WO2020135210A1 - 取代芳基化合物及其制备方法和用途 - Google Patents

取代芳基化合物及其制备方法和用途 Download PDF

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WO2020135210A1
WO2020135210A1 PCT/CN2019/126555 CN2019126555W WO2020135210A1 WO 2020135210 A1 WO2020135210 A1 WO 2020135210A1 CN 2019126555 W CN2019126555 W CN 2019126555W WO 2020135210 A1 WO2020135210 A1 WO 2020135210A1
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alkyl
compound
membered
methyl
ring
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French (fr)
Inventor
刘金明
何婷
蔡家强
李晓勇
罗小勇
田强
宋宏梅
薛彤彤
王利春
王晶翼
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Sichuan Kelun Biotech Biopharmaceutical Co Ltd
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Priority to EP19903101.4A priority Critical patent/EP3904352A4/en
Priority to CN201980071452.XA priority patent/CN113166119B/zh
Priority to US17/289,520 priority patent/US20210395226A1/en
Priority to JP2021523388A priority patent/JP2022515309A/ja
Priority to KR1020217012882A priority patent/KR20210110288A/ko
Publication of WO2020135210A1 publication Critical patent/WO2020135210A1/zh
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/72—Nitrogen atoms
    • C07D213/75—Amino or imino radicals, acylated by carboxylic or carbonic acids, or by sulfur or nitrogen analogues thereof, e.g. carbamates
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom 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 ring carbon atoms
    • C07D213/78—Carbon atoms having three bonds to hetero atoms, with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/84—Nitriles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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

Definitions

  • the present application relates to substituted aryl compounds or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotope-labeled compounds, metabolites, or prodrugs, and methods for their preparation and use.
  • the present application also relates to pharmaceutical compositions containing said compounds and their therapeutic uses.
  • Adenosine is a signaling molecule that suppresses inflammation and immune response in vivo.
  • Adenosine receptors are G protein-coupled receptors (GPCRs).
  • GPCRs G protein-coupled receptors
  • the family of receptors includes A1, A2a, A2b, and A3 receptors. Among them, A2a and A2b receptors are coupled to Gs protein that activates adenylate cyclase, stimulating the production of intracellular cyclic adenosine phosphate (cAMP).
  • Adenosine A2a receptors are expressed on the surface of some cells in the immune system, such as T cells, NK cells, macrophages and dendritic cells.
  • the adenosine produced by the tumor can interact with the adenosine A2a receptor on the surface of the immune cell infiltrated by the tumor tissue, which increases the amount of cAMP in the immune cell, inhibits the ability of the immune cell to attack the tumor, and makes the body immune tolerance, which in turn causes the tumor cell
  • the ability to evade the body's immune surveillance is mainly manifested in two aspects: (1) blocking the activation and function of immune cells that can kill tumor cells; (2) increasing the regulatory T cells that can suppress the response of immune cells to tumor cells (T- regs) quantity.
  • Adenosine A2a receptor knockout mice can enhance the anti-tumor immunity of CD8+ T cells and significantly inhibit tumor proliferation. Transplantation of melanoma or lymphoma cells into wild-type mice is more effective than transplantation into adenosine A2a. Somatic knockout mice are more likely to grow in vivo, and adenosine A2a receptor knockout mice have a better response to tumor vaccines.
  • Adenosine A2a receptors are expressed at high levels on immune cells.
  • the activation of adenosine A2a receptors can promote the body's immune tolerance and promote the formation of "immune escape” or "immunosuppression” of tumor cells, which has created the development of tumors.
  • Adenosine A2a receptor antagonist directly targets the adenosine A2a receptor on the surface of immune cells, inhibits the activation of this receptor, thereby inhibits the production of cAMP in immune cells, and eliminates T cell immune function mediated by adenosine A2a receptor activation Inhibit to achieve the effect of tumor treatment. Therefore, adenosine A2a receptor antagonists have good application prospects as tumor therapeutic drugs in the pharmaceutical industry.
  • Corvus's CPI-444 is a compound that antagonizes the adenosine A2a receptor. The indication is tumor. Prior to this, CPI-444 was used in clinical trials for the treatment of central nervous system diseases.
  • WO01/62233 discloses that the aminopyridine compound has an antagonistic effect on adenosine A2a receptors, and discloses that it can be used as a therapeutic agent for Parkinson's disease or Alzheimer's disease.
  • WO2011/095625 A1 discloses that an aminotriazine compound has an antagonistic effect on adenosine A2a receptors, and discloses that it can be used as a therapeutic agent for dyskinesia, stroke, or Parkinson's disease.
  • adenosine A2a receptor antagonists have good application prospects as pharmaceuticals in the pharmaceutical industry.
  • adenosine A2a receptor antagonists In order to achieve better tumor treatment effects and better meet market demand, there is an urgent need to develop adenosine A2a receptor antagonists for the treatment of tumors, especially with low central nervous system toxicity.
  • the present application relates to a compound represented by formula I or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug,
  • X 1 is N or CR 3 ;
  • X 2 is N or CR 4 ;
  • Ring A 1 is selected from C 3-10 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl and 5-10 membered heteroaryl, said ring A 1 is optionally separated by one or more Substituently selected from the following substituents: halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-10 cycloalkyl, hydroxy, C 1-6 alkoxy, amino , C 1-6 alkyl-amino- and di(C 1-6 alkyl)-amino- and 4-12 membered heterocyclic groups;
  • Ring A 2 is selected from C 3-10 cycloalkyl, 4-12 membered heterocyclic group, C 6-10 aryl group and 5-10 membered heteroaryl group (preferably, the 5-10 membered heteroaryl group is 5 -10 membered nitrogen-containing heteroaryl), the ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, nitro, C 1-6 alkyl, C 1 -6 haloalkyl, C 3-10 cycloalkyl, hydroxy, C 1-6 alkoxy, amino, C 1-6 alkyl-amino- and di(C 1-6 alkyl)-amino- and 4- 12-membered heterocyclic group, and ring A 2 is not 1-isopropyl-6-oxo-1,6-dihydropyridin-3-yl;
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 3-10 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-12 membered heterocyclyl-C 1-6 alkyl- or 5-10 membered heteroaryl-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 3-10 cycloalkyl, 4-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl, 4-12 membered heterocyclyl-C 1-6 alkyl- or 5-10 membered heteroaryl-C 1- 6 alkyl-optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy , C 3-10 cycloalkyl and 4-12 membered heterocyclyl; or,
  • R 1 and R 2 together with the nitrogen atom to which they are connected together form a 4-12 membered nitrogen-containing heterocyclic group (preferably, the 4-12 membered nitrogen-containing heterocyclic group contains one or more heteroatoms selected from nitrogen and oxygen ), the 4-12 membered nitrogen-containing heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkane Group, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkoxy-, C 3-10 cycloalkyl And 4-12 membered heterocyclic groups;
  • R 3 and R 4 are each independently selected from hydrogen, halo, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl , C 1-6 alkyl-amino- and di(C 1-6 alkyl)-amino-, and
  • the compound is not the following compound:
  • the compounds described herein have the structure represented by Formula IIa, Formula IIb, or Formula IIc,
  • ring A 1 , ring A 2 , R 1 , R 2 , R 3 and R 4 is as described in this application.
  • the compounds described herein have the structure represented by Formula IIa, Formula IIb, or Formula IIc, wherein Ring A 1 , Ring A 2 , R 3, and R 4 are as defined in this application,
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 4-7 membered Heterocyclyl-C 1-6 alkyl- or 5-6 membered heteroaryl-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, 4-8 membered Heterocyclyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl-C 1-6 alkyl- or 5-6 membered heteroaryl-C 1-6 alkyl-optionally One or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3-6 cycloalkyl And a 4-7 membered heterocyclic group; or,
  • R 1 and R 2 together with the nitrogen atom to which they are connected together form a 4-12 membered nitrogen-containing heterocyclic group (eg 4-6 membered nitrogen-containing heterocyclic group), the 4-12 membered nitrogen-containing heterocyclic group (eg 4- 6-membered nitrogen-containing heterocyclic group) is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkoxy-, C 3- 10 cycloalkyl and 4-12 member Heterocyclyl.
  • substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1- 6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl-, C 1-6 alkoxy-C
  • the cyclic group contains one or more heteroatoms selected from nitrogen and oxygen
  • the 4-12 membered nitrogen-containing heterocyclic group eg, 4-6 membered nitrogen-containing heterocyclic group
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: ring A 1 is selected from phenyl and 5-6 membered heteroaryl, said ring A 1 is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, nitro , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 4-7 membered heterocyclyl.
  • ring A 1 is selected from phenyl, furan-2-yl and furan-3-yl, said ring A 1 is optionally substituted by one or more substituents independently selected from the group consisting of fluorine, chlorine , Bromine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: ring A 1 is selected from phenyl and furan-2-yl, said ring A 1 is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine, cyano, Nitro, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl.
  • Ring A 1 is selected from phenyl, 4-fluorophenyl, 4-ethylphenyl, 4-nitrophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-methylphenyl , 2-methylphenyl, 3-methylphenyl, 5-methyl-furan-2-yl, 3-methyl-furan-2-yl and 4-methyl-furan-2-yl.
  • Ring A 1 is selected from phenyl, 4-fluorophenyl, 4-ethylphenyl.
  • Ring A 1 is selected from 4-nitrophenyl, 2-fluorophenyl, 3-fluorophenyl.
  • Ring A 1 is selected from 4-methylphenyl, 2-methylphenyl, 3-methylphenyl.
  • Ring A 1 is selected from 5-methyl-furan-2-yl, 3-methyl-furan-2-yl and 4-methyl-furan-2-yl.
  • Ring A 1 is selected from 4-fluorophenyl and 5-methyl-furan-2-yl.
  • ring A 2 is selected from C 6-10 aryl and 5-10 membered heteroaryl, said ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyanide Group, nitro group, C 1-6 alkyl group, C 1-6 haloalkyl group, C 3-6 cycloalkyl group and 4-7 membered heterocyclic group.
  • ring A 2 is selected from C 6-10 aryl and 5-10 membered nitrogen-containing heteroaryl, said ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of: halogen , Cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 4-7 membered heterocyclyl.
  • ring A 2 is selected from phenyl, pyridyl and quinazolinyl, said ring A 2 is optionally substituted by one or more substituents independently selected from the group consisting of halogen, cyano, nitro , C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 4-7 membered heterocyclyl.
  • Ring A 2 is selected from phenyl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, quinazolin-2-yl, quinazolin-4-yl, quinazoline- 5-yl, quinazolin-6-yl, quinazolin-7-yl and quinazolin-8-yl, the ring A 2 is optionally substituted with one or more substituents independently selected from : Halogen, cyano, nitro, C 1-6 alkyl, C 1-6 haloalkyl, C 3-6 cycloalkyl and 4-7 membered heterocyclic group.
  • ring A 2 is selected from phenyl, pyridin-4-yl and quinazolin-6-yl, said ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of: fluorine , Chlorine, bromine, cyano, nitro, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl.
  • ring A 2 is selected from phenyl, pyridin-4-yl and quinazolin-6-yl, said ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of: fluorine , Chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: ring A 2 is selected from phenyl, pyridin-4-yl and quinazolin-6-yl, said ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of: chlorine , Methyl, trifluoromethyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: ring A 2 is selected from pyridin-4-yl and quinazolin-6-yl, said ring A 2 is optionally substituted by one or more substituents independently selected from the group consisting of: chlorine, methyl .
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: Ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of fluorine and chlorine.
  • Ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of bromine, cyano, nitro, methyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: Ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of ethyl, n-propyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: Ring A 2 is optionally substituted with one or more substituents independently selected from the group consisting of isopropyl and trifluoromethyl.
  • Ring A 2 is selected from 3-chloro-5-methylphenyl, 2-chloro-6-methylpyridin-4-yl, 2-chloro-6-(trifluoromethyl)-pyridine-4 -Yl and 4-methylquinazolin-6-yl.
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl-C 1-6 alkyl- or 5-6 membered heteroaryl-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl-C 1-6 alkyl- or 5-6 membered heteroaryl-C 1-6 alkyl- Optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxy, C 1-6 al
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl-C 1-6 alkyl- or 5-6 membered heteroaryl-C 1-6 alkyl-, wherein the C 1-6 alkyl, C 3-6 cycloalkyl, 4-7 membered heterocyclyl, phenyl, 5-6 membered heteroaryl, 4-7 membered heterocyclyl-C 1-6 alkyl- or 5-6 membered heteroaryl-C 1-6 alkyl- Optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine, cyano, hydroxy
  • R 1 and R 2 are each independently selected from hydrogen, C 1-6 alkyl, phenyl, 5-6 membered heteroaryl, wherein the C 1-6 alkyl, phenyl, 5-6
  • the membered heteroaryl group is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl Group, methoxy, ethoxy, propoxy, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl and Piperidin-4-yl.
  • R 1 and R 2 are each independently selected from hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, Cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, phenyl, pyridyl, pyridin-2-ylmethyl, pyridin-2-ylethyl, pyridin-2-ylpropyl, methoxyethyl And 2-hydroxy-2-methyl-propyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 are each independently selected from hydrogen, methyl, methoxyethyl, 2-hydroxy-2-methyl-propyl, phenyl and pyrid-2-ylmethyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 are each independently selected from 2-hydroxy-2-methyl-propyl, phenyl and pyrid-2-ylmethyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 are each independently hydrogen, methyl or 2-methoxyethyl.
  • R 1 is hydrogen or methyl
  • R 2 is hydrogen, methyl, phenyl, pyridin-2-ylmethyl, 2-hydroxy-2-methyl-propyl, or 2-methyl Oxyethyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine where: R 1 is hydrogen or methyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 2 is methyl, phenyl, pyrid-2-ylmethyl, 2-hydroxy-2-methyl-propyl or 2-methoxyethyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 is hydrogen or methyl, and R 2 is hydrogen, methyl, phenyl, pyridin-2-ylmethyl, 2-hydroxy-2-methyl-propyl or 2-methoxyethyl base;
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 is hydrogen or methyl, and R 2 is methyl, pyridin-2-ylmethyl, 2-hydroxy-2-methyl-propyl or 2-methoxyethyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 together with the nitrogen atom to which they are connected together form a 4-7 membered nitrogen-containing heterocyclic group, the 4-7 membered nitrogen-containing heterocyclic group is optionally selected by one or more independently Substituted by the following substituents: halogen, cyano, hydroxy, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl- , C 1-6 alkoxy-C 1-6 alkoxy-, C 3-6 cycloalkyl and 4-7 membered heterocyclic group.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 together with the nitrogen atom to which they are connected together form a 4-7 membered nitrogen-containing heterocyclic group (for example, the 4-7 membered nitrogen-containing heterocyclic group contains one or more selected from oxygen and nitrogen Heteroatoms), the 4-7 membered nitrogen-containing heterocyclic group is optionally substituted with one or more substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkyl, C 1 -6 haloalkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl-, C 1-6 alkoxy-C 1-6 alkoxy- and 4-7 member Heterocyclyl.
  • substituents independently selected from the group consisting of halogen, cyano, hydroxyl, C 1-6 alkyl
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 together with the nitrogen atom to which they are connected together form piperidinyl, morpholinyl or piperazinyl, the piperidinyl, morpholinyl or piperazinyl is optionally substituted by one or more Substitutions independently selected from the following: fluorine, chlorine, bromine, cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl , Cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, trifluoromethyl, methoxy, ethoxy, propoxy, piperidin-1-yl, piperidin-1-yl,
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 together with the nitrogen atom to which they are connected together form piperidinyl or morpholinyl, which is optionally substituted by one or more substituents independently selected from Substitution: fluorine, chlorine, bromine, cyano, hydroxyl, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl , Cyclopentyl, cyclohexyl, trifluoromethyl, methoxy, ethoxy, propoxy, piperidin-1-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3 -Yl, piperidin-4
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 together with the nitrogen atom to which they are connected together form a piperazinyl group, which is optionally substituted with one or more substituents independently selected from the group consisting of fluorine, chlorine, and bromine , Cyano, hydroxy, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl , Trifluoromethyl, methoxy, ethoxy, propoxy, piperidin-1-yl, piperidin-1-yl, piperidin-2-yl, piperidin-3-yl, piperidin-4
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine in which R 1 and R 2 together with the nitrogen atom to which they are connected form piperidinyl, morpholinyl, 4-cyanopiperidinyl, 4-methoxypiperidinyl or 1,4'-piperidine base.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine in which: R 1 and R 2 together with the nitrogen atom to which they are connected together form 4-methylpiperazinyl, 2-methylmorpholinyl, 2,6-dimethylmorpholinyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 together with the nitrogen atom to which they are connected together form piperidinyl, 4-cyanopiperidinyl, and 4-methoxypiperidinyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 together with the nitrogen atom to which they are connected together form 1,4′-piperidinyl, 4-methylpiperazinyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 1 and R 2 together with the nitrogen atom to which they are connected together form a morpholinyl group, which is optionally substituted with one or more substituents independently selected from the group consisting of: methyl, ethyl, N-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine in which: R 1 and R 2 together with the nitrogen atom to which they are connected together form morpholinyl, 2-methylmorpholinyl or 2,6-dimethylmorpholinyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine where: R 1 and R 2 together with the nitrogen atom to which they are connected together form a morpholinyl group.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine in which: R 1 and R 2 together with the nitrogen atom to which they are connected together form a 2-methylmorpholinyl group.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine in which: R 1 and R 2 together with the nitrogen atom to which they are connected together form 2,6-dimethylmorpholinyl.
  • R 3 and R 4 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 3- 6 cycloalkyl, C 1-6 alkyl-amino- and di(C 1-6 alkyl)-amino-.
  • R 3 and R 4 are each independently selected from hydrogen, halogen, cyano, hydroxy, amino, C 1-6 alkyl, C 1-6 haloalkyl, C 1-6 alkoxy, C 1- 6 alkyl-amino- and di(C 1-6 alkyl)-amino-.
  • R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy Group, ethoxy, propoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 3 and R 4 are each independently selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxy, amino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy Group, ethoxy, propoxy, methylamino, ethylamino, dimethylamino and diethylamino.
  • R 3 is selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, Propoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 3 is selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, Propoxy, methylamino, ethylamino, dimethylamino and diethylamino.
  • R 3 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylamino , Ethylamino, dimethylamino and diethylamino.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine where: R 3 is hydrogen, fluorine or chlorine.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 3 is selected from bromine, methyl, ethyl, n-propyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 3 is selected from isopropyl, trifluoromethyl, methoxy, ethoxy.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 3 is selected from propoxy, methylamino, ethylamino.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 3 is selected from dimethylamino and diethylamino.
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, Propoxy, methylamino, ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine, cyano, hydroxyl, amino, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, Propoxy, methylamino, ethylamino, dimethylamino and diethylamino.
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylamino , Ethylamino, dimethylamino, diethylamino, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 4 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, propoxy, methylamino , Ethylamino, dimethylamino and diethylamino.
  • R 4 is selected from hydrogen, fluorine, chlorine.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 4 is selected from bromine, methyl, ethyl, n-propyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 4 is selected from isopropyl, trifluoromethyl, methoxy, ethoxy.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 4 is selected from propoxy, methylamino, ethylamino.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein: R 4 is selected from dimethylamino and diethylamino.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine where: R 4 is hydrogen, chlorine, cyano or cyclopropyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine in which: R 4 is chlorine, cyano or cyclopropyl.
  • the compounds described herein or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or pro Medicine wherein the compound is selected from:
  • the atoms in the compounds described in this application may be replaced by their isotopes.
  • 12 C can be replaced by its isotope 13 C or 14 C;
  • 1 H can be replaced by 2 H (D, deuterium) or 3 H (T, tritium), etc.
  • the present application includes compounds described in Formula I and isotopically-labeled compounds obtained by replacing any atoms in the compounds of Formula I with their isotopes.
  • the present application also relates to a method for preparing the compound, which includes the following synthetic routes:
  • Hal 1 and Hal 2 are each independently the same or different halogen, such as Cl, Br or I;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined in this application.
  • Step A Compound IIa-1 reacts with compound IN-a to obtain compound IIa-A
  • Compound IIa-1 is coupled with compound IN-a to obtain compound IIa-A.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably tetrakis(triphenylphosphine)palladium.
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably sodium carbonate.
  • the coupling reaction is performed in a suitable organic solvent or a mixed solvent of organic solvent and water, and the organic solvent may be selected from 1,4-dioxane, N,N-dimethylformamide, and methanol , Ethanol, toluene or a mixed solvent of the above organic solvent and water, for example, a mixed solvent of toluene, methanol and water.
  • the coupling reaction is carried out under a suitable protective atmosphere (for example, a nitrogen atmosphere).
  • the coupling reaction is carried out at a suitable temperature, which may be 70-100°C, preferably 95°C.
  • the coupling reaction is carried out for a suitable time, which may be 1-24 hours, for example 11 hours.
  • Hal 2 is halogen, such as Cl, Br or I, preferably Br;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined in this application.
  • Step A Compound IIa-A reacts with compound IN-b to obtain compound IIa-2
  • the metal catalyst is a palladium metal catalyst, for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably tetrakis(triphenylphosphine)palladium.
  • a palladium metal catalyst for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)pal
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably potassium carbonate.
  • the coupling reaction is carried out in a suitable organic solvent, and the organic solvent may be selected from 1,4-dioxane, N,N-dimethylformamide, methanol, ethanol, toluene or the above organic solvents
  • the mixed solvent with water is, for example, a mixed solvent of 1,4-dioxane and water.
  • the coupling reaction is carried out under a suitable protective atmosphere (for example, a nitrogen atmosphere).
  • the coupling reaction is carried out at a suitable temperature, which may be 70-100°C, preferably 95°C.
  • the coupling reaction is carried out for a suitable time, which may be 1-24 hours, preferably 12 hours.
  • Step B The compound IIa-2 is reacted with the compound IN-c to obtain the compound of formula IIa
  • Compound IIa-2 can react with triphosgene, convert the amino group to isocyanate, and then react with IN-c to obtain the compound of formula IIa.
  • the reaction is preferably carried out in a suitable organic solvent and base.
  • the organic solvent may be selected from linear or cyclic ethers (such as tetrahydrofuran or diethyl ether), 1,4-dioxane, dichloromethane, dimethyl sulfoxide and any combination thereof, preferably tetrahydrofuran.
  • the base is an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature may be -40°C to 60°C, for example 0-25°C.
  • the reaction is preferably carried out for a suitable time, for example 0.5-2
  • Compound IIa-2 can also be reacted with phenyl chloroformate in a solvent and in the presence of a base, and then with IN-c to obtain a compound of formula IIa.
  • organic bases are usually selected, such as N,N-diisopropylethylamine, triethylamine, pyridine and 4-dimethylaminopyridine, preferably N,N-diisopropyl Ethyl ethylamine.
  • the solvent to be used is as long as it does not inhibit the reaction and can dissolve the raw materials to a certain extent, such as dichloromethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetonitrile, etc., preferably tetrahydrofuran.
  • the reaction temperature is usually 0°C to 60°C, preferably room temperature.
  • the reaction time is usually 1-12 hours, preferably 4 hours.
  • Hal 1 is halogen, such as Cl, Br or I, preferably Br; the remaining groups are as defined in this application.
  • Step A Compound IIb-1 reacts with compound IN-d to obtain compound IIb-2
  • Compound IIb-1 reacts with compound IN-d to obtain compound IIb-2.
  • the reaction is preferably carried out in the absence of a solvent.
  • the reaction can also be carried out in a solvent that does not inhibit the reaction, such as 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, N-methyl Pyrrolidone, benzene or toluene, etc.
  • the reaction temperature is usually room temperature to 120°C, preferably 80°C.
  • the reaction time is usually 6-24 hours, preferably 12 hours.
  • Step B Compound IIb-2 reacts with IN-e to obtain compound IIb-3
  • Compound IIb-2 is reacted with compound IN-e in a solvent and in the presence of a base to obtain compound IIb-3.
  • the guanidine (IN-e) used can form salts with acids such as hydrochloric acid, hydrobromic acid, sulfuric acid or acetic acid, preferably the hydrochloride salt.
  • the base used may be any one that does not inhibit the reaction, and includes alkali metal carbonates such as potassium carbonate, cesium carbonate, sodium carbonate, or alkali metal alkoxides such as sodium methoxide, sodium ethoxide, and potassium t-butoxide, preferably potassium carbonate.
  • the reaction temperature is usually room temperature to 120°C, preferably 80°C.
  • the reaction time is usually 12 to 36 hours, preferably 20 hours.
  • Step C Compound IIb-3 reacts with halogenating agent to obtain compound IIb-A
  • Compound IIb-3 is reacted with a halogenating agent in a solvent to obtain compound IIb-A.
  • the halogenating agent used may be N-bromosuccinimide or bromine, preferably N-bromosuccinimide.
  • the solvent used does not inhibit the reaction and can dissolve the raw materials to a certain extent, such as N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, tetrahydrofuran, 1,4-dioxane Ring, dimethoxyethane, etc., preferably N,N-dimethylformamide.
  • the reaction temperature is usually -20°C to room temperature, preferably 0°C to room temperature.
  • the reaction time is usually 1-24 hours, preferably 12 hours.
  • Hal 1 is halogen, such as Cl, Br or I, preferably Br;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Step A Compound IIb-A reacts with compound IN-b to obtain compound IIb-4
  • the metal catalyst is a palladium metal catalyst, for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl Phosphino)ferrocene]palladium dichloride.
  • a palladium metal catalyst for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, bis(triphen
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably potassium carbonate.
  • the coupling reaction is performed in a suitable organic solvent or a mixed solvent of organic solvent and water, and the organic solvent may be 1,4-dioxane, N,N-dimethylformamide or the above
  • the mixed solvent of organic solvent and water is, for example, a mixed solvent of 1,4-dioxane and water.
  • the coupling reaction is carried out under a suitable protective atmosphere (for example, a nitrogen atmosphere).
  • the coupling reaction is carried out at a suitable temperature, which may be 70-100°C, preferably 100°C.
  • the reaction time is usually 1-8 hours, preferably 4 hours.
  • Step B Compound IIb-4 reacts with IN-c to obtain the compound of formula IIb
  • Compound IIb-4 can react with triphosgene to convert the amino group to isocyanate, and then react with IN-c to obtain the compound of formula IIb.
  • the reaction is preferably carried out in a suitable organic solvent and base.
  • the organic solvent may be selected from linear or cyclic ethers (such as tetrahydrofuran or diethyl ether), 1,4-dioxane, dichloromethane, dimethyl sulfoxide and any combination thereof, preferably tetrahydrofuran.
  • the base is an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature may be -40°C to 60°C, for example 0-25°C.
  • the reaction is preferably carried out for a suitable time, for example 0.5-2
  • Compound IIb-4 can also be reacted with phenyl chloroformate in a solvent and in the presence of a base, and then with IN-c to obtain a compound of formula IIb.
  • organic bases are usually selected, such as N,N-diisopropylethylamine, triethylamine, pyridine and 4-dimethylaminopyridine, preferably N,N-diisopropyl Ethyl ethylamine.
  • the solvent to be used is as long as it does not inhibit the reaction and can dissolve the raw materials to a certain extent, such as dichloromethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetonitrile, etc., preferably tetrahydrofuran.
  • the reaction temperature is usually 0°C to 60°C, preferably room temperature.
  • the reaction time is usually 1-12 hours, preferably 4 hours.
  • Hal 1 is halogen, such as Cl, Br or I, preferably Br;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Step A Compound IIb-A reacts with compound IN-c to obtain compound IIb-5
  • Compound IIb-A can react with triphosgene to convert the amino group to isocyanate, and then react with IN-c to obtain compound IIb-5.
  • the reaction is preferably carried out in a suitable organic solvent and base.
  • the organic solvent may be selected from linear or cyclic ethers (such as tetrahydrofuran or diethyl ether), 1,4-dioxane, dichloromethane, dimethyl sulfoxide and any combination thereof, preferably tetrahydrofuran.
  • the base is an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature may be -40°C to 60°C, for example 0-25°C.
  • the reaction is preferably carried out for a suitable time, for example 0.5-2 hours
  • Compound IIb-A can also be reacted with phenyl chloroformate in a solvent and in the presence of a base, and then reacted with IN-c to obtain compound IIb-5.
  • organic bases are usually selected, such as N,N-diisopropylethylamine, triethylamine, pyridine and 4-dimethylaminopyridine, preferably N,N-diisopropyl Ethyl ethylamine.
  • the solvent to be used is as long as it does not inhibit the reaction and can dissolve the raw materials to a certain extent, such as dichloromethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetonitrile, etc., preferably tetrahydrofuran.
  • the reaction temperature is usually 0°C to 60°C, preferably room temperature.
  • the reaction time is usually 1-12 hours, preferably 4 hours.
  • Step B Compound IIb-5 reacts with compound IN-b to obtain the compound of formula IIb
  • Compound IIb-5 is coupled with compound IN-b to obtain the compound of formula IIb.
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl Phosphino)ferrocene]palladium dichloride.
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably potassium carbonate.
  • the coupling reaction is performed in a suitable organic solvent or a mixed solvent of organic solvent and water, and the organic solvent may be 1,4-dioxane, N,N-dimethylformamide or the above
  • the mixed solvent of organic solvent and water is, for example, a mixed solvent of 1,4-dioxane and water.
  • the coupling reaction is carried out under a suitable protective atmosphere (for example, a nitrogen atmosphere).
  • the coupling reaction is carried out at a suitable temperature, which may be 70-100°C, preferably 80°C.
  • the coupling reaction is performed for a suitable time, which may be 8-24 hours, such as 12 hours.
  • Hal 1 is halogen, such as Cl, Br or I, preferably Br; the remaining groups are as defined above.
  • Step A Compound IIb-1 reacts with oxidant to obtain compound IIc-1
  • Compound IIb-1 is reacted with an oxidizing agent in a solvent to obtain compound IIc-1.
  • the oxidant used may be selenium dioxide, potassium permanganate, sodium periodate, hydrogen peroxide, etc., preferably selenium dioxide.
  • the reaction can be carried out in a solvent that does not inhibit the reaction, such as 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, N-methylpyrrolidone, or a mixed solvent of the above organic solvents and water, A mixed solvent of 1,4-dioxane and water is preferred.
  • the reaction temperature is usually room temperature to 120°C, preferably 110°C.
  • the reaction time is usually 3-14 hours, preferably 5 hours.
  • Step B Compound IIc-1 reacts with compound IN-f to obtain compound IIc-2
  • Compound IIc-1 and compound IN-f are reacted in the presence of an acid to obtain compound IIc-2.
  • the aminoguanidine (IN-f) used can form salts with acids such as hydrochloric acid, carbonic acid, hydroiodic acid, sulfuric acid or acetic acid, preferably bicarbonate.
  • the acid to be used is as long as it does not inhibit the reaction, and includes hydrochloric acid, acetic acid, sulfuric acid, and trifluoroacetic acid, preferably acetic acid.
  • the reaction is preferably carried out without solvent.
  • reaction can also be performed in a solvent that can dissolve the raw materials to a certain extent without inhibiting the reaction, such as 1,4-dioxane, ethanol, tetrahydrofuran, benzene, or toluene.
  • a solvent that can dissolve the raw materials to a certain extent without inhibiting the reaction, such as 1,4-dioxane, ethanol, tetrahydrofuran, benzene, or toluene.
  • the reaction temperature is usually room temperature to 120°C, preferably 100°C.
  • the reaction time is usually 1-12 hours, preferably 6 hours.
  • Step C Compound IIc-2 reacts with halogenating agent to obtain compound IIc-A
  • Compound IIc-2 is reacted with a halogenating agent in a solvent to obtain compound IIc-A.
  • the halogenating agent used may be N-bromosuccinimide or bromine, preferably N-bromosuccinimide.
  • the solvent used does not inhibit the reaction and can dissolve the raw materials to a certain extent, such as N,N-dimethylformamide, N-methylpyrrolidone, methanol, ethanol, tetrahydrofuran, 1,4-dioxane Ring, dimethoxyethane, etc., preferably N,N-dimethylformamide.
  • the reaction temperature is usually -20°C to room temperature, preferably room temperature.
  • the reaction time is usually 1-8 hours, preferably 2 hours.
  • Hal 1 is halogen, such as Cl, Br or I, preferably Br; the remaining groups are as defined above.
  • Step A Compound IIc-3 reacts with compound IN-g to obtain compound IIc-4
  • Compound IIc-3 is reacted with compound IN-g in the presence of an acid to obtain compound IIc-4.
  • the acid used may be any one that does not inhibit the reaction, and includes hydrochloric acid, acetic acid, sulfuric acid, and trifluoroacetic acid, preferably trifluoroacetic acid.
  • the reaction can be carried out in a solvent that can dissolve the raw materials to a certain extent without inhibiting the reaction, such as methylene chloride, chloroform, 1,4-dioxane, tetrahydrofuran, N-methylpyrrolidone, preferably chloroform.
  • the reaction temperature is usually room temperature to 80°C, preferably room temperature.
  • the reaction time is usually 1-8 hours, preferably 2 hours.
  • Step B Compound IIc-4 reacts with oxidant to obtain compound IIc-A
  • Compound IIc-4 is reacted with an oxidant in a solvent to obtain compound IIc-A.
  • the oxidant used may be K 3 [Fe(CN) 6 ], DDQ, manganese dioxide, potassium permanganate, etc., preferably K 3 [Fe(CN) 6 ].
  • the reaction can be carried out in a solvent that can dissolve the raw materials to a certain extent without inhibiting the reaction, such as water, 1,4-dioxane, N,N-dimethylformamide, tetrahydrofuran, dimethyl sulfoxide or the above organic
  • the mixed solvent of the solvent and water is preferably water.
  • the reaction temperature is usually room temperature to 120°C, preferably room temperature.
  • the reaction time is usually 3-14 hours, preferably 12 hours.
  • Hal 1 is halogen, such as Cl, Br or I, preferably Br;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Step A Compound IIc-A reacts with compound IN-b to obtain compound IIc-5
  • the metal catalyst is a palladium metal catalyst, for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably tetrakis(triphenylphosphine)palladium.
  • a palladium metal catalyst for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)pal
  • the base is an inorganic base such as cesium carbonate, potassium carbonate, sodium carbonate, potassium bicarbonate, sodium bicarbonate, preferably potassium carbonate.
  • the coupling reaction is performed in a suitable organic solvent or a mixed solvent of organic solvent and water, and the organic solvent may be 1,4-dioxane, N,N-dimethylformamide or the above
  • the mixed solvent of organic solvent and water is, for example, a mixed solvent of 1,4-dioxane and water.
  • the coupling reaction is carried out under a suitable protective atmosphere (for example, a nitrogen atmosphere).
  • the coupling reaction is carried out at a suitable temperature, which may be 70-100°C, preferably 80°C.
  • the coupling reaction is performed for a suitable time, which may be 1-24 hours, such as 6 hours.
  • Step B Compound IIc-5 reacts with compound IN-c to obtain the compound of formula IIc
  • Compound IIc-5 can react with triphosgene to convert the amino group to isocyanate, and then react with compound IN-c to obtain the compound of formula IIc.
  • the reaction is preferably carried out in a suitable organic solvent and base.
  • the organic solvent may be selected from linear or cyclic ethers (such as tetrahydrofuran or diethyl ether), 1,4-dioxane, dichloromethane, dimethyl sulfoxide and any combination thereof, preferably tetrahydrofuran.
  • the base is an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature may be -40°C to 60°C, for example 0-25°C.
  • the reaction is preferably carried out for a suitable time, for example 0.
  • Compound IIc-5 can also be reacted with phenyl chloroformate in a solvent and in the presence of a base, and then with IN-c to obtain a compound of formula (IIc).
  • organic bases are usually selected, such as N,N-diisopropylethylamine, triethylamine, pyridine and 4-dimethylaminopyridine, preferably N,N-diisopropyl Ethyl ethylamine.
  • the solvent to be used is as long as it does not inhibit the reaction and can dissolve the raw materials to a certain extent, such as dichloromethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetonitrile, etc., preferably tetrahydrofuran.
  • the reaction temperature is usually 0°C to 60°C, preferably room temperature.
  • the reaction time is usually 1-12 hours, preferably 4 hours.
  • Hal 1 is halogen, such as Cl, Br or I, preferably Br;
  • Y is a boric acid or borate group, preferably -B(OH) 2 or The remaining groups are as defined above.
  • Step A Compound IIc-A reacts with compound IN-c to obtain compound IIc-6
  • Compound IIc-A can react with triphosgene to convert the amino group to isocyanate, and then react with compound IN-c to obtain compound IIb-6.
  • the reaction is preferably carried out in a suitable organic solvent and base.
  • the organic solvent may be selected from linear or cyclic ethers (such as tetrahydrofuran or diethyl ether), 1,4-dioxane, dichloromethane, dimethyl sulfoxide and any combination thereof, preferably tetrahydrofuran.
  • the base is an organic base such as N,N-diisopropylethylamine, triethylamine, pyridine, 4-dimethylaminopyridine, preferably N,N-diisopropylethylamine.
  • the reaction is preferably carried out at a suitable temperature.
  • the temperature may be -40°C to 60°C, for example 0-25°C.
  • the reaction is preferably carried out for a suitable time, for example 0.5-2
  • Compound IIc-A can also be reacted with phenyl chloroformate in a solvent and in the presence of a base, and then with compound IN-c to obtain compound IIb-6.
  • organic bases are usually selected, such as N,N-diisopropylethylamine, triethylamine, pyridine and 4-dimethylaminopyridine, preferably N,N-diisopropyl Ethyl ethylamine.
  • the solvent to be used is as long as it does not inhibit the reaction and can dissolve the raw materials to a certain extent, such as dichloromethane, tetrahydrofuran, 1,4-dioxane, diethyl ether, acetonitrile, etc., preferably tetrahydrofuran.
  • the reaction temperature is usually 0°C to 60°C, preferably room temperature.
  • the reaction time is usually 1-12 hours, preferably 4 hours.
  • Step B Compound IIc-6 reacts with compound IN-b to obtain the compound of formula (IIc)
  • the compound IIc-6 is coupled with the compound IN-b to obtain the compound of formula (IIc).
  • the coupling reaction is preferably carried out in the presence of a metal catalyst and a base.
  • the metal catalyst is a palladium metal catalyst, for example, tetrakis(triphenylphosphine)palladium, [1,1'-bis(diphenylphosphino)ferrocene]palladium dichloride, [1,1' -Bis(diphenylphosphine)ferrocene]palladium dichloride dichloromethane complex, bis(triphenylphosphine)palladium dichloride, palladium acetate, preferably [1,1'-bis(diphenyl Phosphino)ferrocene]palladium dichloride.
  • the base is an inorganic base such as potassium carbonate, cesium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, preferably potassium carbonate.
  • the coupling reaction is performed in a suitable organic solvent or a mixed solvent of organic solvent and water, and the organic solvent may be 1,4-dioxane, N,N-dimethylformamide or the above
  • the mixed solvent of organic solvent and water is, for example, a mixed solvent of 1,4-dioxane and water.
  • the coupling reaction is carried out under a suitable protective atmosphere (e.g. nitrogen atmosphere).
  • the coupling reaction is carried out at a suitable temperature, which may be 70-100°C, preferably 80°C.
  • the coupling reaction is performed for a suitable time, which may be 8-24 hours, such as 12 hours.
  • the present application also relates to a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula I described herein or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled Compounds, metabolites or prodrugs, and optionally one or more pharmaceutically acceptable carriers or excipients.
  • the present application also relates to compounds represented by formula I or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs or drugs thereof Use of the composition in the preparation of medicaments as adenosine A2a receptor antagonists.
  • the present application also relates to compounds represented by formula I or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs or drugs thereof Use of the composition in the preparation of a medicament for treating or preventing diseases related to adenosine A2a receptors.
  • the present application also relates to a method for treating and/or preventing diseases associated with adenosine A2a receptors, which comprises administering to a subject in need thereof an effective amount of a compound represented by Formula I or a pharmaceutically acceptable salt thereof , Stereoisomers, polymorphs, solvates, N-oxides, isotopically labeled compounds, metabolites or prodrugs or pharmaceutical compositions thereof.
  • the present application also relates to compounds represented by formula I or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs or drugs thereof A composition for inhibiting adenosine A2a receptor activity.
  • the present application also relates to compounds represented by formula I or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs or drugs thereof
  • a composition for the treatment and/or prevention of diseases associated with adenosine A2a receptors is also relates to compounds represented by formula I or pharmaceutically acceptable salts, stereoisomers, polymorphs, solvates, N-oxides, isotopically-labeled compounds, metabolites or prodrugs or drugs thereof.
  • the disease associated with adenosine A2a receptor is a tumor.
  • the tumors include, but are not limited to: breast cancer, ovarian cancer, colorectal cancer, melanoma, non-small cell lung cancer, small cell lung cancer, gastrointestinal stromal tumor, cervical cancer, pancreatic cancer, prostate cancer, gastric cancer, chronic marrow Leukocytosis, liver cancer, lymphoma, peritoneal cancer, and soft tissue sarcoma.
  • the purpose of the pharmaceutical composition is to promote the administration to the living body, which facilitates the absorption of the active ingredient and thus exerts the biological activity.
  • the carriers mentioned therein include but are not limited to: ion exchangers, alumina, aluminum stearate, lecithin, serum proteins such as human albumin, buffer substances such as phosphate, glycerin, sorbic acid, potassium sorbate, saturated plants Partial glyceride mixture of fatty acids, water, salt or electrolyte, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salt, colloidal silica, magnesium trisilicate, polyvinylpyrrolidone, fiber Vegetarian substances, polyethylene glycol, sodium carboxymethyl cellulose, polyacrylate, beeswax, lanolin.
  • the excipient refers to an addition to the main drug in the pharmaceutical preparation. It is stable in nature, has no compatibility with the main drug, does not produce side effects, does not affect the curative effect, is not easily deformed, cracked, mildewed, moth-eaten, harmless to the human body, has no physiological effect at normal temperature, and does not produce chemical or physical properties with the main drug The effect does not affect the determination of the content of the main drug.
  • the compound of the present application or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug can be administered by the following route: stomach Parenteral, topical, intravenous, oral, subcutaneous, intraarterial, intradermal, transdermal, rectal, intracranial, intraperitoneal, intranasal, intramuscular route or as an inhalant.
  • the pharmaceutical composition may be optionally administered in combination with other agents that have at least a certain effect in the treatment of various diseases.
  • the compound of the present application or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug can be formulated into various forms according to the route of administration A suitable dosage form.
  • the pharmaceutical composition or suitable dosage form described in the present application may contain 0.01 mg to 1000 mg of the compound of the present application.
  • a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug can be prepared Any orally acceptable formulation form, including but not limited to tablets, capsules, aqueous solutions or aqueous suspensions.
  • a compound of the present application or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotopically labeled compound, metabolite, or prodrug can be prepared in the form of a suitable ointment, lotion or cream formulation, in which the active ingredient is suspended or dissolved in one or more carriers.
  • Carriers that can be used in ointment preparations include but are not limited to: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyethylene oxide, polypropylene oxide, emulsifying wax and water; carriers that can be used in lotions or creams include, but are not limited to: minerals Oil, sorbitan monostearate, Tween 60, cetyl ester wax, hexadecenyl alcohol, 2-octyldodecanol, benzyl alcohol and water.
  • the compound of the present application or a pharmaceutically acceptable salt, stereoisomer, polymorph, solvate, N-oxide, isotope-labeled compound, metabolite, or prodrug can also be administered in the form of a sterile injectable preparation , Including sterile injectable water or oil suspension or sterile injectable solution.
  • usable carriers and solvents include water, Ringer's solution and isotonic sodium chloride solution.
  • sterilized non-volatile oils can also be used as solvents or suspending media, such as monoglycerides or diglycerides.
  • the effective amount of the composition of the present application sufficient to achieve a preventive or therapeutic effect is from about 0.001 mg/kg body weight/day to about 10,000 mg/kg body weight/day. Where appropriate, the dosage is from about 0.01 mg/kg body weight/day to about 1000 mg/kg body weight/day.
  • the dosage range may be about 0.01 to 1000 mg/kg of the subject's body weight per day, every two days, or every three days, more usually 0.1 to 500 mg/kg of the subject's body weight.
  • Exemplary treatment regimens are administration once every two days or once a week or once a month.
  • the formulation is usually administered multiple times, and the interval between single doses can be daily, weekly, monthly, or yearly.
  • the preparation may be administered in the form of a sustained-release preparation, in which case, less frequent administration is required.
  • the dosage and frequency vary according to the half-life of the formulation in the subject. It may also differ according to whether it is prophylactic or therapeutic. In prophylactic applications, relatively low doses are administered at relatively low frequency intervals for long periods of time. In therapeutic applications, it is sometimes necessary to administer relatively high doses at relatively short intervals until the progression of the disease is delayed or stopped, and preferably until the individual shows partial or complete improvement of the symptoms of the disease, after which the patient can be given Prevention program.
  • hydrogen and the hydrogen in each group mentioned refer to protium (H), deuterium (D), or tritium (T).
  • halogen refers to fluorine, chlorine, bromine or iodine.
  • C 1-6 alkyl refers to a linear or branched alkyl group having 1-6 carbon atoms, such as C 1-4 alkyl, C 1-2 alkyl, C 1 alkyl, C 2 alkyl, C 3 alkyl, C 4 alkyl, C 5 alkyl or C 6 alkyl. Specific examples include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, n-hexyl, and the like.
  • C 1-6 alkoxy refers to a C 1-6 alkyl group as defined above attached to the parent molecular moiety through an oxygen atom.
  • Representative examples of C 1-6 alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, t-butoxy.
  • C 1-6 haloalkyl refers to a halogen as defined e.g. fluoro, chloro, bromo or iodo mono- or polysubstituted C 1- 6 alkyl group described above.
  • Representative examples of C 1-6 haloalkyl include, but are not limited to, chloromethyl, chloroethyl, dichloroethyl, trifluoromethyl, difluoromethyl, monofluoromethyl, and the like.
  • C 1-6 alkyl-amino- refers to an amino group mono-substituted by C 1-6 alkyl as defined above.
  • Typical examples of "C 1-6 alkyl-amino” include, but are not limited to, methylamino, ethylamino, propylamino, butylamino, and the like.
  • di(C 1-6 alkyl)-amino- refers to an amino group that is disubstituted with C 1-6 alkyl as defined above.
  • Typical examples of "di(C 1-6 alkyl)-amino-” include, but are not limited to, dimethylamino, diethylamino, dipropylamino, dibutylamino, and the like.
  • C 3-10 cycloalkyl refers to a saturated cyclic hydrocarbon group having 3 to 10 carbon atoms and having a monocyclic or bicyclic or multiple fused rings (including fused and bridged ring systems) , For example, having 3-8, 5-8, 3-6 or 5-6 carbon atoms.
  • C 3-10 cycloalkyl include, but are not limited to, monocyclic structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, 1-methylcyclopropyl Group, 2-methylcyclopentyl, 2-methylcyclooctyl and the like; bicyclic structures such as bicyclo[2.2.1]heptyl, and polycyclic structures such as adamantyl and the like.
  • the term "4-12 membered heterocyclyl” refers to a group containing at least one heteroatom (eg, containing 1, 2, 3, 4, or 5) and having 4-12 ring atoms
  • the "4-12 membered heterocyclic group” may be oxo or thio.
  • the "4-12 membered heterocyclic group” described in this application contains 1-2 heteroatoms, such as 1 nitrogen atom, oxygen atom or sulfur atom, or 1 nitrogen atom and 1 oxygen atom.
  • the "4-12 membered heterocyclic group” such as “4-10 membered heterocyclic group”, “4-8 membered heterocyclic group”, “4-6 membered heterocyclic group”, “4-7 membered heterocyclic group” ", "5-6 membered heterocyclic group”, “4-6 membered saturated heterocyclic group”, “5-6 membered saturated heterocyclic group”, “4-8 membered oxygen-containing heterocyclic group”, "4-6 Element oxygen-containing heterocyclic group", "5-6 member oxygen-containing heterocyclic group”, “4-6 member saturated oxygen-containing heterocyclic group”, “4-10 member nitrogen-containing heterocyclic group”, “4-7 member “Nitrogen-containing heterocyclic group”, "4-8 membered nitrogen-containing heterocyclic group”, "5-6 membered nitrogen-containing heterocyclic group”, "5-6 member
  • 4-12 membered heterocyclic group include, but are not limited to: azetidine, 1,4-dioxanyl, 1,3-dioxanyl, 1, 3-dioxolyl, 1,4-dioxanyl, dihydrofuranyl, dihydropyrrolyl, pyrrolidinyl, imidazolidinyl, 4,5-dihydroimidazolyl, pyrazole Alkyl, 4,5-dihydropyrazolyl, 2,5-dihydrothienyl, tetrahydrothienyl, piperazinyl, thiazinyl, piperidinyl, morpholinyl, etc.
  • C 6-10 aryl refers to an unsaturated aromatic carbocyclic group of 6-10 carbon atoms having a single ring or two or more fused rings.
  • the aryl group has, for example, 5-8 or 5-6 carbon atoms.
  • Typical examples of "C 6-10 aryl” include, but are not limited to, phenyl, naphthyl, anthracenyl, and the like.
  • the term "5-10 membered heteroaryl” means a heteroaromatic ring group having 5-10 ring members, including monocyclic heteroaromatic rings and polycyclic aromatic rings, polycyclic aromatic rings The middle monocyclic aromatic ring is fused with one or more other aromatic rings.
  • the "5-10 membered heteroaryl group” has one or two or more heteroatoms selected from O, S or N.
  • heteroaryl as used herein is a group in which an aromatic ring is fused with one or more non-aromatic rings (carbocyclic or heterocyclic), where the linking group or point is located on the aromatic Ring or non-aromatic ring.
  • the heteroaryl group has, for example, 5-6 ring members.
  • Typical examples of "5-10 membered heteroaryl” include but are not limited to furyl, imidazolyl, triazolyl, indolyl, tetrazolyl, pyridyl, pteridyl, pyrimidinyl, triazolyl, Quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl, etc.
  • the substituent may be (1) unsubstituted or (2) substituted. If the carbon of the substituent is described as being optionally substituted by one or more of the list of substituents, one or more hydrogens on the carbon (to the extent of any hydrogen present) can be independently and/or together Selected optional substituents are substituted. If the nitrogen of the substituent is described as optionally substituted by one or more of the list of substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogen present) can each be independently selected Substitution.
  • one or more refers to 1 or more than 1 under reasonable conditions, such as 2, 3, 4, 5, 6, 7, 8, 9, or 10 Pcs.
  • the point of attachment of a substituent may be from any suitable position of the substituent.
  • stereoisomer means an isomer formed due to at least one asymmetric center. In compounds with one or more (eg 1, 2, 3 or 4) asymmetric centers, it can produce racemic mixtures, single enantiomers, diastereomer mixtures and Individual diastereomers. Specific individual molecules may also exist as geometric isomers (cis/trans). Similarly, compounds of the present application may exist as a mixture of two or more structurally different forms in rapid equilibrium (commonly referred to as tautomers). Representative examples of tautomers include keto-enol tautomers, phenol-ketone tautomers, nitroso-oxime tautomers, imine-enamine tautomers Wait. It is to be understood that the scope of the present application covers all such in any ratio (eg 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, 99 %) isomers or mixtures thereof.
  • the compounds of the present application are intended to be stereoisomers (which include cis and trans isomers, optical isomers (such as R and S enantiomers), diastereomers, Geometric isomers, rotamers, conformers, atropisomers, and mixtures thereof exist.
  • the compounds of the present application can exhibit more than one type of isomerism and consist of mixtures thereof (e.g. racemic mixtures and pairs of diastereomers).
  • This application covers all possible crystalline forms or polymorphs of the compounds of this application, which may be a single polymorph or a mixture of more than one polymorph in any ratio.
  • compositions of the present application may exist in free form for therapy, or where appropriate, in the form of pharmaceutically acceptable derivatives.
  • pharmaceutically acceptable derivatives include, but are not limited to, pharmaceutically acceptable salts, solvates, N-oxides, metabolites or prodrugs, after they are administered to patients in need thereof , Can directly or indirectly provide the compound of this application or its metabolites or residues. Therefore, when referring to "a compound of the present application" herein, it is also intended to cover the above-mentioned various derivative forms of the compound.
  • Synthetic methods for preparing N-oxides of heterocycles and tertiary amines are well known to those skilled in the art and include the use of peroxyacids such as peroxyacetic acid and m-chloroperoxybenzoic acid (MCPBA), hydrogen peroxide, alkyl groups Hydrogen peroxide such as tert-butyl hydroperoxide, sodium perborate and dioxirane such as dimethyl dioxirane oxidize the heterocycle and tertiary amine.
  • MCPBA m-chloroperoxybenzoic acid
  • Hydrogen peroxide such as tert-butyl hydroperoxide
  • sodium perborate and dioxirane such as dimethyl dioxirane oxidize the heterocycle and tertiary amine.
  • the compound of the present application may exist in the form of a solvate (such as a hydrate), wherein the compound of the present application contains a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol, or ethanol.
  • a polar solvent as a structural element of the crystal lattice of the compound, particularly, for example, water, methanol, or ethanol.
  • the amount of polar solvents, especially water can be present in stoichiometric or non-stoichiometric ratios.
  • the compounds of the present application or pharmaceutically acceptable salts thereof may also form solvates, such as alcoholates and the like.
  • the compound of the present application may also be in the form of a prodrug or in a form that can release the active ingredient after a metabolic change in the body.
  • the selection and preparation of appropriate prodrug derivatives are well known to those skilled in the art.
  • the compound of the present application may also be in a chemically protected form, the protecting group may be protected on an active group (such as an amino group) of the compound, and the protecting group may be metabolized in the body to release the active ingredient.
  • an active group such as an amino group
  • the term "pharmaceutically acceptable” means that the substance or composition must be chemically and/or toxicologically compatible with the other components making up the formulation and/or the mammal treated with it.
  • pharmaceutically acceptable salts includes conventional salts formed with pharmaceutically acceptable inorganic or organic acids, or inorganic or organic bases.
  • suitable acid addition salts include perchloric acid, propionic acid, succinic acid, glycolic acid, acetamic acid, malonic acid, hydroxymaleic acid, phenylacetic acid, glutamic acid, naphthalene-2-sulfonic acid, hydroxynaphthalene Salt formed by formic acid, hydroiodic acid, malic acid, tannic acid, etc.
  • Suitable base addition salts include sodium, potassium, magnesium, lithium, aluminum, calcium, zinc, N,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenedioxide Salts formed by amines, N-methylglucamine and procaine.
  • composition includes products containing a therapeutically effective amount of a compound of Formula I of the present application, as well as any product produced directly or indirectly from a combination of compounds of Formula I of the present application.
  • the term "effective amount” refers to an amount sufficient to achieve the desired therapeutic effect, for example, an amount that achieves relief of the symptoms associated with the disease to be treated.
  • prevention refers to prophylactic administration to reduce the likelihood of or delay the onset of a disease or symptom.
  • treatment is intended to reduce or eliminate the targeted disease state or disorder. If the subject receives a therapeutic amount of the compound, its optical isomer or a pharmaceutically acceptable salt or pharmaceutical composition thereof according to the methods described herein, the subject exhibits one or more indications and symptoms An observable and/or detectable decrease or improvement, the subject is successfully "treated”. It should also be understood that the treatment of the disease state or disorder includes not only complete treatment but also incomplete treatment, but has achieved some biological or medical related results.
  • subject refers to mammalian subjects (eg, dogs, cats, horses, cattle, sheep, goats, monkeys, etc.) and human subjects, including male and female subjects and including newborns Children, infants, juveniles, adolescents, adults, and elderly subjects, and includes various races and ethnicities, including but not limited to, whites, blacks, Asians, American Indians, and Hispanics.
  • the compounds of the present application have a weak inhibitory capacity on the adenosine A1 receptor and can selectively inhibit the adenosine A2a receptor.
  • the compounds of the present application have low blood-brain barrier permeability, strong peripheral selectivity, and good pharmacokinetic properties. Therefore, the compounds of the present application can activate the T cell immune function mediated by adenosine A2a receptor activation, have good tumor therapy activity, and can avoid toxic and side effects caused by inhibiting the adenosine A2a receptor of the central nervous system.
  • the structure of the compound was determined by nuclear magnetic resonance ( 1 H NMR) or mass spectrometry (MS).
  • 1 H NMR was measured using JEOL Eclipse 400 NMR instrument, and the solvent was deuterated methanol (CD 3 OD), deuterated chloroform (CDCl 3 ) or hexadeuterated dimethyl sulfoxide (DMSO-d 6 ), the internal standard was Tetramethylsilane (TMS), chemical shift ( ⁇ ) is given in units of 10 -6 (ppm).
  • MS uses an Agilent (ESI) mass spectrometer, manufacturer: Agilent, model: Agilent 6120B.
  • mobile phase A is acetonitrile
  • mobile phase B is 0.05% (v/v) formic acid aqueous solution.
  • thin layer chromatography silica gel plates use aluminum plates (20 ⁇ 20 cm) produced by Merck, and the silica gel plates used for thin layer chromatography purification are Yantai GF 254 (1 mm thick).
  • reaction is monitored by thin layer chromatography (TLC) or LC-MS.
  • TLC thin layer chromatography
  • the developing system used is: dichloromethane and methanol system, n-hexane and ethyl acetate system, petroleum ether and ethyl acetate system
  • the volume ratio of the solvent is adjusted according to the polarity of the compound or adjusted by adding triethylamine.
  • column chromatography generally uses 200-300 mesh silica gel as a carrier.
  • the eluent system includes: dichloromethane and methanol system, petroleum ether and ethyl acetate system, the volume ratio of the solvent is adjusted according to the polarity of the compound, or a small amount of triethylamine can be added for adjustment.
  • reaction temperature is room temperature (20°C to 35°C).
  • reagents used in this application were purchased from companies such as Acros Organics, Aldrich Chemical Company, and Tebo Chemical.
  • Step 1 Preparation of 6-bromo-5-(5-methylfuran-2-yl)-4,5-dihydro-1,2,4-triazine-3-amine (In-1-c)
  • Step 4 Preparation of 5-(4-fluorophenyl)-6-(4-methylquinazolin-6-yl)-1,2,4-triazine-3-amine (In-3)
  • Step 3 Preparation of 3-fluoro-6-(4-fluorophenyl)-5(4-methylquinazolin-6-yl)pyridin-2-amine (2)
  • reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Step 1 Preparation of 3-(dimethylamino)-1-(4-fluorophenyl)prop-2-en-1-one (3-2)
  • reaction solution was cooled to room temperature, poured into water, extracted with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated.
  • Piperidine (35-1) was used to replace the methylamine in Example 5 in tetrahydrofuran, 5-(2-chloro-6-methylpyridin-4-yl)-4-(4-fluorophenyl)pyrimidine-2 -Amine (17) instead of 4-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyrimidin-2-amine (3) in Example 5, similar to Example 5 According to the method described above, the title compound (35) (40 mg, yield: 21%) was synthesized.
  • 6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyridin-2-amine (1) was used instead of 5-(4-fluorophenyl)- in Example 23 6-(4-methylquinazolin-6-yl)-1,2,4-triazine-3-amine (In-3), using morpholine (11-1) instead of dimethyl in Example 23
  • morpholine (11-1) instead of dimethyl in Example 23
  • a solution of the amine in tetrahydrofuran was synthesized in a similar manner as described in Example 23 to obtain the title compound (41) (95 mg, yield: 35%).
  • Step 3 Preparation of 4-chloro-6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyridin-2-amine (42-4)
  • the fourth step N-(4-chloro-6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyridin-2-yl)morpholine-4-carboxamide preparation
  • Example 5 Using morpholine (11-1) instead of methylamine in Example 5 in tetrahydrofuran, 4-chloro-6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyridine -2-amine (42-4) instead of 4-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyrimidine-2-amine (3) in Example 5, Similar to the method described in Example 5, the title compound (42) (30 mg, yield: 34%) was synthesized.
  • Step 1 Preparation of 6-amino-2-(4-fluorophenyl)-3-(4-methylquinazolin-6-yl) isonicotinonitrile (43-1)
  • Example 5 Using morpholine (11-1) instead of the methylamine in Example 5 in tetrahydrofuran, 6-amino-2-(4-fluorophenyl)-3-(4-methylquinazolin-6-yl)iso Niacinonitrile (43-1) instead of 4-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyrimidin-2-amine (3) in Example 5 was carried out similarly Using the method described in Example 5, the title compound (43) (35 mg, yield: 18%) was synthesized.
  • Step 1 Preparation of 1-cyclopropyl-3-(4-fluorophenyl)propane-1,3-dione (44-1)
  • Step 2 Preparation of (Z)-3-amino-3-cyclopropyl-1-(4-fluorophenyl)prop-2-en-1-one (44-2)
  • Step 3 Preparation of 4-cyclopropyl-6-(4-fluorophenyl)pyrimidine-2-amine (44-3)
  • Step 4 Preparation of 4-cyclopropyl-6-(4-fluorophenyl)-5-iodopyrimidin-2-amine (44-4)
  • Step 5 Preparation of 4-cyclopropyl-6-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyrimidin-2-amine (44-5)
  • Step 3 Preparation of 6-amino-2’-chloro-2-(4-fluorophenyl)-6’-methyl-[3,4’-bipyridine]-4-carbonitrile (45-3)
  • Step 4 N-(2'-chloro-4-cyano-2-(4-fluorophenyl)-6'-methyl-[3,4'-bipyridyl]-6-yl)morpholine- Preparation of 4-formamide (45)
  • Example 3 Replace Example 3 with 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (46-1) 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (1-3 ), in a similar manner as described in the fourth step of Example 3, the title compound (46-2) (150 mg, yield: 63%) of this step was synthesized.
  • Step 2 Preparation of N-(4-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)pyrimidin-2-yl)morpholine-4-carboxamide (46)
  • Example 5 Using morpholine (11-1) instead of the methylamine in Example 5 in tetrahydrofuran, 4-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)pyrimidine-3-amine ( 46-2) Instead of 4-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyrimidin-2-amine (3) in Example 5, similar to Example 5 According to the method described above, the title compound (46) (30 mg, yield: 18%) was synthesized.
  • Step 1 Preparation of 4-cyclopropyl-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)pyrimidin-2-amine (47-1)
  • Example 44 was replaced with 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (46-1) 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (1-3 ), in a similar manner to that described in the fifth step of Example 44, the title compound (47-1) (260 mg, yield: 63%) of this step was synthesized.
  • Example 5 Using morpholine (11-1) instead of the methylamine in Example 5 in tetrahydrofuran, 4-cyclopropyl-6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl) Pyrimidine-2-amine (47-1) instead of 4-(4-fluorophenyl)-5-(4-methylquinazolin-6-yl)pyrimidine-2-amine (3) in Example 5, In a similar manner to that described in Example 5, the title compound (47) (45 mg, yield: 50%) was synthesized.
  • Step 1 Preparation of 6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)pyridin-2-amine (48-1)
  • Example 2 Use 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinoline (46-1) instead of Example 1 4-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)quinazoline (1-3 ), in a similar manner to that described in the second step of Example 1, the title compound (48-1) of this step (1.2 g, yield: 51%) was synthesized.
  • Step 2 Preparation of N-(6-(4-fluorophenyl)-5-(4-methylquinolin-6-yl)pyridin-2-yl)morpholine-4-carboxamide (48)
  • Step 1 Preparation of 2’-chloro-2-(4-fluorophenyl)-6’-methyl-[3,4-bipyridyl]-6-amine (49-1)
  • A1 receptor cell membrane human source (PerkinElmer, ES-010-M400UA),
  • A2a receptor cell membrane (human source) (PerkinElmer, RBHA2AM400UA),
  • Microscint 20 cocktail scintillation fluid (PerkinElmer, 6013329),
  • PEI Poly ethyleneimine
  • A1 experimental buffer 25 mM HEPES, 5 mM MgCl 2 , 1 mM CaCl 2 , 100 mM NaCl, pH 7.4
  • A1 receptor cell membrane human source
  • [ 3 H]-DPCPX [ 3 H]-DPCPX
  • A1 wash buffer (25 mM HEPES, 5 mM MgCl 2 , 1 mM CaCl 2 , 100 mM NaCl, pH 7.4);
  • A2a experiment buffer 50 mM Tris-HCl, 10 mM MgCl 2 , 1 mM EDTA, pH 7.4
  • A2a receptor cell membrane human source
  • [ 3 H]-CGS-21680 [ 3 H]-CGS-21680
  • A2a wash buffer 50 mM Tris-HCl, 154 mM NaCl, pH 7.4.
  • the A1 receptor cell membrane was diluted to 0.025 ⁇ g/ ⁇ l with A1 experiment buffer, and the A2a receptor cell membrane was diluted to 0.05 ⁇ g/ ⁇ l with A2a experiment buffer to obtain A1 receptor cell membrane dilution and A2a receptor cell membrane dilution.
  • test compound Dilute the test compound and CGS-15943 in DMSO gradient, add 1 ⁇ l of test compound, high value control (0.5% DMSO), low value control (1000 nM CGS-15943) to 96-well plate, add 100 ⁇ l A1 receptor cell membrane to each well Dilute the solution (containing 2.5 ⁇ g cell membrane) to obtain the A1 detection plate; follow the same procedure, add 100 ⁇ l A2a receptor cell membrane dilution solution (containing 5.0 ⁇ g cell membrane) to each well of the 96-well plate to obtain the A2a detection plate;
  • radiolabeled ligand A1 in the assay plate [3 H] -DPCPX (diluted with assay buffer A1 working concentration 1.0nM)
  • A2a 100 ⁇ l assay plate was added radiolabeled ligand [3 H] -CGS- 21680 (diluted with A2a test buffer, working concentration 6.0 nM)
  • use adhesive tape to close the A1 and A2a detection plates, and incubate at room temperature for 1 h and 2 h, respectively.
  • Inhibition rate% 100-(experiment well signal value-low value control signal average value)/(high value control signal average value-low value control signal average value)*100;
  • K i IC 50 /(1+isotopically labeled ligand concentration/K d ), where K d is the dissociation constant of the isotopically labeled ligand.
  • Table 1 shows that the compounds of the present application have a good affinity for the adenosine A2a receptor and a weak affinity for the adenosine A1 receptor.
  • the compound of the present application has very good selectivity for adenosine A2a receptor.
  • Hygromycin B (Invitrogen, 10687010)
  • cAMP detection kit (Cisbio, 62AM4PEB), and
  • ADORA2a/CHOK1 cells Kebai, CBP710157.
  • Preparation of cell culture medium add FBS to 10% (v/v) in Ham’s F-12 medium, add Zeocin to a final concentration of 200 ⁇ g/mL, add Hygromycin B to a final concentration of 100 ⁇ g/mL, and store at 4°C until use.
  • Preparation of 10 ⁇ M adenosine solution accurately weigh a certain amount of adenosine into a 1.5mL EP tube, add a certain volume of cell culture medium, incubate at 37°C for dissolution, and prepare a 10mM stock solution.
  • the cell culture medium was diluted 1:1000 to obtain a 10 ⁇ M adenosine solution.
  • test compound is dissolved in DMSO into a 10 mM stock solution and stored in a refrigerator at 4°C until use.
  • the compound was diluted to 2000 nM and 200 nM with 10 ⁇ M adenosine solution to be tested.
  • Cell seed plate (1) CHO-K1 cells stably expressing ADORA2A receptor are cultured in a 37°C, 5% CO 2 cell incubator. When the confluence of cells reaches about 80%, trypsin digests and disperses the cells Count; (2) Adjust the cell concentration to 6 ⁇ 10 5 cells/mL according to the counting result; (3) Inoculate the cells into a white 384-well cell culture plate, 5 ⁇ L per well (about 3000 cells/well).
  • test reagents (1) Prepare test solution, solution A: take a certain volume of cAMP-d2, dilute Lysis&Detection Buffer according to 1:5; solution B: take a certain volume of cAMP-Cryptate, add Lysis&Detection at 1:5 Buffer dilution. (2) Add the test solution after the 30-minute incubation in the second step. Take out the 384-well plate, add 5 ⁇ L of solution A to each well, and then add solution B at 5 ⁇ L/well. After covering with the sealing film, the 384-well plate was centrifuged at 2500 rpm for 30 s (the test solution and the culture medium were mixed thoroughly), and incubated for 1 h in a 25°C incubator.
  • R Compound means Test compound group R value,
  • R Agonist means Agonist group R value,
  • R Blank means Blank group R value.
  • the detection results of the inhibitory activity (inhibition rate) of the compounds of the present application on ADORA2a/CHOK1 cells are shown in Table 2.
  • the compounds of this application were administered to male SD rats by intravenous (IV) and intragastric (PO), respectively, to investigate the pharmacokinetic characteristics.
  • IV and PO are 1 mg/kg and 5 mg/kg, respectively.
  • the vehicle of IV is a mixture of 5% DMSO, 5% Solutol (polyethylene glycol-15 hydroxystearate) and 90% saline, PO
  • the solvent is 0.5% MC (sodium methyl cellulose).
  • Blood was collected before IV administration (0h) and after administration 0.083h, 0.25h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h, before PO administration (0h) and after administration 0.25 Blood was collected at the time points of h, 0.5h, 1h, 2h, 4h, 6h, 8h and 24h. Blood was anticoagulated with EDTA.K 2 and centrifuged to obtain plasma samples. Compound 11 took brain tissue homogenate at 0.25h, 0.5h, 1h, 4h and 8h, compound 19 and 32 took brain tissue homogenate at 0.25h, 0.5h, 1h and 8h (3 SD rats were selected at each time point) Perform brain tissue distribution experiment), and store at -80°C. Plasma samples and brain tissue homogenates were treated with precipitated proteins for LC-MS/MS analysis.
  • WinNonlin 6.3 software was used to calculate the pharmacokinetic parameters using the non-compartment model. The results are shown in Table 3 and Table 4.
  • the exposures (AUC last ) of the compounds 11, 19, and 32 of the present application administered by IV at a dose of 1 mg/kg were 985 h*ng/mL and 2631 h*ng/mL, respectively.
  • 1822h*ng/mL the maximum blood concentration (C max ) of compounds 11, 19, and 32 in rats were 1311ng/mL, 1150ng/mL, and 1480ng/mL, respectively, indicating that compounds 11, 19, and 32 of this application IV administration has excellent drug exposure in rats.
  • the AUC last of the compounds 11, 19, and 32 of the present application in the rat plasma administered at a dose of 5 mg/kg was 3218h*ng/mL, 11419h*ng/mL, and 7306h*, respectively.
  • ng/mL the AUC last in rat brain tissue was 11.4h*ng/g, 70.2h*ng/g and 52.9h*ng/g, respectively.
  • the ratios of the compound AUC last in rat plasma and the brain tissue AUC last are 282/1, 163/1 and 138/1, indicating that the compounds 11, 19 and 32 of the present application
  • the administration of PO has excellent drug exposure in rat plasma, and the ratio of crossing the blood-brain barrier is very low.

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Abstract

取代芳基化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药及其制备方法和用途，包含所述化合物的药物组合物以及他们的治疗用途。上述化合物或其药物组合物能够抑制腺苷A2a受体活性，可用于治疗或预防与腺苷A2a受体有关疾病，尤其是用于治疗肿瘤。

Description

取代芳基化合物及其制备方法和用途
本申请是以CN申请号为201811616858.5，申请日为2018年12月28日的申请为基础，并主张其优先权，该CN申请的公开内容在此作为整体引入本申请中。
技术领域
本申请涉及取代芳基化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药及其制备方法和用途。本申请还涉及包含所述化合物的药物组合物以及它们的治疗用途。
背景技术
腺苷是一种体内抑制炎症和免疫应答的信号分子，细胞外腺苷主要有2种来源，细胞内腺苷的转运和细胞外腺嘌呤核苷的水解。腺苷受体是一种G蛋白偶联受体(GPCRs)，该家族受体主要包括A1、A2a、A2b和A3四种受体。其中，A2a和A2b受体与激活腺苷酸环化酶的Gs蛋白偶联，刺激产生细胞内环磷酸腺苷(cAMP)。
腺苷A2a受体表达于免疫系统中的一些细胞表面，如T细胞、NK细胞、巨噬细胞和树突状细胞。肿瘤产生的腺苷能与肿瘤组织浸润免疫细胞表面的腺苷A2a受体相互作用，使免疫细胞内cAMP量升高，抑制免疫细胞攻击肿瘤的能力，使机体发生免疫耐受，进而使肿瘤细胞能够逃避机体的免疫监视，主要表现在两个方面：(1)阻断能杀伤肿瘤细胞的免疫细胞活化和发挥功能；(2)增加能抑制免疫细胞对肿瘤细胞应答的调节T细胞(T-regs)数量。在肿瘤细胞向癌细胞演化形成的过程中，它们利用这些机制来逃避免疫系统的监视和攻击，提高自己的生存率。腺苷A2a受体基因敲除的小鼠可以加强CD8+T细胞抗肿瘤的免疫作用，显著抑制肿瘤的增殖，将黑色素瘤或淋巴瘤细胞移植到野生型小鼠体内比移植到腺苷A2a受体基因敲除小鼠体内更容易生长，并且腺苷A2a受体基因敲除小鼠对肿瘤疫苗有更好的应答。
腺苷A2a受体在免疫细胞上高水平表达，腺苷A2a受体的激活可以促使机体产生免疫耐受，促使肿瘤细胞“免疫逃逸”或“免疫抑制”的形成，为肿瘤的发生发展创造了有利条件。腺苷A2a受体拮抗剂直接靶向免疫细胞表面腺苷A2a受体，抑制该受体的激活，进而抑制免疫细胞内cAMP的产生，消除由腺苷A2a受体激活介导的T细胞免疫功能抑制，达到肿瘤治疗的效果。因此，腺苷A2a受体拮抗剂作为肿瘤治疗药物在医药行业具有良好的应用前景。
Corvus公司的CPI-444是对腺苷A2a受体具有拮抗作用的化合物，适应症是肿瘤，在此之前，CPI-444曾用于治疗中枢神经系统疾病的临床试验中。WO01/62233公开了氨基吡啶化合物对腺苷A2a受体具有拮抗作用，并公开了可做为帕金森病或老年痴呆药物的治疗剂。WO2011/095625 A1公开了一种氨基三嗪化合物对腺苷A2a受体具有拮抗作用，并公开了可做为运动障碍、中风、或帕金森病的治疗剂。
因此，腺苷A2a受体拮抗剂作为药物在医药行业具有良好的应用前景。为了达到更好的肿瘤治疗效果，更好地满足市场需求，亟需开发用于治疗肿瘤的、特别是具有低中枢神经系统毒副作用的腺苷A2a受体拮抗剂。
申请内容
本申请涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，
Figure PCTCN2019126555-appb-000001
其中：
X 1为N或CR 3；
X 2为N或CR 4；
且当X 1为CR 3时，X 2不为N；
环A 1选自C 3-10环烷基、4-12元杂环基、C 6-10芳基和5-10元杂芳基，所述环A 1任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、羟基、C 1-6烷氧基、氨基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-和4-12元杂环基；
环A 2选自C 3-10环烷基、4-12元杂环基、C 6-10芳基和5-10元杂芳基(优选地，所述5-10元杂芳基为5-10元含氮杂芳基)，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、羟基、C 1-6烷氧基、氨基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-和4-12元杂环基，且环A 2不为1-异丙基-6-氧代-1,6-二氢吡啶-3-基；
R 1和R 2各自独立地选自氢、C 1-6烷基、C 3-10环烷基、4-12元杂环基、C 6-10芳基、5-10元杂芳基、4-12元杂环基-C 1-6烷基-或5-10元杂芳基-C 1-6烷基-，其中所述C 1-6烷基、C 3-10环烷基、4-12元杂环基、C 6-10芳基、5-10元杂芳基、4-12元杂环基-C 1-6烷基-或5-10元杂芳基-C 1-6烷基-任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-10环烷基和4-12元杂环基；或者，
R 1和R 2连同它们共同连接的氮原子形成4-12元含氮杂环基(优选地，所述4-12元含氮杂环基包含一个或多个选自氮和氧的杂原子)，所述4-12元含氮杂环基任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-、C 3-10环烷基和4-12元杂环基；
R 3和R 4各自独立地选自氢、卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3- 6环烷基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-，并且
所述化合物不是以下化合物：
1-(5,6-二苯基-1,2,4-三嗪-3-基)-3-苯基脲，
1-(5-(2-溴-5-羟基苯基)-4-乙基-6-苯基嘧啶-2-基)脲，
1-(5-(2-氯-5-羟基苯基)-4-乙基-6-苯基嘧啶-2-基)脲，
1-(3,5-二(三氟甲基)苯基)-3-(4-(3-羟基-5-甲基苯基)-5-(吡啶-4-基)嘧啶-2-基)脲，
1-(4-氯-3-(三氟甲基)苯基)-3-(4-(3-羟基-5-甲基苯基)-5-(吡啶-4-基)嘧啶-2-基)脲，
1-(3,5-二(三氟甲基)苯基)-3-(4-(3-甲氧基-5-甲基苯基)-5-(吡啶-4-基)嘧啶-2-基)脲，
1-(4-氯-3-(三氟甲基)苯基)-3-(4-(3-甲氧基5-甲基苯基)-5-(吡啶-4-基)嘧啶-2-基)脲，
1-(4-氯-3-(三氟甲基)苯基)-3-(4-(2-羟基苯基)-5-(4-甲氧基苯基)嘧啶-2-基)脲。
在某些实施方案中，本申请式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中R 3和R 4各自独立地选自氢、卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-。
在某些实施方案中，本申请式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物不是1-(6-(2-氯-6-甲基吡啶-4-基)-5-(4-氟苯基)-1,2,4-三嗪-3-基)脲。
在某些实施方案中，本申请所述的化合物具有式IIa、式IIb或式IIc所示的结构，
Figure PCTCN2019126555-appb-000002
其中：环A 1、环A 2、R 1、R 2、R 3和R 4的定义如本申请所述。
在某些实施方案中，本申请所述的化合物具有式IIa、式IIb或式IIc所示的结构，其中，环A 1、环A 2、R 3和R 4的定义如本申请所述，
R 1和R 2各自独立地选自氢、C 1-6烷基、C 3-8环烷基、4-8元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-，其中所述C 1-6烷基、C 3-8环烷基、4-8元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基和4-7元杂环基；或者，
R 1和R 2连同它们共同连接的氮原子形成4-12元含氮杂环基(例如4-6元含氮杂环基)，所述4-12元含氮杂环基(例如4-6元含氮杂环基)任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-、C 3- 10环烷基和4-12元杂环基。
某些实施方案中，R 1和R 2连同它们共同连接的氮原子形成4-12元含氮杂环基(例如4-6元含氮杂环基)，所述4-12元含氮杂环基包含一个或多个选自氮和氧的杂原子，所述4-12元含氮杂环基(例如 4-6元含氮杂环基)任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-、C 3-10环烷基和4-12元杂环基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1选自苯基和5-6元杂芳基，所述环A 1任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和4-7元杂环基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1选自苯基、呋喃-2-基和呋喃-3-基，所述环A 1任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、硝基、甲基、乙基、正丙基、异丙基、三氟甲基、环丙基、环丁基、环戊基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1选自苯基和呋喃-2-基，所述环A 1任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、硝基、甲基、乙基、正丙基、异丙基、三氟甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1选自苯基、4-氟苯基、4-乙基苯基、4-硝基苯基、2-氟苯基、3-氟苯基、4-甲基苯基、2-甲基苯基、3-甲基苯基、5-甲基-呋喃-2-基、3-甲基-呋喃-2-基和4-甲基-呋喃-2-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1选自苯基、4-氟苯基、4-乙基苯基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1选自4-硝基苯基、2-氟苯基、3-氟苯基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1选自4-甲基苯基、2-甲基苯基、3-甲基苯基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1选自5-甲基-呋喃-2-基、3-甲基-呋喃-2-基和4-甲基-呋喃-2-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1选自4-氟苯基和5-甲基-呋喃-2-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1为4-氟苯基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 1为5-甲基-呋喃-2-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2选自C 6-10芳基和5-10元杂芳基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和4-7元杂环基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2选自C 6-10芳基和5-10元含氮杂芳基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和4-7元杂环基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2选自苯基、吡啶基和喹唑啉基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和4-7元杂环基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2选自苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、喹唑啉-2-基、喹唑啉-4-基、喹唑啉-5-基、喹唑啉-6-基、喹唑啉-7-基和喹唑啉-8-基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和4-7元杂环基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2选自苯基、吡啶-4-基和喹唑啉-6-基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、硝基、甲基、乙基、正丙基、异丙基、三氟甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2选自苯基、吡啶-4-基和喹唑啉-6-基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、甲基、乙基、正丙基、异丙基、三氟甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2选自苯基、吡啶-4-基和喹唑啉-6-基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：氯、甲基、三氟甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2选自吡啶-4-基和喹唑啉-6-基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：氯、甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2为苯基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2为吡啶-4-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2为喹唑啉-6-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：所述环A 2任选地被一个或多个独立地选自下列的取代基取代：氟、氯。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：所述环A 2任选地被一个或多个独立地选自下列的取代基取代：溴、氰基、硝基、甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：所述环A 2任选地被一个或多个独立地选自下列的取代基取代：乙基、正丙基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：所述环A 2任选地被一个或多个独立地选自下列的取代基取代：异丙基、三氟甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2选自3-氯-5-甲基苯基、2-氯-6-甲基吡啶-4-基、2-氯-6-(三氟甲基)-吡啶-4-基和4-甲基喹唑啉-6-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2为4-甲基喹唑啉-6-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2为2-氯-6-甲基吡啶-4-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：环A 2为2-氯-6-(三氟甲基)-吡啶-4-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2各自独立地选自氢、C 1-6烷基、C 3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-，其中所述C 1-6烷基、C 3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基和4-7元杂环基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2各自独立地选自氢、C 1-6烷基、C 3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-，其中所述C 1-6烷基、C 3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、羟基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、哌啶-1-基、哌啶-2-基、哌啶-3-基和哌啶-4-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2各自独立地选自氢、C 1-6烷基、苯基、5-6元杂芳基，其中所述C 1-6烷基、苯基、5-6元杂芳基任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、羟基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、哌啶-1-基、哌啶-2-基、哌啶-3-基和哌啶-4-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2各自独立地选自氢、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、哌啶基、苯基、吡啶基、吡啶-2-基甲基、吡啶-2-基乙基、吡啶-2-基丙基、甲氧基乙基和2-羟基-2-甲基-丙基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2各自独立地选自氢、甲基、甲氧基乙基、2-羟基-2-甲基-丙基、苯基和吡啶-2-基甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2各自独立地选自2-羟基-2-甲基-丙基、苯基和吡啶-2-基甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2各自独立地为氢、甲基或2-甲氧基乙基。
在某些实施方案中，R 1为氢或甲基，且R 2为氢、甲基、苯基、吡啶-2-基甲基、2-羟基-2-甲基-丙基或2-甲氧基乙基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为氢或甲基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 2为甲基、苯基、吡啶-2-基甲基、2-羟基-2-甲基-丙基或2-甲氧基乙基。在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为氢或甲基，且R 2为氢、甲基、苯基、吡啶-2-基甲基、2-羟基-2-甲基-丙基或2-甲氧基乙基；
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1为氢或甲基，且R 2为甲基、吡啶-2-基甲基、2-羟基-2-甲基-丙基或2-甲氧基乙基。在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成4-7元含氮杂环基，所述4-7元含氮杂环基任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-、C 3-6环烷基和4-7元杂环基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成 4-7元含氮杂环基(例如，所述4-7元含氮杂环基含有一个或多个选自氧和氮的杂原子)，所述4-7元含氮杂环基任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-和4-7元杂环基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成哌啶基、吗啉基或哌嗪基，所述哌啶基、吗啉基或哌嗪基任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、三氟甲基、甲氧基、乙氧基、丙氧基、哌啶-1-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成哌啶基或吗啉基，所述哌啶基或吗啉基任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、三氟甲基、甲氧基、乙氧基、丙氧基、哌啶-1-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成哌嗪基，所述哌嗪基或任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、三氟甲基、甲氧基、乙氧基、丙氧基、哌啶-1-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成哌啶基、吗啉基、4-氰基哌啶基、4-甲氧基哌啶基或1,4’-连哌啶基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成4-甲基哌嗪基、2-甲基吗啉基、2,6-二甲基吗啉基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成哌啶基、4-氰基哌啶基、4-甲氧基哌啶基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成1,4’-连哌啶基、4-甲基哌嗪基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成吗啉基，所述吗啉基任选地被一个或多个独立地选自下列的取代基取代：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成吗啉基、2-甲基吗啉基或2,6-二甲基吗啉基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成吗啉基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成2-甲基吗啉基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 1和R 2连同它们共同连接的氮原子形成2,6-二甲基吗啉基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3和R 4各自独立地选自氢、卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3和R 4各自独立地选自氢、卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3和R 4各自独立地选自氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、环丙基、环丁基、环戊基和环己基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3和R 4各自独立地选自氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基和二乙基氨基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3选自氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、环丙基、环丁基、环戊基和环己基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3选自氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基和二乙基氨基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基和二乙基氨基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为氢、氟或氯。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3选自溴、甲基、乙基、正丙基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3选自异丙基、三氟甲基、甲氧基、乙氧基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3选自丙氧基、甲基氨基、乙基氨基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3选自二甲基氨基和二乙基氨基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 3为氟。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4选自氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、环丙基、环丁基、环戊基和环己基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4选自氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基和二乙基氨基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、环丙基、环丁基、环戊基和环己基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基和二乙基氨基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4选自氢、氟、氯。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4选自溴、甲基、乙基、正丙基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4选自异丙基、三氟甲基、甲氧基、乙氧基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4选自丙氧基、甲基氨基、乙基氨基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4选自二甲基氨基和二乙基氨基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为氢、氯、氰基或环丙基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为氢。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：R 4为氯、氰基或环丙基。
在某些实施方案中，本申请所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：
Figure PCTCN2019126555-appb-000003
Figure PCTCN2019126555-appb-000004
Figure PCTCN2019126555-appb-000005
本申请所述化合物中的原子可以被其同位素替代。例如 12C可被其同位素 13C或 14C替代； 1H可被 2H(D，氘)或 3H(T，氚)替代等。本申请包括式I所述化合物以及式I化合物中的任意原子经其同位素替换后得到的同位素标记的化合物。
本申请还涉及制备所述化合物的方法，其包括以下合成路线：
合成路线一：化合物IIa-A的制备方法
Figure PCTCN2019126555-appb-000006
其中：Hal 1和Hal 2各自独立地为相同或不同的卤素，例如Cl、Br或I；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019126555-appb-000007
其余基团如本申请所定义。
步骤A：化合物IIa-1与化合物IN-a反应得到化合物IIa-A
化合物IIa-1与化合物IN-a发生偶联反应得到化合物IIa-A。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选四(三苯基膦)钯。所述碱是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钠。优选地，所述偶联反应在适合的有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺、甲醇、乙醇、甲苯或上述有机溶剂和水的混合溶剂，例如是甲苯、甲醇和水的混合溶剂。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选95℃。优选地，所述偶联反应进行合适的时间，所述时间可以是1-24小时，例如11小时。
合成路线二：化合物IIa的制备方法
Figure PCTCN2019126555-appb-000008
其中：Hal 2为卤素，例如Cl、Br或I，优选为Br；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019126555-appb-000009
其余基团如本申请所定义。
步骤A：化合物IIa-A与化合物IN-b反应得到化合物IIa-2
化合物IIa与化合物IN-b发生偶联反应得到化合物IIa-2。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选四(三苯基膦)钯。所述碱是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钾。优选地，所述偶联反应在适合的有机溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺、甲醇、乙醇、甲苯或上述有机溶剂和水的混合溶剂，例如是1,4-二氧六环和水的混合溶剂。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选95℃。优选地，所述偶联反应进行合适的时间，所述时间可以是1-24小时，优选12小时。
步骤B：将化合物IIa-2与化合物IN-c反应得到式IIa的化合物
化合物IIa-2可以与三光气反应，将氨基转换成异氰酸酯，再与IN-c反应得到式IIa的化合物。所述反应优选在适合的有机溶剂和碱中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、1,4-二氧六环、二氯甲烷、二甲基亚砜及其任意组合，优选四氢呋喃。所述碱是有机碱，例如N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶，优选N,N-二异丙基乙胺。 所述反应优选在适合的温度下进行。所述温度可以是-40℃至60℃，例如0-25℃。所述反应优选进行合适的时间，例如0.5-2小时。
化合物IIa-2也可以在溶剂中并且在碱的存在下先与氯甲酸苯酯反应，再与IN-c反应得到式IIa的化合物。所使用的碱只要其不抑制反应即可，常选有机碱，如N,N-二异丙基乙胺、三乙胺、吡啶和4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如二氯甲烷、四氢呋喃、1,4-二氧六环、乙醚、乙腈等，优选四氢呋喃。反应温度通常为0℃到60℃，优选室温。反应时间通常是1-12小时，优选4小时。
合成路线三：化合物IIb-A的制备方法
Figure PCTCN2019126555-appb-000010
其中：Hal 1为卤素，例如Cl、Br或I，优选为Br；其余基团如本申请所定义。
步骤A：化合物IIb-1与化合物IN-d反应得到化合物IIb-2
化合物IIb-1与化合物IN-d反应得到化合物IIb-2。该反应优选在无溶剂条件下进行，该反应也可以在不会抑制反应的溶剂中进行，如1,4-二氧六环、N,N-二甲基甲酰胺、四氢呋喃、N-甲基吡咯烷酮、苯或甲苯等。反应温度通常为室温到120℃，优选80℃。反应时间通常是6-24小时，优选12小时。
步骤B：化合物IIb-2与IN-e反应得到化合物IIb-3
化合物IIb-2与化合物IN-e在溶剂中并且在碱的存在下反应得到化合物IIb-3。所使用的胍(IN-e)可以与酸例如盐酸、氢溴酸、硫酸或乙酸形成盐，优选盐酸盐。所使用的碱只要其不抑制反应即可，包括碱金属碳酸盐如碳酸钾、碳酸铯、碳酸钠或碱金属醇盐如甲醇钠、乙醇钠、叔丁醇钾，优选碳酸钾。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料和碱即可，如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、二甲基亚砜和乙醇等，优选乙醇。反应温度通常为室温到120℃，优选80℃。反应时间通常是12-36小时，优选20小时。
步骤C：化合物IIb-3与卤化剂反应得到化合物IIb-A
化合物IIb-3与卤化剂在溶剂中反应得到化合物IIb-A。所使用的卤化剂可以是N-溴代丁二酰亚胺或溴素，优选N-溴代丁二酰亚胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、四氢呋喃、1,4-二氧六环和二甲氧基乙烷等，优选N,N-二甲基甲酰胺。反应温度通常为-20℃到室温，优选0℃到室温。反应时间通常是1-24小时，优选12小时。
合成路线四：化合物IIb的制备方法
Figure PCTCN2019126555-appb-000011
其中：Hal 1为卤素，例如Cl、Br或I，优选为Br；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019126555-appb-000012
其余基团如上文所定义。
步骤A：化合物IIb-A与化合物IN-b反应得到化合物IIb-4
化合物IIb-A与化合物IN-b发生偶联反应得到化合物IIb-4。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述碱是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钾。优选地，所述偶联反应在适合的有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺或上述有机溶剂和水的混合溶剂，例如是1,4-二氧六环和水的混合溶剂。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选100℃。反应时间通常是1-8小时，优选4小时。
步骤B：化合物IIb-4与IN-c反应得到式IIb的化合物
化合物IIb-4可以与三光气反应，将氨基转换成异氰酸酯，再与IN-c反应得到式IIb的化合物。所述反应优选在适合的有机溶剂和碱中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、1,4-二氧六环、二氯甲烷、二甲基亚砜及其任意组合，优选四氢呋喃。所述碱是有机碱，例如N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所述反应优选在适合的温度下进行。所述温度可以是-40℃至60℃，例如0-25℃。所述反应优选进行合适的时间，例如0.5-2小时。
化合物IIb-4也可以在溶剂中并且在碱的存在下先与氯甲酸苯酯反应，再与IN-c反应得到式IIb的化合物。所使用的碱只要其不抑制反应即可，常选有机碱，如N,N-二异丙基乙胺、三乙胺、吡啶和4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如二氯甲烷、四氢呋喃、1,4-二氧六环、乙醚、乙腈等，优选四氢呋喃。反应温度通常为0℃到60℃，优选室温。反应时间通常是1-12小时，优选4小时。
合成路线五：化合物IIb的另一种制备方法
Figure PCTCN2019126555-appb-000013
其中：Hal 1为卤素，例如Cl、Br或I，优选为Br；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019126555-appb-000014
其余基团如上文所定义。
步骤A：化合物IIb-A与化合物IN-c反应得到化合物IIb-5
化合物IIb-A可以与三光气反应，将氨基转换成异氰酸酯，再与IN-c反应得到化合物IIb-5。所述反应优选在适合的有机溶剂和碱中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、1,4-二氧六环、二氯甲烷、二甲基亚砜及其任意组合，优选四氢呋喃。所述碱是有机碱，例如N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所述反应优选在适合的温度下进行。所述温度可以是-40℃至60℃，例如0-25℃。所述反应优选进行合适的时间，例如0.5-2小时。
化合物IIb-A也可以在溶剂中并且在碱的存在下先与氯甲酸苯酯反应，再与IN-c反应得到化合物IIb-5。所使用的碱只要其不抑制反应即可，常选有机碱，如N,N-二异丙基乙胺、三乙胺、吡啶和4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如二氯甲烷、四氢呋喃、1,4-二氧六环、乙醚、乙腈等，优选四氢呋喃。反应温度通常为0℃到60℃，优选室温。反应时间通常是1-12小时，优选4小时。
步骤B：化合物IIb-5与化合物IN-b反应得到式IIb的化合物
化合物IIb-5与化合物IN-b发生偶联反应得到式IIb的化合物。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述碱是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钾。优选地，所述偶联反应在适合的有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺或上述有机溶剂和水的混合溶剂，例如是1,4-二氧六环和水的混合溶剂。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，所述时间可以是8-24小时，例如12小时。
合成路线六：化合物IIc-A的制备方法
Figure PCTCN2019126555-appb-000015
其中：Hal 1为卤素，例如Cl、Br或I，优选为Br；其余基团如上文所定义。
步骤A：化合物IIb-1与氧化剂反应得到化合物IIc-1
化合物IIb-1与氧化剂在溶剂中反应得到化合物IIc-1。所使用的氧化剂可以是二氧化硒、高锰酸钾、高碘酸钠、过氧化氢等，优选二氧化硒。该反应可以在不会抑制反应的溶剂中进行，如1,4-二氧六环、N,N-二甲基甲酰胺、四氢呋喃、N-甲基吡咯烷酮或上述有机溶剂和水的混合溶剂，优选1,4-二氧六环和水的混合溶剂。反应温度通常为室温到120℃，优选110℃。反应时间通常是3-14小时，优选5小时。
步骤B：化合物IIc-1与化合物IN-f反应得到化合物IIc-2
化合物IIc-1与化合物IN-f在酸的存在下反应得到化合物IIc-2。所使用的氨基胍(IN-f)可以与酸例如盐酸、碳酸、氢碘酸、硫酸或乙酸形成盐，优选碳酸氢盐。所使用的酸只要其不抑制反应即可，包括盐酸、醋酸、硫酸、三氟醋酸，优选醋酸。该反应优选在无溶剂条件下进行。然而，该反应也能在一定程度上能溶解原料而不会抑制反应的溶剂中进行，如1,4-二氧六环、乙醇、四氢呋喃、苯或甲苯等。反应温度通常为室温到120℃，优选100℃。反应时间通常是1-12小时，优选6小时。
步骤C：化合物IIc-2与卤化剂反应得到化合物IIc-A
化合物IIc-2与卤化剂在溶剂中反应得到化合物IIc-A。所使用的卤化剂可以是N-溴代丁二酰亚胺或溴素，优选N-溴代丁二酰亚胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如N,N-二甲基甲酰胺、N-甲基吡咯烷酮、甲醇、乙醇、四氢呋喃、1,4-二氧六环和二甲氧基乙烷等，优选N,N-二甲基甲酰胺。反应温度通常为-20℃到室温，优选室温。反应时间通常是1-8小时，优选2小时。
合成路线七：化合物IIc-A的另一种制备方法
Figure PCTCN2019126555-appb-000016
其中：Hal 1为卤素，例如Cl、Br或I，优选为Br；其余基团如上文所定义。
步骤A：化合物IIc-3与化合物IN-g反应得到化合物IIc-4
化合物IIc-3与化合物IN-g在酸的存在下反应得到化合物IIc-4。所使用的酸只要其不抑制反应即可，包括盐酸、醋酸、硫酸、三氟醋酸，优选三氟醋酸。该反应能在一定程度上能溶解原料 而不会抑制反应的溶剂中进行，如二氯甲烷、氯仿、1,4-二氧六环、四氢呋喃、N-甲基吡咯烷酮，优选氯仿。反应温度通常为室温到80℃，优选室温。反应时间通常是1-8小时，优选2小时。
步骤B：化合物IIc-4与氧化剂反应得到化合物IIc-A
化合物IIc-4与氧化剂在溶剂中反应得到化合物IIc-A。所使用的氧化剂可以是K 3[Fe(CN) 6]、DDQ、二氧化锰、高锰酸钾等，优选K 3[Fe(CN) 6]。该反应能在一定程度上能溶解原料而不会抑制反应的溶剂中进行，如水、1,4-二氧六环、N,N-二甲基甲酰胺、四氢呋喃、二甲亚砜或上述有机溶剂和水的混合溶剂，优选水。反应温度通常为室温到120℃，优选室温。反应时间通常是3-14小时，优选12小时。
合成路线八：化合物IIc的制备方法
Figure PCTCN2019126555-appb-000017
其中：Hal 1为卤素，例如Cl、Br或I，优选为Br；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019126555-appb-000018
其余基团如上文所定义。
步骤A：化合物IIc-A与化合物IN-b反应得到化合物IIc-5
化合物IIc-A与化合物IN-b发生偶联反应得到化合物IIc-5。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选四(三苯基膦)钯。所述碱是无机碱，例如碳酸铯、碳酸钾、碳酸钠、碳酸氢钾、碳酸氢钠，优选碳酸钾。优选地，所述偶联反应在适合的有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺或上述有机溶剂和水的混合溶剂，例如是1,4-二氧六环和水的混合溶剂。优选地，所述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，所述时间可以是1-24小时，例如6小时。
步骤B：化合物IIc-5与化合物IN-c反应得到式IIc的化合物
化合物IIc-5可以与三光气反应，将氨基转换成异氰酸酯，再与化合物IN-c反应得到式IIc的化合物。所述反应优选在适合的有机溶剂和碱中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、1,4-二氧六环、二氯甲烷、二甲基亚砜及其任意组合，优选四氢呋喃。所述碱是有机碱，例如N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所述反应优选在适合的温度下进行。所述温度可以是-40℃至60℃，例如0-25℃。所述反应优选进行合适的时间，例如0.5-2小时。
化合物IIc-5也可以在溶剂中并且在碱的存在下先与氯甲酸苯酯反应，再与IN-c反应得到式(IIc)的化合物。所使用的碱只要其不抑制反应即可，常选有机碱，如N,N-二异丙基乙胺、三乙胺、吡啶和4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如二氯甲烷、四氢呋喃、1,4-二氧六环、乙醚、乙腈等，优选四氢呋喃。反应温度通常为0℃到60℃，优选室温。反应时间通常是1-12小时，优选4小时。
合成路线九：化合物IIc的另一种制备方法
Figure PCTCN2019126555-appb-000019
其中：Hal 1为卤素，例如Cl、Br或I，优选为Br；Y为硼酸或硼酸酯基团，优选为-B(OH) 2或者
Figure PCTCN2019126555-appb-000020
其余基团如上文所定义。
步骤A：化合物IIc-A与化合物IN-c反应得到化合物IIc-6
化合物IIc-A可以与三光气反应，将氨基转换成异氰酸酯，再与化合物IN-c反应得到化合物IIb-6。所述反应优选在适合的有机溶剂和碱中进行。所述有机溶剂可选自直链或环状醚类(例如四氢呋喃或乙醚等)、1,4-二氧六环、二氯甲烷、二甲基亚砜及其任意组合，优选四氢呋喃。所述碱是有机碱，例如N,N-二异丙基乙胺、三乙胺、吡啶、4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所述反应优选在适合的温度下进行。所述温度可以是-40℃至60℃，例如0-25℃。所述反应优选进行合适的时间，例如0.5-2小时。
化合物IIc-A也可以在溶剂中并且在碱的存在下先与氯甲酸苯酯反应，再与化合物IN-c反应得到化合物IIb-6。所使用的碱只要其不抑制反应即可，常选有机碱，如N,N-二异丙基乙胺、三乙胺、吡啶和4-二甲氨基吡啶，优选N,N-二异丙基乙胺。所使用的溶剂只要其不抑制反应并且可以在一定程度上溶解原料即可，如二氯甲烷、四氢呋喃、1,4-二氧六环、乙醚、乙腈等，优选四氢呋喃。反应温度通常为0℃到60℃，优选室温。反应时间通常是1-12小时，优选4小时。
步骤B：化合物IIc-6与化合物IN-b反应得到式(IIc)的化合物
化合物IIc-6与化合物IN-b发生偶联反应得到式(IIc)的化合物。所述偶联反应优选在金属催化剂和碱的存在下进行。优选地，所述金属催化剂是钯金属催化剂，例如四(三苯基膦)钯、[1,1'-双(二苯基膦基)二茂铁]二氯化钯、[1,1'-双(二苯基膦)二茂铁]二氯化钯二氯甲烷络合物、二(三苯基膦)二氯化钯、醋酸钯，优选[1,1'-双(二苯基膦基)二茂铁]二氯化钯。所述碱是无机碱，例如碳酸钾、碳酸铯、碳酸钠、碳酸氢钠、碳酸氢钾，优选碳酸钾。优选地，所述偶联反应在适合的有机溶剂或有机溶剂和水的混合溶剂中进行，所述有机溶剂可选1,4-二氧六环、N,N-二甲基甲酰胺或上述有机溶剂和水的混合溶剂，例如是1,4-二氧六环和水的混合溶剂。优选地，所 述偶联反应在适合的保护气氛(例如氮气环境)下进行。优选地，所述偶联反应在适合的温度下进行，所述温度可以是70-100℃，优选80℃。优选地，所述偶联反应进行合适的时间，所述时间可以是8-24小时，例如12小时。
上述各反应步骤的具体条件为本领域公知，对此本申请不作具体限定。根据本申请的教导结合本领域公知常识，本领域技术人员可以对通式中的各取代基进行选择替换以制备得到不同的化合物，这些选择和替换均在本申请的保护范围之内。
本申请还涉及药物组合物，其包含本申请所述式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及任选的一种或多种药学上可接受的载体或赋形剂。
本申请还涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或其药物组合物在制备作为腺苷A2a受体拮抗剂的药物中的用途。
本申请还涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或其药物组合物在制备用于治疗或预防与腺苷A2a受体有关疾病的药物中的用途。
本申请还涉及一种治疗和/或预防与腺苷A2a受体有关疾病的方法，其包括向有需要的受试者施用有效量的本申请式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或其药物组合物。
本申请还涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或其药物组合物，其用于抑制腺苷A2a受体活性。
本申请还涉及式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或其药物组合物，其用于治疗和/或预防与腺苷A2a受体有关的疾病。
在部分实施方案中，所述与腺苷A2a受体有关的疾病为肿瘤。所述肿瘤包括但不限于：乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
本申请中，所述药物组合物的目的是促进对生物体的给药，利于活性成分的吸收进而发挥生物活性。其中所述的载体包括但不限于：离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白如人血白蛋白、缓冲物质如磷酸盐、甘油、山梨酸、山梨酸钾、饱和植物脂肪酸的部分甘油酯混合物、水、盐或电解质、如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶态氧化硅、三硅酸镁、聚乙烯吡咯烷酮、纤维素物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜂蜡、羊毛脂。
所述赋形剂是指在药物制剂中除主药以外的附加物。其性质稳定，与主药无配伍禁忌，不产生副作用，不影响疗效，在常温下不易变形、干裂、霉变、虫蛀、对人体无害、无生理作用，不与主药产生化学或物理作用，不影响主药的含量测定等。如片剂中的黏合剂、填充剂、崩解剂、润滑剂；中药丸剂中的酒、醋、药汁等；半固体制剂软膏剂、霜剂中的基质部分；液体制剂中的防腐剂、抗氧剂、矫味剂、芳香剂、助溶剂、乳化剂、增溶剂、渗透压调节剂、着色剂等均可称为赋形剂。
本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药可以通过以下途径给药：胃肠外、局部、静脉内、口服、皮下、动脉内、真皮内、经皮、直肠、颅内、腹膜内、鼻内、肌内途径或作为吸入剂。所述药物组合物可以任选地与在治疗各种疾病中至少有一定效果的其它试剂联合给药。
本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药可根据给药途径配成各种适宜的剂型。
本申请所述的药物组合物或适宜的剂型可以含有0.01mg至1000mg的本申请化合物。
当口服用药时，本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药可制成任意口服可接受的制剂形式，包括但不限于片剂、胶囊、水溶液或水悬浮液。
当皮肤局部施用时，本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药可制成适当的软膏、洗剂或霜剂制剂形式，其中将活性成分悬浮或溶解于一种或多种载体中。软膏制剂可使用的载体包括但不限于：矿物油、液体凡士林、白凡士林、丙二醇、聚氧化乙烯、聚氧化丙烯、乳化蜡和水；洗剂或霜剂可使用的载体包括但不限于：矿物油、脱水山梨糖醇单硬脂酸、吐温60、十六烷酯蜡、十六碳烯芳醇、2-辛基十二烷醇、苄醇和水。
本申请的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药还可以无菌注射制剂形式用药，包括无菌注射水或油悬浮液或无菌注射溶液。其中，可使用的载体和溶剂包括水、林格氏溶液和等渗氯化钠溶液。另外，灭菌的非挥发油也可用作溶剂或悬浮介质，如单甘油酯或二甘油酯。
在本申请的实施方案中，进行合适的体外或体内测定来确定本申请药物组合物的效果以及给药是否适用于治疗个体所患疾病或医学疾病状态。这些测定的实例在下文非限制性实施例结合具体疾病或医学治疗进行了描述。通常，足以实现预防或治疗效果的本申请组合物的有效量为约0.001mg/千克体重/天至约10,000mg/千克体重/天。合适的情况下，剂量为约0.01mg/千克体重/天至约1000mg/千克体重/天。剂量范围可以为每天、每两天或每三天约0.01至1000mg/kg受试者体重，更通常为0.1至500mg/kg受试者体重。示例性的治疗方案为每两天一次或每周一次或每月一次给药。通常多次给予所述制剂，单次剂量之间的间隔可以是每天、每周、每月或每年。或者，可以以缓释制剂的形式给予所述制剂，在这种情况下，需要较少的给药频率。剂量和频率根据制剂在受试者中的半衰期而不同。也可以根据是预防性处理还是治疗性处理而不同。在预防性应用中，以相对低频率的间隔长期给予相对低的剂量。在治疗性应用中，有时需要以相对短的间隔给予相对高的剂量，直至疾病的进展被延缓或停止，并优选地直至个体表现出疾病症状的部分或完全改善，在此之后，可以给予患者预防方案。
以下对本申请的术语进行解释，对于特定的术语，如果本申请中的含义与本领域技术人员通常理解的含义不一致，以本申请中的含义为准；如果在本申请中没有定义，则其具有本领域技术人员通常理解的含义。除非有相反陈述，本申请中使用的术语具有下述含义：
本申请所用术语“包括”、“包含”、“具有”、“含有”或“涉及”及其在本文中的其它变体形式为包含性的(inclusive)或开放式的，且不排除其它未列举的元素或方法步骤。
本申请所用术语“氢”及所述的各基团中的氢，是指氕(H)、氘(D)或氚(T)。
本申请所用术语“卤素”是指氟、氯、溴或碘。
本申请所用术语“C 1-6烷基”是指具有1-6个碳原子的直链或支链烷基，例如C 1-4烷基、C 1-2烷基、C 1烷基、C 2烷基、C 3烷基、C 4烷基、C 5烷基或C 6烷基。具体的实例包括但不限于甲基、乙基、丙基、异丙基、正丁基、异丁基、仲丁基、叔丁基、正戊基、正己基等。
本申请所用术语“C 1-6烷氧基”是指通过氧原子连接至母体分子部分的如上文所定义的C 1-6烷基。C 1-6烷氧基的代表性实例包括但不限于甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、叔丁氧基。
本申请所用术语“C 1-6卤代烷基”是指被卤素例如氟，氯，溴或碘单或多取代的如上文所定义的C 1- 6烷基。C 1-6卤代烷基的代表性实例包括但不限于氯甲基、氯乙基、二氯乙基、三氟甲基、二氟甲基、单氟甲基等。
本申请中使用的术语“C 1-6烷基-氨基-”是指被如上文所定义的C 1-6烷基单取代的氨基。“C 1-6烷基-氨基”的典型实例包括但不限于甲氨基，乙氨基，丙氨基，丁氨基等。
本申请中使用的术语“二(C 1-6烷基)-氨基-”是指被如上文所定义的C 1-6烷基二取代的氨基。“二(C 1-6烷基)-氨基-”的典型实例包括但不限于二甲氨基，二乙氨基，二丙氨基，二丁氨基等。
本文中使用的术语“C 3-10环烷基”是指具有3-10个碳原子并且具有单环或二环或多个稠合环(包括稠合和桥连环系)的饱和环状烃基，例如具有3-8，5-8，3-6或5-6个碳原子。“C 3-10环烷基”的典型实例包括但不限于单环结构，诸如环丙基，环丁基，环戊基，环己基、环庚基、环辛基，1-甲基环丙基，2-甲基环戊基，2-甲基环辛基等；二环结构，诸如二环[2.2.1]庚基，和多环结构，例如金刚烷基等。
本申请使用的术语“4-12元杂环基”是指至少含有一个杂原子(例如，含有1个、2个、3个、4个或5个)且环原子数为4-12个的饱和或部分饱和的且不具有芳香性的单环或二环或多个稠合环的环状基团，所述杂原子为氮原子、氧原子和/或硫原子。所述“4-12元杂环基”可以被氧代或硫代。例如，本申请所述的“4-12元杂环基”含有1-2个杂原子，例如含有1个氮原子、氧原子或硫原子，或含有1个氮原子和1个氧原子。所述“4-12元杂环基”例如“4-10元杂环基”、“4-8元杂环基”、“4-6元杂环基”、“4-7元杂环基”、“5-6元杂环基”、“4-6元饱和杂环基”、“5-6元饱和杂环基”、“4-8元含氧杂环基”、“4-6元含氧杂环基”、“5-6元含氧杂环基”、“4-6元饱和含氧杂环基”、“4-10元含氮杂环基”、“4-7元含氮杂环基”、“4-8元含氮杂环基”、“5-6元含氮杂环基”、“5-6元饱和含氮杂环基”等。“4-12元杂环基”的具体实例包括但不仅限于：氮杂环丁烷基、1,4-二氧杂环己烷基、1,3-二氧杂环己烷基、1,3-二氧杂环戊烷基、1,4-二氧杂环己二烯基、四氢呋喃基、二氢吡咯基、吡咯烷基、咪唑烷基、4,5-二氢咪唑基、吡唑烷基、4,5-二氢吡唑基、2,5-二氢噻吩基、四氢噻吩基、哌嗪基、噻嗪基、哌啶基、吗啉基等。
本申请所用的术语“C 6-10芳基”是指具有一个单环或两个或多个稠合环的6-10个碳原子的不饱和芳族碳环基。所述芳基例如具有5-8或5-6个碳原子。“C 6-10芳基”的典型实例包括但不限于苯基，萘基和蒽基等。
本文所用的术语“5-10元杂芳基”表示意指具有5-10个环成员的杂芳族环基团，包括单环杂芳族环和多环芳族环，多环芳族环中单环芳族环与一个或多个其他芳族环稠合。“5-10元杂芳基”中具有一 个或两个或多个选自O，S或N的杂原子。本申请所用的术语“杂芳基”范围内还包括的是其中芳族环与一个或多个非芳族环(碳环或杂环)稠合的基团，其中连接基团或点位于芳族环或非芳族环上。所述杂芳基例如具有5-6个环成员。“5-10元杂芳基”的典型实例包括但不限于呋喃基，咪唑基，三氮唑基、吲哚基，四氮唑基、吡啶基，蝶啶基，嘧啶基，三唑基，喹啉基，异喹啉基，喹唑啉基，喹喔啉基等。
如果取代基被描述为“任选地被…取代”，则取代基可(1)未被取代或(2)被取代。如果取代基的碳被描述为任选地被取代基列表中的一个或多个取代，则碳上的一个或多个氢(至存在的任何氢的程度)可单独和/或一起被独立地选择的任选的取代基替代。如果取代基的氮被描述为任选地被取代基列表中的一个或多个取代，则氮上的一个或多个氢(至存在的任何氢的程度)可各自被独立地选择的任选的取代基替代。
本申请所用术语“一个或多个”是指在合理条件下的1个或超过1个，例如2个、3个、4个、5个、6个、7个、8个、9个或10个。
除非指明，否则如本文中所使用，取代基的连接点可来自取代基的任意适宜位置。
本申请所用术语“立体异构体”表示由于至少一个不对称中心形成的异构体。在具有一个或多个(例如1个、2个、3个或4个)不对称中心的化合物中，其可产生外消旋混合物、单一对映异构体、非对映异构体混合物和单独的非对映异构体。特定个别分子也可以几何异构体(顺式/反式)存在。类似地，本申请的化合物可以两种或更多种处于快速平衡的结构不同的形式的混合物(通常称作互变异构体)存在。互变异构体的代表性实例包括酮-烯醇互变异构体、苯酚-酮互变异构体、亚硝基-肟互变异构体、亚胺-烯胺互变异构体等。要理解，本申请的范围涵盖所有这样的以任意比例(例如60％、65％、70％、75％、80％、85％、90％、95％、96％、97％、98％、99％)的异构体或其混合物。
除非另外指明，否则本申请的化合物意欲可以立体异构体(其包括顺式及反式异构体、光学异构体(例如R及S对映异构体)、非对映异构体、几何异构体、旋转异构体、构象异构体、阻转异构体及其混合物)的形式存在。本申请的化合物可表现一种以上类型的异构现象，且由其混合物(例如外消旋混合物及非对映异构体对)组成。
本申请涵盖本申请的化合物的所有可能的结晶形式或多晶型物，其可为单一多晶型物或多于一种多晶型物的任意比例的混合物。
还应当理解，本申请的某些化合物可以游离形式存在用于治疗，或适当时，以其药学上可接受的衍生物形式存在。在本申请中，药学上可接受的衍生物包括但不限于，药学上可接受的盐、溶剂合物、N-氧化物、代谢物或前药，在将它们向需要其的患者给药后，能够直接或间接提供本申请的化合物或其代谢物或残余物。因此，当在本文中提及“本申请的化合物”时，也意在涵盖化合物的上述各种衍生物形式。
本领域技术人员会理解，由于氮需要可用的孤对电子来氧化成氧化物，因此并非所有的含氮杂环都能够形成N-氧化物；本领域技术人员会识别能够形成N-氧化物的含氮杂环。本领域技术人员还会认识到叔胺能够形成N-氧化物。用于制备杂环和叔胺的N-氧化物的合成方法是本领域技术人员熟知的，包括用过氧酸如过氧乙酸和间氯过氧苯甲酸(MCPBA)、过氧化氢、烷基过氧化氢如叔丁基过氧化氢、过硼酸钠和双环氧乙烷(dioxirane)如二甲基双环氧乙烷来氧化杂环和叔胺。这些用于制备N-氧化物的方法已在文献中得到广泛描述和综述，参见例如：T.L.Gilchrist,Comprehensive Organic Synthesis, vol.7,pp 748-750；A.R.Katritzky和A.J.Boulton,Eds.,Academic Press；以及G.W.H.Cheeseman和E.S.G.Werstiuk，Advances in Heterocyclic Chemistry,vol.22,pp 390-392,A.R.Katritzky和A.J.Boulton,Eds.,Academic Press。
本申请的化合物可以溶剂合物(如水合物)的形式存在，其中本申请的化合物包含作为所述化合物晶格的结构要素的极性溶剂，特别是例如水、甲醇或乙醇。极性溶剂特别是水的量可以化学计量比或非化学计量比存在。
本申请的化合物或其药学上可接受的盐还可以形成溶剂合物，例如醇合物等。
本申请的化合物还可以是前药或以或可在体内代谢变化后释放出所述活性成分的形式。选择和制备适当的前药衍生物是本领域技术人员公知技术。
本申请的化合物还可以是化学保护的形式，所述保护基可保护在化合物的活性基团(如氨基)上，所述保护基可在体内代谢释放出活性成分。选择和制备适当的化学保护的形式是本领域技术人员公知技术。
本申请所用术语“药学上可接受的”是指物质或组合物必须与构成制剂的其他组分和/或用其治疗的哺乳动物在化学和/或毒理学上相容。
本申请所用术语“药学上可接受的盐”包括与药学上可以接受的无机酸或者有机酸、或者无机碱或有机碱形成的常规盐。合适的酸加成盐的例子包括高氯酸、丙酸、琥珀酸、羟基乙酸、扑酸、丙二酸、羟基马来酸、苯乙酸、谷氨酸、萘-2-磺酸、羟基萘甲酸、氢碘酸、苹果酸、鞣酸等形成的盐。合适的碱加成盐的例子包括钠、钾、镁、锂、铝、钙、锌、N,N’-二苄基乙二胺、氯代普鲁卡因、胆碱、二乙醇胺、乙二胺、N-甲基葡糖胺和普鲁卡因等形成的盐。
适合的盐的综述参见Stahl及Wermuth的“Handbook of Pharmaceutical Salts:Properties,Selection,and Use”(Wiley-VCH,2002)。用于制备本申请的化合物的药学上可接受的盐的方法为本领域技术人员已知的。
本申请所用术语“药物组合物”包括包含治疗有效量的本申请式I的化合物的产品，以及直接地或间接地由本申请式I化合物的组合产生的任何产品。
本申请所用术语“有效量”是指足以实现所需治疗效果的量，例如，实现减轻与待治疗疾病相关的症状的量。
本申请所用的术语“预防”是指预防性给药以降低疾病或症状发作的可能性或延迟该疾病或症状的发作。
本申请所用的术语“治疗”目的是减轻或消除所针对的疾病状态或病症。如果受试者按照本文所述方法接受了治疗量的化合物、其光学异构体或其药学上可接受的盐或其药物组合物，该受试者一种或多种指征和症状表现出可观察到的和/或可检测出的降低或改善，则受试者被成功地“治疗”了。还应当理解，所述的疾病状态或病症的治疗的不仅包括完全地治疗，还包括未达到完全地治疗，但实现了一些生物学或医学相关的结果。
本申请所用术语“受试者”是指哺乳动物受试者(例如，狗、猫、马、牛、绵羊、山羊、猴等)和人受试者，包括男性和女性受试者且包括新生儿、婴儿、少年、青少年、成人和老年受试者，并且包括各种种族和族裔，包括但不限于，白人、黑人、亚洲人、美洲印第安人和西班牙裔。
本申请中所述的化合物，对于同一化合物而言，若名称与结构式不一致，以化合物结构式为准。
本申请的有益效果
通过大量研究，令人惊奇地发现，本申请的化合物对腺苷A1受体的抑制能力弱，能够选择性的抑制腺苷A2a受体。此外，本申请的化合物血脑屏障透过性低，具有很强的外周选择性，同时具有良好的药代动力学性质。因此，本申请化合物能够激活由腺苷A2a受体激活介导的T细胞免疫功能，具有良好的肿瘤治疗的活性，并且能够避免由于抑制中枢神经系统的腺苷A2a受体而引起的毒副作用。
具体实施方式
下面将结合实施例对本申请的实施方案进行详细描述，但是本领域技术人员会理解，下列实施例仅用于说明本申请，而不应视为限制本申请的范围。实施例中未注明具体条件者，按照常规条件或制造商建议的条件进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规产品。
以下实施例中，化合物的结构通过核磁共振( 1H NMR)或质谱(MS)来确定。 1H NMR的测定采用JEOL Eclipse 400核磁仪，测定溶剂为氘代甲醇(CD 3OD)、氘代氯仿(CDCl 3)或六氘代二甲基亚砜(DMSO-d 6)，内标为四甲基硅烷(TMS)，化学位移(δ)以10 -6(ppm)作为单位给出。
以下实施例中，MS的测定采用Agilent(ESI)质谱仪，生产商：Agilent，型号：Agilent 6120B。
以下实施例中，采用制备型高效液相色谱仪进行纯化时，采用的仪器型号为Agilent 1260，色谱柱为Waters SunFire Prep C18 OBD(19mm×150mm×5.0μm)。色谱条件如下：
色谱柱温：25℃；
流速：20.0mL/min；
检测波长：214nm；
洗脱梯度：(0min：10％(v/v)A，90％(v/v)B；16.0min：90％(v/v)A，10％(v/v)B)；
其中，流动相A为乙腈；流动相B为0.05％(v/v)甲酸水溶液。
以下实施例中，薄层色谱硅胶板(TLC)使用Merck产的铝板(20×20cm)，薄层层析分离纯化采用的硅胶板是烟台产GF 254(1mm厚)。
以下实施例中，反应的监测采用薄层色谱法(TLC)或LC-MS，使用的展开剂体系有：二氯甲烷和甲醇体系，正己烷和乙酸乙酯体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节或者加入三乙胺等进行调节。
以下实施例中，微波反应使用Biotage Initiator+(400W,RT～300℃)微波反应器。
以下实施例中，柱层析一般使用200～300目硅胶为载体。洗脱剂的体系包括：二氯甲烷和甲醇体系，石油醚和乙酸乙酯体系，溶剂的体积比根据化合物的极性不同而进行调节，也可以加入少量的三乙胺进行调节。
以下实施例中无特殊说明，反应的温度为室温(20℃～35℃)。
以下实施例中，本申请所使用的试剂购自Acros Organics、Aldrich Chemical Company、特伯化学等公司。
在常规的合成法以及本申请的化合物和中间体合成例中，各缩写的意思如以下所示。
缩写 含义
DMF N,N-二甲基甲酰胺
dppf 1,1'-双(二苯基膦基)二茂铁
TLC 薄层色谱法
Pd(dppf)Cl 2 [1,1'-双(二苯基膦基)二茂铁]二氯化钯
Pd(amphos)Cl 2 二氯二叔丁基-(4-二甲基氨基苯基)膦钯
DIPEA N,N-二异丙基乙胺
K 3[Fe(CN) 6] 铁氰化钾
中间体的制备：
中间体制备例1：6-溴-5-(5-甲基呋喃基-2-基)-1,2,4-三嗪-3-胺(In-1)的制备
Figure PCTCN2019126555-appb-000021
第一步：6-溴-5-(5-甲基呋喃-2-基)-4,5-二氢-1,2,4-三嗪-3-胺(In-1-c)的制备
0℃下，向3-氨基-6-溴-1,2,4-三嗪(In-1-a)(10.0g,114.4mmol)和2-甲基呋喃(In-1-b)(9.4g,114.3mmol)的氯仿(50mL)溶液中滴加三氟乙酸(50mL)，滴加完毕升至室温，继续搅拌2小时。完全反应后，向反应液中加入饱和碳酸钠溶液，调节pH至8-9，搅拌20分钟，加正庚烷打浆，过滤，滤渣用正庚烷洗涤，真空干燥，得到本步的标题化合物(In-1-c)(14g，收率：95％)。
MS m/z(ESI):257.0[M+H] +。
第二步：6-溴-5-(5-甲基呋喃基-2-基)-1,2,4-三嗪-3-胺(In-1)的制备
向6-溴-5-(5-甲基呋喃-2-基)-4-5-二氢-1,2,4-三嗪-3-胺(In-1-c)(14.0g,54.5mmol)和K 3[Fe(CN) 6](In-1-d)(35.9g,108.9mmol)的二氯甲烷(180mL)溶液中加入氢氧化钾(7.3g,130.7mmol)的水(90mL)溶液，室温反应过夜。反应完毕后，向反应液中加入水(250mL)和正庚烷(250mL)打浆，抽滤，滤渣用正庚烷洗涤，真空干燥，得到标题化合物(In-1)(11g，收率：79％)。
MS m/z(ESI):255.0[M+H] +。
中间体制备例2：4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉的制备
Figure PCTCN2019126555-appb-000022
第一步：6-溴-4-甲基喹唑啉(In-2-b)的制备
将1-(2-氨基-5-溴苯基)乙酮(In-2-a)(3g,14mmol)、原甲酸三乙酯(3.1g,21mmol)和乙酸铵(1.62g,21mmol)加入到反应瓶中，100℃反应过夜。反应完毕后，冷却至室温，浓缩反应液，剩余物加水稀释，并用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，滤液浓缩，剩余物用硅胶柱 层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝3/1(v/v))，得到本步的标题化合物(In-2-b)(2.6g，收率：83％)。
MS m/z(ESI):223.0[M+H] +。
第二步：4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(In-2)的制备
氮气氛围下，向6-溴-4-甲基喹唑啉(In-2-b)(2g,8.9mmol)的1,4-二氧六环溶液(50mL)中依次加入联硼酸频哪醇酯(In-2-c)(3.4g,13.5mmol)、醋酸钾(1.76g,16.9mmol)和Pd(dppf)Cl 2(0.65g,0.9mmol)，80℃反应6小时。反应完毕后，冷却至室温，浓缩反应液，剩余物加水稀释，并用乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝2/1(v/v))，得到标题化合物(In-2)(2.1g，收率：87％)。
MS m/z(ESI):271.2[M+H] +。
中间体制备例3：5-(4-氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺(In-3)的制备
Figure PCTCN2019126555-appb-000023
第一步：2-(4-氟苯基)-2-氧代乙醛(In-3-b)的制备
氮气氛围下，向二氧化硒(3.3g,29.7mmol)的1,4-二氧六环(50mL)溶液中加入水(5mL)，60℃搅拌0.5小时至二氧化硒完全溶解，加入1-(4-氟苯基)乙酮(In-3-a)(1.3g,9.7mmol)，110℃反应5小时。冷却至室温，抽滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/1(v/v))，得到本步的标题化合物(In-3-b)(1.2g，收率：92％)。
MS m/z(ESI):153.0[M+H] +。
第二步：5-(4-氟苯基)-1,2,4-三嗪-3-胺(In-3-c)的制备
将2-(4-氟苯基)-2-氧代乙醛(In-3-b)(1.2g,7.9mmol)溶于醋酸(20mL)中，分批次加入氨基胍(1.2g,15.8mmol)，100℃反应6小时。冷却至室温，剩余物加水稀释，乙酸乙酯萃取。合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/1(v/v))，得到本步的标题化合物(In-3-c)(0.9g，收率：60％)。
MS m/z(ESI):191.1[M+H] +。
第三步：6-溴-5-(4-氟苯基)-1,2,4-三嗪-3-胺(In-3-d)的制备
冰浴下，向5-(4-氟苯基)-1,2,4-三嗪-3-胺(In-3-c)(0.9g,4.7mmol)的DMF(10mL)溶液中分批次加入N-溴代丁二酰亚胺(1.1g,6.1mmol)，室温反应2小时。反应液倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，得到本步的标题化合物(In-3-d)(1g，收率：80％)。
MS m/z(ESI):269.0[M+H] +。
第四步：5-(4-氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺(In-3)的制备
将6-溴-5-(4-氟苯基)-1,2.4-三嗪-3-胺(In-3-d)(1g,3.7mmol)、4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(In-3-e)(1.2g,4.4mmol)和碳酸钾(1.1g,7.4mmol)加入到1,4-二氧六环(20mL)和水(4mL)的混合溶剂中，置换氮气三次，加入四(三苯基膦)钯(0.4g,0.4mmol)，80℃反应6小时。反应完毕后，冷却至室温，浓缩反应液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：甲醇/二氯甲烷＝1/10(v/v))，得到标题化合物(In-3)(0.9g，收率：75％)。
MS m/z(ESI):333.1[M+H] +。
中间体制备例4：2-氯-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-4)的制备
Figure PCTCN2019126555-appb-000024
氮气氛围下，向2-甲基-6-氯吡啶(In-4-a)(1.0g,7.8mmol)的环己烷溶液(40mL)中依次加入联硼酸频哪醇酯(In-4-b)(3.0g,11.8mmol)、4,4′-二叔丁基-2,2′-联吡啶(11mg,0.78mmol)和二(1,5-环辛二烯)二-Μ-甲氧基二铱(I)(520mg,0.78mmol)，80℃反应6小时。反应完毕后，冷却至室温，浓缩反应液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/2(v/v))，得到标题化合物(In-4)(1.9g，收率：96％)。
MS m/z(ESI):254.1[M+H] +。
中间体制备例5：2-(3-氯-5-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(In-5)的制备
Figure PCTCN2019126555-appb-000025
用1-氯-3-甲苯(In-5-a)代替中间体制备例4中的2-甲基-6-氯吡啶，以类似中间体制备例4所述的方法，合成得到标题化合物(In-5)(3.91g，收率：81.1％)。
MS m/z(ESI):253.1[M+H] +。
中间体制备例6：2-氯-6-三氟甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-6)的制备
Figure PCTCN2019126555-appb-000026
用2-氯-6-三氟甲基吡啶(In-6-a)代替中间体制备例4中的2-甲基-6-氯吡啶，以类似中间体制备例4所述的方法，合成得到标题化合物(In-6)(1.5g，收率：88％)。
MS m/z(ESI):308.1[M+H] +。
中间体制备例7：3-(5-溴-4-(4-氟苯基)嘧啶-2-基)-1-甲基-1-(2-吡啶基甲基)脲(In-7)的制 备
Figure PCTCN2019126555-appb-000027
将5-溴-4-(4-氟苯基)嘧啶-2-胺(In-7-a)(300mg,1.12mmol)溶于四氢呋喃(5mL)与DIPEA(1mL)的混合溶剂，0℃下加入三光气(332mg,1.12mmol)，混合物维持0℃搅拌0.5小时，然后加入N-甲基-1-吡啶-2-甲胺(In-7-b)(342mg,2.80mmol)，0℃下反应1.5小时。反应完毕后，向反应液中加甲醇淬灭，浓缩，剩余物用制备型高效液相色谱仪纯化，得到标题化合物(In-7)(400mg，收率：86％)。
MS m/z(ESI):416.0[M+H] +。
中间体制备例8：N-(6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)-[1,4′-联哌啶]-1′-甲酰胺(In-8)的制备
Figure PCTCN2019126555-appb-000028
第一步：[1,4′-联哌啶]-1′-甲酸苄酯(In-8-c)的制备
0℃下，向4-氧代哌啶-1-甲酸苄酯(In-8-a)(5g,21.44mmol)的二氯甲烷(100mL)溶液中，加入哌啶(In-8-b)(1.83g,21.44mmol)和钛酸四异丙酯(6.70g,23.58mmol)，室温搅拌反应2小时后，分批次加入氰基硼氢化钠(1.35g,21.44mmol)，25℃反应12小时。加入水淬灭反应，搅拌10分钟，静置，抽滤，浓缩滤液，剩余物溶于乙酸乙酯，抽滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/3(v/v))，得到本步的标题化合物(In-8-c)(3.2g，收率：49.4％)。
MS m/z(ESI):303.2[M+H] +。
第二步：1,4′-联哌啶(In-8-d)的制备
[1,4′-联哌啶]-1′-甲酸苄酯(In-8-c)(3.2g,10.58mmol)溶于甲醇(30mL)中，加入钯碳(0.3g,1.06mmol)，置换氢气三次，在氢气氛围下反应12小时。反应液垫硅藻土过滤，少量甲醇洗涤滤饼，浓缩滤液，得到本步的标题化合物(In-8-d)(1.4g，收率：78.6％)。
MS m/z(ESI):169.2[M+H] +。
第三步：N-(6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)-[1,4′-联哌啶]-1′-甲酰胺(In-8)的制备
0℃下，向6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺(In-8-e)(200mg,0.78mmol)的四氢呋喃(10mL)溶液中加入DIPEA(304mg,2.35mmol)和氯甲酸苯酯(245mg,1.57mmol)，室温搅拌反应1.5小时后，加入1,4′-联哌啶(In-8-d)(395mg,2.35mmol)，室温反应4小时。反应完全后，加 水淬灭反应，浓缩反应液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/3(v/v))，得到标题化合物(In-8)(250mg，收率：71％)。
MS m/z(ESI):449.1[M+H] +。
中间体制备例9：5-(5-甲基呋喃-2-基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺(In-9)的制备
Figure PCTCN2019126555-appb-000029
6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺(In-9-a)(0.5g,1.9mmol)、4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(In-9-b)(0.65g,2.4mmol)和碳酸钾(0.53g,3.8mmol)加入1,4-二氧六环(10mL)和水(4mL)的混合溶剂中，置换氮气三次，加入四(三苯基膦)钯(0.1g,0.1mmol)，80℃反应6小时。反应完毕后，将反应液冷却至室温，浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：甲醇/二氯甲烷＝1/10(v/v))，得到标题化合物(In-9)(0.45g，收率：71％)。
MS m/z(ESI):319.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.17(s,1H),8.44(s,1H),8.04(d,J＝1.2Hz,2H),7.46(br,2H),6.34(d,J＝3.6Hz,1H),6.19(d,J＝3.2Hz,1H),2.91(s,3H),2.18(s,3H)。
中间体制备例10：5-(3-氯-5-甲基苯基)-4-(4-氟苯基)嘧啶-2-胺(In-10)的制备
Figure PCTCN2019126555-appb-000030
用2-(3-氯-5-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(In-10-b)代替中间体制备例9的4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉，用5-溴-4-(4-氟苯基)嘧啶-2-胺(In-10-a)代替6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺，以类似中间体制备例9所述的方法，合成得到标题化合物(In-10)(170mg，收率：72.6％)。
MS m/z(ESI):314.1[M+H] +。
中间体制备例11：5-(3-氯-5-甲基苯基)-4-(5-甲基呋喃-2-基)嘧啶-2-胺(In-11)的制备
Figure PCTCN2019126555-appb-000031
用5-溴-4-(5-甲基呋喃-2-基)嘧啶-2-胺(In-11-a)代替中间体制备例9的6-溴-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺，2-(3-氯-5-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(In-11-b)代替4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉，以类似中间体制备例9所述的方法，合成得到标题化合物(In-11)(220mg，收率：93.2％)。
MS m/z(ESI):300.1[M+H] +。
中间体制备例12：6-(2-氯-6-甲基吡啶-4-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺(In-12)的制备
Figure PCTCN2019126555-appb-000032
用2-氯-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-12-b)代替中间体制备例9中的4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉，以类似中间体制备例9所述的方法，合成得到标题化合物(In-12)(0.3g，收率：80％)。
MS m/z(ESI):302.1[M+H] +。
实施例1：6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-胺的制备(化合物1)
Figure PCTCN2019126555-appb-000033
第一步：5-溴-6-(4-氟苯基)吡啶-2-胺(1-2)的制备
将5,6-二溴吡啶-2-胺(1-1)(2g,7.94mmol)、4-氟苯硼酸(1.11g,7.94mmol)和碳酸钠(1.68g,15.88mmol)加入到甲苯(40mL)、甲醇(4mL)和水(8mL)的混合溶剂中，置换氮气三次，加入四(三苯基膦)钯(459mg,0.4mmol)，95℃反应11小时。反应完全后，反应液冷却至室温，浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/3(v/v))，得到本步的标题化合物(1-2)(2g，收率：94.31％)。
MS m/z(ESI):267.0[M+H] +。
第二步：6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-胺(1)的制备
将5-溴-6-(4-氟苯基)吡啶-2-胺(1-2)(1.14g,4.27mmol)、4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)(1.5g,5.55mmol)和碳酸钾(1.18g,8.54mmol)加入到1,4-二氧六环(20mL)和水(2mL)的混合溶剂中，置换氮气三次，加入四(三苯基膦)钯(246.9mg,0.21mmol)， 95℃反应12小时。反应完全后，反应液冷却至室温，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝3/2(v/v))，得到标题化合物(1)(1.15g，收率：81.5％)。
MS m/z(ESI):331.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.05(s,1H),8.01(d,J＝1.6Hz,1H),7.75(d,J＝8.4Hz,1H),7.68(d,J＝8.4Hz,1H),7.53(dd,J＝8.8,2Hz,1H),7.30-7.27(m,2H),7.06(t,J＝9.2Hz,2H),6.60(d,J＝8.4Hz,1H),6.31(s,2H),2.79(s,3H)。
实施例2：3-氟-6-(4-氟苯基)-5(4-甲基喹唑啉-6-基)吡啶-2-胺的制备(化合物2)
Figure PCTCN2019126555-appb-000034
第一步：3-氟-6-(4-氟苯基)吡啶-2-胺(2-3)的制备
将6-氯-3-氟吡啶-2-胺(2-1)(220mg,1.5mmol)加入到1,4-二氧六环(5mL)和水(1mL)的混合溶剂中，依次加入4-氟苯硼酸(315mg,2.3mmol)、磷酸钾(637mg,3.0mmol)和Pd(amphos)Cl 2(53mg,0.08mmol)，氮气置换，微波加热至120℃，反应2小时。反应完毕后，反应液冷却至室温，倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/2(v/v))，得到本步的标题化合物(2-3)(240mg，收率：78％)。
MS m/z(ESI):207.1[M+H] +。
第二步：5-溴-3-氟-6-(4-氟苯基)吡啶-2-胺(2-4)的制备
将3-氟-6-(4-氟苯基)吡啶-2-胺(2-3)(220mg,1.1mmol)加入到无水DMF(5mL)中，冷却至0℃，加入N-溴代丁二酰亚胺(285mg,1.6mmol)，升至室温反应2小时。反应液加水稀释，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/1(v/v))，得到本步的标题化合物(2-4)(150mg，收率：49％)。
MS m/z(ESI):285.0[M+H] +。
第三步：3-氟-6-(4-氟苯基)-5(4-甲基喹唑啉-6-基)吡啶-2-胺(2)的制备
将5-溴-3-氟-6-(4-氟苯基)吡啶-2-胺(2-4)(150mg,0.53mmol)溶于1,4-二氧六环(5mL)和水(1mL)的混合溶剂中，依次加入4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)(213mg,0.79mmol)、碳酸钾(146mg,1.1mmol)和Pd(dppf)Cl 2(22mg,0.026mmol)，氮气置换3次，80℃反应过夜。反应完毕后，反应液冷却至室温，倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝3/1(v/v))，得到标题化合物(2)(120mg，收率：62％)。
MS m/z(ESI):349.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.06(s,1H),8.09(d,J＝2.0Hz,1H),7.77-7.61(m,2H),7.55-7.53(m, 1H),7.27-7.25(m,2H),7.06(t,J＝8.8Hz,2H),6.61(s,2H),2.81(s,3H)。
实施例3：4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺的制备(化合物3)
Figure PCTCN2019126555-appb-000035
第一步：3-(二甲氨基)-1-(4-氟苯基)丙-2-烯-1-酮(3-2)的制备
将1-(4-氟苯基)乙酮(3-1)(5.0g,40.3mmol)加入到N,N-二甲基甲酰胺二甲基缩醛(50mL)中，氮气置换，80℃反应过夜。反应完毕后，反应液冷却至室温，浓缩，剩余物用无水乙醚打浆，抽滤，滤饼用无水乙醚洗涤，真空干燥，得到本步的标题化合物(3-2)(2.1g，收率：30％)。
MS m/z(ESI):194.1[M+H] +。
第二步：4-(4-氟苯基)嘧啶-2-胺(3-4)的制备
将3-(二甲氨基)-1-(4-氟苯基)丙-2-烯-1-酮(3-2)(2.1g,10.9mmol)、盐酸胍(3-3)(1.2g,12.0mmol)和碳酸钾(3.0g,21.8mmol)加入到无水乙醇(20mL)中，80℃反应20小时。浓缩反应液，剩余物加水稀释，抽滤，无水乙醚洗涤滤饼，真空干燥，得到本步的标题化合物(3-4)(1.9g，收率：92％)。
MS m/z(ESI):190.1[M+H] +。
第三步：5-溴-4-(4-氟苯基)嘧啶-2-胺(3-5)的制备
将4-(4-氟苯基)嘧啶-2-胺(3-4)(1.9g,10.1mmol)加入到无水DMF(20mL)中，冷却至0℃，加入N-溴代丁二酰亚胺(2.0g,11.1mmol)，维持0℃搅拌1小时后，自然升至室温搅拌过夜。浓缩反应液，剩余物加水稀释，抽滤，无水乙醚洗涤滤饼，真空干燥，得到本步的标题化合物(3-5)(2.6g，收率：95％)。
MS m/z(ESI):268.0[M+H] +。
第四步：4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)的制备
将5-溴-4-(4-氟苯基)嘧啶-2-胺(3-5)(1.0g,3.7mmol)加入到1,4-二氧六环(100mL)和水(4mL)的混合溶剂中，依次加入4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)(1.2g,4.5mmol)、碳酸钾(1.1g,7.5mmol)和Pd(dppf)Cl 2(0.3g,0.4mmol)，氮气置换3次后，100℃反应4小时。反应完毕后，反应液冷却至室温，倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝3/1(v/v))，得到标题化合物(3)(0.9g，收率：73％)。
MS m/z(ESI):332.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.08(s,1H),8.51(s,1H),8.18(d,J＝1.6Hz,1H),7.79(d,J＝8.8Hz,1H),7.53-7.50(m,1H),7.42-7.31(m,2H),7.14(t,J＝8.8Hz,2H),7.02(s,2H),2.86(s,3H)。
实施例4：3-(3-氟-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-基)-1-甲基-1-(吡啶-2-基甲基) 脲的制备(化合物4)
Figure PCTCN2019126555-appb-000036
3-氟-6-(4-氟苯基)-5(4-甲基喹唑啉-6-基)吡啶-2-胺(2)(50mg,0.14mmol)溶于四氢呋喃(2mL)与DIPEA(0.5mL)的混合溶剂，0℃下加入三光气(43mg,0.14mmol)，混合物维持0℃搅拌0.5小时，加入N-甲基-1-吡啶-2-甲胺(In-7-b)(35mg,0.28mmol)，0℃下反应1.5小时。反应完毕后，加甲醇淬灭，浓缩反应液，剩余物用制备型高效液相色谱仪纯化，得到标题化合物(4)(25mg，收率：30％)。
MS m/z(ESI):497.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.57(s,1H),9.11(s,1H),8.58(d,J＝4.4Hz,1H),8.27(d,J＝1.6Hz,1H),8.06(d,J＝10.4Hz,1H),7.85-7.82(m,2H),7.64-7.61(m,1H),7.36-7.32(m,4H),7.13-7.09(m,2H),4.68(s,2H),3.04(s,3H),2.86(s,3H)。
实施例5：1-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-3-甲基脲的制备(化合物5)
Figure PCTCN2019126555-appb-000037
将4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)(100.0mg,0.3mmol)溶于四氢呋喃(15mL)，-40℃下加入DIPEA(0.6mL,3.2mmol)和三光气(89.0mg,0.3mmol)，维持-40℃搅拌1小时后，加入甲胺的四氢呋喃溶液(0.3mL,2mol/L,0.6mmol)，0℃下反应2小时。反应完毕后，向反应液中加水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯)，得到标题化合物(5)(20.0mg，收率：17％)。
MS m/z(ESI):389.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.06(s,1H),9.12(s,1H),8.91(d,J＝4.8Hz,1H),8.81(s,1H),8.32(d,J＝1.6Hz,1H),7.86(d,J＝8.4Hz,1H),7.60-7.58(m,1H),7.52-7.37(m,2H),7.21-7.17(m,2H),2.88(s,3H),2.83(d,J＝4.4Hz,3H)。
实施例6：1-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-3(吡啶-2-甲基)脲的制备(化合物6)
Figure PCTCN2019126555-appb-000038
用2-氨甲基吡啶(6-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(6)(30.0mg，收率：21％)。
MS m/z(ESI):466.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.21(s,1H),9.74(t,J＝5.4Hz,1H),9.12(s,1H),8.85(s,1H),8.51-8.50(m,1H),8.34(d,J＝1.6Hz,1H),7.86-7.77(m,2H),7.61-7.59(m,1H),7.51-7.44(m,2H),7.42(d,J＝8.0Hz,1H),7.33-7.30(m,1H),7.18-7.14(m,2H),4.61(d,J＝5.2Hz,2H),2.88(s,3H)。
实施例7：1-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-3-(2-羟基-2-甲基丙基)脲的制备(化合物7)
Figure PCTCN2019126555-appb-000039
用1-氨基-2-甲基-2-丙醇(7-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(7)(35.0mg，收率：28％)。
MS m/z(ESI):447.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.02(s,1H),9.27(t,J＝5.6Hz,1H),9.12(s,1H),8.84(s,1H),8.36(d,J＝1.6Hz,1H),7.85(d,J＝8.4Hz,1H),7.67-7.43(m,3H),7.15(t,J＝8.8Hz,2H),4.60(s,1H),3.23(d,J＝5.6Hz,2H),2.89(s,3H),1.13(s,6H)。
实施例8：1-[4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基]-2-(2-甲氧基乙基)脲的制备(化合物8)
Figure PCTCN2019126555-appb-000040
用2-甲氧基乙胺(8-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(8)(50.0mg，收率：38％)。
MS m/z(ESI):433.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.09(s,1H),9.24(s,1H),9.12(s,1H),8.84(s,1H),8.34(d,J＝1.6Hz,1H),7.85(d,J＝8.8Hz,1H),7.60-7.58(m,1H),7.55-7.40(m,2H),7.18(t,J＝8.8Hz,2H),3.46-3.43(m,4H),3.26(s,3H),2.89(s,3H)。
实施例9：3-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-1-甲基-1-(吡啶-2-甲基)脲的制备(化合物9)
Figure PCTCN2019126555-appb-000041
用N-甲基-1-吡啶-2-甲胺(In-7-b)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(9)(50.0mg，收率：36％)。
MS m/z(ESI):480.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.0(s,1H),9.12(s,1H),8.80(s,1H),8.59(d,J＝4.4Hz,1H),8.32(d,J＝1.6Hz,1H),7.98-7.68(m,2H),7.62-7.61(m,1H),7.51-7.27(m,4H),7.17(t,J＝8.8Hz,2H),4.69(s,2H),3.03(s,3H),2.89(s,3H)。
实施例10：4-氰基-N-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)哌啶-1-甲酰胺的制备(化合物10)
Figure PCTCN2019126555-appb-000042
用4-氰基哌啶(10-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(10)(32.0mg，收率：23％)。
MS m/z(ESI):468.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.90(s,1H),9.12(s,1H),8.79(s,1H),8.32(d,J＝2.0Hz,1H),7.85(d,J＝8.8Hz,1H),7.61-7.59(m,1H),7.52-7.36(m,2H),7.16(t,J＝8.4Hz,2H),3.81-3.65(m,2H),3.34-3.30(m,2H),3.13(dt,J＝12.8,4.8Hz,1H),3.04-2.82(m,3H),2.00-1.83(m,2H),1.81-1.61(m,2H)。
实施例11：N-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)吗啉-4-甲酰胺的制备(化合物11)
Figure PCTCN2019126555-appb-000043
用吗啉(11-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(11)(50.0mg，收率：39％)。
MS m/z(ESI):445.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.89(s,1H),9.12(s,1H),8.79(s,1H),8.32(d,J＝1.6Hz,1H),7.85(d,J＝8.4Hz,1H),7.62-7.59(m,1H),7.46-7.43(m,2H),7.17(t,J＝8.8Hz,2H),3.68-3.56(m,4H),3.56-3.43(m,4H),2.89(s,3H)。
实施例12：3-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-1-甲基-1-苯基脲的制备(化合物12)
Figure PCTCN2019126555-appb-000044
用N-甲基苯胺(12-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(12)(50.0mg，收率：36％)。
MS m/z(ESI):465.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.36(s,1H),9.12(s,1H),8.76(s,1H),8.31(d,J＝1.6Hz,1H),7.85(d,J＝8.4Hz,1H),7.60-7.58(m,1H),7.49-7.32(m,6H),7.31-7.22(m,1H),7.20-7.07(m,2H),3.34(s,3H),2.88(s,3H)。
实施例13：N-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-4-甲氧基哌啶-1-甲酰胺的制备(化合物13)
Figure PCTCN2019126555-appb-000045
用4-甲氧基哌啶(13-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(13)(55.0mg，收率：38％)。
MS m/z(ESI):473.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.82(s,1H),9.12(s,1H),8.77(s,1H),8.31(d,J＝1.6Hz,1H),7.85(d,J＝8.8Hz,1H),7.61-7.59(m,1H),7.52-7.36(m,2H),7.16-7.14(m,2H),3.80-3.75(m,2H),3.49-3.37(m,1H),3.27(s,3H),3.25-3.13(m,2H),2.88(s,3H),1.94-1.77(m,2H),1.48-1.20(m,2H)。
实施例14：3-(5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-基)-1-甲基-1-(吡啶-2-基甲基)脲的制备(化合物14)
Figure PCTCN2019126555-appb-000046
3-(5-溴-4-(4-氟苯基)嘧啶-2-基)-1-甲基-1-(吡啶-2-基甲基)-脲(In-7)(50mg,0.12mmol)溶于1,4-二氧六环(5mL)和水(1mL)的混合溶剂中，依次加入2-氯-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-4)(46mg,0.18mmol)、碳酸钾(33mg,0.24mmol)和Pd(dppf)Cl 2(5mg,0.006mmol)，氮气置换3次，升温至80℃，反应过夜。反应完毕后，反应液冷却至室温倒入水中，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，剩余物用制备型高效液相色谱仪纯化，得到标题化合物(14)(10mg，收率：18％)
MS m/z(ESI):463.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.06(s,1H),8.65(s,1H),8.57(d,J＝4.4Hz,1H),7.82-7.79(m,1H),7.46-7.43(m,2H),7.38(d,J＝8.0Hz,1H),7.34-7.31(m,1H),7.25-7.23(m,2H),7.16(d,J＝1.2Hz,2H),4.67(s,2H),3.01(s,3H),2.39(s,3H)。
实施例15：3-(5-(3-氯-5-甲基苯基)-4-(4-氟苯基)嘧啶-2-基)-1-甲基-1-(吡啶-2-基甲基)脲的制备(化合物15)
Figure PCTCN2019126555-appb-000047
用2-(3-氯-5-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(In-5)代替实施例14的2-氯-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-4)，以类似实施例14所述的方法，合成得到标题化合物(15)(15mg，收率：11％)。
MS m/z(ESI):462.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.95(s,1H),8.58(d,J＝5.6Hz,2H),7.83-7.79(m,1H),7.45-7.38(m,3H),7.34-7.31(m,1H),7.23-7.19(m,3H),7.05(d,J＝11.6Hz,2H),4.67(s,2H),3.01(s,3H),2.25(s,3H)。
实施例16：3-(5-(2-氯-6-(三氟甲基)吡啶-4-基)-4-(4-氟苯基)嘧啶-2-基)-1-甲基-1-(吡啶-2-基甲基)脲的制备(化合物16)
Figure PCTCN2019126555-appb-000048
用2-氯-6-三氟甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-6)代替实施例14的2-氯-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-4)，以类似实施例14所述的方法，合成得到标题化合物(16)(6mg，收率：5％)。
MS m/z(ESI):517.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.15(s,1H),8.80(s,1H),8.57(d,J＝4.4Hz,1H),7.83-7.80(m,2H),7.66(s,1H),7.47-7.44(m,2H),7.39(d,J＝7.6Hz,1H),7.34-7.31(m,1H),7.26(t,J＝8.8Hz,2H),4.68(s,2H),3.02(s,3H)。
实施例17：5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-胺的制备(化合物17)
Figure PCTCN2019126555-appb-000049
5-溴-4-(4-氟苯基)嘧啶-2-胺(In-10-a)(200mg,0.75mmol)、2-氯-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-4)(283mg,1.12mmol)和碳酸钾(206mg,1.49mmol)加入到1,4-二氧六环(5mL)和水(1mL)的混合溶剂中，置换氮气三次，加[1,1'-双(二苯基膦基)二茂铁]二氯化钯(30mg,0.037mmol)，80℃反应12小时。反应完全后，反应液冷却至室温，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/1(v/v))，得到标题化合物(17)(220mg，收率：93.7％)。
MS m/z(ESI):315.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:8.37(s,1H),7.39-7.35(m,2H),7.21(t,J＝8.8Hz,2H),7.12(s,2H),7.04(s,1H),6.99(s,1H),2.35(s,3H)。
实施例18：N-(5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-基)-4-氰基哌啶-1-甲酰胺的制备(化合物18)
Figure PCTCN2019126555-appb-000050
用4-氰基哌啶(18-1)代替实施例5中的甲胺的四氢呋喃溶液，5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-胺(17)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(18)(20mg，收率：16.6％)。
MS m/z(ESI):451.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.94(s,1H),8.63(s,1H),7.45-7.41(m,2H),7.24(t,J＝8.8Hz,2H),7.15(s,2H),3.73-3.69(m,2H),3.31-3.27(m,2H),3.11-3.09(m,1H),2.39(s,3H),1.92-1.88(m,2H),1.73-1.68(m,2H)。
实施例19：N-(5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-基)吗啉-4-甲酰胺的制备(化合物19)
Figure PCTCN2019126555-appb-000051
用吗啉(11-1)代替实施例5中的甲胺的四氢呋喃溶液，5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-胺(17)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(19)(40mg，收率：14.0％)。
MS m/z(ESI):427.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.94(s,1H),8.64(s,1H),7.45-7.42(m,2H),7.24(t,J＝8.8Hz,2H),7.15(s,2H),3.61-3.58(m,4H),3.47-3.45(m,4H),2.39(s,3H)。
实施例20：N-(5-(3-氯-5-甲基苯基)-4-(4-氟苯基)嘧啶-2-基)-4-氰基哌啶-1-甲酰胺的制备(化合物20)
Figure PCTCN2019126555-appb-000052
用4-氰基哌啶(18-1)代替实施例5中的甲胺的四氢呋喃溶液，5-(3-氯-5-甲基苯基)-4-(4-氟苯基)嘧啶-2-胺(In-10)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(20)(50mg，收率：43.7％)。
MS m/z(ESI):450.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.82(s,1H),8.56(s,1H),7.43-7.40(m,2H),7.23-7.20(m,3H),7.04(d,J＝11.2Hz,2H),3.74-3.68(m,2H),3.31-3.29(m,2H),3.11-3.10(m,1H),2.25(s,3H),1.92-1.88(m,2H),1.73-1.68(m,2H)。
实施例21：N-(5-(3-氯-5-甲基苯基)-4-(4-氟苯基)嘧啶-2-基)-[1,4'-二哌啶]-1'-甲酰胺的制备(化合物21)
Figure PCTCN2019126555-appb-000053
用1,4'-二哌啶(In-8-d)代替实施例5中的甲胺的四氢呋喃溶液，5-(3-氯-5-甲基苯基)-4-(4-氟苯基)嘧啶-2-胺(In-10)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(21)(25mg，收率：15.7％)。
MS m/z(ESI):508.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.69(s,1H),8.54(s,1H),8.19(s,1H),7.43-7.39(m,2H),7.23-7.18(m,2H),7.03(d,J＝10.8Hz,2H),4.12(d,J＝13.2Hz,2H),2.83-2.76(m,2H),2.50-2.44(m,5H),2.25(s,3H),1.70(d,J＝12.4Hz,2H),1.53-1.45(m,4H),1.41-1.32(m,4H)。
实施例22：N-(5-(3-氯-5-甲基苯基)-4-(5-甲基呋喃-2-基)嘧啶-2-基)-[1,4'-联哌啶]-1'-甲酰胺的制备(化合物22)
Figure PCTCN2019126555-appb-000054
用1,4'-二哌啶(In-8-d)代替实施例5中的甲胺的四氢呋喃溶液，5-(3-氯-5-甲基苯基)-4-(5-甲基呋喃-2-基)嘧啶-2-胺(In-11)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(22)(15mg，收率：7.9％)。
MS m/z(ESI):494.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.60(s,1H),8.35(s,1H),7.35(s,1H),7.21(s,1H),7.13(s,1H),6.32(d,J＝3.6Hz,1H),6.19(dd,J＝3.2,0.8Hz,1H),4.13(d,J＝12.8Hz,2H),2.81(t,J＝12.0Hz,2H),2.65-2.54(m,5H),2.34(s,3H),2.20(s,3H),1.76(d,J＝11.6Hz,2H),1.58-1.45(m,4H),1.44-1.35(m,4H)。
实施例23：3-(5-(4-氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-基)-1,1-二甲基脲的制备(化合物23)
Figure PCTCN2019126555-appb-000055
将5-(4-氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺(In-3)(100.0mg,0.3mmol)溶于四氢呋喃(4mL)，0℃下加入DIPEA(0.6mL,3.2mmol)和三光气(89.0mg,0.3mmol)，维持0℃搅拌0.5小时，然后加入二甲胺(23-1)的四氢呋喃溶液(0.3mL,2mol/L,0.6mmol)，0℃下反应1小 时。反应完毕后，反应液中加水，乙酸乙酯萃取，合并有机相，无水硫酸钠干燥，过滤，浓缩滤液，剩余物用硅胶柱层析色谱法纯化(洗脱剂：甲醇/二氯甲烷＝1/10(v/v))，得到标题化合物(23)(50mg，收率：42％)。
MS m/z(ESI):404.2[M+H] +。
1H NMR(400MHz,MeOD)δ:9.10(s,1H),8.49(s,1H),8.03-7.95(m,2H),7.66-7.61(m,2H),7.10(t,J＝8.8Hz,2H),3.15(s,6H),2.88(s,3H)。
实施例24：3-(5-(4-氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-基)-1-甲基-1-(吡啶-2-甲基)脲的制备(化合物24)
Figure PCTCN2019126555-appb-000056
用N-甲基-1-(吡啶-2-基)甲胺(In-7-b)代替实施例23中的二甲胺的四氢呋喃溶液，以类似实施例23所述的方法，合成得到标题化合物(24)(40mg，收率：28％)。
MS m/z(ESI):480.2[M+H] +。
1H NMR(400MHz,MeOD)δ:9.10(s,1H),8.61(s,1H),8.49(s,1H),8.04-7.95(m,2H),7.87(t,J＝8.0Hz,1H),7.66-7.63(m,2H),7.52(t,J＝8.4Hz,1H),7.39(t,J＝8.0Hz,1H),7.10(t,J＝8.0Hz,2H),4.79(s,2H),3.15(s,3H),2.88(s,3H)。
实施例25：1-甲基-3-(5-(5-甲基呋喃-2-基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-基)-1-(吡啶-2-基甲基)脲的制备(化合物25)
Figure PCTCN2019126555-appb-000057
用5-(5-甲基呋喃-2-基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺(In-9)代替实施例23中的5-(4-氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺(In-3)，用N-甲基-1-(吡啶-2-基)甲胺(In-7-b)代替实施例23中的二甲胺的四氢呋喃溶液，以类似实施例23所述的方法，合成得到标题化合物(25)(40mg，收率：28％)。
MS m/z(ESI):467.2[M+H] +。
1H NMR(400MHz,MeOD)δ:9.15(s,1H),8.61-8.59(m,2H),8.17-8.09(m,2H),7.90-7.86(m,1H),7.53(d,J＝7.6Hz,1H),7.39(dd,J＝7.2,5.2Hz,1H),7.05(d,J＝3.6Hz,1H),6.22(dd,J＝3.6,0.8Hz,1H),4.78(s,2H),3.15(s,3H),3.00(s,3H),2.10(s,3H)。
实施例26：N-(6-(2-氯-6-甲基吡啶-4-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)-[1,4'-连哌啶]- 1'-甲酰胺的制备(化合物26)
Figure PCTCN2019126555-appb-000058
用6-(2-氯-6-甲基吡啶-4-基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-胺(In-12)代替实施例23中的5-(4-氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺(In-3)，1,4'-二哌啶(In-8-d)代替实施例23中的二甲胺的四氢呋喃溶液，以类似实施例23所述的方法，合成得到标题化合物(26)(100mg，收率：30％)。
MS m/z(ESI):496.2[M+H] +。
1H NMR(400MHz,MeOD)δ:8.50(s,1H),7.47(d,J＝9.6Hz,2H),7.20(d,J＝3.6Hz,1H),6.29(d,J＝3.6Hz,1H),4.42(d,J＝13.2Hz,2H),3.36-3.20(m,5H),3.05(t,J＝12.8Hz,2H),2.58(s,3H),2.21(s,3H),2.15(d,J＝12.8Hz,2H),1.86-1.66(m,8H)。
实施例27：N-(5-(5-甲基呋喃-2-基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-基)-[1,4’-联哌啶]-1’-甲酰胺的制备(化合物27)
Figure PCTCN2019126555-appb-000059
将N-(6-溴-5-(5-甲基呋喃-2-基)1,2,4-三嗪-3-基)-[1,4’-联哌啶]-1’-甲酰胺(In-8)(30mg,0.07mmol)、4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)(27.05mg,0.10mmol)和碳酸铯(43.53mg,0.13mmol)加入到1,4-二氧六环(5mL)中，置换氮气三次，加入四(三苯基膦)钯(3.86mg,3.34μmol)，80℃反应12小时。反应完全后，反应液冷却至室温，过滤，浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：甲醇/二氯甲烷＝1/15(v/v))，得到标题化合物(27)(10.0mg，收率：29％)。
MS m/z(ESI):513.3[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.16(s,1H),9.20(s,1H),8.54(d,J＝1.2Hz,1H),8.17-8.05(m,2H),6.48(d,J＝3.6Hz,1H),6.24(d,J＝3.2Hz,1H),4.17(d,J＝12.8Hz,2H),2.98-2.80(m,5H),2.46-2.43(m,5H),2.19(s,3H),1.75(d,J＝11.2Hz,2H),1.56-1.29(m,8H)。
实施例28：N-(6-(3-氯-5-甲基苯基)-5-(5-甲基呋喃-2-基)-1,2,4-三嗪-3-基)-[1,4’-联哌啶]-1’-甲酰胺(化合物28)
Figure PCTCN2019126555-appb-000060
用2-(3-氯-5-甲基苯基)-4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊烷(In-5)代替实施例27中的4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)，以类似实施例27所述的方法，合成得到标题化合物(28)(9mg，收率：11.8％)。
MS m/z(ESI):495.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.10(s,1H),7.46-7.34(m,3H),6.41(d,J＝3.6Hz,1H),6.29-6.28(m,1H),4.15(d,J＝13.2Hz,2H),2.88-2.82(m,2H),2.47-2.45(m,5H),2.41(s,3H),2.27(s,3H),1.75-1.72(m,2H),1.48-1.38(m,8H)。
实施例29：3-(6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-基)-1-甲基-1-(吡啶-2-甲基)脲的制备(化合物29)
Figure PCTCN2019126555-appb-000061
用6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-胺(1)代替实施例4中的3-氟-6-(4-氟苯基)-5(4-甲基喹唑啉-6-基)吡啶-2-胺(2)，以类似实施例4所述的方法，合成得到标题化合物(29)(45mg，收率：31％)。
MS m/z(ESI):479.2[M+H] +。
1H NMR(400MHz,MeOD)δ:9.03(s,1H),8.56(d,J＝4.4Hz,1H),8.12(s,1H),8.06-7.95(m,2H),7.87-7.82(m,2H),7.70(d,J＝8.4Hz,1H),7.45(d,J＝8.0Hz,1H),7.38-7.33(m,3H),6.99(t,J＝8.0Hz,2H),4.74(s,2H),3.14(s,3H),2.85(s,3H)。
实施例30：N-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-4-甲基哌嗪-1-甲酰胺的制备(化合物30)
Figure PCTCN2019126555-appb-000062
用N-甲基哌嗪(30-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(30)(61mg，收率：21％)。
MS m/z(ESI):462.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.81(s,1H),9.12(s,1H),8.78(s,1H),8.30(d,J＝1.6Hz,1H),7.85(d,J＝8.8Hz,1H),7.60(dd,J＝8.8,2.0Hz,1H),7.52-7.38(m,2H),7.16(t,J＝8.8Hz,2H),3.58-3.39(m,4H),2.88(s,3H),2.41-2.27(m,4H),2.20(s,3H)。
实施例31：3-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-1-(2-甲氧基乙基)-1-甲基脲的制备(化合物31)
Figure PCTCN2019126555-appb-000063
用2-甲氧基-N-甲基乙胺(31-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(31)(63mg，收率：22％)。
MS m/z(ESI):447.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.48(s,1H),9.12(s,1H),8.78(s,1H),8.30(d,J＝1.6Hz,1H),7.85(d,J＝8.8Hz,1H),7.61(dd,J＝8.8,2.0Hz,1H),7.52-7.38(m,2H),7.24-7.09(m,2H),3.54(s,4H),3.32(s,3H),3.00(s,3H),2.88(s,3H)。
实施例32：N-(3-氟-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-基)吗啉-4-甲酰胺的制备(化合物32)
Figure PCTCN2019126555-appb-000064
用吗啉(11-1)代替实施例4中的N-甲基-1-吡啶-2-甲胺(In-7-b)，以类似实施例4所述的方法，合成得到标题化合物(32)(625mg，收率：64％)。
MS m/z(ESI):462.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.41(s,1H),9.10(s,1H),8.26(d,J＝1.6Hz,1H),8.05(d,J＝10.4Hz,1H),7.82(d,J＝8.8Hz,1H),7.64-7.61(m,1H),7.35-7.31(m,2H),7.10(t,J＝8.8Hz,2H),3.63(t,J＝4.6Hz,4H),3.49(t,J＝4.4Hz,4H),2.85(s,3H)。
实施例33：N-(5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-基)-4-甲基哌嗪-1-甲酰胺的制备(化合物33)
Figure PCTCN2019126555-appb-000065
用N-甲基哌嗪(30-1)代替实施例5中的甲胺的四氢呋喃溶液，5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-胺(17)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(33)(73mg，收率：25％)。
MS m/z(ESI):441.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.87(s,1H),8.63(s,1H),7.49-7.37(m,2H),7.31-7.19(m,2H),7.15(s,2H),3.54-3.38(m,4H),2.39(s,3H),2.32(dd,J＝13.6,8.8Hz,4H),2.24-2.12(m,3H)。
实施例34：(S)-N-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-2-甲基吗啉-4-甲酰胺的制备(化合物34)
Figure PCTCN2019126555-appb-000066
用(S)-2-甲基吗啉(34-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(34)(52mg，收率：34％)。
MS m/z(ESI):459.2[M+H] +。
1H NMR(400MHz,MeOD)δ:9.07(s,1H),8.73(s,1H),8.27(d,J＝1.6Hz,1H),7.89(d,J＝8.8Hz,1H),7.69-7.67(m,1H),7.51-7.48(m,2H),7.06-6.99(m,2H),4.10-4.02(m,2H),3.94-3.90(m,1H),3.66-3.60(m,2H),3.15-3.08(m,1H),2.92(s,3H),2.80-2.74(m,1H),1.23-1.16(m,3H)。
实施例35：N-(5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-基)哌啶-1-甲酰胺的制备(化合物35)
Figure PCTCN2019126555-appb-000067
用哌啶(35-1)代替实施例5中的甲胺的四氢呋喃溶液，5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-胺(17)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(35)(40mg，收率：21％)。
MS m/z(ESI):426.1[M+H] +。
1H NMR(400MHz,MeOD)δ:8.55(s,1H),7.51-7.47(m,2H),7.18-7.05(m,4H),3.57(d,J＝5.2Hz,4H),2.43(s,3H),1.78-1.56(m,6H)。
实施例36：(S)-N-(5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-基)-2-甲基吗啉-4-甲酰胺的制备(化合物36)
Figure PCTCN2019126555-appb-000068
用(S)-2-甲基吗啉(34-1)代替实施例5中的甲胺的四氢呋喃溶液，5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-胺(17)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(36)(40mg，收率：21％)。
MS m/z(ESI):442.1[M+H] +。
1H NMR(400MHz,MeOD)δ:8.57(s,1H),7.54-7.45(m,2H),7.16-7.06(m,4H),4.08-4.03(m,2H),3.92-3.88(m,1H),3.64-3.58(m,2H),3.15-3.05(m,1H),2.78-2.76(m,1H),2.42(d,J＝14.0Hz,3H),1.18(d,J＝6.0Hz,3H)。
实施例37：(2R,6S)-N-(5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-基)-2,6-二甲基吗啉-4-甲酰胺的制备(化合物37)
Figure PCTCN2019126555-appb-000069
用(2R,6S)-2,6-二甲基吗啉(37-1)代替实施例5中的甲胺的四氢呋喃溶液，5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-胺(17)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(37)(40mg，收率：14％)。
MS m/z(ESI):456.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.90(s,1H),8.64(s,1H),7.45-7.42(m,2H),7.24(t,J＝8.8Hz,2H),7.15(s,2H),3.99(d,J＝12.8Hz,2H),3.55-3.50(m,2H),2.55-2.51(m,2H),2.39(s,3H),1.09(d,J＝6.0Hz,6H)。
实施例38：(R)-N-(5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-基)-2-甲基吗啉-4-甲酰胺的制备(化合物38)
Figure PCTCN2019126555-appb-000070
用(R)-2-甲基吗啉(38-1)代替实施例5中的甲胺的四氢呋喃溶液，5-(2-氯-6-甲基吡啶-4-基)-4-(4-氟苯基)嘧啶-2-胺(17)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(38)(100mg，收率：35％)。
MS m/z(ESI):442.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.92(s,1H),8.64(s,1H),7.45-7.42(m,2H),7.27-7.22(m,2H),7.15(s,2H),4.00-3.80(m,3H),3.49-3.33(m,2H),2.94(t,J＝9.6Hz,1H),2.64-2.58(m,1H),2.39(s,3H),1.09(d,J＝6.0Hz,3H)。
实施例39：(2R,6S)-N-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-2,6-二甲基吗啉-4-甲酰胺的制备(化合物39)
Figure PCTCN2019126555-appb-000071
用(2R,6S)-2,6-二甲基吗啉(37-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(39)(55mg，收率：19％)。
MS m/z(ESI):473.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.84(s,1H),9.12(s,1H),8.79(s,1H),8.31(d,J＝1.6Hz,1H),7.85(d,J＝8.8Hz,1H),7.60(dd,J＝8.8,1.6Hz,1H),7.45-7.43(m,2H),7.16(dd,J＝12.4,5.6Hz,2H),4.02(d,J＝12.8Hz,2H),3.57-3.52(m,2H),2.88(s,3H),2.57-2.51(m,2H),1.11(d,J＝6.4Hz,6H)。
实施例40：(R)-N-(4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)-2-甲基吗啉-4-甲酰胺的制备(化合物40)
Figure PCTCN2019126555-appb-000072
用(R)-2-甲基吗啉(38-1)代替实施例5中的甲胺的四氢呋喃溶液，以类似实施例5所述的方法，合成得到标题化合物(40)(55mg，收率：19％)。
MS m/z(ESI):459.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.85(s,1H),9.12(s,1H),8.79(s,1H),8.31(d,J＝1.6Hz,1H),7.85(d,J＝8.8Hz,1H),7.61(dd,J＝8.4,3.2Hz,1H),7.46-7.43(m,2H),7.16(dd,J＝12.4,5.6Hz,2H),4.02-3.81(m,3H),3.50-3.44(m,2H),2.99-2.93(m,1H),2.88(s,3H),2.66-2.60(m,1H),1.11(d,J＝6.4Hz,3H)。
实施例41：N-(6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-基)吗啉-4-甲酰胺的制备(化合物41)
Figure PCTCN2019126555-appb-000073
用6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-胺(1)代替实施例23中的5-(4-氟苯基)-6-(4-甲基喹唑啉-6-基)-1,2,4-三嗪-3-胺(In-3)，用吗啉(11-1)替代实施例23中的二甲胺的四氢呋喃溶液，以类似实施例23所述的方法，合成得到标题化合物(41)(95mg，收率：35％)。
MS m/z(ESI):462.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.46(s,1H),9.09(s,1H),8.15(d,J＝1.8Hz,1H),7.96(dd,J＝26.0,8.6Hz,2H),7.81(d,J＝8.8Hz,1H),7.60(dd,J＝8.8,2.0Hz,1H),7.41-7.32(m,2H),7.11(dd,J＝12.4,5.6Hz,2H),3.68-3.59(m,4H),3.54-3.47(m,4H),2.83(s,3H)。
实施例42：N-(4-氯-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-基)吗啉-4-甲酰胺的制备(化合物42)
Figure PCTCN2019126555-appb-000074
第一步：4-氯-6-(4-氟苯基)吡啶-2-胺(42-2)的制备
用4,6-二氯吡啶-2-胺(42-1)代替实施例2第一步中的6-氯-3-氟吡啶-2-胺(2-1)，以类似实施例2第一步所述的方法，合成得到标题化合物(42-2)(0.5g，收率：45％)。
MS m/z(ESI):223.1[M+H] +。
第二步：5-溴-4-氯-6-(4-氟苯基)吡啶-2-胺(42-3)的制备
用4-氯-6-(4-氟苯基)吡啶-2-胺(42-2)代替实施例2第二步中的3-氟-6-(4-氟苯基)吡啶-2-胺(2-3)以类似实施例2第二步所述的方法，合成得到标题化合物(42-3)(0.3g，收率：60％)。
MS m/z(ESI):300.8[M+H] +。
第三步：4-氯-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-胺(42-4)的制备
用4-氯-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-胺(42-4)代替实施例2第三步中的5-溴-3-氟-6-(4-氟苯基)吡啶-2-胺(2-4)以类似实施例2第三步所述的方法，合成得到标题化合物(42-3)(0.3g，收率：60％)。
MS m/z(ESI):365.1[M+H] +。
第四步：N-(4-氯-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-基)吗啉-4-甲酰胺的制备
用吗啉(11-1)代替实施例5中的甲胺的四氢呋喃溶液，4-氯-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-胺(42-4)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(42)(30mg，收率：34％)。
MS m/z(ESI):478.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.72(s,1H),9.10(s,1H),8.13(d,J＝1.6Hz,1H),8.09(s,1H),7.90(d,J＝8.8Hz,1H),7.78(dd,J＝8.8,1.6Hz,1H),7.34-7.27(m,2H),7.03-6.98(m,2H),3.65-3.57(m,4H),3.55-3.48(m,4H),2.78(s,3H)。
实施例43：N-(4-氰基-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-基)吗啉-4-甲酰胺的制备(化合物43)
Figure PCTCN2019126555-appb-000075
第一步：6-氨基-2-(4-氟苯基)-3-(4-甲基喹唑啉-6-基)异烟腈(43-1)的制备
在10ml微波管中，依次加入4-氯-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-胺(42-4)(170mg,0.47mmol)、锌粉(3.0mg,0.47mmol)、氰化锌(55mg,0.47mmol)和DMF(2mL)，向反应溶液中鼓氮气五分钟，向反应混合物中加入三(二亚苄基丙酮)二钯(46mg,0.05mmol)、dppf(56mg,0.1mmol)，反应混合物用微波加热至140℃反应5小时。冷却至室温，反应混合物倒入20mL水中，搅拌5分钟，乙酸乙酯萃取三次，有机相饱和食盐水洗涤三次，无水硫酸钠干燥，过滤，滤液浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/1(v/v))，得到标题化合物(43-1)(160mg，收率：96％)。
MS m/z(ESI):356.1[M+H] +。
第二步：N-(4-氰基-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-基)吗啉-4-甲酰胺(43)的制备
用吗啉(11-1)代替实施例5中的甲胺的四氢呋喃溶液，6-氨基-2-(4-氟苯基)-3-(4-甲基喹唑啉-6-基)异烟腈(43-1)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(43)(35mg，收率：18％)。
MS m/z(ESI):469.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.96(s,1H),9.15(s,1H),8.38(d,J＝1.6Hz,1H),8.27(s,1H),7.92(d,J＝8.8Hz,1H),7.76(dd,J＝8.8,2.0Hz,1H),7.35-7.32(m,2H),7.10-7.05(m,2H),3.64-3.62(m,4H),3.54-3.52(m,4H),2.83(s,3H)。
实施例44：N-(4-环丙基-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)吗啉-4-甲酰胺的合成(44)
Figure PCTCN2019126555-appb-000076
第一步：1-环丙基-3-(4-氟苯基)丙烷-1,3-二酮的制备(44-1)
向100mL单口瓶中，依次加入4-氟苯乙酮(In-3-a)(3g,21.7mmol)和四氢呋喃(60mL)，置换氮气三次，冷却至0℃，向其中加入氢化钠(2.37g,59.3mmol,60％)，搅拌1小时后，再加入环丙甲酸甲酯(4.35g,43.5mmol)，混合物25℃反应16小时。向反应混合物中加入饱和氯化铵水溶液淬灭反应，乙酸乙酯萃取三次，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，滤液浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/10(v/v))，得到本步的标题化合物(44-1)(2.8g,收率：63％)。
MS m/z(ESI):207.1[M+H] +。
第二步：(Z)-3-氨基-3-环丙基-1-(4-氟苯基)丙-2-烯-1-酮(44-2)的制备
向100mL的单口瓶中，依次加入1-环丙基-3-(4-氟苯基)丙烷-1,3-二酮(44-1)(2.0g,9.7mmol)、醋酸铵(7.47g,97.1mmol)和无水甲醇(25mL)，65℃反应16小时，反应混合物冷却至室温，浓缩，向所得残渣中加入水和乙酸乙酯，水相乙酸乙酯萃取三次，所得有机相合并，饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液浓缩，得到本步的标题化合物(44-2)(1.8g,收率：90％)。
MS m/z(ESI):206.1[M+H] +。
第三步：4-环丙基-6-(4-氟苯基)嘧啶-2-胺(44-3)的制备
向50mL的圆底烧瓶中加入(Z)-3-氨基-3-环丙基-1-(4-氟苯基)丙-2-烯-1-酮(44-2)(1.8g,8.8mmol)和50％氰胺水溶液(20mL)，120℃反应2小时。冷却至室温，反应液浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/3(v/v))，得到本步的标题化合物(44-3)(1.4g,收率：70％)。
MS m/z(ESI):230.1[M+H] +。
第四步：4-环丙基-6-(4-氟苯基)-5-碘嘧啶-2-胺(44-4)的制备
向100mL的圆底烧瓶中，加入4-环丙基-6-(4-氟苯基)嘧啶-2-胺(44-3)(1.2g,5.2mmol)和冰乙酸(10mL)，搅拌条件下，向其中缓慢滴加氯化碘的冰乙酸溶液(2.2g,13.1mmol,2mL)，25℃反 应16小时，反应混合物倒入水中，乙酸乙酯萃取三次，有机相用饱和亚硫酸钠水溶液洗涤三次，饱和食盐水洗涤两次，无水硫酸钠干燥，过滤，滤液浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/5(v/v))，得到本步的标题化合物(44-4)(1.5g,收率：82％)。
MS m/z(ESI):356.0[M+H] +。
第五步：4-环丙基-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(44-5)的制备
向100mL的圆底烧瓶中，依次加入4-环丙基-6-(4-氟苯基)-5-碘嘧啶-2-胺(44-4)(1.0g,2.8mmol)、4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)(0.9g,3.4mmol)、碳酸钾(0.8g,5.6mmol)、1,4-二氧六环(10mL)和水(1mL)，置换氮气三次，向反应混合物中加入Pd(dppf)Cl 2(115mg,0.14mmol)，80℃反应8小时。反应液冷却至室温，浓缩，剩余物用硅胶柱层析色谱法纯化(洗脱剂：乙酸乙酯/石油醚＝1/1(v/v))，得到本步的标题化合物(44-5)(0.9g,收率：85％)。
MS m/z(ESI):372.2[M+H] +。
第六步：N-(4-环丙基-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-基)吗啉-4-甲酰胺(44)的制备
用吗啉(11-1)代替实施例5中的甲胺的四氢呋喃溶液，4-环丙基-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(44-5)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(44)(50mg，收率：25％)。
MS m/z(ESI):485.2[M+H] +。
1H NMR(400MHz,CDCl 3)δ:9.21(s,1H),8.06(d,J＝8.8Hz,1H),7.89(s,1H),7.75(dd,J＝8.8,1.6Hz,1H),7.32-7.27(m,2H),6.88(t,J＝8.8Hz,2H),3.77-3.74(m,4H),3.65-3.63(m,4H),2.84(s,3H),1.82-1.79(m,1H),1.41(bs,2H),1.03(br,2H)。
实施例45：N-(2’-氯-4-氰基-2-(4-氟苯基)-6’-甲基-[3,4’-联吡啶]-6-基)吗啉-4-甲酰胺的制备(化合物45)
Figure PCTCN2019126555-appb-000077
第一步：2-氨基-6-(4-氟苯基)异烟腈(45-1)的制备
用4-氯-6-(4-氟苯基)吡啶-2-胺(42-2)代替实施例43第一步中的4-氯-6-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)吡啶-2-胺(42-4)，以类似实施例43第一步所述的方法，合成得到本步的标题化合物(45-1)(1.2g，收率：60％)。
MS m/z(ESI):214.1[M+H] +。
第二步：6-氨基-3-溴-2-(4-氟苯基)异烟腈(45-2)的制备
用2-氨基-6-(4-氟苯基)异烟腈(45-1)代替实施例2第二步中的3-氟-6-(4-氟苯基)吡啶-2-胺(2-3)，以类似实施例2第二步所述的方法，合成得到本步的标题化合物(45-2)(0.8g，收率：63％)。
MS m/z(ESI):292.0[M+H] +。
第三步：6-氨基-2’-氯-2-(4-氟苯基)-6’-甲基-[3,4’-联吡啶]-4-腈(45-3)的制备
用6-氨基-3-溴-2-(4-氟苯基)异烟腈(45-2)代替实施例2第三步中的5-溴-3-氟-6-(4-氟苯基)吡啶-2-胺(2-4)，用2-氯-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-4)代替实施例2第三步中的4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)，以类似实施例2第三步所述的方法，合成得到本步的标题化合物(45-3)(0.4g，收率：72％)。
MS m/z(ESI):339.1[M+H] +。
第四步：N-(2’-氯-4-氰基-2-(4-氟苯基)-6’-甲基-[3,4’-联吡啶]-6-基)吗啉-4-甲酰胺(45)的制备
用吗啉(11-1)代替实施例5中的甲胺的四氢呋喃溶液，6-氨基-2’-氯-2-(4-氟苯基)-6’-甲基-[3,4’-联吡啶]-4-腈(45-3)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(45)(90mg，收率：43.0％)。
MS m/z(ESI):452.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:10.0(s,1H),8.22(s,1H),7.33(t,J＝7.2Hz,3H),7.23(s,1H),7.17(t,J＝8.8Hz,2H),3.65-3.58(m,4H),3.54-3.48(m,4H),2.40(s,3H)。
实施例46：N-(4-(4-氟苯基)-5-(4-甲基喹啉-6-基)嘧啶-2-基)吗啉-4-甲酰胺的制备(化合物46)
Figure PCTCN2019126555-appb-000078
第一步：4-(4-氟苯基)-5-(4-甲基喹啉-6-基)嘧啶-3-胺(46-2)的制备
用4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹啉(46-1)代替实施例3第四步中的4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)，以类似实施例3第四步所述的方法，合成得到本步的标题化合物(46-2)(150mg，收率：63％)。
MS m/z(ESI):331.1[M+H] +。
第二步：N-(4-(4-氟苯基)-5-(4-甲基喹啉-6-基)嘧啶-2-基)吗啉-4-甲酰胺(46)的制备
用吗啉(11-1)代替实施例5中的甲胺的四氢呋喃溶液，4-(4-氟苯基)-5-(4-甲基喹啉-6-基)嘧 啶-3-胺(46-2)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(46)(30mg，收率：18％)。
MS m/z(ESI):444.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.85(s,1H),8.77(s,1H),8.76(d,J＝8.8Hz,1H),8.70(s,1H),7.90(s,1H),7.46-7.39(m,4H),7.18-7.14(m,2H),3.62-3.60(m,4H),3.49-3.47(m,4H),2.62(s,3H)。
实施例47：N-(4-环丙基-6-(4-氟苯基)-5-(4-甲基喹啉-6-基)嘧啶-2-基)吗啉-4-甲酰胺的制备(化合物47)
Figure PCTCN2019126555-appb-000079
第一步：4-环丙基-6-(4-氟苯基)-5-(4-甲基喹啉-6-基)嘧啶-2-胺(47-1)的制备
用4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹啉(46-1)代替实施例44第五步中的4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)，以类似实施例44第五步所述的方法，合成得到本步的标题化合物(47-1)(260mg，收率：63％)。
MS m/z(ESI):371.2[M+H] +。
第二步：N-(4-环丙基-6-(4-氟苯基)-5-(4-甲基喹啉-6-基)嘧啶-2-基)吗啉-4-甲酰胺(48)的制备
用吗啉(11-1)代替实施例5中的甲胺的四氢呋喃溶液，4-环丙基-6-(4-氟苯基)-5-(4-甲基喹啉-6-基)嘧啶-2-胺(47-1)代替实施例5中的4-(4-氟苯基)-5-(4-甲基喹唑啉-6-基)嘧啶-2-胺(3)，以类似实施例5所述的方法，合成得到标题化合物(47)(45mg，收率：50％)。
MS m/z(ESI):484.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.50(s,1H),8.76(d,J＝8.8Hz,1H),7.97(s,2H),7.59(d,J＝8.8Hz,1H),7.38(d,J＝4.0Hz,1H),7.33-7.30(m,2H),7.05(t,J＝8.8Hz,2H),3.61(t,J＝8.8Hz,4H),3.46(t,J＝8.8Hz,4H),2.56(s,3H),1.78(s,1H),1.13(s,2H),0.90(s,2H)。
实施例48：N-(6-(4-氟苯基)-5-(4-甲基喹啉-6-基)吡啶-2-基)吗啉-4-甲酰胺的制备(化合物48)
Figure PCTCN2019126555-appb-000080
第一步：6-(4-氟苯基)-5-(4-甲基喹啉-6-基)吡啶-2-胺(48-1)的制备
用4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹啉(46-1)代替实施例1第二步中的4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)，以类似实施例1第二步所述的方法，合成得到本步的标题化合物(48-1)(1.2g，收率：51％)。
MS m/z(ESI):330.1[M+H] +。
第二步：N-(6-(4-氟苯基)-5-(4-甲基喹啉-6-基)吡啶-2-基)吗啉-4-甲酰胺(48)的制备
用吗啉(11-1)代替实施例4中的N-甲基-1-吡啶-2-甲胺(In-7-b)，6-(4-氟苯基)-5-(4-甲基喹啉-6-基)吡啶-2-胺(48-1)代替实施例4中的3-氟-6-(4-氟苯基)-5(4-甲基喹唑啉-6-基)吡啶-2-胺(2)，以类似实施例4所述的方法，合成得到标题化合物(48)(12mg，收率：15％)。
MS m/z(ESI):443.2[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:8.78(s,1H),8.24-8.17(m,2H),7.93(d,J＝8.8Hz,1H),7.84(m,1H),7.50(d,J＝8.8Hz,1H),7.35-7.30(m,3H),6.97(t,J＝8.8Hz,2H),3.80(t,J＝8.8Hz,4H),3.62(s,4H),2.64(s,3H)。
实施例49：N-(2’-氯-2-(4-氟苯基)-6’-甲基-[3,4-联吡啶]-6-基)吗啉-4-甲酰胺的制备(化合物49)
Figure PCTCN2019126555-appb-000081
第一步：2’-氯-2-(4-氟苯基)-6’-甲基-[3,4-联吡啶]-6-胺(49-1)的制备
用2-氯-6-甲基-4-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)吡啶(In-4)代替实施例1第二步中的4-甲基-6-(4,4,5,5-四甲基-1,3,2-二氧杂硼杂环戊-2-基)喹唑啉(1-3)，以类似实施例1第二步所述的方法，合成得到本步的标题化合物(50-1)(170mg，收率：56％)。
MS m/z(ESI):314.1[M+H] +。
第二步：N-(2’-氯-2-(4-氟苯基)-6’-甲基-[3,4-联吡啶]-6-基)吗啉-4-甲酰胺(49)的制备
用吗啉(11-1)代替实施例4中的N-甲基-1-吡啶-2-甲胺(In-7-b)，2’-氯-2-(4-氟苯基)-6’-甲基-[3,4-联吡啶]-6-胺(49-1)代替实施例4中的3-氟-6-(4-氟苯基)-5(4-甲基喹唑啉-6-基)吡啶-2-胺(2)，以类似实施例4所述的方法，合成得到标题化合物(49)(100mg，收率：42％)。
MS m/z(ESI):427.1[M+H] +。
1H NMR(400MHz,DMSO-d 6)δ:9.50(s,1H),7.87(d,J＝6.4Hz,2H),7.40-7.32(m,2H),7.20-7.16(m,2H),7.08(s,1H),7.01(s,1H),3.59(d,J＝4.8Hz,4H),3.49(d,J＝4.4Hz,4H),2.36(s,3H)。
生物学测试
实验例1.对腺苷A1、A2a受体的竞争性抑制常数(Ki)测定
实验用试剂：
[ 3H]-DPCPX(PerkinElmer，NET974250UC)，
[ 3H]-CGS-21680(PerkinElmer，NET1021250UC)，
A1受体细胞膜(人源)(PerkinElmer，ES-010-M400UA)，
A2a受体细胞膜(人源)(PerkinElmer，RBHA2AM400UA)，
Microscint 20 cocktail闪烁液(PerkinElmer，6013329)，
PEI(Poly ethyleneimine)(Sigma，P3143)，和
CGS-15943(Sigma，C199)。
实验用的缓冲液：
A1实验缓冲液(25mM HEPES，5mM MgCl 2，1mM CaCl 2，100mM NaCl，pH7.4)，用于稀释A1受体细胞膜(人源)与[ 3H]-DPCPX；
A1洗涤缓冲液(25mM HEPES，5mM MgCl 2，1mM CaCl 2，100mM NaCl，pH7.4)；
A2a实验缓冲液(50mM Tris-HCl，10mM MgCl 2，1mM EDTA，pH7.4)，用于稀释A2a受体细胞膜(人源)与[ 3H]-CGS-21680；和
A2a洗涤缓冲液(50mM Tris-HCl，154mM NaCl，pH7.4)。
实验方法：
采用A1实验缓冲液稀释A1受体细胞膜至0.025μg/μl，采用A2a实验缓冲液稀释A2a受体细胞膜至0.05μg/μl，得到A1受体细胞膜稀释液和A2a受体细胞膜稀释液。
以DMSO梯度稀释待测化合物和CGS-15943，将1μl待测化合物、高值对照(0.5％DMSO)、低值对照(1000nM CGS-15943)加至96孔板，每孔加入100μl A1受体细胞膜稀释液(含2.5μg细胞膜)，得到A1检测板；按照同样的步骤，在96孔板的每孔中加入100μl A2a受体细胞膜稀释液(含5.0μg细胞膜)，得到A2a检测板；
在A1检测板中加入100μl放射性同位素标记配体[ 3H]-DPCPX(用A1实验缓冲液稀释，工作浓度1.0nM)，A2a检测板中加入100μl放射性同位素标记配体[ 3H]-CGS-21680(用A2a实验缓冲液稀释，工作浓度6.0nM)，使用胶带封闭A1和A2a检测板，室温条件下，分别孵育1h和2h。
准备Unifilter-96 GF/C过滤板，在Unifilter-96 GF/C过滤板的每孔中加入50μl 0.3％PEI，室温条件下孵育不少于0.5h。
孵育结束后，转移A1检测板和A2a检测板中的反应液至两块Unifilter-96 GF/C过滤板中，并使用预冷的A1洗涤缓冲液和A2a洗涤缓冲液洗涤，然后烘干过滤板，封闭过滤板底部后加入50μl Microscint 20 cocktail闪烁液，封闭过滤板顶部后，使用计数器MicroBeta2 Reader读板。
数据分析：
使用如下公式计算抑制率：
抑制率％＝100-(实验孔信号值-低值对照信号平均值)/(高值对照信号平均值-低值对照信号平均值)*100；
采用EXCEL XLfit拟合IC 50；
竞争性抑制常数(Ki)的计算公式为：K i＝IC 50/(1+同位素标记配体浓度/K d)，其中K d为同位素标记的配体的解离常数。
本申请化合物对腺苷A2a、A1受体的竞争抑制常数(Ki)的检测结果详见表1。
表1本申请化合物对腺苷A2a、A1受体的竞争抑制常数(Ki)
Figure PCTCN2019126555-appb-000082
Figure PCTCN2019126555-appb-000083
表1中的数据表明本申请化合物对腺苷A2a受体具有较好的亲和力，对腺苷A1受体的亲和力较弱。本申请化合物对腺苷A2a受体具有很好的选择性。
实验例2：对ADORA2a/CHOK1细胞的抑制活性研究
实验用试剂：
腺苷(Sigma，A4036)，
Ham’s F-12培养基：(Hyclone，SH30526.01)
Hygromycin B：(Invitrogen，10687010)
Zeocin(Invitrogen，R25001)，
cAMP检测试剂盒(Cisbio，62AM4PEB)，和
ADORA2a/CHOK1细胞(科佰，CBP71017)。
溶液配制：
细胞培养基配制：Ham’s F-12培养基中加入FBS至10％(v/v)，添加Zeocin至终浓度200μg/mL，添加Hygromycin B至终浓度100μg/mL，4℃储存备用。
10μM腺苷溶液配制：精确称取一定量的腺苷于1.5mL EP管中，加入一定体积的细胞培养基，37℃温育助溶，配制成10mM储备液。以细胞培养基按1：1000稀释即得10μM腺苷溶液。
待测化合物配制：待测化合物用DMSO溶解为10mM储备液，4℃冰箱保存备用。以10μM腺苷溶液将化合物稀释为2000nM、200nM待测。
实验方法：
1.细胞种板：(1)稳定表达ADORA2A受体的CHO-K1细胞培养于37℃，5％CO 2细胞培养箱中，当细胞汇合度达到80％左右时，胰酶消化、分散细胞并计数；(2)根据计数结果将细胞浓度调整至6×10 5个细胞/mL；(3)接种细胞至白色384孔细胞培养板，每孔5μL(约3000个细胞/孔)。
2.化合物与细胞共孵育：所有组别均设置复孔，Blank组加入无腺苷细胞培养基(5μL/孔)；Agonist组加入10μM的腺苷溶液(5μL/孔)；待测化合物组加入稀释后化合物(5μL/孔)。加入化合物后离心384孔板，2500rpm离心30s，使化合物与培养基充分混合。将384孔板置于25℃恒温箱中孵育30min。
3.加检测试剂：(1)配制检测液，A液：取一定体积的cAMP-d2，按1:5加入Lysis&Detection Buffer稀释；B液：取一定体积的cAMP-Cryptate，按1:5加入Lysis&Detection Buffer稀释。(2)第2步30min孵育结束后加检测液。取出384孔板，每孔加入5μL A液，再按5μL/孔加入B液。盖上封板膜后2500rpm离心384孔板30s(使检测液与培养基充分混合)，25℃恒温箱中孵育1h。
4.读板：孵育结束后取出384孔板，使用PHERA Star FS读取数据，检测波长：620nm/665nm。
数据分析，原始数据处理与抑制率计算：
原始数据处理：(665nm读值/620nm读值)*10000即为R值，抑制率％＝(1-(R Compound-R Blank)/(R Agonist- R Blank))*100％；R Compound表示待测化合物组R值，R Agonist表示Agonist组R值，R Blank表示Blank组R值。
本申请化合物对ADORA2a/CHOK1细胞的抑制活性(抑制率)检测结果详见表2。
表2本申请化合物对ADORA2a/CHOK1细胞的抑制活性(抑制率)
化合物编号 1000nM抑制率(％) 100nM抑制率(％)
11 111.8 72.0
19 94.4 33.9
43 100.2 59.1
44 104.0 64.8
表2中的数据表明本申请化合物对CHOK1细胞的A2a受体具有较好的拮抗活性。
实验例3：大鼠药代动力学(PK)和脑组织分布研究
分别通过静脉(IV)和灌胃(PO)给予雄性SD大鼠本申请的化合物，考察药代动力学特点。IV和PO的给药剂量分别是1mg/kg和5mg/kg，IV的溶媒为5％DMSO、5％Solutol(聚乙二醇-15羟基硬脂酸酯)和90％生理盐水的混合物，PO的溶媒为0.5％MC(甲基纤维素钠)。在IV给药前(0h)以及给药后0.083h、0.25h、0.5h、1h、2h、4h、6h、8h和24h时间点收集血液，在PO给药前(0h)以及给药后0.25h、0.5h、1h、2h、4h、6h、8h和24h时间点收集血液，血液采用EDTA.K 2抗凝、离心后得到血浆样品。化合物11在0.25h、0.5h、1h、4h和8h取脑组织匀浆，化合物19和32在0.25h、0.5h、1h和8h取脑组织匀浆(每个时间点选取3只SD大鼠进行脑组织分布实验)，保存于-80℃。血浆样品和脑组织匀浆液经沉淀蛋白处理后进行LC-MS/MS分析。
应用WinNonlin 6.3软件，采用非房室模型计算药代动力学参数，结果见表3和表4。
表3：IV给药的化合物在大鼠体内的药代动力学参数
Figure PCTCN2019126555-appb-000084
如表3所示，通过以1mg/kg的剂量IV给药的本申请化合物11、19、32在大鼠体内的暴露量(AUC last)分别为为985h*ng/mL、2631h*ng/mL、1822h*ng/mL，化合物11、19、32在大鼠体内的最大血药浓度(C max)分别为1311ng/mL、1150ng/mL、1480ng/mL，表明本申请的化合物11、19、32通过IV给药在大鼠体内具有优良的药物暴露量。
表4：PO给药的化合物在大鼠体内的药代动力学参数
Figure PCTCN2019126555-appb-000085
Figure PCTCN2019126555-appb-000086
如表4所示，通过以5mg/kg的剂量PO给药的本申请的化合物11、19和32在大鼠血浆中的AUC last分别为3218h*ng/mL、11419h*ng/mL和7306h*ng/mL，在大鼠脑组织的AUC last分别为11.4h*ng/g、70.2h*ng/g和52.9h*ng/g。由此可得，化合物11、19和32在大鼠血浆的AUC last和脑组织的AUC last的比值分别为282/1、163/1和138/1，表明本申请的化合物11、19和32通过PO给药在大鼠血浆中均具有优良的药物暴露量，并且透过血脑屏障的比例很低。
经计算，与静脉给药相比，大鼠口服化合物11、19和32的生物利用度为65.3％、86.8％和80.2％，表明本申请的化合物(例如化合物11、19和32)在大鼠体内具有优良的口服吸收效果。
尽管本申请的具体实施方式已经得到详细的描述，但本领域技术人员将理解：根据已经公开的所有教导，可以对细节进行各种修改和变动，并且这些改变均在本申请的保护范围之内。本申请的全部范围由所附权利要求及其任何等同物给出。

Claims (16)

  1. 式I所示化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：
    Figure PCTCN2019126555-appb-100001
    X 1为N或CR 3；
    X 2为N或CR 4；
    且当X 1为CR 3时，X 2不为N；
    环A 1选自C 3-10环烷基、4-12元杂环基、C 6-10芳基和5-10元杂芳基，所述环A 1任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、羟基、C 1-6烷氧基、氨基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-和4-12元杂环基；
    环A 2选自C 3-10环烷基、4-12元杂环基、C 6-10芳基和5-10元杂芳基；优选地，所述5-10元杂芳基为5-10元含氮杂芳基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-10环烷基、羟基、C 1-6烷氧基、氨基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-和4-12元杂环基，且环A 2不为1-异丙基-6-氧代-1,6-二氢吡啶-3-基；
    R 1和R 2各自独立地选自氢、C 1-6烷基、C 3-10环烷基、4-12元杂环基、C 6-10芳基、5-10元杂芳基、4-12元杂环基-C 1-6烷基-或5-10元杂芳基-C 1-6烷基-，其中所述C 1-6烷基、C 3-10环烷基、4-12元杂环基、C 6-10芳基、5-10元杂芳基、4-12元杂环基-C 1-6烷基-或5-10元杂芳基-C 1-6烷基-任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-10环烷基和4-12元杂环基；或者，
    R 1和R 2连同它们共同连接的氮原子形成4-12元含氮杂环基，优选地，所述4-12元含氮杂环基包含一个或多个选自氮和氧的杂原子；所述4-12元含氮杂环基任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-、C 3-10环烷基和4-12元杂环基；
    R 3和R 4各自独立地选自氢、卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3- 6环烷基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-；优选地，所述R 3和R 4各自独立地选自氢、卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷基-氨基-和二(C 1-6烷基)-氨基-)，
    并且
    所述化合物不是以下化合物：
    1-(5,6-二苯基-1,2,4-三嗪-3-基)-3-苯基脲，
    1-(5-(2-溴-5-羟基苯基)-4-乙基-6-苯基嘧啶-2-基)脲，
    1-(5-(2-氯-5-羟基苯基)-4-乙基-6-苯基嘧啶-2-基)脲，
    1-(3,5-二(三氟甲基)苯基)-3-(4-(3-羟基-5-甲基苯基)-5-(吡啶-4-基)嘧啶-2-基)脲，
    1-(4-氯-3-(三氟甲基)苯基)-3-(4-(3-羟基-5-甲基苯基)-5-(吡啶-4-基)嘧啶-2-基)脲，
    1-(3,5-二(三氟甲基)苯基)-3-(4-(3-甲氧基-5-甲基苯基)-5-(吡啶-4-基)嘧啶-2-基)脲，
    1-(4-氯-3-(三氟甲基)苯基)-3-(4-(3-甲氧基5-甲基苯基)-5-(吡啶-4-基)嘧啶-2-基)脲，
    1-(4-氯-3-(三氟甲基)苯基)-3-(4-(2-羟基苯基)-5-(4-甲氧基苯基)嘧啶-2-基)脲。
  2. 权利要求1所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物不是1-(6-(2-氯-6-甲基吡啶-4-基)-5-(4-氟苯基)-1,2,4-三嗪-3-基)脲。
  3. 权利要求1所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物具有式IIa、式IIb或式IIc所示的结构，
    Figure PCTCN2019126555-appb-100002
    其中：环A 1、环A 2、R 1、R 2、R 3和R 4的定义如权利要求1所述。
  4. 权利要求1至3任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：
    环A 1、环A 2、R 3和R 4的定义如权利要求2所述，
    R 1和R 2各自独立地选自氢、C 1-6烷基、C 3-8环烷基、4-8元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-，其中所述C 1-6烷基、C 3-8环烷基、4-8元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基和4-7元杂环基；或者，
    R 1和R 2连同它们共同连接的氮原子形成4-12元含氮杂环基(例如4-6元含氮杂环基)，优选地，所述4-12元含氮杂环基包含一个或多个选自氮和氧的杂原子；所述4-12元含氮杂环基(例如4-6元含氮杂环基)任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-、C 3-10环烷基和4-12元杂环基；
    优选地，R 3为氟；
    优选地，R 4为氢。
  5. 权利要求1至4任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：
    环A 1选自苯基和5-6元杂芳基，所述环A 1任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和4-7元杂环基；
    优选地，环A 1选自苯基和呋喃基，所述环A 1任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、硝基、甲基、乙基、正丙基、异丙基、三氟甲基、环丙基、环丁基、环戊基；
    优选地，环A 1选自苯基、呋喃-2-基和呋喃-3-基，所述环A 1任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、硝基、甲基、乙基、正丙基、异丙基、三氟甲基、环丙基、环丁基、环戊基；
    优选地，环A 1选自苯基和呋喃-2-基，所述环A 1任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、硝基、甲基、乙基、正丙基、异丙基、三氟甲基；
    优选地，环A 1选自苯基、4-氟苯基、4-乙基苯基、4-硝基苯基、2-氟苯基、3-氟苯基、4-甲基苯基、2-甲基苯基、3-甲基苯基、5-甲基-呋喃-2-基、3-甲基-呋喃-2-基和4-甲基-呋喃-2-基；
    优选地，环A 1选自4-氟苯基和5-甲基-呋喃-2-基；
    优选地，环A 1为4-氟苯基。
  6. 权利要求1至5任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：
    环A 2选自C 6-10芳基和5-10元杂芳基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和4-7元杂环基；
    优选地，环A 2选自苯基、吡啶基和喹唑啉基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和4-7元杂环基；
    优选地，环A 2选自苯基、吡啶-2-基、吡啶-3-基、吡啶-4-基、喹唑啉-2-基、喹唑啉-4-基、喹唑啉-5-基、喹唑啉-6-基、喹唑啉-7-基和喹唑啉-8-基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、硝基、C 1-6烷基、C 1-6卤代烷基、C 3-6环烷基和4-7元杂环基；
    优选地，环A 2选自苯基、吡啶-4-基和喹唑啉-6-基，所述环A 2任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、硝基、甲基、乙基、正丙基、异丙基、三氟甲基；
    优选地，环A 2选自3-氯-5-甲基苯基、2-氯-6-甲基吡啶-4-基、2-氯-6-(三氟甲基)-吡啶-4-基和4-甲基喹唑啉-6-基；优选地，环A 2为4-甲基喹唑啉-6-基；
    优选地，环A 2为2-氯-6-甲基吡啶-4-基。
  7. 权利要求1至6任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：
    R 1和R 2各自独立地选自氢、C 1-6烷基、C 3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-，其中所述C 1-6烷基、C 3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 3-6环烷基和4-7元杂环基；
    优选地，R 1和R 2各自独立地选自氢、C 1-6烷基、C 3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-，其中所述C 1-6烷基、C 3-6环烷基、4-7元杂环基、苯基、5-6元杂芳基、4-7元杂环基-C 1-6烷基-或5-6元杂芳基-C 1-6烷基-任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、羟基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、环丙基、环丁基、环戊基、环己基、哌啶-1-基、哌啶-2-基、哌啶-3-基和哌啶-4-基；
    优选地，R 1和R 2各自独立地选自氢、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、哌啶基、苯基、吡啶基、吡啶-2-基甲基、吡啶-2-基乙基、吡啶-2-基丙基、甲氧基乙基和2-羟基-2-甲基-丙基；
    优选地，R 1和R 2各自独立地选自氢、甲基、甲氧基乙基、2-羟基-2-甲基-丙基、苯基和吡啶-2-基甲基；
    优选地，R 1为氢或甲基，且R 2为氢、甲基、苯基、吡啶-2-基甲基、2-羟基-2-甲基-丙基或2-甲氧基乙基。
  8. 权利要求1至7任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：
    R 1和R 2连同它们共同连接的氮原子形成4-7元含氮杂环基，所述4-7元含氮杂环基任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-、C 3-6环烷基和4-7元杂环基；
    优选地，R 1和R 2连同它们共同连接的氮原子形成4-7元含氮杂环基，所述4-7元含氮杂环基包含一个或多个选自氮和氧的杂原子；所述4-7元含氮杂环基任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-、C 3-6环烷基和4-7元杂环基；
    优选地，R 1和R 2连同它们共同连接的氮原子形成6元含氮杂环基，所述6元含氮杂环基包含一个或多个选自氮和氧的杂原子；所述6元含氮杂环基任选地被一个或多个独立地选自下列的取代基取代：卤素、氰基、羟基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1-6烷氧基-C 1-6烷基-、C 1-6烷氧基-C 1-6烷氧基-、C 3-6环烷基和4-7元杂环基；
    优选地，R 1和R 2连同它们共同连接的氮原子形成哌啶基或吗啉基，所述哌啶基或吗啉基任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊基、环己基、三氟甲基、甲氧基、乙氧基、丙氧基、哌啶-1-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基；或者，R 1和R 2连同它们共同连接的氮原子形成哌嗪基，所述哌嗪基任选地被一个或多个独立地选自下列的取代基取代：氟、氯、溴、氰基、羟基、甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、环丙基、环丁基、环戊 基、环己基、三氟甲基、甲氧基、乙氧基、丙氧基、哌啶-1-基、哌啶-1-基、哌啶-2-基、哌啶-3-基、哌啶-4-基；
    优选地，R 1和R 2连同它们共同连接的氮原子形成哌啶基、吗啉基、4-氰基哌啶基、4-甲氧基哌啶基或1,4’-连哌啶基；
    优选地，R 1和R 2连同它们共同连接的氮原子形成吗啉基，所述吗啉基任选地被一个或多个独立地选自下列的取代基取代：甲基、乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基；
    优选地，R 1和R 2连同它们共同连接的氮原子形成吗啉基、2-甲基吗啉基或2,6-二甲基吗啉基。
  9. 权利要求1至8任一项所述的化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中：
    R 3和R 4各自独立地选自氢、卤素、氰基、羟基、氨基、C 1-6烷基、C 1-6卤代烷基、C 1-6烷氧基、C 1- 6烷基-氨基-和二(C 1-6烷基)-氨基-；
    优选地，R 3和R 4各自独立地选自氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、环丙基、环丁基、环戊基和环己基；
    优选地，R 3和R 4各自独立地选自氢、氟、氯、溴、氰基、羟基、氨基、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基和二乙基氨基；
    优选地，R 3选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基和二乙基氨基；
    优选地，R 4选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基、二乙基氨基、环丙基、环丁基、环戊基和环己基；
    优选地，R 4选自氢、氟、氯、溴、甲基、乙基、正丙基、异丙基、三氟甲基、甲氧基、乙氧基、丙氧基、甲基氨基、乙基氨基、二甲基氨基和二乙基氨基；优选地，R 4为氢、氯、氰基或环丙基；
    优选地，R 4为氢。
  10. 化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，其中所述化合物选自：
    Figure PCTCN2019126555-appb-100003
    Figure PCTCN2019126555-appb-100004
    Figure PCTCN2019126555-appb-100005
  11. 药物组合物，其包含权利要求1-10任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药，以及任选的一种或多种药学上可接受的载体或赋形剂。
  12. 权利要求1-10任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或权利要求10的药物组合物在制备作为腺苷A2a受体拮抗剂的药物中的用途。
  13. 权利要求1-10任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或权利要求10的药物组合物，其用于抑制腺苷A2a受体活性。
  14. 权利要求1至10任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或权利要求10的药物组合物在制备用于预防和/或治疗与腺苷受体A2a有关的疾病的药物中的用途，
    优选地，所述与腺苷受体A2a有关的疾病为肿瘤，
    优选地，所述肿瘤选自：乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
  15. 一种治疗和/或预防与腺苷A2a受体有关疾病的方法，其包括向有需要的受试者施用有效量的权利要求1至10任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或其药物组合物，
    优选地，所述与腺苷A2a受体有关的疾病为肿瘤，
    优选地，所述肿瘤包括但不限于：乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
  16. 权利要求1至10任一项所述化合物或其药学上可接受的盐、立体异构体、多晶型物、溶剂合物、N-氧化物、同位素标记的化合物、代谢物或前药或其药物组合物，其用于治疗和/或预防与腺苷A2a受体有关的疾病，
    优选地，所述与腺苷A2a受体有关的疾病为肿瘤，
    优选地，所述肿瘤包括但不限于：乳腺癌、卵巢癌、结直肠癌、黑色素瘤、非小细胞肺癌、小细胞肺癌、胃肠道间质瘤、宫颈癌、胰腺癌、前列腺癌、胃癌、慢性髓样白细胞过多症、肝癌、淋巴瘤、腹膜癌和软组织肉瘤。
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220017483A1 (en) * 2018-12-28 2022-01-20 Sichuan-Kelun-Biotech Biopharmaceutical Co., Ltd Aminopyridine compound, preparation method therefor and use thereof
CN115974844A (zh) * 2022-10-20 2023-04-18 广东省科学院动物研究所 3,4,5-三甲氧基苯基衍生物及其应用
WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers
WO2025137640A1 (en) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Azaspiro wrn inhibitors

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062233A2 (en) 2000-02-25 2001-08-30 F. Hoffmann La Roche Ag Adenosine receptor modulators
WO2003035640A1 (en) * 2001-10-22 2003-05-01 Eisai Co., Ltd. Pyrimidone compounds and pharmaceutical compositions containing the same
CN1507436A (zh) * 2001-03-02 2004-06-23 用作放射增敏剂和化疗增敏剂的芳基和杂芳基脲chk1抑制剂
CN1575290A (zh) * 2001-10-22 2005-02-02 卫材株式会社 嘧啶化合物以及含有该化合物的药物组合物
CN1809354A (zh) * 2003-04-24 2006-07-26 麦克公司 Akt活性抑制剂
CN101268064A (zh) * 2005-07-29 2008-09-17 奥米罗实验室有限公司 用作腺苷受体拮抗剂的吡嗪衍生物
WO2011095625A1 (en) 2010-02-05 2011-08-11 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
WO2019158070A1 (zh) * 2018-02-15 2019-08-22 杭州阿诺生物医药科技有限公司 A2a和/或a2b受体拮抗剂

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20050004134A1 (en) * 2001-11-08 2005-01-06 Hideo Tsutsumi Thiazole derivative and pharmaceutical use thereof
CN101033224B (zh) * 2006-03-10 2011-04-27 中国科学院上海药物研究所 一类新型嘧啶类小分子化合物、其制备方法及其用途
WO2007104254A1 (en) * 2006-03-10 2007-09-20 Shanghai Institute Of Materia Medica, Chinese Academy Of Sciences A type of new pyrimidine derivatives having small molecule, preparation methods and uses thereof
WO2019018584A1 (en) * 2017-07-18 2019-01-24 GiraFpharma LLC HETEROCYCLIC COMPOUNDS AS ADENOSINE ANTAGONISTS
WO2019141096A1 (zh) * 2018-01-19 2019-07-25 四川科伦博泰生物医药股份有限公司 取代脲类化合物及其制备方法和用途
CN111440148B (zh) * 2018-02-15 2021-07-30 杭州阿诺生物医药科技有限公司 一种腺苷受体拮抗剂的制备方法
CN112955441B (zh) * 2018-10-24 2024-06-18 里德埃克斯普洛股份公司 官能化氨基三嗪

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001062233A2 (en) 2000-02-25 2001-08-30 F. Hoffmann La Roche Ag Adenosine receptor modulators
CN1438890A (zh) * 2000-02-25 2003-08-27 弗·哈夫曼-拉罗切有限公司 腺苷受体调制剂
CN1507436A (zh) * 2001-03-02 2004-06-23 用作放射增敏剂和化疗增敏剂的芳基和杂芳基脲chk1抑制剂
WO2003035640A1 (en) * 2001-10-22 2003-05-01 Eisai Co., Ltd. Pyrimidone compounds and pharmaceutical compositions containing the same
CN1575290A (zh) * 2001-10-22 2005-02-02 卫材株式会社 嘧啶化合物以及含有该化合物的药物组合物
CN1809354A (zh) * 2003-04-24 2006-07-26 麦克公司 Akt活性抑制剂
CN101268064A (zh) * 2005-07-29 2008-09-17 奥米罗实验室有限公司 用作腺苷受体拮抗剂的吡嗪衍生物
WO2011095625A1 (en) 2010-02-05 2011-08-11 Heptares Therapeutics Limited 1,2,4-triazine-4-amine derivatives
WO2019158070A1 (zh) * 2018-02-15 2019-08-22 杭州阿诺生物医药科技有限公司 A2a和/或a2b受体拮抗剂

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
G. W. H CHEESEMANE. S. G. WERSTIUK: "Handbook of Pharmaceutical Salts: Properties, Selection, and Use", vol. 22, 2002, ACADEMIC PRESS, pages: 390 - 392
See also references of EP3904352A4
TAKAGI, K. ET AL.: "Synthèse de Pyrimidines et de Pyrazoles à partir d'Acyl-3 halogéno-5 benzofurannes", CHEM.PHARM.BULL., vol. 23, no. 10, 31 December 1975 (1975-12-31), XP002963771, ISSN: 0009-2363, DOI: 20200305152335X *
TAKAGI, K. ET AL.: "Synthèse de Pyrimidines et de Pyrazoles à partir d'Acyl-3 halogéno-5 benzofurannes", CHEM.PHARM.BULL., vol. 23, no. 10, 31 December 1975 (1975-12-31), XP002963771, ISSN: 0009-2363, DOI: 20200305154924X *
TL GILCHRIST, COMPREHENSIVE ORGANIC SYNTHESIS, vol. 7, pages 748 - 750

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20220017483A1 (en) * 2018-12-28 2022-01-20 Sichuan-Kelun-Biotech Biopharmaceutical Co., Ltd Aminopyridine compound, preparation method therefor and use thereof
WO2023201267A1 (en) 2022-04-13 2023-10-19 Gilead Sciences, Inc. Combination therapy for treating trop-2 expressing cancers
CN115974844A (zh) * 2022-10-20 2023-04-18 广东省科学院动物研究所 3,4,5-三甲氧基苯基衍生物及其应用
CN115974844B (zh) * 2022-10-20 2023-09-26 广东省科学院动物研究所 3,4,5-三甲氧基苯基衍生物及其应用
WO2025137640A1 (en) 2023-12-22 2025-06-26 Gilead Sciences, Inc. Azaspiro wrn inhibitors

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