted compound I-E;
Figure PCTCN2018122557-appb-000100
Figure PCTCN2018122557-appb-000100
其中，R 1、R 2、R 3、R 4、R 5、X、Y、Z、V、j、m、n、o、p、R 0、R 6b和R 6c的定义如上所述。 Wherein R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, V, j, m, n, o, p, R 0 , R 6b and R 6c are as defined above.
在另一优选例中，化合物I-F的制备方法包括以下步骤：化合物E在碱性条件下被化合物C取代得到化合物I-F；In another preferred embodiment, the preparation method of the compound I-F includes the following steps: the compound E is substituted with the compound C under basic conditions to obtain the compound I-F;
Figure PCTCN2018122557-appb-000101
Figure PCTCN2018122557-appb-000101
其中，R 1、R 2、R 3、R 4、X、Y、Z、
Figure PCTCN2018122557-appb-000102
m、n、o、p、R 0和R 6d的定义如上所述。 Wherein R 1 , R 2 , R 3 , R 4 , X, Y, Z,
Figure PCTCN2018122557-appb-000102
The definitions of m, n, o, p, R 0 and R 6d are as described above.
本发明还提供一种化合物A，The invention also provides a compound A,
Figure PCTCN2018122557-appb-000103
Figure PCTCN2018122557-appb-000103
其中，W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、
Figure PCTCN2018122557-appb-000104
m、n、o、p和R 0的定义如上所述。 Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
Figure PCTCN2018122557-appb-000104
The definitions of m, n, o, p and R 0 are as described above.
本发明还提供了一种如上所述的化合物A的制备方法，其包括如下步骤：化合物B 在碱性条件下被化合物C取代得到化合物A；The present invention also provides a preparation method of Compound A as described above, which comprises the steps of: Compound B is substituted with Compound C under basic conditions to obtain Compound A;
Figure PCTCN2018122557-appb-000105
Figure PCTCN2018122557-appb-000105
其中，W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、
Figure PCTCN2018122557-appb-000106
m、n、o、p和R 0的定义如上所述。 Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
Figure PCTCN2018122557-appb-000106
The definitions of m, n, o, p and R 0 are as described above.
本发明还提供了化合物A的另一种制备方法，其包括如下步骤：化合物D在活性试剂(如BOP-Cl)活化后被化合物C取代得到化合物A；The present invention also provides another preparation method of Compound A, which comprises the steps of: Compound D is substituted with Compound C after activation of active agent (such as BOP-Cl) to obtain Compound A;
Figure PCTCN2018122557-appb-000107
Figure PCTCN2018122557-appb-000107
其中，W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、
Figure PCTCN2018122557-appb-000108
m、n、o、p和R 0的定义如上所述。 Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
Figure PCTCN2018122557-appb-000108
The definitions of m, n, o, p and R 0 are as described above.
本发明还提供一种化合物B，The invention also provides a compound B,
Figure PCTCN2018122557-appb-000109
Figure PCTCN2018122557-appb-000109
其中，W、R 4和R 5的定义如上所述。 Wherein, W, R 4 and R 5 are as defined above.
本发明还提供一种如上所述的化合物B的制备方法，其包括如下步骤：化合物B-a在碱性条件下转变成化合物B-b；化合物B-b氮烷基化取代后得到化合物B；The present invention also provides a method for preparing the compound B as described above, which comprises the steps of: converting compound B-a to compound B-b under basic conditions; and compound B-b by nitrogen alkylation to obtain compound B;
Figure PCTCN2018122557-appb-000110
Figure PCTCN2018122557-appb-000110
其中，W、R 4和R 5的定义如上所述。 Wherein, W, R 4 and R 5 are as defined above.
本发明还提供化合物B的另一种制备方法，其包括如下步骤：化合物B-c经过适当的保护基(如Boc、二苯甲基等)保护后得到化合物B-d；化合物B-d在碱性条件下烷基化得到化合物B-e；然后，化合物B-e脱保护得到化合物B-f后转化成化合物B；The present invention also provides another preparation method of Compound B, which comprises the steps of: Compound Bc is protected by a suitable protecting group (such as Boc, diphenylmethyl, etc.) to obtain Compound Bd; Compound Bd is alkyl under basic conditions. Compound Be is obtained; then, compound Be is deprotected to obtain compound Bf and then converted into compound B;
Figure PCTCN2018122557-appb-000111
Figure PCTCN2018122557-appb-000111
其中，W、R 4和R 5的定义如上所述。 Wherein, W, R 4 and R 5 are as defined above.
本发明还提供一种化合物D,The invention also provides a compound D,
Figure PCTCN2018122557-appb-000112
Figure PCTCN2018122557-appb-000112
其中，W、R 4和R 5的定义如上所述。 Wherein, W, R 4 and R 5 are as defined above.
本发明还提供了一种如上所述的化合物D的制备方法，其包括以下步骤：通过对化合物D-a进行卤代反应来制备；The present invention also provides a process for the preparation of the compound D as described above, which comprises the steps of: preparing a compound D-a by halogenation;
Figure PCTCN2018122557-appb-000113
Figure PCTCN2018122557-appb-000113
其中，W、R 4和R 5的定义如上所述。 Wherein, W, R 4 and R 5 are as defined above.
本发明还提供了一种化合物E，The invention also provides a compound E,
Figure PCTCN2018122557-appb-000114
Figure PCTCN2018122557-appb-000114
其中，R 4和R 6d的定义如上所述。 Wherein R 4 and R 6d are as defined above.
本发明还提供了一种化合物E的制备方法，其包括如下步骤：化合物E-a与甲醇氨加成得到化合物E-b，然后与缩醛缩合后得到化合物E-c；化合物E-c甲基化后得到化合物E-d；然后与化合物E-e在碱性条件下缩合得到化合物E-f；最后，氧化化合物E-f的硫醚得到化合物E；The invention also provides a preparation method of the compound E, which comprises the steps of: compound Ea is added with methanol ammonia to obtain compound Eb, and then condensed with acetal to obtain compound Ec; compound Ec is methylated to obtain compound Ed; Condensation with the compound Ee under basic conditions to obtain the compound Ef; finally, oxidizing the thioether of the compound Ef to obtain the compound E;
Figure PCTCN2018122557-appb-000115
Figure PCTCN2018122557-appb-000115
其中，R 4合R 6d的定义如上所述。 Wherein R 4 and R 6d are as defined above.
本发明还提供一种化合物C1或C2，The invention also provides a compound C1 or C2,
Figure PCTCN2018122557-appb-000116
Figure PCTCN2018122557-appb-000116
其中，R 1、R 2和R 3的定义如上所述。 Wherein R 1 , R 2 and R 3 are as defined above.
本发明还提供一种如上所述的化合物C1或C2的制备方法，其包括如下步骤：化合物C1-a经取代酚羟基得到化合物C1-b后分子内缩合得到化合物C1-c，需要指出的是当R 3是氢时，缩合过程生成的副产物化合物C1-d可通过下一步转化为氰基后用柱层析的方法分离去除；化合物C1-c经氰基化后得到化合物C1-e；化合物C1-e经还原氰基后得到化合物C2； The present invention also provides a process for the preparation of the compound C1 or C2 as described above, which comprises the steps of: the compound C1-a is substituted with a phenolic hydroxyl group to obtain the compound C1-b and then intramolecularly condensed to obtain a compound C1-c. When R 3 is hydrogen, the by-product compound C1-d formed by the condensation process can be separated and removed by column chromatography after the next step; the compound C1-c is cyanated to obtain the compound C1-e; Compound C1-e is obtained by reducing cyano group to obtain compound C2;
化合物C2氢化还原后得到化合物C1。另外化合物C1-e也可通过氢化还原呋喃和氰基的同时Boc保护生成的氨基而得到C1-f；最后，化合物C1-f经脱Boc保护后得到化合物C1；Compound C2 is hydrogenated and reduced to give compound C1. In addition, the compound C1-e can also be obtained by hydrogenating the furan and the cyano group while Boc protecting the resulting amino group to obtain C1-f; finally, the compound C1-f is de Boc-protected to obtain the compound C1;
Figure PCTCN2018122557-appb-000117
Figure PCTCN2018122557-appb-000117
其中，R 1、R 2和R 3的定义如上所述。 Wherein R 1 , R 2 and R 3 are as defined above.
本发明还提供一种化合物C3,The invention also provides a compound C3,
Figure PCTCN2018122557-appb-000118
Figure PCTCN2018122557-appb-000118
其中，R 1、R 2和R 3的定义如上所述。 Wherein R 1 , R 2 and R 3 are as defined above.
本发明还提供一种如上所述的化合物C3的制备方法，其包括如下步骤：将化合物C1-a经取代酚羟基被炔丙基取代后得到化合物C3-a；化合物C3-a在高温的条件下发生重排得到化合物C3-b，类似的，当R 3是氢时，会生成化合物C3-c；得到化合物C3-b后，经过与合成C1的类似方法可以得到化合物C3； The invention also provides a preparation method of the compound C3 as described above, which comprises the steps of: substituting a compound C1-a with a substituted phenolic hydroxyl group by a propargyl group to obtain a compound C3-a; the condition of the compound C3-a at a high temperature The rearrangement occurs to obtain the compound C3-b. Similarly, when R 3 is hydrogen, the compound C3-c is formed; after the compound C3-b is obtained, the compound C3 can be obtained by a similar method to the synthesis of C1;
Figure PCTCN2018122557-appb-000119
Figure PCTCN2018122557-appb-000119
本发明还提供一种化合物C4，The invention also provides a compound C4,
Figure PCTCN2018122557-appb-000120
Figure PCTCN2018122557-appb-000120
其中，R 1、R 2和R 3的定义如上所述。 Wherein R 1 , R 2 and R 3 are as defined above.
本发明还提供一种如上所述的化合物C4的制备方法，其包括如下步骤：烯丙基取代化合物C4-a后得到化合物C4-b；化合物C4-b经过加热重排后得到化合物C4-c；再一次烯丙基化后得到化合物C4-d；化合物C4-d经过RCM环化后得到化合物C4-e，然后氢化氰基和双键并同时Boc保护后得到化合物C4-f；最后脱Boc保护后得到化合物C4；The present invention also provides a process for the preparation of the compound C4 as described above, which comprises the steps of: ally-substituted compound C4-a to obtain compound C4-b; compound C4-b after heat rearrangement to obtain compound C4-c Further allylation gives compound C4-d; compound C4-d is cyclized by RCM to give compound C4-e, then hydrogenation of cyano and double bond and simultaneous Boc protection affords compound C4-f; After the protection, the compound C4 is obtained;
Figure PCTCN2018122557-appb-000121
Figure PCTCN2018122557-appb-000121
本发明还提供一种化合物C5，The invention also provides a compound C5,
Figure PCTCN2018122557-appb-000122
Figure PCTCN2018122557-appb-000122
其中R 1、R 2和R 3的定义同上所述。 Wherein R 1 , R 2 and R 3 are as defined above.
本发明还提供一种如上所述的化合物C5的制备方法，其包括如下步骤：化合物C5-a经取代酚羟基得到化合物C5-b后分子内缩合得到化合物C5-c；化合物C5-c经氰基化后得到化合物C5-d；化合物C5-d经还原呋喃和氰基的同时Boc保护生成的氨基而得到化合物C5-e；化合物C5-e经脱Boc保护后得到化合物C5；The invention also provides a preparation method of the compound C5 as described above, which comprises the steps of: the compound C5-a is substituted by a phenolic hydroxyl group to obtain the compound C5-b and then intramolecularly condensed to obtain a compound C5-c; the compound C5-c is cyanide After compounding, the compound C5-d is obtained; the compound C5-d is simultaneously Boc-protected to form the compound C5-e by reducing the furan and the cyano group; the compound C5-e is de Boc-protected to obtain the compound C5;
Figure PCTCN2018122557-appb-000123
Figure PCTCN2018122557-appb-000123
本发明还提供一种化合物C6，The invention also provides a compound C6,
Figure PCTCN2018122557-appb-000124
Figure PCTCN2018122557-appb-000124
其中R 1、R 2和R 3的定义如上所述。 Wherein R 1 , R 2 and R 3 are as defined above.
本发明还提供一种如上所述的化合物C6的制备方法，其包括如下步骤：化合物C6-a脱甲基后得到化合物C6-b；化合物C6-b环烷基化得到化合物C6-c后引入醛基取代得到化合物C6-d；化合物C6-d与羟胺缩合后得到化合物C6-e；还原甲醛肟的同时Boc保护后得到化合物C6-f；最后，脱保护后得到化合物C6；The present invention also provides a process for the preparation of the compound C6 as described above, which comprises the steps of: decarboxylating the compound C6-a to obtain the compound C6-b; and ring-alkylating the compound C6-b to obtain the compound C6-c. Substituting aldehyde group to obtain compound C6-d; compound C6-d is condensed with hydroxylamine to obtain compound C6-e; while reducing formaldehyde oxime, Boc protection gives compound C6-f; finally, deprotection to obtain compound C6;
Figure PCTCN2018122557-appb-000125
Figure PCTCN2018122557-appb-000125
本发明还提供一种化合物C7，The invention also provides a compound C7,
Figure PCTCN2018122557-appb-000126
Figure PCTCN2018122557-appb-000126
其中R 1、R 2和R 3的定义如上所述。 Wherein R 1 , R 2 and R 3 are as defined above.
本发明还提供一种如上所述的化合物C7的制备方法，包含其包括如下步骤：化合物C7-a在LDA/DMF作用下引入醛基后得到化合物C7-b；甲氧基取代化合物C7-b的氟后得到化合物C7-c；化合物C7-c在路易斯酸的作用下脱除甲基得到化合物C7-d；化合物C7-d在碱性条件下与三甲基碘化亚砜加成缩合后得到化合物C7-e；化合物C7-e氰基化后得到化合物C7-f，然后还原氰基得到化合物C7；The present invention also provides a process for the preparation of the compound C7 as described above, which comprises the steps of: the compound C7-a is introduced into the aldehyde group by the action of LDA/DMF to obtain the compound C7-b; the methoxy substituted compound C7-b After the fluorine, the compound C7-c is obtained; the compound C7-c is removed by a Lewis acid to obtain the compound C7-d; and the compound C7-d is condensed with trimethylsulfoxonium under basic conditions. Obtaining the compound C7-e; the compound C7-e is cyanated to obtain the compound C7-f, and then the cyano group is reduced to obtain the compound C7;
Figure PCTCN2018122557-appb-000127
Figure PCTCN2018122557-appb-000127
本发明还提供一种化合物C8，The invention also provides a compound C8,
Figure PCTCN2018122557-appb-000128
Figure PCTCN2018122557-appb-000128
其中R 1、R 2和R 3的定义如上所述。 Wherein R 1 , R 2 and R 3 are as defined above.
本发明还提供一种如上所述的化合物C8的制备方法，其包括如下步骤：还原化合物C7-d醛基后得到化合物C8-a，然后环化二羟基得到化合物C8-b；化合物C8-b经过氰基化后得到化合物C8-c并还原氰基得到化合物C8；The present invention also provides a process for the preparation of the compound C8 as described above, which comprises the steps of: reducing the compound C7-d aldehyde group to obtain the compound C8-a, and then cyclizing the dihydroxy group to obtain the compound C8-b; the compound C8-b After cyanation, the compound C8-c is obtained and the cyano group is reduced to obtain the compound C8;
Figure PCTCN2018122557-appb-000129
Figure PCTCN2018122557-appb-000129
本发明还提供一种化合物C9，The invention also provides a compound C9,
Figure PCTCN2018122557-appb-000130
Figure PCTCN2018122557-appb-000130
其中，R 2和R 3同上所述。 Wherein R 2 and R 3 are as defined above.
本发明还提供一种如上所述的化合物C9的制备方法，其包括如下步骤：化合物C9-a氰基化转化后得到化合物C9-b，然后氢化条件还原氰基和呋喃环的同时Boc保护得到化合物C9-c；最后脱保护得到化合物C9；The present invention also provides a preparation method of the compound C9 as described above, which comprises the steps of: c9-b after compounding C9-a to give a compound C9-b, and then reducing the cyano group and the furan ring by hydrogenation to obtain Boc protection Compound C9-c; finally deprotected to give compound C9;
Figure PCTCN2018122557-appb-000131
Figure PCTCN2018122557-appb-000131
在另一优选例中，化合物I-A的制备方法，包括如下步骤：化合物A与相应的硼酸在偶联的条件下，生成化合物I-A；In another preferred embodiment, the preparation method of the compound I-A includes the following steps: the compound A and the corresponding boric acid are coupled to form the compound I-A;
Figure PCTCN2018122557-appb-000132
Figure PCTCN2018122557-appb-000132
其中，W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、j、m、n、o、p、k、R 0、R 6b、R 6c、R 6e、
Figure PCTCN2018122557-appb-000133
环A和环B的定义如上所述。 Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z, j, m, n, o, p, k, R 0 , R 6b , R 6c , R 6e ,
Figure PCTCN2018122557-appb-000133
The definitions of ring A and ring B are as described above.
本发明所涉及到的惰性溶剂选自：二氯甲烷、氯仿、1,2-二氯乙烷、二氧六环、DMF、乙腈、DMSO、NMP、THF或其组合。The inert solvent to which the present invention relates is selected from the group consisting of dichloromethane, chloroform, 1,2-dichloroethane, dioxane, DMF, acetonitrile, DMSO, NMP, THF or a combination thereof.
本发明所涉及到的碱包括有机碱和/或无机碱。The base to which the present invention relates includes an organic base and/or an inorganic base.
本发明所涉及到的有机碱选自：TEA、DIPEA或其组合。The organic base to which the present invention relates is selected from the group consisting of TEA, DIPEA, or a combination thereof.
本发明所涉及到的无机碱选自：氢化钠、碳酸钾、碳酸钠、碳酸铯、叔丁醇钾、叔丁醇钠、LiHMDS、LDA、丁基锂或其组合。The inorganic base to which the present invention relates is selected from the group consisting of sodium hydride, potassium carbonate, sodium carbonate, cesium carbonate, potassium t-butoxide, sodium t-butoxide, LiHMDS, LDA, butyl lithium or a combination thereof.
本发明所述的通式(I)所示化合物的同位素标记化合物可通过与未标记化合物类似的合成方法来制备，所不同的是把未标记的起始原料和/或试剂换成同位素标记的起始原料和/或试剂。The isotopically labeled compound of the compound of the formula (I) according to the present invention can be prepared by a synthetic method similar to the unlabeled compound, except that the unlabeled starting material and/or reagent is replaced with an isotope-labeled Starting materials and/or reagents.
第四方面，本发明提供了一种药物组合物，其包含如上所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如上所述的同位素标记化合物，以及药学上可接受的辅料。所述药学上可接受的辅料可以为稀释剂、吸收剂、润湿剂、粘合剂、崩解剂和润滑剂中的一种或多种。In a fourth aspect, the present invention provides a pharmaceutical composition comprising a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt as described above , or an isotopically labeled compound as described above, and a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be one or more of a diluent, an absorbent, a wetting agent, a binder, a disintegrant, and a lubricant.
第五方面，本发明提供了一种所述的如上所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如上所述的同位素标记化合物，或如上所述的药物组合物在制备用于治疗与EED蛋白和/或PRC2蛋白复合物作用机理相关的癌症的药物中的应用。作为优选，所述癌症包括但不局限于包括扩散大B细胞淋巴癌、滤泡性淋巴瘤等淋巴癌、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、 肝癌、***癌、乳腺癌、脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、***、结肠癌、黑色素瘤、子宫内膜癌、食管癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾癌、直肠癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等等。In a fifth aspect, the present invention provides the pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate thereof, as described above, or as described above Use of the isotopically labeled compound, or a pharmaceutical composition as described above, in the manufacture of a medicament for the treatment of a cancer associated with the mechanism of action of an EED protein and/or PRC2 protein complex. Preferably, the cancer includes, but is not limited to, lymphoma including diffuse large B cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer , breast cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nose Throat cancer, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma, and the like.
本发明还提供了一种如上所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如上所述的同位素标记化合物，或如上所述的药物组合物在制备治疗癌症的药物中的应用。作为优选，所述癌症包括但不局限于包括扩散大B细胞淋巴癌、滤泡性淋巴瘤等淋巴癌、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝癌、***癌、乳腺癌、脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、***、结肠癌、黑色素瘤、子宫内膜癌、食管癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾癌、直肠癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等等。The present invention also provides a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, or an isotopically-labeled compound as described above, as described above Or the use of a pharmaceutical composition as described above for the preparation of a medicament for treating cancer. Preferably, the cancer includes, but is not limited to, lymphoma including diffuse large B-cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer , breast cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nose Throat cancer, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma, and the like.
第六方面，本发明提供了一种药物制剂，其包含如上所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如上所述的同位素标记化合物，或如上所述的药物组合物，可以合适的方式服用，比如作为片剂、胶囊(如持续释放或定时释放的胶囊)、药丸、粉末、颗粒(如小颗粒)、酏剂、酊剂、悬浮液(如纳米混悬液、微悬浮液)和喷雾干燥的分散体等形式的悬浮物、糖浆、乳液、溶液等形式，可用于口服、舌下含服、包括皮下注射、静脉注射、肌肉注射、胸骨内注射、注入等形式的注射、鼻部服用(比如鼻膜吸入)、局部表面(如乳霜和药膏)、直肠给药(如栓剂)等等方式。本发明公开的化合物可以单独服用也可以与适当的药物载体一起服用。In a sixth aspect, the present invention provides a pharmaceutical preparation comprising a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, as described above, Or an isotopically-labeled compound as described above, or a pharmaceutical composition as described above, may be administered in a suitable manner, such as as a tablet, a capsule (such as a sustained release or timed release capsule), a pill, a powder, a granule (such as a small granule). In the form of suspensions, syrups, emulsions, solutions, etc. in the form of elixirs, elixirs, elixirs, suspensions (such as nanosuspensions, microsuspensions), spray-dried dispersions, etc., for oral, sublingual, including Injections in the form of subcutaneous injections, intravenous injections, intramuscular injections, intrasternal injections, injections, nasal administration (such as nasal inhalation), topical surfaces (such as creams and ointments), rectal administration (such as suppositories), and the like. The compounds disclosed herein may be administered alone or together with a suitable pharmaceutical carrier.
第七方面，本发明提供了第六方面所述的药物制剂可配方成适当的药物剂量以方便并控制药物的服用量。本发明公开的化合物的剂量方案根据具体的因素有所不同，比如药效学及服用的方式、服用对象、性别、年龄、健康状况以及服药对象的体重、病情特征、其它同时服药状况、服药的频率、肝肾功能以及想达到的效果等等。本发明公开的化合物可以每天单剂量的服用，也可以总剂量分多次服用(比如每天两至四次)。In a seventh aspect, the present invention provides the pharmaceutical preparation of the sixth aspect which can be formulated into an appropriate pharmaceutical dosage to facilitate and control the dosage of the medicament. The dosage regimen of the compounds disclosed herein varies according to specific factors, such as pharmacodynamics and manner of administration, subject, sex, age, health status, weight of the subject, condition, other concurrent medication, medication Frequency, liver and kidney function, and the effect you want to achieve. The compounds disclosed herein may be administered in a single dose per day or in multiple doses (e.g., two to four times per day).
第八方面，本发明提供了如上所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如上所述的同位素标记化合物，或如上所述的药物组合物与其他药物联合使用，所述其他药物选自：抗癌药、肿瘤免疫药物、抗过敏药、止吐药、镇痛药、细胞保护药物等等，一起联用具有更好的效果。In an eighth aspect, the present invention provides a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, or an isotopic label as described above, as described above a compound, or a pharmaceutical composition as described above, for use in combination with other drugs selected from the group consisting of: anticancer drugs, tumor immunopharmaceuticals, antiallergic agents, antiemetics, analgesics, cytoprotective drugs, etc., together The combination has a better effect.
第九方面，本发明提供了一种治疗癌症的方法，其包括向需要此治疗的患者给予治疗有效量的如上所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如上所述的同位素标记化合物，或如上所述的药物组合物。所述 的癌症包括但不局限于包括扩散大B细胞淋巴癌、滤泡性淋巴瘤等淋巴癌、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝癌、***癌、乳腺癌、脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、***、结肠癌、黑色素瘤、子宫内膜癌、食管癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾癌、直肠癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等等。In a ninth aspect, the present invention provides a method of treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a pyrimidinone compound as shown in formula (I) as described above, which is pharmaceutically acceptable a salt or a solvate thereof, or a solvate of the salt, or an isotopically-labeled compound as described above, or a pharmaceutical composition as described above. The cancer includes, but is not limited to, lymphoma including diffuse large B cell lymphoma, follicular lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast. Cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal carcinoma , ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma.
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。It is to be understood that within the scope of the present invention, the various technical features of the present invention and the various technical features specifically described hereinafter (as in the embodiments) may be combined with each other to constitute a new or preferred technical solution. Due to space limitations, we will not repeat them here.
术语说明Terminology
除非另外定义，否则本文中所用的全部技术与科学术语均具有如本发明所属领域的普通技术人员通常理解的相同含义。All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs, unless otherwise defined.
如本文所用，在提到具体列举的数值中使用时，术语“约”意指该值可以从列举的值变动不多于1％。例如，如本文所用，表述“约100”包括99和101和之间的全部值(例如，99.1、99.2、99.3、99.4等)。As used herein, when used in reference to a particular recited value, the term "about" means that the value can vary by no more than 1% from the recited value. For example, as used herein, the expression "about 100" includes all values between 99 and 101 and (eg, 99.1, 99.2, 99.3, 99.4, etc.).
如本文所用，术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…构成”、或“由…构成”。As used herein, the terms "containing" or "including" may be open, semi-closed, and closed. In other words, the terms also include "consisting essentially of," or "consisting of."
基团定义Group definition
可在参考文献(包括Carey and Sundberg"ADVANCED ORGANIC CHEMISTRY 4TH ED."Vols.A(2000)and B(2001),Plenum Press,New York)中找到对标准化学术语的定义。除非另有说明，否则采用本领域技术范围内的常规方法，如质谱、NMR、IR和UV/VIS光谱法和药理学方法。除非提出具体定义，否则本文在分析化学、有机合成化学以及药物和药物化学的有关描述中采用的术语是本领域已知的。可在化学合成、化学分析、药物制备、制剂和递送，以及对患者的治疗中使用标准技术。例如，可利用厂商对试剂盒的使用说明，或者按照本领域公知的方式或本发明的说明来实施反应和进行纯化。通常可根据本说明书中引用和讨论的多个概要性和较具体的文献中的描述，按照本领域熟知的常规方法实施上述技术和方法。在本说明书中，可由本领域技术人员选择基团及其取代基以提供稳定的结构部分和化合物。The definition of standard chemical terms can be found in references (including Carey and Sundberg "ADVANCED ORGANIC CHEMISTRY 4TH ED." Vols. A (2000) and B (2001), Plenum Press, New York. Conventional methods within the skill of the art, such as mass spectrometry, NMR, IR and UV/VIS spectroscopy and pharmacological methods, are employed unless otherwise indicated. Unless specifically defined, the terms used herein in the descriptions of analytical chemistry, organic synthetic chemistry, and pharmaceutical and pharmaceutical chemistry are known in the art. Standard techniques can be used in chemical synthesis, chemical analysis, pharmaceutical preparation, formulation and delivery, and treatment of patients. For example, the reaction can be carried out and purified using the manufacturer's instructions for use of the kit, or in a manner well known in the art or as described in the present invention. The above techniques and methods can generally be carried out according to conventional methods well known in the art, as described in the various summaries and more specific references cited and discussed in this specification. In the present specification, the group and its substituents can be selected by those skilled in the art to provide stable structural moieties and compounds.
当通过从左向右书写的常规化学式描述取代基时，该取代基也同样包括从右向左书写结构式时所得到的在化学上等同的取代基。举例而言，-CH 2O-等同于-OCH 2-。 When a substituent is described by a conventional chemical formula written from left to right, the substituent also includes the chemically equivalent substituent obtained when the structural formula is written from right to left. For example, -CH 2 O- is equivalent to -OCH 2 -.
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。本申请中引用的所有文献或文献部分包括但不限于专利、专利申请、文章、书籍、操作手 册和论文，均通过引用方式整体并入本文。The section headings used herein are for the purpose of organizing articles only and are not to be construed as limiting the subject matter. All documents or parts of the literature cited in this application, including but not limited to patents, patent applications, articles, books, operating manuals, and papers, are hereby incorporated by reference in their entirety.
在本文中定义的某些化学基团前面通过简化符号来表示该基团中存在的碳原子总数。例如，C 1-6烷基是指具有总共1至6个(如1、2、3、4、5或6个)碳原子的如下文所定义的烷基。简化符号中的碳原子总数不包括可能存在于所述基团的取代基中的碳。 Certain chemical groups defined herein are preceded by a simplified symbol to indicate the total number of carbon atoms present in the group. For example, C1-6 alkyl refers to an alkyl group as defined below having a total of from 1 to 6 (e.g., 1, 2, 3, 4, 5 or 6) carbon atoms. The total number of carbon atoms in the simplified symbol does not include carbon that may be present in the substituents of the group.
除前述以外，当用于本申请的说明书及权利要求书中时，除非另外特别指明，否则以下术语具有如下所示的含义。In addition to the foregoing, when used in the specification and claims of the present application, the following terms have the meanings indicated below unless otherwise specifically indicated.
在本申请中，术语“卤素”是指氟、氯、溴或碘。In the present application, the term "halogen" means fluoro, chloro, bromo or iodo.
“羟基”是指-OH基团。"Hydroxy" means an -OH group.
“羟基烷基”是指被羟基(-OH)取代的如下文所定义的烷基。"Hydroxyalkyl" means an alkyl group as defined below which is substituted by a hydroxy group (-OH).
“羰基”是指-C(＝O)-基团。当
Figure PCTCN2018122557-appb-000134
中的R为羰基时，
Figure PCTCN2018122557-appb-000135
为
Figure PCTCN2018122557-appb-000136
"Carbonyl" means a -C(=O)- group. when
Figure PCTCN2018122557-appb-000134
When R in the carbonyl group,
Figure PCTCN2018122557-appb-000135
for
Figure PCTCN2018122557-appb-000136
“氰基”是指-CN。"Cyano" means -CN.
“氨基”是指-NH 2。 "Amino" means -NH 2 .
“酯基”是指
Figure PCTCN2018122557-appb-000137
R可以为烷基、烯基、芳基、杂芳基、环烷基、环烯基、芳基烷基或杂芳基烷基等。 "Ester group" means
Figure PCTCN2018122557-appb-000137
R may be an alkyl group, an alkenyl group, an aryl group, a heteroaryl group, a cycloalkyl group, a cycloalkenyl group, an arylalkyl group or a heteroarylalkyl group.
“酰胺”是指
Figure PCTCN2018122557-appb-000138
每个R可以独立地为氢、烷基、烯基、芳基、杂芳基、环烷基、环烯基、芳基烷基或杂芳基烷基等。 "Amide" means
Figure PCTCN2018122557-appb-000138
Each R may independently be hydrogen, alkyl, alkenyl, aryl, heteroaryl, cycloalkyl, cycloalkenyl, arylalkyl or heteroarylalkyl, and the like.
“取代的氨基”是指被一个或两个各自独立的如下文所定义的烷基、烷基羰基、芳烷基、杂芳烷基取代的氨基，例如，单烷基氨基、二烷基氨基、烷基酰氨基、芳烷基氨基、杂芳烷基氨基。"Substituted amino" means an amino group substituted with one or two independent alkyl, alkylcarbonyl, aralkyl, heteroaralkyl groups as defined below, for example, monoalkylamino, dialkylamino , alkyl amido, aralkylamino, heteroarylalkylamino.
“羧基”是指-COOH。"Carboxyl" means -COOH.
在本申请中，作为基团或是其它基团的一部分(例如用在卤素取代的烷基等基团中)，术语“烷基”是指完全饱和的直链或支链的烃链基，仅由碳原子和氢原子组成、具有例如1至12个(优选为1至8个，更优选为1至6个，更优选为1至4个)碳原子，且通过单键与分子的其余部分连接，例如包括但不限于甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、2-甲基丁基、2,2-二甲基丙基、正己基、庚基、2-甲基己基、3-甲基己基、辛基、壬基和癸基等。In the present application, as a group or part of another group (for example, in a group such as a halogen-substituted alkyl group), the term "alkyl" means a fully saturated straight or branched hydrocarbon chain group, It consists only of carbon atoms and hydrogen atoms, has, for example, 1 to 12 (preferably 1 to 8, more preferably 1 to 6, more preferably 1 to 4) carbon atoms, and passes through a single bond with the rest of the molecule Partial linkages, including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, 2-methylbutyl, 2 , 2-dimethylpropyl, n-hexyl, heptyl, 2-methylhexyl, 3-methylhexyl, octyl, decyl and decyl.
在本申请中，作为基团或是其它基团的一部分，术语“卤代烷基”是指烷基(如本发明中所定义)中的一个或多个氢原子被卤素(如本发明中所定义)所取代，卤素的个数可以为一个或多个；当卤素的个数为多个时，卤素相同或不同。例如，氟代烷基是指烷基被一 个或多个氟取代。卤代烷基的例子包括但不限于三氟甲基和二氟甲基。In the present application, the term "haloalkyl" as a group or part of another group means that one or more hydrogen atoms in the alkyl group (as defined in the present invention) are halogen (as defined in the present invention) The number of halogens may be one or more; when the number of halogens is plural, the halogens are the same or different. For example, fluoroalkyl means that the alkyl group is substituted by one or more fluorines. Examples of haloalkyl groups include, but are not limited to, trifluoromethyl and difluoromethyl.
在本申请中，作为基团或是其它基团的一部分，术语“烯基”意指仅由碳原子和氢原子组成、含有至少一个双键、具有例如2至14个(优选为2至10个，更优选为2至6个，更优选为2至4个)碳原子且通过单键与分子的其余部分连接的直链或支链的烃链基团，例如但不限于乙烯基、丙烯基、烯丙基、丁-1-烯基、丁-2-烯基、戊-1-烯基、戊-1,4-二烯基等。In the present application, the term "alkenyl" as a group or part of another group means consisting only of carbon atoms and hydrogen atoms, containing at least one double bond, having, for example, 2 to 14 (preferably 2 to 10) More preferably, from 2 to 6, more preferably from 2 to 4, carbon atoms and a straight or branched hydrocarbon chain group attached to the remainder of the molecule by a single bond, such as, but not limited to, vinyl, propylene Alkyl group, allyl group, but-1-enyl group, but-2-enyl group, penten-1-alkenyl group, pentane-1,4-dienyl group and the like.
在本申请中，作为基团或是其它基团的一部分，术语“环烃基”意指仅由碳原子和氢原子组成的稳定的非芳香族单环或多环烃基，其可包括稠合环体系、桥环体系或螺环体系，具有3至15个碳原子，优选具有3至10个碳原子，更优选具有3至8个碳原子，且其为饱和或不饱和并可经由任何适宜的碳原子通过单键与分子的其余部分连接。除非本说明书中另外特别指明，环烃基中的碳原子可以任选地被氧化。环烃基的实例包括但不限于环丙基、环丁基、环戊基、环戊烯基、环己基、环己烯基、环己二烯基、环庚基、环辛基、1H-茚基、2,3-二氢化茚基、1,2,3,4-四氢-萘基、5,6,7,8-四氢-萘基、8,9-二氢-7H-苯并环庚烯-6-基、6,7,8,9-四氢-5H-苯并环庚烯基、5,6,7,8,9,10-六氢-苯并环辛烯基、芴基、二环[2.2.1]庚基、7,7-二甲基-二环[2.2.1]庚基、二环[2.2.1]庚烯基、二环[2.2.2]辛基、二环[3.1.1]庚基、二环[3.2.1]辛基、二环[2.2.2]辛烯基、二环[3.2.1]辛烯基、金刚烷基、八氢-4,7-亚甲基-1H-茚基和八氢-2,5-亚甲基-并环戊二烯基等。In the present application, the term "cycloalkyl" as a group or part of another group means a stable non-aromatic monocyclic or polycyclic hydrocarbon group consisting solely of carbon atoms and hydrogen atoms, which may include a fused ring. a system, a bridged ring system or a spiro ring system having from 3 to 15 carbon atoms, preferably from 3 to 10 carbon atoms, more preferably from 3 to 8 carbon atoms, and which is saturated or unsaturated and may be via any suitable The carbon atom is attached to the rest of the molecule by a single bond. Unless otherwise specifically indicated in the specification, a carbon atom in a cyclic hydrocarbon group may be optionally oxidized. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cyclooctyl, 1H-indole Base, 2,3-indanyl, 1,2,3,4-tetrahydro-naphthyl, 5,6,7,8-tetrahydro-naphthyl, 8,9-dihydro-7H-benzo Cycloheptene-6-yl, 6,7,8,9-tetrahydro-5H-benzocycloheptenyl, 5,6,7,8,9,10-hexahydro-benzocyclooctenyl, Indenyl, bicyclo[2.2.1]heptyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl, bicyclo[2.2.1]heptenyl, bicyclo[2.2.2]octyl Base, bicyclo [3.1.1] heptyl, bicyclo [3.2.1] octyl, bicyclo [2.2.2] octenyl, bicyclo [3.2.1] octenyl, adamantyl, octahydro -4,7-Methylene-1H-indenyl and octahydro-2,5-methylene-cyclopentadienyl and the like.
在本申请中，作为基团或是其它基团的一部分，术语“环烷基”意指饱和的环烃基。In the present application, the term "cycloalkyl" as a group or part of another group means a saturated cyclic hydrocarbon group.
在本申请中，作为基团或是其它基团的一部分，术语“环烯基”意指具有至少一个双键(如碳碳双键)的环烃基。环烯基可以通过其中的双键的原子与分子的其余部分连接。In the present application, the term "cycloalkenyl" as a group or part of another group means a cyclic hydrocarbon group having at least one double bond (such as a carbon-carbon double bond). The cycloalkenyl group may be attached to the remainder of the molecule through the atoms of the double bond therein.
在本申请中，作为基团或是其它基团的一部分，术语“杂环基”意指由2至14个碳原子以及1至6个选自氮、磷、氧和硫的杂原子组成的稳定的3元至20元非芳香族环状基团。除非本说明书中另外特别指明，否则杂环基可以为单环、双环、三环或更多环的环体系，其可包括稠合环体系、桥环体系或螺环体系；其杂环基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化；且杂环基可为部分或完全饱和。杂环基可以经由碳原子或者杂原子并通过单键与分子其余部分连接。在包含稠环的杂环基中，一个或多个环可以是下文所定义的芳基或杂芳基，条件是与分子其余部分的连接点为非芳香族环原子。就本发明的目的而言，杂环基优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至11元非芳香性单环、双环、桥环或螺环基团，更优选为包含1至3个选自氮、氧和硫的杂原子的稳定的4元至8元非芳香性单环、双环、桥环或螺环基团。杂环基的实例包括但不限于：吡咯烷基、吗啉基、哌嗪基、高哌嗪基、哌啶基、硫代吗啉基、2,7- 二氮杂-螺[3.5]壬烷-7-基、2-氧杂-6-氮杂-螺[3.3]庚烷-6-基、2,5-二氮杂-双环[2.2.1]庚烷-2-基、氮杂环丁烷基、吡喃基、四氢吡喃基、噻喃基、四氢呋喃基、噁嗪基、二氧环戊基、四氢异喹啉基、十氢异喹啉基、咪唑啉基、咪唑烷基、喹嗪基、噻唑烷基、异噻唑烷基、异噁唑烷基、二氢吲哚基、八氢吲哚基、八氢异吲哚基、吡咯烷基、吡唑烷基、邻苯二甲酰亚氨基等。In the present application, the term "heterocyclyl" as a group or part of another group means consisting of 2 to 14 carbon atoms and 1 to 6 heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. A stable 3- to 20-membered non-aromatic cyclic group. Unless otherwise specified in the specification, a heterocyclic group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, which may include a fused ring system, a bridged ring system or a spiro ring system; The nitrogen, carbon or sulfur atom may optionally be oxidized; the nitrogen atom may optionally be quaternized; and the heterocyclic group may be partially or fully saturated. The heterocyclic group may be attached to the remainder of the molecule via a carbon atom or a hetero atom and through a single bond. In the heterocyclic group containing a fused ring, one or more of the rings may be an aryl or heteroaryl group as defined hereinafter, provided that the point of attachment to the rest of the molecule is a non-aromatic ring atom. For the purposes of the present invention, the heterocyclic group is preferably a stable 4 to 11 membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. More preferably, it is a stable 4- to 8-membered non-aromatic monocyclic, bicyclic, bridged or spiro group containing from 1 to 3 heteroatoms selected from nitrogen, oxygen and sulfur. Examples of heterocyclic groups include, but are not limited to, pyrrolidinyl, morpholinyl, piperazinyl, homopiperazinyl, piperidinyl, thiomorpholinyl, 2,7-diaza-spiro[3.5]fluorene. Alkan-7-yl, 2-oxa-6-aza-spiro[3.3]heptane-6-yl, 2,5-diaza-bicyclo[2.2.1]heptan-2-yl, aza Cyclobutane, pyranyl, tetrahydropyranyl, thiopyranyl, tetrahydrofuranyl, oxazinyl, dioxocyclopentyl, tetrahydroisoquinolinyl, decahydroisoquinolinyl, imidazolinyl, Imidazolidinyl, quinazolinyl, thiazolidinyl, isothiazolidinyl, isoxazolidinyl, indanyl, octahydroindenyl, octahydroisodecyl, pyrrolidinyl, pyrazolidinyl , phthalimido and the like.
在本申请中，作为基团或是其它基团的一部分，术语“杂环烯基”意指具有至少一个双键(如碳碳双键)的杂环基。杂环烯基可以通过其中的双键的原子与分子的其余部分连接。In the present application, the term "heterocyclenyl" as a group or part of another group means a heterocyclic group having at least one double bond (such as a carbon-carbon double bond). The heterocyclenyl group may be attached to the remainder of the molecule through the atoms of the double bond therein.
在本申请中，作为基团或是其它基团的一部分，术语“芳基”意指具有6至18个碳原子(优选具有6至10个碳原子)的共轭烃环体系基团。就本发明的目的而言，芳基可以为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是芳基经由芳香环上的原子通过单键与分子的其余部分连接。芳基的实例包括但不限于苯基、萘基、蒽基、菲基、芴基、2,3-二氢-1H-异吲哚基、2-苯并噁唑啉酮、2H-1,4-苯并噁嗪-3(4H)-酮-7-基等。In the present application, the term "aryl" as a group or part of another group means a conjugated hydrocarbon ring system group having 6 to 18 carbon atoms, preferably having 6 to 10 carbon atoms. For the purposes of the present invention, an aryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that the aryl group is via The atoms on the aromatic ring are connected to the rest of the molecule by a single bond. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, phenanthryl, anthracenyl, 2,3-dihydro-1H-isoindolyl, 2-benzoxazolinone, 2H-1, 4-benzoxazine-3(4H)-one-7-yl and the like.
在本申请中，术语“芳基烷基”是指被上文所定义的芳基所取代的上文所定义的烷基。In the present application, the term "arylalkyl" refers to an alkyl group as defined above substituted with an aryl group as defined above.
在本申请中，作为基团或是其它基团的一部分，术语“杂芳基”意指环内具有1至15个碳原子(优选具有1至10个碳原子)和1至6个选自氮、氧和硫的杂原子的5元至16元共轭环系基团。除非本说明书中另外特别指明，否则杂芳基可为单环、双环、三环或更多环的环体系，还可以与上文所定义的环烷基或杂环基稠合，条件是杂芳基经由芳香环上的原子通过单键与分子的其余部分连接。杂芳基中的氮、碳或硫原子可任选地被氧化；氮原子可任选地被季铵化。就本发明的目的而言，杂芳基优选为包含1至5个选自氮、氧和硫的杂原子的稳定的5元至12元芳香性基团，更优选为包含1至4个选自氮、氧和硫的杂原子的稳定的5元至10元芳香性基团或者包含1至3个选自氮、氧和硫的杂原子的5元至6元芳香性基团。杂芳基的实例包括但不限于噻吩基、咪唑基、吡唑基、噻唑基、噁唑基、噁二唑基、异噁唑基、吡啶基、嘧啶基、吡嗪基、哒嗪基、苯并咪唑基、苯并吡唑基、吲哚基、呋喃基、吡咯基、***基、四唑基、三嗪基、吲嗪基、异吲哚基、吲唑基、异吲唑基、嘌呤基、喹啉基、异喹啉基、二氮萘基、萘啶基、喹噁啉基、蝶啶基、咔唑基、咔啉基、菲啶基、菲咯啉基、吖啶基、吩嗪基、异噻唑基、苯并噻唑基、苯并噻吩基、噁***基、噌啉基、喹唑啉基、苯硫基、中氮茚基、邻二氮杂菲基、异噁唑基、吩噁嗪基、吩噻嗪基、4,5,6,7-四氢苯并[b]噻吩基、萘并吡啶基、[1,2,4]***并[4,3-b]哒嗪、[1,2,4]***并[4,3-a]吡嗪、[1,2,4]***并[4,3-c]嘧啶、[1,2,4]***并[4,3-a]吡啶、咪唑并[1,2- a]吡啶、咪唑并[1,2-b]哒嗪、咪唑并[1,2-a]吡嗪等。In the present application, the term "heteroaryl" as a group or part of another group means having from 1 to 15 carbon atoms (preferably having from 1 to 10 carbon atoms) and from 1 to 6 selected from nitrogen in the ring. a 5- to 16-membered conjugated ring system of a hetero atom of oxygen and sulfur. Unless otherwise specifically indicated in the specification, a heteroaryl group may be a monocyclic, bicyclic, tricyclic or more cyclic ring system, and may also be fused to a cycloalkyl or heterocyclic group as defined above, provided that The aryl group is attached to the remainder of the molecule via a single bond through an atom on the aromatic ring. The nitrogen, carbon or sulfur atom in the heteroaryl group can be optionally oxidized; the nitrogen atom can optionally be quaternized. For the purposes of the present invention, the heteroaryl group is preferably a stable 5- to 12-membered aromatic group containing from 1 to 5 heteroatoms selected from nitrogen, oxygen and sulfur, more preferably from 1 to 4 selected A stable 5- to 10-membered aromatic group derived from a hetero atom of nitrogen, oxygen, and sulfur or a 5- to 6-membered aromatic group containing 1 to 3 hetero atoms selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, but are not limited to, thienyl, imidazolyl, pyrazolyl, thiazolyl, oxazolyl, oxadiazolyl, isoxazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, Benzimidazolyl, benzopyrazolyl, fluorenyl, furyl, pyrrolyl, triazolyl, tetrazolyl, triazinyl, pyridazinyl, isodecyl, oxazolyl, isoxazolyl , fluorenyl, quinolyl, isoquinolyl, diaza naphthyl, naphthyridinyl, quinoxalinyl, pteridinyl, oxazolyl, porphyrin, phenanthryl, phenanthroline, acridine Base, phenazinyl, isothiazolyl, benzothiazolyl, benzothienyl, oxatriazole, porphyrin, quinazolinyl, phenylthio, guanidinium, phenanthroline, Isoxazolyl, phenoxazinyl, phenothiazine, 4,5,6,7-tetrahydrobenzo[b]thienyl, naphthopyridyl, [1,2,4]triazolo[4 , 3-b]pyridazine, [1,2,4]triazolo[4,3-a]pyrazine, [1,2,4]triazolo[4,3-c]pyrimidine, [1, 2,4]triazolo[4,3-a]pyridine, imidazo[1,2- a]pyridine, imidazo[1,2-b]pyridazine, imidazo[1,2-a]pyrazine Wait.
在本申请中，术语“杂芳基烷基”是指被上文所定义的杂芳基所取代的上文所定义的烷基。In the present application, the term "heteroarylalkyl" refers to an alkyl group as defined above which is substituted by a heteroaryl group as defined above.
在本申请中，“任选地”或“任选地”表示随后描述的事件或状况可能发生也可能不发生，且该描述同时包括该事件或状况发生和不发生的情况。例如，“任选地被取代的芳基”表示芳基被取代或未被取代，且该描述同时包括被取代的芳基与未被取代的芳基。本发明权利要求书和说明书部分所述的“任选地”的取代基选自烷基、烯基、炔基、卤素、卤代烷基、卤代烯基、卤代炔基、氰基、硝基、任选取代的芳基、任选取代的杂芳基、任选取代的环烃基、任选取代的杂环烃基。In the present application, "optionally" or "optionally" means that the subsequently described event or condition may or may not occur, and that the description includes both the occurrence and non-occurrence of the event or condition. For example, "optionally substituted aryl" means that the aryl group is substituted or unsubstituted, and the description includes both the substituted aryl group and the unsubstituted aryl group. The "optionally" substituents described in the claims and the specification of the present invention are selected from the group consisting of alkyl, alkenyl, alkynyl, halogen, haloalkyl, haloalkenyl, haloalkynyl, cyano, nitro An optionally substituted aryl group, an optionally substituted heteroaryl group, an optionally substituted cycloalkyl group, an optionally substituted heterocyclic hydrocarbon group.
在本发明中，术语“取代”或“取代基”是指一个或多个氢原子被指定的基团所代替。当没有指明取代基的个数时，取代基可以为一个或多个；当没有指明取代位置时，取代可以在任何位置，但是只有形成一个稳定的或者是化学意义上可行的化学物才是被允许的。In the present invention, the term "substituted" or "substituent" means that one or more hydrogen atoms are replaced by a designated group. When the number of substituents is not indicated, the substituent may be one or more; when no substitution position is indicated, the substitution may be at any position, but only a stable or chemically feasible chemical is formed. Allowed.
当任何变量(例如R)在化合物的组成或结构中出现一次以上时，其在每一种情况下的定义都是独立的。因此，例如，如果一个基团被0-2个R所取代，则所述基团可以任选地至多被两个R所取代，并且每种情况下的R都有独立的选项。例如，在
Figure PCTCN2018122557-appb-000139
中，当n为2时，表示苯环被2个R取代，并且每个R都有独立的选项，即2个R可以相同，也可以不同。此外，取代基和/或其变体的组合只有在这样的组合会产生稳定的化合物的情况下才是被允许的。 When any variable (eg, R) occurs more than once in the composition or structure of a compound, its definition in each case is independent. Thus, for example, if a group is substituted with 0-2 R, the group may optionally be substituted with at most two R, and each case has an independent option. For example, in
Figure PCTCN2018122557-appb-000139
In the case where n is 2, it means that the benzene ring is substituted by 2 R, and each R has an independent option, that is, 2 Rs may be the same or different. Furthermore, combinations of substituents and/or variants thereof are permissible only if such combinations result in stable compounds.
本文所用术语“部分”、“结构部分”、“化学部分”、“基团”、“化学基团”是指分子中的特定片段或官能团。化学部分通常被认为是嵌入或附加到分子上的化学实体。The terms "part," "structural moiety," "chemical moiety," "group," and "chemical group", as used herein, refer to a particular fragment or functional group in a molecule. A chemical moiety is generally considered to be a chemical entity that is embedded or attached to a molecule.
当本发明的化合物中含有烯双键时，除非另有说明，否则本发明的化合物旨在包含E-和Z-几何异构体。When the compound of the present invention contains an olefinic double bond, the compounds of the present invention are intended to include E- and Z-geometric isomers unless otherwise stated.
“互变异构体”是指质子从分子的一个原子转移至相同分子的另一个原子而形成的异构体。本发明的化合物的所有互变异构形式也将包含在本发明的范围内。"Tautomer" refers to an isomer formed by the transfer of a proton from one atom of a molecule to another atom of the same molecule. All tautomeric forms of the compounds of the invention will also be embraced within the scope of the invention.
本发明的化合物或其药学上可接受的盐可能含有一个或多个手性碳原子，且因此可产生对映异构体、非对映异构体及其它立体异构形式。每个手性碳原子可以基于立体化学而被定义为(R)-或(S)-。本发明旨在包括所有可能的异构体，以及其外消旋体和光学纯形式。本发明的化合物的制备可以选择外消旋体、非对映异构体或对映异构体作为原料或中间体。光学活性的异构体可以使用手性合成子或手性试剂来制备，或者使用常规技术进行拆分，例如采用结晶以及手性色谱等方法。The compounds of the invention, or pharmaceutically acceptable salts thereof, may contain one or more chiral carbon atoms, and thus may give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral carbon atom can be defined as (R)- or (S)- based on stereochemistry. The invention is intended to include all possible isomers, as well as racemic and optically pure forms thereof. The preparation of the compounds of the invention may employ racemates, diastereomers or enantiomers as starting materials or intermediates. Optically active isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, such as by crystallization and chiral chromatography.
制备/分离个别异构体的常规技术包括由合适的光学纯前体的手性合成，或者使用例 如手性高效液相色谱法拆分外消旋体(或盐或衍生物的外消旋体)，例如可参见Gerald Gübitz and Martin G.Schmid(Eds.),Chiral Separations,Methods and Protocols,Methods in Molecular Biology,Vol.243,2004；A.M.Stalcup,Chiral Separations,Annu.Rev.Anal.Chem.3:341-63,2010；Fumiss et al.(eds.),VOGEL’S ENCYCLOPEDIAOF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED.,Longman Scientific and Technical Ltd.,Essex,1991,809-816；Heller,Acc.Chem.Res.1990,23,128。Conventional techniques for the preparation/isolation of individual isomers include chiral synthesis from a suitable optically pure precursor, or resolution of the racemate (or racemic form of a salt or derivative) using, for example, chiral high performance liquid chromatography. For example, see Gerald Gübitz and Martin G. Schmid (Eds.), Chiral Separations, Methods and Protocols, Methods in Molecular Biology, Vol. 243, 2004; AMStalcup, Chiral Separations, Annu. Rev. Anal. : 341-63, 2010; Fumiss et al. (eds.), VOGEL'S ENCYCLOPEDIAOF PRACTICAL ORGANIC CHEMISTRY 5.sup.TH ED., Longman Scientific and Technical Ltd., Essex, 1991, 809-816; Heller, Acc. Res. 1990, 23, 128.
在本申请中，术语“药学上可接受的盐”包括药学上可接受的酸加成盐和药学上可接受的碱加成盐。In the present application, the term "pharmaceutically acceptable salt" includes pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts.
“药学上可接受的酸加成盐”是指能够保留游离碱的生物有效性而无其它副作用的，与无机酸或有机酸所形成的盐。无机酸盐包括但不限于盐酸盐、氢溴酸盐、硫酸盐、硝酸盐、磷酸盐等；有机酸盐包括但不限于甲酸盐、乙酸盐、2,2-二氯乙酸盐、三氟乙酸盐、丙酸盐、己酸盐、辛酸盐、癸酸盐、十一碳烯酸盐、乙醇酸盐、葡糖酸盐、乳酸盐、癸二酸盐、己二酸盐、戊二酸盐、丙二酸盐、草酸盐、马来酸盐、琥珀酸盐、富马酸盐、酒石酸盐、柠檬酸盐、棕榈酸盐、硬脂酸盐、油酸盐、肉桂酸盐、月桂酸盐、苹果酸盐、谷氨酸盐、焦谷氨酸盐、天冬氨酸盐、苯甲酸盐、甲磺酸盐、苯磺酸盐、对甲苯磺酸盐、海藻酸盐、抗坏血酸盐、水杨酸盐、4-氨基水杨酸盐、萘二磺酸盐等。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable acid addition salt" means a salt formed with an inorganic or organic acid which retains the bioavailability of the free base without any other side effects. Inorganic acid salts include, but are not limited to, hydrochlorides, hydrobromides, sulfates, nitrates, phosphates, and the like; organic acid salts include, but are not limited to, formate, acetate, 2,2-dichloroacetate , trifluoroacetate, propionate, hexanoate, octoate, decanoate, undecylenate, glycolate, gluconate, lactate, sebacate, hexane Acid salt, glutarate, malonate, oxalate, maleate, succinate, fumarate, tartrate, citrate, palmitate, stearate, oleate , cinnamate, laurate, malate, glutamate, pyroglutamate, aspartate, benzoate, methanesulfonate, besylate, p-toluenesulfonate , alginate, ascorbate, salicylate, 4-aminosalicylate, naphthalene disulfonate, and the like. These salts can be prepared by methods known in the art.
“药学上可接受的碱加成盐”是指能够保持游离酸的生物有效性而无其它副作用的、与无机碱或有机碱所形成的盐。衍生自无机碱的盐包括但不限于钠盐、钾盐、锂盐、铵盐、钙盐、镁盐、铁盐、锌盐、铜盐、锰盐、铝盐等。优选的无机盐为铵盐、钠盐、钾盐、钙盐及镁盐。衍生自有机碱的盐包括但不限于以下的盐：伯胺类、仲胺类及叔胺类，被取代的胺类，包括天然的被取代胺类、环状胺类及碱性离子交换树脂，例如氨、异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙醇胺、三乙醇胺、二甲基乙醇胺、2-二甲氨基乙醇、2-二乙氨基乙醇、二环己胺、赖氨酸、精氨酸、组氨酸、咖啡因、普鲁卡因、胆碱、甜菜碱、乙二胺、葡萄糖胺、甲基葡萄糖胺、可可碱、嘌呤、哌嗪、哌啶、N-乙基哌啶、聚胺树脂等。优选的有机碱包括异丙胺、二乙胺、乙醇胺、三甲胺、二环己基胺、胆碱及咖啡因。这些盐可通过本专业已知的方法制备。"Pharmaceutically acceptable base addition salt" refers to a salt formed with an inorganic or organic base which is capable of retaining the biological effectiveness of the free acid without other side effects. Salts derived from inorganic bases include, but are not limited to, sodium salts, potassium salts, lithium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, aluminum salts, and the like. Preferred inorganic salts are ammonium, sodium, potassium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, the following salts: primary amines, secondary amines and tertiary amines, substituted amines, including naturally substituted amines, cyclic amines, and basic ion exchange resins. For example, ammonia, isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, diethanolamine, triethanolamine, dimethylethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, bicyclo Hexylamine, lysine, arginine, histidine, caffeine, procaine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, hydrazine, piperazine, piperazine Pyridine, N-ethylpiperidine, polyamine resin, and the like. Preferred organic bases include isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline, and caffeine. These salts can be prepared by methods known in the art.
在本申请中，“药物组合物”是指本发明化合物与本领域通常接受的用于将生物活性化合物输送至哺乳动物(例如人)的介质的制剂。该介质包括药学上可接受的载体。药物组合物的目的是促进生物体的给药，利于活性成分的吸收进而发挥生物活性。In the present application, "pharmaceutical composition" refers to a formulation of a compound of the invention and a medium generally accepted in the art for delivery of a biologically active compound to a mammal, such as a human. The medium includes a pharmaceutically acceptable carrier. The purpose of the pharmaceutical composition is to promote the administration of the organism, thereby facilitating the absorption of the active ingredient and thereby exerting biological activity.
本文所用术语“药学上可接受的”是指不影响本发明化合物的生物活性或性质的物质 (如载体或稀释剂)，并且相对无毒，即该物质可施用于个体而不造成不良的生物反应或以不良方式与组合物中包含的任意组分相互作用。The term "pharmaceutically acceptable" as used herein, refers to a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compound of the invention, and is relatively non-toxic, ie, the substance can be administered to an individual without causing undesirable organisms. The reaction or in an undesirable manner interacts with any of the components contained in the composition.
在本申请中，“药学上可接受的赋形剂”包括但不限于任何被相关的政府管理部门许可为可接受供人类或家畜使用的佐剂、载体、赋形剂、助流剂、增甜剂、稀释剂、防腐剂、染料/着色剂、矫味剂、表面活性剂、润湿剂、分散剂、助悬剂、稳定剂、等渗剂、溶剂或乳化剂。In the present application, "pharmaceutically acceptable excipients" include, but are not limited to, any adjuvants, carriers, excipients, glidants, supplements approved by the relevant government authorities for acceptable use by humans or domestic animals. Sweeteners, diluents, preservatives, dyes/colorants, flavoring agents, surfactants, wetting agents, dispersing agents, suspending agents, stabilizers, isotonic agents, solvents or emulsifiers.
本发明所述“肿瘤”包括但不限于脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、肉瘤、黑色素瘤、关节软骨瘤、胆管瘤、白血病、胃肠间质瘤、扩散大B细胞淋巴癌、滤泡性淋巴瘤等淋巴癌、组织细胞性淋巴瘤、非小细胞肺癌、小细胞肺癌、胰腺癌、肺鳞癌、肺腺癌、乳腺癌、***癌、肝癌、皮肤癌、上皮细胞癌、***、卵巢癌、肠癌、鼻咽癌、脑癌、骨癌、食道癌、黑色素瘤、肾癌、口腔癌、多发性骨髓瘤、间皮瘤、恶性横纹肌样瘤、子宫内膜癌、头颈癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等疾病。The "tumor" of the present invention includes, but is not limited to, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, sarcoma, melanoma, articular chondrocarcinoma, cholangiocarcinoma, leukemia, gastrointestinal Lymphoma, disseminated large B-cell lymphoma, follicular lymphoma and other lymphoma, histiocytic lymphoma, non-small cell lung cancer, small cell lung cancer, pancreatic cancer, lung squamous cell carcinoma, lung adenocarcinoma, breast cancer, prostate Cancer, liver cancer, skin cancer, epithelial cell carcinoma, cervical cancer, ovarian cancer, colon cancer, nasopharyngeal cancer, brain cancer, bone cancer, esophageal cancer, melanoma, kidney cancer, oral cancer, multiple myeloma, mesothelioma , malignant rhabdoid tumor, endometrial cancer, head and neck cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma.
本文所用术语“预防的”、“预防”和“防止”包括使病患减少疾病或病症的发生或恶化的可能性。The terms "preventing", "preventing" and "preventing" as used herein include the possibility of reducing the occurrence or progression of a disease or condition by a patient.
本文所用的术语“治疗”和其它类似的同义词包括以下含义：The term "treatment" and other similar synonyms as used herein includes the following meanings:
(i)预防疾病或病症在哺乳动物中出现，特别是当这类哺乳动物易患有该疾病或病症，但尚未被诊断为已患有该疾病或病症时；(i) preventing a disease or condition from occurring in a mammal, particularly when such a mammal is susceptible to the disease or condition, but has not been diagnosed as having the disease or condition;
(ii)抑制疾病或病症，即遏制其发展；(ii) inhibiting a disease or condition, ie, curbing its development;
(iii)缓解疾病或病症，即，使该疾病或病症的状态消退；或者(iii) alleviating the disease or condition, ie, causing the condition of the disease or condition to subside; or
(iv)减轻该疾病或病症所造成的症状。(iv) alleviating the symptoms caused by the disease or condition.
本文所使用术语“有效量”、“治疗有效量”或“药学有效量”是指服用后足以在某种程度上缓解所治疗的疾病或病症的一个或多个症状的至少一种药剂或化合物的量。其结果可以为迹象、症状或病因的消减和/或缓解，或生物***的任何其它所需变化。例如，用于治疗的“有效量”是在临床上提供显著的病症缓解效果所需的包含本文公开化合物的组合物的量。可使用诸如剂量递增试验的技术测定适合于任意个体病例中的有效量。The term "effective amount," "therapeutically effective amount," or "pharmaceutically effective amount," as used herein, refers to at least one agent or compound that, after administration, is sufficient to alleviate one or more symptoms of the disease or condition being treated to some extent. The amount. The result can be a reduction and/or alleviation of signs, symptoms or causes, or any other desired change in the biological system. For example, an "effective amount" for treatment is an amount of a composition comprising a compound disclosed herein that is required to provide a significant conditional relief effect in the clinic. An effective amount suitable for any individual case can be determined using techniques such as dose escalation testing.
本文所用术语“服用”、“施用”、“给药”等是指能够将化合物或组合物递送到进行生物作用的所需位点的方法。这些方法包括但不限于口服途径、经十二指肠途径、胃肠外注射(包括静脉内、皮下、腹膜内、肌内、动脉内注射或输注)、局部给药和经直肠给药。本领域技术人员熟知可用于本文所述化合物和方法的施用技术，例如在Goodman and Gilman,The Pharmacological Basis of Therapeutics,current ed.；Pergamon；and Remington’s, Pharmaceutical Sciences(current edition),Mack Publishing Co.,Easton,Pa中讨论的那些。在优选的实施方案中，本文讨论的化合物和组合物通过口服施用。The terms "administering," "administering," "administering," and the like, as used herein, refers to a method of delivering a compound or composition to a desired site for biological action. These methods include, but are not limited to, oral routes, duodenal routes, parenteral injections (including intravenous, subcutaneous, intraperitoneal, intramuscular, intraarterial injection or infusion), topical administration, and rectal administration. The techniques of administration of the compounds and methods described herein are well known to those skilled in the art, for example, in Goodman and Gilman, The Pharmacological Basis of Therapeutics, current ed.; Pergamon; and Remington's, Pharmaceutical Sciences (current edition), Mack Publishing Co., Easton, those discussed in Pa. In a preferred embodiment, the compounds and compositions discussed herein are administered orally.
本文所使用术语“药物组合”、“药物联用”、“联合用药”、“施用其它治疗”、“施用其它治疗剂”等是指通过混合或组合不止一种活性成分而获得的药物治疗，其包括活性成分的固定和不固定组合。术语“固定组合”是指以单个实体或单个剂型的形式向患者同时施用至少一种本文所述的化合物和至少一种协同药剂。术语“不固定组合”是指以单独实体的形式向患者同时施用、合用或以可变的间隔时间顺次施用至少一种本文所述的化合物和至少一种协同制剂。这些也应用到鸡尾酒疗法中，例如施用三种或更多种活性成分。The terms "pharmaceutical combination", "drug combination", "combination", "administering other treatments", "administering other therapeutic agents" and the like, as used herein, mean a pharmaceutical treatment obtained by mixing or combining more than one active ingredient, It includes both fixed and unfixed combinations of active ingredients. The term "fixed combination" refers to the simultaneous administration of at least one compound described herein and at least one synergistic agent to a patient in the form of a single entity or a single dosage form. The term "unfixed combination" refers to the simultaneous administration, combination or sequential administration of at least one of the compounds described herein and at least one synergistic formulation to the patient in the form of separate entities. These are also applied to cocktail therapy, for example the administration of three or more active ingredients.
本领域技术人员还应当理解，在下文所述的方法中，中间体化合物官能团可能需要由适当的保护基保护。这样的官能团包括羟基、氨基、巯基及羧酸。合适的羟基保护基包括三烷基甲硅烷基或二芳基烷基甲硅烷基(例如叔丁基二甲基甲硅烷基、叔丁基二苯基甲硅烷基或三甲基甲硅烷基)、四氢吡喃基、苄基等。合适的氨基、脒基及胍基的保护基包括叔丁氧羰基、苄氧羰基等。合适的巯基保护基包括-C(O)-R”(其中R”为烷基、芳基或芳烷基)、对甲氧基苄基、三苯甲基等。合适的羧基保护基包括烷基、芳基或芳烷基酯类。It will also be understood by those skilled in the art that in the methods described below, the intermediate compound functional groups may need to be protected by a suitable protecting group. Such functional groups include a hydroxyl group, an amino group, a thiol group, and a carboxylic acid. Suitable hydroxy protecting groups include trialkylsilyl or diarylalkylsilyl groups (e.g., tert-butyldimethylsilyl, tert-butyldiphenylsilyl or trimethylsilyl) , tetrahydropyranyl, benzyl, and the like. Suitable protecting groups for amino, mercapto and fluorenyl include t-butoxycarbonyl, benzyloxycarbonyl and the like. Suitable mercapto protecting groups include -C(O)-R" (wherein R" is alkyl, aryl or aralkyl), p-methoxybenzyl, trityl and the like. Suitable carboxy protecting groups include alkyl, aryl or aralkyl esters.
保护基可根据本领域技术人员已知的和如本文所述的标准技术来引入和除去。保护基的使用详述于Greene,T.W.与P.G.M.Wuts,Protective Groups in Organi Synthesis,(1999),4th Ed.,Wiley中。保护基还可为聚合物树脂。Protecting groups can be introduced and removed according to standard techniques known to those skilled in the art and as described herein. The use of protecting groups is described in detail in Greene, T. W. and P. G. M. Wuts, Protective Groups in Organi Synthesis, (1999), 4th Ed., Wiley. The protecting group can also be a polymeric resin.
具体实施方式Detailed ways
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。The invention is further illustrated by the following examples, which are not intended to limit the invention. The experimental methods in the following examples which do not specify the specific conditions are selected according to conventional methods and conditions, or according to the product specifications.
下述实施例中所用的起始物可由化学品销售商如Aldrich、TCI、Alfa Aesar、毕得、安耐吉等处购得，或者可通过已知的方法来合成。The starting materials used in the following examples can be purchased from chemical distributors such as Aldrich, TCI, Alfa Aesar, Bied, Angie, etc., or can be synthesized by known methods.
下述实施例中，冰浴是指-5摄氏度至0摄氏度，室温是指10摄氏度至30摄氏度，回流温度一般是指溶剂常压下溶剂回流温度。反应过夜是指时间为8-15小时。下述实施例中，未限定具体操作温度的，均在室温下进行。In the following examples, the ice bath means -5 degrees Celsius to 0 degrees Celsius, and the room temperature means 10 degrees Celsius to 30 degrees Celsius. The reflux temperature generally means the solvent reflux temperature under normal pressure of the solvent. The reaction overnight means that the time is 8-15 hours. In the following examples, the specific operating temperatures were not limited and were carried out at room temperature.
下述实施例中，中间体和最终产物的分离提纯是通过正相或反相色谱柱分离或者其它合适的方法。正相快速色谱柱是用乙酸乙酯和正己烷或甲醇和二氯甲烷等作为流动相。反相制备性高压液相色谱(HPLC)是用C18柱并用UV 214nm和254nm来检测，其流动相为A(水和0.1％甲酸)、B(乙腈)或者流动相A(水和0.1％碳酸氢铵)、B(乙腈)。In the following examples, the separation and purification of the intermediate and final product is carried out by normal phase or reverse phase chromatography column or other suitable method. The normal phase flash column uses ethyl acetate and n-hexane or methanol and dichloromethane as the mobile phase. Reversed phase preparative high pressure liquid chromatography (HPLC) was performed on a C18 column with UV 214 nm and 254 nm. The mobile phase was A (water and 0.1% formic acid), B (acetonitrile) or mobile phase A (water and 0.1% carbonic acid). Ammonium hydroxide), B (acetonitrile).
各实施例中：In each embodiment:
LCMS仪器：Pump Agilent 1260 UV检测器：Agilent 1260 DADLCMS instrument: Pump Agilent 1260 UV detector: Agilent 1260 DAD
Mass Spectrometer API 3000Mass Spectrometer API 3000
层析柱：Waters sunfire C18,4.6×50mm,5umColumn: Waters sunfire C18, 4.6×50mm, 5um
流动相：A-H 2O(0.1％HCOOH)；B-乙腈 Mobile phase: AH 2 O (0.1% HCOOH); B-acetonitrile
NMR仪器：Bruker Ascend 400M( 1H NMR:400MHz； 13C NMR:100MHz)。 NMR instrument: Bruker Ascend 400M ( 1 H NMR: 400 MHz; 13 C NMR: 100 MHz).
实施例1：中间体5-溴-2-氯-3-甲基嘧啶-4(3H)-酮(B1)Example 1: Intermediate 5-Bromo-2-chloro-3-methylpyrimidin-4(3H)-one (B1)
步骤一:5-溴-2-氯嘧啶-4(3H)-酮(B1-b)的合成Step 1: Synthesis of 5-bromo-2-chloropyrimidine-4(3H)-one (B1-b)
Figure PCTCN2018122557-appb-000140
Figure PCTCN2018122557-appb-000140
在干燥的100mL单口瓶中依次加入5-溴-2,4-二氯嘧啶B1-a(2.28g,10mmol)和30mL的四氢呋喃，在冰浴下搅拌加入2N的氢氧化钠水溶液(10mL,20mmol)。反应温度升到室温并在室温搅拌反应6小时。反应完毕后，反应液冷却到0摄氏度，使用6N盐酸溶液调节反应液的pH到3-4。用三氯甲烷(50mL×3)萃取，合并有机相,无水硫酸钠干燥，过滤，滤液减压浓缩，得到浅黄色固体产物5-溴-2-氯嘧啶-4(3H)-酮B1-b(1.8g，86％产率)。5-Bromo-2,4-dichloropyrimidine B1-a (2.28 g, 10 mmol) and 30 mL of tetrahydrofuran were sequentially added to a dry 100 mL one-necked flask, and a 2N aqueous sodium hydroxide solution (10 mL, 20 mmol) was stirred under ice-cooling. ). The reaction temperature was raised to room temperature and the reaction was stirred at room temperature for 6 hours. After completion of the reaction, the reaction solution was cooled to 0 ° C, and the pH of the reaction solution was adjusted to 3-4 using a 6N hydrochloric acid solution. The mixture was extracted with chloroform (50 mL×3). EtOAc (EtOAc m. b (1.8 g, 86% yield).
1H NMR(400MHz,DMSO):δ13.33(br s,1H),8.35(s,1H)ppm；LC-MS:m/z 208.9[M+H] +. 1 H NMR (400 MHz, DMSO): δ 13.33 (br s, 1 H), 8.35 (s, 1 H) ppm; LC-MS: m/z 208.9 [M+H] + .
步骤二:5-溴-2-氯-3-甲基嘧啶-4(3H)-酮(B1)：Step 2: 5-Bromo-2-chloro-3-methylpyrimidin-4(3H)-one (B1):
Figure PCTCN2018122557-appb-000141
Figure PCTCN2018122557-appb-000141
在干燥的100mL单口烧瓶中依次加入5-溴-2-氯嘧啶-4(3H)-酮B1-b(1.8g,8.61mmol)和N,N-二甲基甲酰胺(20mL)和DME(5mL)的混合溶剂，在0摄氏度下加入氢化锂粉末(83mg,10.33mmol)并在该温度下搅拌5分钟。然后加入碘甲烷(2.45g，17.22mmol)，60摄氏度下搅拌反应2小时。反应完毕后，使用饱和氯化铵淬灭反应，用乙酸乙酯(50mL×3)萃取。有机相依次用水(20mL×1)，饱和食盐水(20mL×1)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用柱层析法(乙酸乙酯:石油醚＝1:3)纯化得到白色固体5-溴-2-氯-3-甲基嘧啶-4(3H)-酮B1(1.3g，68％产率)。5-Bromo-2-chloropyrimidine-4(3H)-one B1-b (1.8 g, 8.61 mmol) and N,N-dimethylformamide (20 mL) and DME were sequentially added to a dry 100 mL one-neck flask. 5 mL) of a mixed solvent, lithium hydride powder (83 mg, 10.33 mmol) was added at 0 ° C and stirred at this temperature for 5 minutes. Methyl iodide (2.45 g, 17.22 mmol) was then added and the reaction was stirred at 60 ° C for 2 hours. After completion of the reaction, the reaction was quenched with EtOAc (EtOAc) The organic phase was washed successively with water (20 mL×1) and brine (20 mL×1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated. Purification by column chromatography (ethyl acetate: petroleum ether = 1 : 3) afforded 5-bromo-2-chloro-3-methylpyrimidine-4(3H)-one B1 (1.3 g, 68% yield ).
1H NMR(400MHz,DMSO-d6):δ8.17(s,1H),3.28(s,3H)ppm. 1 H NMR (400 MHz, DMSO-d6): δ 8.17 (s, 1H), 3.28 (s, 3H) ppm.
使用实施例1的方法，用中间体B1-b分别和碘乙烷、烯丙基溴及氘代碘甲烷反应可相应得到B2、B3和B5；用5-溴-2,4-二氯-6-甲基嘧啶为起始原料可以得到中间体B4；用5-碘-2,4-二氯嘧啶和5-氟-2,4-二氯嘧啶为起始原料可以相应地得到中间体B6和B7。Using the method of Example 1, the intermediates B1-b were respectively reacted with ethyl iodide, allyl bromide and deuterated methyl iodide to obtain B2, B3 and B5, respectively; using 5-bromo-2,4-dichloro- Intermediate B4 can be obtained by using 6-methylpyrimidine as a starting material; intermediate B6 can be obtained by using 5-iodo-2,4-dichloropyrimidine and 5-fluoro-2,4-dichloropyrimidine as starting materials. And B7.
Figure PCTCN2018122557-appb-000142
Figure PCTCN2018122557-appb-000142
实施例2：中间体(2,3-二氢苯并呋喃-4-基)甲胺(C1-1)和苯并呋喃-4-基甲胺(C2-1)的合成Example 2: Synthesis of intermediate (2,3-dihydrobenzofuran-4-yl)methylamine (C1-1) and benzofuran-4-ylmethylamine (C2-1)
步骤一：中间体溴-3-(2,2-二乙氧基乙氧基)苯(C1-1b)Step 1: Intermediate bromo-3-(2,2-diethoxyethoxy)benzene (C1-1b)
Figure PCTCN2018122557-appb-000143
Figure PCTCN2018122557-appb-000143
在500mL的单口烧瓶中依次加入间溴苯酚C1-1a(13g,75.14mmol)和N,N二甲基甲酰胺(150mL)。在0℃条件下，加入氢化钠(1.98g，82.66mmol)并搅拌半个小时。然后，向反应液中加入2-溴-1,1-二乙氧基乙烷(16.29g，82.66mmol)，升温到120℃并搅拌过夜。冷却至室温后，将反应液用100mL水淬灭，用乙酸乙酯萃取(500mL x 2)。合并的有机相用盐水洗涤两次，经无水硫酸钠干燥，过滤，在减压下浓缩，得到21g产物C1-1b。M-bromophenol C1-1a (13 g, 75.14 mmol) and N,N-dimethylformamide (150 mL) were sequentially added to a 500 mL one-neck flask. Sodium hydride (1.98 g, 82.66 mmol) was added at 0 ° C and stirred for half an hour. Then, 2-bromo-1,1-diethoxyethane (16.29 g, 82.66 mmol) was added to the reaction mixture, and the mixture was heated to 120 ° C and stirred overnight. After cooling to room temperature, the reaction was quenched with EtOAc (EtOAc) The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate.
1H NMR(400MHz,CDCl 3)δ7.16-7.06(m,3H),6.88-6.83(m,1H),4.81(t,J＝5.2Hz,1H),3.98(d,J＝5.2Hz,2H),3.80-3.71(m,2H),3.67-3.59(m,2H),1.26-1.23(m,6H)ppm；LCMS:m/z 289.0[M+H] + 1 H NMR (400MHz, CDCl 3 ) δ7.16-7.06 (m, 3H), 6.88-6.83 (m, 1H), 4.81 (t, J = 5.2Hz, 1H), 3.98 (d, J = 5.2Hz, 2H), 3.80-3.71 (m, 2H), 3.67-3.59 (m, 2H), 1.26-1.23 (m, 6H) ppm; LCMS: m/z 289.0 [M+H] +
步骤二：中间体4-溴苯并呋喃(C1-1c)Step 2: Intermediate 4-bromobenzofuran (C1-1c)
Figure PCTCN2018122557-appb-000144
Figure PCTCN2018122557-appb-000144
在500mL的单口烧瓶中依次加入溴-3-(2,2-二乙氧基乙氧基)苯C1-1b(21g，72.6mmol)，150mL甲苯和多聚磷酸(10.68g，108.93mmol)。反应液于95℃加热并搅拌4个小时。冷却至室温后，反应液用1L冰水淬灭，用乙酸乙酯萃取(500mL x 3)。合并的有机相用盐水洗涤两次，经无水硫酸钠干燥，过滤，在减压下浓缩，得到C1-1c和C1-1d的混合物粗品共5g。Bromine-3-(2,2-diethoxyethoxy)benzene C1-1b (21 g, 72.6 mmol), 150 mL of toluene and polyphosphoric acid (10.68 g, 108.93 mmol) were sequentially added to a 500 mL one-neck flask. The reaction solution was heated at 95 ° C and stirred for 4 hours. After cooling to room temperature, the reaction mixture was diluted with EtOAc (EtOAc) The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate.
步骤三：中间体苯并呋喃-4-甲腈(C1-1e)Step 3: Intermediate benzofuran-4-carbonitrile (C1-1e)
Figure PCTCN2018122557-appb-000145
Figure PCTCN2018122557-appb-000145
在100mL的三口烧瓶中依次加入C1-1c和C1-1d的混合物(5g，25.1mmol)，氰化锌(4.2g，37.7mmol)，四三苯基膦钯(2.9g,2.5mmol)和无水N,N-二甲基甲酰胺(50mL)。反应混合物在氮气下100℃加热搅拌18个小时。冷却至室温后，加入200mL水， 用乙酸乙酯萃取(200mL X 3)。合并的有机相用盐水洗涤两次，经无水硫酸钠干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(石油醚：乙酸乙酯＝100：1)，得到苯并呋喃-4-甲腈C1-1e(1.1g，30％产率)，为淡黄色固体。C1-1d的转化产物C1-2在这一步分离除去。A mixture of C1-1c and C1-1d (5 g, 25.1 mmol), zinc cyanide (4.2 g, 37.7 mmol), tetrakistriphenylphosphine palladium (2.9 g, 2.5 mmol) and none were added to a 100 mL three-necked flask. Water N,N-dimethylformamide (50 mL). The reaction mixture was heated and stirred at 100 ° C for 18 hours under nitrogen. After cooling to room temperature, 200 mL of water was added and extracted with ethyl acetate (200 mL EtOAc). The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate The residue was purified with EtOAc EtOAc (EtOAc:EtOAc: The conversion product C1-2 of C1-1d was separated and removed in this step.
1H NMR(400MHz,DMSO-d 6)δ8.31(d,J＝2.2Hz,1H),8.03(d,J＝8.4Hz,1H),7.84-7.71(m,1H),7.58-7.46(m,1H),7.20(dd,J＝2.2,1.0Hz,1H)ppm。 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.31 (d, J = 2.2 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.84 - 7.71 (m, 1H), 7.58 - 7.46 ( m, 1H), 7.20 (dd, J = 2.2, 1.0 Hz, 1 H) ppm.
步骤四：中间体苯并呋喃-4-基甲胺(C2-1)Step 4: Intermediate benzofuran-4-ylmethylamine (C2-1)
Figure PCTCN2018122557-appb-000146
Figure PCTCN2018122557-appb-000146
在单口烧瓶中加入苯并呋喃-4-甲腈C1-1e(300mg，2.09mmol)，甲醇(50mL),氯化镍(543mg,4.19mmol),慢慢加入硼氢化钠(159mg，4.19mmol)，室温反应2个小时。混合物经硅藻土过滤，用甲醇洗涤，滤液减压浓缩得到粗品。粗品在硅胶上纯化(二氯甲烷：甲醇＝10：1)，得到苯并呋喃-4-基甲胺C2-1(50mg，16.2％产率)，为黄色固体。Add benzofuran-4-carbonitrile C1-1e (300 mg, 2.09 mmol), methanol (50 mL), nickel chloride (543 mg, 4.19 mmol), and slowly add sodium borohydride (159 mg, 4.19 mmol). , react at room temperature for 2 hours. The mixture was filtered through celite, washed with methanol and evaporated The crude was purified over EtOAc (EtOAc:EtOAc:EtOAc
1H NMR(400MHz,DMSO-d 6)δ9.20-7.80(m,3H),7.60(d,J＝8.2Hz,1H),7.44(d,J＝7.3Hz,1H),7.35(t,J＝7.8Hz,1H),7.28(dt,J＝9.6,4.8Hz,1H),4.23(s,2H)ppm； 1 H NMR (400MHz, DMSO- d 6) δ9.20-7.80 (m, 3H), 7.60 (d, J = 8.2Hz, 1H), 7.44 (d, J = 7.3Hz, 1H), 7.35 (t, J = 7.8 Hz, 1H), 7.28 (dt, J = 9.6, 4.8 Hz, 1H), 4.23 (s, 2H) ppm;
LCMS:m/z 148.1[M+H] +。 LCMS: m/z 148.1 [M+H] + .
步骤五：中间体((2,3-二氢苯并呋喃-4-基)甲基)氨基甲酸叔丁酯(C1-1f)Step 5: Intermediate ((2,3-dihydrobenzofuran-4-yl)methyl)carbamic acid tert-butyl ester (C1-1f)
Figure PCTCN2018122557-appb-000147
Figure PCTCN2018122557-appb-000147
在100mL单口瓶中依次加入苯并呋喃-4-甲腈C1-1e(1.1g，7.68mmol)，BOC酸酐(2.5g，11.52mmol)，甲醇(50mL)和10％钯碳(2g,含50％水)。反应混合物用氢气鼓气5分钟，用氢气球换气三次，在氢气球下60℃搅拌18小时。混合物经硅藻土过滤，用甲醇(50mL X 2)洗涤，滤液减压浓缩，得到化合物C1-1f(1.5g，79％产率)。Add benzofuran-4-carbonitrile C1-1e (1.1 g, 7.68 mmol), BOC anhydride (2.5 g, 11.52 mmol), methanol (50 mL) and 10% palladium on carbon (2 g, containing 50) in a 100 mL vial. %water). The reaction mixture was purged with hydrogen for 5 minutes, ventilated three times with a hydrogen balloon, and stirred at 60 ° C for 18 hours under a hydrogen balloon. The mixture was filtered over EtOAc (EtOAc)EtOAc.
LCMS:m/z 195.1[M+H- tBu] +。 LCMS: m / z 195.1 [M + H- t Bu] +.
步骤六：中间体(2,3-二氢苯并呋喃-4-基)甲胺(C1-1)Step 6: Intermediate (2,3-dihydrobenzofuran-4-yl)methylamine (C1-1)
Figure PCTCN2018122557-appb-000148
Figure PCTCN2018122557-appb-000148
在50mL单口瓶中依次加入((2,3-二氢苯并呋喃-4-基)甲基)氨基甲酸叔丁酯C1-1f(1.3g，5.21mmol)和15mL HCl/二恶烷(4M)，室温搅拌4小时。反应完毕，混合物在减压下浓缩。残余物用混合溶剂(甲醇:乙腈＝1：10，50mL)稀释，然后加入碳酸钾(2g，14.6mmol)。混合物于60℃加热并搅拌3小时，冷却至室温，过滤，滤液减压浓缩，得到化合物C1-1(700mg,90％产率)，为白色固体。Add ((2,3-dihydrobenzofuran-4-yl)methyl)carbamic acid tert-butyl ester C1-1f (1.3 g, 5.21 mmol) and 15 mL HCl / dioxane (4M) in a 50 mL vial. ), stirring at room temperature for 4 hours. After the reaction was completed, the mixture was concentrated under reduced pressure. The residue was diluted with a mixed solvent (methanol: acetonitrile = 1:10, 50mL), and then potassium carbonate (2 g, 14.6 mmol). The mixture was heated and stirred at 60 ° C for 3 hours, cooled to EtOAc EtOAc (EtOAc)
1H NMR(400MHz,CD 3OD)δ7.15(t,J＝7.8Hz,1H),6.89(d,J＝7.7Hz,1H),6.72(d,J＝8.0Hz,1H),4.59(t,J＝8.7Hz,2H),3.93(s,2H),3.27(t,J＝8.7Hz,2H)ppm；LCMS:m/z150.1[M+H] +. 1 H NMR (400 MHz, CD 3 OD) δ 7.15 (t, J = 7.8 Hz, 1H), 6.89 (d, J = 7.7 Hz, 1H), 6.72 (d, J = 8.0 Hz, 1H), 4.59 ( t, J = 8.7 Hz, 2H), 3.93 (s, 2H), 3.27 (t, J = 8.7 Hz, 2H) ppm; LCMS: m/z 150.1 [M+H] + .
使用实施例2的方法，用类似的起始原料得到中间体C2-2、C1-2、C1-4和C1-6。以3-溴-4-氟苯酚为原料并在步骤四中用氘代硼氢化钠替代硼氢化钠即可得到C2-3；C1-5和C5-1的原料分别为5-溴-2-氟苯酚和3-溴-2-氟苯酚，酚羟基邻位有一个取代基所以关环反应只有一个产物。Intermediate C2-2, C1-2, C1-4 and C1-6 were obtained using a similar starting material using the procedure of Example 2. Starting from 3-bromo-4-fluorophenol and replacing sodium borohydride with sodium borohydride in step four, C2-3 can be obtained; the raw materials of C1-5 and C5-1 are 5-bromo-2-, respectively. Fluorophenol and 3-bromo-2-fluorophenol have a substituent in the ortho position of the phenolic hydroxyl group, so there is only one product in the ring closure reaction.
Figure PCTCN2018122557-appb-000149
Figure PCTCN2018122557-appb-000149
Figure PCTCN2018122557-appb-000150
Figure PCTCN2018122557-appb-000150
实施例3：(5-氟-2,3-二氢苯并呋喃-4-基)氘代甲基-胺(C1-3)Example 3: (5-Fluoro-2,3-dihydrobenzofuran-4-yl)deuterated methyl-amine (C1-3)
Figure PCTCN2018122557-appb-000151
Figure PCTCN2018122557-appb-000151
在25mL单口瓶中依次加入(5-氟苯并呋喃-4-基)氘代甲基-胺(C2-3)(200mg,1.2mmol)，甲醇(10mL)和10％钯碳(40mg)。溶液在氢气氛围下50℃搅拌过夜。反应结束后过滤，滤饼用甲醇(10mL)洗，滤液减压浓缩，残余物用柱层析纯化(甲醇：乙酸乙酯＝1:4)得产物(5-氟-2,3-二氢苯并呋喃-4-基)氘代甲基-胺(C1-3)(180mg,89％),为无色油状物。(5-Fluorobenzofuran-4-yl)deuterated methyl-amine (C2-3) (200 mg, 1.2 mmol), methanol (10 mL) and 10% palladium carbon (40 mg) were sequentially added to a 25-mL one-necked flask. The solution was stirred at 50 ° C overnight under a hydrogen atmosphere. After completion of the reaction, the mixture was filtered, and the filtered cake was washed with methanol (10 mL). Benzofuran-4-yl)deuteromethyl-amine (C1-3) (180 mg, 89%) as a colourless oil.
LC-MS:m/z 170.1[M+H] +. LC-MS: m/z 170.1 [M+H] + .
实施例4：中间体(6-氟苯并二氢吡喃-5-基)甲胺(C3-1)Example 4: Intermediate (6-fluorochroman-5-yl)methylamine (C3-1)
步骤一：中间体2-溴-1-氟-4-(丙-2-炔-1-基氧基)苯(C3-1b)Step 1: Intermediate 2-bromo-1-fluoro-4-(prop-2-yn-1-yloxy)benzene (C3-1b)
Figure PCTCN2018122557-appb-000152
Figure PCTCN2018122557-appb-000152
在干燥的2L单口烧瓶瓶中室温下加入3-溴-4-氟苯酚C3-1a(87g，455.5mmol)，干燥的N,N-二甲基甲酰胺(800mL)。用氮气置换体系空气三次,在冰水浴下历时30分钟分批次加入60％的氢化钠(20g,501mmol)。反应液室温下搅拌15分钟后用冰水浴冷却，然后加入氯丙炔(50.9g,683.3mmol)。反应液室温下搅拌18小时。反应完毕后，加入水(1L)，用乙酸乙酯(1L)萃取三次。有机相用饱和氯化钠水溶液(500mL)洗涤一次，有机相用硫酸钠干燥，过滤，减压蒸馏得到粗产品。通过硅胶柱(石油醚：乙酸乙酯＝20:1)纯化得到产品黄色油状液体2-溴-1-氟-4-(丙-2-炔-1-基氧基)苯C3-1b(80g,76.7％产率)。3-bromo-4-fluorophenol C3-1a (87 g, 455.5 mmol) was added to dry <RTI ID=0.0>#2 </RTI> <RTI ID=0.0> The system air was replaced with nitrogen three times, and 60% sodium hydride (20 g, 501 mmol) was added in portions over 30 minutes in an ice water bath. The reaction solution was stirred at room temperature for 15 min then cooled with ice-water-br., then chloropropyne (50.9 g, 68. The reaction solution was stirred at room temperature for 18 hours. After completion of the reaction, water (1 L) was added, and the mixture was extracted three times with ethyl acetate (1L). The organic phase was washed once with a saturated aqueous solution of sodium chloride (500 mL). Purified by silica gel column (petroleum ether: ethyl acetate = 20:1) to give the product as a yellow oily liquid 2-bromo-1-fluoro-4-(prop-2-yn-1-yloxy)benzene C3-1b (80 g , 76.7% yield).
1H NMR(400MHz,CDCl 3)δ7.17(dd,J＝5.5,3.0Hz,1H),7.05(dd,J＝9.0,8.1Hz,1H),6.89(ddd,J＝9.1,3.7,3.2Hz,1H),4.66(d,J＝2.4Hz,2H),2.54(t,J＝2.4Hz,1H)ppm。 1 H NMR (400 MHz, CDCl 3 ) δ 7.17 (dd, J = 5.5, 3.0 Hz, 1H), 7.05 (dd, J = 9.0, 8.1 Hz, 1H), 6.89 (ddd, J = 9.1, 3.7, 3.2 Hz, 1H), 4.66 (d, J = 2.4 Hz, 2H), 2.54 (t, J = 2.4 Hz, 1 H) ppm.
步骤二：中间体5-溴-6-氟-2H-色烯(C3-1c)Step 2: Intermediate 5-bromo-6-fluoro-2H-chromene (C3-1c)
Figure PCTCN2018122557-appb-000153
Figure PCTCN2018122557-appb-000153
在干燥的20mL微波管中加入2-溴-1-氟-4-(丙-2-炔-1-基氧基)苯C3-1b(2g,8.7mmol)和N，N-二乙基苯胺(15mL)。反应液在微波合成仪中加热至250℃反应2.5小时。反应完毕后，用乙酸乙酯(100mL)稀释，用2N盐酸洗涤除去N，N-二乙基苯胺。有机相用饱和氯化钠水溶液(50mL)洗涤一次，有机相用硫酸钠干燥，过滤，减压蒸馏得到粗产品。粗产品通过硅胶柱(石油醚：乙酸乙酯＝20:1)纯化得到C3-1c和C3-1d的棕色油状混合物(1.88g,94％产率)。Add 2-bromo-1-fluoro-4-(prop-2-yn-1-yloxy)benzene C3-1b (2 g, 8.7 mmol) and N,N-diethylaniline to a dry 20 mL microwave tube (15mL). The reaction solution was heated to 250 ° C for 2.5 hours in a microwave synthesizer. After completion of the reaction, it was diluted with ethyl acetate (100 mL) and washed with 2N hydrochloric acid to remove N,N-diethylaniline. The organic phase was washed once with a saturated aqueous solution of sodium chloride (50 mL). The crude product was purified by EtOAc EtOAc EtOAc (EtOAc:EtOAc
步骤三：中间体6-氟-2H-色烯-5-腈(C3-1e)Step 3: Intermediate 6-Fluoro-2H-chromene-5-carbonitrile (C3-1e)
Figure PCTCN2018122557-appb-000154
Figure PCTCN2018122557-appb-000154
在干燥的500mL三口瓶中依次加入C3-1c和C3-1d的棕色油状混合物(20.2g,88.2mmol)，氰化锌(13.5g,115mmol),无水N,N二甲基甲酰胺(250mL)和四三苯基膦钯(10.2g,8.8mmol)。反应液在氮气保护条件下110℃下搅拌18小时。反应完毕后，冷却到室温，加入1L水，用乙酸乙酯(500mL)萃取三次。有机相用饱和氯化钠水溶液(500mL)洗涤一次，有机相用硫酸钠干燥，过滤，减压蒸馏得到粗产品。通过硅胶柱(石油醚：乙酸乙酯＝50:1～10:1)纯化得到产品白色固体6-氟-2H-色烯-5-腈C3-1e(8.12g,52.6％产率)。C3-1d的转化产物被分离除去。A brown oily mixture of C3-1c and C3-1d (20.2 g, 88.2 mmol), zinc cyanide (13.5 g, 115 mmol), anhydrous N,N-dimethylformamide (250 mL) was added to a dry 500 mL three-necked flask. And tetrakistriphenylphosphine palladium (10.2 g, 8.8 mmol). The reaction solution was stirred at 110 ° C for 18 hours under nitrogen atmosphere. After completion of the reaction, it was cooled to room temperature, 1 L of water was added, and extracted three times with ethyl acetate (500 mL). The organic phase was washed once with a saturated aqueous solution of sodium chloride (500 mL). Purification by silica gel column (peel ether: ethyl acetate = 50:1 - 10:1) afforded product white solid 6-fluoro-2H-chromene-5-carbonitrile C3-1e (8.12 g, 52.6% yield). The conversion product of C3-1d was isolated and removed.
1H NMR(400MHz,CDCl 3)δ7.02-6.85(m,2H),6.70(dt,J＝10.0,1.8Hz,1H),6.07(dt,J＝10.0,3.6Hz,1H),4.88(dd,J＝3.6,2.0Hz,2H)ppm；LC-MS:m/z 176.1[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ7.02-6.85 (m, 2H), 6.70 (dt, J = 10.0,1.8Hz, 1H), 6.07 (dt, J = 10.0,3.6Hz, 1H), 4.88 ( Dd, J = 3.6, 2.0 Hz, 2H) ppm; LC-MS: m/z 176.1 [M+H] + .
步骤四：中间体((6-氟苯并二氢吡喃-5-基)甲基)氨基甲酸叔丁酯(C3-1f)Step 4: Intermediate ((6-fluorochroman-5-yl)methyl)carbamic acid tert-butyl ester (C3-1f)
Figure PCTCN2018122557-appb-000155
Figure PCTCN2018122557-appb-000155
在500mL单口瓶中依次加入6-氟-2H-色烯-5-腈C3-1e(4.6g,26.3mmol)，BOC酸酐(7.45g,34.1mmol),甲醇(200mL)和10％钯碳(1.6g,50％)。反应液先用氢气鼓泡5分钟，然后装上氢气球换气三次，在氢气中加热到60℃搅拌过夜。反应完毕后，冷却到室温，反应液过滤，减压蒸馏得到较纯的产品C3-1f(7.4g，100％)，直接用于下一步。6-Fluoro-2H-chromene-5-carbonitrile C3-1e (4.6 g, 26.3 mmol), BOC anhydride (7.45 g, 34.1 mmol), methanol (200 mL) and 10% palladium on carbon were sequentially added to a 500 mL single-mouth flask. 1.6g, 50%). The reaction solution was bubbled with hydrogen for 5 minutes, then charged with a hydrogen balloon for three times, and heated to 60 ° C in hydrogen to stir overnight. After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was filtered, and then evaporated to dryness to give the product C3-1f (7.4 g, 100%).
1H NMR(400MHz,CDCl 3)δ6.81(t,J＝9.1Hz,1H),6.70(dd,J＝9.0,4.9Hz,1H),4.75(s,1H),4.32(d,J＝5.2Hz,2H),4.18-4.05(m,2H),3.49(d,J＝1.8Hz,2H),2.86(t,J＝6.4Hz,2H),2.10-1.91(m,2H),1.45(d,J＝8.0Hz,9H)ppm；LC-MS:m/z 226.1[M-tBu+H] +。 1 H NMR (400MHz, CDCl 3 ) δ6.81 (t, J = 9.1Hz, 1H), 6.70 (dd, J = 9.0,4.9Hz, 1H), 4.75 (s, 1H), 4.32 (d, J = 5.2 Hz, 2H), 4.18-4.05 (m, 2H), 3.49 (d, J = 1.8 Hz, 2H), 2.86 (t, J = 6.4 Hz, 2H), 2.10 - 1.91 (m, 2H), 1.45 ( d, J = 8.0 Hz, 9H) ppm; LC-MS: m/z 226.1 [M-tBu+H] + .
步骤五：中间体(6-氟苯并二氢吡喃-5-基)甲胺(C3-1)Step 5: Intermediate (6-fluorochroman-5-yl)methylamine (C3-1)
Figure PCTCN2018122557-appb-000156
Figure PCTCN2018122557-appb-000156
在50mL单口瓶中依次加入C3-1f(1.0g，3.55mmol)和10mL HCl/二恶烷溶液(4M)，室温搅拌4小时。反应完毕，混合物在减压下浓缩，得到化合物C3-1(612mg,95％产率)，为白色固体。C3-1f (1.0 g, 3.55 mmol) and 10 mL of HCl/dioxane solution (4M) were sequentially added to a 50 mL single-necked flask, and stirred at room temperature for 4 hours. After the reaction was completed, the mixture was evaporated.
1H NMR(400MHz,CD 3OD)δ6.98(t,J＝9.2Hz,1H),6.86(dd,J＝9.1,5.1Hz,1H),4.28-4.07(m,4H),2.89(t,J＝6.4Hz,2H),2.14-2.01(m,2H)ppm；LC-MS:m/z 182.1[M+H] +。 1 H NMR (400 MHz, CD 3 OD) δ 6.98 (t, J = 9.2 Hz, 1H), 6.86 (dd, J = 9.1, 5.1 Hz, 1H), 4.28-4.07 (m, 4H), 2.89 (t) , J = 6.4 Hz, 2H), 2.14 - 2.01 (m, 2H) ppm; LC-MS: m/z 182.1 [M+H] + .
实施例5：中间体(7-氟-2,3,4,5-四氢苯并[b]噁庚-6-基)甲胺(C4-1)Example 5: Intermediate (7-fluoro-2,3,4,5-tetrahydrobenzo[b]oxe-6-yl)methylamine (C4-1)
步骤一：5-(烯丙氧基)-2-氟苄腈(C4-1b)Step 1: 5-(Allyloxy)-2-fluorobenzonitrile (C4-1b)
Figure PCTCN2018122557-appb-000157
Figure PCTCN2018122557-appb-000157
在250mL单口瓶中依次加入C4-1a(5g,36mmol)，DMF(50mL),然后冰浴下，分批缓慢加入NaH(1.6g,40mmol)。反应液在室温下反应1小时。然后将反应液再次放入冰浴中，缓慢滴加烯丙基溴(5.3g,44mmol)。将反应液室温搅拌1h。向反应液中加入冰水淬灭反应，用乙酸乙酯(300mL)萃取2次，然后有机相用饱和食盐水洗，用硫酸钠干燥。混合物在减压下浓缩，得到化合物C4-1b(5.2g,62％产率)，为白色固体。C4-1a (5 g, 36 mmol), DMF (50 mL) was added successively to a 250 mL one-necked flask, and then NaH (1.6 g, 40 mmol) was slowly added in portions. The reaction solution was allowed to react at room temperature for 1 hour. The reaction solution was again placed in an ice bath, and allyl bromide (5.3 g, 44 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 1 h. The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The mixture was concentrated under reduced pressure to give Compound C??
1H NMR(400MHz,CDCl 3)δ7.21-7.10(m,2H),7.08(dt,J＝4.1,3.5Hz,1H),6.01(ddd,J＝22.5,10.5,5.2Hz,1H),5.37(ddd,J＝13.9,11.7,1.2Hz,2H),4.53(d,J＝5.2Hz,2H)ppm. 1 H NMR (400 MHz, CDCl 3 ) δ 7.21-7.10 (m, 2H), 7.08 (dt, J = 4.1, 3.5 Hz, 1H), 6.01 (ddd, J = 22.5, 10.5, 5.2 Hz, 1H), 5.37 (ddd, J = 13.9, 11.7, 1.2 Hz, 2H), 4.53 (d, J = 5.2 Hz, 2H) ppm.
步骤二：2-烯丙基-6-氟-3-羟基苄腈(C4-1c)Step 2: 2-allyl-6-fluoro-3-hydroxybenzonitrile (C4-1c)
Figure PCTCN2018122557-appb-000158
Figure PCTCN2018122557-appb-000158
在30ML微波管中依次加入C4-1b(2g,11mmol)和10mL N,N-二甲基苯胺。然后反应液在230℃微波条件下反应3小时。反应完后，反应液用1M盐酸调节到pH 4左右，然后水相用乙酸乙酯萃取2次。减压浓缩后，固体用二氯甲烷打浆，得到化合物C4-1c(600mg,30％产率)，为白色固体。C4-1b (2 g, 11 mmol) and 10 mL of N,N-dimethylaniline were sequentially added to a 30 mL microwave tube. The reaction solution was then reacted under microwave conditions at 230 ° C for 3 hours. After the completion of the reaction, the reaction mixture was adjusted to pH 4 with 1M hydrochloric acid, and then the aqueous phase was extracted twice with ethyl acetate. After concentrating under reduced pressure, EtOAc (EtOAc m.
1H NMR(400MHz,CDCl 3)δ7.08–6.91(m,2H),5.96(ddt,J＝16.4,10.2,6.2Hz,1H),5.28(s,1H),5.24–5.12(m,2H),3.63(dt,J＝6.2,1.5Hz,2H)ppm. 1 H NMR (400 MHz, CDCl 3 ) δ 7.08 - 6.91 (m, 2H), 5.96 (dd, J = 16.4, 10.2, 6.2 Hz, 1H), 5.28 (s, 1H), 5.24 - 5.12 (m, 2H) ), 3.63 (dt, J = 6.2, 1.5 Hz, 2H) ppm.
步骤三：2-烯丙基-3-(烯丙氧基)-6-氟苄腈(C4-1d)Step 3: 2-Allyl-3-(allyloxy)-6-fluorobenzonitrile (C4-1d)
Figure PCTCN2018122557-appb-000159
Figure PCTCN2018122557-appb-000159
在100mL单口瓶中依次加入C4-1c(600mg,3.39mmol)、DMF(10mL),然后冰浴下，分批缓慢加入NaH(149mg,3.73mmol)。反应液在室温下反应1小时。然后将反应液再次放入冰浴中，缓慢滴加烯丙基溴(429mg,4.07mmol)。将反应液室温搅拌1h。C4-1c (600 mg, 3.39 mmol) and DMF (10 mL) were sequentially added to a 100 mL one-necked flask, and then NaH (149 mg, 3.73 mmol) was slowly added portionwise in an ice bath. The reaction solution was allowed to react at room temperature for 1 hour. The reaction solution was again placed in an ice bath, and allyl bromide (429 mg, 4.07 mmol) was slowly added dropwise. The reaction was stirred at room temperature for 1 h.
向反应液中加入冰水淬灭反应，用乙酸乙酯萃取2次，然后有机相用饱和食盐水洗，用硫酸钠干燥。混合物在减压下浓缩，得到化合物C4-1d(600mg,85％产率)，为白色固体。The reaction mixture was quenched with EtOAc (EtOAc)EtOAc. The mixture was concentrated under reduced pressure to give compound C sd.
1H NMR(400MHz,CDCl 3)δ7.06-6.91(m,2H),6.10-5.79(m,2H),5.49-5.23(m,2H),5.10(ddq,J＝17.4,10.0,1.5Hz,2H),4.55(dt,J＝5.0,1.6Hz,2H),3.62(dt,J＝6.4,1.3Hz,2H)ppm. 1 H NMR (400 MHz, CDCl 3 ) δ 7.06-6.91 (m, 2H), 6.10-5.79 (m, 2H), 5.49-5.23 (m, 2H), 5.10 (ddq, J = 17.4, 10.0, 1.5 Hz , 2H), 4.55 (dt, J = 5.0, 1.6 Hz, 2H), 3.62 (dt, J = 6.4, 1.3 Hz, 2H) ppm.
步骤四：7-氟-2,5-二氢苯并[b]氧杂-6-甲腈(C4-1e)Step 4: 7-Fluoro-2,5-dihydrobenzo[b]oxa-6-carbonitrile (C4-1e)
Figure PCTCN2018122557-appb-000160
Figure PCTCN2018122557-appb-000160
在100mL单口瓶中依次加入C4-1d(600mg,2.76mmol)，Grubbs二代催化剂(150mg)和DCM(100mL),然后室温下，反应过夜。将反应液过滤，混合物减压浓缩，得到化合物C4-1e(390mg,72.5％产率)，为淡黄色固体。C4-1d (600 mg, 2.76 mmol), Grubbs second generation catalyst (150 mg) and DCM (100 mL) were sequentially added to a 100 mL one-necked flask, and then allowed to react overnight at room temperature. The reaction mixture was filtered and the~~~~~~~~~
1H NMR(400MHz,CDCl 3)δ7.27(t,J＝3.1Hz,1H),7.26(d,J＝5.1Hz,1H),7.01(dd,J＝10.7,6.4Hz,1H),5.93-5.74(m,1H),5.56-5.43(m,1H),4.65-4.54(m,2H),3.71(dt,J＝7.4,2.1Hz,2H)ppm.LC-MS:m/z 190[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.27 (t, J = 3.1 Hz, 1H), 7.26 (d, J = 5.1 Hz, 1H), 7.01 (dd, J = 10.7, 6.4 Hz, 1H), 5.93 -5.74 (m, 1H), 5.56-5.43 (m, 1H), 4.65-4.54 (m, 2H), 3.71 (dt, J = 7.4, 2.1 Hz, 2H) ppm. LC-MS: m/z 190 [ M+H] + .
步骤五：((7-氟-2,3,4,5-四氢苯并[b]氧杂-6-基)甲基)氨基甲酸叔丁酯(C4-1f)Step 5: ((7-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxa-6-yl)methyl)carbamic acid tert-butyl ester (C4-1f)
Figure PCTCN2018122557-appb-000161
Figure PCTCN2018122557-appb-000161
在100mL单口瓶中依次加入C4-1e(330mg,1.75mmol)，BOC酸酐(570mg,2.62mmol),甲醇(30mL)和10％钯碳(500mg,50％水)。反应液先用氢气鼓泡5分钟，然后装上氢气球换气三次，在氢气中加热到60℃搅拌过夜。反应完毕后，冷却到室温，反应液过滤，减压浓缩得到较纯的产品C4-1f(350mg，产率定量)，直接用于下一步。C4-1e (330 mg, 1.75 mmol), BOC anhydride (570 mg, 2.62 mmol), methanol (30 mL) and 10% palladium on carbon (500 mg, 50% water) were sequentially added to a 100 mL single-necked flask. The reaction solution was bubbled with hydrogen for 5 minutes, then charged with a hydrogen balloon for three times, and heated to 60 ° C in hydrogen to stir overnight. After completion of the reaction, the mixture was cooled to room temperature, and the reaction mixture was filtered.
LC-MS:m/z 240.1[M+H-tBu] +. LC-MS: m/z 240.1 [M+H-tBu] + .
步骤六：(7-氟-2,3,4,5-四氢-苯并[b]氧杂-6-基)甲胺(C4-1)Step 6: (7-Fluoro-2,3,4,5-tetrahydro-benzo[b]oxa-6-yl)methylamine (C4-1)
Figure PCTCN2018122557-appb-000162
Figure PCTCN2018122557-appb-000162
在50mL单口瓶中依次加入C4-1f(350mg，1.18mmol)和20mL二氯甲烷，室温下加入三氟乙酸(1.53g，13mmol)并搅拌1小时。反应完毕，混合物在减压下浓缩，得到化合物C4-1的三氟乙酸盐(400mg,产率定量)，为白色固体。C4-1f (350 mg, 1.18 mmol) and 20 mL of dichloromethane were successively added to a 50 mL one-necked flask, and trifluoroacetic acid (1.53 g, 13 mmol) was added at room temperature and stirred for 1 hour. After completion of the reaction, the mixture was concentrated under reduced pressure to give Compound C??
1H NMR(400MHz,MeOD)δ7.12-7.04(m,1H),7.05-6.97(m,1H),4.30-4.19(m,2H),4.04-3.96(m,2H),2.98-2.89(m,2H),2.04-1.96(m,2H),1.81-1.73(m,2H)ppm；LC-MS:m/z 196.1[M+H] +. 1 H NMR (400 MHz, MeOD) δ 7.12-7.04 (m, 1H), 7.05-6.97 (m, 1H), 4.30-4.19 (m, 2H), 4.04-3.96 (m, 2H), 2.98-2.89 ( m, 2H), 2.04-1.96 (m, 2H), 1.81-1.73 (m, 2H) ppm; LC-MS: m/z 196.1 [M+H] + .
实施例6：中间体(5-氟苯并[d][1,3]二氧杂环戊烯-4-基)甲胺(C6-1)Example 6: Intermediate (5-fluorobenzo[d][1,3]dioxol-4-yl)methylamine (C6-1)
步骤一：中间体4-氟苯-1,2-二醇(C6-1b)Step 1: Intermediate 4-fluorobenzene-1,2-diol (C6-1b)
Figure PCTCN2018122557-appb-000163
Figure PCTCN2018122557-appb-000163
将4-氟-1,2-二甲氧基苯C6-1a(10g，64.0mmol)溶于无水二氯甲烷(120mL)中。在-78℃下，将三溴化硼(1摩尔的二氯甲烷溶液)缓慢加入到反应液中。反应混合物升到室温并继续搅拌16小时。将反应混合物倒入碎冰(200g)中，并用乙酸乙酯(3x 50mL)萃取。有机相用饱和氯化钠水溶液(100mL)洗涤一次，有机相用硫酸钠干燥，过滤，减压蒸馏得到4-氟苯-1,2-二醇C6-1b(8.0g,100％)，为无色液体。4-Fluoro-1,2-dimethoxybenzene C6-1a (10 g, 64.0 mmol) was dissolved in anhydrous dichloromethane (120 mL). Boron tribromide (1 mole of a dichloromethane solution) was slowly added to the reaction solution at -78 °C. The reaction mixture was allowed to warm to room temperature and stirring was continued for 16 h. The reaction mixture was poured into EtOAc (EtOAc) (EtOAc) The organic phase was washed once with a saturated aqueous solution of sodium chloride (100 mL), and the organic phase was dried over sodium sulfate, filtered and evaporated to give 4-fluorobenzene-1,2-diol C6-1b (8.0 g, 100%) Colorless liquid.
1H NMR(400MHz,CDCl 3):δ6.80-6.77(m,1H),6.65-6.63(m,1H),6.50-6.46(m,1H),6.25(s,1H),5.81(s,1H)ppm. 1 H NMR (400MHz, CDCl 3 ): δ6.80-6.77 (m, 1H), 6.65-6.63 (m, 1H), 6.50-6.46 (m, 1H), 6.25 (s, 1H), 5.81 (s, 1H)ppm.
步骤二：中间体5-氟苯并[d][1,3]二氧杂环戊烯(C6-1c)Step 2: Intermediate 5-fluorobenzo[d][1,3]dioxole (C6-1c)
Figure PCTCN2018122557-appb-000164
Figure PCTCN2018122557-appb-000164
将4-氟苯-1,2-二醇C6-1b(8.0g，62.5mmol)溶于DMF(25.0mL)，在室温下缓慢加入碳酸铯(30.4g，93.75mmol)并在相同温度下搅拌10分钟。在相同温度下，在3分钟内向该反应混合物中分批加入氯溴甲烷(5.5mL，93.75mmol)。所得反应混合物在120℃搅拌1小时。将反应混合物冷却至室温并倒入碎冰(200mL)中并搅拌15分钟，然后用***(3×50mL)萃取。合并的有机相用盐水(200mL)洗涤，无水硫酸钠干燥并减压浓缩。粗产物通过硅胶柱(石油醚：乙酸乙酯＝20:1)纯化得到5-氟苯并[d][1,3]间二氧杂环戊烯C6-1c(4.0克，粗品)为无色液体。4-Fluorobenzene-1,2-diol C6-1b (8.0 g, 62.5 mmol) was dissolved in DMF (25.0 mL), and cesium carbonate (30.4 g, 93.75 mmol) was slowly added at room temperature and stirred at the same temperature. 10 minutes. Chlorobromomethane (5.5 mL, 93.75 mmol) was added portionwise to the reaction mixture over 3 min at the same temperature. The resulting reaction mixture was stirred at 120 ° C for 1 hour. The reaction mixture was cooled to room rt and poured over EtOAc EtOAc EtOAc. The combined organic layers were washed with EtOAc EtOAc m. The crude product was purified by silica gel column ( petroleum ether: ethyl acetate = 20:1) to yield 5-fluorobenzo[d][1,3]dioxole C6-1c (4.0 g, crude) Color liquid.
GC-MS:m/z 139.1[M+H] +. GC-MS: m/z 139.1 [M+H] + .
步骤三：中间体5-氟苯并[d][1,3]二氧杂环戊烯-4-甲醛(C6-1d)Step 3: Intermediate 5-fluorobenzo[d][1,3]dioxol-4-carbaldehyde (C6-1d)
Figure PCTCN2018122557-appb-000165
Figure PCTCN2018122557-appb-000165
将5-氟苯并[d][1,3]间二氧杂环戊烯C6-1c(4.0g，28.57mmol)溶于无水THF(50mL)。反应液冷却至-78℃，在氮气保护下历时15分钟加入二异丙基氨基锂(2M的THF溶液，28.57mL，57.14mmol)，在相同温度下继续搅拌1小时。向反应液中加入DMF(4.17mL，57.14mmol)，并将反应混合物缓慢升至室温并搅拌16h。反应完毕后，将反应混合物倒入碎冰(200mL)中，搅拌15分钟，用乙酸乙酯(2×50mL)萃取。合并的有机相用盐水(200mL)洗涤，无水硫酸钠干燥并减压浓缩。粗产物通过硅胶柱(石油醚：乙酸乙酯＝20:1)纯化得到5-氟苯并[d][1,3]间二氧杂环戊烯-4-酮C6-1d(1.5g，两步产率76％)，为黄色固体。5-Fluorobenzo[d][1,3]dioxole C6-1c (4.0 g, 28.57 mmol) was dissolved in dry THF (50 mL). The reaction solution was cooled to -78.degree. C., and then evaporated and evaporated. DMF (4.17 mL, 57.14 mmol) was added <RTI ID=0.0> After completion of the reaction, the reaction mixture was poured into EtOAc (EtOAc) The combined organic layers were washed with EtOAc EtOAc m. The crude product was purified through silica gel column ( petroleum ether: ethyl acetate = 20:1) to afford 5-fluorobenzo[d][1,3]dioxol-4-one C6-1d (1.5 g, The yield in two steps was 76%) as a yellow solid.
1H NMR(400MHz,CDCl3):δ10.26(s,1H),6.92(dd,J＝8.5,4.0Hz,1H),6.60(dd,J＝10.5,9.0Hz,1H),6.16(s,2H)ppm. 1 H NMR (400MHz, CDCl3) : δ10.26 (s, 1H), 6.92 (dd, J = 8.5,4.0Hz, 1H), 6.60 (dd, J = 10.5,9.0Hz, 1H), 6.16 (s, 2H) ppm.
步骤四：中间体5-氟苯并[d][1,3]间二氧杂环戊烯-4-甲醛肟(C6-1e)Step 4: Intermediate 5-fluorobenzo[d][1,3]dioxole-4-carbaldehyde oxime (C6-1e)
Figure PCTCN2018122557-appb-000166
Figure PCTCN2018122557-appb-000166
将5-氟苯并[d][1,3]间二氧杂环戊烯-4-甲醛C6-1d(1.5g，8.92mmol)溶于乙醇(10mL)，加入溶解在乙醇(10mL)中的氢氧化钠(535mg，13.38mmol)，水(8.0mL)和羟胺盐酸盐(727mg，10.70mmol)。反应液在室温下搅拌30分钟。反应完成后，将反应物倒入冷水中。过滤收集固体沉淀物，用水(100mL)洗涤并干燥，得到5-氟苯并[d][1,3]间二氧杂环戊烯-4-甲醛肟C6-1e(1.2g，75％产率)，为淡黄色固体。5-Fluorobenzo[d][1,3]dioxole-4-carbaldehyde C6-1d (1.5 g, 8.92 mmol) was dissolved in ethanol (10 mL) and dissolved in ethanol (10 mL) Sodium hydroxide (535 mg, 13.38 mmol), water (8.0 mL) and hydroxylamine hydrochloride (727 mg, 10.70 mmol). The reaction solution was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction was poured into cold water. The solid precipitate was collected by filtration, washed with water (100 mL) and dried to give 5-fluorobenzo[d][1,3]dioxole-4-carboxime C6-1e (1.2 g, 75% yield) Rate), as a pale yellow solid.
1H NMR(400MHz,CDCl 3):δ9.20(s,1H),8.30(s,1H),6.76-6.73(m,1H),6.60-6.56(m,1H),6.61(s,2H)ppm. 1 H NMR (400MHz, CDCl 3 ): δ9.20 (s, 1H), 8.30 (s, 1H), 6.76-6.73 (m, 1H), 6.60-6.56 (m, 1H), 6.61 (s, 2H) Ppm.
步骤五：中间体((5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲基)氨基甲酸叔丁酯(C6-1f)Step 5: Intermediate ((5-fluorobenzo[d][1,3]dioxol-4-yl)methyl)carbamic acid tert-butyl ester (C6-1f)
Figure PCTCN2018122557-appb-000167
Figure PCTCN2018122557-appb-000167
在0℃下，向5-氟苯并[d][1,3]间二氧杂环戊烯-4-甲醛肟C6-1e(1.2g，6.55mmol)的MeOH(10mL)溶液中加入六水氯化镍(1.86g，7.86mmol)。搅拌5分钟后，历时3分钟分批加入硼氢化钠(2.48g，65.5mmol)，然后加入(Boc) 2O(1.71g，7.86mmol)。反应液在室温下继续搅拌30分钟后用乙酸乙酯(50mL)稀释并通过硅藻土过滤。将滤液减压浓缩后得到的粗产物通过硅胶柱(石油醚：乙酸乙酯＝20:1)纯化得到((5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲基)氨基甲酸叔丁酯C6-1f(1.2g，68％产率)，为灰白色固体。 To a solution of 5-fluorobenzo[d][1,3]dioxole-4-carbazide C6-1e (1.2 g, 6.55 mmol) in MeOH (10 mL) Water nickel chloride (1.86 g, 7.86 mmol). After stirring for 5 minutes, sodium borohydride (2.48 g, 65.5 mmol) was added portionwise over 3 min then (Boc) 2 O (1.71 g, 7.86 mmol). The reaction was stirred at room temperature for 30 min then diluted with EtOAc (EtOAc) The crude product obtained by concentrating the filtrate under reduced pressure was purified by silica gel column ( petroleum ether: ethyl acetate = 20:1) ((5-fluorobenzo[d][1,3]-dioxole- tert-Butyl 4-methyl)methyl)carbamate C6-1f (1.2 g, 68% yield)
1H NMR(400MHz,CDCl 3):δ6.65-6.63(m,1H),6.52-6.49(m,1H),6.01(s,2H),4.93(bs,1H),4.35(s,2H),1.44(s,9H),ppm. 1 H NMR (400MHz, CDCl 3 ): δ6.65-6.63 (m, 1H), 6.52-6.49 (m, 1H), 6.01 (s, 2H), 4.93 (bs, 1H), 4.35 (s, 2H) , 1.44 (s, 9H), ppm.
步骤六：中间体(5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲胺(C6-1)Step 6: Intermediate (5-fluorobenzo[d][1,3]dioxol-4-yl)methylamine (C6-1)
Figure PCTCN2018122557-appb-000168
Figure PCTCN2018122557-appb-000168
将((5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲基)氨基甲酸叔丁酯C6-1f(1.2g，10.11mmol)溶于二氯甲烷(15mL)中，加入4M HCl的二氧六环溶液(15mL，60.6mmol)。搅拌30分钟后，减压蒸馏除去挥发物。粗产物用乙酸乙酯(10mL)打浆并过滤，得到(5-氟苯并[d][1,3]间二氧杂环戊烯-4-基)甲胺的盐酸盐C6-1(800mg，定量)， 为白色固体。((5-Fluorobenzo[d][1,3]dioxol-4-yl)methyl)carbamic acid tert-butyl ester C6-1f (1.2 g, 10.11 mmol) was dissolved in dichloro A solution of 4M HCl in dioxane (15 mL, 60.6 mmol) was then. After stirring for 30 minutes, the volatiles were evaporated under reduced pressure. The crude product was pulverized with ethyl acetate (10 mL) and filtered to give (5-fluorobenzo[d][1,3]dioxol-4-yl)methylamine hydrochloride salt. 800 mg, quantitative), as a white solid.
1H NMR(400MHz,CDCl 3):δ8.46(s,D 2O exchangeable,3H),6.98-6.95(m,2H),6.75(t,J＝2.0Hz,2H),6.13(s,2H),3.96(s,2H)ppm；LC-MS:m/z 170.1[M+H] + . 1 H NMR (400MHz, CDCl 3 ): δ8.46 (s, D 2 O exchangeable, 3H), 6.98-6.95 (m, 2H), 6.75 (t, J = 2.0Hz, 2H), 6.13 (s, 2H ), 3.96 (s, 2H) ppm; LC-MS: m/z 170.1 [M+H] + .
使用实施例6的方法，使用起始原料4-氟-1,2-二甲氧基苯C6-1a，并在步骤二中使用1,2-二溴乙烷替代氯溴甲烷可得到以下化合物：Using the procedure of Example 6, using the starting material 4-fluoro-1,2-dimethoxybenzene C6-1a, and using 1,2-dibromoethane in place of chlorobromomethane in step two, the following compounds were obtained:
实施例7：中间体(6-氟-2,3-二氢苯并[b][1,4]二氧杂环己烯-5-基)甲胺(C6-2)。Example 7: Intermediate (6-fluoro-2,3-dihydrobenzo[b][1,4]dioxine-5-yl)methylamine (C6-2).
Figure PCTCN2018122557-appb-000169
Figure PCTCN2018122557-appb-000169
1H NMR(400MHz,DMSO-d 6):δ6.89(dd,J＝9.0,5.5Hz,1H),6.73(t,J＝9.0Hz,1H),4.33-4.31(m,2H),4.24-4.22(m,2H),3.86(d,J＝1.0Hz,2H)ppm；LC-MS:m/z 184.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6): δ6.89 (dd, J = 9.0,5.5Hz, 1H), 6.73 (t, J = 9.0Hz, 1H), 4.33-4.31 (m, 2H), 4.24 -4.22 (m, 2H), 3.86 (d, J = 1.0 Hz, 2H) ppm; LC-MS: m/z 184.1 [M+H] + .
实施例8：中间体4-(氨基甲基)-5-氟-2,3-二氢苯并呋喃-3-醇(C7-1)：Example 8: Intermediate 4-(Aminomethyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol (C7-1):
步骤一：中间体2-溴-3,6-二氟苯甲醛(C7-1b)：Step 1: Intermediate 2-bromo-3,6-difluorobenzaldehyde (C7-1b):
Figure PCTCN2018122557-appb-000170
Figure PCTCN2018122557-appb-000170
在500mL干燥的三口烧瓶中加入2-溴-1,4-二氟苯(C7-1a)(22g,114mmol)和干燥的THF(200mL)，冷却至–70℃。二异丙基氨基锂(2M,68.4mL)缓慢滴加入反应液中。反应液在相同温度下搅拌45分钟后，加入DMF(17.8mL,228mmol)。反应液在相同温度下搅拌两小时后升至0℃。饱和氯化铵(200mL)加入到反应液中。反应液用EtOAc(200mL X 2)萃取。合并的有机相用盐水洗涤一次，经无水硫酸钠干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(石油醚：乙酸乙酯＝100：1)，得到2-溴-3,6-二氟苯甲醛(C7-1b)(20g，79.4％产率)，为淡黄色固体。To a 500 mL dry three-necked flask was added 2-bromo-1,4-difluorobenzene (C7-1a) (22 g, 114 mmol) and dry THF (200 mL) and cooled to -70 °C. Lithium diisopropylamide (2M, 68.4 mL) was slowly added dropwise to the reaction mixture. After the reaction mixture was stirred at the same temperature for 45 minutes, DMF (17.8 mL, 228 mmol) was added. The reaction solution was stirred at the same temperature for two hours and then raised to 0 °C. Saturated ammonium chloride (200 mL) was added to the reaction mixture. The reaction was extracted with EtOAc (200 mL EtOAc). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate. The residue was purified on EtOAc EtOAc (EtOAc:EtOAc:EtOAc .
1H NMR(400MHz,CDCl3)δ10.34(s,1H),7.34(ddd,J＝9.2,7.4,4.5Hz,1H),7.16(td,J＝9.3,4.0Hz,1H)ppm. 1 H NMR (400 MHz, CDCl 3 ) δ 10.34 (s, 1H), 7.34 (ddd, J = 9.2, 7.4, 4.5 Hz, 1H), 7.16 (td, J = 9.3, 4.0 Hz, 1H) ppm.
步骤二：中间体2-溴-3-氟-6-甲氧基苯甲醛(C7-1c)Step 2: Intermediate 2-bromo-3-fluoro-6-methoxybenzaldehyde (C7-1c)
Figure PCTCN2018122557-appb-000171
Figure PCTCN2018122557-appb-000171
在2L的三口烧瓶中加入2-溴-3,6-二氟苯甲醛(C7-1b)(20g,90.5mmol)，用无水THF(1000ml)和MeOH(200ml)搅拌溶解。加入甲醇钠(5.87g,108.6mmol)，反应液在60℃。搅拌18小时。减压蒸馏除去大部分溶剂，加入500mL水。悬浊液搅拌30分钟后过滤，收集固体。固体用石油醚和乙酸乙酯(5:1)混合液打浆，过滤得到固体，减压干燥得到2-溴-3-氟-6-甲氧基苯甲醛(C7-1c)(18g,85％产率)，为黄色固体。To a 2 L three-necked flask was added 2-bromo-3,6-difluorobenzaldehyde (C7-1b) (20 g, 90.5 mmol), which was dissolved in anhydrous THF (1000 ml) and MeOH (200 ml). Sodium methoxide (5.87 g, 108.6 mmol) was added and the reaction was taken at 60 °C. Stir for 18 hours. Most of the solvent was distilled off under reduced pressure, and 500 mL of water was added. The suspension was stirred for 30 minutes, filtered, and a solid was collected. The solid was slurried with a mixture of petroleum ether and ethyl acetate (5:1), and filtered to give a solid, which was dried under reduced pressure to give 2-bromo-3-fluoro-6-methoxybenzaldehyde (C7-1c) (18 g, 85%) Yield) as a yellow solid.
LC-MS:m/z 233.1[M+H] + LC-MS: m/z 233.1 [M+H] +
步骤三：中间体2-溴-3-氟-6-羟基苯甲醛(C7-1d)：Step 3: Intermediate 2-bromo-3-fluoro-6-hydroxybenzaldehyde (C7-1d):
Figure PCTCN2018122557-appb-000172
Figure PCTCN2018122557-appb-000172
在1L的单口烧瓶中加入2-溴-3-氟-6-甲氧基苯甲醛(C7-1c)(16.8g,72.1mmol)和二氯甲烷(300mL)。在-78℃下缓慢滴加三溴化硼(21.7g,86.5mmol),反应液升至室温，并搅拌18小时。反应液用二氯甲烷(300mL)稀释，缓慢加入饱和碳酸氢钠(300mL)。有机相用盐水洗涤两次，经无水硫酸钠干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(石油醚：乙酸乙酯＝50：1)，得到2-溴-3-氟-6-羟基苯甲醛(C7-1d)(10g，63.3％产率)，为淡黄色固体。To a 1 L one-necked flask was added 2-bromo-3-fluoro-6-methoxybenzaldehyde (C7-1c) (16.8 g, 72.1 mmol) and dichloromethane (300 mL). Boron tribromide (21.7 g, 86.5 mmol) was slowly added dropwise at -78 ° C, and the reaction mixture was warmed to room temperature and stirred for 18 hours. The reaction was diluted with dichloromethane (300 mL) and EtOAc (EtOAc) The organic phase was washed twice with brine, dried over anhydrous sodium sulfate The residue was purified on EtOAc (EtOAc:EtOAc:EtOAc:EtOAc solid.
1H NMR(400MHz,CDCl3)δ11.77(s,1H),10.34(s,1H),7.29(dt,J＝12.7,6.3Hz,1H),6.94(dd,J＝9.3,4.1Hz,1H)ppm. 1 H NMR (400MHz, CDCl3) δ11.77 (s, 1H), 10.34 (s, 1H), 7.29 (dt, J = 12.7,6.3Hz, 1H), 6.94 (dd, J = 9.3,4.1Hz, 1H )ppm.
步骤四：中间体4-溴-5-氟-2,3-二氢苯并呋喃-3-醇(C7-1e)：Step 4: Intermediate 4-bromo-5-fluoro-2,3-dihydrobenzofuran-3-ol (C7-1e):
Figure PCTCN2018122557-appb-000173
Figure PCTCN2018122557-appb-000173
在干燥的三口烧瓶中加入三甲基碘化亚砜(9.73g,44.2mmol)和DMSO(50ml)。在冰水浴下加入叔丁醇钠(4.25g,44.2mmol)。反应液在室温下搅拌2小时，加入2-溴-3-氟-6-羟基苯甲醛(C7-1d)(8.8g，40.2mmol)。反应液在室温下搅拌18小时后，加入乙 酸乙酯(250ml)和水(250ml)，用乙酸乙酯萃取(250ml X 2)。有机相用水和盐水分别洗涤一次，经无水硫酸钠干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(石油醚：乙酸乙酯＝10：1)，得到4-溴-5-氟-2,3-二氢苯并呋喃-3-醇(C7-1e)(6.2g，66.2％产率)，为白色固体。Trimethyl iodide (9.73 g, 44.2 mmol) and DMSO (50 ml) were added to a dry three-neck flask. Sodium tert-butoxide (4.25 g, 44.2 mmol) was added under ice water bath. The reaction solution was stirred at room temperature for 2 hr, and then 2-bromo-3-fluoro-6-hydroxybenzaldehyde (C7-1d) (8.8 g, 40.2 mmol). After the reaction mixture was stirred at room temperature for 18 hr, ethyl acetate (250 ml) and water (250 ml). The organic phase was washed once with water and brine, dried over anhydrous sodium sulfate. The residue was purified on silica gel (EtOAc:EtOAc:EtOAc:EtOAc: 66.2% yield) as a white solid.
1H NMR(400MHz,CDCl 3)δ7.03(t,J＝8.7Hz,1H),6.76(dd,J＝8.8,3.5Hz,1H),5.51-5.40(m,1H),4.58(ddd,J＝13.4,10.8,4.6Hz,2H),2.33(d,J＝4.9Hz,1H)ppm. 1 H NMR (400 MHz, CDCl 3 ) δ 7.03 (t, J = 8.7 Hz, 1H), 6.76 (dd, J = 8.8, 3.5 Hz, 1H), 5.51-5.40 (m, 1H), 4.58 (ddd, J=13.4, 10.8, 4.6 Hz, 2H), 2.33 (d, J=4.9 Hz, 1H) ppm.
步骤五：中间体5-氟-3-羟基-2,3-二氢苯并呋喃-4-甲腈(C7-1f)：Step 5: Intermediate 5-Fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-carbonitrile (C7-1f):
Figure PCTCN2018122557-appb-000174
Figure PCTCN2018122557-appb-000174
在干燥的单口烧瓶中依次加入4-溴-5-氟-2,3-二氢苯并呋喃-3-醇(C7-1e)(2.7g,11.6mmol)，氰化锌(2.04g,17.4mmol)，DMF(50ml)和四三苯基膦钯(1.34g,1.16mmol)。反应液在氮气保护下加热至120℃，搅拌18小时。反应液冷却至室温，用乙酸乙酯(200mL X 3)和水(200ml)萃取。有机相用水和盐水分别洗涤一次，经无水硫酸钠干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(石油醚：乙酸乙酯＝5：1)，得到5-氟-3-羟基-2,3-二氢苯并呋喃-4-甲腈(C7-1f)(1.6g,77％产率),为白色固体。4-Bromo-5-fluoro-2,3-dihydrobenzofuran-3-ol (C7-1e) (2.7 g, 11.6 mmol), zinc cyanide (2.04 g, 17.4) was added successively to a dry one-neck flask. Methyl), DMF (50 ml) and tetrakistriphenylphosphine palladium (1.34 g, 1.16 mmol). The reaction solution was heated to 120 ° C under a nitrogen atmosphere and stirred for 18 hours. The reaction solution was cooled to room temperature and extracted with EtOAc EtOAc. The organic phase was washed once with water and brine, dried over anhydrous sodium sulfate. The residue was purified on silica gel (EtOAc:EtOAc:EtOAc:EtOAc: , 77% yield) as a white solid.
1H NMR(400MHz,CDCl 3)δ7.20-6.99(m,2H),5.63(dd,J＝6.9,2.9Hz,1H),4.69(dd,J＝10.8,7.1Hz,1H),4.55(dd,J＝10.8,3.1Hz,1H),2.74(s,1H)ppm. 1 H NMR (400MHz, CDCl 3 ) δ7.20-6.99 (m, 2H), 5.63 (dd, J = 6.9,2.9Hz, 1H), 4.69 (dd, J = 10.8,7.1Hz, 1H), 4.55 ( Dd, J = 10.8, 3.1 Hz, 1H), 2.74 (s, 1H) ppm.
步骤六：中间体4-(氨基甲基)-5-氟-2,3-二氢苯并呋喃-3-醇(C7-1)：Step 6: Intermediate 4-(Aminomethyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol (C7-1):
Figure PCTCN2018122557-appb-000175
Figure PCTCN2018122557-appb-000175
在100mL单口烧瓶中加入5-氟-3-羟基-2,3-二氢苯并呋喃-4-甲腈(C7-1f)(1.6g,8.9mmol)和四氢呋喃(10mL)。在冰水浴下，缓慢加入硼烷四氢呋喃(1M，36mL)。反应液在60℃下反应for 18小时。反应结束后，冷却至室温。缓慢滴加甲醇(10mL)，继续加热至60℃搅拌半小时。反应液减压浓缩，残余物用甲醇(50mL)溶解,继续加热至60℃搅拌半小时。反应液减压浓缩，得到4-(氨基甲基)-5-氟-2,3-二氢苯并呋喃-3-醇(C7-1)。To a 100 mL one-necked flask was added 5-fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-carbonitrile (C7-1f) (1.6 g, 8.9 mmol) and tetrahydrofuran (10 mL). Under ice water bath, borane tetrahydrofuran (1 M, 36 mL) was slowly added. The reaction solution was reacted at 60 ° C for 18 hours. After the reaction was completed, it was cooled to room temperature. Methanol (10 mL) was slowly added dropwise, and the mixture was further heated to 60 ° C and stirred for half an hour. The reaction mixture was concentrated under reduced pressure and the residue was evaporated mjjjjjjjj The reaction solution was concentrated under reduced pressure to give 4-(aminomethyl)-5-fluoro-2,3-dihydrobenzofuran-3-ol (C7-1).
实施例9：中间体(6-氟-4H-苯并[d][1,3]二氧杂环己烯-5-基)甲胺(C8-1)：Example 9: Intermediate (6-fluoro-4H-benzo[d][1,3]dioxine-5-yl)methylamine (C8-1):
步骤一：中间体3-溴-4-氟-2-(羟甲基)苯酚(C8-1a)：Step 1: Intermediate 3-bromo-4-fluoro-2-(hydroxymethyl)phenol (C8-1a):
Figure PCTCN2018122557-appb-000176
Figure PCTCN2018122557-appb-000176
在100mL单口瓶中加入2-溴-3-氟-6-羟基苯甲醛(C7-1d)(1g,4.6mmol)和甲醇(10ml)，冰浴下加入硼氢化钠(259mg,6.9mmol)。反应液在室温搅拌1小时。反应结束后，加入乙酸乙酯(200mL)稀释，并用水洗2次(100mL X 2)，有机相用硫酸钠干燥，旋蒸浓缩，残余物用硅胶柱(甲醇：二氯甲烷＝1:20)纯化得3-溴-4-氟-2-(羟甲基)苯酚(C8-1a)(680mg，67％产率)，为黄色油状物。To a 100 mL single-mouth bottle was added 2-bromo-3-fluoro-6-hydroxybenzaldehyde (C7-1d) (1 g, 4.6 mmol) and methanol (10 ml), and sodium borohydride (259 mg, 6.9 mmol). The reaction solution was stirred at room temperature for 1 hour. After completion of the reaction, the mixture was diluted with EtOAc (EtOAc) (EtOAc) Purification of 3-bromo-4-fluoro-2-(hydroxymethyl)phenol (C8-1a) ( 680 mg, 67% yield)
1H NMR(400MHz,CDCl 3)δ6.96(t,J＝8.4Hz,1H),6.79(dd,J＝9.0,4.5Hz,1H),5.09(s,2H),3.49(s,2H)ppm；LC-MS:m/z 223.1[M+H] + 1 H NMR (400 MHz, CDCl 3 ) δ 6.96 (t, J = 8.4 Hz, 1H), 6.79 (dd, J = 9.0, 4.5 Hz, 1H), 5.09 (s, 2H), 3.49 (s, 2H) Ppm; LC-MS: m/z 223.1 [M+H] +
步骤二：中间体5-溴-6-氟-4H-苯并[d][1,3]二氧杂环己烯(C8-1b)：Step 2: Intermediate 5-bromo-6-fluoro-4H-benzo[d][1,3]dioxine (C8-1b):
Figure PCTCN2018122557-appb-000177
Figure PCTCN2018122557-appb-000177
在干燥的50mL单口瓶中加入3-溴-4-氟-2-(羟甲基)苯酚(C8-1a)(500mg，2.26mmol)和无水DMF(25ml)，冰浴下加入60％的氢化钠(190mg，4.75mmol)。反应液于室温搅拌5分钟后加入碘化钠(339mg，2.26mmol)和氯溴甲烷(351mg,2.57mmol)。反应液在70℃搅拌3小时。反应结束后冷却至室温，加入100mL水，用乙酸乙酯萃取2次(50mL X 2)，有机相用食盐水(50mL)洗涤后用硫酸钠干燥，减压浓缩，残余物硅胶柱(纯石油醚)纯化得5-溴-6-氟-4H-苯并[d][1,3]二氧杂环己烯(C8-1b)(150mg，28％产率)，为无色固体。Add 3-bromo-4-fluoro-2-(hydroxymethyl)phenol (C8-1a) (500 mg, 2.26 mmol) and anhydrous DMF (25 ml) to a dry 50 mL vial and add 60% to the ice bath. Sodium hydride (190 mg, 4.75 mmol). After the reaction mixture was stirred at room temperature for 5 minutes, sodium iodide (339 mg, 2.26 mmol) and chlorobromomethane (351 mg, 2.57 mmol). The reaction solution was stirred at 70 ° C for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, and then added with 100 mL of EtOAc (EtOAc). Purification of 5-bromo-6-fluoro-4H-benzo[d][1,3]dioxine (C8-1b) (150 mg, 28% yield).
1H NMR(400MHz,CDCl 3)δ6.98(dd,J＝8.9,8.2Hz,1H),6.83(dd,J＝9.0,4.3Hz,1H),5.18(s,2H),4.82(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ6.98 (dd, J = 8.9,8.2Hz, 1H), 6.83 (dd, J = 9.0,4.3Hz, 1H), 5.18 (s, 2H), 4.82 (s, 2H).
步骤三：中间体6-氟-4H-苯并[d][1,3]二氧杂环己烯-5-腈(C8-1c)：Step 3: Intermediate 6-Fluoro-4H-benzo[d][1,3]dioxine-5-carbonitrile (C8-1c):
Figure PCTCN2018122557-appb-000178
Figure PCTCN2018122557-appb-000178
在50mL的三口烧瓶中依次加入5-溴-6-氟-4H-苯并[d][1,3]二氧杂环己烯(C8-1b)(150mg,0.64mmol)，氰化锌(113mg,0.97mmol)，四三苯基膦钯(74mg,0.064mmol)和无水N,N-二甲基甲酰胺(5mL)。反应混合物在氮气下100℃加热搅拌18个小时。冷却至室温后，加入20mL水，用乙酸乙酯萃取(20mL X 3)。合并的有机相用盐水洗涤两次，经无水硫酸钠干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(石油醚：乙酸乙酯＝100：1)，得到6-氟-4H-苯并[d][1,3]二氧杂环己烯-5-腈(C8-1c)(85mg，74％产率)，为白色固体。5-Bromo-6-fluoro-4H-benzo[d][1,3]dioxine (C8-1b) (150 mg, 0.64 mmol), zinc cyanide (5-mL) was placed in a 50 mL three-necked flask. 113 mg, 0.97 mmol), tetrakistriphenylphosphine palladium (74 mg, 0.064 mmol) and anhydrous N,N-dimethylformamide (5 mL). The reaction mixture was heated and stirred at 100 ° C for 18 hours under nitrogen. After cooling to room temperature, 20 mL of water was added and extracted with ethyl acetate (20 mL EtOAc). The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate The residue was purified on silica gel (EtOAc:EtOAc:EtOAc:EtOAc:EtOAc (85 mg, 74% yield) as a white solid.
1H NMR(400MHz,CDCl 3)δ7.11(dd,J＝9.2,4.7Hz,1H),7.04(t,J＝8.7Hz,1H),5.25(s,2H),5.01(s,2H). 1 H NMR (400MHz, CDCl 3 ) δ7.11 (dd, J = 9.2,4.7Hz, 1H), 7.04 (t, J = 8.7Hz, 1H), 5.25 (s, 2H), 5.01 (s, 2H) .
步骤四：中间体(6-氟-4H-苯并[d][1,3]二氧杂环己烯-5-基)甲胺(C8-1)：Step 4: Intermediate (6-fluoro-4H-benzo[d][1,3]dioxine-5-yl)methylamine (C8-1):
Figure PCTCN2018122557-appb-000179
Figure PCTCN2018122557-appb-000179
在25mL单口烧瓶中加入6-氟-4H-苯并[d][1,3]二氧杂环己烯-5-腈(C8-1c)(85mg,0.5mmol)和四氢呋喃(2mL)。在冰水浴下，缓慢加入BH 3的四氢呋喃溶液(1M in THF，2mL)。反应液在60℃下反应18小时。反应结束后，冷却至室温。缓慢滴加甲醇(1mL)，继续加热至60℃搅拌半小时。反应液减压浓缩，残余物用甲醇(10mL)溶解,继续加热至60℃搅拌半小时。反应液减压浓缩，得到的粗产品(6-氟-4H-苯并[d][1,3]二氧杂环己烯-5-基)甲胺(C8-1)(80mg,94％产率)。 In a 25 mL single-necked flask was added 6-fluoro-4H-benzo[d][1,3]dioxine-5-carbonitrile (C8-1c) (85 mg, 0.5 mmol) and tetrahydrofuran (2 mL). Under ice-cooling, tetrahydrofuran was slowly added BH 3. (1M in THF, 2mL). The reaction solution was reacted at 60 ° C for 18 hours. After the reaction was completed, it was cooled to room temperature. Methanol (1 mL) was slowly added dropwise, and the mixture was further heated to 60 ° C and stirred for half an hour. The reaction solution was concentrated under reduced pressure and the residue was evaporated mjjjl The reaction solution was concentrated under reduced pressure to give crude crystals ((-(4-(4-)))) Yield).
LCMS:m/z 184.1[M+H] +. LCMS: m/z 184.1 [M+H] + .
实施例10：(2,3-二氢呋喃并[3,2-c]吡啶-4-基)甲胺(C9-1)：Example 10: (2,3-Dihydrofuro[3,2-c]pyridin-4-yl)methylamine (C9-1):
步骤一：呋喃并[3,2-c]吡啶-4-甲腈(C9-1b)Step 1: furo[3,2-c]pyridine-4-carbonitrile (C9-1b)
Figure PCTCN2018122557-appb-000180
Figure PCTCN2018122557-appb-000180
在100mL的三口烧瓶中依次加入C9-1a(1.53g，10mmol)，氰化锌(0.94g，8mmol)，六水氯化镍(65mg,0.5mmol),1,1'-双(二苯基膦)二茂铁(332mg,0.6mmol),4-二甲氨基吡啶(1.12g,10mmol),Zn(520mg,8mmol)和无水乙腈(50mL)。反应混合物在氮气下80℃加热搅拌18个小时。冷却至室温后，加入200mL水，用乙酸乙酯萃取(200mL X 3)。合并的有机相用盐水洗涤两次，经无水硫酸钠干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(石油醚：乙酸乙酯＝5：1)，得到白色固体呋喃并[3,2-c]吡啶-4-甲腈C9-1b(300mg，21％产率)。C9-1a (1.53 g, 10 mmol), zinc cyanide (0.94 g, 8 mmol), nickel hexahydrate (65 mg, 0.5 mmol), 1,1'-bis(diphenyl) were sequentially added to a 100 mL three-necked flask. Phosphine) ferrocene (332 mg, 0.6 mmol), 4-dimethylaminopyridine (1.12 g, 10 mmol), Zn (520 mg, 8 mmol) and anhydrous acetonitrile (50 mL). The reaction mixture was heated and stirred at 80 ° C for 18 hours under nitrogen. After cooling to room temperature, 200 mL of water was added and extracted with ethyl acetate (200 mL EtOAc). The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate The residue was purified with EtOAc EtOAc EtOAc (EtOAc:EtOAc
1H NMR(400MHz,CDCl 3)δ8.62(d,J＝5.6Hz,1H),7.85(d,J＝2.3Hz,1H),7.67(dd,J＝5.6,1.0Hz,1H),7.08(dd,J＝2.3,1.0Hz,1H)ppm；LCMS:m/z 145.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.62 (d, J = 5.6 Hz, 1H), 7.85 (d, J = 2.3 Hz, 1H), 7.67 (dd, J = 5.6, 1.0 Hz, 1H), 7.08 (dd, J = 2.3, 1.0 Hz, 1H) ppm; LCMS: m/z 145.1 [M+H] + .
步骤二：((2,3-二氢呋喃并[3,2-c]吡啶-4-基)甲基)氨基甲酸叔丁酯(C9-1c)Step 2: ((2,3-Dihydrofuro[3,2-c]pyridin-4-yl)methyl)carbamic acid tert-butyl ester (C9-1c)
Figure PCTCN2018122557-appb-000181
Figure PCTCN2018122557-appb-000181
在100mL单口瓶中依次加入呋喃并[3,2-c]吡啶-4-甲腈C9-1b(150mg，1.04mmol)，BOC酸酐(227mg，1.04mmol)，甲醇(20mL)和10％钯碳(15mg,含50％水)。反应混合物用氢气鼓气5分钟，用氢气球换气三次，在氢气球下60℃搅拌18小时。混合物经硅藻土过滤，用甲醇(50mL X 2)洗涤，滤液减压浓缩，得到标题化合物C9-1c(200mg,77％产率)。Furano[3,2-c]pyridine-4-carbonitrile C9-1b (150 mg, 1.04 mmol), BOC anhydride (227 mg, 1.04 mmol), methanol (20 mL) and 10% palladium carbon were sequentially added to a 100 mL vial. (15 mg, containing 50% water). The reaction mixture was purged with hydrogen for 5 minutes, ventilated three times with a hydrogen balloon, and stirred at 60 ° C for 18 hours under a hydrogen balloon. The mixture was filtered over EtOAc (EtOAc)EtOAc.
1H NMR(400MHz,CDCl 3)δ8.14(d,J＝5.4Hz,1H),7.23(t,J＝5.7Hz,1H),6.74(d,J＝5.4Hz,1H),4.61(t,J＝8.9Hz,2H),4.17(t,J＝10.9Hz,2H),3.19(t,J＝8.8Hz,2H),1.39(s,9H)ppm；LCMS:m/z 251.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.14 (d, J = 5.4Hz, 1H), 7.23 (t, J = 5.7Hz, 1H), 6.74 (d, J = 5.4Hz, 1H), 4.61 (t , J=8.9 Hz, 2H), 4.17 (t, J = 10.9 Hz, 2H), 3.19 (t, J = 8.8 Hz, 2H), 1.39 (s, 9H) ppm; LCMS: m/z 251.1 [M+ H] + .
步骤三：(2,3-二氢呋喃并[3,2-c]吡啶-4-基)甲胺(C9-1)Step 3: (2,3-dihydrofuro[3,2-c]pyridin-4-yl)methylamine (C9-1)
Figure PCTCN2018122557-appb-000182
Figure PCTCN2018122557-appb-000182
在50mL单口瓶中依次加入((2,3-二氢呋喃并[3,2-c]吡啶-4-基)甲基)氨基甲酸叔丁酯C9-1b(200mg，0.8mmol)和15mL CF 3COOH/二氯甲烷(1：1)，室温搅拌4小时。反应完毕，混合物在减压下浓缩，得到白色固体(2,3-二氢呋喃并[3,2-c]吡啶-4-基)甲胺C9-1c(100mg，83％产率)。 Add ((2,3-dihydrofuro[3,2-c]pyridin-4-yl)methyl)carbamic acid tert-butyl ester C9-1b (200 mg, 0.8 mmol) and 15 mL CF in a 50 mL vial. 3 COOH/dichloromethane (1:1), stirred at room temperature for 4 hours. After completion of the reaction, the mixture was evaporated. mjjjjjjjjjj
1H NMR(400MHz,DMSO)δ8.34(t,J＝7.6Hz,3H),6.96(dd,J＝17.2,8.7Hz,1H),4.71(t,J＝8.9Hz,2H),4.10(s,2H),3.31-3.18(m,2H)ppm；LCMS:m/z 151.1[M+H] +. 1 H NMR (400 MHz, DMSO) δ 8.34 (t, J = 7.6 Hz, 3H), 6.96 (dd, J = 17.2, 8.7 Hz, 1H), 4.71 (t, J = 8.9 Hz, 2H), 4.10 ( s, 2H), 3.31-3.18 (m, 2H) ppm; LCMS: m/z 151.1 [M+H] + .
实施例11：中间体5-溴-2–(((2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮(A-1)Example 11: Intermediate 5-bromo-2 -(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methylpyrimidin-4(3H)-one (A- 1)
Figure PCTCN2018122557-appb-000183
Figure PCTCN2018122557-appb-000183
在干燥的50mL圆底烧瓶中依次加入5-溴-2-氯-3-甲基嘧啶-4(3H)-酮B1(100mg，0.45mmol)，(2,3-二氢苯并呋喃-4-基)甲胺C1-1(67mg,0.45mmol)，碳酸氢钠(75.6mg，0.9mmol)和正丁醇10毫升，60摄氏度下反应8小时。加水20毫升，乙酸乙酯萃取3次，有机相用无水硫酸钠干燥，减压浓缩。浓缩液用硅胶柱层析法纯化，以展开剂体系(石油醚:乙酸乙酯＝2:1)洗脱，得到产物5-溴-2-(((2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮A-1(80mg，产率52.9％)，淡黄色固体。5-Bromo-2-chloro-3-methylpyrimidin-4(3H)-one B1 (100 mg, 0.45 mmol), (2,3-dihydrobenzofuran-4) was added sequentially to a dry 50 mL round bottom flask. Methylamine C1-1 (67 mg, 0.45 mmol), sodium hydrogencarbonate (75.6 mg, 0.9 mmol) and n-butanol 10 ml, and reacted at 60 ° C for 8 hours. After adding 20 ml of water, the mixture was extracted with EtOAc. The concentrate was purified by silica gel column chromatography eluting with EtOAc EtOAc (EtOAc:EtOAc 4-yl)methyl)amino)-3-methylpyrimidin-4(3H)-one A-1 (80 mg, yield 52.9%), pale yellow solid.
1H NMR(400MHz,CDCl 3)δ7.94(s,1H),7.17(d,J＝7.3Hz,1H),7.09(d,J＝7.6Hz,1H),6.84(t,J＝7.5Hz,1H),5.54(s,1H),4.68–4.57(m,4H),3.44(s,3H),3.25(t,J＝8.7Hz,2H)ppm；LCMS:m/z 336.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.94 (s, 1H), 7.17 (d, J = 7.3 Hz, 1H), 7.09 (d, J = 7.6 Hz, 1H), 6.84 (t, J = 7.5 Hz) , 1H), 5.54 (s, 1H), 4.68 - 4.57 (m, 4H), 3.44 (s, 3H), 3.25 (t, J = 8.7 Hz, 2H) ppm; LCMS: m/z 336.1 [M+H ] + .
使用实施例11的方法，用类似的中间体原料反应得到中间体A-2、A-3、A-4、A-5、A-6、A-7、A-8、A-9、A-10、A-11、A-12、A-13、A-14、A-15、A-16、A-17、A-18、A-19、A-20、A-21。Using the method of Example 11, a similar intermediate starting material was reacted to give intermediates A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A. -10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19, A-20, A-21.
Figure PCTCN2018122557-appb-000184
Figure PCTCN2018122557-appb-000184
Figure PCTCN2018122557-appb-000185
Figure PCTCN2018122557-appb-000185
Figure PCTCN2018122557-appb-000186
Figure PCTCN2018122557-appb-000186
Figure PCTCN2018122557-appb-000187
Figure PCTCN2018122557-appb-000187
Figure PCTCN2018122557-appb-000188
Figure PCTCN2018122557-appb-000188
Figure PCTCN2018122557-appb-000189
Figure PCTCN2018122557-appb-000189
实施例12：化合物2-(((2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 12: Compound 2-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-(methylsulfonyl)phenyl)pyrimidine- 4(3H)-ketone
Figure PCTCN2018122557-appb-000190
Figure PCTCN2018122557-appb-000190
在20mL的封管中室温下依次加入中间体A-1(60mg,0.18mmol)，1,4-二氧六环(2mL),纯净水(0.5mL)，(4-(甲基磺酰基)苯基)硼酸(54mg，0.27mmol)，[1,1'-双(二苯基膦基)二茂铁]二氯化钯(13mg，0.018mmol)和碳酸钾(50mg，0.36mmol)。氮气鼓泡一分钟，封管加热至80摄氏度，反应6个小时。反应完毕，向反应液中加入20mL水并用乙酸乙酯(50mL×3)萃取。有机相依次用水(20mL×1)，饱和食盐水(20mL×1)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱法(石油醚：乙酸乙酯＝1：1)得到粗产物。然后粗产品溶于甲醇(3mL)，用高效液相色谱柱纯化得到2–(((2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(甲基磺酰基)苯基)嘧啶-4(3H)-酮(16.3mg，产率：22.1％)，为白色固体。Intermediate A-1 (60 mg, 0.18 mmol), 1,4-dioxane (2 mL), purified water (0.5 mL), (4-(methylsulfonyl)). Phenyl)boronic acid (54 mg, 0.27 mmol), [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride (13 mg, 0.018 mmol) and potassium carbonate (50 mg, 0.36 mmol). Nitrogen was bubbled for one minute, and the tube was heated to 80 ° C for 6 hours. After completion of the reaction, 20 mL of water was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 3). The organic phase was washed successively with water (20 mL×1) and brine (20 mL×1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated. The crude product was obtained by column chromatography ( petroleum ether: ethyl acetate = 1:1). The crude product was then dissolved in methanol (3 mL) and purified by high-performance liquid chromatography column to give 2-(((2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5- (4-(Methylsulfonyl)phenyl)pyrimidine-4(3H)-one (16.3 mg, yield: 22.1%) as a white solid.
1H NMR(400MHz,CD 3OD)δ7.92(s,1H),7.80(q,J＝8.8Hz,4H),6.96(t,J＝7.8Hz,1H),6.72(d,J＝7.7Hz,1H),6.54(d,J＝7.9Hz,1H),4.54(d,J＝13.3Hz,2H),4.46(t,J＝8.7Hz,2H),3.42(s,3H),3.15(d,J＝8.8Hz,2H),3.02(s,3H)ppm；LCMS:m/z 412.1,[M+H] +。 1 H NMR (400 MHz, CD 3 OD) δ 7.92 (s, 1H), 7.80 (q, J = 8.8 Hz, 4H), 6.96 (t, J = 7.8 Hz, 1H), 6.72 (d, J = 7.7) Hz, 1H), 6.54 (d, J = 7.9 Hz, 1H), 4.54 (d, J = 13.3 Hz, 2H), 4.46 (t, J = 8.7 Hz, 2H), 3.42 (s, 3H), 3.15 ( d, J = 8.8 Hz, 2H), 3.02 (s, 3H) ppm; LCMS: m/z 412.1, [M+H] + .
采用实施例12的方法，使用中间体A-1、A-2、A-3、A-4、A-5、A-6、A-7、A-8、A-9、A-10、A-11、A-12、A-13、A-14、A-15、A-16、A-17、A-18、A-19、A-20、A-21和对应的硼酸或硼酸酯可以合成以下化合物：Using the method of Example 12, intermediates A-1, A-2, A-3, A-4, A-5, A-6, A-7, A-8, A-9, A-10, A-11, A-12, A-13, A-14, A-15, A-16, A-17, A-18, A-19, A-20, A-21 and the corresponding boric acid or boric acid Esters can be synthesized into the following compounds:
实施例13：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 13: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-(methylsulfonyl)phenyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000191
Figure PCTCN2018122557-appb-000191
1H NMR(400MHz,CDCl 3)δ7.98(s,1H),7.92(d,J＝8.6Hz,2H),7.86-7.80(m,2H),6.91-6.78(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.27(s,1H),4.70(d,J＝5.5Hz,2H),4.63(t,J＝8.7Hz,2H),3.46(s,3H),3.38(t,J＝8.5Hz,2H),3.05(s,3H)ppm；LC-MS:m/z430.1[M+H] +。 1 H NMR (400MHz, CDCl 3 ) δ7.98 (s, 1H), 7.92 (d, J = 8.6Hz, 2H), 7.86-7.80 (m, 2H), 6.91-6.78 (m, 1H), 6.67 ( Dd, J = 8.7, 4.0 Hz, 1H), 5.27 (s, 1H), 4.70 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.46 (s, 3H), 3.38 (t, J = 8.5 Hz, 2H), 3.05 (s, 3H) ppm; LC-MS: m/z 430.1 [M+H] + .
实施例14：2-(((6-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 14: 2-(((6-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-(methylsulfonyl)phenyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000192
Figure PCTCN2018122557-appb-000192
1H NMR(400MHz,CDCl 3)δ7.97(s,1H),7.92(s,2H),7.84(d,J＝10.4Hz,2H),6.51(ddd,J＝19.7,9.5,2.2Hz,2H),5.08(t,J＝5.1Hz,1H),4.67(t,J＝8.7Hz,2H),4.63(d,J＝5.3Hz,2H),3.51(s,3H),3.22-3.16(m,2H),3.05(s,3H)ppm；LC-MS:m/z 430.1[M+H] + 1 H NMR (400MHz, CDCl 3 ) δ7.97 (s, 1H), 7.92 (s, 2H), 7.84 (d, J = 10.4Hz, 2H), 6.51 (ddd, J = 19.7,9.5,2.2Hz, 2H), 5.08 (t, J = 5.1 Hz, 1H), 4.67 (t, J = 8.7 Hz, 2H), 4.63 (d, J = 5.3 Hz, 2H), 3.51 (s, 3H), 3.22-3.16 ( m, 2H), 3.05 (s, 3H) ppm; LC-MS: m/z 430.1 [M+H] +
实施例15：2-(((7-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 15: 2-(((7-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-(methylsulfonyl)phenyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000193
Figure PCTCN2018122557-appb-000193
1H NMR(400MHz,DMSO-d6)δ8.08(s,1H),7.99(t,J＝5.4Hz,1H),7.93(d,J＝8.5Hz,2H),7.85(d,J＝8.5Hz,2H),6.98(dd,J＝10.7,8.6Hz,1H),6.81(dd,J＝8.4,4.2Hz,1H),4.67(t,J＝8.8Hz,2H),4.53(d,J＝5.2Hz,2H),3.43(s,3H),3.29(d,J＝8.8Hz,2H),3.20(s,3H)ppm；LC-MS:m/z 430.1[M+H] +。 1 H NMR (400MHz, DMSO- d6) δ8.08 (s, 1H), 7.99 (t, J = 5.4Hz, 1H), 7.93 (d, J = 8.5Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 6.98 (dd, J = 10.7, 8.6 Hz, 1H), 6.81 (dd, J = 8.4, 4.2 Hz, 1H), 4.67 (t, J = 8.8 Hz, 2H), 4.53 (d, J) = 5.2 Hz, 2H), 3.43 (s, 3H), 3.29 (d, J = 8.8 Hz, 2H), 3.20 (s, 3H) ppm; LC-MS: m/z 430.1 [M+H] + .
实施例16：3-甲基-2-(((5-甲基-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 16: 3-Methyl-2-(((5-methyl-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(4-(methylsulfonyl)benzene Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000194
Figure PCTCN2018122557-appb-000194
1H NMR(400MHz,CDCl 3-d1)δ8.03(s,1H),7.98-7.91(m,2H),7.89-7.82(m,2H),7.01(t,J＝7.5Hz,1H),6.72(t,J＝7.5Hz,1H),4.61(dt,J＝15.0,4.3Hz,5H),3.43(s,3H),3.31-3.22(m,2H),3.06(s,3H),2.33(d,J＝9.8Hz,3H)ppm；LC-MS:m/z 426.1[M+H] +。 1 H NMR (400 MHz, CDCl 3 -d1) δ 8.03 (s, 1H), 7.98-7.91 (m, 2H), 7.89-7.82 (m, 2H), 7.01 (t, J = 7.5 Hz, 1H), 6.72 (t, J = 7.5 Hz, 1H), 4.61 (dt, J = 15.0, 4.3 Hz, 5H), 3.43 (s, 3H), 3.31-3.22 (m, 2H), 3.06 (s, 3H), 2.33 (d, J = 9.8 Hz, 3H) ppm; LC-MS: m/z 426.1 [M+H] + .
实施例17：2-(((5-氟苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 17: 2-(((5-Fluorobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-(methylsulfonyl)phenyl)pyrimidine-4 (3H) -ketone
Figure PCTCN2018122557-appb-000195
Figure PCTCN2018122557-appb-000195
1H NMR(400MHz,CD 3OD)δ8.04(s,1H),7.92(d,J＝8.6Hz,2H),7.85(d,J＝8.7Hz,2H),7.56-7.45(m,1H),7.42(dd,J＝8.9,3.8Hz,1H),7.06(dd,J＝13.6,5.3Hz,2H),4.97(s,2H),3.45(s,3H),3.10(d,J＝1.3Hz,3H)ppm；LC-MS:m/z 428.1[M+H] +. 1 H NMR (400MHz, CD 3 OD) δ8.04 (s, 1H), 7.92 (d, J = 8.6Hz, 2H), 7.85 (d, J = 8.7Hz, 2H), 7.56-7.45 (m, 1H ), 7.42 (dd, J = 8.9, 3.8 Hz, 1H), 7.06 (dd, J = 13.6, 5.3 Hz, 2H), 4.97 (s, 2H), 3.45 (s, 3H), 3.10 (d, J = 1.3 Hz, 3H) ppm; LC-MS: m/z 428.1 [M+H] + .
实施例18：2-(((6-氟-2,3-二氢苯并呋喃-7-基)甲基)氨基)-3-甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 18: 2-(((6-Fluoro-2,3-dihydrobenzofuran-7-yl)methyl)amino)-3-methyl-5-(4-(methylsulfonyl)phenyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000196
Figure PCTCN2018122557-appb-000196
1H NMR(400MHz,CDCl 3)δ8.02(s,1H),7.97-7.88(m,2H),7.85-7.79(m,1H),7.18-6.91(m,1H),6.62(dd,J＝10.0,8.2Hz,1H),5.58(t,J＝5.0Hz,1H),4.76(d,J＝5.1Hz,2H),4.71(t,J＝8.7Hz,2H),3.47(s,3H),3.23(t,J＝8.7Hz,2H),3.05(s,3H)ppm；LC-MS:m/z430.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.02 (s, 1H), 7.97-7.88 (m, 2H), 7.85-7.79 (m, 1H), 7.18-6.91 (m, 1H), 6.62 (dd, J =10.0, 8.2 Hz, 1H), 5.58 (t, J = 5.0 Hz, 1H), 4.76 (d, J = 5.1 Hz, 2H), 4.71 (t, J = 8.7 Hz, 2H), 3.47 (s, 3H) ), 3.23 (t, J = 8.7 Hz, 2H), 3.05 (s, 3H) ppm; LC-MS: m/z 430.1 [M+H] + .
实施例19：1-乙基-6-(((6-氟-2,3-二氢苯并呋喃-7-基)甲基)氨基)-5'-甲基-[3,3'-联吡啶]-2(1H)-酮Example 19: 1-Ethyl-6-(((6-fluoro-2,3-dihydrobenzofuran-7-yl)methyl)amino)-5'-methyl-[3,3'- Bipyridyl]-2(1H)-one
Figure PCTCN2018122557-appb-000197
Figure PCTCN2018122557-appb-000197
1H NMR(400MHz,DMSO-d 6)δ7.81(t,J＝5.0Hz,1H),7.72(d,J＝1.0Hz,1H),7.45(td,J＝8.6,6.9Hz,1H),7.27-7.16(m,1H),7.07(td,J＝8.6,2.5Hz,1H),6.89(dd,J＝17.4,7.0Hz,1H),6.65(dt,J＝7.7,3.8Hz,1H),4.57-4.48(m,4H),4.01(q,J＝7.0Hz,2H),3.28(d,J＝8.7Hz,2H),1.16-1.09(m,3H)ppm；LC-MS:m/z 381.1[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.81 (t, J = 5.0 Hz, 1H), 7.72 (d, J = 1.0 Hz, 1H), 7.45 (td, J = 8.6, 6.9 Hz, 1H) , 7.27-7.16 (m, 1H), 7.07 (td, J = 8.6, 2.5 Hz, 1H), 6.89 (dd, J = 17.4, 7.0 Hz, 1H), 6.65 (dt, J = 7.7, 3.8 Hz, 1H) ), 4.57-4.48 (m, 4H), 4.01 (q, J = 7.0 Hz, 2H), 3.28 (d, J = 8.7 Hz, 2H), 1.16-1.09 (m, 3H) ppm; LC-MS: m /z 381.1[M+H] + .
实施例20：3-乙基-2-(((5-氟苯并[d][1,3]二噁唑-4-基)甲基)氨基)-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 20: 3-ethyl-2-(((5-fluorobenzo[d][1,3]dioxazol-4-yl)methyl)amino)-5-(4-methylpyridine- 3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000198
Figure PCTCN2018122557-appb-000198
1H NMR(400MHz,CDCl 3)δ8.46(s,1H),8.41(d,J＝5.0Hz,1H),7.70(s,1H),7.13(d,J＝5.0Hz,1H),6.72(dd,J＝8.6,4.3Hz,1H),6.60(dd,J＝10.5,8.6Hz,1H),6.04(s,2H),5.30(t,J＝5.0Hz,1H),4.76(d,J＝5.2Hz,2H),4.06(q,J＝7.3Hz,2H),2.25(s,3H),1.34(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 383.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.46 (s, 1H), 8.41 (d, J = 5.0Hz, 1H), 7.70 (s, 1H), 7.13 (d, J = 5.0Hz, 1H), 6.72 (dd, J = 8.6, 4.3 Hz, 1H), 6.60 (dd, J = 10.5, 8.6 Hz, 1H), 6.04 (s, 2H), 5.30 (t, J = 5.0 Hz, 1H), 4.76 (d, J = 5.2 Hz, 2H), 4.06 (q, J = 7.3 Hz, 2H), 2.25 (s, 3H), 1.34 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 383.1 [M +H] + .
实施例21：2-(((5-氟苯并[d][1,3]二噁唑-4-基)甲基)氨基)-3-甲基-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 21: 2-(((5-Fluorobenzo[d][1,3]dioxazol-4-yl)methyl)amino)-3-methyl-5-(4-methylpyridine- 3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000199
Figure PCTCN2018122557-appb-000199
1H NMR(400MHz,MeOD)δ8.38(s,1H),8.33(d,J＝5.0Hz,1H),7.73(s,1H),7.23(d,J＝5.1Hz,1H),6.70(dd,J＝8.5,4.3Hz,1H),6.56(dd,J＝10.6,8.6Hz,1H),6.00(s,2H),4.72(s,2H),3.47(s,3H)ppm；LC-MS:m/z 369.1[M+H] + 。 1 H NMR (400MHz, MeOD) δ8.38 (s, 1H), 8.33 (d, J = 5.0Hz, 1H), 7.73 (s, 1H), 7.23 (d, J = 5.1Hz, 1H), 6.70 ( Dd, J = 8.5, 4.3 Hz, 1H), 6.56 (dd, J = 10.6, 8.6 Hz, 1H), 6.00 (s, 2H), 4.72 (s, 2H), 3.47 (s, 3H) ppm; LC- MS: m/z 369.1 [M + H] + .
实施例22：2-(((5-氟-3-羟基-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 22: 2-(((5-Fluoro-3-hydroxy-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-(methylsulfonate) Acyl)phenyl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000200
Figure PCTCN2018122557-appb-000200
1H NMR(400MHz,DMSO-d 6)δ8.09(s,1H),7.94(d,J＝8.7Hz,2H),7.90-7.83(m,2H),7.07(dd,J＝10.2,8.8Hz,1H),6.79(dd,J＝8.7,3.7Hz,1H),5.92(d,J＝5.8Hz,1H),5.57(t,J＝5.0Hz,1H),4.84-4.73(m,1H),4.62(dd,J＝14.5,4.7Hz,1H),4.54(dd,J＝10.3,6.7Hz,1H),4.33(dd,J＝10.3,2.4Hz,1H),3.37(s,3H),3.21(s,3H)ppm；LC-MS:m/z 456.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.09 (s, 1H), 7.94 (d, J = 8.7Hz, 2H), 7.90-7.83 (m, 2H), 7.07 (dd, J = 10.2,8.8 Hz, 1H), 6.79 (dd, J = 8.7, 3.7 Hz, 1H), 5.92 (d, J = 5.8 Hz, 1H), 5.57 (t, J = 5.0 Hz, 1H), 4.84 - 4.73 (m, 1H) ), 4.62 (dd, J = 14.5, 4.7 Hz, 1H), 4.54 (dd, J = 10.3, 6.7 Hz, 1H), 4.33 (dd, J = 10.3, 2.4 Hz, 1H), 3.37 (s, 3H) , 3.21 (s, 3H) ppm; LC-MS: m/z 456.1 [M+H] + .
实施例23:2-(((5-氟-3-氧代-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(甲基磺酰基)苯基)嘧啶-4(3H)-酮Example 23: 2-(((5-Fluoro-3-oxo-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-(A) Sulfonyl)phenyl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000201
Figure PCTCN2018122557-appb-000201
1H NMR(400MHz,CDCl 3)δ8.50(d,J＝3.9Hz,1H),7.68(s,1H),7.58(d,J＝7.2Hz,1H),7.26-7.15(m,1H),6.86(t,J＝9.5Hz,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.15(s,1H),4.63(t,J＝8.8Hz,2H),3.47(s,3H),3.39(t,J＝8.6Hz,2H),2.53(s,3H)ppm. 1 H NMR (400MHz, CDCl 3 ) δ8.50 (d, J = 3.9Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 7.2Hz, 1H), 7.26-7.15 (m, 1H) , 6.86 (t, J = 9.5 Hz, 1H), 6.69 (dd, J = 8.6, 3.9 Hz, 1H), 5.15 (s, 1H), 4.63 (t, J = 8.8 Hz, 2H), 3.47 (s, 3H), 3.39 (t, J = 8.6 Hz, 2H), 2.53 (s, 3H) ppm.
实施例24：2-(((6-氟色烷-5-基)甲基)氨基)-3-甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 24: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(4-(methylsulfonyl)phenyl)pyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000202
Figure PCTCN2018122557-appb-000202
1H NMR(400MHz,CDCl 3)δ8.00(s,1H),7.98-7.90(m,2H),7.90-7.81(m,2H),6.88(t,J＝9.3Hz,1H),6.78(dd,J＝9.0,5.1Hz,1H),5.02(s,1H),4.72(dd,J＝5.2,1.4Hz,2H),4.19-4.10(m,2H),3.45(s,3H),3.05(s,3H),2.95(t,J＝6.6Hz,2H),2.11-1.98(m,2H)ppm；LC-MS:m/z 444[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.00 (s, 1H), 7.98-7.90 (m, 2H), 7.90-7.81 (m, 2H), 6.88 (t, J = 9.3Hz, 1H), 6.78 ( Dd, J=9.0, 5.1 Hz, 1H), 5.02 (s, 1H), 4.72 (dd, J=5.2, 1.4 Hz, 2H), 4.19-4.10 (m, 2H), 3.45 (s, 3H), 3.05 (s, 3H), 2.95 (t, J = 6.6 Hz, 2H), 2.11-1.98 (m, 2H) ppm; LC-MS: m/z 444 [M+H] + .
实施例25：2-(((6-氟-2,3-二氢苯并[b][1,4]二氧杂环己烯-5-基)甲基)氨基)-3-甲基-5-(2-甲基吡啶-3-基)嘧啶4(3H)-酮Example 25: 2-(((6-Fluoro-2,3-dihydrobenzo[b][1,4]dioxine-5-yl)methyl)amino)-3-methyl -5-(2-methylpyridin-3-yl)pyrimidine 4(3H)-one
Figure PCTCN2018122557-appb-000203
Figure PCTCN2018122557-appb-000203
1H NMR(400MHz,CDCl 3)δ8.48(d,J＝4.0Hz,1H),7.72(s,1H),7.53(d,J＝7.2Hz,1H),7.22-7.12(m,1H),6.84(dd,J＝9.0,5.5Hz,1H),6.65(t,J＝9.0Hz,1H),5.16(s,1H),4.75(d,J＝4.8Hz,2H),4.32(dd,J＝31.8,3.9Hz,4H),3.45(s,3H),2.51(s,3H)ppm；LCMS:m/z383.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.48 (d, J = 4.0Hz, 1H), 7.72 (s, 1H), 7.53 (d, J = 7.2Hz, 1H), 7.22-7.12 (m, 1H) , 6.84 (dd, J = 9.0, 5.5 Hz, 1H), 6.65 (t, J = 9.0 Hz, 1H), 5.16 (s, 1H), 4.75 (d, J = 4.8 Hz, 2H), 4.32 (dd, J = 31.8, 3.9 Hz, 4H), 3.45 (s, 3H), 2.51 (s, 3H) ppm; LCMS: m/z 383.1 [M+H] + .
实施例26：2-(((6-氟-4H-苯并[d][1,3]二氧杂环己烯-5-基)甲基)氨基)-3-甲基-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 26: 2-(((6-Fluoro-4H-benzo[d][1,3]dioxe-5-yl)methyl)amino)-3-methyl-5- ( 2-methylpyridin-3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000204
Figure PCTCN2018122557-appb-000204
1H NMR(400MHz,CDCl 3)δ8.49(d,J＝4.0Hz,1H),7.68(s,1H),7.53(d,J＝6.5Hz,1H),7.19(dd,J＝7.4,5.2Hz,1H),6.97(t,J＝9.4Hz,1H),6.86(dd,J＝9.0,4.8Hz,1H),5.21(s,4H),5.12(s,1H),4.57(d,J＝5.1Hz,2H),3.45(s,3H),2.50(s,3H)ppm；LCMS:m/z 383.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.49 (d, J = 4.0Hz, 1H), 7.68 (s, 1H), 7.53 (d, J = 6.5Hz, 1H), 7.19 (dd, J = 7.4, 5.2 Hz, 1H), 6.97 (t, J = 9.4 Hz, 1H), 6.86 (dd, J = 9.0, 4.8 Hz, 1H), 5.21 (s, 4H), 5.12 (s, 1H), 4.57 (d, J = 5.1 Hz, 2H), 3.45 (s, 3H), 2.50 (s, 3H) ppm; LCMS: m/z 383.1 [M+H] + .
实施例27：2-(((7-氟-2,3,4,5-四氢苯并[b]噁庚-6-基)甲基)氨基)-3-甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 27: 2-(((7-Fluoro-2,3,4,5-tetrahydrobenzo[b]oxo-6-yl)methyl)amino)-3-methyl-5-(4 -(Methanesulfonyl)phenyl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000205
Figure PCTCN2018122557-appb-000205
1H NMR(400MHz,MeOD)δ8.05(s,1H),7.94(d,J＝8.4Hz,2H),7.87(d,J＝8.4Hz,2H),6.97(dd,J＝8.6,5.1Hz,1H),6.88(t,J＝9.1Hz,1H),4.72(d,J＝8.8Hz,2H),4.05-3.95(m,2H),3.42(d,J＝12.8Hz,3H),3.12(s,3H),3.00-2.91(m,2H),1.99(dd,J＝10.6,5.4Hz,2H),1.73(d,J＝5.1Hz,2H)ppm；LC-MS:m/z 458.1[M+H] +. 1 H NMR (400MHz, MeOD) δ8.05 (s, 1H), 7.94 (d, J = 8.4Hz, 2H), 7.87 (d, J = 8.4Hz, 2H), 6.97 (dd, J = 8.6,5.1 Hz, 1H), 6.88 (t, J = 9.1 Hz, 1H), 4.72 (d, J = 8.8 Hz, 2H), 4.05 - 3.95 (m, 2H), 3.42 (d, J = 12.8 Hz, 3H), 3.12(s,3H), 3.00-2.91 (m, 2H), 1.99 (dd, J = 10.6, 5.4 Hz, 2H), 1.73 (d, J = 5.1 Hz, 2H) ppm; LC-MS: m/z 458.1 [M+H] + .
实施例28：2–(((2,3-二氢呋喃并[3,2-c]吡啶-4-基)甲基)氨基)-3-甲基-5-(4-(三氟甲基)苯基)嘧啶-4(3H)-酮Example 28: 2 - ((2,3-dihydrofuro[3,2-c]pyridin-4-yl)methyl)amino)-3-methyl-5-(4-(trifluoromethyl) Phenyl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000206
Figure PCTCN2018122557-appb-000206
1H NMR(400MHz,DMSO)δ8.19(d,J＝5.5Hz,1H),8.04(s,1H),7.98(s,1H),7.88(d,J＝8.3Hz,2H),7.68(d,J＝8.2Hz,2H),6.77(d,J＝5.3Hz,1H),4.64(t,J＝7.2Hz,4H),3.44(s,3H),2(m,2H)；LCMS:m/z 403.1[M+H] +. 1 H NMR (400 MHz, DMSO) δ 8.19 (d, J = 5.5 Hz, 1H), 8.04 (s, 1H), 7.78 (s, 1H), 7.78 (d, J = 8.3 Hz, 2H), 7.68 ( d, J = 8.2 Hz, 2H), 6.77 (d, J = 5.3 Hz, 1H), 4.64 (t, J = 7.2 Hz, 4H), 3.44 (s, 3H), 2 (m, 2H); LCMS: m/z 403.1 [M+H] + .
实施例29：2-(((5-氟苯并呋喃-4-基)氘代甲基)氨基)-3-甲基-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 29: 2-(((5-Fluorobenzofuran-4-yl)deuteromethyl)amino)-3-methyl-5-(4-methylpyridin-3-yl)pyrimidine-4 ( 3H)-ketone
Figure PCTCN2018122557-appb-000207
Figure PCTCN2018122557-appb-000207
1H NMR(400MHz,CDCl 3)δ8.52(d,J＝3.9Hz,1H),8.43(d,J＝5.0Hz,1H),7.75(s,1H),7.71(d,J＝2.2Hz,1H),7.46(ddd,J＝8.9,3.9,0.8Hz,1H),7.19(d,J＝5.1Hz,1H),7.09(dd,J＝10.2,9.0Hz,1H),7.01(t,J＝3.7Hz,1H),5.10(s,1H),3.44(s,3H),2.27(s,3H)ppm；LC-MS:m/z 367.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.52 (d, J = 3.9 Hz, 1H), 8.43 (d, J = 5.0 Hz, 1H), 7.75 (s, 1H), 7.71 (d, J = 2.2 Hz) , 1H), 7.46 (ddd, J = 8.9, 3.9, 0.8 Hz, 1H), 7.19 (d, J = 5.1 Hz, 1H), 7.09 (dd, J = 10.2, 9.0 Hz, 1H), 7.01 (t, J = 3.7 Hz, 1H), 5.10 (s, 1H), 3.44 (s, 3H), 2.27 (s, 3H) ppm; LC-MS: m/z 367.1 [M+H] + .
实施例30：2-(((5-氟-2,3-二氢苯并呋喃-4-基)氘代甲基)氨基)-3-甲基-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 30: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)deuteromethyl)amino)-3-methyl-5-(2-methylpyridine-3 -yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000208
Figure PCTCN2018122557-appb-000208
1H NMR(400MHz,CDCl 3)δ8.50(d,J＝3.9Hz,1H),7.68(s,1H),7.58(d,J＝7.2Hz,1H),7.26-7.15(m,1H),6.86(t,J＝9.5Hz,1H),6.69(dd,J＝8.6,3.9Hz,1H),5.15(s,1H),4.63(t,J＝8.8Hz,2H),3.47(s,3H),3.39(t,J＝8.6Hz,2H),2.53(s,3H)ppm；LC-MS:m/z369.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.50 (d, J = 3.9Hz, 1H), 7.68 (s, 1H), 7.58 (d, J = 7.2Hz, 1H), 7.26-7.15 (m, 1H) , 6.86 (t, J = 9.5 Hz, 1H), 6.69 (dd, J = 8.6, 3.9 Hz, 1H), 5.15 (s, 1H), 4.63 (t, J = 8.8 Hz, 2H), 3.47 (s, 3H), 3.39 (t, J = 8.6 Hz, 2H), 2.53 (s, 3H) ppm; LC-MS: m/z 369.1 [M+H] + .
实施例31：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-氘代甲基-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 31: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-deuteromethyl-5-(4-(methylsulfonyl) Phenyl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000209
Figure PCTCN2018122557-appb-000209
1H NMR(400MHz,CDCl 3)δ7.98(s,1H),7.93(d,J＝8.5Hz,2H),7.84(d,J＝8.5Hz,2H),6.90-6.80(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.19(t,J＝5.3Hz,1H),4.75-4.57(m,4H),3.39(t,J＝8.7Hz,2H),3.05(s,3H)ppm；LCMS:m/z 433.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.98 (s, 1H), 7.93 (d, J = 8.5Hz, 2H), 7.84 (d, J = 8.5Hz, 2H), 6.90-6.80 (m, 1H) , 6.67 (dd, J = 8.7, 4.0 Hz, 1H), 5.19 (t, J = 5.3 Hz, 1H), 4.75 - 4.57 (m, 4H), 3.39 (t, J = 8.7 Hz, 2H), 3.05 ( s, 3H) ppm; LCMS: m/z 433.1 [M+H] + .
实施例32：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-氘代甲基-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 32: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-deuteromethyl-5-(2-methylpyridine-3 -yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000210
Figure PCTCN2018122557-appb-000210
1H NMR(400MHz,CDCl 3)δ8.48(d,J＝3.5Hz,1H),7.67(s,1H),7.50(d,J＝7.6Hz,1H),7.15(dd,J＝7.5,4.9Hz,1H),6.90-6.83(m,1H),6.69(dd,J＝8.6,4.0Hz,1H),5.10(s,1H),4.72-4.59(m,4H),3.39(t,J＝8.7Hz,2H),2.49(s,3H)ppm；LC-MS:m/z 370.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.48 (d, J = 3.5 Hz, 1H), 7.67 (s, 1H), 7.50 (d, J = 7.6 Hz, 1H), 7.15 (dd, J = 7.5, 4.9 Hz, 1H), 6.90-6.83 (m, 1H), 6.69 (dd, J=8.6, 4.0 Hz, 1H), 5.10 (s, 1H), 4.72-4.59 (m, 4H), 3.39 (t, J) = 8.7 Hz, 2H), 2.49 (s, 3H) ppm; LC-MS: m/z 370.1 [M+H] + .
实施例33：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-氘代甲基-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 33: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-deuteromethyl-5-(4-methylpyridine-3 -yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000211
Figure PCTCN2018122557-appb-000211
1H NMR(400MHz,CDCl 3)δ8.39(d,J＝4.5Hz,1H),8.31(s,1H),7.69(s,1H),7.17(d,J＝4.8Hz,1H),6.88-6.76(m,1H),6.65(dd,J＝8.7,4.0Hz,1H),5.67(t,J＝5.2Hz,1H),4.73-4.53(m,4H),3.37(t,J＝8.7Hz,2H),2.26(s,3H)ppm；LCMS:m/z 383.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.39 (d, J = 4.5Hz, 1H), 8.31 (s, 1H), 7.69 (s, 1H), 7.17 (d, J = 4.8Hz, 1H), 6.88 -6.76 (m, 1H), 6.65 (dd, J = 8.7, 4.0 Hz, 1H), 5.67 (t, J = 5.2 Hz, 1H), 4.73-4.53 (m, 4H), 3.37 (t, J = 8.7) Hz, 2H), 2.26 (s, 3H) ppm; LCMS: m/z 383.1 [M+H] + .
实施例34:2-(((5-氟-2,3-二氢苯并呋喃-4-基)氘代甲基)氨基)-3-氘代甲基-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 34: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)deuteromethyl)amino)-3-deuteromethyl-5-(2-methylpyridine -3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000212
Figure PCTCN2018122557-appb-000212
1H NMR(400MHz,CDCl 3)δ8.48(dd,J＝4.9,1.6Hz,1H),7.69(s,1H),7.51(dd,J＝7.6,1.5Hz,1H),7.16(dd,J＝7.5,4.9Hz,1H),6.91-6.83(m,1H),6.69(dd,J＝8.7,4.0Hz,1H),5.09(s,1H),4.62(t,J＝8.7Hz,2H),3.40(t,J＝8.7Hz,2H),2.50(s,3H)ppm；LCMS:m/z372.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.48 (dd, J = 4.9,1.6Hz, 1H), 7.69 (s, 1H), 7.51 (dd, J = 7.6,1.5Hz, 1H), 7.16 (dd, J = 7.5, 4.9 Hz, 1H), 6.91-6.83 (m, 1H), 6.69 (dd, J = 8.7, 4.0 Hz, 1H), 5.09 (s, 1H), 4.62 (t, J = 8.7 Hz, 2H) ), 3.40 (t, J = 8.7 Hz, 2H), 2.50 (s, 3H) ppm; LCMS: m/z 372.1 [M+H] + .
实施例35：2-(((6-氟苯并二氢吡喃-5-基)甲基)氨基)-3-氘代甲基-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 35: 2-(((6-Fluorobenzopyran-5-yl)methyl)amino)-3-deuteromethyl-5-(2-methylpyridin-3-yl)pyrimidine -4(3H)-ketone
Figure PCTCN2018122557-appb-000213
Figure PCTCN2018122557-appb-000213
1H NMR(400MHz,CDCl 3)δ8.49(s,1H),7.70(s,1H),7.51(d,J＝7.9Hz,1H),7.16(s,1H),6.90(t,J＝9.3Hz,1H),6.80(d,J＝4.4Hz,1H),4.87(s,1H),4.71(s,2H),4.15(s,2H),2.96(s,2H),2.50(s,3H),2.05(s,2H)ppm；LCMS:m/z 384.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.49 (s, 1H), 7.70 (s, 1H), 7.51 (d, J = 7.9Hz, 1H), 7.16 (s, 1H), 6.90 (t, J = 9.3 Hz, 1H), 6.80 (d, J = 4.4 Hz, 1H), 4.87 (s, 1H), 4.71 (s, 2H), 4.15 (s, 2H), 2.96 (s, 2H), 2.50 (s, 3H), 2.05 (s, 2H) ppm; LCMS: m/z 384.1 [M+H] + .
实施例36:2-(((6-氟苯并二氢吡喃-5-基)甲基)氨基)-3-氘代甲基-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 36: 2-(((6-Fluorobenzopyran-5-yl)methyl)amino)-3-deuteromethyl-5-(4-methylpyridin-3-yl)pyrimidine -4(3H)-ketone
Figure PCTCN2018122557-appb-000214
Figure PCTCN2018122557-appb-000214
1H NMR(400MHz,CDCl 3)δ8.42(d,J＝5.0Hz,1H),8.35(s,1H),7.72(s,1H),7.17(d,J＝5.0Hz,1H),6.89(t,J＝9.2Hz,1H),6.79(dd,J＝9.0,5.0Hz,1H),4.92(d,J＝4.7Hz,1H),4.70(dd,J＝5.1,1.3Hz,2H),4.22-4.10(m,2H),2.96(t,J＝6.6Hz,2H),2.27(s,3H),2.09-2.01(m,2H)ppm；LCMS:m/z 384.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.42 (d, J = 5.0Hz, 1H), 8.35 (s, 1H), 7.72 (s, 1H), 7.17 (d, J = 5.0Hz, 1H), 6.89 (t, J = 9.2 Hz, 1H), 6.79 (dd, J = 9.0, 5.0 Hz, 1H), 4.92 (d, J = 4.7 Hz, 1H), 4.70 (dd, J = 5.1, 1.3 Hz, 2H) , 4.22-4.10 (m, 2H), 2.96 (t, J = 6.6 Hz, 2H), 2.27 (s, 3H), 2.09-2.01 (m, 2H) ppm; LCMS: m/z 384.1 [M+H] + .
实施例37：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-氘代甲基-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 37: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-deuteromethyl-5-(4-methylpyridine-3 -yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000215
Figure PCTCN2018122557-appb-000215
1H NMR(400MHz,CDCl 3)δ8.39(d,J＝4.5Hz,1H),8.31(s,1H),7.69(s,1H),7.17(d,J＝4.8Hz,1H),6.88-6.76(m,1H),6.65(dd,J＝8.7,4.0Hz,1H),5.67(t,J＝5.2Hz,1H),4.73-4.53(m,4H),3.37(t,J＝8.7Hz,2H),2.26(s,3H)ppm；LCMS:m/z 383.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.39 (d, J = 4.5Hz, 1H), 8.31 (s, 1H), 7.69 (s, 1H), 7.17 (d, J = 4.8Hz, 1H), 6.88 -6.76 (m, 1H), 6.65 (dd, J = 8.7, 4.0 Hz, 1H), 5.67 (t, J = 5.2 Hz, 1H), 4.73-4.53 (m, 4H), 3.37 (t, J = 8.7) Hz, 2H), 2.26 (s, 3H) ppm; LCMS: m/z 383.1 [M+H] + .
实施例38：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 38: 3-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(4-(methylsulfonyl)phenyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000216
Figure PCTCN2018122557-appb-000216
1H NMR(400MHz,CDCl 3)δ7.95(s,1H),7.93(d,J＝8.6Hz,2H),7.87-7.82(m,2H),6.89-6.82(m,1H),6.67(dd,J＝8.6,4.0Hz,1H),5.25(s,1H),4.68(d,J＝5.6Hz,2H),4.64(t,J＝8.7Hz,2H),4.06(q,J＝7.2Hz,2H),3.40(t,J＝8.7Hz,2H),3.05(s,3H),1.34(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 444.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.95 (s, 1H), 7.93 (d, J = 8.6Hz, 2H), 7.87-7.82 (m, 2H), 6.89-6.82 (m, 1H), 6.67 ( Dd, J = 8.6, 4.0 Hz, 1H), 5.25 (s, 1H), 4.68 (d, J = 5.6 Hz, 2H), 4.64 (t, J = 8.7 Hz, 2H), 4.06 (q, J = 7.2) Hz, 2H), 3.40 (t, J = 8.7 Hz, 2H), 3.05 (s, 3H), 1.34 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 444.1 [M+H] + .
实施例39：3-烯丙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(4-(甲磺酰)苯基)嘧啶-4(3H)-酮Example 39: 3-allyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(4-(methylsulfonyl)benzene Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000217
Figure PCTCN2018122557-appb-000217
1H NMR(400MHz,CDCl 3)δ7.99(s,1H),7.92(d,J＝8.5Hz,2H),7.85(d,J＝8.5Hz,2H),6.88-6.79(m,1H),6.66(dd,J＝8.6,4.0Hz,1H),5.97-5.79(m,1H),5.43(t,J＝5.4Hz,1H),5.34(dd,J＝21.6,13.9Hz,2H),4.72(d,J＝5.4Hz,2H),4.68-4.56(m,4H),3.38(t,J＝8.7Hz,2H),3.05(s,3H)ppm；LC-MS:m/z 456.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.99 (s, 1H), 7.92 (d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H), 6.88-6.79 (m, 1H) , 6.66 (dd, J = 8.6, 4.0 Hz, 1H), 5.97-5.79 (m, 1H), 5.43 (t, J = 5.4 Hz, 1H), 5.34 (dd, J = 21.6, 13.9 Hz, 2H), 4.72 (d, J = 5.4 Hz, 2H), 4.68-4.56 (m, 4H), 3.38 (t, J = 8.7 Hz, 2H), 3.05 (s, 3H) ppm; LC-MS: m/z 456.1 [ M+H] + .
实施例40：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(5-氟吡啶-3-基)-3,6-二甲基嘧啶-4(3H)-酮Example 40: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(5-fluoropyridin-3-yl)-3,6- Dimethylpyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000218
Figure PCTCN2018122557-appb-000218
1H NMR(400MHz,DMSO-d 6)δ8.46(d,J＝2.8Hz,1H),8.29(t,J＝1.8Hz,1H),7.77(t,J＝5.2Hz,1H),7.60(ddd,J＝10.2,2.8,1.7Hz,1H),6.89(dd,J＝10.4,8.6Hz,1H),6.66(dd,J＝8.6,3.8Hz,1H),4.62-4.49(m,4H),3.33(s,2H),3.31(s,3H),2.02(s,3H)ppm；LCMS:m/z385.1[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.46 (d, J = 2.8 Hz, 1H), 8.29 (t, J = 1.8 Hz, 1H), 7.77 (t, J = 5.2 Hz, 1H), 7.60 (ddd, J = 10.2, 2.8, 1.7 Hz, 1H), 6.89 (dd, J = 10.4, 8.6 Hz, 1H), 6.66 (dd, J = 8.6, 3.8 Hz, 1H), 4.62-4.49 (m, 4H) ), 3.33 (s, 2H), 3.31 (s, 3H), 2.02 (s, 3H) ppm; LCMS: m/z 385.1 [M+H] + .
实施例41：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3,6-二甲基-5-(吡啶-4-基)嘧啶-4(3H)-酮Example 41: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3,6-dimethyl-5-(pyridin-4-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000219
Figure PCTCN2018122557-appb-000219
1H NMR(400MHz,DMSO-d 6)δ8.57-8.48(m,2H),7.74(t,J＝5.3Hz,1H),7.31-7.18(m,2H),6.89(dd,J＝10.4,8.6Hz,1H),6.65(dd,J＝8.6,3.8Hz,1H),4.59-4.50(m,4H),3.33(s,2H),3.31(s,3H),2.01(s,3H)ppm；LCMS:m/z 367.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.57-8.48 (m, 2H), 7.74 (t, J = 5.3Hz, 1H), 7.31-7.18 (m, 2H), 6.89 (dd, J = 10.4 , 8.6 Hz, 1H), 6.65 (dd, J = 8.6, 3.8 Hz, 1H), 4.59-4.50 (m, 4H), 3.33 (s, 2H), 3.31 (s, 3H), 2.01 (s, 3H) Ppm; LCMS: m/z 367.1 [M+H] + .
实施例42：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3,6-二甲基-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 42: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3,6-dimethyl-5-(4-methylpyridine- 3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000220
Figure PCTCN2018122557-appb-000220
1H NMR(400MHz,CDCl 3)δ8.43(s,1H),8.37(s,1H),6.94(d,J＝10.8Hz,1H),6.83-6.76(m,1H),6.61(dd,J＝8.6,3.9Hz,1H),5.02(s,1H),4.59(dt,J＝17.4,7.1Hz,4H),3.40-3.33(m,5H),2.08(s,3H),1.89(s,3H)ppm；LC-MS:m/z 381.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.43 (s, 1H), 8.37 (s, 1H), 6.94 (d, J = 10.8Hz, 1H), 6.83-6.76 (m, 1H), 6.61 (dd, J=8.6, 3.9 Hz, 1H), 5.02 (s, 1H), 4.59 (dt, J = 17.4, 7.1 Hz, 4H), 3.40-3.33 (m, 5H), 2.08 (s, 3H), 1.89 (s) , 3H) ppm; LC-MS: m/z 381.1 [M+H] + .
实施例43:2-(((6-氟苯并二氢吡喃-5-基)甲基)氨基)-3,6-二甲基-5-(4-(甲基磺酰基)苯基)嘧啶-4(3H)-酮Example 43: 2-(((6-Fluorobenzopyran-5-yl)methyl)amino)-3,6-dimethyl-5-(4-(methylsulfonyl)phenyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000221
Figure PCTCN2018122557-appb-000221
1H NMR(400MHz,DMSO-d 6)δ7.88(d,J＝8.4Hz,2H),7.53-7.44(m,3H),6.93(t,J＝9.3Hz,1H),6.72(dd,J＝9.0,4.8Hz,1H),4.51(d,J＝4.8Hz,2H),4.08(dd,J＝5.9,4.1Hz,2H),3.29(s,3H),3.24(s,2H),2.94(t,J＝6.5Hz,2H),2.01(s,3H),1.93(dd,J＝6.1,5.4Hz,2H)ppm；LCMS:m/z 358.1[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.88 (d, J = 8.4 Hz, 2H), 7.53 - 7.44 (m, 3H), 6.93 (t, J = 9.3 Hz, 1H), 6.72 (dd, J=9.0, 4.8 Hz, 1H), 4.51 (d, J=4.8 Hz, 2H), 4.08 (dd, J=5.9, 4.1 Hz, 2H), 3.29 (s, 3H), 3.24 (s, 2H), 2.94 (t, J = 6.5 Hz, 2H), 2.01 (s, 3H), 1.93 (dd, J = 6.1, 5.4 Hz, 2H) ppm; LCMS: m/z 358.1 [M+H] + .
实施例44:4-(2-(((6-氟苯并二氢吡喃-5-基)甲基)氨基)-1,4-二甲基-6-氧代-1,6-二氢嘧啶-5-基)苯甲酰胺Example 44: 4-(2-((6-fluorochroman-5-yl)methyl)amino)-1,4-dimethyl-6-oxo-1,6-di Hydropyrimidin-5-yl)benzamide
Figure PCTCN2018122557-appb-000222
Figure PCTCN2018122557-appb-000222
1H NMR(400MHz,DMSO-d 6)δ7.97(s,1H),7.86-7.76(m,2H),7.46-7.31(m,2H),7.27(d,J＝8.3Hz,2H),6.93(t,J＝9.3Hz,1H),6.71(dd,J＝8.9,4.8Hz,1H),4.57-4.40(m,2H),4.17-4.03(m,2H),3.28(s,3H),2.94(t,J＝6.5Hz,2H),1.99(s,3H),1.93(p,J＝6.2Hz,2H)ppm；LCMS:m/z 423.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ7.97 (s, 1H), 7.86-7.76 (m, 2H), 7.46-7.31 (m, 2H), 7.27 (d, J = 8.3Hz, 2H), 6.93 (t, J = 9.3 Hz, 1H), 6.71 (dd, J = 8.9, 4.8 Hz, 1H), 4.57-4.40 (m, 2H), 4.17-4.03 (m, 2H), 3.28 (s, 3H) , 2.94 (t, J = 6.5 Hz, 2H), 1.99 (s, 3H), 1.93 (p, J = 6.2 Hz, 2H) ppm; LCMS: m/z 423.1 [M+H] + .
实施例45:2-(((6-氟苯并二氢吡喃-5-基)甲基)氨基)-3,6-二甲基-5-(吡啶-4-基)嘧啶-4(3H)-酮Example 45: 2-(((6-Fluorobenzopyran-5-yl)methyl)amino)-3,6-dimethyl-5-(pyridin-4-yl)pyrimidine-4 ( 3H)-ketone
Figure PCTCN2018122557-appb-000223
Figure PCTCN2018122557-appb-000223
1H NMR(400MHz,DMSO-d 6)δ8.60-8.47(m,2H),7.51(t,J＝4.8Hz,1H),7.29-7.13(m,2H),6.92(t,J＝9.3Hz,1H),6.71(dd,J＝9.0,4.8Hz,1H),4.51(d,J＝4.7Hz,2H),4.07(dd,J＝5.9,4.2Hz,2H),3.29(s,3H),2.93(t,J＝6.5Hz,2H),2.03(s,3H),1.96-1.85(m,2H)ppm；LCMS:m/z 381.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.60-8.47 (m, 2H), 7.51 (t, J = 4.8Hz, 1H), 7.29-7.13 (m, 2H), 6.92 (t, J = 9.3 Hz, 1H), 6.71 (dd, J = 9.0, 4.8 Hz, 1H), 4.51 (d, J = 4.7 Hz, 2H), 4.07 (dd, J = 5.9, 4.2 Hz, 2H), 3.29 (s, 3H) ), 2.93 (t, J = 6.5 Hz, 2H), 2.03 (s, 3H), 1.96-1.85 (m, 2H) ppm; LCMS: m/z 381.1 [M+H] + .
实施例46:2-(((6-氟苯并二氢吡喃-5-基)甲基)氨基)-3,6-二甲基-5-(4-(三氟甲基)苯基)嘧啶-4(3H)-酮Example 46: 2-(((6-Fluorobenzopyran-5-yl)methyl)amino)-3,6-dimethyl-5-(4-(trifluoromethyl)phenyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000224
Figure PCTCN2018122557-appb-000224
1H NMR(400MHz,DMSO-d 6)δ7.69(d,J＝8.1Hz,2H),7.44(d,J＝8.0Hz,3H),6.93(t,J＝9.3Hz,1H),6.72(dd,J＝9.0,4.8Hz,1H),4.51(d,J＝4.6Hz,2H),4.08(t,J＝5.1Hz,2H),3.29(s,3H),2.94(t,J＝6.6Hz,2H),2.00(s,3H),1.92(q,J＝6.3,5.9Hz,2H)ppm；LCMS:m/z 448.1[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 7.69 (d, J = 8.1 Hz, 2H), 7.44 (d, J = 8.0 Hz, 3H), 6.93 (t, J = 9.3 Hz, 1H), 6.72 (dd, J = 9.0, 4.8 Hz, 1H), 4.51 (d, J = 4.6 Hz, 2H), 4.08 (t, J = 5.1 Hz, 2H), 3.29 (s, 3H), 2.94 (t, J = 6.6 Hz, 2H), 2.00 (s, 3H), 1.92 (q, J = 6.3, 5.9 Hz, 2H) ppm; LCMS: m/z 448.1 [M+H] + .
实施例47:3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-6-甲基-5-(6-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 47: 3-ethyl-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-methyl-5-(6-methyl) Pyridin-3-yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000225
Figure PCTCN2018122557-appb-000225
1H NMR(400MHz,CDCl 3)δ8.36(d,J＝1.8Hz,1H),7.54(dd,J＝8.0,2.2Hz,1H),7.18(d,J＝8.0Hz,1H),6.90-6.80(m,1H),6.66(dd,J＝8.6,4.0Hz,1H),5.18(t,J＝5.7Hz,1H),4.74-4.54(m,4H),3.99(q,J＝7.2Hz,2H),3.46(t,J＝8.7Hz,2H),2.57(s,3H),2.11(s,3H),1.29(t,J＝7.3Hz,3H)ppm；LCMS:m/z 395.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.36 (d, J = 1.8 Hz, 1H), 7.54 (dd, J = 8.0, 2.2 Hz, 1H), 7.18 (d, J = 8.0 Hz, 1H), 6.90 -6.80 (m, 1H), 6.66 (dd, J = 8.6, 4.0 Hz, 1H), 5.18 (t, J = 5.7 Hz, 1H), 4.74 - 4.54 (m, 4H), 3.99 (q, J = 7.2) Hz, 2H), 3.46 (t, J = 8.7 Hz, 2H), 2.57 (s, 3H), 2.11 (s, 3H), 1.29 (t, J = 7.3 Hz, 3H) ppm; LCMS: m/z 395.1 [M+H] + .
实施例48：3-乙基-2-(((6-氟苯并二氢吡喃-5-基)甲基)氨基)-6-甲基-5-(6-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 48: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-6-methyl-5-(6-methylpyridine-3- Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000226
Figure PCTCN2018122557-appb-000226
1H NMR(400MHz,CDCl 3)δ8.37(s,1H),7.56(d,J＝7.0Hz,1H),7.18(d,J＝7.7Hz,1H),6.95-6.70(m,2H),5.00(s,1H),4.67(s,2H),4.15(s,2H),3.98(d,J＝6.5Hz,2H),3.08(s,2H),2.57(s,3H),2.12(s,3H),2.04(s,2H),1.28(s,3H)ppm；LCMS:m/z 409.2[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.37 (s, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.18 (d, J = 7.7 Hz, 1H), 6.95-6.70 (m, 2H) , 5.00 (s, 1H), 4.67 (s, 2H), 4.15 (s, 2H), 3.98 (d, J = 6.5 Hz, 2H), 3.08 (s, 2H), 2.57 (s, 3H), 2.12 ( s, 3H), 2.04 (s, 2H), 1.28 (s, 3H) ppm; LCMS: m/z 409.2 [M+H] + .
实施例49：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(4-氟苯基)-3-甲基嘧啶-4(3H)-酮Example 49: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(4-fluorophenyl)-3-methylpyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000227
Figure PCTCN2018122557-appb-000227
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.63-7.49(m,2H),7.14-7.01(m,2H),6.91-6.77(m,1H),6.66(dd,J＝8.7,4.0Hz,1H),5.06(s,1H),4.67(d,J＝5.5Hz,2H),4.62(t,J＝8.7Hz,2H),3.44(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 371.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.84 (s, 1H), 7.63-7.49 (m, 2H), 7.14-7.01 (m, 2H), 6.91-6.77 (m, 1H), 6.66 (dd, J = 8.7, 4.0 Hz, 1H), 5.06 (s, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.62 (t, J = 8.7 Hz, 2H), 3.44 (s, 3H), 3.38 (t , J = 8.7 Hz, 2H) ppm; LC-MS: m/z 371.1 [M+H] + .
实施例50：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(3-氟苯基)-3-甲基嘧啶-4(3H)-酮Example 50: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(3-fluorophenyl)-3-methylpyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000228
Figure PCTCN2018122557-appb-000228
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.76(t,J＝5.2Hz,1H),7.51(dd,J＝18.7,9.6Hz,2H),7.36(dd,J＝14.6,7.9Hz,1H),7.09-6.99(m,1H),6.94-6.83(m,1H),6.65(dd,J＝8.6,3.8Hz,1H),4.59(d,J＝5.1Hz,2H),4.53(t,J＝8.7Hz,2H),3.37(s,3H),3.27(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 370.1[M+H] + 1 H NMR (400MHz, DMSO- d6) δ8.03 (s, 1H), 7.76 (t, J = 5.2Hz, 1H), 7.51 (dd, J = 18.7,9.6Hz, 2H), 7.36 (dd, J =14.6, 7.9 Hz, 1H), 7.09-6.99 (m, 1H), 6.94-6.83 (m, 1H), 6.65 (dd, J = 8.6, 3.8 Hz, 1H), 4.59 (d, J = 5.1 Hz, 2H), 4.53 (t, J = 8.7 Hz, 2H), 3.37 (s, 3H), 3.27 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 370.1 [M+H] +
实施例51：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(2-氟苯基)-3-甲基嘧啶-4(3H)-酮Example 51: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(2-fluorophenyl)-3-methylpyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000229
Figure PCTCN2018122557-appb-000229
1H NMR(400MHz,CDCl 3)δ7.84(d,J＝1.4Hz,1H),7.44(td,J＝7.6,1.8Hz,1H),7.31-7.26(m,1H),7.18-7.06(m,2H),6.89-6.80(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.09(t,J＝5.0Hz,1H),4.68(d,J＝5.5Hz,2H),4.62(t,J＝8.7Hz,2H),3.44(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LCMS:m/z 370.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.84 (d, J = 1.4 Hz, 1H), 7.44 (td, J = 7.6, 1.8 Hz, 1H), 7.31 - 7.26 (m, 1H), 7.18 - 7.06 ( m, 2H), 6.89-6.80 (m, 1H), 6.67 (dd, J = 8.7, 4.0 Hz, 1H), 5.09 (t, J = 5.0 Hz, 1H), 4.68 (d, J = 5.5 Hz, 2H) ), 4.62 (t, J = 8.7 Hz, 2H), 3.44 (s, 3H), 3.38 (t, J = 8.7 Hz, 2H) ppm; LCMS: m/z 370.1 [M+H] + .
实施例52：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-(三氟甲基)苯基)嘧啶-4(3H)-酮Example 52: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-(trifluoromethyl)benzene Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000230
Figure PCTCN2018122557-appb-000230
1H NMR(400MHz,DMSO-d6)δ8.07(s,1H),7.89(d,J＝8.2Hz,2H),7.83(t,J＝5.2Hz,1H),7.67(d,J＝8.4Hz,2H),6.94-6.86(m,1H),6.66(dd,J＝8.6,3.8Hz,1H),4.60(d,J＝5.1Hz,2H),4.53(t,J＝8.7Hz,2H),3.38(s,3H),3.28(t,J＝8.7Hz,2H)ppm；LC-MS:m/z420.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.07 (s, 1H), 7.89 (d, J = 8.2Hz, 2H), 7.83 (t, J = 5.2Hz, 1H), 7.67 (d, J = 8.4 Hz, 2H), 6.94 - 6.86 (m, 1H), 6.66 (dd, J = 8.6, 3.8 Hz, 1H), 4.60 (d, J = 5.1 Hz, 2H), 4.53 (t, J = 8.7 Hz, 2H) ), 3.38 (s, 3H), 3.28 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 420.1 [M+H] + .
实施例53：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(4-甲氧苯基)-3-甲基嘧啶-4(3H)-酮Example 53: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(4-methoxyphenyl)-3-methylpyrimidine- 4(3H)-ketone
Figure PCTCN2018122557-appb-000231
Figure PCTCN2018122557-appb-000231
1H NMR(400MHz,CDCl 3)δ7.83(s,1H),7.56-7.50(m,2H),6.96-6.89(m,2H),6.88-6.80(m,1H),6.66(dd,J＝8.7,4.0Hz,1H),4.98(s,1H),4.66(d,J＝5.5Hz,2H),4.62(t,J＝8.7Hz,2H),3.82(s,3H),3.44(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 382.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.83 (s, 1H), 7.56-7.50 (m, 2H), 6.96-6.89 (m, 2H), 6.88-6.80 (m, 1H), 6.66 (dd, J = 8.7, 4.0 Hz, 1H), 4.98 (s, 1H), 4.66 (d, J = 5.5 Hz, 2H), 4.62 (t, J = 8.7 Hz, 2H), 3.82 (s, 3H), 3.44 (s) , 3H), 3.38 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 382.1 [M+H] + .
实施例54：4-(2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-基)苯酰胺Example 54: 4-(2-((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl-1,6-di Hydropyrimidin-5-yl)benzamide
Figure PCTCN2018122557-appb-000232
Figure PCTCN2018122557-appb-000232
1H NMR(400MHz,DMSO-d6)δ8.03(s,1H),7.91(s,1H),7.83(d,J＝8.4Hz,2H),7.76(t,J＝5.2Hz,1H),7.73(d,J＝8.4Hz,2H),7.28(s,1H),6.94-6.86(m,1H),6.65(dd,J＝8.6,3.8Hz,1H),4.59(d,J＝5.1Hz,2H),4.53(t,J＝8.7Hz,2H),3.38(s,3H),3.28(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 395.1[M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 8.03 (s, 1H), 7.91 (s, 1H), 7.83 (d, J = 8.4 Hz, 2H), 7.76 (t, J = 5.2 Hz, 1H), 7.73 (d, J = 8.4 Hz, 2H), 7.28 (s, 1H), 6.94 - 6.86 (m, 1H), 6.65 (dd, J = 8.6, 3.8 Hz, 1H), 4.59 (d, J = 5.1 Hz) , 2H), 4.53 (t, J = 8.7 Hz, 2H), 3.38 (s, 3H), 3.28 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 395.1 [M+H] + .
实施例55：5-(2,3-二氯苯基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 55: 5-(2,3-Dichlorophenyl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000233
Figure PCTCN2018122557-appb-000233
1H NMR(400MHz,CDCl 3)δ7.74(s,1H),7.43(dd,J＝6.6,3.0Hz,1H),7.23-7.18(m,2H),6.90-6.81(m,1H),6.68(dd,J＝8.7,4.0Hz,1H),5.12(s,1H),4.68(d,J＝5.5Hz,2H),4.63(t,J＝8.7Hz,2H),3.45(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 420.0[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.74 (s, 1H), 7.43 (dd, J = 6.6,3.0Hz, 1H), 7.23-7.18 (m, 2H), 6.90-6.81 (m, 1H), 6.68 (dd, J=8.7, 4.0 Hz, 1H), 5.12 (s, 1H), 4.68 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.45 (s, 3H) ), 3.38 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 420.0 [M+H] + .
实施例56：5-(2,4-二氟苯基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 56: 5-(2,4-Difluorophenyl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000234
Figure PCTCN2018122557-appb-000234
1H NMR(400MHz,DMSO-d6)δ7.78-7.70(m,2H),7.44(td,J＝8.6,6.9Hz,1H),7.22(td,J＝10.0,2.6Hz,1H),7.07(td,J＝8.6,2.4Hz,1H),6.95-6.86(m,1H),6.66(dd,J＝8.6,3.9Hz,1H),4.61-4.46(m,4H),3.35(s,3H),3.28(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 388.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.78-7.70 (m, 2H), 7.44 (td, J = 8.6,6.9Hz, 1H), 7.22 (td, J = 10.0,2.6Hz, 1H), 7.07 (td, J=8.6, 2.4 Hz, 1H), 6.95-6.86 (m, 1H), 6.66 (dd, J=8.6, 3.9 Hz, 1H), 4.61-4.46 (m, 4H), 3.35 (s, 3H) ), 3.28 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 388.1 [M+H] + .
实施例57：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(1-甲基-1H-吡唑-4-基)嘧啶-4(3H)-酮Example 57: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(1-methyl-1H-pyrazole -4-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000235
Figure PCTCN2018122557-appb-000235
1H NMR(400MHz,CDCl 3)δ8.04(s,1H),8.01(s,1H),7.76(s,1H),6.87-6.80(m,1H),6.65(dd,J＝8.6,4.0Hz,1H),4.99(s,1H),4.63(dd,J＝15.4,6.9Hz,4H),3.91(s,3H),3.45(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 356.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.04 (s, 1H), 8. s (s, 1H), 7.76 (s, 1H), 6.87-6.80 (m, 1H), 6.65 (dd, J = 8.6, 4.0 Hz, 1H), 4.99 (s, 1H), 4.63 (dd, J = 15.4, 6.9 Hz, 4H), 3.91 (s, 3H), 3.45 (s, 3H), 3.38 (t, J = 8.7 Hz, 2H) ) ppm; LC-MS: m/z 356.1 [M+H] + .
实施例58：5-(1,3-二甲基-1H-吡唑-4-基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 58: 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl Amino)-3-methylpyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000236
Figure PCTCN2018122557-appb-000236
1H NMR(400MHz,CDCl 3)δ7.84(s,1H),7.77(s,1H),6.88-6.80(m,1H),6.67(dd,J＝8.6,4.0Hz,1H),4.96(s,1H),4.63(dd,J＝16.3,7.2Hz,4H),3.84(s,3H),3.44(s,3H),3.37(t,J＝8.7Hz,2H),2.35(s,3H)ppm；LC-MS:m/z 370.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.84 (s, 1H), 7.77 (s, 1H), 6.88-6.80 (m, 1H), 6.67 (dd, J = 8.6,4.0Hz, 1H), 4.96 ( s, 1H), 4.63 (dd, J = 16.3, 7.2 Hz, 4H), 3.84 (s, 3H), 3.44 (s, 3H), 3.37 (t, J = 8.7 Hz, 2H), 2.35 (s, 3H) ) ppm; LC-MS: m/z 370.1 [M+H] + .
实施例59：5-(3,5-二甲基异噻唑-4-基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 59: 5-(3,5-Dimethylisothiazol-4-yl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino) -3-methylpyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000237
Figure PCTCN2018122557-appb-000237
1H NMR(400MHz,DMSO-d6)δ7.70(d,J＝6.6Hz,2H),6.95-6.83(m,1H),6.66(dd,J＝8.7,3.7Hz,1H),4.54(dd,J＝14.9,6.7Hz,4H),3.35(s,3H),3.28(t,J＝8.8Hz,2H),2.25(s,3H),2.08(s,3H)ppm；LC-MS:m/z 371.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.70 (d, J = 6.6Hz, 2H), 6.95-6.83 (m, 1H), 6.66 (dd, J = 8.7,3.7Hz, 1H), 4.54 (dd , J = 14.9, 6.7 Hz, 4H), 3.35 (s, 3H), 3.28 (t, J = 8.8 Hz, 2H), 2.25 (s, 3H), 2.08 (s, 3H) ppm; LC-MS: m /z 371.1[M+H] + .
实施例60：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(呋喃-2-基)-3-甲基嘧啶-4(3H)-酮Example 60: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(furan-2-yl)-3-methylpyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000238
Figure PCTCN2018122557-appb-000238
1H NMR(400MHz,CDCl 3)δ8.26(s,1H),7.38(s,1H),6.99(s,1H),6.92-6.78(m,1H),6.66(d,J＝8.7Hz,1H),6.45(s,1H),5.07(s,1H),4.74-4.63(m,3H),4.62(t,J＝8.7Hz,2H),3.45(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 342.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.26 (s, 1H), 7.38 (s, 1H), 6.99 (s, 1H), 6.92-6.78 (m, 1H), 6.66 (d, J = 8.7Hz, 1H), 6.45 (s, 1H), 5.07 (s, 1H), 4.74 - 4.63 (m, 3H), 4.62 (t, J = 8.7 Hz, 2H), 3.45 (s, 3H), 3.38 (t, J) = 8.7 Hz, 2H) ppm; LC-MS: m/z 342.1 [M+H] + .
实施例61：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(5-氟苯并呋喃-2-基)-3-甲基嘧啶-4(3H)-酮Example 61: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(5-fluorobenzofuran-2-yl)-3- Methylpyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000239
Figure PCTCN2018122557-appb-000239
1H NMR(400MHz,CDCl 3)δ8.47(s,1H),7.38(s,1H),7.34(dd,J＝8.9,4.1Hz,1H),7.19(dd,J＝8.6,2.6Hz,1H),6.92(td,J＝9.1,2.6Hz,1H),6.87-6.80(m,1H),6.66(dd,J＝8.7,4.0Hz,1H),5.20(t,J＝5.0Hz,1H),4.72(d,J＝5.6Hz,2H),4.63(t,J＝8.7Hz,2H),3.48(s,3H),3.40(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 410.0[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.47 (s, 1H), 7.38 (s, 1H), 7.34 (dd, J = 8.9,4.1Hz, 1H), 7.19 (dd, J = 8.6,2.6Hz, 1H), 6.92 (td, J = 9.1, 2.6 Hz, 1H), 6.87-6.80 (m, 1H), 6.66 (dd, J = 8.7, 4.0 Hz, 1H), 5.20 (t, J = 5.0 Hz, 1H) ), 4.72 (d, J = 5.6 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.48 (s, 3H), 3.40 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 410.0 [M+H] + .
实施例62:2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-[5,5'-联嘧啶]-4(3H)-酮Example 62: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-[5,5'-bipyrimidine]-4 ( 3H)-ketone
Figure PCTCN2018122557-appb-000240
Figure PCTCN2018122557-appb-000240
1H NMR(400MHz,CDCl 3)δ9.11(s,1H),9.01(s,2H),7.96(s,1H),6.92-6.79(m,1H),6.68(dd,J＝8.7,4.0Hz,1H),5.23(s,1H),4.70(d,J＝5.5Hz,2H),4.64(t,J＝8.7Hz,2H),3.48(s,3H),3.39(t,J＝8.7Hz,2H)ppm；LCMS:m/z 354.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 9.11 (s, 1H), 9.1 (s, 2H), 7.96 (s, 1H), 6.92-6.79 (m, 1H), 6.68 (dd, J = 8.7, 4.0) Hz, 1H), 5.23 (s, 1H), 4.70 (d, J = 5.5 Hz, 2H), 4.64 (t, J = 8.7 Hz, 2H), 3.48 (s, 3H), 3.39 (t, J = 8.7) Hz, 2H) ppm; LCMS: m/z 354.1 [M+H] + .
实施例63：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(噻唑-5-基)嘧啶-4(3H)-酮Example 63: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(thiazol-5-yl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000241
Figure PCTCN2018122557-appb-000241
1H NMR(400MHz,CDCl 3)δ8.78(s,1H),8.20(s,2H),6.84(s,1H),6.68(s,1H),5.19(s,1H),4.67(d,J＝26.2Hz,4H),3.49(s,3H),3.39(s,2H)ppm；LC-MS:m/z 359.0[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.78 (s, 1H), 8.20 (s, 2H), 6.84 (s, 1H), 6.68 (s, 1H), 5.19 (s, 1H), 4.67 (d, J = 26.2 Hz, 4H), 3.49 (s, 3H), 3.39 (s, 2H) ppm; LC-MS: m/z 359.0 [M+H] + .
实施例64：(E)-乙基3-(2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-基)丙烯酰酸酯Example 64: (E)-Ethyl 3-(2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl -1,6-dihydropyrimidin-5-yl)acryloyl ester
Figure PCTCN2018122557-appb-000242
Figure PCTCN2018122557-appb-000242
1H NMR(400MHz,CDCl 3)δ7.91(s,1H),7.44(d,J＝15.7Hz,1H),6.94(d,J＝15.7Hz,1H),6.86-6.78(m,1H),6.66(d,J＝8.6Hz,1H),5.27(s,1H),4.69(d,J＝5.6Hz,2H),4.64(s,2H),4.22(t,J＝10.7Hz,2H),3.35(t,J＝8.7Hz,2H),1.31(d,J＝7.1Hz,3H)ppm；LC-MS:m/z 374.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.44 (d, J = 15.7 Hz, 1H), 6.94 (d, J = 15.7 Hz, 1H), 6.86-6.78 (m, 1H) , 6.66 (d, J = 8.6 Hz, 1H), 5.27 (s, 1H), 4.69 (d, J = 5.6 Hz, 2H), 4.64 (s, 2H), 4.22 (t, J = 10.7 Hz, 2H) , 3.35 (t, J = 8.7 Hz, 2H), 1.31 (d, J = 7.1 Hz, 3H) ppm; LC-MS: m/z 374.1 [M+H] + .
实施例65：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-乙烯基嘧啶-4(3H)-酮Example 65: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-vinylpyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000243
Figure PCTCN2018122557-appb-000243
1H NMR(400MHz,DMSO-d6)δ7.80(s,1H),7.69(s,1H),6.94-6.83(m,1H),6.64(dd,J＝8.6,3.8Hz,1H),6.43(dd,J＝17.6,11.5Hz,1H),5.93(dd,J＝17.6,2.4Hz,1H),4.99(dd,J＝11.5,2.4Hz,1H),4.59-4.48(m,4H),3.32-3.31(m,3H),3.22(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 302.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.80 (s, 1H), 7.69 (s, 1H), 6.94-6.83 (m, 1H), 6.64 (dd, J = 8.6,3.8Hz, 1H), 6.43 (dd, J = 17.6, 11.5 Hz, 1H), 5.93 (dd, J = 17.6, 2.4 Hz, 1H), 4.99 (dd, J = 11.5, 2.4 Hz, 1H), 4.59-4.48 (m, 4H), 3.32-3.31 (m, 3H), 3.22 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 302.1 [M+H] + .
实施例66：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(丙-1-烯-2-基)嘧啶-4(3H)-酮Example 66: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(prop-1-en-2-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000244
Figure PCTCN2018122557-appb-000244
1H NMR(400MHz,DMSO-d6)δ7.73(s,1H),7.60(t,J＝5.4Hz,1H),6.88(t,J＝9.5Hz,1H),6.64(dd,J＝8.7,3.8Hz,1H),5.73(d,J＝3.0Hz,1H),4.92(d,J＝2.3Hz,1H),4.68-4.32(m,4H),3.31(s,3H),3.23(t,J＝8.7Hz,2H),1.96(s,3H)ppm；LC-MS:m/z 316.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.73 (s, 1H), 7.60 (t, J = 5.4Hz, 1H), 6.88 (t, J = 9.5Hz, 1H), 6.64 (dd, J = 8.7 , 3.8 Hz, 1H), 5.73 (d, J = 3.0 Hz, 1H), 4.92 (d, J = 2.3 Hz, 1H), 4.68 - 4.32 (m, 4H), 3.31 (s, 3H), 3.23 (t , J = 8.7 Hz, 2H), 1.96 (s, 3H) ppm; LC-MS: m/z 316.1 [M+H] + .
实施例67：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3,5-二甲基嘧啶-4(3H)-酮Example 67: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3,5-dimethylpyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000245
Figure PCTCN2018122557-appb-000245
1H NMR(400MHz,DMSO-d6)δ7.51(s,1H),7.30(s,1H),6.90-6.83(m,1H),6.63(dd,J＝8.6,3.9Hz,1H),4.50(dd,J＝10.0,7.1Hz,4H),3.29(s,3H),3.21(d,J＝8.0Hz,3H),1.79(s,3H)ppm；LC-MS:m/z 290.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.51 (s, 1H), 7.30 (s, 1H), 6.90-6.83 (m, 1H), 6.63 (dd, J = 8.6,3.9Hz, 1H), 4.50 (dd, J = 10.0, 7.1 Hz, 4H), 3.29 (s, 3H), 3.21 (d, J = 8.0 Hz, 3H), 1.79 (s, 3H) ppm; LC-MS: m/z 290.1 [M +H] + .
实施例68：5-环丙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 68: 5-Cyclopropyl-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methylpyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000246
Figure PCTCN2018122557-appb-000246
1H NMR(400MHz,DMSO-d6)δ7.34(d,J＝7.9Hz,2H),6.93-6.75(m,1H),6.63(dd,J＝8.6,3.9Hz,1H),4.50(dd,J＝15.6,6.9Hz,4H),3.29(s,3H),3.22(t,J＝8.7Hz,2H),1.61(ddd,J＝13.6,8.3,5.2Hz,1H),0.68-0.63(m,1H),0.51-0.47(m,1H)ppm；LC-MS:m/z 316.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.34 (d, J = 7.9Hz, 2H), 6.93-6.75 (m, 1H), 6.63 (dd, J = 8.6,3.9Hz, 1H), 4.50 (dd , J = 15.6, 6.9 Hz, 4H), 3.29 (s, 3H), 3.22 (t, J = 8.7 Hz, 2H), 1.61 (ddd, J = 13.6, 8.3, 5.2 Hz, 1H), 0.68-0.63 ( m, 1H), 0.51 - 0.47 (m, 1 H) ppm; LC-MS: m/z 316.1 [M+H] + .
实施例69：5-(环己-1-烯-1-基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 69: 5-(cyclohex-1-en-1-yl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3- Methylpyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000247
Figure PCTCN2018122557-appb-000247
1H NMR(400MHz,CDCl 3)δ7.84(d,J＝1.4Hz,1H),7.44(td,J＝7.6,1.8Hz,1H),7.31–7.26(m,1H),7.18–7.06(m,2H),6.89–6.80(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.09(d,J＝5.0Hz,1H),4.68(d,J＝5.5Hz,2H),4.62(t,J＝8.7Hz,2H),3.44(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LCMS:m/z 356.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.84 (d, J = 1.4Hz, 1H), 7.44 (td, J = 7.6,1.8Hz, 1H), 7.31-7.26 (m, 1H), 7.18-7.06 ( m, 2H), 6.89 - 6.80 (m, 1H), 6.67 (dd, J = 8.7, 4.0 Hz, 1H), 5.09 (d, J = 5.0 Hz, 1H), 4.68 (d, J = 5.5 Hz, 2H) ), 4.62 (t, J = 8.7 Hz, 2H), 3.44 (s, 3H), 3.38 (t, J = 8.7 Hz, 2H) ppm; LCMS: m/z 356.1 [M+H] + .
实施例70：5-(4,4-二氟环己-1-烯-1-基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 70: 5-(4,4-Difluorocyclohex-1-en-1-yl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl) Amino)-3-methylpyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000248
Figure PCTCN2018122557-appb-000248
1H NMR(400MHz,CDCl 3)δ7.66(s,1H),6.90-6.77(m,1H),6.72-6.59(m,1H),6.01(s,1H),4.97(s,1H),4.67-4.57(m,4H),3.38(m,5H),2.65(d,J＝15.0Hz,4H),2.21-2.06(m,2H)ppm；LC-MS:m/z 392.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.66 (s, 1H), 6.90-6.77 (m, 1H), 6.72-6.59 (m, 1H), 6.01 (s, 1H), 4.97 (s, 1H), 4.67-4.57 (m, 4H), 3.38 (m, 5H), 2.65 (d, J = 15.0 Hz, 4H), 2.21-2.06 (m, 2H) ppm; LC-MS: m/z 392.1 [M+H ] + .
实施例71：5-(3,6-二氢-2H-吡喃-4-基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 71: 5-(3,6-Dihydro-2H-pyran-4-yl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl) Amino)-3-methylpyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000249
Figure PCTCN2018122557-appb-000249
1H NMR(400MHz,CDCl 3)δ7.69(s,1H),6.90-6.75(m,1H),6.66(dd,J＝8.7,4.0Hz,1H),6.52-6.41(m,1H),4.96(d,J＝5.1Hz,1H),4.62(dd,J＝10.3,7.1Hz,4H),4.30(dd,J＝5.3,2.6Hz,2H),3.89(t,J＝5.5Hz,2H),3.39(s,3H),3.35(t,J＝8.7Hz,2H),2.45(td,J＝5.4,2.8Hz,2H)ppm；LC-MS:m/z 358.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.69 (s, 1H), 6.90-6.75 (m, 1H), 6.66 (dd, J = 8.7,4.0Hz, 1H), 6.52-6.41 (m, 1H), 4.96 (d, J = 5.1 Hz, 1H), 4.62 (dd, J = 10.3, 7.1 Hz, 4H), 4.30 (dd, J = 5.3, 2.6 Hz, 2H), 3.89 (t, J = 5.5 Hz, 2H) ), 3.39 (s, 3H), 3.35 (t, J = 8.7 Hz, 2H), 2.45 (td, J = 5.4, 2.8 Hz, 2H) ppm; LC-MS: m/z 358.1 [M+H] + .
实施例72：叔-丁基4-(2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-基)-5,6-二氢吡啶-1(2H)-羧酸酯Example 72: tert-Butyl 4-(2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl-1 ,6-dihydropyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate
Figure PCTCN2018122557-appb-000250
Figure PCTCN2018122557-appb-000250
1H NMR(400MHz,DMSO-d6)δ7.65(s,1H),7.57(t,J＝5.2Hz,1H),6.98-6.84(m,1H),6.64(dd,J＝8.6,3.8Hz,1H),6.32(s,1H),4.52(dd,J＝10.3,7.1Hz,4H),3.92(s,2H),3.44(d,J＝6.0Hz,3H),3.30(s,3H),3.23(d,J＝8.1Hz,2H),2.34(s,2H),1.41(s,9H)ppm；LC-MS:m/z 457.2[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.65 (s, 1H), 7.57 (t, J = 5.2Hz, 1H), 6.98-6.84 (m, 1H), 6.64 (dd, J = 8.6,3.8Hz , 1H), 6.32 (s, 1H), 4.52 (dd, J = 10.3, 7.1 Hz, 4H), 3.92 (s, 2H), 3.44 (d, J = 6.0 Hz, 3H), 3.30 (s, 3H) , 3.23 (d, J = 8.1 Hz, 2H), 2.34 (s, 2H), 1.41 (s, 9H) ppm; LC-MS: m/z 457.2 [M+H] + .
实施例73：叔-丁基(4-(2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-o氧-1,6-二氢嘧啶-5-基)环己-3-烯-1-基)氨基甲酸酯Example 73: tert-Butyl (4-(2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-ooxy) -1,6-dihydropyrimidin-5-yl)cyclohex-3-en-1-yl)carbamate
Figure PCTCN2018122557-appb-000251
Figure PCTCN2018122557-appb-000251
1H NMR(400MHz,DMSO-d6)δ7.58(s,1H),7.49(t,J＝5.1Hz,1H),6.91-6.84(m,1H),6.75(d,J＝7.6Hz,1H),6.64(dd,J＝8.6,3.8Hz,1H),6.08(s,1H),4.51(t,J＝8.7Hz,4H),3.28(s,3H),3.23(s,2H),2.40-2.24(m,4H),1.99(s,2H),1.79(s,1H),1.38(s,9H)ppm；LC-MS:m/z 434.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.58 (s, 1H), 7.49 (t, J = 5.1Hz, 1H), 6.91-6.84 (m, 1H), 6.75 (d, J = 7.6Hz, 1H ), 6.64 (dd, J = 8.6, 3.8 Hz, 1H), 6.08 (s, 1H), 4.51 (t, J = 8.7 Hz, 4H), 3.28 (s, 3H), 3.23 (s, 2H), 2.40 -2.24 (m, 4H), 1.99 (s, 2H), 1.79 (s, 1H), 1.38 (s, 9H) ppm; LC-MS: m/z 434.1 [M+H] + .
实施例74：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(1-甲基-1,2,3,6-四氢吡啶-4-基)嘧啶-4(3H)-酮Example 74: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(1-methyl-1,2, 3,6-tetrahydropyridin-4-yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000252
Figure PCTCN2018122557-appb-000252
1H NMR(400MHz,CDCl 3)δ7.68(s,1H),6.87-6.79(m,1H),6.66(dd,J＝8.7,4.0Hz,1H),6.34(s,1H),4.90(s,1H),4.62(dd,J＝11.4,6.0Hz,4H),3.39-3.31(m,5H),3.09(d,J＝3.1Hz,2H),2.63(t,J＝5.7Hz,2H),2.53(s,2H),2.37(s,3H)ppm；LCMS:m/z 371.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.68 (s, 1H), 6.87-6.79 (m, 1H), 6.66 (dd, J = 8.7,4.0Hz, 1H), 6.34 (s, 1H), 4.90 ( s, 1H), 4.62 (dd, J = 11.4, 6.0 Hz, 4H), 3.39-3.31 (m, 5H), 3.09 (d, J = 3.1 Hz, 2H), 2.63 (t, J = 5.7 Hz, 2H) ), 2.53 (s, 2H), 2.37 (s, 3H) ppm; LCMS: m/z 371.1 [M+H] + .
实施例75：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(6-氟吡啶-3-基)-3-甲基嘧啶-4(3H)-酮Example 75: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(6-fluoropyridin-3-yl)-3-methyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000253
Figure PCTCN2018122557-appb-000253
1H NMR(400MHz,CDCl 3)δ8.34(d,J＝2.4Hz,1H),8.20-8.05(m,1H),7.89(s,1H),6.94(dd,J＝8.5,2.8Hz,1H),6.89-6.77(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.18(t,J＝5.3Hz,1H),4.68(d,J＝5.5Hz,2H),4.63(t,J＝8.7Hz,2H),3.46(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 371.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.34 (d, J = 2.4Hz, 1H), 8.20-8.05 (m, 1H), 7.89 (s, 1H), 6.94 (dd, J = 8.5,2.8Hz, 1H), 6.89-6.77 (m, 1H), 6.67 (dd, J = 8.7, 4.0 Hz, 1H), 5.18 (t, J = 5.3 Hz, 1H), 4.68 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.46 (s, 3H), 3.38 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 371.1 [M+H] + .
实施例76：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(6-(三氟甲基)吡啶-3-基)嘧啶-4(3H)-酮Example 76: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(6-(trifluoromethyl)pyridine -3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000254
Figure PCTCN2018122557-appb-000254
1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝2.3Hz,1H),7.86(s,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.61(t,J＝5.1Hz,1H),6.96-6.78(m,2H),6.65(dd,J＝8.7,3.8Hz,1H),4.59-4.47(m,4H),3.48(s,4H),3.36(s,3H),3.26(t,J＝8.8Hz,2H),2.43(s,4H),2.24(s,3H)ppm；LC-MS:m/z 421.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.33 (d, J = 2.3Hz, 1H), 7.86 (s, 1H), 7.78 (dd, J = 8.8,2.4Hz, 1H), 7.61 (t, J =5.1 Hz, 1H), 6.96-6.78 (m, 2H), 6.65 (dd, J = 8.7, 3.8 Hz, 1H), 4.59-4.47 (m, 4H), 3.48 (s, 4H), 3.36 (s, 3H), 3.26 (t, J = 8.8 Hz, 2H), 2.43 (s, 4H), 2.24 (s, 3H) ppm; LC-MS: m/z 421.1 [M+H] + .
实施例77：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-4(3H)-酮Example 77: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(6-(4-methylpiperazine) -1-yl)pyridin-3-yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000255
Figure PCTCN2018122557-appb-000255
1H NMR(400MHz,DMSO-d6)δ8.33(d,J＝2.3Hz,1H),7.86(s,1H),7.78(dd,J＝8.8,2.4Hz,1H),7.61(t,J＝5.1Hz,1H),6.96–6.78(m,2H),6.65(dd,J＝8.7,3.8Hz,1H),4.59-4.47(m,4H),3.48(s,4H),3.36(s,3H),3.26(t,J＝8.8Hz,2H),2.43(s,4H),2.24(s,3H)ppm；LC-MS:m/z 451.2[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.33 (d, J = 2.3Hz, 1H), 7.86 (s, 1H), 7.78 (dd, J = 8.8,2.4Hz, 1H), 7.61 (t, J =5.1 Hz, 1H), 6.96–6.78 (m, 2H), 6.65 (dd, J=8.7, 3.8 Hz, 1H), 4.59-4.47 (m, 4H), 3.48 (s, 4H), 3.36 (s, 3H), 3.26 (t, J = 8.8 Hz, 2H), 2.43 (s, 4H), 2.24 (s, 3H) ppm; LC-MS: m/z 451.2 [M+H] + .
实施例78：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(6-吗啉代吡啶-3-基)嘧啶-4(3H)-酮Example 78: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(6-morpholinopyridine-3- Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000256
Figure PCTCN2018122557-appb-000256
1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝2.3Hz,1H),7.87(s,1H),7.81(dd,J＝8.8,2.5Hz,1H),7.62(t,J＝5.3Hz,1H),6.93-6.86(m,1H),6.82(d,J＝8.9Hz,1H),6.65(dd,J＝8.6,3.9Hz,1H),4.60-4.49(m,4H),3.74-3.66(m,4H),3.47-3.40(m,4H),3.36(s,3H),3.26(t,J＝8.6Hz,2H)ppm；LC-MS:m/z 438.2[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.35 (d, J = 2.3Hz, 1H), 7.87 (s, 1H), 7.81 (dd, J = 8.8,2.5Hz, 1H), 7.62 (t, J = 5.3 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.82 (d, J = 8.9 Hz, 1H), 6.65 (dd, J = 8.6, 3.9 Hz, 1H), 4.60-4.49 (m, 4H) , 3.74-3.66 (m, 4H), 3.47-3.40 (m, 4H), 3.36 (s, 3H), 3.26 (t, J = 8.6 Hz, 2H) ppm; LC-MS: m/z 438.2 [M+ H] + .
实施例79：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 79: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(2-methylpyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000257
Figure PCTCN2018122557-appb-000257
1H NMR(400MHz,CD 3OD)δ8.41-8.33(m,1H),7.74-7.66(m,1H),7.55(d,J＝11.0Hz,1H),7.23(d,J＝3.7Hz,1H),6.90-6.78(m,1H),6.66(dd,J＝8.6,3.9Hz,1H),4.67(d,J＝2.2Hz,2H),4.62(t,J＝8.7Hz,2H),3.49-3.43(m,3H),3.40(d,J＝6.9Hz,2H),2.46(d,J＝1.4Hz,3H)ppm；LC-MS:m/z 367.1[M+H] +. 1 H NMR (400 MHz, CD 3 OD) δ 8.41 - 8.33 (m, 1H), 7.74 - 7.66 (m, 1H), 7.55 (d, J = 11.0 Hz, 1H), 7.23 (d, J = 3.7 Hz) , 1H), 6.90-6.78 (m, 1H), 6.66 (dd, J = 8.6, 3.9 Hz, 1H), 4.67 (d, J = 2.2 Hz, 2H), 4.62 (t, J = 8.7 Hz, 2H) , 3.49-3.43 (m, 3H), 3.40 (d, J = 6.9 Hz, 2H), 2.46 (d, J = 1.4 Hz, 3H) ppm; LC-MS: m/z 367.1 [M+H] + .
实施例80：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 80: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(4-methylpyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000258
Figure PCTCN2018122557-appb-000258
1H NMR(400MHz,CDCl 3)δ8.46(s,1H),8.41(d,J＝4.9Hz,1H),7.69(s,1H),7.12(d,J＝5.0Hz,1H),6.92-6.80(m,1H),6.68(dd,J＝8.7,4.0Hz,1H),5.24(d,J＝4.9Hz,1H),4.68(d,J＝5.5Hz,2H),4.63(t,J＝8.7Hz,2H),3.45(s,2H),3.38(t,J＝8.7Hz,2H),2.25(s,3H)ppm；LC-MS:m/z 367.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.46 (s, 1H), 8.41 (d, J = 4.9Hz, 1H), 7.69 (s, 1H), 7.12 (d, J = 5.0Hz, 1H), 6.92 -6.80 (m, 1H), 6.68 (dd, J = 8.7, 4.0 Hz, 1H), 5.24 (d, J = 4.9 Hz, 1H), 4.68 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.45 (s, 2H), 3.38 (t, J = 8.7 Hz, 2H), 2.25 (s, 3H) ppm; LC-MS: m/z 367.1 [M+H] + .
实施例81：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(5-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 81: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(5-methylpyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000259
Figure PCTCN2018122557-appb-000259
1H NMR(400MHz,CDCl 3)δ8.54(d,J＝1.9Hz,1H),8.33(s,1H),7.91(s,1H),7.85(s,1H),6.89-6.79(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.18(s,1H),4.68(d,J＝5.5Hz,2H),4.63(t,J＝8.7Hz,2H),3.46(s,3H),3.38(t,J＝8.7Hz,2H),2.35(s,3H)ppm；LC-MS:m/z367.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.54 (d, J = 1.9Hz, 1H), 8.33 (s, 1H), 7.91 (s, 1H), 7.85 (s, 1H), 6.89-6.79 (m, 1H), 6.67 (dd, J=8.7, 4.0 Hz, 1H), 5.18 (s, 1H), 4.68 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.46 ( s, 3H), 3.38 (t, J = 8.7 Hz, 2H), 2.35 (s, 3H) ppm; LC-MS: m/z 367.1 [M+H] + .
实施例82：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(6-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 82: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(6-methylpyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000260
Figure PCTCN2018122557-appb-000260
1H NMR(400MHz,CDCl 3)δ8.65(d,J＝2.0Hz,1H),8.01(dd,J＝8.1,2.2Hz,1H),7.92(s,1H),7.21(d,J＝8.1Hz,1H),6.89-6.81(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.13(s,1H),4.74-4.58(m,4H),3.46(s,3H),3.39(t,J＝8.7Hz,2H),2.60(s,3H)ppm；LCMS:m/z 367.1,[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.65 (d, J = 2.0 Hz, 1H), 8.1 (dd, J = 8.1, 2.2 Hz, 1H), 7.92 (s, 1H), 7.21. (d, J = 8.1 Hz, 1H), 6.89-6.81 (m, 1H), 6.67 (dd, J=8.7, 4.0 Hz, 1H), 5.13 (s, 1H), 4.74-4.58 (m, 4H), 3.46 (s, 3H) ), 3.39 (t, J = 8.7 Hz, 2H), 2.60 (s, 3H) ppm; LCMS: m/z 367.1, [M+H] + .
实施例83：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(5-氟吡啶-3-基)-3-甲基嘧啶-4(3H)-酮Example 83: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(5-fluoropyridin-3-yl)-3-methyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000261
Figure PCTCN2018122557-appb-000261
1H NMR(400MHz,CDCl 3)δ8.59(s,1H),8.36(d,J＝2.7Hz,1H),7.98(s,1H),7.93-7.81(m,1H),6.90-6.79(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.19(s,1H),4.70(d,J＝5.6Hz,2H),4.63(t,J＝8.7Hz,2H),3.48(d,J＝6.7Hz,3H),3.38(dd,J＝11.4,6.0Hz,2H)ppm；LC-MS:m/z 371.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.59 (s, 1H), 8.36 (d, J = 2.7Hz, 1H), 7.98 (s, 1H), 7.93-7.81 (m, 1H), 6.90-6.79 ( m,1H), 6.67 (dd, J=8.7, 4.0 Hz, 1H), 5.19 (s, 1H), 4.70 (d, J = 5.6 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.48 (d, J = 6.7 Hz, 3H), 3.38 (dd, J = 11.4, 6.0 Hz, 2H) ppm; LC-MS: m/z 371.1 [M+H] + .
实施例84：5-(5-氯吡啶-3-基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 84: 5-(5-chloropyridin-3-yl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000262
Figure PCTCN2018122557-appb-000262
1H NMR(400MHz,DMSO-d6)δ8.81(d,J＝1.9Hz,1H),8.45(d,J＝2.4Hz,1H),8.22(t,J＝2.1Hz,1H),8.16(s,1H),7.90(t,J＝5.2Hz,1H),6.94-6.86(m,1H),6.66(dd,J＝8.6,3.9Hz,1H),4.60(d,J＝5.1Hz,2H),4.53(t,J＝8.7Hz,2H),3.38(s,3H),3.28(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 387.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.81 (d, J = 1.9Hz, 1H), 8.45 (d, J = 2.4Hz, 1H), 8.22 (t, J = 2.1Hz, 1H), 8.16 ( s, 1H), 7.90 (t, J = 5.2 Hz, 1H), 6.94 - 6.86 (m, 1H), 6.66 (dd, J = 8.6, 3.9 Hz, 1H), 4.60 (d, J = 5.1 Hz, 2H) ), 4.53 (t, J = 8.7 Hz, 2H), 3.38 (s, 3H), 3.28 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 387.1 [M+H] + .
实施例85：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(吡啶-3-基)嘧啶-4(3H)-酮Example 85: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(pyridin-3-yl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000263
Figure PCTCN2018122557-appb-000263
1H NMR(400MHz,CD 3OD)δ8.73(s,1H),8.41(d,J＝4.4Hz,1H),8.04(d,J＝7.8Hz,1H),7.95(s,1H),7.40(d,J＝4.4Hz,1H),6.83(t,J＝9.4Hz,1H),6.64(dd,J＝8.5,3.7Hz,1H),4.62(t,J＝8.7Hz,2H),4.50(s,2H),3.47(s,3H),3.39(d,J＝8.6Hz,2H)ppm；LC-MS:m/z 353.1[M+H] +. 1 H NMR (400 MHz, CD 3 OD) δ 8.73 (s, 1H), 8.41 (d, J = 4.4 Hz, 1H), 8.04 (d, J = 7.8 Hz, 1H), 7.95 (s, 1H), 7.40 (d, J = 4.4 Hz, 1H), 6.83 (t, J = 9.4 Hz, 1H), 6.64 (dd, J = 8.5, 3.7 Hz, 1H), 4.62 (t, J = 8.7 Hz, 2H), 4.50 (s, 2H), 3.47 (s, 3H), 3.39 (d, J = 8.6 Hz, 2H) ppm; LC-MS: m/z 353.1 [M+H] + .
实施例86：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(2-氟吡啶-3-基)-3-甲基嘧啶-4(3H)-酮Example 86: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(2-fluoropyridin-3-yl)-3-methyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000264
Figure PCTCN2018122557-appb-000264
1H NMR(400MHz,DMSO-d6)δ8.13(d,J＝4.8Hz,1H),7.99(ddd,J＝9.6,7.4,1.9Hz,1H),7.86(d,J＝1.1Hz,1H),7.83(t,J＝5.2Hz,1H),7.35(ddd,J＝7.0,4.8,1.9Hz,1H),6.95-6.86(m,1H),6.66(dd,J＝8.6,3.9Hz,1H),4.59(d,J＝5.1Hz,2H),4.53(t,J＝8.7Hz,2H),3.36(s,3H),3.28(t,J＝8.7Hz,2H)ppm；LC-MS:m/z 371.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.13 (d, J = 4.8Hz, 1H), 7.99 (ddd, J = 9.6,7.4,1.9Hz, 1H), 7.86 (d, J = 1.1Hz, 1H ), 7.83 (t, J = 5.2 Hz, 1H), 7.35 (ddd, J = 7.0, 4.8, 1.9 Hz, 1H), 6.95-6.86 (m, 1H), 6.66 (dd, J = 8.6, 3.9 Hz, 1H), 4.59 (d, J = 5.1 Hz, 2H), 4.53 (t, J = 8.7 Hz, 2H), 3.36 (s, 3H), 3.28 (t, J = 8.7 Hz, 2H) ppm; LC-MS :m/z 371.1[M+H] + .
实施例87：5-(5-氯-2-氟吡啶-3-基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 87: 5-(5-Chloro-2-fluoropyridin-3-yl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)- 3-methylpyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000265
Figure PCTCN2018122557-appb-000265
1H NMR(400MHz,DMSO-d6)δ8.22-8.19(m,1H),8.17(dd,J＝8.0,2.6Hz,1H),7.95(d,J＝1.1Hz,2H),6.93-6.87(m,1H),6.66(dd,J＝8.6,3.8Hz,1H),4.59(d,J＝2.5Hz,2H),4.53(t,J＝8.7Hz,2H),3.37(s,3H),3.28(t,J＝8.6Hz,2H)ppm；LC-MS:m/z 405.1[M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 8.22-8.19 (m, 1 H), 8.17 (dd, J = 8.0, 2.6 Hz, 1H), 7.95 (d, J = 1.1 Hz, 2H), 6.93-6.87 (m, 1H), 6.66 (dd, J = 8.6, 3.8 Hz, 1H), 4.59 (d, J = 2.5 Hz, 2H), 4.53 (t, J = 8.7 Hz, 2H), 3.37 (s, 3H) , 3.28 (t, J = 8.6 Hz, 2H) ppm; LC-MS: m/z 405.1 [M+H] + .
采用实施例12相同的方法，得到化合物2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(吡啶-4-基)嘧啶-4(3H)-酮的同时也得到脱溴产物2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮。In the same manner as in Example 12, the compound 2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(pyridine-4) was obtained. -yl)pyrimidine-4(3H)-one also gives debrominated product 2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl Pyrimidine-4(3H)-one.
实施例88：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(吡啶-4-基)嘧啶- 4(3H)-酮Example 88: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(pyridin-4-yl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000266
Figure PCTCN2018122557-appb-000266
1H NMR(400MHz,CDCl 3)δ8.56(dd,J＝4.7,1.5Hz,2H),8.04(s,1H),7.61(dd,J＝4.6,1.6Hz,2H),6.89-6.80(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.30(s,1H),4.70(d,J＝5.5Hz,2H),4.63(t,J＝8.7Hz,2H),3.46(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LC-MS:m/z353.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.56 (dd, J = 4.7,1.5Hz, 2H), 8.04 (s, 1H), 7.61 (dd, J = 4.6,1.6Hz, 2H), 6.89-6.80 ( m,1H), 6.67 (dd, J=8.7, 4.0 Hz, 1H), 5.30 (s, 1H), 4.70 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.46 (s, 3H), 3.38 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 353.1 [M+H] + .
实施例89：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 89: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methylpyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000267
Figure PCTCN2018122557-appb-000267
1H NMR(400MHz,CDCl 3)δ7.65(d,J＝6.4Hz,1H),6.88-6.79(m,1H),6.66(dd,J＝8.7,4.0Hz,1H),5.90(d,J＝6.4Hz,1H),4.97(s,1H),4.62(dd,J＝10.6,7.0Hz,4H),3.41-3.31(m,5H)ppm；LC-MS:m/z 276.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.65 (d, J = 6.4Hz, 1H), 6.88-6.79 (m, 1H), 6.66 (dd, J = 8.7,4.0Hz, 1H), 5.90 (d, J = 6.4 Hz, 1H), 4.97 (s, 1H), 4.62 (dd, J = 10.6, 7.0 Hz, 4H), 3.41-3.31 (m, 5H) ppm; LC-MS: m/z 276.1 [M+ H] + .
实施例90：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(2-氟吡啶-4-基)-3-甲基嘧啶-4(3H)-酮Example 90: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(2-fluoropyridin-4-yl)-3-methyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000268
Figure PCTCN2018122557-appb-000268
1H NMR(400MHz,CDCl 3)δ8.17(d,J＝5.4Hz,1H),8.08(s,1H),7.50(d,J＝5.3Hz,1H),7.35(s,1H),6.89-6.78(m,1H),6.68(dd,J＝8.7,4.0Hz,1H),5.26(s,1H),4.71(d,J＝5.6Hz,2H),4.63(t,J＝8.7Hz,2H),3.47(s,3H),3.38(t,J＝8.7Hz,2H)ppm；LC-MS:m/z371.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.17 (d, J = 5.4Hz, 1H), 8.08 (s, 1H), 7.50 (d, J = 5.3Hz, 1H), 7.35 (s, 1H), 6.89 -6.78 (m, 1H), 6.68 (dd, J = 8.7, 4.0 Hz, 1H), 5.26 (s, 1H), 4.71 (d, J = 5.6 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.47 (s, 3H), 3.38 (t, J = 8.7 Hz, 2H) ppm; LC-MS: m/z 371.1 [M+H] + .
实施例91：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(4-甲氧苯基)嘧啶-4(3H)-酮Example 91: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(4-methoxyphenyl)pyrimidine- 4(3H)-ketone
Figure PCTCN2018122557-appb-000269
Figure PCTCN2018122557-appb-000269
1H NMR(400MHz,CDCl 3)δ7.81(s,1H),7.57-7.48(m,2H),6.95-6.89(m,2H),6.88-6.79(m,1H),6.66(dd,J＝8.6,4.0Hz,1H),5.03(d,J＝5.5Hz,1H),4.69-4.55(m,4H),4.03(q,J＝7.1Hz,2H),3.82(s,3H),3.39(t,J＝8.7Hz,2H),1.32(t,J＝7.2Hz,3H)ppm；LCMS:m/z 396.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.81 (s, 1H), 7.57-7.48 (m, 2H), 6.95-6.89 (m, 2H), 6.88-6.79 (m, 1H), 6.66 (dd, J = 8.6, 4.0 Hz, 1H), 5.03 (d, J = 5.5 Hz, 1H), 4.69 - 4.55 (m, 4H), 4.03 (q, J = 7.1 Hz, 2H), 3.82 (s, 3H), 3.39 (t, J = 8.7 Hz, 2H), 1.32 (t, J = 7.2 Hz, 3H) ppm; LCMS: m/z 396.1 [M+H] + .
实施例92：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(4-氟苯基)嘧啶-4(3H)-酮Example 92: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(4-fluorophenyl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000270
Figure PCTCN2018122557-appb-000270
1H NMR(400MHz,CDCl 3)δ7.82(s,1H),7.62-7.51(m,2H),7.09-7.01(m,2H),6.89-6.80(m,1H),6.66(dd,J＝8.7,4.0Hz,1H),5.11(d,J＝5.2Hz,1H),4.70-4.53(m,4H),4.04(q,J＝7.3Hz,2H),3.39(t,J＝8.7Hz,2H),1.32(t,J＝7.3Hz,3H)ppm；LCMS:m/z 384.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.82 (s, 1H), 7.62-7.51 (m, 2H), 7.09-7.01 (m, 2H), 6.89-6.80 (m, 1H), 6.66 (dd, J =8.7, 4.0 Hz, 1H), 5.11 (d, J = 5.2 Hz, 1H), 4.70 - 4.53 (m, 4H), 4.04 (q, J = 7.3 Hz, 2H), 3.39 (t, J = 8.7 Hz) , 2H), 1.32 (t, J = 7.3 Hz, 3H) ppm; LCMS: m/z 384.1 [M+H] + .
实施例93：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(2-氟苯基)嘧啶-4(3H)-酮Example 93: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(2-fluorophenyl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000271
Figure PCTCN2018122557-appb-000271
1H NMR(400MHz,CDCl 3)δ7.82(d,J＝1.5Hz,1H),7.47(td,J＝7.6,1.8Hz,1H),7.30-7.26(m,1H),7.18-7.05(m,2H),6.88-6.80(m,1H),6.67(dd,J＝8.6,4.0Hz,1H),5.14(s,1H),4.71-4.57(m,4H),4.05(q,J＝7.3Hz,2H),3.40(t,J＝8.7Hz,2H),1.32(dd,J＝9.6,4.9Hz,3H)ppm；LC-MS:m/z 384.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.82 (d, J = 1.5Hz, 1H), 7.47 (td, J = 7.6,1.8Hz, 1H), 7.30-7.26 (m, 1H), 7.18-7.05 ( m, 2H), 6.88-6.80 (m, 1H), 6.67 (dd, J = 8.6, 4.0 Hz, 1H), 5.14 (s, 1H), 4.71-4.57 (m, 4H), 4.05 (q, J = 7.3 Hz, 2H), 3.40 (t, J = 8.7 Hz, 2H), 1.32 (dd, J = 9.6, 4.9 Hz, 3H) ppm; LC-MS: m/z 384.1 [M+H] + .
实施例94：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(3-氟苯基)嘧啶-4(3H)-酮Example 94: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(3-fluorophenyl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000272
Figure PCTCN2018122557-appb-000272
1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.84(t,J＝5.2Hz,1H),7.67-7.45(m,2H),7.35(td,J＝8.0,6.4Hz,1H),7.13-7.02(m,1H),6.90(dd,J＝10.5,8.6Hz,1H),6.65(dd,J＝8.6,3.9Hz,1H),4.70-4.43(m,4H),4.03(q,J＝7.0Hz,2H),3.27(d,J＝8.7Hz,2H),1.15(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 384.1[M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 8.00 (s, 1H), 7.84 (t, J = 5.2 Hz, 1H), 7.67-7.45 (m, 2H), 7.35 (td, J = 8.0, 6.4 Hz , 1H), 7.13 - 7.02 (m, 1H), 6.90 (dd, J = 10.5, 8.6 Hz, 1H), 6.65 (dd, J = 8.6, 3.9 Hz, 1H), 4.70 - 4.43 (m, 4H), 4.03 (q, J = 7.0 Hz, 2H), 3.27 (d, J = 8.7 Hz, 2H), 1.15 (t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 384.1 [M+H] + .
实施例95：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(4-(三氟甲基)苯基)嘧啶-4(3H)-酮Example 95: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(4-(trifluoromethyl)benzene Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000273
Figure PCTCN2018122557-appb-000273
1H NMR(400MHz,DMSO-d6)δ8.05(s,1H),7.89(t,J＝7.9Hz,3H),7.66(d,J＝8.4Hz,2H),6.95-6.83(m,1H),6.65(dd,J＝8.6,3.9Hz,1H),4.55(dd,J＝15.6,6.9Hz,4H),4.04(q,J＝7.0Hz,2H),3.28(d,J＝8.9Hz,2H),1.16(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 434.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.05 (s, 1H), 7.89 (t, J = 7.9Hz, 3H), 7.66 (d, J = 8.4Hz, 2H), 6.95-6.83 (m, 1H ), 6.65 (dd, J = 8.6, 3.9 Hz, 1H), 4.55 (dd, J = 15.6, 6.9 Hz, 4H), 4.04 (q, J = 7.0 Hz, 2H), 3.28 (d, J = 8.9 Hz) , 2H), 1.16 (t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 434.1 [M+H] + .
实施例96：5-(2,3-二氯苯基)-3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮Example 96: 5-(2,3-Dichlorophenyl)-3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000274
Figure PCTCN2018122557-appb-000274
1H NMR(400MHz,CDCl 3)δ7.72(s,1H),7.42(dd,J＝7.6,2.0Hz,1H),7.25-7.15(m,2H),6.95-6.80(m,1H),6.68(dd,J＝8.7,4.0Hz,1H),5.18(d,J＝4.9Hz,1H),4.66(d,J＝5.5Hz,2H),4.63(t,J＝8.7Hz,2H),4.04(q,J＝7.3Hz,2H),3.39(t,J＝8.7Hz,2H),1.32(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 385.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.72 (s, 1H), 7.42 (dd, J = 7.6,2.0Hz, 1H), 7.25-7.15 (m, 2H), 6.95-6.80 (m, 1H), 6.68 (dd, J = 8.7, 4.0 Hz, 1H), 5.18 (d, J = 4.9 Hz, 1H), 4.66 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 4.04 (q, J = 7.3 Hz, 2H), 3.39 (t, J = 8.7 Hz, 2H), 1.32 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 385.1 [M+H] + .
实施例97：4-(1-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-6-羰基-1,6-二氢嘧啶-5-基)苯酰胺Example 97: 4-(1-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-6-carbonyl-1,6-di Hydropyrimidin-5-yl)benzamide
Figure PCTCN2018122557-appb-000275
Figure PCTCN2018122557-appb-000275
1H NMR(400MHz,DMSO-d6)δ8.00(s,1H),7.91(s,1H),7.83(d,J＝8.2Hz,3H),7.72(d,J＝8.3Hz,2H),7.27(s,1H),6.99-6.83(m,1H),6.65(dd,J＝8.6,3.8Hz,1H),4.53(d,J＝8.7Hz,4H),4.04(d,J＝7.1Hz,2H),3.28(d,J＝8.9Hz,2H),1.15(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 409.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.00 (s, 1H), 7.91 (s, 1H), 7.83 (d, J = 8.2Hz, 3H), 7.72 (d, J = 8.3Hz, 2H), 7.27 (s, 1H), 6.99-6.83 (m, 1H), 6.65 (dd, J = 8.6, 3.8 Hz, 1H), 4.53 (d, J = 8.7 Hz, 4H), 4.04 (d, J = 7.1 Hz) , 2H), 3.28 (d, J = 8.9 Hz, 2H), 1.15 (t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 409.1 [M+H] + .
实施例98：5-(2,4-二氟苯基)-3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮Example 98: 5-(2,4-Difluorophenyl)-3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000276
Figure PCTCN2018122557-appb-000276
1H NMR(400MHz,DMSO-d6)δ7.81(t,J＝5.0Hz,1H),7.72(d,J＝1.0Hz,1H),7.45(td,J＝8.6,6.9Hz,1H),7.27-7.16(m,1H),7.07(td,J＝8.6,2.5Hz,1H),6.89(dd,J＝17.4,7.0Hz,1H),6.65(dt,J＝7.7,3.8Hz,1H),4.57-4.48(m,4H),4.01(q,J＝7.0Hz,2H),3.28(d,J＝8.7Hz,2H),1.16-1.09(m,3H)ppm；LC-MS:m/z 402.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.81 (t, J = 5.0Hz, 1H), 7.72 (d, J = 1.0Hz, 1H), 7.45 (td, J = 8.6,6.9Hz, 1H), 7.27-7.16(m,1H),7.07(td,J=8.6,2.5Hz,1H), 6.89(dd,J=17.4,7.0Hz,1H),6.65(dt,J=7.7,3.8Hz,1H) , 4.57-4.48 (m, 4H), 4.01 (q, J = 7.0 Hz, 2H), 3.28 (d, J = 8.7 Hz, 2H), 1.16-1.09 (m, 3H) ppm; LC-MS: m/ z 402.1[M+H] + .
实施例99：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(1-甲基-1H-吡唑-4-基)嘧啶-4(3H)-酮Example 99: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(1-methyl-1H-pyrazole -4-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000277
Figure PCTCN2018122557-appb-000277
1H NMR(400MHz,CDCl 3)δ8.03(d,J＝8.5Hz,1H),7.97(d,J＝8.6Hz,1H),7.74(d,J＝8.6Hz,1H),6.87-6.76(m,1H),6.65(dd,J＝8.6,3.8Hz,1H),5.03(s,1H),4.69-4.57(m,4H),4.04(d,J＝7.3Hz,2H),3.89(d,J＝8.6Hz,3H),3.46-3.30(m,2H),1.36-1.23(m,3H)ppm；LC-MS:m/z 370.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.03 (d, J = 8.5 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 7.74 (d, J = 8.6 Hz, 1H), 6.87-6.76 (m, 1H), 6.65 (dd, J = 8.6, 3.8 Hz, 1H), 5.03 (s, 1H), 4.69-4.57 (m, 4H), 4.04 (d, J = 7.3 Hz, 2H), 3.89 ( d, J = 8.6 Hz, 3H), 3.46-3.30 (m, 2H), 1.36-1.23 (m, 3H) ppm; LC-MS: m/z 370.1 [M+H] + .
实施例100：5-(1,3-二甲基-1H-吡唑-4-基)-3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮Example 100: 5-(1,3-Dimethyl-1H-pyrazol-4-yl)-3-ethyl-2-(((5-fluoro-2,3-dihydrobenzofuran-4) -yl)methyl)amino)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000278
Figure PCTCN2018122557-appb-000278
1H NMR(400MHz,CDCl 3)δ7.83(s,1H),7.80(s,1H),6.89-6.81(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.00(s,1H),4.63(t,J＝8.0Hz,4H),4.03(q,J＝7.3Hz,2H),3.84(s,3H),3.38(t,J＝8.7Hz,2H),2.35(s,3H),1.31(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 384.2[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.83 (s, 1H), 7.80 (s, 1H), 6.89-6.81 (m, 1H), 6.67 (dd, J = 8.7,4.0Hz, 1H), 5.00 ( s, 1H), 4.63 (t, J = 8.0 Hz, 4H), 4.03 (q, J = 7.3 Hz, 2H), 3.84 (s, 3H), 3.38 (t, J = 8.7 Hz, 2H), 2.35 ( s, 3H), 1.31 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 384.2 [M+H] + .
实施例101：5-(3,5-二甲基异噻唑-4-基)-3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮Example 101: 5-(3,5-Dimethylisothiazol-4-yl)-3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl) Methyl)amino)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000279
Figure PCTCN2018122557-appb-000279
1H NMR(400MHz,DMSO-d 6)δ7.77(t,J＝5.2Hz,1H),7.67(s,1H),6.90(dd,J＝10.5,8.6Hz,1H),6.65(dd,J＝8.6,3.9Hz,1H),4.60-4.50(m,4H),4.01(q,J＝7.0Hz,2H),3.27(d,J＝8.7Hz,2H),2.25(s,3H),2.08(s,3H),1.13(t,J＝7.0Hz,3H)；ppm；LC-MS:m/z 385.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ7.77 (t, J = 5.2Hz, 1H), 7.67 (s, 1H), 6.90 (dd, J = 10.5,8.6Hz, 1H), 6.65 (dd, J = 8.6, 3.9 Hz, 1H), 4.60-4.50 (m, 4H), 4.01 (q, J = 7.0 Hz, 2H), 3.27 (d, J = 8.7 Hz, 2H), 2.25 (s, 3H), 2.08 (s, 3H), 1.13 (t, J = 7.0 Hz, 3H); ppm; LC-MS: m/z 385.1 [M+H] + .
实施例102：5-(环己-1-烯-1-基)-3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮Example 102: 5-(cyclohex-1-en-1-yl)-3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl) Amino)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000280
Figure PCTCN2018122557-appb-000280
1H NMR(400MHz,CDCl 3)δ7.60(s,1H),6.88-6.77(m,1H),6.65(dd,J＝8.7,4.0Hz,1H),6.21-6.09(m,1H),4.93(d,J＝5.2Hz,1H),4.68-4.51(m,4H),3.97(q,J＝7.3Hz,2H),3.37(t,J＝8.7Hz,2H),2.31(dd,J＝6.1,2.0Hz,2H),2.16(tt,J＝6.1,3.0Hz,2H),1.76-1.68(m,2H),1.67-1.61(m,2H),1.27(t,J＝7.2Hz,3H)ppm；LCMS:m/z 370.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.60 (s, 1H), 6.88-6.77 (m, 1H), 6.65 (dd, J = 8.7,4.0Hz, 1H), 6.21-6.09 (m, 1H), 4.93 (d, J = 5.2 Hz, 1H), 4.68-4.51 (m, 4H), 3.97 (q, J = 7.3 Hz, 2H), 3.37 (t, J = 8.7 Hz, 2H), 2.31 (dd, J = 6.1, 2.0 Hz, 2H), 2.16 (tt, J = 6.1, 3.0 Hz, 2H), 1.76-1.68 (m, 2H), 1.67-1.61 (m, 2H), 1.27 (t, J = 7.2 Hz, 3H) ppm; LCMS: m/z 370.1 [M+H] + .
实施例103：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(四氢-2H-吡喃-4-基)嘧啶-4(3H)-酮Example 103: 3-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(tetrahydro-2H-pyran-4 -yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000281
Figure PCTCN2018122557-appb-000281
1H NMR(400MHz,CDCl 3)δ7.66(s,1H),6.89-6.78(m,1H),6.66(dd,J＝8.7,4.0Hz,1H),6.53-6.44(m,1H),5.02(s,1H),4.62(dd,J＝11.5,6.0Hz,4H),4.30(q,J＝2.6Hz,2H),3.98(q,J＝7.2Hz,2H),3.89(t,J＝5.5Hz,2H),3.37(t,J＝8.7Hz,2H),2.44(td,J＝5.4,2.8Hz,2H),1.27(d,J＝7.3Hz,3H)ppm；LCMS:m/z 372.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.66 (s, 1H), 6.89-6.78 (m, 1H), 6.66 (dd, J = 8.7,4.0Hz, 1H), 6.53-6.44 (m, 1H), 5.02 (s, 1H), 4.62 (dd, J = 11.5, 6.0 Hz, 4H), 4.30 (q, J = 2.6 Hz, 2H), 3.98 (q, J = 7.2 Hz, 2H), 3.89 (t, J) =5.5 Hz, 2H), 3.37 (t, J = 8.7 Hz, 2H), 2.44 (td, J = 5.4, 2.8 Hz, 2H), 1.27 (d, J = 7.3 Hz, 3H) ppm; LCMS: m/ z 372.1[M+H] + .
实施例104：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(6-吗啉代吡啶-3-基)嘧啶-4(3H)-酮Example 104: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(6-morpholinopyridine-3- Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000282
Figure PCTCN2018122557-appb-000282
1H NMR(400MHz,DMSO-d6)δ8.35(d,J＝2.3Hz,1H),7.88-7.78(m,2H),7.70(t,J＝5.1Hz,1H),6.94-6.85(m,1H),6.81(d,J＝8.9Hz,1H),6.65(dd,J＝8.6,3.8Hz,1H),4.54(t,J＝8.7Hz,4H),4.02(q,J＝6.8Hz,2H),3.73-3.67(m,4H),3.43(d,J＝1.6Hz,4H),3.28(t,J＝8.7Hz,2H),1.14(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 452.2[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.35 (d, J = 2.3Hz, 1H), 7.88-7.78 (m, 2H), 7.70 (t, J = 5.1Hz, 1H), 6.94-6.85 (m , 1H), 6.81 (d, J = 8.9 Hz, 1H), 6.65 (dd, J = 8.6, 3.8 Hz, 1H), 4.54 (t, J = 8.7 Hz, 4H), 4.02 (q, J = 6.8 Hz) , 2H), 3.73-3.67 (m, 4H), 3.43 (d, J = 1.6 Hz, 4H), 3.28 (t, J = 8.7 Hz, 2H), 1.14 (t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 452.2 [M+H] + .
实施例105：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(5-氟吡啶-3-基)嘧啶-4(3H)-酮Example 105: 3-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(5-fluoropyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000283
Figure PCTCN2018122557-appb-000283
1H NMR(400MHz,CDCl 3)δ8.58(s,1H),8.35(d,J＝2.7Hz,1H),7.96(s,1H),7.92-7.83(m,1H),6.89-6.81(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.27(s,1H),4.69-4.60(m,4H),4.06(q,J＝7.2Hz,2H),3.40(t,J＝8.7Hz,2H),1.33(t,J＝7.3Hz,3H)ppm；LCMS:m/z385.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.58 (s, 1H), 8.35 (d, J = 2.7Hz, 1H), 7.96 (s, 1H), 7.92-7.83 (m, 1H), 6.89-6.81 ( m,1H), 6.67 (dd, J=8.7, 4.0 Hz, 1H), 5.27 (s, 1H), 4.69-4.60 (m, 4H), 4.06 (q, J = 7.2 Hz, 2H), 3.40 (t , J = 8.7 Hz, 2H), 1.33 (t, J = 7.3 Hz, 3H) ppm; LCMS: m/z 385.1 [M+H] + .
实施例106：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 106: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(2-methylpyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000284
Figure PCTCN2018122557-appb-000284
1H NMR(400MHz,DMSO-d6)δ8.36(dd,J＝4.7,1.4Hz,1H),8.14(s,1H),7.77(t,J＝4.9Hz,1H),7.65(s,1H),7.50(dd,J＝7.6,1.3Hz,1H),7.19(dd,J＝7.6,4.9Hz,1H),6.95-6.86(m,1H),6.66(dd,J＝8.6,3.8Hz,1H),4.54(t,J＝8.7Hz,4H),4.03(q,J＝6.9Hz,2H),2.32(s,3H),1.14(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 381.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.36 (dd, J = 4.7,1.4Hz, 1H), 8.14 (s, 1H), 7.77 (t, J = 4.9Hz, 1H), 7.65 (s, 1H ), 7.50 (dd, J = 7.6, 1.3 Hz, 1H), 7.19 (dd, J = 7.6, 4.9 Hz, 1H), 6.95-6.86 (m, 1H), 6.66 (dd, J = 8.6, 3.8 Hz, 1H), 4.54 (t, J = 8.7 Hz, 4H), 4.03 (q, J = 6.9 Hz, 2H), 2.32 (s, 3H), 1.14 (t, J = 7.0 Hz, 3H) ppm; LC-MS :m/z 381.1[M+H] + .
采用实施例12相同的方法，得到化合物5-(5-氯吡啶-3-基)-3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮的同时得到脱溴产物3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮。The same procedure as in Example 12 gave the compound 5-(5-chloropyridin-3-yl)-3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl). Methyl)amino)pyrimidine-4(3H)-one simultaneously gives debrominated product 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl Amino)pyrimidine-4(3H)-one.
实施例107：5-(5-氯吡啶-3-基)-3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮Example 107: 5-(5-Chloropyridin-3-yl)-3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000285
Figure PCTCN2018122557-appb-000285
1H NMR(400MHz,DMSO-d6)δ8.80(d,J＝1.8Hz,1H),8.45(d,J＝2.3Hz,1H),8.22(t,J＝2.1Hz,1H),8.14(s,1H),7.98(t,J＝5.0Hz,1H),6.95-6.85(m,1H),6.65(dd,J＝8.6,3.9Hz,1H),4.55(dd,J＝14.1,6.2Hz,4H),4.04(q,J＝7.0Hz,2H),3.28(d,J＝8.7Hz,2H),1.15(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 401.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.80 (d, J = 1.8Hz, 1H), 8.45 (d, J = 2.3Hz, 1H), 8.22 (t, J = 2.1Hz, 1H), 8.14 ( s, 1H), 7.98 (t, J = 5.0 Hz, 1H), 6.95-6.85 (m, 1H), 6.65 (dd, J = 8.6, 3.9 Hz, 1H), 4.55 (dd, J = 14.1, 6.2 Hz , 4H), 4.04 (q, J = 7.0 Hz, 2H), 3.28 (d, J = 8.7 Hz, 2H), 1.15 (t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 401.1 [ M+H] + .
实施例108：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮Example 108: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000286
Figure PCTCN2018122557-appb-000286
1H NMR(400MHz,DMSO-d6)δ7.66-7.53(m,2H),6.92-6.81(m,1H),6.64(dd,J＝8.6,3.8Hz,1H),5.63(d,J＝6.3Hz,1H),4.51(dd,J＝15.2,6.7Hz,4H),3.94(q,J＝7.0Hz,2H),3.24(t,J＝8.7Hz,2H),1.09(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 290.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.66-7.53 (m, 2H), 6.92-6.81 (m, 1H), 6.64 (dd, J = 8.6,3.8Hz, 1H), 5.63 (d, J = 6.3 Hz, 1H), 4.51 (dd, J = 15.2, 6.7 Hz, 4H), 3.94 (q, J = 7.0 Hz, 2H), 3.24 (t, J = 8.7 Hz, 2H), 1.09 (t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 290.1 [M+H] + .
实施例109：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-4(3H)-酮Example 109: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(6-(4-methylpiperazine) -1-yl)pyridin-3-yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000287
Figure PCTCN2018122557-appb-000287
1H NMR(400MHz,DMSO-d6)δ8.32(d,J＝1.9Hz,1H),8.17(s,1H),7.83(s,1H),7.78(dd,J＝8.9,2.2Hz,1H),7.68(t,J＝5.0Hz,1H),6.89(t,J＝9.5Hz,1H),6.80(d,J＝8.9Hz,1H),6.64(dd,J＝8.6,3.6Hz,1H),4.54(t,J＝8.6Hz,4H),4.02(q,J＝6.9Hz,2H),3.45(s,4H),3.27(d,J＝7.4Hz,2H),2.40(s,4H),2.22(s,3H),1.14(t,J＝6.9Hz,3H)ppm；LC-MS:m/z 465.2[M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 8.32 (d, J = 1.9 Hz, 1H), 8.17 (s, 1H), 7.83 (s, 1H), 7.78 (dd, J = 8.9, 2.2 Hz, 1H) ), 7.68 (t, J = 5.0 Hz, 1H), 6.89 (t, J = 9.5 Hz, 1H), 6.80 (d, J = 8.9 Hz, 1H), 6.64 (dd, J = 8.6, 3.6 Hz, 1H) ), 4.54 (t, J = 8.6 Hz, 4H), 4.02 (q, J = 6.9 Hz, 2H), 3.45 (s, 4H), 3.27 (d, J = 7.4 Hz, 2H), 2.40 (s, 4H) ), 2.22 (s, 3H), 1.14 (t, J = 6.9 Hz, 3H) ppm; LC-MS: m/z 465.2 [M+H] + .
实施例110：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(5-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 110: 3-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(5-methylpyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000288
Figure PCTCN2018122557-appb-000288
1H NMR(400MHz,CDCl 3)δ8.54(s,1H),8.33(s,1H),7.88(s,2H),6.85(t,J＝9.3Hz,1H),6.67(dd,J＝7.8,3.1Hz,1H),5.21(s,1H),4.64(dd,J＝16.6,7.5Hz,4H),4.05(dd,J＝14.3,7.0Hz,2H),3.40(t,J＝8.7Hz,2H),2.35(s,3H),1.33(t,J＝6.9Hz,3H)ppm；LC-MS:m/z 381.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.54 (s, 1H), 8.33 (s, 1H), 7.88 (s, 2H), 6.85 (t, J = 9.3Hz, 1H), 6.67 (dd, J = 7.8, 3.1 Hz, 1H), 5.21 (s, 1H), 4.64 (dd, J = 16.6, 7.5 Hz, 4H), 4.05 (dd, J = 14.3, 7.0 Hz, 2H), 3.40 (t, J = 8.7) Hz, 2H), 2.35 (s, 3H), 1.33 (t, J = 6.9 Hz, 3H) ppm; LC-MS: m/z 381.1 [M+H] + .
实施例111：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(6-氟吡啶-3-基)嘧啶-4(3H)-酮Example 111: 3-ethyl-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(6-fluoropyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000289
Figure PCTCN2018122557-appb-000289
1H NMR(400MHz,CDCl 3)δ8.34(d,J＝2.3Hz,1H),8.14(td,J＝8.2,2.5Hz,1H),7.87(s,1H),6.93(dd,J＝8.6,2.9Hz,1H),6.89-6.79(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.23(t,J＝5.1Hz,1H),4.67(d,J＝5.9Hz,2H),4.62(d,J＝8.7Hz,2H),4.05(q,J＝7.3Hz,2H),3.40(t,J＝8.7Hz,2H),1.33(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 385.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.34 (d, J = 2.3 Hz, 1H), 8.14 (td, J = 8.2, 2.5 Hz, 1H), 7.78 (s, 1H), 6.93 (dd, J = 8.6, 2.9 Hz, 1H), 6.89-6.79 (m, 1H), 6.67 (dd, J = 8.7, 4.0 Hz, 1H), 5.23 (t, J = 5.1 Hz, 1H), 4.67 (d, J = 5.9) Hz, 2H), 4.62 (d, J = 8.7 Hz, 2H), 4.05 (q, J = 7.3 Hz, 2H), 3.40 (t, J = 8.7 Hz, 2H), 1.33 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 385.1 [M+H] + .
实施例112：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(吡啶-3-基)嘧啶-4(3H)-酮Example 112: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(pyridin-3-yl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000290
Figure PCTCN2018122557-appb-000290
1H NMR(400MHz,DMSO-d6)δ8.80(d,J＝2.2Hz,1H),8.41(d,J＝4.7Hz,1H),8.15(s,1H),8.08-7.92(m,2H),7.86(t,J＝5.3Hz,1H),7.34(dd,J＝8.0,4.8Hz,1H),6.98-6.83(m,1H),6.65(dd,J＝8.7,3.8Hz,1H),4.71-4.41(m,4H),4.04(q,J＝7.0Hz,2H),3.29(s,2H),1.15(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 367.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.80 (d, J = 2.2Hz, 1H), 8.41 (d, J = 4.7Hz, 1H), 8.15 (s, 1H), 8.08-7.92 (m, 2H ), 7.86 (t, J = 5.3 Hz, 1H), 7.34 (dd, J = 8.0, 4.8 Hz, 1H), 6.98-6.83 (m, 1H), 6.65 (dd, J = 8.7, 3.8 Hz, 1H) , 4.71-4.41 (m, 4H), 4.04 (q, J = 7.0 Hz, 2H), 3.29 (s, 2H), 1.15 (t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 367.1 [M+H] + .
实施例113：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(2-氟吡啶-3-基)嘧啶-4(3H)-酮Example 113: 3-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(2-fluoropyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000291
Figure PCTCN2018122557-appb-000291
1H NMR(400MHz,DMSO-d6)δ8.12(dd,J＝5.0,1.5Hz,1H),8.00(ddd,J＝9.6,7.4,1.9Hz,1H),7.90(t,J＝5.0Hz,1H),7.84(d,J＝1.4Hz,1H),7.34(ddd,J＝7.0,4.9,1.9Hz,1H),6.90(dd,J＝10.5,8.7Hz,1H),6.65(dd,J＝8.7,3.8Hz,1H),4.54(dd,J＝10.1,7.1Hz,4H),4.02(q,J＝7.0Hz,2H),3.28(d,J＝8.7Hz,2H),1.14(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 385.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ8.12 (dd, J = 5.0,1.5Hz, 1H), 8.00 (ddd, J = 9.6,7.4,1.9Hz, 1H), 7.90 (t, J = 5.0Hz , 1H), 7.84 (d, J = 1.4 Hz, 1H), 7.34 (ddd, J = 7.0, 4.9, 1.9 Hz, 1H), 6.90 (dd, J = 10.5, 8.7 Hz, 1H), 6.65 (dd, J = 8.7, 3.8 Hz, 1H), 4.54 (dd, J = 10.1, 7.1 Hz, 4H), 4.02 (q, J = 7.0 Hz, 2H), 3.28 (d, J = 8.7 Hz, 2H), 1.14 ( t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 385.1 [M+H] + .
实施例114：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 114: 3-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(4-methylpyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000292
Figure PCTCN2018122557-appb-000292
1H NMR(400MHz,DMSO-d6)δ8.49-8.27(m,2H),7.84(t,J＝5.3Hz,1H),7.69(s,1H),7.16(d,J＝5.0Hz,1H),6.90(dd,J＝10.5,8.6Hz,1H),6.66(dd,J＝8.6,3.8Hz,1H),4.66-4.41(m,4H),4.03(q,J＝7.0Hz,2H),3.29(t,J＝8.6Hz,2H),2.14(s,3H),1.14(t,J＝7.0Hz,3H).LC-MS:m/z 381.2[M+H] + 1 H NMR (400MHz, DMSO- d6) δ8.49-8.27 (m, 2H), 7.84 (t, J = 5.3Hz, 1H), 7.69 (s, 1H), 7.16 (d, J = 5.0Hz, 1H ), 6.90 (dd, J = 10.5, 8.6 Hz, 1H), 6.66 (dd, J = 8.6, 3.8 Hz, 1H), 4.66 - 4.41 (m, 4H), 4.03 (q, J = 7.0 Hz, 2H) , 3.29 (t, J = 8.6 Hz, 2H), 2.14 (s, 3H), 1.14 (t, J = 7.0 Hz, 3H). LC-MS: m/z 381.2 [M+H] +
实施例115：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(6-(三氟甲基)吡啶-3-基)嘧啶-4(3H)-酮Example 115: 3-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(6-(trifluoromethyl)pyridine -3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000293
Figure PCTCN2018122557-appb-000293
1H NMR(400MHz,DMSO-d6)δ9.03(d,J＝2.1Hz,1H),8.36(dd,J＝8.3,2.1Hz,1H),8.18(s,1H),8.02(t,J＝5.3Hz,1H),7.85(d,J＝8.3Hz,1H),6.90(dd,J＝10.5,8.7Hz,1H),6.66(dd,J＝8.6,3.8Hz,1H),4.66–4.47(m,4H),4.06(q,J＝7.0Hz,2H),3.28(d,J＝8.7Hz,2H),1.16(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 435.1[M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 9.03 (d, J = 2.1 Hz, 1H), 8. s (dd, J = 8.3, 2.1 Hz, 1H), 8.18 (s, 1H), 8.02 (t, J) = 5.3 Hz, 1H), 7.85 (d, J = 8.3 Hz, 1H), 6.90 (dd, J = 10.5, 8.7 Hz, 1H), 6.66 (dd, J = 8.6, 3.8 Hz, 1H), 4.66 - 4.47 (m, 4H), 4.06 (q, J = 7.0 Hz, 2H), 3.28 (d, J = 8.7 Hz, 2H), 1.16 (t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 435.1 [M+H] + .
实施例116：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(2-氟吡啶-4-基)嘧啶-4(3H)-酮Example 116: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(2-fluoropyridin-4-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000294
Figure PCTCN2018122557-appb-000294
1H NMR(400MHz,CDCl 3)δ8.16(d,J＝5.3Hz,1H),8.06(s,1H),7.50(dd,J＝3.8,1.6Hz,1H),7.36(s,1H),6.93-6.80(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.36(s,1H),4.69(d,J＝5.6Hz,2H),4.64(t,J＝8.7Hz,2H),4.06(q,J＝7.3Hz,2H),3.40(t,J＝8.7Hz,2H),1.33(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 385.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.16 (d, J = 5.3Hz, 1H), 8.06 (s, 1H), 7.50 (dd, J = 3.8,1.6Hz, 1H), 7.36 (s, 1H) , 6.93-6.80 (m, 1H), 6.67 (dd, J = 8.7, 4.0 Hz, 1H), 5.36 (s, 1H), 4.69 (d, J = 5.6 Hz, 2H), 4.64 (t, J = 8.7) Hz, 2H), 4.06 (q, J = 7.3 Hz, 2H), 3.40 (t, J = 8.7 Hz, 2H), 1.33 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 385.1 [M+H] + .
实施例117：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(吡啶-4-基)嘧啶-4(3H)-酮Example 117: 3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(pyridin-4-yl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000295
Figure PCTCN2018122557-appb-000295
1H NMR(400MHz,CDCl 3)δ8.57(s,2H),8.06(s,1H),7.73(d,J＝5.1Hz,2H),6.89-6.80(m,1H),6.67(dd,J＝8.7,4.0Hz,1H),5.37(s,1H),4.69(d,J＝5.5Hz,2H),4.64(t,J＝8.7Hz,2H),4.06(q,J＝7.2Hz,2H),3.40(t,J＝8.7Hz,2H),1.33(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 367.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.57 (s, 2H), 8.06 (s, 1H), 7.73 (d, J = 5.1Hz, 2H), 6.89-6.80 (m, 1H), 6.67 (dd, J = 8.7, 4.0 Hz, 1H), 5.37 (s, 1H), 4.69 (d, J = 5.5 Hz, 2H), 4.64 (t, J = 8.7 Hz, 2H), 4.06 (q, J = 7.2 Hz, 2H), 3.40 (t, J = 8.7 Hz, 2H), 1.33 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 367.1 [M+H] + .
实施例118：2-(((6-氟色烷-5-基)甲基)氨基)-5-(3-氟苯基)-3-甲基嘧啶-4(3H)-酮Example 118: 2-(((6-fluorochroman-5-yl)methyl)amino)-5-(3-fluorophenyl)-3-methylpyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000296
Figure PCTCN2018122557-appb-000296
1H NMR(400MHz,CDCl 3)δ7.93(s,1H),7.36(ddd,J＝23.4,9.4,4.2Hz,3H),6.97(ddd,J＝9.3,3.1,1.6Hz,1H),6.88(t,J＝9.3Hz,1H),6.78(dd,J＝9.0,5.1Hz,1H),4.85(s,1H),4.70(dd,J＝5.2,1.3Hz,2H),4.19-4.08(m,2H),3.44(s,3H),2.94(t,J＝6.6Hz,2H),2.11-1.98(m,2H)ppm；LC-MS:m/z 384.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.93 (s, 1H), 7.36 (ddd, J = 23.4,9.4,4.2Hz, 3H), 6.97 (ddd, J = 9.3,3.1,1.6Hz, 1H), 6.88 (t, J = 9.3 Hz, 1H), 6.78 (dd, J = 9.0, 5.1 Hz, 1H), 4.85 (s, 1H), 4.70 (dd, J = 5.2, 1.3 Hz, 2H), 4.19-4.08 (m, 2H), 3.44 (s, 3H), 2.94 (t, J = 6.6 Hz, 2H), 2.11-1.98 (m, 2H) ppm; LC-MS: m/z 384.1 [M+H] + .
实施例119：4-(2-(((6-氟色烷-5-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-基)苯酰胺Example 119: 4-(2-((6-fluorochroman-5-yl)methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyrimidin-5-yl)benzene Amide
Figure PCTCN2018122557-appb-000297
Figure PCTCN2018122557-appb-000297
1H NMR(400MHz,DMSO-d 6)δ8.05(s,1H),7.95(d,J＝10.3Hz,1H),7.85(s,2H),7.73(d,J＝8.4Hz,2H),7.28(s,1H),6.94(d,J＝18.7Hz,1H),6.77(s,1H),4.58-4.56(m,2H),4.08(s,2H),3.35(s,3H),2.85(d,J＝6.7Hz,2H),1.91(d,J＝5.4Hz,2H)ppm；LC-MS:m/z 409.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.05 (s, 1H), 7.95 (d, J = 10.3Hz, 1H), 7.85 (s, 2H), 7.73 (d, J = 8.4Hz, 2H) , 7.28(s,1H), 6.94(d,J=18.7Hz,1H),6.77(s,1H),4.58-4.56(m,2H),4.08(s,2H),3.35(s,3H), 2.85 (d, J = 6.7 Hz, 2H), 1.91 (d, J = 5.4 Hz, 2H) ppm; LC-MS: m/z 409.1 [M+H] + .
实施例120：2-(((6-氟色烷-5-基)甲基)氨基)-3-甲基-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 120: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(4-methylpyridin-3-yl)pyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000298
Figure PCTCN2018122557-appb-000298
1H NMR(400MHz,CDCl 3)δ8.46(s,1H),8.42(d,J＝4.6Hz,1H),7.71(s,1H),7.13(s,1H),6.89(s,1H),6.79(s,1H),4.96(s,1H),4.71(dd,J＝5.1,1.3Hz,2H),4.39-4.02(m,2H),3.44(s,2H),2.94(d,J＝6.6Hz,3H),2.26(s,2H),2.04(dd,J＝5.9,4.6Hz,3H),1.62(s,2H)ppm；LC-MS:m/z 381.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.46 (s, 1H), 8.42 (d, J = 4.6Hz, 1H), 7.71 (s, 1H), 7.13 (s, 1H), 6.89 (s, 1H) , 6.79 (s, 1H), 4.96 (s, 1H), 4.71 (dd, J = 5.1, 1.3 Hz, 2H), 4.39-4.02 (m, 2H), 3.44 (s, 2H), 2.94 (d, J) = 6.6 Hz, 3H), 2.26 (s, 2H), 2.04 (dd, J = 5.9, 4.6 Hz, 3H), 1.62 (s, 2H) ppm; LC-MS: m/z 381.1 [M+H] + .
实施例121：2-(((6-氟色烷-5-基)甲基)氨基)-5-(2-氟吡啶-3-基)-3-甲基嘧啶-4(3H)-酮Example 121: 2-(((6-fluorochroman-5-yl)methyl)amino)-5-(2-fluoropyridin-3-yl)-3-methylpyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000299
Figure PCTCN2018122557-appb-000299
1H NMR(400MHz,CDCl 3)δ8.12(d,J＝4.8Hz,1H),8.09-8.02(m,1H),7.99(d,J＝2.1Hz,1H),7.23-7.20(m,1H),6.88(t,J＝9.3Hz,1H),6.78(dd,J＝9.0,5.0Hz,1H),4.95(s,1H),4.72(d,J＝4.1Hz,2H),4.18-4.09(m,2H),3.44(s,3H),2.95(t,J＝6.5Hz,2H),2.09-1.99(m,2H)ppm；LC-MS:m/z 385.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.12 (d, J = 4.8Hz, 1H), 8.09-8.02 (m, 1H), 7.99 (d, J = 2.1Hz, 1H), 7.23-7.20 (m, 1H), 6.88 (t, J = 9.3 Hz, 1H), 6.78 (dd, J = 9.0, 5.0 Hz, 1H), 4.95 (s, 1H), 4.72 (d, J = 4.1 Hz, 2H), 4.18- 4.09 (m, 2H), 3.44 (s, 3H), 2.95 (t, J = 6.5 Hz, 2H), 2.09-1.99 (m, 2H) ppm; LC-MS: m/z 385.1 [M+H] + .
实施例122：2-(((6-氟色烷-5-基)甲基)氨基)-5-(5-氟吡啶-3-基)-3-甲基嘧啶-4(3H)-酮Example 122: 2-(((6-fluorochroman-5-yl)methyl)amino)-5-(5-fluoropyridin-3-yl)-3-methylpyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000300
Figure PCTCN2018122557-appb-000300
1H NMR(400MHz,DMSO-d 6)δ8.85(s,1H),8.49(d,J＝2.8Hz,1H),8.27(s,1H),8.11(dt,J＝11.0,2.4Hz,1H),7.68(t,J＝4.7Hz,1H),7.02(t,J＝9.3Hz,1H),6.82(dd,J＝9.0,4.8Hz,1H),4.66(d,J＝4.5Hz,2H),4.19-4.10(m,2H),3.44(s,3H),2.92(t,J＝6.5Hz,2H),2.05-1.94(m,2H)ppm；LC-MS:m/z 385.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.85 (s, 1H), 8.49 (d, J = 2.8Hz, 1H), 8.27 (s, 1H), 8.11 (dt, J = 11.0,2.4Hz, 1H), 7.68 (t, J = 4.7 Hz, 1H), 7.02 (t, J = 9.3 Hz, 1H), 6.82 (dd, J = 9.0, 4.8 Hz, 1H), 4.66 (d, J = 4.5 Hz, 2H), 4.19-4.10 (m, 2H), 3.44 (s, 3H), 2.92 (t, J = 6.5 Hz, 2H), 2.05-1.94 (m, 2H) ppm; LC-MS: m/z 385.1 [ M+H] + .
实施例123：2-(((6-氟色烷-5-基)甲基)氨基)-3-甲基-5-(吡啶-3-基)嘧啶-4(3H)-酮Example 123: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(pyridin-3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000301
Figure PCTCN2018122557-appb-000301
1H NMR(400MHz,CDCl 3)δ8.77(d,J＝2.0Hz,1H),8.51(dd,J＝4.8,1.5Hz,1H),8.04(dt,J＝8.0,1.9Hz,1H),7.95(s,1H),7.30(dd,J＝7.9,4.8Hz,1H),6.88(t,J＝9.3Hz,1H),6.79(d,J＝5.0Hz,1H),4.93(s,1H),4.71(dd,J＝5.1,1.2Hz,2H),4.19-4.11(m,2H),3.44(s,3H),2.95(d,J＝6.6Hz,2H),2.12-1.95(m,2H)ppm；LC-MS:m/z 467.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.77 (d, J = 2.0Hz, 1H), 8.51 (dd, J = 4.8,1.5Hz, 1H), 8.04 (dt, J = 8.0,1.9Hz, 1H) , 7.95 (s, 1H), 7.30 (dd, J = 7.9, 4.8 Hz, 1H), 6.88 (t, J = 9.3 Hz, 1H), 6.79 (d, J = 5.0 Hz, 1H), 4.93 (s, 1H), 4.71 (dd, J=5.1, 1.2 Hz, 2H), 4.19-4.11 (m, 2H), 3.44 (s, 3H), 2.95 (d, J = 6.6 Hz, 2H), 2.12-1.95 (m , 2H) ppm; LC-MS: m/z 467.1 [M+H] + .
实施例124:2-(((6-氟色烷-5-基)甲基)氨基)-3-甲基-5-(5-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 124: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(5-methylpyridin-3-yl)pyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000302
Figure PCTCN2018122557-appb-000302
1H NMR(400MHz,CDCl 3)δ8.54-8.50(m,1H),8.33-8.26(m,1H),7.93(s,1H),7.86(s,1H),6.90(s,1H),6.78(d,J＝9.0Hz,1H),4.94(s,1H),4.71(d,J＝5.1Hz,2H),4.21-4.05(m,2H),3.44(s,3H),2.94(t,J＝6.6Hz,2H),2.36(s,3H),2.16-1.95(m,2H)ppm；LC-MS:m/z381.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.54-8.50 (m, 1H), 8.33-8.26 (m, 1H), 7.93 (s, 1H), 7.86 (s, 1H), 6.90 (s, 1H), 6.78 (d, J = 9.0 Hz, 1H), 4.94 (s, 1H), 4.71 (d, J = 5.1 Hz, 2H), 4.21-4.05 (m, 2H), 3.44 (s, 3H), 2.94 (t , J = 6.6 Hz, 2H), 2.36 (s, 3H), 2.16 - 1.95 (m, 2H) ppm; LC-MS: m/z 381.1 [M+H] + .
实施例125:2-(((6-氟色烷-5-基)甲基)氨基)-3-甲基-5-(6-(三氟甲基)吡啶-3-基)嘧啶-4(3H)-酮Example 125: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000303
Figure PCTCN2018122557-appb-000303
1H NMR(400MHz,DMSO-d 6)δ9.05(d,J＝2.1Hz,1H),8.37(dd,J＝8.3,2.1Hz,1H),8.23(s,1H),7.86(d,J＝8.3Hz,1H),7.65(t,J＝4.7Hz,1H),6.94(t,J＝9.3Hz,1H),6.74(dd,J＝9.0,4.8Hz,1H),4.66-4.50(m,2H),4.08(dd,J＝5.8,4.3Hz,2H),3.39(s,3H),2.84(t,J＝6.5Hz,2H),1.92(dt,J＝10.5,6.2Hz,2H)ppm；LC-MS:m/z 435.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ9.05 (d, J = 2.1Hz, 1H), 8.37 (dd, J = 8.3,2.1Hz, 1H), 8.23 (s, 1H), 7.86 (d, J=8.3 Hz, 1H), 7.65 (t, J=4.7 Hz, 1H), 6.94 (t, J=9.3 Hz, 1H), 6.74 (dd, J=9.0, 4.8 Hz, 1H), 4.66-4.50 ( m, 2H), 4.08 (dd, J = 5.8, 4.3 Hz, 2H), 3.39 (s, 3H), 2.84 (t, J = 6.5 Hz, 2H), 1.92 (dt, J = 10.5, 6.2 Hz, 2H) ) ppm; LC-MS: m/z 435.1 [M+H] + .
实施例126:2-(((6-氟色烷-5-基)甲基)氨基)-3-甲基-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 126: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(2-methylpyridin-3-yl)pyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000304
Figure PCTCN2018122557-appb-000304
1H NMR(400MHz,DMSO-d 6)δ8.38(dd,J＝4.7,1.5Hz,1H),7.70(s,1H),7.50(dd,J＝7.6,1.4Hz,1H),7.38(t,J＝4.3Hz,1H),7.20(dd,J＝7.5,4.9Hz,1H),6.94(t,J＝9.3Hz,1H),6.74(dd,J＝9.0,4.8Hz,1H),4.54(d,J＝3.8Hz,2H),4.11-4.03(m,2H),3.34(s,3H),2.85(t,J＝6.4Hz,2H),2.34(s,3H),1.93(dd,J＝11.0,5.7Hz,2H)ppm；LC-MS:m/z 381.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.38 (dd, J = 4.7,1.5Hz, 1H), 7.70 (s, 1H), 7.50 (dd, J = 7.6,1.4Hz, 1H), 7.38 ( t, J = 4.3 Hz, 1H), 7.20 (dd, J = 7.5, 4.9 Hz, 1H), 6.94 (t, J = 9.3 Hz, 1H), 6.74 (dd, J = 9.0, 4.8 Hz, 1H), 4.54 (d, J = 3.8 Hz, 2H), 4.11-4.03 (m, 2H), 3.34 (s, 3H), 2.85 (t, J = 6.4 Hz, 2H), 2.34 (s, 3H), 1.93 (dd , J = 11.0, 5.7 Hz, 2H) ppm; LC-MS: m/z 381.1 [M+H] + .
实施例127:2-(((6-氟色烷-5-基)甲基)氨基)-3-甲基-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-4(3H)-酮Example 127: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(6-(4-methylpiperazin-1-yl)pyridine-3 -yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000305
Figure PCTCN2018122557-appb-000305
1H NMR(400MHz,CDCl 3)δ8.33(s,1H),7.87(d,J＝12.1Hz,2H),6.88(t,J＝9.3Hz, 1H),6.78(d,J＝8.6Hz,1H),6.69(d,J＝8.8Hz,1H),4.79(s,1H),4.68(d,J＝4.3Hz,2H),4.25-4.08(m,2H),3.68(s,4H),3.42(s,3H),2.93(t,J＝6.3Hz,2H),2.69(s,4H),2.44(s,3H),2.12-1.96(m,2H)ppm；LC-MS:m/z 545.2[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (s, 1H), 7.78 (d, J = 12.1 Hz, 2H), 6.88 (t, J = 9.3 Hz, 1H), 6.78 (d, J = 8.6 Hz) , 1H), 6.69 (d, J = 8.8 Hz, 1H), 4.79 (s, 1H), 4.68 (d, J = 4.3 Hz, 2H), 4.25 - 4.08 (m, 2H), 3.68 (s, 4H) , 3.42 (s, 3H), 2.93 (t, J = 6.3 Hz, 2H), 2.69 (s, 4H), 2.44 (s, 3H), 2.12-1.96 (m, 2H) ppm; LC-MS: m/ z 545.2[M+H] + .
实施例128:2-(((6-氟色烷-5-基)甲基)氨基)-3-甲基-5-(1-甲基-1H-吡唑-4-基)嘧啶-4(3H)-酮Example 128: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-methyl-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000306
Figure PCTCN2018122557-appb-000306
1H NMR(400MHz,DMSO-d 6)δ8.08(s,2H),7.83(s,1H),7.22(s,1H),6.93(s,1H),6.73(d,J＝4.8Hz,1H),4.52(dd,J＝4.7,1.5Hz,2H),4.07(d,J＝1.5Hz,2H),3.82(s,3H),2.83(s,2H),1.99-1.85(m,2H)ppm；LC-MS:m/z 381.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.08 (s, 2H), 7.83 (s, 1H), 7.22 (s, 1H), 6.93 (s, 1H), 6.73 (d, J = 4.8Hz, 1H), 4.52 (dd, J = 4.7, 1.5 Hz, 2H), 4.07 (d, J = 1.5 Hz, 2H), 3.82 (s, 3H), 2.83 (s, 2H), 1.99-1.85 (m, 2H) ) ppm; LC-MS: m/z 381.1 [M+H] + .
实施例129:5-(3,5-二甲基异噻唑-4-基)-2-(((6-氟色烷-5-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 129: 5-(3,5-Dimethylisothiazol-4-yl)-2-(((6-fluorochroman-5-yl)methyl)amino)-3-methylpyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000307
Figure PCTCN2018122557-appb-000307
1H NMR(400MHz,CDCl 3)δ7.64(s,1H),6.89(t,J＝9.2Hz,1H),6.79(dd,J＝9.0,5.0Hz,1H),4.88(s,1H),4.69(d,J＝4.1Hz,2H),4.19-4.07(m,2H),3.42(s,3H),2.94(t,J＝6.6Hz,2H),2.34(s,3H),2.21(s,3H),2.08-1.99(m,2H)ppm；LC-MS:m/z 385.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.64 (s, 1H), 6.89 (t, J = 9.2Hz, 1H), 6.79 (dd, J = 9.0,5.0Hz, 1H), 4.88 (s, 1H) , 4.69 (d, J = 4.1 Hz, 2H), 4.19 - 4.07 (m, 2H), 3.42 (s, 3H), 2.94 (t, J = 6.6 Hz, 2H), 2.34 (s, 3H), 2.21 ( s, 3H), 2.08-1.99 (m, 2H) ppm; LC-MS: m/z 385.1 [M+H] + .
实施例130:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(6-(4-甲基哌嗪-1-基)吡啶-3-基)嘧啶-4(3H)-酮Example 130: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(6-(4-methylpiperazin-1-yl)pyridine-3 -yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000308
Figure PCTCN2018122557-appb-000308
1H NMR(400MHz,CDCl 3)δ8.33(d,J＝2.2Hz,1H),7.90(dd,J＝8.8,2.4Hz,1H),7.83(s,1H),6.88(t,J＝9.3Hz,1H),6.77(dd,J＝9.0,5.0Hz,1H),6.70(d,J＝8.9Hz,1H),4.90(s,1H),4.66(d,J＝4.1Hz,2H),4.23-4.09(m,2H),4.01(q,J＝7.2Hz,2H),3.81-3.62(m,3H), 2.95(t,J＝6.6Hz,3H),2.88-2.81(m,5H),2.53(s,3H),2.10-1.96(m,2H),1.29(t,J＝7.2Hz,3H)ppm；LC-MS:m/z 379.2[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.33 (d, J = 2.2 Hz, 1H), 7.90 (dd, J = 8.8, 2.4 Hz, 1H), 7.83 (s, 1H), 6.88 (t, J = 9.3 Hz, 1H), 6.77 (dd, J = 9.0, 5.0 Hz, 1H), 6.70 (d, J = 8.9 Hz, 1H), 4.90 (s, 1H), 4.66 (d, J = 4.1 Hz, 2H) , 4.3-4.09 (m, 2H), 4.01 (q, J = 7.2 Hz, 2H), 3.81-3.62 (m, 3H), 2.95 (t, J = 6.6 Hz, 3H), 2.88-2.81 (m, 5H) ), 2.53 (s, 3H), 2.10 - 1.96 (m, 2H), 1.29 (t, J = 7.2 Hz, 3H) ppm; LC-MS: m/z 379.2 [M+H] + .
实施例131:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(5-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 131: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(5-methylpyridin-3-yl)pyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000309
Figure PCTCN2018122557-appb-000309
1H NMR(400MHz,CDCl 3)δ8.57(s,1H),8.35(s,1H),7.94(d,J＝9.5Hz,2H),6.88(t,J＝9.3Hz,1H),6.77(dd,J＝9.0,5.1Hz,1H),5.06(s,1H),4.69(d,J＝4.8Hz,2H),4.19-4.10(m,2H),4.03(q,J＝7.2Hz,2H),2.97(t,J＝6.5Hz,2H),2.37(s,3H),2.13-1.95(m,2H),1.31(t,J＝7.2Hz,3H)ppm；LC-MS:m/z 395.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.57 (s, 1H), 8.35 (s, 1H), 7.94 (d, J = 9.5Hz, 2H), 6.88 (t, J = 9.3Hz, 1H), 6.77 (dd, J=9.0, 5.1 Hz, 1H), 5.06 (s, 1H), 4.69 (d, J = 4.8 Hz, 2H), 4.19-4.10 (m, 2H), 4.03 (q, J = 7.2 Hz, 2H), 2.97 (t, J = 6.5 Hz, 2H), 2.37 (s, 3H), 2.13-1.95 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H) ppm; LC-MS: m/ z 395.1[M+H] + .
实施例132:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(5-氟吡啶-3-基)嘧啶-4(3H)-酮Example 132: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(5-fluoropyridin-3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000310
Figure PCTCN2018122557-appb-000310
1H NMR(400MHz,CDCl 3)δ8.60(s,1H),8.36(d,J＝2.6Hz,1H),7.98(s,1H),7.90(d,J＝10.2Hz,1H),6.89(t,J＝9.3Hz,1H),6.78(dd,J＝9.0,5.1Hz,1H),5.05(s,1H),4.70(d,J＝5.0Hz,2H),4.20-4.11(m,2H),4.04(q,J＝7.2Hz,2H),2.97(t,J＝6.5Hz,2H),2.14-1.99(m,2H),1.32(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 399.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.60 (s, 1H), 8.36 (d, J = 2.6Hz, 1H), 7.98 (s, 1H), 7.90 (d, J = 10.2Hz, 1H), 6.89 (t, J = 9.3 Hz, 1H), 6.78 (dd, J = 9.0, 5.1 Hz, 1H), 5.05 (s, 1H), 4.70 (d, J = 5.0 Hz, 2H), 4.20 - 4.11 (m, 2H), 4.04 (q, J = 7.2 Hz, 2H), 2.97 (t, J = 6.5 Hz, 2H), 2.14-1.99 (m, 2H), 1.32 (t, J = 7.3 Hz, 3H) ppm; LC -MS: m/z 399.1 [M+H] + .
实施例133:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(吡啶-3-基)嘧啶-4(3H)-酮Example 133: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(pyridin-3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000311
Figure PCTCN2018122557-appb-000311
1H NMR(400MHz,DMSO-d 6)δ8.85-8.73(m,1H),8.42(dd,J＝4.7,1.6Hz,1H),8.03(d,J＝8.3Hz,2H),7.57(t,J＝4.7Hz,1H),7.41-7.28(m,1H),6.94(t,J＝9.3Hz,1H),6.73(dd,J＝9.0,4.8Hz,1H),4.61-4.48(m,2H),4.13-3.97(m,4H),2.85(t,J＝6.5Hz,2H),1.93(q,J＝6.2Hz,2H),1.11(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 381.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.85-8.73 (m, 1H), 8.42 (dd, J = 4.7,1.6Hz, 1H), 8.03 (d, J = 8.3Hz, 2H), 7.57 ( t, J = 4.7 Hz, 1H), 7.41-7.28 (m, 1H), 6.94 (t, J = 9.3 Hz, 1H), 6.73 (dd, J = 9.0, 4.8 Hz, 1H), 4.61-4.48 (m , 2H), 4.13 - 3.97 (m, 4H), 2.85 (t, J = 6.5 Hz, 2H), 1.93 (q, J = 6.2 Hz, 2H), 1.11 (t, J = 7.0 Hz, 3H) ppm; LC-MS: m/z 381.1 [M+H] + .
实施例134:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(3-氟苯基)嘧啶-4(3H)-酮Example 134: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(3-fluorophenyl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000312
Figure PCTCN2018122557-appb-000312
1H NMR(400MHz,CDCl 3)δ7.91(s,1H),7.40(dd,J＝8.0,5.0Hz,2H),7.36-7.30(m,1H),6.97(dt,J＝8.9,5.6Hz,1H),6.88(t,J＝9.2Hz,1H),6.77(dd,J＝9.0,5.0Hz,1H),4.92(s,1H),4.68(d,J＝4.2Hz,2H),4.19-4.11(m,2H),4.03(q,J＝7.3Hz,2H),2.96(t,J＝6.6Hz,2H),2.09-1.96(m,2H),1.31(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 398.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 7.91 (s, 1H), 7.40 (dd, J = 8.0, 5.0 Hz, 2H), 7.36-7.30 (m, 1H), 6.97 (dt, J = 8.9, 5.6 Hz, 1H), 6.88 (t, J = 9.2 Hz, 1H), 6.77 (dd, J = 9.0, 5.0 Hz, 1H), 4.92 (s, 1H), 4.68 (d, J = 4.2 Hz, 2H), 4.19-4.11 (m, 2H), 4.03 (q, J = 7.3 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 2.09-1.96 (m, 2H), 1.31 (t, J = 7.3 Hz) , 3H) ppm; LC-MS: m/z 398.1 [M+H] + .
实施例135:4-(1-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-6-羰基-1,6-二氢嘧啶-5-基)苯酰胺Example 135: 4-(1-Ethyl-2-((6-fluorochroman-5-yl)methyl)amino)-6-carbonyl-1,6-dihydropyrimidin-5-yl)benzene Amide
Figure PCTCN2018122557-appb-000313
Figure PCTCN2018122557-appb-000313
1H NMR(400MHz,DMSO-d 6)δ8.02(s,1H),7.92(s,1H),7.84(d,J＝8.5Hz,2H),7.77-7.67(m,2H),7.55(d,J＝4.7Hz,1H),7.28(s,1H),6.94(t,J＝9.2Hz,1H),6.73(dd,J＝9.0,4.8Hz,1H),4.55(d,J＝4.3Hz,2H),4.10-3.92(m,4H),2.85(t,J＝6.5Hz,2H),1.93(d,J＝6.4Hz,2H),1.12(t,J＝7.0Hz,3H)ppm；LC-MS:m/z 423.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.02 (s, 1H), 7.92 (s, 1H), 7.84 (d, J = 8.5Hz, 2H), 7.77-7.67 (m, 2H), 7.55 ( d, J = 4.7 Hz, 1H), 7.28 (s, 1H), 6.94 (t, J = 9.2 Hz, 1H), 6.73 (dd, J = 9.0, 4.8 Hz, 1H), 4.55 (d, J = 4.3) Hz, 2H), 4.10-3.92 (m, 4H), 2.85 (t, J = 6.5 Hz, 2H), 1.93 (d, J = 6.4 Hz, 2H), 1.12 (t, J = 7.0 Hz, 3H) ppm LC-MS: m/z 423.1 [M+H] + .
实施例136:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(2-氟吡啶-3-基)嘧啶-4(3H)-酮Example 136: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(2-fluoropyridin-3-yl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000314
Figure PCTCN2018122557-appb-000314
1H NMR(400MHz,CDCl 3)δ8.14-8.05(m,2H),7.97(d,J＝2.2Hz,1H),7.24-7.17(m,1H),6.88(t,J＝9.3Hz,1H),6.77(dd,J＝9.0,5.0Hz,1H),5.03(s,1H),4.70(d,J＝4.4Hz,2H),4.18-4.12(m,2H),4.03(q,J＝7.2Hz,2H),2.97(t,J＝6.6Hz,2H),2.10-1.98(m,2H),1.31(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 399.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.14-8.05 (m, 2H), 7.97 (d, J = 2.2Hz, 1H), 7.24-7.17 (m, 1H), 6.88 (t, J = 9.3Hz, 1H), 6.77 (dd, J=9.0, 5.0 Hz, 1H), 5.03 (s, 1H), 4.70 (d, J = 4.4 Hz, 2H), 4.18-4.12 (m, 2H), 4.03 (q, J) = 7.2 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 2.10 - 1.98 (m, 2H), 1.31 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 399.1 [ M+H] + .
实施例137:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(6-(三氟甲基)吡啶-3-基)嘧啶-4(3H)-酮Example 137: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(6-(trifluoromethyl)pyridin-3-yl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000315
Figure PCTCN2018122557-appb-000315
1H NMR(400MHz,CDCl 3)δ8.89(d,J＝1.8Hz,1H),8.28(dd,J＝8.2,1.7Hz,1H),7.67(d,J＝8.2Hz,1H),6.89(t,J＝9.3Hz,1H),6.78(dd,J＝9.0,5.1Hz,1H),5.08(s,1H),4.77-4.63(m,2H),4.21-4.09(m,2H),4.04(q,J＝7.3Hz,2H),3.03-2.88(m,2H),2.19-1.91(m,2H),1.30(dt,J＝13.6,7.2Hz,3H)ppm；LC-MS:m/z 449.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.89 (d, J = 1.8 Hz, 1H), 8.28 (dd, J = 8.2, 1.7 Hz, 1H), 7.67 (d, J = 8.2 Hz, 1H), 6.89 (t, J = 9.3 Hz, 1H), 6.78 (dd, J = 9.0, 5.1 Hz, 1H), 5.08 (s, 1H), 4.77-4.63 (m, 2H), 4.21-4.09 (m, 2H), 4.04 (q, J = 7.3 Hz, 2H), 3.03-2.88 (m, 2H), 2.19-1.91 (m, 2H), 1.30 (dt, J = 13.6, 7.2 Hz, 3H) ppm; LC-MS: m /z 449.1[M+H] + .
实施例138:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 138: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(2-methylpyridin-3-yl)pyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000316
Figure PCTCN2018122557-appb-000316
1H NMR(400MHz,CDCl 3)δ8.47(dd,J＝4.8,1.5Hz,1H),7.67(s,1H),7.52(dd,J＝7.6,1.4Hz,1H),7.15(dd,J＝7.6,4.9Hz,1H),6.89(t,J＝9.3Hz,1H),6.78(dd,J＝9.0,5.0Hz,1H),4.96(s,1H),4.68(d,J＝4.3Hz,2H),4.14(dd,J＝12.3,7.1Hz,2H),4.03(q,J＝7.3Hz,2H),2.97(t,J＝6.6Hz,2H),2.50(s,3H),2.14-1.96(m,2H),1.28(dt,J＝13.0,7.1Hz,3H)ppm；LC-MS:m/z 395.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.47 (dd, J = 4.8,1.5Hz, 1H), 7.67 (s, 1H), 7.52 (dd, J = 7.6,1.4Hz, 1H), 7.15 (dd, J = 7.6, 4.9 Hz, 1H), 6.89 (t, J = 9.3 Hz, 1H), 6.78 (dd, J = 9.0, 5.0 Hz, 1H), 4.96 (s, 1H), 4.68 (d, J = 4.3) Hz, 2H), 4.14 (dd, J = 12.3, 7.1 Hz, 2H), 4.03 (q, J = 7.3 Hz, 2H), 2.97 (t, J = 6.6 Hz, 2H), 2.50 (s, 3H), 2.14-1.96 (m, 2H), 1.28 (dt, J = 13.0, 7.1 Hz, 3H) ppm; LC-MS: m/z 395.1 [M+H] + .
实施例139:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 139: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(4-methylpyridin-3-yl)pyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000317
Figure PCTCN2018122557-appb-000317
1H NMR(400MHz,CDCl 3)δ8.44(d,J＝20.4Hz,2H),7.69(s,1H),7.15(d,J＝4.5Hz,1H),6.88(d,J＝9.4Hz,1H),6.81-6.75(m,1H),5.01(s,1H),4.69(d,J＝4.6Hz,2H),4.19-4.11(m,2H),4.03(d,J＝7.1Hz,2H),2.97(t,J＝6.3Hz,2H),2.26(s,3H),2.09-2.01(m,2H),1.31(t,J＝7.2Hz,3H)ppm；LC-MS:m/z 395.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ8.44 (d, J = 20.4Hz, 2H), 7.69 (s, 1H), 7.15 (d, J = 4.5Hz, 1H), 6.88 (d, J = 9.4Hz , 1H), 6.81-6.75 (m, 1H), 5.01 (s, 1H), 4.69 (d, J = 4.6 Hz, 2H), 4.19 - 4.11 (m, 2H), 4.03 (d, J = 7.1 Hz, 2H), 2.97 (t, J = 6.3 Hz, 2H), 2.26 (s, 3H), 2.09-2.01 (m, 2H), 1.31 (t, J = 7.2 Hz, 3H) ppm; LC-MS: m/ z 395.1[M+H] + .
实施例140:3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)-5-(1-甲基-1H-吡唑-4-基)嘧啶-4(3H)-酮Example 140: 3-ethyl-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(1-methyl-1H-pyrazol-4-yl)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000318
Figure PCTCN2018122557-appb-000318
1H NMR(400MHz,CDCl 3)δ8.05(s,1H),8.01(s,1H),7.77(s,1H),6.87(t,J＝9.3Hz,1H),6.76(dd,J＝9.0,5.0Hz,1H),4.82(s,1H),4.66(d,J＝5.1Hz,2H),4.17-4.11(m,2H),4.02(q,J＝7.3Hz,2H),3.91(s,3H),2.95(t,J＝6.5Hz,2H),2.11-1.97(m,2H),1.29(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 384.1[M+H] +. 1 H NMR (400 MHz, CDCl 3 ) δ 8.05 (s, 1H), 8. (s, 1H), 7.77 (s, 1H), 6.87 (t, J = 9.3 Hz, 1H), 6.76 (dd, J = 9.0, 5.0 Hz, 1H), 4.82 (s, 1H), 4.66 (d, J = 5.1 Hz, 2H), 4.17 - 4.11 (m, 2H), 4.02 (q, J = 7.3 Hz, 2H), 3.91 ( s, 3H), 2.95 (t, J = 6.5 Hz, 2H), 2.11-1.97 (m, 2H), 1.29 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 384.1 [M+ H] + .
实施例141:5-(3,5-二甲基异噻唑-4-基)-3-乙基-2-(((6-氟色烷-5-基)甲基)氨基)嘧啶-4(3H)-酮Example 141: 5-(3,5-Dimethylisothiazol-4-yl)-3-ethyl-2-((6-fluorochroman-5-yl)methyl)amino)pyrimidine-4 (3H)-ketone
Figure PCTCN2018122557-appb-000319
Figure PCTCN2018122557-appb-000319
1H NMR(400MHz,CDCl3)δ7.61(s,1H),6.89(t,J＝9.3Hz,1H),6.78(dd,J＝9.0,5.0Hz,1H),4.94(s,1H),4.67(dd,J＝5.1,1.2Hz,2H),4.21-4.10(m,2H),4.01(q,J＝7.2Hz,2H),2.96(t,J＝6.6Hz,2H),2.34(s,3H),2.22(s,3H),2.10-1.98(m,2H),1.30(t,J＝7.3Hz,3H)ppm；LC-MS:m/z 399.1[M+H] +. 1 H NMR (400MHz, CDCl3) δ7.61 (s, 1H), 6.89 (t, J = 9.3Hz, 1H), 6.78 (dd, J = 9.0,5.0Hz, 1H), 4.94 (s, 1H), 4.67 (dd, J = 5.1, 1.2 Hz, 2H), 4.21-4.10 (m, 2H), 4.01 (q, J = 7.2 Hz, 2H), 2.96 (t, J = 6.6 Hz, 2H), 2.34 (s) , 3H), 2.22 (s, 3H), 2.10 - 1.98 (m, 2H), 1.30 (t, J = 7.3 Hz, 3H) ppm; LC-MS: m/z 399.1 [M+H] + .
实施例142:2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(1,2,3,6-四氢吡啶-4-基)嘧啶-4(3H)-酮Example 142: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(1,2,3,6-tetra Hydropyridin-4-yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000320
Figure PCTCN2018122557-appb-000320
在干燥的50mL圆底烧瓶中依次加入叔-丁基4-(2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-基)-5,6-二氢吡啶-1(2H)-羧酸酯(20mg,0.043mmol)和盐酸的1，4-二氧六环溶液(7M,5mL)，室温反应1小时。反应液减压蒸馏，所得粗产品用反相高效液相色谱纯化得到产物2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(1,2,3,6-四氢吡啶-4-基)嘧啶-4(3H)-酮(5mg,32.7％产率)Add tert-butyl 4-(2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl) in a dry 50 mL round bottom flask -6-carbonyl-1,6-dihydropyrimidin-5-yl)-5,6-dihydropyridine-1(2H)-carboxylate (20 mg, 0.043 mmol) and 1,4-dioxane hydrochloride The ring solution (7M, 5 mL) was reacted at room temperature for 1 hour. The reaction liquid was distilled under reduced pressure, and the obtained crude product was purified by reverse-phase high-purity liquid chromatography to give the product 2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3- Methyl-5-(1,2,3,6-tetrahydropyridin-4-yl)pyrimidin-4(3H)-one (5 mg, 32.7% yield)
1H NMR(400MHz,DMSO-d 6)δ8.76(s,2H),7.73(d,J＝7.2Hz,2H),6.93-6.85(m,1H),6.65(dd,J＝8.6,3.8Hz,1H),6.50(s,1H),4.52(dd,J＝11.9,5.6Hz,4H),3.69(s,2H),3.31(s, 3H),3.24(t,J＝8.4Hz,4H),2.57(s,2H)ppm；LCMS:m/z 357.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.76 (s, 2H), 7.73 (d, J = 7.2Hz, 2H), 6.93-6.85 (m, 1H), 6.65 (dd, J = 8.6,3.8 Hz, 1H), 6.50 (s, 1H), 4.52 (dd, J = 11.9, 5.6 Hz, 4H), 3.69 (s, 2H), 3.31 (s, 3H), 3.24 (t, J = 8.4 Hz, 4H) ), 2.57 (s, 2H) ppm; LCMS: m/z 357.1 [M+H] + .
按照实施例142的方法可合成以下化合物The following compounds were synthesized according to the method of Example 142.
实施例143:5-(4-氨基环己-1-烯-1-基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 143: 5-(4-Aminocyclohex-1-en-1-yl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino) -3-methylpyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000321
改为
Figure PCTCN2018122557-appb-000321
Changed to
Figure PCTCN2018122557-appb-000322
Figure PCTCN2018122557-appb-000322
1H NMR(400MHz,DMSO-d 6)δ8.42(s,1H),7.57(d,J＝20.8Hz,2H),6.88(dd,J＝10.4,8.6Hz,1H),6.64(dd,J＝8.6,3.9Hz,1H),6.19-6.07(m,1H),4.56-4.43(m,3H),3.29(s,3H),3.22(d,J＝8.7Hz,3H),3.08(s,2H),2.38(s,2H),2.04(dd,J＝16.9,9.3Hz,1H),1.91(d,J＝12.2Hz,1H),1.51(dt,J＝11.2,5.7Hz,1H)ppm；LC-MS:m/z 371.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ8.42 (s, 1H), 7.57 (d, J = 20.8Hz, 2H), 6.88 (dd, J = 10.4,8.6Hz, 1H), 6.64 (dd, J=8.6, 3.9 Hz, 1H), 6.19-6.07 (m, 1H), 4.56-4.43 (m, 3H), 3.29 (s, 3H), 3.22 (d, J = 8.7 Hz, 3H), 3.08 (s) , 2H), 2.38 (s, 2H), 2.04 (dd, J = 16.9, 9.3 Hz, 1H), 1.91 (d, J = 12.2 Hz, 1H), 1.51 (dt, J = 11.2, 5.7 Hz, 1H) Ppm; LC-MS: m/z 371.1 [M+H] + .
实施例144：5-环己基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮的合成：Example 144: 5-cyclohexyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methylpyrimidin-4(3H)-one Synthesis:
Figure PCTCN2018122557-appb-000323
Figure PCTCN2018122557-appb-000323
在100mL单口瓶中依次加入5-(环己-1-烯-1-基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮(20mg，56μmol)，甲醇(5mL)和10％钯碳(8mg，含50％水)。反应混合物用氢气球换气三次，在氢气球下室温搅拌18小时。反应液经硅藻土过滤，用甲醇(50mL X 2)洗涤，滤液减压浓缩，得到化合物5-环己基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮(18mg，89.5％产率)。5-(cyclohex-1-en-1-yl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino) was added sequentially to a 100 mL single-mouth bottle. 3-Methylpyrimidin-4(3H)-one (20 mg, 56 μmol), methanol (5 mL) and 10% palladium on carbon (8 mg, 50% water). The reaction mixture was exchanged three times with a hydrogen balloon and stirred at room temperature under a hydrogen balloon for 18 hours. The reaction solution was filtered through EtOAc (EtOAc) (EtOAcjjjjjjjj Methyl)amino)-3-methylpyrimidine-4(3H)-one (18 mg, 89.5% yield).
1H NMR(400MHz,CDCl 3)δ7.51(s,1H),6.89-6.78(m,1H),6.65(dd,J＝8.7,4.0Hz,1H),4.81(t,J＝4.9Hz,1H),4.61(dd,J＝15.1,6.6Hz,4H),3.43-3.27(m,5H),2.70-2.53(m,1H),1.93-1.68(m,5H),1.49-1.13(m,5H)ppm；LC-MS:m/z 358.2[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.51 (s, 1H), 6.89-6.78 (m, 1H), 6.65 (dd, J = 8.7,4.0Hz, 1H), 4.81 (t, J = 4.9Hz, 1H), 4.61 (dd, J = 15.1, 6.6 Hz, 4H), 3.43-3.27 (m, 5H), 2.70-2.53 (m, 1H), 1.93-1.68 (m, 5H), 1.49-1.13 (m, 5H) ppm; LC-MS: m/z 358.2 [M+H] + .
按照实施例144的方法可合成以下化合物The following compounds were synthesized according to the method of Example 144.
实施例145：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(四氢-2H-吡喃-4-基)嘧啶-4(3H)-酮Example 145: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(tetrahydro-2H-pyran-4 -yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000324
Figure PCTCN2018122557-appb-000324
1H NMR(400MHz,CDCl 3)δ7.52(s,1H),6.89-6.77(m,1H),6.65(dd,J＝8.7,4.0Hz,1H),4.87(t,J＝5.0Hz,1H),4.62(dd,J＝11.2,6.6Hz,4H),4.03(dd,J＝11.1,3.8Hz,2H),3.61-3.46(m,2H),3.46-3.29(m,5H),2.98-2.79(m,1H),1.64(qd,J＝12.5,4.3Hz,4H)ppm；LC-MS:m/z 360.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.52 (s, 1H), 6.89-6.77 (m, 1H), 6.65 (dd, J = 8.7,4.0Hz, 1H), 4.87 (t, J = 5.0Hz, 1H), 4.62 (dd, J = 11.2, 6.6 Hz, 4H), 4.03 (dd, J = 11.1, 3.8 Hz, 2H), 3.61-3.46 (m, 2H), 3.46-3.29 (m, 5H), 2.98 -2.79 (m, 1H), 1.64 (qd, J = 12.5, 4.3 Hz, 4H) ppm; LC-MS: m/z 360.1 [M+H] + .
实施例146：5-环己基-3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)嘧啶-4(3H)-酮Example 146: 5-cyclohexyl-3-ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000325
Figure PCTCN2018122557-appb-000325
1H NMR(400MHz,CDCl 3)δ7.47(s,1H),6.82(dd,J＝19.4,9.1Hz,1H),6.65(dd,J＝8.6,4.0Hz,1H),4.86(s,1H),4.65-4.54(m,4H),3.97(q,J＝7.3Hz,2H),3.36(t,J＝8.7Hz,2H),2.61(tt,J＝11.8,3.1Hz,1H),1.76(ddd,J＝62.8,33.7,23.8Hz,6H),1.45-1.29(m,4H),1.26(d,J＝5.2Hz,3H)ppm；LCMS:m/z 372.2[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.47 (s, 1H), 6.82 (dd, J = 19.4,9.1Hz, 1H), 6.65 (dd, J = 8.6,4.0Hz, 1H), 4.86 (s, 1H), 4.65-4.54 (m, 4H), 3.97 (q, J = 7.3 Hz, 2H), 3.36 (t, J = 8.7 Hz, 2H), 2.61 (tt, J = 11.8, 3.1 Hz, 1H), 1.76 (ddd, J=62.8, 33.7, 23.8 Hz, 6H), 1.45-1.29 (m, 4H), 1.26 (d, J = 5.2 Hz, 3H) ppm; LCMS: m/z 372.2 [M+H] + .
实施例147：3-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(四氢-2H-吡喃-4-基)嘧啶-4(3H)-酮Example 147: 3-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(tetrahydro-2H-pyran-4 -yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000326
Figure PCTCN2018122557-appb-000326
1H NMR(400MHz,CDCl 3)δ7.49(s,1H),6.88-6.79(m,1H),6.65(dd,J＝8.6,4.0Hz,1H),4.93(s,1H),4.65-4.57(m,4H),4.00(ddd,J＝22.0,12.9,5.6Hz,4H),3.52(dd,J＝11.6,10.3Hz,2H),3.37(t,J＝8.7Hz,2H),2.88(tt,J＝12.0,3.5Hz,1H),1.77(d,J＝11.3Hz,2H),1.69-1.62(m,2H),1.26(d,J＝7.4Hz,3H)ppm；LCMS:m/z 374.2[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.49 (s, 1H), 6.88-6.79 (m, 1H), 6.65 (dd, J = 8.6,4.0Hz, 1H), 4.93 (s, 1H), 4.65- 4.57 (m, 4H), 4.00 (ddd, J = 22.0, 12.9, 5.6 Hz, 4H), 3.52 (dd, J = 11.6, 10.3 Hz, 2H), 3.37 (t, J = 8.7 Hz, 2H), 2.88 (tt, J = 12.0, 3.5 Hz, 1H), 1.77 (d, J = 11.3 Hz, 2H), 1.69 - 1.62 (m, 2H), 1.26 (d, J = 7.4 Hz, 3H) ppm; LCMS: m /z 374.2[M+H] + .
实施例148：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-异丙基-3-甲基嘧啶-4(3H)-酮Example 148: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-isopropyl-3-methylpyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000327
Figure PCTCN2018122557-appb-000327
1H NMR(400MHz,DMSO-d 6)δ7.47(s,1H),7.32(t,J＝5.3Hz,1H),6.87(dd,J＝10.4,8.7Hz,1H),6.63(dd,J＝8.6,3.9Hz,1H),4.61-4.41(m,4H),3.29(s,3H),3.24(t,J＝8.7Hz,2H),2.77(q,J＝6.9Hz,1H),1.09(s,3H),1.07(s,3H)ppm；LC-MS:m/z 318.1[M+H] +. 1 H NMR (400MHz, DMSO- d 6) δ7.47 (s, 1H), 7.32 (t, J = 5.3Hz, 1H), 6.87 (dd, J = 10.4,8.7Hz, 1H), 6.63 (dd, J = 8.6, 3.9 Hz, 1H), 4.61-4.41 (m, 4H), 3.29 (s, 3H), 3.24 (t, J = 8.7 Hz, 2H), 2.77 (q, J = 6.9 Hz, 1H), 1.09 (s, 3H), 1.07 (s, 3H) ppm; LC-MS: m/z 318.1 [M+H] + .
实施例149：5-乙基-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 149: 5-Ethyl-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methylpyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000328
Figure PCTCN2018122557-appb-000328
Figure PCTCN2018122557-appb-000329
Figure PCTCN2018122557-appb-000329
1H NMR(400MHz,DMSO-d6)δ7.48(s,1H),7.31(t,J＝5.1Hz,1H),6.93–6.84(m,1H),6.63(dd,J＝8.6,3.8Hz,1H),4.54–4.45(m,4H),3.29(s,3H),3.22(d,J＝8.8Hz,2H),2.23(q,J＝7.4Hz,2H),1.02(t,J＝7.4Hz,3H)ppm；LCMS:m/z 304.1[M+H] +. 1 H NMR (400MHz, DMSO- d6) δ7.48 (s, 1H), 7.31 (t, J = 5.1Hz, 1H), 6.93-6.84 (m, 1H), 6.63 (dd, J = 8.6,3.8Hz , 1H), 4.54–4.45 (m, 4H), 3.29 (s, 3H), 3.22 (d, J = 8.8 Hz, 2H), 2.23 (q, J = 7.4 Hz, 2H), 1.02 (t, J = 7.4 Hz, 3H) ppm; LCMS: m/z 304.1 [M+H] + .
实施例150：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-甲腈Example 150: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyrimidine- 5-carbonitrile
Figure PCTCN2018122557-appb-000330
Figure PCTCN2018122557-appb-000330
在10mL的微波管中依次加入中间体A-2(200mg，0.56mmol)，氰化锌(100mg，0.85mmol)，四三苯基膦钯(98mg,0.085mmol)和无水N,N-二甲基甲酰胺(3mL)。反应混合物在氮气下100℃微波反应1个小时。冷却至室温后，加入20mL水，用乙酸乙酯萃取(20mL X 3)。合并的有机相用盐水洗涤两次，经无水硫酸钠干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(石油醚：乙酸乙酯＝1：1)，得到化合物2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-甲腈(150mg，88％产率)，为白色固体。Intermediate A-2 (200 mg, 0.56 mmol), zinc cyanide (100 mg, 0.85 mmol), tetrakistriphenylphosphine palladium (98 mg, 0.085 mmol) and anhydrous N,N-di were sequentially added to a 10 mL microwave tube. Methylformamide (3 mL). The reaction mixture was subjected to microwave reaction at 100 ° C for 1 hour under nitrogen. After cooling to room temperature, 20 mL of water was added and extracted with ethyl acetate (20 mL EtOAc). The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate The residue was purified on silica gel (EtOAc (EtOAc:EtOAc) 1-Methyl-6-carbonyl-1,6-dihydropyrimidine-5-carbonitrile (150 mg, 88% yield) as a white solid.
1H NMR(400MHz,CD 3OD)δ8.11(s,1H),6.81-6.61(m,1H),6.51(d,J＝12.4Hz,1H),4.61(s,2H),4.46(t,J＝8.7Hz,2H),3.29(s,3H)ppm；LC-MS:m/z 301.1[M+H] +. 1 H NMR (400 MHz, CD 3 OD) δ 8.11 (s, 1H), 6.81-6.61 (m, 1H), 6.51 (d, J = 12.4 Hz, 1H), 4.61 (s, 2H), 4.46 (t) , J = 8.7 Hz, 2H), 3.29 (s, 3H) ppm; LC-MS: m/z 301.1 [M+H] + .
实施例151：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-甲酰胺Example 151: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl-1,6-dihydropyrimidine- 5-carboxamide
Figure PCTCN2018122557-appb-000331
Figure PCTCN2018122557-appb-000331
在25mL的圆底烧瓶中依次加入2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-甲腈(60mg，0.2mmol)，碳酸钾(27.6mg，0.2mmol)，30％的双氧水(1mL)和二甲基亚砜(5mL)。反应混合物在氮气下70℃反应1个小时。冷却至室温后，加入20mL水，用乙酸乙酯萃取(20mL X 3)。合并的有机相用盐水洗涤两次， 经无水硫酸钠干燥，过滤，在减压下浓缩。残余物经高效液相纯化色谱得到化合物2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-1-甲基-6-羰基-1,6-二氢嘧啶-5-甲酰胺(1.6mg，2.5％产率)，为白色固体。2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl-1,6 was added sequentially to a 25 mL round bottom flask. Dihydropyrimidine-5-carbonitrile (60 mg, 0.2 mmol), potassium carbonate (27.6 mg, 0.2 mmol), 30% hydrogen peroxide (1 mL) and dimethyl sulfoxide (5 mL). The reaction mixture was reacted at 70 ° C for 1 hour under nitrogen. After cooling to room temperature, 20 mL of water was added and extracted with ethyl acetate (20 mL EtOAc). The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate The residue was subjected to high performance liquid chromatography to give the compound 2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-1-methyl-6-carbonyl-1, 6-Dihydropyrimidine-5-carboxamide (1.6 mg, 2.5% yield) as a white solid.
1H NMR(400MHz,MeOD)δ8.60(s,1H),6.77-6.67(m,1H),6.55(dd,J＝8.6,3.9Hz,1H),4.61(s,2H),4.52(t,J＝8.7Hz,2H),3.35-3.29(m,3H),3.24(s,2H)LCMS:m/z 319.1,[M+H] +. 1 H NMR (400MHz, MeOD) δ8.60 (s, 1H), 6.77-6.67 (m, 1H), 6.55 (dd, J = 8.6,3.9Hz, 1H), 4.61 (s, 2H), 4.52 (t , J=8.7 Hz, 2H), 3.35-3.29 (m, 3H), 3.24 (s, 2H) LCMS: m/z 319.1, [M+H] + .
实施例152：6-氨基-5-溴-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 152: 6-Amino-5-bromo-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methylpyrimidine-4 (3H )-ketone
步骤一:中间体6-氨基-5-溴-2-羟基-3-甲基嘧啶-4(3H)-酮(D1)Step 1: Intermediate 6-Amino-5-bromo-2-hydroxy-3-methylpyrimidin-4(3H)-one (D1)
Figure PCTCN2018122557-appb-000332
Figure PCTCN2018122557-appb-000332
在干燥的100mL单口烧瓶中依次加入中间体6-氨基-2-羟基-3-甲基嘧啶-4(3H)-酮D1-a(1.41g,10mmol)和N,N-二甲基甲酰胺(20mL)，在室温下加入N-溴代丁二酰亚胺(3.56g,20mmol)并在该温度下搅拌2小时。反应完毕后，加入50mL纯净水，有大量白色固体生成，然后过滤，固体使用50mL纯净水清洗三次，烘干得到白色固体6-氨基-5-溴-2-羟基-3-甲基嘧啶-4(3H)-酮D1(1.8g，产率：81.8％)。The intermediate 6-amino-2-hydroxy-3-methylpyrimidin-4(3H)-one D1-a (1.41 g, 10 mmol) and N,N-dimethylformamide were sequentially added to a dry 100 mL one-neck flask. (20 mL), N-bromosuccinimide (3.56 g, 20 mmol) was added at room temperature and stirred at this temperature for 2 hr. After the reaction was completed, 50 mL of purified water was added, a large amount of white solid was formed, and then filtered, and the solid was washed three times with 50 mL of purified water to obtain a white solid 6-amino-5-bromo-2-hydroxy-3-methylpyrimidine-4. (3H)-ketone D1 (1.8 g, yield: 81.8%).
1H NMR(400MHz,DMSO-d6)δ10.71(s,1H),6.40(s,2H),3.09(s,3H)ppm；LC-MS:m/z 220[M+H] +. 1 H NMR (400 MHz, DMSO-d6) δ 10.71 (s, 1H), 6.40 (s, 2H), 3.09 (s, 3H) ppm; LC-MS: m/z 220[M+H] + .
步骤二：6-氨基-5-溴-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Step 2: 6-Amino-5-bromo-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methylpyrimidine-4 (3H) -ketone
Figure PCTCN2018122557-appb-000333
Figure PCTCN2018122557-appb-000333
在干燥的100mL单口烧瓶中依次加入中间体6-氨基-5-溴-2-羟基-3-甲基嘧啶-4(3H)-酮D1(1.1g,5mmol)和N,N-二甲基甲酰胺(5mL)，在室温下依次加入BOP(2.65g,6mmol)和(5-氟-2,3-二氢苯并呋喃-4-基)甲胺C1-2(1.25g,7.5mmol)并在该温度下搅拌15分钟，再加入DBU(1.52g,10mmol),然后在该温度下反应2小时。反应完毕后， 加入50mL纯净水，乙酸乙酯萃取(3X 50mL),合并有机相，无水硫酸钠干燥，过滤，得到粗产品通过硅胶柱(石油醚：乙酸乙酯＝1:1)纯化得到产品白色固体6-氨基-5-溴-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮(300mg，16.3％产率)。The intermediate 6-amino-5-bromo-2-hydroxy-3-methylpyrimidin-4(3H)-one D1 (1.1 g, 5 mmol) and N,N-dimethyl were added sequentially to a dry 100 mL one-neck flask. Formamide (5 mL), BOP (2.65 g, 6 mmol) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine C1-2 (1.25 g, 7.5 mmol) were added sequentially at room temperature. After stirring at this temperature for 15 minutes, DBU (1.52 g, 10 mmol) was further added, and then reacted at this temperature for 2 hours. After completion of the reaction, 50 mL of purified water was added, and ethyl acetate (3×50 mL) was evaporated. Product white solid 6-amino-5-bromo-2-((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methylpyrimidine-4 (3H) - Ketone (300 mg, 16.3% yield).
1H NMR(400MHz,DMSO)δ7.32(t,J＝5.1Hz,1H),6.93-6.86(m,1H),6.65(dd,J＝8.6,3.9Hz,1H),6.19(s,2H),4.52(dd,J＝10.4,7.0Hz,4H),3.25-3.19(m,5H).ppm；LC-MS:m/z 369.1[M+H] +. 1 H NMR (400 MHz, DMSO) δ 7.32 (t, J = 5.1 Hz, 1H), 6.93 - 6.86 (m, 1H), 6.65 (dd, J = 8.6, 3.9 Hz, 1H), 6.19 (s, 2H) ), 4.52 (dd, J = 10.4, 7.0 Hz, 4H), 3.25-3.19 (m, 5H). ppm; LC-MS: m/z 369.1 [M+H] + .
实施例153：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-甲氧基-3-甲基嘧啶-4(3H)-酮Example 153: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-methoxy-3-methylpyrimidine-4(3H)- ketone
步骤一：中间体1-甲硫基脲(E1-b)Step 1: Intermediate 1-methylthiourea (E1-b)
Figure PCTCN2018122557-appb-000334
Figure PCTCN2018122557-appb-000334
向氨的甲醇溶液(7M，58mL)中加入异硫氰酸甲酯E1-a(6g,82.1mmol)。反应液于50℃下搅拌6个小时。反应液冷却至室温后过滤得到固体，并用少量甲醇溶液洗涤，干燥，得到N-甲硫脲E1-b粗品(6.5g，53％产率)。Methyl isothiocyanate E1-a (6 g, 82.1 mmol) was added to a solution of ammonia in methanol (7M, 58 mL). The reaction solution was stirred at 50 ° C for 6 hours. The reaction mixture was cooled to room temperature and then filtered to give a crystallite crystallite.
1H NMR(400MHz,CDCl3)δ6.35(s,1H),5.74(s,2H),2.92(s,3H)ppm. 1 H NMR (400MHz, CDCl3) δ6.35 (s, 1H), 5.74 (s, 2H), 2.92 (s, 3H) ppm.
步骤二:中间体(E)-N,N-二甲基-N'-(甲基氨基甲硫杂酰)甲脒(E1-c)Step 2: Intermediate (E)-N,N-Dimethyl-N'-(methylaminomethylthiazyl)formamidine (E1-c)
Figure PCTCN2018122557-appb-000335
Figure PCTCN2018122557-appb-000335
将N-甲硫脲E1-b(6.5g,72.1mmol)溶于50mL二氯甲烷，加入N,N-二甲基甲酰胺二甲缩醛(10.31g,86.5mmol)。反应液在室温下搅拌2个小时。将反应液倒入100mL水中，用二氯甲烷萃取(100mL X 2)。合并的有机相用盐水洗涤两次，经无水Na 2SO4干燥，过滤，在减压下浓缩，得到(E)-N,N-二甲基-N'-(甲基氨基甲硫杂酰)甲脒(E1-c)粗品(9g，52％产率)。 N-methylthiourea E1-b (6.5 g, 72.1 mmol) was dissolved in 50 mL of dichloromethane, and N,N-dimethylformamide dimethyl acetal (10.31 g, 86.5 mmol) was added. The reaction solution was stirred at room temperature for 2 hours. The reaction solution was poured into 100 mL of water and extracted with dichloromethane (100 mL X 2). The combined organic phases were washed twice with brine, dried over anhydrous Na 2 SO4, filtered, and concentrated under reduced pressure, to give (E) -N, N- dimethyl -N '- (methylamino methylthio heteroaryl acyloxy A large amount of formazan (E1-c) (9 g, 52% yield).
1H NMR(400MHz,CDCl3)δ8.87(s,1H),6.96(s,1H),3.19(d,J＝2.5Hz,3H),3.15(s,3H),3.04(s,3H)ppm. 1 H NMR (400MHz, CDCl3) δ8.87 (s, 1H), 6.96 (s, 1H), 3.19 (d, J = 2.5Hz, 3H), 3.15 (s, 3H), 3.04 (s, 3H) ppm .
步骤三：中间体碘化(Z,E)-1-((二甲氨基)亚甲基)-2,3-二甲基异硫代糖醛正离子(E1-d)Step 3: Intermediate iodide (Z,E)-1-((dimethylamino)methylene)-2,3-dimethylisothiosaccharide cation (E1-d)
Figure PCTCN2018122557-appb-000336
Figure PCTCN2018122557-appb-000336
将E1-c(9.0g,62.0mmol)溶于50mL四氢呋喃中，室温下加入碘甲烷(9.68g,68.2mmol)。反应液在室温下搅拌3个小时。将反应液过滤得到固体并用少量四氢呋喃溶液洗涤，干燥，得到(Z,E)-1-((二甲氨基)亚甲基)-2,3-二甲基异硫代糖醛正离子(E1-d)粗品(17g，57％产率)。E1-c (9.0 g, 62.0 mmol) was dissolved in 50 mL of tetrahydrofuran, and iodomethane (9.68 g, 68.2 mmol) was added at room temperature. The reaction solution was stirred at room temperature for 3 hours. The reaction solution was filtered to give a solid, which was washed with a small portion of tetrahydrofuran and dried to give (Z,E)-1-((dimethylamino)methylene)-2,3-dimethylisothiouronic acid cation (E1) -d) crude (17 g, 57% yield).
1H NMR(400MHz,CDCl3)δ9.90(s,1H),8.94(s,1H),3.42(s,3H),3.18(s,3H),3.07(s,3H),2.52(s,3H)ppm. 1 H NMR (400MHz, CDCl3) δ9.90 (s, 1H), 8.94 (s, 1H), 3.42 (s, 3H), 3.18 (s, 3H), 3.07 (s, 3H), 2.52 (s, 3H )ppm.
步骤四：中间体5-甲氧基-3-甲基-2-(甲硫基)嘧啶-4(3H)-酮(E1-f)Step 4: Intermediate 5-methoxy-3-methyl-2-(methylthio)pyrimidin-4(3H)-one (E1-f)
Figure PCTCN2018122557-appb-000337
Figure PCTCN2018122557-appb-000337
将E1-d(2g,6.96mmol)和三乙胺(2.82g,27.86mmol)溶于20mL二氯甲烷中，冰水浴下加入2-甲氧基乙酰氯(2.27g,20.89mmol)。反应液升至室温并搅拌3个小时。将反应液用20mL水淬灭，用EtOAc萃取(100mL X 2)。合并的有机相用盐水洗涤两次，经无水Na 2SO 4干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(PE:EtOAc＝10：3)，得到5-甲氧基-3-甲基-2-(甲硫基)嘧啶-4(3H)-酮(E1-f)(750mg,58％产率)，为淡黄色固体。 E1-d (2 g, 6.96 mmol) and triethylamine (2.82 g, 27.86 mmol) were dissolved in dichloromethane (20 mL), and 2-methoxyacetyl chloride (2.27 g, 20.89 mmol). The reaction solution was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic phases were washed twice with brine, dried over anhydrous Na 2 SO 4, filtered, and concentrated under reduced pressure. The residue was purified on silica gel (EtOAc:EtOAc:EtOAc:EtOAc) , 58% yield) as a pale yellow solid.
LCMS:m/z 187.0[M+H] + LCMS: m/z 187.0 [M+H] +
步骤五：中间体5-甲氧基-3-甲基-2-(甲基亚硫酰基<亚磺酰>)嘧啶-4(3H)-酮的合成(E1)Step 5: Synthesis of intermediate 5-methoxy-3-methyl-2-(methylsulfinyl <sulfinyl)pyrimidine-4(3H)-one (E1)
Figure PCTCN2018122557-appb-000338
Figure PCTCN2018122557-appb-000338
将E1-f(500mg,2.68mmol)溶于15mL二氯甲烷，加入3-氯过氧苯甲酸(463.31mg,2.68mmol)。反应液升至室温并搅拌3个小时。将反应液用10mL水淬灭，用EtOAc萃取(100mL X 2)。合并的有机相用盐水洗涤两次，经无水硫酸钠干燥，过滤，在减压下浓缩.残余物在硅胶上纯化(PE:EtOAc＝10：3)，得到5-甲氧基-3-甲基-2-(甲基亚硫酰基<亚磺酰>)嘧啶-4(3H)-酮的合成(E1)(300mg,55％产率),为白色固体.E1-f (500 mg, 2.68 mmol) was dissolved in 15 mL dichloromethane and 3-chloroperoxybenzoic acid (463.31 mg, 2.68 mmol). The reaction solution was allowed to warm to room temperature and stirred for 3 hours. The reaction was quenched with EtOAc (EtOAc)EtOAc. The combined organic phases were washed with EtOAc EtOAc EtOAc EtOAc. Synthesis of methyl-2-(methylsulfinyl <sulfinyl)pyrimidine-4(3H)-one (E1) (300 mg, 55% yield) as white solid.
1H NMR(400MHz,CDCl 3)δ7.49(s,1H),3.91(s,3H),3.82(s,3H),2.99(s,3H)ppm；LCMS:m/z 203.0[M+H] + 1 H NMR (400MHz, CDCl 3 ) δ7.49 (s, 1H), 3.91 (s, 3H), 3.82 (s, 3H), 2.99 (s, 3H) ppm; LCMS: m / z 203.0 [M + H ] +
步骤六：化合物2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-甲氧基-3-甲基嘧啶-4(3H)-酮Step 6: Compound 2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-methoxy-3-methylpyrimidine-4(3H)- ketone
Figure PCTCN2018122557-appb-000339
Figure PCTCN2018122557-appb-000339
将E1(150mg,0.74mmol)和三乙胺(150mg,1.48mmol)溶于DMF(5mL)中，室温下加入(5-氟-2,3-二氢苯并呋喃-4-基)甲胺(370mg,2.23mmol)。反应液在65℃加热并搅拌20个小时。向反应液加入10mL水，用EtOAc萃取(30mL X 2)。合并的有机相用盐水洗涤两次，经无水硫酸钠干燥，过滤，在减压下浓缩。残余物在硅胶上纯化(石油醚:乙酸乙酯＝10：7)得到2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-甲氧基-3-甲基嘧啶-4(3H)-酮(69mg,31％产率),为白色固体。E1 (150 mg, 0.74 mmol) and triethylamine (150 mg, 1.48 mmol) were dissolved in DMF (5 mL) and (5-fluoro-2,3-dihydrobenzofuran-4-yl)methylamine (370 mg, 2.23 mmol). The reaction solution was heated and stirred at 65 ° C for 20 hours. 10 mL of water was added to the reaction mixture, which was extracted with EtOAc (30 mL). The combined organic phases were washed twice with brine, dried over anhydrous sodium sulfate The residue was purified on silica gel (EtOAc (EtOAc:EtOAc:EtOAc) Methoxy-3-methylpyrimidin-4(3H)-one (69 mg, 31% yield) as a white solid.
1H NMR(400MHz,CDCl 3)δ7.33(s,1H),6.85-6.77(m,1H),6.64(dd,J＝8.6,4.0Hz,1H),4.74(d,J＝4.9Hz,1H),4.62(t,J＝8.7Hz,2H),4.56(d,J＝5.4Hz,2H),3.78(s,3H),3.41(s,3H),3.34(t,J＝8.7Hz,2H)ppm；LCMS:m/z 306.1[M+H] +. 1 H NMR (400MHz, CDCl 3 ) δ7.33 (s, 1H), 6.85-6.77 (m, 1H), 6.64 (dd, J = 8.6,4.0Hz, 1H), 4.74 (d, J = 4.9Hz, 1H), 4.62 (t, J = 8.7 Hz, 2H), 4.56 (d, J = 5.4 Hz, 2H), 3.78 (s, 3H), 3.41 (s, 3H), 3.34 (t, J = 8.7 Hz, 2H) ppm; LCMS: m/z 306.1 [M+H] + .
实施例154:2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-(吡啶-3-基氨基)嘧啶-4(3H)-酮Example 154: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(pyridin-3-ylamino)pyrimidine- 4(3H)-ketone
Figure PCTCN2018122557-appb-000340
Figure PCTCN2018122557-appb-000340
在干燥的30mL微波管中依次加入中间体A-2(60mg,0.17mmol)，吡啶-3-胺(32mg,0.34mmol)，2-(二环己基膦)-3,6-二甲氧基-2'-4'-6'-三-I-丙基-11'-联苯(9mg,0.017mmol)，Cs 2CO 3(111mg,0.34mmol)，三(二亚苄基丙酮)二钯(31mg,0.034mmol)和1，4-二氧六环(3mL)，氮气鼓泡一分钟，封管加热至100摄氏度反应2小时。冷却至室温，将反应体系缓慢滴加进冰水(30mL)中，再用乙酸乙酯(30mL×2)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用薄层层析制备板以展开剂体系(二氯甲烷:甲醇＝50:1)纯化所得粗产品，再通过高效液相制备得到产物2-(((5-氟-2,3-二氢苯并呋喃-4-基) 甲基)氨基)-3-甲基-5-(吡啶-3-基氨基)嘧啶-4(3H)-酮(20mg，产率32％)，白色固体。 Intermediate A-2 (60 mg, 0.17 mmol), pyridin-3-amine (32 mg, 0.34 mmol), 2-(dicyclohexylphosphine)-3,6-dimethoxy group were sequentially added to a dry 30 mL microwave tube. -2'-4'-6'-Tri-I-propyl-11'-biphenyl (9 mg, 0.017 mmol), Cs 2 CO 3 (111 mg, 0.34 mmol), tris(dibenzylideneacetone) palladium (31 mg, 0.034 mmol) and 1,4-dioxane (3 mL), nitrogen was bubbled for one minute, and the tube was heated to 100 ° C for 2 hours. After cooling to room temperature, the reaction system was slowly added dropwise to ice water (30 mL), and then ethyl acetate (30mL×2). The combined organic layers were dried with anhydrous sodium s The residue was purified by preparative thin-layer chromatography to purify the crude product (dichloromethane:methanol = 50:1), and the product was obtained by high-performance liquid chromatography to give the product 2-(((5-fluoro-2,3-) Dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-(pyridin-3-ylamino)pyrimidin-4(3H)-one (20 mg, yield 32%), white solid .
1H NMR(400MHz,DMSO)δ8.03(d,J＝2.6Hz,1H),7.82(d,J＝4.1Hz,1H),7.68(s,1H),7.42(t,J＝5.1Hz,1H),7.24(s,1H),7.06(dd,J＝8.3,4.5Hz,1H),6.91(dd,J＝19.9,9.7Hz,2H),6.65(dd,J＝8.6,3.9Hz,1H),4.53(dd,J＝11.0,6.2Hz,4H),3.34(s,3H),3.25(d,J＝7.1Hz,2H)ppm；LCMS:m/z 368.1[M+H] +. 1 H NMR (400 MHz, DMSO) δ 8.03 (d, J = 2.6 Hz, 1H), 7.82 (d, J = 4.1 Hz, 1H), 7.68 (s, 1H), 7.42 (t, J = 5.1 Hz, 1H), 7.24 (s, 1H), 7.06 (dd, J = 8.3, 4.5 Hz, 1H), 6.91 (dd, J = 19.9, 9.7 Hz, 2H), 6.65 (dd, J = 8.6, 3.9 Hz, 1H) ), 4.53 (dd, J = 11.0, 6.2 Hz, 4H), 3.34 (s, 3H), 3.25 (d, J = 7.1 Hz, 2H) ppm; LCMS: m/z 368.1 [M+H] + .
按照实施例154的方法可合成以下化合物The following compounds were synthesized according to the method of Example 154.
实施例155:5-(苯甲基氨基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 155: 5-(Benzylamino)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methylpyrimidine-4 ( 3H)-ketone
Figure PCTCN2018122557-appb-000341
Figure PCTCN2018122557-appb-000341
1H NMR(400MHz,DMSO)δ7.30(dd,J＝7.0,5.0Hz,4H),7.21(dd,J＝5.5,3.0Hz,1H),6.88-6.82(m,1H),6.72(s,1H),6.69(t,J＝5.2Hz,1H),6.61(dd,J＝8.6,3.8Hz,1H),4.92(t,J＝6.2Hz,1H),4.48(t,J＝8.7Hz,2H),4.36(d,J＝5.0Hz,2H),4.16(d,J＝5.8Hz,2H),3.33(s,3H),3.19(t,J＝8.7Hz,2H)ppm；LCMS:m/z 381.1[M+H] +. 1 H NMR (400MHz, DMSO) δ7.30 (dd, J = 7.0,5.0Hz, 4H), 7.21 (dd, J = 5.5,3.0Hz, 1H), 6.88-6.82 (m, 1H), 6.72 (s , 1H), 6.69 (t, J = 5.2 Hz, 1H), 6.61 (dd, J = 8.6, 3.8 Hz, 1H), 4.92 (t, J = 6.2 Hz, 1H), 4.48 (t, J = 8.7 Hz) , 2H), 4.36 (d, J = 5.0 Hz, 2H), 4.16 (d, J = 5.8 Hz, 2H), 3.33 (s, 3H), 3.19 (t, J = 8.7 Hz, 2H) ppm; LCMS: m/z 381.1 [M+H] + .
实施例156：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-((2-(三氟甲基)吡啶-3-基)硫代)嘧啶-4(3H)-酮Example 156: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-((2-(trifluoromethyl)) Pyridin-3-yl)thio)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000342
Figure PCTCN2018122557-appb-000342
在干燥的20mL微波管中依次加入2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-碘-3-甲基嘧啶-4(3H)-酮(60mg,0.17mmol)，2-(三氟甲基)吡啶-3-硫醇(61mg,0.34mmol)，1,10-菲罗啉(6mg，0.034mmol),K 3PO 4(72mg,0.34mmol)，CuI(6.5mg,0.034mmol)和1，4-二氧六环(3mL)，氮气鼓泡一分钟，封管加热至100摄氏度反应2小时。冷却至室温，将反应体系缓慢滴加进冰水(30mL)中，再用乙酸乙酯(30mL×2)萃取。合并有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。残余物用薄层层析制备板以展开剂体系(二氯甲烷:甲醇＝50:1)纯化所得残余物，再通过高效液相制备得到产物2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基-5-((2-(三氟甲基)吡啶-3-基)硫 基)嘧啶-4(3H)-酮(15.8mg，产率21％)，为白色固体。 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-iodo-3-methylpyrimidine-4 was added sequentially to a dry 20 mL microwave tube ( 3H)-ketone (60 mg, 0.17 mmol), 2-(trifluoromethyl)pyridine-3-thiol (61 mg, 0.34 mmol), 1,10-phenanthroline (6 mg, 0.034 mmol), K 3 PO 4 (72 mg, 0.34 mmol), CuI (6.5 mg, 0.034 mmol) and 1,4-dioxane (3 mL), nitrogen was bubbled for one minute, and the tube was heated to 100 ° C for 2 hours. After cooling to room temperature, the reaction system was slowly added dropwise to ice water (30 mL), and then ethyl acetate (30mL×2). The combined organic layers were dried with anhydrous sodium s The residue was purified by a thin layer chromatography chromatography (yield: methylene chloride:methanol = 50:1) to yield the residue. Dihydrobenzofuran-4-yl)methyl)amino)-3-methyl-5-((2-(trifluoromethyl)pyridin-3-yl)thio)pyrimidin-4(3H)-one (15.8 mg, 21% yield) as a white solid.
1H NMR(400MHz,CDCl3)δ8.41(d,J＝3.8Hz,1H),8.12(s,1H),7.54(t,J＝9.1Hz,1H),7.28(d,J＝4.6Hz,1H),6.89-6.81(m,1H),6.68(dd,J＝8.7,4.0Hz,1H),5.33(d,J＝5.5Hz,1H),4.69(d,J＝5.6Hz,2H),4.63(t,J＝8.7Hz,2H),3.44(s,3H),3.37(t,J＝8.7Hz,2H)ppm；LCMS:m/z 453.1[M+H] +. 1 H NMR (400MHz, CDCl3) δ8.41 (d, J = 3.8Hz, 1H), 8.12 (s, 1H), 7.54 (t, J = 9.1Hz, 1H), 7.28 (d, J = 4.6Hz, 1H), 6.89-6.81 (m, 1H), 6.68 (dd, J = 8.7, 4.0 Hz, 1H), 5.33 (d, J = 5.5 Hz, 1H), 4.69 (d, J = 5.6 Hz, 2H), 4.63 (t, J = 8.7 Hz, 2H), 3.44 (s, 3H), 3.37 (t, J = 8.7 Hz, 2H) ppm; LCMS: m/z 453.1 [M+H] + .
按照实施例156的方法可合成以下化合物The following compounds were synthesized according to the method of Example 156.
实施例157：5-((2-氨基-3-氯吡啶-4-基)硫基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-甲基嘧啶-4(3H)-酮Example 157: 5-((2-Amino-3-chloropyridin-4-yl)thio)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl) Amino)-3-methylpyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000343
Figure PCTCN2018122557-appb-000343
1H NMR(400MHz,DMSO-d 6)δ8.05(d,J＝7.5Hz,2H),7.63(d,J＝5.3Hz,1H),6.91(t,J＝9.5Hz,1H),6.67(dd,J＝8.5,3.7Hz,1H),6.24(s,2H),5.98(d,J＝5.3Hz,1H),4.59(d,J＝4.8Hz,2H),4.54(t,J＝8.7Hz,2H),3.34(s,3H),3.27(t,J＝8.7Hz,2H)ppm；LCMS:m/z434.0[M+H] +. 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.05 (d, J = 7.5 Hz, 2H), 7.63 (d, J = 5.3 Hz, 1H), 6.91 (t, J = 9.5 Hz, 1H), 6.67 (dd, J = 8.5, 3.7 Hz, 1H), 6.24 (s, 2H), 5.98 (d, J = 5.3 Hz, 1H), 4.59 (d, J = 4.8 Hz, 2H), 4.54 (t, J = 8.7 Hz, 2H), 3.34 (s, 3H), 3.27 (t, J = 8.7 Hz, 2H) ppm; LCMS: m/z 434.0 [M+H] + .
实施例158：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-异丙基-5-(4-(甲基磺酰基)苯基)嘧-4(3H)-酮Example 158: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-isopropyl-5-(4-(methylsulfonyl) Phenyl)pyrimidine-4(3H)-one
步骤一：中间体1-二苯甲基-5-溴嘧啶-2,4(1H,3H)-二酮Step 1: Intermediate 1-diphenylmethyl-5-bromopyrimidine-2,4(1H,3H)-dione
Figure PCTCN2018122557-appb-000344
Figure PCTCN2018122557-appb-000344
在干燥的500mL单口烧瓶中依次加入双-(三甲基硅烷基)乙酰胺(13.28g,65.45mmol)、5-溴尿嘧啶(5.0g,26.18mmol)和乙腈(100mL)，在室温下搅拌5分钟，直到形成澄清的溶液。然后加入二苯基溴甲烷(9.69g,39.26mmol)的乙腈(50mL)溶液和催化量的单质碘，80摄氏度下搅拌反应3小时，再室温反应12小时。反应完毕后，反应液倒入冰水中并有大量固体析出，过滤得到固体，用水洗涤并干燥得到白色固体1-二苯甲基-5-溴嘧啶-2,4(1H,3H)-二酮(7.0g，产率75％)。In a dry 500 mL one-necked flask, bis-(trimethylsilyl)acetamide (13.28 g, 65.45 mmol), 5-bromouracil (5.0 g, 26.18 mmol) and acetonitrile (100 mL) were sequentially added and stirred at room temperature. 5 minutes until a clear solution formed. Then, a solution of diphenylbromomethane (9.69 g, 39.26 mmol) in acetonitrile (50 mL) and a catalytic amount of elemental iodine were added, and the reaction was stirred at 80 ° C for 3 hours and then at room temperature for 12 hours. After completion of the reaction, the reaction mixture was poured into ice water and a large amount of solid was precipitated, which was filtered to give a solid, which was washed with water and dried to give a white solid 1-diphenylmethyl-5-bromopyrimidine-2,4(1H,3H)-dione (7.0 g, yield 75%).
1H-NMR(500MHz,CDCl 3):δ7.44-7.36(m,7H),7.16-7.18(m,4H),7.03(s,1H)ppm； LCMS:m/z 357.0[M+H] +. 1 H-NMR (500 MHz, CDCl 3 ): δ 7.44 - 7.36 (m, 7H), 7.16-7.18 (m, 4H), 7.03 (s, 1H) ppm; LCMS: m/z 357.0 [M+H] + .
步骤二：中间体1-二苯甲基-5-溴-3-异丙基嘧啶-2,4(1H,3H)-二酮的合成Step 2: Synthesis of intermediate 1-diphenylmethyl-5-bromo-3-isopropylpyrimidine-2,4(1H,3H)-dione
Figure PCTCN2018122557-appb-000345
Figure PCTCN2018122557-appb-000345
在干燥的100mL单口烧瓶中依次1-二苯甲基-5-溴嘧啶-2,4(1H,3H)-二酮(3.0g,8.39mmol)、2-碘代丙烷(1.71g,10.08mmol)、DBU(1.91g,12.60mmol)和乙腈(60mL)。在70摄氏度下搅拌反应4小时，TLC监测。反应结束后，反应液倒入120mL的水中，乙酸乙酯萃取(2*120mL)。有机相用无水硫酸钠干燥，过滤，滤液减压浓缩。所得残余物经硅胶柱色谱法(乙酸乙酯：石油醚＝1：10)纯化得到白色固体1-二苯甲基-5-溴-3-异丙基嘧啶-2,4(1H,3H)-二酮(1.8g，产率：54％)。1-Diphenylmethyl-5-bromopyrimidine-2,4(1H,3H)-dione (3.0 g, 8.39 mmol), 2-iodopropane (1.71 g, 10.08 mmol) in a dry 100 mL one-neck flask ), DBU (1.91 g, 12.60 mmol) and acetonitrile (60 mL). The reaction was stirred at 70 ° C for 4 hours and monitored by TLC. After completion of the reaction, the reaction solution was poured into 120 mL of water and extracted with ethyl acetate (2*120 mL). The organic phase was dried over anhydrous sodium sulfate and filtered and evaporated. The residue was purified by silica gel column chromatography (EtOAcjjjjjjj -Dione (1.8 g, yield: 54%).
1H-NMR(500MHz,CDCl 3):δ7.42-7.36(m,6H),7.29(s,1H),7.26(s,1H),7.15-7.14(m,4H),7.06(s,1H),5.25-5.20(m,1H),1.47(d,J＝7.0Hz,6H)ppm；LCMS:m/z 399.1[M+H] +. 1 H-NMR (500MHz, CDCl 3 ): δ 7.42 - 7.36 (m, 6H), 7.29 (s, 1H), 7.26 (s, 1H), 7.15-7.14 (m, 4H), 7.06 (s, 1H) ), 5.25-5.20 (m, 1H), 1.47 (d, J = 7.0 Hz, 6H) ppm; LCMS: m/z 399.1 [M+H] + .
步骤三：中间体1-二苯甲基-3-异丙基-5-(4-(甲基磺酰基)苯基)嘧啶-2,4(1H,3H)-二酮的合成Step 3: Synthesis of the intermediate 1-diphenylmethyl-3-isopropyl-5-(4-(methylsulfonyl)phenyl)pyrimidine-2,4(1H,3H)-dione
Figure PCTCN2018122557-appb-000346
Figure PCTCN2018122557-appb-000346
在100mL的三口烧瓶中室温下依次加入1-二苯甲基-5-溴-3-异丙基嘧啶-2,4(1H,3H)-二酮(1.8g,4.51mmol)，1,4-二氧六环(48mL),纯净水(12mL)，(4-(甲基磺酰基)苯基)硼酸(1.35g,6.766mmol)，双三苯基磷二氯化钯(316mg,0.451mmol)和碳酸钾(1.24g,9.02mmol)。氮气鼓泡一分钟，加热回流反应1小时。反应完毕，向反应液中加入100mL水并用乙酸乙酯(100mL×3)萃取。有机相依次用水(100mL×1)，饱和食盐水(100mL×1)洗涤。收集有机相，无水硫酸钠干燥，过滤，滤液减压浓缩。用层析柱法(石油醚：乙酸乙酯＝3：1)得到1-二苯甲基-3-异丙基-5-(4-(甲基磺酰基)苯基)嘧啶-2,4(1H,3H)-二酮(1.2g，产率56％)，为白色固体。1-Diphenylmethyl-5-bromo-3-isopropylpyrimidine-2,4(1H,3H)-dione (1.8 g, 4.51 mmol), 1, 4 was added in a 100 mL three-necked flask at room temperature. - dioxane (48 mL), purified water (12 mL), (4-(methylsulfonyl)phenyl)boronic acid (1.35 g, 6.766 mmol), bistriphenylphosphine palladium dichloride (316 mg, 0.451 mmol) And potassium carbonate (1.24 g, 9.02 mmol). Nitrogen gas was bubbled for one minute and heated to reflux for 1 hour. After completion of the reaction, 100 mL of water was added to the reaction mixture and extracted with ethyl acetate (100 mL × 3). The organic phase was washed successively with water (100 mL×1) and brine (100 mL×1). The organic phase was collected, dried over anhydrous sodium sulfate, filtered and evaporated. Column chromatography (petroleum ether: ethyl acetate = 3:1) gave 1-diphenylmethyl-3-isopropyl-5-(4-(methylsulfonyl)phenyl)pyrimidine-2,4 (1H,3H)-Dione (1.2 g, yield 56%) as a white solid.
1H-NMR(500MHz,CDCl 3):δ7.87(d,J＝10.5Hz,2H),7.52(d,J＝11.0Hz,2H),7.45-7.38(m,6H),7.22-7.17(m,6H),5.32-5.27(m,1H),3.02(s,3H),1.50(d,J＝7.5Hz,6H)ppm.LCMS:m/z 475.1[M+H] +. 1 H-NMR (500MHz, CDCl 3 ): δ 7.87 (d, J = 10.5 Hz, 2H), 7.52 (d, J = 11.0 Hz, 2H), 7.45 - 7.38 (m, 6H), 7.22 - 7.17 ( m, 6H), 5.32-5.27 (m, 1H), 3.02 (s, 3H), 1.50 (d, J = 7.5 Hz, 6H) ppm. LCMS: m/z 475.1 [M+H] + .
步骤四：中间体3-异丙基-5-(4-(甲基磺酰基)苯基)嘧啶-2,4(1H,3H)-二酮的合成Step 4: Synthesis of the intermediate 3-isopropyl-5-(4-(methylsulfonyl)phenyl)pyrimidine-2,4(1H,3H)-dione
Figure PCTCN2018122557-appb-000347
Figure PCTCN2018122557-appb-000347
将三氟甲酸(5.0mL)和三氟甲磺酸(0.5mL)的混合溶液冷却到0摄氏度，然后一次性加入1-二苯甲基-3-异丙基-5-(4-(甲基磺酰基)苯基)嘧啶-2,4(1H,3H)-二酮(750mg,1.58mmol)。反应液在0摄氏度搅拌反应30分钟，使用薄层色谱检测反应。反应结束后，把反应液倒入碎冰中，有大量固体析出，过滤，并用水洗涤固体，固体干燥得到粗产物，进一步使用***洗涤得到白色固体3-异丙基-5-(4-(甲基磺酰基)苯基)嘧啶-2,4(1H,3H)-二酮(450mg,92％产率)。A mixed solution of trifluorocarboxylic acid (5.0 mL) and trifluoromethanesulfonic acid (0.5 mL) was cooled to 0 ° C, and then 1-diphenylmethyl-3-isopropyl-5-(4-(A) was added in one portion. Sulfosyl)phenyl)pyrimidine-2,4(1H,3H)-dione (750 mg, 1.58 mmol). The reaction solution was stirred at 0 ° C for 30 minutes, and the reaction was examined using thin layer chromatography. After the reaction was completed, the reaction mixture was poured into crushed ice, a large amount of solid was precipitated, filtered, and the solid was washed with water, and the solid was dried to give a crude product, which was washed with diethyl ether to give a white solid 3-isopropyl-5-(4-( Methylsulfonyl)phenyl)pyrimidine-2,4(1H,3H)-dione (450 mg, 92% yield).
1H-NMR(500MHz,CDCl 3):δ9.50-9.48(m,1H),7.95(d,J＝11.0Hz,2H),7.72(d,J＝10.5Hz,2H),7.40(d,J＝8.0Hz,1H),7.28-7.26(m,1H),5.27-5.22(m,1H),3.06(s,3H),1.53(d,J＝8.5Hz,6H)ppm.LCMS:m/z 307.0[M+H] +. 1 H-NMR (500MHz, CDCl 3 ): δ 9.50-9.48 (m, 1H), 7.95 (d, J = 11.0 Hz, 2H), 7.72 (d, J = 10.5 Hz, 2H), 7.40 (d, J=8.0 Hz, 1H), 7.28-7.26 (m, 1H), 5.27-5.22 (m, 1H), 3.06 (s, 3H), 1.53 (d, J = 8.5 Hz, 6H) ppm. LCMS: m/ z 307.0[M+H] + .
步骤五：中间体2-氯-3-异丙基-5-(4-(甲基磺酰基)苯基)嘧啶-4(3H)-酮的合成Step 5: Synthesis of the intermediate 2-chloro-3-isopropyl-5-(4-(methylsulfonyl)phenyl)pyrimidin-4(3H)-one
Figure PCTCN2018122557-appb-000348
Figure PCTCN2018122557-appb-000348
在50mL的单口烧瓶中室温下依次加入3-异丙基-5-(4-(甲基磺酰基)苯基)嘧啶-2,4(1H,3H)-二酮(350mg,1.14mmol),三氯氧磷(8.0mL)和N,N-二甲基苯胺(0.5mL)，加热回流36小时。反应结束后，减压浓缩除去过量的三氯氧磷，所得残余物加入碳酸氢钠的饱和溶液(50mL)，二氯甲烷萃取(2×40mL)。有机相使用无水硫酸钠干燥，过滤，滤液减压浓缩，用层析柱法(石油醚：乙酸乙酯＝6：1)得到2-氯-3-异丙基-5-(4-(甲基磺酰基)苯基)嘧啶-4(3H)-酮(180mg，49％产率)。3-isopropyl-5-(4-(methylsulfonyl)phenyl)pyrimidine-2,4(1H,3H)-dione (350 mg, 1.14 mmol) was added in a 50 mL one-neck flask at room temperature. Phosphorus oxychloride (8.0 mL) and N,N-dimethylaniline (0.5 mL) were heated to reflux for 36 hours. After the reaction was completed, the excess phosphorus oxychloride was evaporated to dryness. The organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was evaporated, evaporated, mjjjjjjjjjjjj Methylsulfonyl)phenyl)pyrimidine-4(3H)-one (180 mg, 49% yield).
1H-NMR(500MHz,CDCl 3):δ8.02(d,J＝8.5Hz,2H),7.92(s,1H),7.84(d,J＝8.0Hz,2H),5.40-5.20(m,1H),3.08(s,3H),1.69(d,J＝6.5Hz,6H)ppm；LCMS:m/z 327.1[M+H] +. 1 H-NMR (500MHz, CDCl 3): δ8.02 (d, J = 8.5Hz, 2H), 7.92 (s, 1H), 7.84 (d, J = 8.0Hz, 2H), 5.40-5.20 (m, 1H), 3.08 (s, 3H), 1.69 (d, J = 6.5 Hz, 6H) ppm; LCMS: m/z 327.1 [M+H] + .
步骤六：化合物2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-异丙基-5-(4-(甲基磺酰基)苯基)嘧-4(3H)-酮的合成Step 6: Compound 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-isopropyl-5-(4-(methylsulfonyl) Synthesis of Phenyl)pyrim-4(3H)-one
Figure PCTCN2018122557-appb-000349
Figure PCTCN2018122557-appb-000349
在干燥的50mL圆底烧瓶中依次加入2-氯-3-异丙基-5-(4-(甲基磺酰基)苯基)嘧啶-4(3H)-酮(180mg,0.55mmol)，(2,3-二氢苯并呋喃-4-基)甲胺(110mg,0.66mmol)，N,N- 二异丙基乙胺(0.22mL,1.65mmol)和2毫升的N,N-二甲基甲酰胺，90摄氏度下反应16小时。加水30毫升，乙酸乙酯萃取3次，有机相用无水硫酸钠干燥，减压浓缩。浓缩液直接用反相高效液相色谱(酸法)纯化，然后通过制备型TLC(使用在石油醚：乙酸乙酯＝1：1作为洗脱剂)进一步纯化得到白色固体2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-异丙基-5-(4-(甲基磺酰基)苯基)嘧-4(3H)-酮(30mg，12％产率)。2-Chloro-3-isopropyl-5-(4-(methylsulfonyl)phenyl)pyrimidin-4(3H)-one (180 mg, 0.55 mmol) was added sequentially to a dry 50 mL round bottom flask ( 2,3-Dihydrobenzofuran-4-yl)methylamine (110 mg, 0.66 mmol), N,N-diisopropylethylamine (0.22 mL, 1.65 mmol) and 2 mL of N,N-dimethyl The carboxamide was reacted at 90 ° C for 16 hours. The mixture was extracted with EtOAc (3 mL). The concentrate was directly purified by reverse-phase high performance liquid chromatography (acid method), and then purified by preparative TLC (using petroleum ether: ethyl acetate = 1:1 as eluent) to give a white solid 2-(((5) -fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-isopropyl-5-(4-(methylsulfonyl)phenyl)pyrimidine-4(3H)- Ketone (30 mg, 12% yield).
1H-NMR(500MHz,CDCl 3):δ7.93-7.89(m,3H),7.82-7.80(m,2H),6.87-6.83(m,1H),6.68-6.65(m,1H),5.54(brs,1H),5.35(t,D 2O exchangeable,1H),4.67(d,J＝5.5Hz,2H),4.63(t,J＝8.5Hz,2H),3.41(t,J＝8.5Hz,2H),3.04(s,3H),1.53(d,J＝8.0Hz,6H)ppm；LCMS:m/z 458.2[M+H] +. 1 H-NMR (500MHz, CDCl 3 ): δ7.93-7.89 (m, 3H), 7.82-7.80 (m, 2H), 6.87-6.83 (m, 1H), 6.68-6.65 (m, 1H), 5.54 (brs, 1H), 5.35 (t, D 2 O exchangeable, 1H), 4.67 (d, J = 5.5 Hz, 2H), 4.63 (t, J = 8.5 Hz, 2H), 3.41 (t, J = 8.5 Hz) , 2H), 3.04 (s, 3H), 1.53 (d, J = 8.0 Hz, 6H) ppm; LCMS: m/z 458.2 [M+H] + .
按照实施例158的方法可合成以下化合物：The following compounds were synthesized according to the method of Example 158:
实施例159：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(3-氟吡啶-4-基)-3-异丙基嘧啶-4(3H)-酮Example 159: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(3-fluoropyridin-4-yl)-3-isopropyl Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000350
Figure PCTCN2018122557-appb-000350
1H NMR(400MHz,CDCl 3):δ8.46(brs,1H),8.38(brs,1H),7.94(s,1H),7.60(s,1H),6.85(t,J＝9.2Hz,1H),6.69-6.66(m,1H),5.70-5.49(m,1H),5.40(m,D 2O exchangeable,1H),4.69-4.61(m,4H),3.40(t,J＝8.8Hz,2H),1.53(d,J＝7.2Hz,6H)ppm；LCMS:m/z 399.2[M+H] +. 1 H NMR (400MHz, CDCl 3 ): δ8.46 (brs, 1H), 8.38 (brs, 1H), 7.94 (s, 1H), 7.60 (s, 1H), 6.85 (t, J = 9.2Hz, 1H ), 6.69-6.66 (m, 1H), 5.70-5.49 (m, 1H), 5.40 (m, D 2 O exchangeable, 1H), 4.69-4.61 (m, 4H), 3.40 (t, J = 8.8 Hz, 2H), 1.53 (d, J = 7.2 Hz, 6H) ppm; LCMS: m/z 399.2 [M+H] + .
实施例160：2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-3-异丙基-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 160: 2-(((5-Fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-3-isopropyl-5-(2-methylpyridine-3- Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000351
Figure PCTCN2018122557-appb-000351
1H NMR(400MHz,DMSO-d6):δ8.35(dd,J＝1.5Hz,1H),7.18(qt,J＝5Hz,1H),6.89(qt,J＝9.5Hz,1H),6.65(dd,J＝3.5Hz,1H),4.71(bs,1H),4.56-4.52(m,4H),3.29-3.25(m,2H),2.31(s,3H),1.49(d,J＝7.0Hz,6H)ppm；LCMS:m/z 395.2[M+H] +. 1 H NMR (400MHz, DMSO- d6): δ8.35 (dd, J = 1.5Hz, 1H), 7.18 (qt, J = 5Hz, 1H), 6.89 (qt, J = 9.5Hz, 1H), 6.65 ( Dd, J=3.5 Hz, 1H), 4.71 (bs, 1H), 4.56-4.52 (m, 4H), 3.29-3.25 (m, 2H), 2.31 (s, 3H), 1.49 (d, J = 7.0 Hz) , 6H) ppm; LCMS: m/z 395.2 [M+H] + .
实施例161：2-(((6-氟色烷-5-基)甲基)氨基)-3-异丙基-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 161: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-isopropyl-5-(2-methylpyridin-3-yl)pyrimidine-4 (3H) -ketone
Figure PCTCN2018122557-appb-000352
Figure PCTCN2018122557-appb-000352
1H NMR(400MHz,DMSO-d6):δ8.37-8.34(m,2H),7.61(s,1H),7.50(dd,J＝2.0,8.0Hz,1H),7.39-7.36(m,1H),7.20-7.17(m,1H),6.94(t,1H),6.74-6.71(m,1H),4.66-4.64(m,1H),4.49(d,J＝4.0Hz,2H),4.08(t,J＝5.0Hz,2H),2.84(t,J＝6.5Hz,2H),2.32(s,3H),1.94-1.91(m,2H),1.46(d,J＝7.0Hz,6H)ppm；LCMS:m/z 409.2[M+H] +. 1 H NMR (400MHz, DMSO- d6): δ8.37-8.34 (m, 2H), 7.61 (s, 1H), 7.50 (dd, J = 2.0,8.0Hz, 1H), 7.39-7.36 (m, 1H ), 7.20-7.17 (m, 1H), 6.94 (t, 1H), 6.74-6.71 (m, 1H), 4.66-4.64 (m, 1H), 4.49 (d, J = 4.0 Hz, 2H), 4.08 ( t, J = 5.0 Hz, 2H), 2.84 (t, J = 6.5 Hz, 2H), 2.32 (s, 3H), 1.94-1.91 (m, 2H), 1.46 (d, J = 7.0 Hz, 6H) ppm LCMS: m/z 409.2 [M+H] + .
实施例162：2-(((6-氟色烷-5-基)甲基)氨基)-3-异丙基-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 162: 2-(((6-fluorochroman-5-yl)methyl)amino)-3-isopropyl-5-(4-methylpyridin-3-yl)pyrimidine-4 (3H) -ketone
Figure PCTCN2018122557-appb-000353
Figure PCTCN2018122557-appb-000353
1H NMR(400MHz,CDCl 3):δ8.42(d,J＝5.0Hz,1H),8.38(s,1H),7.65(s,1H),7.25-7.24(m,1H),6.90(t,J＝9.5Hz,1H),6.79-6.76(m,1H),5.44(brs,1H),5.13(s,D2O Exchangeable,1H),4.69(d,J＝4.0Hz,2H),4.15(t,J＝5.0Hz,2H),2.99(t,J＝6.5Hz,2H),2.31(s,3H),2.07-2.02(m,2H),1.50(d,J＝7.0Hz,6H)ppm；LCMS:m/z 409.2[M+H] +. 1 H NMR (400MHz, CDCl 3 ): δ8.42 (d, J = 5.0Hz, 1H), 8.38 (s, 1H), 7.65 (s, 1H), 7.25-7.24 (m, 1H), 6.90 (t , J = 9.5 Hz, 1H), 6.79-6.76 (m, 1H), 5.44 (brs, 1H), 5.13 (s, D2O Exchangeable, 1H), 4.69 (d, J = 4.0 Hz, 2H), 4.15 (t , J=5.0 Hz, 2H), 2.99 (t, J=6.5 Hz, 2H), 2.31 (s, 3H), 2.07-2.02 (m, 2H), 1.50 (d, J = 7.0 Hz, 6H) ppm; LCMS: m/z 409.2 [M+H] + .
实施例163：3-(2,2-二氟乙基)-2-(((5-氟-2,3-二氢苯并呋喃-4-基)甲基)氨基)-5-(2-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 163: 3-(2,2-Difluoroethyl)-2-(((5-fluoro-2,3-dihydrobenzofuran-4-yl)methyl)amino)-5-(2 -methylpyridin-3-yl)pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000354
Figure PCTCN2018122557-appb-000354
1H NMR(400MHz,DMSO-d6):δ8.39-8.37(m,1H),7.92(s,1H),7.72(s,1H),7.52(dd,J＝2.0,7.5Hz,1H),7.22-7.19(m,1H),6.91(t,J＝10.0Hz,1H),6.69-6.66(m,1H),6.22(tt,J＝4.5,55.5,Hz,1H),4.56-4.51(m,6H),3.30-3.27(m,2H),2.32(s,3H)ppm；LCMS:m/z 417.2[M+H] +. 1 H NMR (400MHz, DMSO- d6): δ8.39-8.37 (m, 1H), 7.92 (s, 1H), 7.72 (s, 1H), 7.52 (dd, J = 2.0,7.5Hz, 1H), 7.22-7.19(m,1H), 6.91(t,J=10.0Hz,1H),6.69-6.66(m,1H),6.22(tt,J=4.5,55.5,Hz,1H),4.56-4.51(m , 6H), 3.30-3.27 (m, 2H), 2.32 (s, 3H) ppm; LCMS: m/z 417.2 [M+H] + .
实施例164：3-(2,2-二氟乙基)-2-(((6-氟色烷-5-基)甲基)氨基)-5-(4-甲基吡啶-3-基)嘧啶-4(3H)-酮Example 164: 3-(2,2-Difluoroethyl)-2-(((6-fluorochroman-5-yl)methyl)amino)-5-(4-methylpyridin-3-yl) Pyrimidine-4(3H)-one
Figure PCTCN2018122557-appb-000355
Figure PCTCN2018122557-appb-000355
1H NMR(400MHz,CDCl 3):δ8.49(d,J＝3.2Hz,1H),7.74(s,1H),7.51(d,J＝8.0Hz,1H),7.17(m,1H),6.90(t,J＝9.2Hz,1H),6.80-6.77(m,1H),6.07(tt,J＝4.4,56.4,Hz,1H),5.19(brs,1H),4.64(d,J＝4.4Hz,2H),4.36-4.28(m,2H),4.15(t,J＝5.2Hz,2H),2.93(d,J＝6.4Hz,2H),2.49(s,3H),2.07-2.01(m,2H)ppm；LCMS:m/z 431.2[M+H] +. 1 H NMR (400MHz, CDCl 3 ): δ8.49 (d, J = 3.2Hz, 1H), 7.74 (s, 1H), 7.51 (d, J = 8.0Hz, 1H), 7.17 (m, 1H), 6.90 (t, J = 9.2 Hz, 1H), 6.80-6.77 (m, 1H), 6.07 (tt, J = 4.4, 56.4, Hz, 1H), 5.19 (brs, 1H), 4.64 (d, J = 4.4) Hz, 2H), 4.36-4.28 (m, 2H), 4.15 (t, J = 5.2 Hz, 2H), 2.93 (d, J = 6.4 Hz, 2H), 2.49 (s, 3H), 2.07-2.01 (m , 2H) ppm; LCMS: m/z 431.2 [M+H] + .
药理学及应用Pharmacology and application
EED作为PRC2蛋白复合物的主要组成部分之一，虽然并不具有酶催化的活性，但是它对PRC2的整体功能具有重要的作用。EED对PRC2的作用具体表现为两个方面：1)EED直接与三甲基化的H3K27Me3结合，这样能够把PCR2复合物定位在需要修饰的染色质上；2)EED对EZH2的酶催化功能有很大的变构促进作用。因此，开发作为变构蛋白EED的靶点化合物为提供抑制EZH2酶活性提供了新策略。而且这样的抑制剂具有比EZH2酶催化位点抑制剂具有更好或互补的优势，比如当病人对于EZH2酶抑制剂产生耐药性时，EED抑制剂同样可以起到抑制EZH2酶活性的作用。本发明公开了嘧啶酮化合物可以作为EED靶点抑制剂，并对与EED和/或PRC2作用机理相关的疾病有治疗作用。EED, as one of the major components of the PRC2 protein complex, does not have enzyme-catalyzed activity, but it plays an important role in the overall function of PRC2. The effect of EED on PRC2 is manifested in two aspects: 1) EED is directly bound to trimethylated H3K27Me3, which can position the PCR2 complex on the chromatin to be modified; 2) EED has the enzymatic function of EZH2 Great allosteric promotion. Therefore, the development of a target compound as an allosteric protein EED provides a new strategy for providing inhibition of EZH2 enzyme activity. Moreover, such inhibitors have the advantage of being better or more complementary than the EZH2 enzyme catalytic site inhibitor. For example, when the patient is resistant to the EZH2 enzyme inhibitor, the EED inhibitor can also inhibit the activity of the EZH2 enzyme. The present invention discloses that a pyrimidinone compound can be used as an EED target inhibitor and has a therapeutic effect on diseases associated with the mechanism of action of EED and/or PRC2.
本发明公开化合物的生物学功能在生化以及细胞水平的测试中得到了证明。比如在生化测试中，本发明公开的化合物能够与和EED蛋白结合的H3K27Me3多肽有很强的竞争结合作用(IC 50可达<10nM)。在细胞水平上，本发明公开化合物不仅可以抑制组蛋白H3K27的甲基化水平而且也可以通过这一作用抑制癌细胞的增殖。 The biological function of the compounds disclosed herein has been demonstrated in biochemical and cellular level assays. For example, in biochemical tests, the compounds of the present invention is disclosed to have a strong competitive with H3K27Me3 EED polypeptide and binding protein binding (IC 50 of up to <10nM). At the cellular level, the compounds disclosed herein not only inhibit the methylation level of histone H3K27 but also inhibit the proliferation of cancer cells by this action.
通过AlphaScreen(a-筛选)方法评价化合物在阻断EED与H3K27me3结合的效果Evaluation of the effect of compounds blocking the binding of EED to H3K27me3 by AlphaScreen (a-screening) method
首先配置不同浓度梯度的化合物溶液。化合物粉末用DMSO溶解成母液。取1.5μl化合物母液至198.5μl反应缓冲液(25mM HEPES(pH 8.0)，50mM NaCl，0.015％Tween20，0.5％BSA)中混匀，再用含有0.75％DMSO的上述缓冲液进行3-倍梯度稀释，同一化合物设置9个不同的测试浓度。取5μL不同浓度梯度的化合物至ProxiPlate-384Plus, White检测板(PerkinElmer，6008280)中,每个浓度梯度设置2个平行重复。First, compound solutions of different concentration gradients are configured. The compound powder was dissolved in DMSO to form a mother liquor. 1.5 μl of the compound mother solution was mixed into 198.5 μl of reaction buffer (25 mM HEPES (pH 8.0), 50 mM NaCl, 0.015% Tween 20, 0.5% BSA), and then subjected to 3-fold gradient dilution with the above buffer containing 0.75% DMSO. The same compound was set to 9 different test concentrations. 5 [mu]L of different concentration gradients of compound were applied to a ProxiPlate-384 Plus, White assay plate (PerkinElmer, 6008280) with 2 parallel replicates for each concentration gradient.
其次进行结合阻断反应。用上述缓冲液稀释带有His6标签的全长EED蛋白(441个氨基酸)至60nM,以及生物素标记的多肽片段H3K27me3(第19-33位氨基酸)(Biotinylated-H3K27me3)至75nM。分别转移5μl浓度为75nM多肽片段以及5μl的60nM蛋白至含有化合物的检测孔内，薄膜封住检测板，室温孵育30分钟。Next, a binding blocking reaction is carried out. The His6-tagged full-length EED protein (441 amino acids) was diluted to 60 nM with the above buffer, and the biotinylated polypeptide fragment H3K27me3 (amino acid 19-33) (Biotinylated-H3K27me3) to 75 nM. 5 μl of a 75 nM polypeptide fragment and 5 μl of 60 nM protein were separately transferred to the test well containing the compound, and the test plate was sealed with a film and incubated at room temperature for 30 minutes.
最后AlphaScreen方法检测。临用前，镍螯合受体珠与链霉抗生物素供体珠以1:1的比例(Perkin Elmer，产品号6760619M)混入上述反应缓冲液中，再向各检测孔中加入5μl上述预混的检测液，供体珠和受体珠终浓度均为5μg/mL。锡箔遮封住检测板，室温避光放置1小时。使用Spectra max i3上的AlphaScreen检测器读取信号。根据阳性对照(最大信号对照)和阴性对照(最小信号对照)获得的读数对AlphaScreen信号进行标准化，以给出不同浓度化合物的抑制率,之后用GraphPad Prism 5进行非线性回归分析，通过Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))剂量响应方程做出抑制曲线，得到各化合物的IC50值。Finally, the AlphaScreen method detects. Before use, nickel chelate acceptor beads and streptavidin donor beads were mixed into the above reaction buffer in a ratio of 1:1 (Perkin Elmer, product number 6760619M), and 5 μl of the above pre-supplement was added to each detection well. The mixed test solution, the final concentration of donor beads and acceptor beads were both 5 μg/mL. The test strip was sealed with tin foil and allowed to stand at room temperature for 1 hour. The signal is read using the AlphaScreen detector on the Spectra max i3. The AlphaScreen signal was normalized to the readings obtained from the positive control (maximum signal control) and the negative control (minimum signal control) to give inhibition rates for different concentrations of compound, followed by non-linear regression analysis with GraphPad Prism 5, by Y=Bottom+ (Top-Bottom)/(1+10^((LogIC50-X)*HillSlope)) The dose response equation was subjected to an inhibition curve to obtain IC50 values of the respective compounds.
为了排除由于化合物干扰AlphaScreen检测***而产生的假阳性，以同样的方法稀释化合物，用生物素标记的多肽Biotinylated-(His) 6代替检测体系中的EED和多肽H3K27me3,孵育同等时间后，在Spectra max i3上读取信号值。以同样的方法处理数据。 To rule out false positives due to compound interference with the AlphaScreen detection system, dilute the compound in the same manner, replace the EED and peptide H3K27me3 in the detection system with the biotinylated peptide Biotinylated-(His) 6 and incubate for the same time in Spectra. The signal value is read on max i3. Process the data in the same way.
结果result
下表显示了本发明部分化合物的IC 50值。 The following table shows the IC 50 values of some compounds of the present invention.
字母A代表IC 50小于100nM； The letter A represents an IC 50 of less than 100 nM;
字母B代表IC 50为100nM至1000nM； The letter B represents an IC 50 of 100 nM to 1000 nM;
字母C代表IC 50为1000nM以上 The letter C represents an IC 50 of 1000 nM or more.
Figure PCTCN2018122557-appb-000356
Figure PCTCN2018122557-appb-000356
Figure PCTCN2018122557-appb-000357
Figure PCTCN2018122557-appb-000357
Figure PCTCN2018122557-appb-000358
Figure PCTCN2018122557-appb-000358
Figure PCTCN2018122557-appb-000359
Figure PCTCN2018122557-appb-000359
Figure PCTCN2018122557-appb-000360
Figure PCTCN2018122557-appb-000360
Figure PCTCN2018122557-appb-000361
Figure PCTCN2018122557-appb-000361
Figure PCTCN2018122557-appb-000362
Figure PCTCN2018122557-appb-000362
Figure PCTCN2018122557-appb-000363
Figure PCTCN2018122557-appb-000363
Figure PCTCN2018122557-appb-000364
Figure PCTCN2018122557-appb-000364
Figure PCTCN2018122557-appb-000365
Figure PCTCN2018122557-appb-000365
Figure PCTCN2018122557-appb-000366
Figure PCTCN2018122557-appb-000366
ELISA(H3K27三甲基化)分析ELISA (H3K27 trimethylation) analysis
将代表性的本公开内容的化合物用DMSO中进行3-倍梯度稀释，每化合物检测10个浓度梯度，最高测定浓度为10μM。化合物200-倍稀释到在96-孔板中培养的G401细胞中(DMSO终浓度为0.5％)。给药细胞培养72小时后，ELISA方法检测组蛋白H3K27三甲基化水平。Representative compounds of the present disclosure were subjected to 3-fold gradient dilutions in DMSO, and 10 concentration gradients were detected per compound up to a maximum assay concentration of 10 [mu]M. Compounds were diluted 200-fold into G401 cells cultured in 96-well plates (final concentration of DMSO 0.5%). After 72 hours of administration of the cells, the histone H3K27 trimethylation level was measured by an ELISA method.
组蛋白提取:96-孔板中化合物处理的细胞用1x PBS(10x PBS缓冲液(80g NaCl(Sigma,产品号S3014),2g KCl(Sigma,产品号60128),14.4g Na 2HP04(Sigma,产品号S5136),2.4g KH 2P04(Sigma,产品号P9791)至1L水中，pH至7.4)洗涤三次，每孔加入100μL 0.4N HCl，置于4℃，温和振摇2小时裂解细胞。细胞裂解液再用80μL中和缓冲液(0.5M磷酸氢二钠，pH 12.5,2.5mM DTT；1％cocktail(Sigma，产品号P8340)中和(充分混匀细胞裂解液与中和缓冲液)。 Histone extraction: Compound-treated cells in 96-well plates were treated with 1 x PBS (10x PBS buffer (80 g NaCl (Sigma, product number S3014), 2 g KCl (Sigma, product number 60128), 14.4 g Na 2 HP04 (Sigma, Product No. S5136), 2.4 g KH 2 P04 (Sigma, product number P9791) to 1 L water, pH to 7.4) was washed three times, 100 μL of 0.4 N HCl was added to each well, placed at 4 ° C, and gently shaken for 2 hours to lyse the cells. The lysate was further neutralized with 80 μL of neutralization buffer (0.5 M disodium hydrogen phosphate, pH 12.5, 2.5 mM DTT; 1% cocktail (Sigma, product number P8340) (to thoroughly mix the cell lysate with the neutralization buffer).
ELISA检测方法:将细胞裂解液平行转移至2个384-孔检测板(PerkinElmer，OptiPlate-384HB,产品号6007290)中，一块板用于检测H3K27三甲基化水平，另一块板用于测定H3的水平，PBS调至终体积为50μL/孔，4℃包被过夜。次日，弃去孔内溶液，用TBST缓冲液(lxTBS(10xTBS:24.2g Tris(Sigma,产品号T6066),80g NaCl(Sigma，产品号S3014)至1L水中，HCl调pH至7.6),0.1％Tween-20)洗涤5次，于吸水纸上扣干水分。将70μL封闭缓冲液(TBST,5％BSA)加入已包被之反应孔中，于室温孵育1小时。弃去封闭缓冲液，加入一级抗体(30μL/孔)。所需一级抗体均用封闭缓冲液稀释，稀释倍数如下：抗H3K27me3抗体(Cell Signaling Technology,产品号9733)，1:2000稀释；抗H3抗体(Cell Signaling Technology,产品号4499),1：10000稀释。加入一抗后，置室温孵育1小时。TBST洗涤5次后，扣干水分，各反应孔加入二级抗体(30μL/孔)，室温孵育1小时。二级抗体(抗兔抗体(Jackson ImmunoResearch,产品号111-035-003))用封闭缓冲液稀释2000倍后使用。1小时后，TBST洗涤，扣干水分。于各孔中加入30μL的ECL底物(Pierce，产品号34080)，2000rpm离心30秒。利用Molecular Devices，SpectraMax检测各样品信号。数据处理：H3K27甲基化读数先用H3信号进行标准化，0.5％DMSO处理的样品作为对照，计算出化合物的抑制百分率。采用GraphPad prisim5程序将数据拟合为剂量响应曲线，得到测试化合物的IC 50值。 ELISA assay: Cell lysates were transferred in parallel to two 384-well assay plates (PerkinElmer, OptiPlate-384HB, product number 6007290), one for H3K27 trimethylation and the other for H3 The level of PBS was adjusted to a final volume of 50 μL/well and coated at 4 °C overnight. The next day, the solution in the well was discarded, using TBST buffer (lxTBS (10xTBS: 24.2 g Tris (Sigma, product number T6066), 80 g NaCl (Sigma, product number S3014) to 1 L water, HCl adjusted to pH 7.6), 0.1 %Tween-20) Washed 5 times and buckled on the absorbent paper. 70 μL of blocking buffer (TBST, 5% BSA) was added to the coated reaction wells and incubated for 1 hour at room temperature. The blocking buffer was discarded and primary antibody (30 μL/well) was added. The desired primary antibodies were diluted in blocking buffer at the following dilutions: anti-H3K27me3 antibody (Cell Signaling Technology, product number 9733), 1:2000 dilution; anti-H3 antibody (Cell Signaling Technology, product number 4499), 1:10000 dilution. After the primary antibody was added, it was incubated at room temperature for 1 hour. After washing TBST 5 times, the water was dehydrated, and secondary antibody (30 μL/well) was added to each reaction well, and the mixture was incubated at room temperature for 1 hour. A secondary antibody (anti-rabbit antibody (Jackson ImmunoResearch, product number 111-035-003)) was diluted 2000 times with blocking buffer and used. After 1 hour, the TBST was washed and dehydrated. 30 μL of ECL substrate (Pierce, product number 34080) was added to each well and centrifuged at 2000 rpm for 30 seconds. Each sample signal was detected using Molecular Devices, SpectraMax. Data processing: H3K27 methylation readings were first normalized with the H3 signal and 0.5% DMSO treated samples were used as controls to calculate the percent inhibition of the compound. Using the program GraphPad prisim5 fitting the data to the dose response curves to obtain IC 50 values of test compounds.
结果result
下表显示了本发明部分化合物的IC 50值。 The following table shows the IC 50 values of some compounds of the present invention.
字母A代表IC 50小于100nM； The letter A represents an IC 50 of less than 100 nM;
字母B代表IC 50为100nM至1000nM； The letter B represents an IC 50 of 100 nM to 1000 nM;
字母C代表IC 50为1000nM以上 The letter C represents an IC 50 of 1000 nM or more.
Figure PCTCN2018122557-appb-000367
Figure PCTCN2018122557-appb-000367
Figure PCTCN2018122557-appb-000368
Figure PCTCN2018122557-appb-000368
Figure PCTCN2018122557-appb-000369
Figure PCTCN2018122557-appb-000369
Figure PCTCN2018122557-appb-000370
Figure PCTCN2018122557-appb-000370
Figure PCTCN2018122557-appb-000371
Figure PCTCN2018122557-appb-000371
Figure PCTCN2018122557-appb-000372
Figure PCTCN2018122557-appb-000372
Figure PCTCN2018122557-appb-000373
Figure PCTCN2018122557-appb-000373
细胞增殖分析Cell proliferation analysis
采用标准细胞培养条件，人类B细胞非霍奇金淋巴瘤细胞KARPAS-422培养在培养瓶中。培养基为含15％胎牛血清(FBS，Invitrogen，产品号10099-141)，1％青霉素/链霉素溶液(P/S)RPMI-1640(Invitrogen，产品号11875)，培养瓶置于温度37℃，相对湿度95％，5％CO2的无菌培养箱中培养。为了检测PRC2抑制剂对细胞增殖的影响，取指数生长期的细胞，以1x10 4细胞/孔的密度接种到96孔板(Corning，产品号3904)中，每孔加入100μL培养基。随后，将本文公开内容的、不同浓度的化合物加入到已接种细胞的孔中(每个化合物设置9个浓度梯度，最高检测浓度为10μM,3-倍梯度稀释)，每个处理浓度设置2个平行重复，DMSO终浓度为0.5％。之后每隔3～4天用Vi-CELL(Beckman Coulter)测定存活细胞数。每次计过数的细胞以同等密度(1X 10 4个细胞/孔)接种到新的96-孔板中，补充新鲜培养基至100μL，同时加入不同浓度的化合物。培养至第13天，每孔加入100μL的CellTiter-Glo(CTG)(Promega,产品号G7573),室温避光放置10～20分钟，利用Molecular Devices,SpectraMax i3X读取发光信号。采用GraphPad prisim5将数据拟合为剂量响应曲线，从而得到测试化合物的IC 50值。 Human B-cell non-Hodgkin's lymphoma cell KARPAS-422 was cultured in culture flasks using standard cell culture conditions. The medium was containing 15% fetal bovine serum (FBS, Invitrogen, product number 10099-141), 1% penicillin/streptomycin solution (P/S) RPMI-1640 (Invitrogen, product number 11875), and the culture flask was placed at temperature. Incubate in a sterile incubator at 37 ° C, 95% relative humidity, 5% CO2. To examine the effect of PRC2 inhibitors on cell proliferation, cells in exponential growth phase were seeded at a density of 1 x 10 4 cells/well into 96-well plates (Corning, product number 3904), and 100 μL of medium was added to each well. Subsequently, various concentrations of compounds of the disclosure disclosed were added to the wells of the seeded cells (9 concentration gradients per compound, up to a concentration of 10 μM, 3-fold gradient dilution), 2 for each treatment concentration Repeat in parallel with a final DMSO concentration of 0.5%. Thereafter, the number of viable cells was measured by Vi-CELL (Beckman Coulter) every 3 to 4 days. The counted cells were seeded at the same density (1×10 4 cells/well) into new 96-well plates, supplemented with fresh medium to 100 μL, and various concentrations of compounds were added. On the 13th day of culture, 100 μL of CellTiter-Glo (CTG) (Promega, product number G7573) was added to each well, and allowed to stand at room temperature for 10 to 20 minutes in the dark, and the luminescence signal was read using Molecular Devices, SpectraMax i3X. The data were fitted using GraphPad prisim5 dose response curves to obtain IC 50 values of the test compound.
结果result
下表显示了本发明部分化合物的IC 50值。 The following table shows the IC 50 values of some compounds of the present invention.
字母A代表IC 50小于100nM； The letter A represents an IC 50 of less than 100 nM;
字母B代表IC 50为100nM至1000nM； The letter B represents an IC 50 of 100 nM to 1000 nM;
字母C代表IC 50为1000nM以上 The letter C represents an IC 50 of 1000 nM or more.
Figure PCTCN2018122557-appb-000374
Figure PCTCN2018122557-appb-000374
Figure PCTCN2018122557-appb-000375
Figure PCTCN2018122557-appb-000375
本发明公开的化合物可用于治疗与EED蛋白和/或PRC2蛋白复合物作用机理相关的癌症，包括但不局限于包括扩散大B细胞淋巴癌、滤泡性淋巴瘤等等淋巴癌、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝癌、***癌、乳腺癌、脑瘤 包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、***、结肠癌、黑色素瘤、子宫内膜癌、食管癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾癌、直肠癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤等等。The compounds disclosed herein are useful for treating cancers associated with the mechanism of action of EED proteins and/or PRC2 protein complexes, including but not limited to, including large cell B lymphoma, follicular lymphoma, and the like, lymphoma, leukemia, multiple Myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, brain tumor including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon Cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor, and soft tissue sarcoma.

Claims (32)

  1. 一种如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物；a pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt;
    Figure PCTCN2018122557-appb-100001
    Figure PCTCN2018122557-appb-100001
    其中，among them,
    Figure PCTCN2018122557-appb-100002
    为单键或双键；
    Figure PCTCN2018122557-appb-100002
    For single or double keys;
    m独立地为0或1；m is independently 0 or 1;
    n独立地为0或1；n is independently 0 or 1;
    o独立地为0或1；o is independently 0 or 1;
    p独立地为0或1；p is independently 0 or 1;
    X独立地为C、O或CH 2O； X is independently C, O or CH 2 O;
    Y独立地为C或O；Y is independently C or O;
    Z独立地为C或N；Z is independently C or N;
    当X为C时，R 0独立地为氢、羟基、卤素、取代或未取代的烷氧基或羰基； When X is C, R 0 is independently hydrogen, hydroxy, halogen, substituted or unsubstituted alkoxy or carbonyl;
    当X为O时，R 0不存在； When X is O, R 0 does not exist;
    当Z为C时，R 1独立地为氢、卤素或C 1-4烷基； When Z is C, R 1 is independently hydrogen, halogen or C 1-4 alkyl;
    当Z为N时，R 1不存在； When Z is N, R 1 does not exist;
    R 2和R 3各自独立地为氢、卤素或C 1-4烷基； R 2 and R 3 are each independently hydrogen, halogen or C 1-4 alkyl;
    R 4独立地为氢、R 4a取代或未取代的C 1-4烷基、R 4a取代或未取代的C 1-4卤代烷基、C 3-8环烷基或C 2-6烯基； R 4 is independently hydrogen, R 4a substituted or unsubstituted C 1-4 alkyl, R 4a substituted or unsubstituted C 1-4 haloalkyl, C 3-8 cycloalkyl or C 2-6 alkenyl;
    每个R 4a独立地为氘、卤素或C 1-4烷基； Each R 4a is independently hydrazine, halogen or C 1-4 alkyl;
    R 5独立地为氢、C 1-4烷基或氨基； R 5 is independently hydrogen, C 1-4 alkyl or amino;
    R 6独立地为氢、卤素、氰基、R 6a取代或未取代的C 1-8烷基、C 1-8烷氧基、C 1-8卤代烷基、R 6a取代或未取代的C 3-8环烷基、R 6b取代或未取代的C 3-8环烷基、R 6b取代或未取代的C 3-8杂环基、R 6c取代或未取代的烯基、R 6b取代或未取代的C 5-8环烯基、R 6b取代或未取代的C 5-8杂环烯基、R 6d取代或未取代的氨基、R 6d取代或未取代的氧基、R 6d取代或未取代的巯基、R 6d取代或未取代的酰胺、0-3个R 6e取代的C 6-10芳基或“0-3个R 6e取代 的具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”； R 6 is independently hydrogen, halogen, cyano, R 6a substituted or unsubstituted C 1-8 alkyl, C 1-8 alkoxy, C 1-8 haloalkyl, R 6a substituted or unsubstituted C 3 -8 cycloalkyl, R 6b substituted or unsubstituted C 3-8 cycloalkyl, R 6b substituted or unsubstituted C 3-8 heterocyclyl, R 6c substituted or unsubstituted alkenyl, R 6b substituted or Unsubstituted C 5-8 cycloalkenyl, R 6b substituted or unsubstituted C 5-8 heterocycloalkenyl, R 6d substituted or unsubstituted amino, R 6d substituted or unsubstituted oxy, R 6d substituted or Unsubstituted indenyl, R 6d substituted or unsubstituted amide, 0-3 R 6e substituted C 6-10 aryl or "0-3 R 6e substituted with C 1-20 carbon and 1-4 a heteroaryl group independently selected from the heteroatoms of N, NR 6e1 , O and S(O) 0-2 ";
    每个R 6a和R 6b各自独立地为C 1-4烷氧基、-C(＝O)NR 6e1R 6e2、C 1-4烷基、C 1-4卤代烷基、氨基、保护基团保护的氨基、单氟或多氟； Each of R 6a and R 6b is independently C 1-4 alkoxy, -C(=O)NR 6e1 R 6e2 , C 1-4 alkyl, C 1-4 haloalkyl, amino, protecting group protection Amino, monofluoro or polyfluoro;
    每个R 6c独立地为C 1-4烷基或酯基； Each R 6c is independently a C 1-4 alkyl or ester group;
    每个R 6d独立地为C 1-20烷基、苄基、R 7d取代或未取代的C 6-10芳基、R 7d取代或未取代的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”； Each R 6d is independently C 1-20 alkyl, benzyl, R 7d substituted or unsubstituted C 6-10 aryl, R 7d substituted or unsubstituted "having a C 1-20 carbon atom and 1-4 a heteroaryl group independently selected from the heteroatoms of N, NR 6e1 , O and S(O) 0-2 ";
    每个R 7d独立地为卤素、C 1-4烷基、C 1-4烷氧基、-C(＝O)NR 6e1R 6e2、C 1-4卤代烷基、氨基或
    Figure PCTCN2018122557-appb-100003
    Each R 7d is independently halogen, C 1-4 alkyl, C 1-4 alkoxy, -C(=O)NR 6e1 R 6e2 , C 1-4 haloalkyl, amino or
    Figure PCTCN2018122557-appb-100003
    R 8d为C 1-4烷基； R 8d is C 1-4 alkyl;
    R 6e独立地为卤素、R 4a取代或未取代的C 1-4烷氧基、R 4a取代或未取代的C 1-4烷基、-C(＝O)NR 6e1R 6e2、-S(＝O) 2R 6e3、NR 6e1R 6e2、R 7e取代或未取代的C 3-10环烷基、R 7e取代或未取代的“具有C 1-20碳原子及1-4个独立选自NR 6e1、O和S(O) 0-2的杂原子的杂环基”； R 6e is independently halogen, R 4a substituted or unsubstituted C 1-4 alkoxy, R 4a substituted or unsubstituted C 1-4 alkyl, -C(=O)NR 6e1 R 6e2 , -S( =O) 2 R 6e3 , NR 6e1 R 6e2 , R 7e substituted or unsubstituted C 3-10 cycloalkyl, R 7e substituted or unsubstituted "having a C 1-20 carbon atom and 1-4 independently selected from a heterocyclic group of a hetero atom of NR 6e1 , O and S(O) 0-2 ";
    每个R 7e独立地为卤素、C 1-4烷基、C 1-4烷氧基、-C(＝O)NR 6e1R 6e2或C 1-4卤代烷基； Each R 7e is independently halogen, C 1-4 alkyl, C 1-4 alkoxy, -C(=O)NR 6e1 R 6e2 or C 1-4 haloalkyl;
    每个R 6e1独立地为氢或C 1-4烷基；每个R 6e2独立地为氢或C 1-4烷基；R 6e3为C 1-4烷基。 Each R 6e1 is independently hydrogen or C 1-4 alkyl; each R 6e2 is independently hydrogen or C 1-4 alkyl; and R 6e3 is C 1-4 alkyl.
  2. 如权利要求1所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中，The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein
    Figure PCTCN2018122557-appb-100004
    为单键或双键；
    Figure PCTCN2018122557-appb-100004
    For single or double keys;
    m独立地为0或1；m is independently 0 or 1;
    n独立地为0或1；n is independently 0 or 1;
    o独立地为0或1；o is independently 0 or 1;
    p独立地为0或1；p is independently 0 or 1;
    X独立地为C、O或CH 2O； X is independently C, O or CH 2 O;
    Y独立地为C或O；Y is independently C or O;
    Z独立地为C或N；Z is independently C or N;
    当X为C时，R 0独立地为氢、卤素、取代或未取代的烷氧基或羰基； When X is C, R 0 is independently hydrogen, halogen, substituted or unsubstituted alkoxy or carbonyl;
    当X为O时，R 0不存在； When X is O, R 0 does not exist;
    当Z为C时，R 1独立地为氢、卤素或C 1-4烷基； When Z is C, R 1 is independently hydrogen, halogen or C 1-4 alkyl;
    当Z为N时，R 1不存在； When Z is N, R 1 does not exist;
    R 2和R 3独立地为氢、卤素或C 1-4烷基； R 2 and R 3 are independently hydrogen, halogen or C 1-4 alkyl;
    R 4独立地为氢、R 4a取代或未取代的C 1-4烷基、R 4a取代或未取代的C 1-4卤代烷基、C 3-8环烷基或C 2-6烯基； R 4 is independently hydrogen, R 4a substituted or unsubstituted C 1-4 alkyl, R 4a substituted or unsubstituted C 1-4 haloalkyl, C 3-8 cycloalkyl or C 2-6 alkenyl;
    R 4a独立地为卤素或C 1-4烷基； R 4a is independently halogen or C 1-4 alkyl;
    R 5独立地为氢、C 1-4烷基或氨基； R 5 is independently hydrogen, C 1-4 alkyl or amino;
    R 6独立地为氢、卤素、氰基、C 1-8烷基、C 1-8卤代烷基、R 6a取代或未取代的C 3-8环烷基、R 6b取代或未取代的C 3-8杂环基、R 6c取代或未取代的烯基、R 6b取代或未取代的C 5- 8环烯基、R 6b取代或未取代的C 5-8杂环烯基、R 6d取代或未取代的氨基、R 6d取代或未取代的氧基、R 6d取代或未取代的酰胺、0-3个R 6e取代的C 6-10芳基或0-3个R 6e取代的含有C 1-20碳原子及1-4个N、NR 6e1、O或S(O) 0-2杂原子的杂芳环； R 6 is independently hydrogen, halogen, cyano, C 1-8 alkyl, C 1-8 haloalkyl, R 6a substituted or unsubstituted C 3-8 cycloalkyl, R 6b substituted or unsubstituted C 3 -8 heterocyclyl, R 6c substituted or unsubstituted alkenyl group, R 6b a substituted or unsubstituted C 5- 8 cycloalkenyl, R 6b a substituted or unsubstituted C 5-8 heterocycloalkenyl group, R 6d substituted Or unsubstituted amino, R 6d substituted or unsubstituted oxy, R 6d substituted or unsubstituted amide, 0-3 R 6e substituted C 6-10 aryl or 0-3 R 6e substituted C a heteroaryl ring of 1-20 carbon atoms and 1-4 N, NR 6e1 , O or S(O) 0-2 heteroatoms;
    R 6a和R 6b独立地为氨基、保护基团保护的氨基、单氟或多氟； R 6a and R 6b are independently amino, protecting group protected amino, monofluoro or polyfluoro;
    R 6c独立地为C 1-4烷基、酯基； R 6c is independently C 1-4 alkyl, ester group;
    R 6d独立地为C 1-20烷基、苄基、取代或未取代的C 6-10芳基、取代或未取代的含有C 1- 20碳原子及1-4个N、NR 6e1、O或S(O) 0-2等杂原子的杂芳环； R 6d is independently a C 1-20 alkyl group, a benzyl group, a substituted or unsubstituted C 6-10 aryl group, a substituted or unsubstituted C 1- 20 containing 1-4 carbon atoms and N, NR 6e1, O Or a heteroaromatic ring of a hetero atom such as S(O) 0-2 ;
    R 6e独立地为卤素、R 4a取代或未取代的C 1-4烷氧基、R 4a取代或未取代的C 1-4烷基、-C(＝O)NR 6e1R 6e2、-S(＝O) 2R 6e3、NR 6e1R 6e2、含有C 1-20碳原子及1-4个NR 6e1、O或S(O) 0- 2等杂原子的杂环； R 6e is independently halogen, R 4a substituted or unsubstituted C 1-4 alkoxy, R 4a substituted or unsubstituted C 1-4 alkyl, -C(=O)NR 6e1 R 6e2 , -S( = O) 2 R 6e3, NR 6e1 R 6e2, C 1-20 carbon atoms and containing 1-4 NR 6e1, O, or S (O) 0- 2 other hetero atom;
    其中，R 6e1独立地为氢或C 1-4烷基；R 6e2独立地为氢或C 1-4烷基；R 6e3为C 1-4烷基。 Wherein R 6e1 is independently hydrogen or C 1-4 alkyl; R 6e2 is independently hydrogen or C 1-4 alkyl; and R 6e3 is C 1-4 alkyl.
  3. 如权利要求1或2所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中：The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, according to claim 1 or 2, wherein:
    当Y为O，X为C时，o和p为1；
    Figure PCTCN2018122557-appb-100005
    为单键或双键；m为0或1；n为0或1；或者，
    Figure PCTCN2018122557-appb-100006
    为单键或双键，m为0，p为1，n为0或1；     When Y is O and X is C, o and p are 1;
    Figure PCTCN2018122557-appb-100005
    Is a single bond or a double bond; m is 0 or 1; n is 0 or 1; or,
    Figure PCTCN2018122557-appb-100006
    Is a single bond or double bond, m is 0, p is 1, n is 0 or 1;
    当Y为O，X为O时，
    Figure PCTCN2018122557-appb-100007
    为单键；m和o为1；p为0或1；     When Y is O and X is O,
    Figure PCTCN2018122557-appb-100007
    Is a single bond; m and o are 1; p is 0 or 1;
    当X为O，Y为C时，
    Figure PCTCN2018122557-appb-100008
    为单键；m和p为1；n和o为0；     When X is O and Y is C,
    Figure PCTCN2018122557-appb-100008
    Is a single bond; m and p are 1; n and o are 0;
    当Y为O，X为CH 2O时，p为0，m和o为1；n为1或2。 When Y is O and X is CH 2 O, p is 0, m and o are 1; n is 1 or 2.
  4. 如权利要求1-3中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中：The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, according to any one of claims 1 to 3, wherein:
    当X为C时，R 0独立地为氢、F或羰基； When X is C, R 0 is independently hydrogen, F or carbonyl;
    当X为O时，R 0不存在。 When X is 0, R 0 does not exist.
  5. 如权利要求1-4中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中：The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, according to any one of claims 1 to 4, wherein:
    当Z为C时，R 1为H、F或甲基； When Z is C, R 1 is H, F or methyl;
    当Z为N时，R 1不存在。 When Z is N, R 1 does not exist.
  6. 如权利要求1-5中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中R 2为H或F。 The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein R 2 is H or F.
  7. 如权利要求1-6中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中R 3为H或F。 The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein R 3 is H or F.
  8. 如权利要求1-7中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中R 4为氢、甲基、氘代甲基、乙基、烯丙基、异丙基或二氟乙基。 The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein R 4 is hydrogen, or a solvate thereof, according to any one of claims 1 to 7 Methyl, deuterated methyl, ethyl, allyl, isopropyl or difluoroethyl.
  9. 如权利要求1-8中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中R 5为氢、甲基或氨基。 A pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein R 5 is hydrogen, or a solvate thereof, according to any one of claims 1 to 8 Methyl or amino.
  10. 如权利要求1-9任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中R 6为氢、卤素、氰基、C 1-8烷基、C 1-8卤代烷基或以下任一结构： The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein R 6 is hydrogen or halogen, according to any one of claims 1 to 9 , cyano, C 1-8 alkyl, C 1-8 haloalkyl or any of the following structures:
    Figure PCTCN2018122557-appb-100009
    Figure PCTCN2018122557-appb-100009
    其中，每个j独立地为0、1、2或3；k为0、1、2、3或4；每个l独立地为0、1或2；每个V独立地为C、N或O，且在同一环中最多同时有两个N或O；环A为含有1-3个杂原子的取代或未取代的C 5-10杂芳基；每个环B独立地为含有1-4个杂原子的取代或未取代的C 5-10杂芳基，其中所述杂原子独立地为N、O或S；Q为N、O或S。 Wherein each j is independently 0, 1, 2 or 3; k is 0, 1, 2, 3 or 4; each l is independently 0, 1 or 2; each V is independently C, N or O, and at most two N or O at the same time in the same ring; ring A is a substituted or unsubstituted C 5-10 heteroaryl group containing 1-3 heteroatoms; each ring B is independently 1- a substituted or unsubstituted C 5-10 heteroaryl group of 4 heteroatoms wherein the hetero atom is independently N, O or S; Q is N, O or S.
  11. 如权利要求1所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中，The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein
    当X为C时，R 0为卤素时，所述的卤素为氟； When X is C, when R 0 is halogen, the halogen is fluorine;
    和/或，当Z为C时，R 1为卤素时，所述的卤素为氟； And/or, when Z is C, when R 1 is halogen, the halogen is fluorine;
    和/或，当Z为C时，R 1为C 1-4烷基时，所述的C 1-4烷基为甲基； And/or, when Z is C, when R 1 is C 1-4 alkyl, the C 1-4 alkyl group is a methyl group;
    和/或，当R 2和R 3各自独立地为卤素时，所述的卤素为氟； And/or, when R 2 and R 3 are each independently halogen, the halogen is fluorine;
    和/或，当R 2和R 3各自独立地为C 1-4烷基时，所述的C 1-4烷基为甲基； And/or, when R 2 and R 3 are each independently C 1-4 alkyl, the C 1-4 alkyl group is a methyl group;
    和/或，当R 4为R 4a取代或未取代的C 1-4烷基时，所述的C 1-4烷基为甲基、乙基、正丙基或异丙基； And/or, when R 4 is R 4a substituted or unsubstituted C 1-4 alkyl, the C 1-4 alkyl group is methyl, ethyl, n-propyl or isopropyl;
    和/或，当R 4为R 4a取代或未取代的C 1-4卤代烷基时，所述的C 1-4卤代烷基为C 1-4氟代烷基； And/or, when R 4 is R 4a substituted or unsubstituted C 1-4 haloalkyl, the C 1-4 haloalkyl is C 1-4 fluoroalkyl;
    和/或，当R 4为C 2-6烯基时，所述C 2-6烯基为烯丙基； And/or, when R 4 is a C 2-6 alkenyl group, the C 2-6 alkenyl group is an allyl group;
    和/或，当R 4a为卤素时，所述的卤素为氟； And/or, when R 4a is halogen, the halogen is fluorine;
    和/或，当R 5为C 1-4烷基时，所述的C 1-4烷基为甲基； And/or, when R 5 is C 1-4 alkyl, the C 1-4 alkyl group is a methyl group;
    和/或，当R 6为卤素时，所述的卤素为氟、溴或碘； And/or, when R 6 is halogen, the halogen is fluorine, bromine or iodine;
    和/或，当R 6为R 6a取代或未取代的C 1-8烷基时，所述的C 1-8烷基为C 1-4烷基； And/or, when R 6 is R 6a substituted or unsubstituted C 1-8 alkyl, the C 1-8 alkyl group is C 1-4 alkyl;
    和/或，当R 6为C 1-8烷氧基时，所述C 1-8烷氧基为C 1-4烷氧基； And/or, when R 6 is a C 1-8 alkoxy group, the C 1-8 alkoxy group is a C 1-4 alkoxy group;
    和/或，当R 6为C 1-8卤代烷基时，所述的C 1-8卤代烷基为C 1-4卤代烷基； And/or, when R 6 is a C 1-8 haloalkyl group, the C 1-8 haloalkyl group is a C 1-4 haloalkyl group;
    和/或，当R 6为R 6a取代或未取代的C 3-8环烷基时，所述的C 3-8环烷基为环己基； And/or, when R 6 is R 6a substituted or unsubstituted C 3-8 cycloalkyl, the C 3-8 cycloalkyl is cyclohexyl;
    和/或，当R 6为R 6b取代或未取代的C 3-8环烷基时，所述的C 3-8环烷基为环己基； And/or, when R 6 is R 6b substituted or unsubstituted C 3-8 cycloalkyl, the C 3-8 cycloalkyl is cyclohexyl;
    和/或，当R 6为R 6b取代或未取代的C 3-8杂环基时，所述的C 3-8杂环基为具有1至3个独立选自氮、氧和硫的杂原子的C 3-8杂环基； And/or, when R 6 is a R 6b substituted or unsubstituted C 3-8 heterocyclic group, the C 3-8 heterocyclic group has 1 to 3 independently selected from nitrogen, oxygen and sulfur. a C 3-8 heterocyclic group of an atom;
    和/或，当R 6为R 6c取代或未取代的烯基时，所述的烯基为C 2-10烯基； And/or, when R 6 is R 6c substituted or unsubstituted alkenyl, the alkenyl group is a C 2-10 alkenyl group;
    和/或，当R 6为R 6b取代或未取代的C 5-8环烯基时，所述的C 5-8环烯基为
    Figure PCTCN2018122557-appb-100010
    And/or, when R 6 is a R 6b substituted or unsubstituted C 5-8 cycloalkenyl group, the C 5-8 cycloalkenyl group is
    Figure PCTCN2018122557-appb-100010
    和/或，当R 6为R 6b取代或未取代的C 5-8杂环烯基时，所述的C 5-8杂环烯基为具有1至3个独立选自氮、氧和硫的杂原子的C 5-8杂环烯基； And/or, when R 6 is a R 6b substituted or unsubstituted C 5-8 heterocycloalkenyl group, the C 5-8 heterocycloalkenyl group has 1 to 3 independently selected from nitrogen, oxygen and sulfur. a hetero atom of a C 5-8 heterocycloalkenyl group;
    和/或，当R 6为0-3个R 6e取代的C 6-10芳基时，所述的C 6-10芳基为苯基； And/or, when R 6 is 0-3 R 6e substituted C 6-10 aryl groups, the C 6-10 aryl group is a phenyl group;
    和/或，当R 6为0-3个R 6e取代的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”时，所述的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”为“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”； And/or when R 6 is 0-3 R 6e substituted "having a C 1-20 carbon atom and 1-4 heteroatoms independently selected from N, NR 6e1 , O and S(O) 0-2 "heteroaryl", said "heteroaryl having C 1-20 carbon atoms and 1-4 heteroatoms independently selected from N, NR 6e1 , O and S(O) 0-2 " a C 1-10 carbon atom and 1-4 heteroaryl groups independently selected from hetero atoms of N, NR 6e1 , O and S(O) 0-2 ";
    和/或，当R 6a为C 1-4烷基时，所述的C 1-4烷基为甲基； And/or, when R 6a is C 1-4 alkyl, the C 1-4 alkyl group is a methyl group;
    和/或，当R 6b为C 1-4烷基时，所述的C 1-4烷基为甲基； And/or, when R 6b is C 1-4 alkyl, the C 1-4 alkyl group is a methyl group;
    和/或，当R 6a为C 1-4卤代烷基时，所述的C 1-4卤代烷基为三氟甲基； And/or, when R 6a is a C 1-4 haloalkyl group, the C 1-4 haloalkyl group is a trifluoromethyl group;
    和/或，当R 6b为C 1-4卤代烷基时，所述的C 1-4卤代烷基为三氟甲基； And/or, when R 6b is a C 1-4 haloalkyl group, the C 1-4 haloalkyl group is a trifluoromethyl group;
    和/或，当R 6a为保护基团保护的氨基时，所述的保护基团为
    Figure PCTCN2018122557-appb-100011
    R 7b为C 1-4烷基或C 1-4烷氧基；     And/or, when R 6a is an amino group protected by a protecting group, the protecting group is
    Figure PCTCN2018122557-appb-100011
    R 7b is C 1-4 alkyl or C 1-4 alkoxy;
    和/或，当R 6b为保护基团保护的氨基时，所述的保护基团为
    Figure PCTCN2018122557-appb-100012
    R 7b为C 1-4烷基或C 1-4烷氧基；     And/or, when R 6b is an amino group protected by a protecting group, the protecting group is
    Figure PCTCN2018122557-appb-100012
    R 7b is C 1-4 alkyl or C 1-4 alkoxy;
    和/或，当R 6c为酯基时，所述的酯基为
    Figure PCTCN2018122557-appb-100013
    其中R 7c为C 1-4烷基；     And/or, when R 6c is an ester group, the ester group is
    Figure PCTCN2018122557-appb-100013
    Wherein R 7c is C 1-4 alkyl;
    和/或，当R 6d为C 1-20烷基时，所述的C 1-20烷基为C 1-8烷基； And/or, when R 6d is a C 1-20 alkyl group, the C 1-20 alkyl group is a C 1-8 alkyl group;
    和/或，当R 6d为R 7d取代或未取代的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”时，所述的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”为“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”； And/or when R 6d is R 7d substituted or unsubstituted, "having a C 1-20 carbon atom and 1-4 heteroatoms independently selected from N, NR 6e1 , O and S(O) 0-2 In the case of an aryl group, the "heteroaryl group having a C 1-20 carbon atom and 1-4 hetero atoms independently selected from N, NR 6e1 , O and S(O) 0-2 " is "having C" a 1-10 carbon atom and 1-4 heteroaryl groups independently selected from hetero atoms of N, NR 6e1 , O and S(O) 0-2 ";
    和/或，当R 7d为卤素时，所述的卤素为氟或氯； And/or, when R 7d is halogen, the halogen is fluorine or chlorine;
    和/或，当R 7d为C 1-4卤代烷基时，所述的C 1-4卤代烷基为三氟甲基； And/or, when R 7d is a C 1-4 haloalkyl group, the C 1-4 haloalkyl group is a trifluoromethyl group;
    和/或，当R 6e为卤素时，所述的卤素为氟或氯； And/or, when R 6e is halogen, the halogen is fluorine or chlorine;
    和/或，当R 6e为R 4a取代或未取代的C 1-4烷氧基时，所述的C 1-4烷氧基为甲氧基； And/or, when R 6e is a substituted or unsubstituted C 1-4 alkoxy group of R 4a , the C 1-4 alkoxy group is a methoxy group;
    和/或，当R 6e为R 4a取代或未取代的C 1-4烷基时，所述的C 1-4烷基为甲基、乙基、正丙基或异丙基； And/or, when R 6e is R 4a substituted or unsubstituted C 1-4 alkyl, the C 1-4 alkyl group is methyl, ethyl, n-propyl or isopropyl;
    和/或，当R 6e为-C(＝O)NR 6e1R 6e2时，所述的-C(＝O)NR 6e1R 6e2为-C(＝O)NH 2； And/or, when R 6e is -C(=O)NR 6e1 R 6e2 , the -C(=O)NR 6e1 R 6e2 is -C(=O)NH 2 ;
    和/或，当R 6e为-S(＝O) 2R 6e3时，所述的-S(＝O) 2R 6e3为-S(＝O) 2Me； And/or, when R 6e is -S(=O) 2 R 6e3 , the -S(=O) 2 R 6e3 is -S(=O) 2 Me;
    和/或，当R 6e为NR 6e1R 6e2时，所述的NR 6e1R 6e2为-NH 2； And/or, when R 6e is NR 6e1 R 6e2 , the NR 6e1 R 6e2 is -NH 2 ;
    和/或，当R 6e为R 7e取代或未取代的C 3-10环烷基时，所述的C 3-10环烷基为C 3-8环烷基； And/or, when R 6e is a R 7e substituted or unsubstituted C 3-10 cycloalkyl group, the C 3-10 cycloalkyl group is a C 3-8 cycloalkyl group;
    和/或，当R 6e为R 7e取代或未取代的“具有C 1-20碳原子及1-4个独立选自NR 6e1、O和S(O) 0-2的杂原子的杂环基”时，所述的“具有C 1-20碳原子及1-4个独立选自NR 6e1、O和S(O) 0-2的杂原子的杂环基”为“具有C 1-10碳原子及1-4个独立选自NR 6e1、O和S(O) 0-2的杂原子的杂环基”。 And/or when R 6e is R 7e substituted or unsubstituted heterocyclic group having a C 1-20 carbon atom and 1-4 hetero atoms independently selected from NR 6e1 , O and S(O) 0-2 "the heterocyclic group having a C 1-20 carbon atom and 1-4 hetero atoms independently selected from NR 6e1 , O and S(O) 0-2 " is "having a C 1-10 carbon" Atom and 1-4 heterocyclic groups independently selected from heteroatoms of NR 6e1 , O and S(O) 0-2 ".
  12. 如权利要求11所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中，The pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the salt, according to claim 11, wherein
    当R 4为R 4a取代或未取代的C 1-4卤代烷基时，所述的C 1-4卤代烷基为2,2-二氟乙基； When R 4 is R 4a substituted or unsubstituted C 1-4 haloalkyl, the C 1-4 haloalkyl is 2,2-difluoroethyl;
    和/或，当R 6为R 6a取代或未取代的C 1-8烷基时，所述的C 1-8烷基为甲基、乙基、正丙基或异丙基； And/or, when R 6 is R 6a substituted or unsubstituted C 1-8 alkyl, the C 1-8 alkyl group is methyl, ethyl, n-propyl or isopropyl;
    和/或，当R 6为C 1-8烷氧基时，所述的C 1-8烷氧基为甲氧基、乙氧基、正丙氧基或异丙氧基； And/or, when R 6 is a C 1-8 alkoxy group, the C 1-8 alkoxy group is a methoxy group, an ethoxy group, a n-propoxy group or an isopropoxy group;
    和/或，当R 6为R 6b取代或未取代的C 3-8杂环基时，所述的C 3-8杂环基为
    Figure PCTCN2018122557-appb-100014
    And/or, when R 6 is a R 6b substituted or unsubstituted C 3-8 heterocyclic group, the C 3-8 heterocyclic group is
    Figure PCTCN2018122557-appb-100014
    和/或，当R 6为R 6c取代或未取代的烯基时，所述的烯基为C 2-6烯基； And/or, when R 6 is R 6c substituted or unsubstituted alkenyl, the alkenyl group is a C 2-6 alkenyl group;
    和/或，当R 6为R 6b取代或未取代的C 5-8杂环烯基时，所述的C 5-8杂环烯基为
    Figure PCTCN2018122557-appb-100015
    Figure PCTCN2018122557-appb-100016
    And/or, when R 6 is a R 6b substituted or unsubstituted C 5-8 heterocycloalkenyl group, the C 5-8 heterocycloalkenyl group is
    Figure PCTCN2018122557-appb-100015
    Figure PCTCN2018122557-appb-100016
    和/或，当R 6为“0-3个R 6e取代的具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”时，所述的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”为“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0- 2的杂原子的5-12元杂芳基”，例如
    Figure PCTCN2018122557-appb-100017
    Figure PCTCN2018122557-appb-100018
    And/or when R 6 is "0-3 R 6e substituted heteroatoms having a C 1-20 carbon atom and 1-4 independently selected from N, NR 6e1 , O and S(O) 0-2 "heteroaryl", said "heteroaryl having C 1-20 carbon atoms and 1-4 heteroatoms independently selected from N, NR 6e1 , O and S(O) 0-2 " C 1-10 carbon atoms and 1-4 heteroatoms independently selected from N, NR 6e1, O, and S (O) 0-2 heteroatoms 5-12 membered heteroaryl ", e.g.
    Figure PCTCN2018122557-appb-100017
    Figure PCTCN2018122557-appb-100018
    和/或，当R 6a为保护基团保护的氨基时，所述的保护基团为叔丁氧羰基； And/or, when R 6a is an amino group protected by a protecting group, the protecting group is a tert-butoxycarbonyl group;
    和/或，当R 6d为C 1-20烷基时，所述的C 1-20烷基为C 1-6烷基； And/or, when R 6d is a C 1-20 alkyl group, the C 1-20 alkyl group is a C 1-6 alkyl group;
    和/或，当R 6d为R 7d取代或未取代的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”时，所述的“具有C 1-20碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的杂芳基”为“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的5-12元杂芳基”； And/or when R 6d is R 7d substituted or unsubstituted, "having a C 1-20 carbon atom and 1-4 heteroatoms independently selected from N, NR 6e1 , O and S(O) 0-2 In the case of an aryl group, the "heteroaryl group having a C 1-20 carbon atom and 1-4 hetero atoms independently selected from N, NR 6e1 , O and S(O) 0-2 " is "having C" a 1-10 carbon atom and 1-4 5-12 membered heteroaryl groups independently selected from the heteroatoms of N, NR 6e1 , O and S(O) 0-2 ";
    和/或，当R 6e为R 7e取代或未取代的“具有C 1-20碳原子及1-4个独立选自NR 6e1、O和S(O) 0-2的杂原子的杂环基”时，所述的“具有C 1-20碳原子及1-4个独立选自NR 6e1、O和S(O) 0-2的杂原子的杂环基”为“具有C 1-10碳原子及1-4个独立选自N、NR 6e1、O和S(O) 0-2的杂原子的5-12元杂环基”，例如
    Figure PCTCN2018122557-appb-100019
    And/or when R 6e is R 7e substituted or unsubstituted heterocyclic group having a C 1-20 carbon atom and 1-4 hetero atoms independently selected from NR 6e1 , O and S(O) 0-2 "the heterocyclic group having a C 1-20 carbon atom and 1-4 hetero atoms independently selected from NR 6e1 , O and S(O) 0-2 " is "having a C 1-10 carbon" An atom and a 5-12 membered heterocyclic group of 1-4 independently selected from N, NR 6e1 , O and S(O) 0-2 , for example,
    Figure PCTCN2018122557-appb-100019
  13. 如权利要求1所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中，The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein
    式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100020
    为
    Figure PCTCN2018122557-appb-100021
    Figure PCTCN2018122557-appb-100022
    In the pyrimidinone compound represented by the formula (I)
    Figure PCTCN2018122557-appb-100020
    for
    Figure PCTCN2018122557-appb-100021
    Figure PCTCN2018122557-appb-100022
    和/或，R 6为氢、氟、溴、碘、甲基、乙基、异丙基、环丙基、氰基、甲氧基、
    Figure PCTCN2018122557-appb-100023
    Figure PCTCN2018122557-appb-100024
    And/or R 6 is hydrogen, fluorine, bromine, iodine, methyl, ethyl, isopropyl, cyclopropyl, cyano, methoxy,
    Figure PCTCN2018122557-appb-100023
    Figure PCTCN2018122557-appb-100024
  14. 如权利要求13所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中，The pyrimidinone compound represented by the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the salt, according to claim 13, wherein
    当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100025
    为
    Figure PCTCN2018122557-appb-100026
    时，
    Figure PCTCN2018122557-appb-100027
    为
    Figure PCTCN2018122557-appb-100028
    In the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100025
    for
    Figure PCTCN2018122557-appb-100026
    Time,
    Figure PCTCN2018122557-appb-100027
    for
    Figure PCTCN2018122557-appb-100028
    和/或，当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100029
    为
    Figure PCTCN2018122557-appb-100030
    时，
    Figure PCTCN2018122557-appb-100031
    为
    Figure PCTCN2018122557-appb-100032
    And/or, in the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100029
    for
    Figure PCTCN2018122557-appb-100030
    Time,
    Figure PCTCN2018122557-appb-100031
    for
    Figure PCTCN2018122557-appb-100032
    和/或，当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100033
    为
    Figure PCTCN2018122557-appb-100034
    时，
    Figure PCTCN2018122557-appb-100035
    为
    Figure PCTCN2018122557-appb-100036
    And/or, in the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100033
    for
    Figure PCTCN2018122557-appb-100034
    Time,
    Figure PCTCN2018122557-appb-100035
    for
    Figure PCTCN2018122557-appb-100036
    和/或，当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100037
    为
    Figure PCTCN2018122557-appb-100038
    时，
    Figure PCTCN2018122557-appb-100039
    为
    Figure PCTCN2018122557-appb-100040
    And/or, in the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100037
    for
    Figure PCTCN2018122557-appb-100038
    Time,
    Figure PCTCN2018122557-appb-100039
    for
    Figure PCTCN2018122557-appb-100040
    和/或，当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100041
    为
    Figure PCTCN2018122557-appb-100042
    时，
    Figure PCTCN2018122557-appb-100043
    为
    Figure PCTCN2018122557-appb-100044
    And/or, in the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100041
    for
    Figure PCTCN2018122557-appb-100042
    Time,
    Figure PCTCN2018122557-appb-100043
    for
    Figure PCTCN2018122557-appb-100044
    和/或，当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100045
    为
    Figure PCTCN2018122557-appb-100046
    时，
    Figure PCTCN2018122557-appb-100047
    为
    Figure PCTCN2018122557-appb-100048
    And/or, in the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100045
    for
    Figure PCTCN2018122557-appb-100046
    Time,
    Figure PCTCN2018122557-appb-100047
    for
    Figure PCTCN2018122557-appb-100048
    和/或，当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100049
    为
    Figure PCTCN2018122557-appb-100050
    时，
    Figure PCTCN2018122557-appb-100051
    为
    Figure PCTCN2018122557-appb-100052
    And/or, in the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100049
    for
    Figure PCTCN2018122557-appb-100050
    Time,
    Figure PCTCN2018122557-appb-100051
    for
    Figure PCTCN2018122557-appb-100052
    和/或，当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100053
    为
    Figure PCTCN2018122557-appb-100054
    时，
    Figure PCTCN2018122557-appb-100055
    为
    Figure PCTCN2018122557-appb-100056
    And/or, in the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100053
    for
    Figure PCTCN2018122557-appb-100054
    Time,
    Figure PCTCN2018122557-appb-100055
    for
    Figure PCTCN2018122557-appb-100056
    和/或，当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100057
    为
    Figure PCTCN2018122557-appb-100058
    时，
    Figure PCTCN2018122557-appb-100059
    为
    Figure PCTCN2018122557-appb-100060
    And/or, in the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100057
    for
    Figure PCTCN2018122557-appb-100058
    Time,
    Figure PCTCN2018122557-appb-100059
    for
    Figure PCTCN2018122557-appb-100060
    和/或，当式(I)所示的嘧啶酮化合物中的
    Figure PCTCN2018122557-appb-100061
    为
    Figure PCTCN2018122557-appb-100062
    时，
    Figure PCTCN2018122557-appb-100063
    为
    Figure PCTCN2018122557-appb-100064
    And/or, in the pyrimidinone compound represented by formula (I)
    Figure PCTCN2018122557-appb-100061
    for
    Figure PCTCN2018122557-appb-100062
    Time,
    Figure PCTCN2018122557-appb-100063
    for
    Figure PCTCN2018122557-appb-100064
  15. 如权利要求1所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中所述如式(I)所示的嘧啶酮化合物选自下列任一结构：The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein the pyrimidine of the formula (I) The ketone compound is selected from any of the following structures:
    Figure PCTCN2018122557-appb-100065
    Figure PCTCN2018122557-appb-100065
    Figure PCTCN2018122557-appb-100066
    Figure PCTCN2018122557-appb-100066
    其中，n、R 0、R 1、R 2、R 3、R 4、R 5、R 6和
    Figure PCTCN2018122557-appb-100067
    的定义如权利要求1-12中任一项所述。     Wherein n, R 0 , R 1 , R 2 , R 3 , R 4 , R 5 , R 6 and
    Figure PCTCN2018122557-appb-100067
    The definition is as set forth in any one of claims 1-12.
  16. 如权利要求1所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，其中所述如式(I)所示的嘧啶酮化合物选自下列任一化合物：The pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, wherein the pyrimidine of the formula (I) The ketone compound is selected from any of the following compounds:
    Figure PCTCN2018122557-appb-100068
    Figure PCTCN2018122557-appb-100068
    Figure PCTCN2018122557-appb-100069
    Figure PCTCN2018122557-appb-100069
    Figure PCTCN2018122557-appb-100070
    Figure PCTCN2018122557-appb-100070
    Figure PCTCN2018122557-appb-100071
    Figure PCTCN2018122557-appb-100071
    Figure PCTCN2018122557-appb-100072
    Figure PCTCN2018122557-appb-100072
    Figure PCTCN2018122557-appb-100073
    Figure PCTCN2018122557-appb-100073
  17. 一种如权利要求1-16中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物的同位素标记化合物，所述的同位素选自 2H、 3H、 11C、 13C、 14C、 15N、 18F、 31P、 32P、 35S、 36Cl和 125I。 A pyrimidone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt thereof, according to any one of claims 1 to 16, The isotope is selected from the group consisting of 2 H, 3 H, 11 C, 13 C, 14 C, 15 N, 18 F, 31 P, 32 P, 35 S, 36 Cl and 125 I.
  18. 一种如式(I)所示的嘧啶酮化合物的制备方法，其包括如下步骤：A method for preparing a pyrimidinone compound represented by formula (I), which comprises the steps of:
    将化合物A进行偶联反应后得到如式(I)所示的嘧啶酮化合物；The compound A is subjected to a coupling reaction to obtain a pyrimidinone compound represented by the formula (I);
    Figure PCTCN2018122557-appb-100074
    Figure PCTCN2018122557-appb-100074
    其中，W为卤素，优选Br或I；R 1、R 2、R 3、R 4、R 5、X、Y、Z、
    Figure PCTCN2018122557-appb-100075
    m、n、 o、p、R 0和R 6的定义如权利要求1-16中任一项所述。     Wherein W is halogen, preferably Br or I; R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
    Figure PCTCN2018122557-appb-100075
    m, n, o, p, R 0 and R 6 are as defined in any one of claims 1-16.
  19. 一种化合物A的制备方法，其包括如下步骤：A method for preparing a compound A, comprising the steps of:
    化合物B在碱性条件下被化合物C取代得到化合物A；Compound B is substituted with compound C under basic conditions to obtain compound A;
    Figure PCTCN2018122557-appb-100076
    Figure PCTCN2018122557-appb-100076
    其中，W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、
    Figure PCTCN2018122557-appb-100077
    m、n、o、p和R 0的定义如权利要求18所述。     Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
    Figure PCTCN2018122557-appb-100077
    The definitions of m, n, o, p and R 0 are as set forth in claim 18.
  20. 一种化合物A的制备方法，其包括如下步骤：A method for preparing a compound A, comprising the steps of:
    化合物D在活性试剂活化后被化合物C取代得到化合物A；Compound D is substituted with compound C after activation of the active agent to obtain compound A;
    Figure PCTCN2018122557-appb-100078
    Figure PCTCN2018122557-appb-100078
    其中，W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、
    Figure PCTCN2018122557-appb-100079
    m、n、o、p和R 0的定义如权利要求18所述。     Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
    Figure PCTCN2018122557-appb-100079
    The definitions of m, n, o, p and R 0 are as set forth in claim 18.
  21. 一种化合物B的制备方法，其包括如下步骤：A method for preparing a compound B, comprising the steps of:
    化合物B-a在碱性条件下转变成化合物B-b；化合物B-b氮烷基化取代后得到化合物B；Compound B-a is converted to compound B-b under basic conditions; compound B-b is substituted by nitrogen alkylation to obtain compound B;
    Figure PCTCN2018122557-appb-100080
    Figure PCTCN2018122557-appb-100080
    其中，W、R 4和R 5的定义如权利要求18所述。 Wherein, W, R 4 and R 5 are as defined in claim 18.
  22. 一种化合物B的制备方法，其包括如下步骤：A method for preparing a compound B, comprising the steps of:
    化合物B-c经过适当的保护基，例如Boc、二苯甲基等，保护后得到化合物B-d；化合物B-d在碱性条件下烷基化得到化合物B-e；然后，化合物B-e脱保护得到化合物B-f后转化成化合物B；Compound Bc is protected with a suitable protecting group, such as Boc, diphenylmethyl, etc., to obtain compound Bd; compound Bd is alkylated under basic conditions to obtain compound Be; then, compound Be is deprotected to obtain compound Bf and then converted into compound B;
    Figure PCTCN2018122557-appb-100081
    Figure PCTCN2018122557-appb-100081
    其中，W、R 4和R 5的定义如权利要求18所述。 Wherein, W, R 4 and R 5 are as defined in claim 18.
  23. 一种化合物D的制备方法，其包括如下步骤：A method for preparing a compound D, comprising the steps of:
    通过对化合物D-a进行卤代反应来制备：Prepared by halogenation of compound D-a:
    Figure PCTCN2018122557-appb-100082
    Figure PCTCN2018122557-appb-100082
    其中，W、R 4和R 5的定义如权利要求18所述。 Wherein, W, R 4 and R 5 are as defined in claim 18.
  24. 一种化合物，其结构为：a compound whose structure is:
    Figure PCTCN2018122557-appb-100083
    Figure PCTCN2018122557-appb-100083
    其中W、R 1、R 2、R 3、R 4、R 5、X、Y、Z、
    Figure PCTCN2018122557-appb-100084
    m、n、o、p、R 0和R 6d的定义如权利要求18所述。     Wherein W, R 1 , R 2 , R 3 , R 4 , R 5 , X, Y, Z,
    Figure PCTCN2018122557-appb-100084
    m, n, o, p, R 0 and R 6d are as defined in claim 18.
  25. 一种如权利要求1-16中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如权利要求17所述的同位素标记化合物在制备用于治疗与EED蛋白和/或PRC2蛋白复合物作用机理相关的癌症的药物中的 应用。A pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, according to any one of claims 1 to 16, or as claimed Use of the isotopically labeled compound of 17 for the preparation of a medicament for the treatment of a cancer associated with the mechanism of action of an EED protein and/or PRC2 protein complex.
  26. 一种如权利要求25所述的应用，其中所述癌症选自扩散大B细胞淋巴癌、滤泡性淋巴瘤等淋巴癌、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝癌、***癌、乳腺癌、脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、***、结肠癌、黑色素瘤、子宫内膜癌、食管癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾癌、直肠癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤。An application according to claim 25, wherein said cancer is selected from the group consisting of diffusing large B-cell lymphoma, follicular lymphoma and other lymphoma, leukemia, multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor , liver cancer, prostate cancer, breast cancer, brain tumors including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer, colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck Cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma.
  27. 一种药物组合物，其包含如权利要求1-16中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如权利要求17所述的同位素标记化合物，以及药学上可接受的辅料。A pharmaceutical composition comprising the pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvent of the salt, according to any one of claims 1 to 16. A compound, or an isotopically labeled compound according to claim 17, and a pharmaceutically acceptable adjuvant.
  28. 一种药物制剂，其包含如权利要求1-16中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如权利要求17所述的同位素标记化合物，所述药物制剂选自片剂、胶囊、药丸、粉末、颗粒、酏剂、酊剂、悬浮物、糖浆、乳液和溶液。A pharmaceutical preparation comprising the pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof, or a solvate thereof, or a solvate of the salt, according to any one of claims 1 to 16. Or an isotope-labeled compound according to claim 17, which is selected from the group consisting of a tablet, a capsule, a pill, a powder, a granule, an elixir, an elixir, a suspension, a syrup, an emulsion, and a solution.
  29. 一种如权利要求28所述的药物制剂，其中所述药物制剂的给予方式选自口服、舌下含服、皮下注射、静脉注射、肌肉注射、胸骨内注射、鼻部服用、局部表面给药和直肠给药。A pharmaceutical preparation according to claim 28, wherein the pharmaceutical preparation is administered in a form selected from the group consisting of oral administration, sublingual administration, subcutaneous injection, intravenous injection, intramuscular injection, intrasternal injection, nasal administration, topical surface administration. And rectal administration.
  30. 一种如权利要求28或29所述的药物制剂，其中所述药物制剂每天单次服用或多次服用。A pharmaceutical preparation according to claim 28 or 29, wherein the pharmaceutical preparation is administered in a single administration or multiple times a day.
  31. 一种如权利要求1-16中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如权利要求17所述的同位素标记化合物与其他药物联合使用，所述其他药物选自抗癌药、肿瘤免疫药物、抗过敏药、止吐药、镇痛药和细胞保护药物。A pyrimidinone compound of the formula (I), a pharmaceutically acceptable salt thereof or a solvate thereof, or a solvate of the salt, according to any one of claims 1 to 16, or as claimed The isotopically labeled compound described in 17 is used in combination with other drugs selected from the group consisting of anticancer drugs, tumor immunopharmaceuticals, antiallergic agents, antiemetics, analgesics, and cytoprotective drugs.
  32. 一种治疗癌症的方法，其包括向需要此治疗的患者给予治疗有效量的如权利要求1-16中任一项所述的如式(I)所示的嘧啶酮化合物、其药学上可接受的盐或其溶剂化物、或该盐的溶剂化物，或如权利要求17所述的同位素标记化合物，所述的癌症可以选自扩散大B细胞淋巴癌、滤泡性淋巴瘤等淋巴癌、白血病、多发性骨髓瘤、间皮瘤、胃癌、恶性横纹肌样瘤、肝癌、***癌、乳腺癌、脑瘤包括神经母细胞瘤、胶质瘤、胶质母细胞瘤和星形细胞瘤、***、结肠癌、黑色素瘤、子宫内膜癌、食管癌、头颈癌、肺癌、鼻咽癌、卵巢癌、胰腺癌、肾癌、直肠癌、甲状腺癌、甲状旁腺肿瘤、子宫肿瘤和软组织肉瘤。A method of treating cancer comprising administering to a patient in need of such treatment a therapeutically effective amount of a pyrimidinone compound of formula (I) according to any one of claims 1 to 16, which is pharmaceutically acceptable a salt or a solvate thereof, or a solvate of the salt, or an isotopically-labeled compound according to claim 17, wherein the cancer may be selected from the group consisting of diffusing large B-cell lymphoma, follicular lymphoma, and the like, lymphoma, leukemia , multiple myeloma, mesothelioma, gastric cancer, malignant rhabdoid tumor, liver cancer, prostate cancer, breast cancer, brain tumor including neuroblastoma, glioma, glioblastoma and astrocytoma, cervical cancer Colon cancer, melanoma, endometrial cancer, esophageal cancer, head and neck cancer, lung cancer, nasopharyngeal cancer, ovarian cancer, pancreatic cancer, kidney cancer, rectal cancer, thyroid cancer, parathyroid tumor, uterine tumor and soft tissue sarcoma.
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