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WO2019096322A1 - 一种吡唑酮并嘧啶类化合物、其制备方法及应用 - Google Patents

一种吡唑酮并嘧啶类化合物、其制备方法及应用 Download PDF

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WO2019096322A1
WO2019096322A1 PCT/CN2018/116352 CN2018116352W WO2019096322A1 WO 2019096322 A1 WO2019096322 A1 WO 2019096322A1 CN 2018116352 W CN2018116352 W CN 2018116352W WO 2019096322 A1 WO2019096322 A1 WO 2019096322A1
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nitrogen
substituted
alkyl
oxygen
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PCT/CN2018/116352
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English (en)
French (fr)
Inventor
王倩
夏广新
霍国永
舒思杰
石辰
张霖
葛辉
张智慧
毛煜
余建鑫
刘彦君
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上海医药集团股份有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/4045—Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/04—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms
    • C07D215/06—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to the ring carbon atoms having only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/02—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines
    • C07D217/04—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with only hydrogen atoms or radicals containing only carbon and hydrogen atoms, directly attached to carbon atoms of the nitrogen-containing ring; Alkylene-bis-isoquinolines with hydrocarbon or substituted hydrocarbon radicals attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/14—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D223/16—Benzazepines; Hydrogenated benzazepines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention relates to a pyrazolone pyrimidine compound, a preparation method thereof and application thereof.
  • the cell cycle is closely related to the DNA damage repair process.
  • the cell cycle refers to the whole process that cell division undergoes, and is divided into two phases: interphase and mitotic phase (M).
  • M mitotic phase
  • the cell cycle checkpoint is a key point in regulating the cell cycle. The main function is to ensure that each event in the cycle can be completed in time and in order, and the cell state is adjusted to suit the external environment.
  • the main test points of the cells are: 1) G 1 /S checkpoint: called R (restriction) point in mammals, control cells from the stationary G 1 phase into the DNA synthesis phase; 2) S phase checkpoint: DNA replication Whether it is completed; 3) G 2 /M checkpoint: is the control point that regulates the cell into the splitting phase; 4) the middle-late checkpoint: also known as the spindle assembly checkpoint, if the centromere is not properly connected to the spindle , it will cause the interruption of the cell cycle. If there are abnormalities in some processes in the cell division cycle, such as DNA damage, the checkpoint will sense it in time and initiate repair.
  • P53 protein is an important protein regulating G 1 checkpoint.
  • WEE1 kinase is a cell cycle regulatory protein that regulates the phosphorylation status of cyclin-dependent kinase 1 (CDK1), thereby regulating the activity of CDK1 and cyclinB complexes. Regulation of the cell cycle and an important regulatory role for DNA damage checkpoints. WEE1 is a key gene for G 2 /M phase arrest and plays an important role in monitoring.
  • WEE1 kinase inhibitors are key in anticancer therapy.
  • the role has become a hot spot for research and development of anticancer agents.
  • WEE1 kinase inhibitors are disclosed in international patent applications WO2010098367, WO2010067886, WO2008115742, WO2008115738, WO2007126122, WO2007126128, WO2004007499, etc., but there is currently no small molecule WEE1 kinase inhibitor listed, and there is a need to develop new anticancer activity in the field.
  • a highly safe WEE1 kinase inhibitor is disclosed in international patent applications WO2010098367, WO2010067886, WO2008115742, WO2008115738, WO2007126122, WO2007126128, WO2004007499, etc.
  • the technical problem to be solved by the present invention is that the existing compound has poor inhibitory activity against WEE1 kinase, and therefore, the present invention provides a pyrazolone pyrimidine compound, a preparation method thereof and application thereof, and the compound inhibits WEE1 kinase The activity is better.
  • the present invention provides a pyrazolone pyrimidine compound of the formula I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable form thereof.
  • n and n are independently 0, 1, 2 or 3, and m+n is 2, 3 or 4 ⁇ for example, m+n is 2 or 3; for example, “m is 0, n is 2", “m 2, n is 0", “m is 1, n is 1”, “m is 1, n is 2", or "m is 2, n is 1" ⁇ ;
  • Y is N or CH
  • C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms ⁇ wherein the number of R 1-21 is one or more [for example, 2, 3 or 4 Wherein , when a plurality of R 1-21 are present, said R 1-21 is the same or different; said "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus Kind, C 3 ⁇ C 7 heterocycloalkyl alkyl group having 1 to 4 atoms of "example” is a heteroatom or an oxygen atom, the number of nitrogen and / or hetero atoms of 1 or 2 of C 3 ⁇ C 5 heterocycloalkyl ", and For example, "a nitrogen hetero atom, hetero atom number of 1 to 2 is C 3 ⁇ C 5 heterocycloalkyl" or "hetero atom is oxygen, the number of hetero atoms of 1 or 2 of C 3 ⁇ C 5 heterocycloalkyl base".
  • heteroatom is nitrogen, the number of hetero atoms of 1 or 2 of C 3 ⁇ C 5 heterocycloalkyl
  • hetero atom is nitrogen, the number of hetero atoms of 1 or 2 hetero C 3 ⁇ C 5 a cycloalkyl group, and a heterocycloalkyl group is bonded to Y through a nitrogen atom" or "a hetero atom is a nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is passed through a carbon atom. Connect with Y".
  • the "hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to Y through a nitrogen atom", for example
  • the "hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to Y through a carbon atom", for example
  • the "hetero atom is oxygen, and the C 3 - C 5 heterocycloalkyl group having 1 to 2 hetero atoms" is, for example, ⁇ , unsubstituted or R 1-22 substituted C 6 -C 10 aryl ⁇ wherein the number of R 1-22 is one or more [eg 2, 3 or 4], when there are multiple R 1 to 22 , the R 1-22 is the same or different ⁇ , unsubstituted or R 1-23 substituted "hetero atom is one or more of boron
  • R 1-1-1 , R 1-1-2 and R 1-1-3 are independently C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen, and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or a "hetero atom” , one or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms";
  • All R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1-10 are independently hydroxy, C 1 -C 7 alkyl ⁇ eg C 1 -C 4 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further methyl, halo substituted C 1 to C 7 alkyl ⁇ wherein the number of halogens is one or more [for example, 2, 3 or 4], and when a plurality of halogens are present, the halogens are the same or different; "Independently, it is fluorine, chlorine, bromine or iodine; the "C 1 -C 7 alkyl group” is, for example, a C 1 -C 4 alkyl group, and further, for example, methyl, ethyl, n-propyl, is
  • C 1 ⁇ C 4 alkoxy group and for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy or tert Alkoxy, such as methoxy ⁇ and "one or more hetero atoms, number of heteroatoms boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus in the range of 1 to 4 hetero C 3 ⁇ C 7 a cycloalkyl group, a C 6 -C 10 aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C 1 to have 1 to 4 hetero atoms.
  • C 7 heteroaryl or, NR 1-4-1 R 1-4-2 ;
  • All R 1-4-1 and R 1-4-2 are independently hydrogen, C 1 -C 7 alkyl ⁇ eg C 1 -C 4 alkyl, for example methyl, ethyl, n-propyl, iso a propyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 to C 10 An aryl group or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1
  • R 1-11 , R 1-12 , R 1-13 , R 1-14 and R 1-15 are independently H, cyano, hydroxy, C 1 -C 7 alkoxy, unsubstituted or R 1 1-11-1 substituted C 1 -C 7 alkyl ⁇ wherein the number of R 1-11-1 is one or more [for example, 2, 3 or 4], when a plurality of R 1-11 are present When -1 , the R 1-11-1 is the same or different; the "C 1 -C 7 alkyl" is, for example, a C 1 -C 4 alkyl group, and further, for example, a methyl group, an ethyl group, a n-propyl group, Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl ⁇ , C 3 -C 7 cycloalkyl, "a hetero atom is one of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus Or
  • All R 1-11-1 are independently halogen, hydroxy, cyano, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkane, C 3 -C 7 naphthenic a C 1 -C 7 heterocycloalkyl group, a C 6 -C 10 aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ⁇ 4 C 1 -C 7 heteroaryl" or C 1 -C 7 alkoxy;
  • All R 1-16 , R 1-17 , R 1-18 , R 1-19 , R 1-20 , R 1-21 , R 1-22 , R 1-23 , R 1-24 and R 1- 25 is independently halogen ⁇ e.g., fluorine, chlorine, bromine or iodine, for example, fluorine ⁇ , nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkylsilyl ⁇ e.g.
  • the atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms" ⁇ where R 1-16-
  • the number of 6 is one or more [for example, 2, 3 or 4], and when there are a plurality of R 1-16-6 , the R 1-16-6 are the same or different;
  • the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms.
  • the hetero atom is nitrogen and / or oxygen hetero atoms, the number 1 or 2 of C 3 ⁇ C 5 heterocycloalkyl ", and such as” hetero atom is nitrogen, the number of hetero atoms, C 3 ⁇ C 5 heterocycloalkyl group of 1 to 2 "," C 3 where the hetero atom is oxygen and the number of hetero atoms is 1 or 2 ⁇ C 5 heterocycloalkyl" or
  • the "heteroatom is nitrogen, the number of hetero atoms of 1 or 2 of C 3 ⁇ C 5 heterocycloalkyl" e.g.
  • hetero atom is nitrogen, the number of hetero atoms of 1 or 2 hetero C 3 ⁇ C 5 a cycloalkyl group, and a heterocycloalkyl group is bonded to another group [for example, C 1 -C 7 alkyl group] through a nitrogen atom or a C 3 -C 5 hetero atom having a hetero atom of nitrogen and having 1 to 2 hetero atoms.
  • a cycloalkyl group, and a heterocycloalkyl group is bonded to another group [for example, C 1 -C 7 alkyl group] through a carbon atom.
  • the "hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to another group through a nitrogen atom", for example
  • the "hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to another group through a carbon atom", for example
  • the "hetero atom is oxygen, and the C 3 - C 5 heterocycloalkyl group having 1 to 2 hetero atoms" is, for example, ⁇ , C 6 -C 10 aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 1 -C 7 heteroatoms having 1 to 4 heteroatoms
  • Aryl C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, -NR 1-16-1 R
  • All R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 , R 1-16-6 and R 1-16-7 are independently hydrogen, hydroxy, Halogen, cyano, C 1 -C 7 alkyl ⁇ eg C 1 -C 4 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or Tert-butyl, for example, methyl ⁇ , C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen And one or more of phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, One or more of seleni
  • All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms" ⁇ eg "heteroatoms are boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen, and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, and which is bonded to a carbonyl group through a nitrogen atom, and The atom is one or more of oxygen, sulfur and nitrogen, a C 3 -C 7 heterocycloalkyl group having 1 to 2 hetero atoms, and which is bonded to the carbonyl group through
  • the alkyl group for example, "a hetero atom is nitrogen, a C 3 -C 7 heterocycloalkyl group having 1 to 2 hetero atoms, and which is bonded to a carbonyl group through a nitrogen atom".
  • the "halogenated hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms"
  • a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 1 -C 7 heteroatoms having 1 to 4 heteroatoms
  • Aryl -NR 1-16-5-1 R 1-16-5-2 or -OR 1-16-5-3 ;
  • R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen , R 1-16-5-1- 1 unsubstituted or substituted with C 1 ⁇ C 7 alkyl group ⁇ wherein R 1-16-5-1-1 number of one or more [e.g., 2, 3 Or 4], when a plurality of R 1-16-5-1-1 are present, the R 1-16-5-1-1 is the same or different; the "C 1 -C 7 alkyl group”
  • C 1 -C 4 alkyl for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, again such as methyl or ethyl ⁇ a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group (for example, a C 2 -C 4 alkynyl group,
  • All R 1-16-5-1-1 are independently halogen, hydroxy, cyano, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, C 1 to C 7 alkylsilyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more of them, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • z 0, 1 or 2;
  • All R 2 are independently halogen, hydroxy, cyano, amino, unsubstituted or R 2-1 substituted C 1 -C 7 alkyl ⁇ wherein the number of R 2-1 is one or more [eg 2 , 3 or 4], when a plurality of R 2-1 are present, the R 2-1 is the same or different ⁇ , unsubstituted or R 2-2 substituted C 2 -C 8 alkenyl ⁇ where The number of R 2-2 is one or more [for example, 2, 3 or 4], and when a plurality of R 2-2 are present, the R 2-2 is the same or different ⁇ , unsubstituted or R 2-3 substituted C 2 -C 7 alkynyl ⁇ wherein the number of R 2-3 is one or more [for example, 2, 3 or 4], when a plurality of R 2-3 are present, R 2-3 is the same or different ⁇ , unsubstituted or R 2-4 substituted C 1 -C 7 alkyl group ⁇ wherein the number of R 2-4 is one or more
  • One or more of the number of phosphorus heteroatoms is 1 to 4 of C 1 ⁇ C 7 heteroaryl " ⁇ wherein, R 2-6 is the number of one or more [e.g. 2, 3 or 4], when a plurality of R 2-6 are present, the R 2-6 is the same or different ⁇ , a C 3 -C 7 cycloalkyl group, or an unsubstituted or R 2-7 substituted C 1 -C 7 alkoxy ⁇ wherein the number of R 2-7 is one or more [eg 2, 3 or 4], when a plurality of R 2-7 are present, the R 2-7 is the same or different ⁇ ;
  • both R 2 are hydroxyl groups and are attached to the same carbon atom, which means that two R 2 together with the carbon atom to which they are attached form a carbonyl group ⁇
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 , R 2-6 and R 2-7 are independently halogen, nitro, cyano, C 1 ⁇ C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, oxygen, sulfur , one or more of selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group, "a hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", C 1 -C 7 alkoxy group, C 1 -C 7 Alkyl fluorenyl, -NR 2-1-1 R 2-1-21-2
  • R 2-1-1 , R 2-1-2 , R 2-1-3 and R 2-1-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ⁇ 4 C 1 -C 7 heteroaryl groups";
  • All R 2-1-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • two R 2 linkages together form an unsubstituted or R 2-8 substituted C 3 -C 7 cycloalkyl group on the same carbon atom ⁇ wherein the number of R 2-8 is one or more [eg 2 , 3 or 4], when a plurality of R 2-8 are present, the R 2-8 is the same or different ⁇ , or the unsubstituted or R 2-9 substituted C 1 -C 7 heterocycloalkyl Wherein the number of R 2-9 is one or more [eg 2, 3 or 4], and when a plurality of R 2-9 are present, the R 2-9 is the same or different; "C 1 -C 7 heterocycloalkyl" such as "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 of a heteroatom number of 1 to 4" C 7 heterocycloalkyl" ⁇ ;
  • R 2-8 and R 2-9 are independently halogen, cyano, fluorenyl, hydroxy, amino, C 1 -C 7 alkoxy or C 1 -C 7 alkanoyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n and n are independently 0, 1, 2 or 3, and m+n is 2 or 3.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n and n are independently 0, 1, 2 or 3, and m+n is 3.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n and n are independently 1 or 2, and m+n is 3.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • Y is N.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • Y is N, and the atom connected to Y in R 1 is not N.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • Y is CH.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1 is -NR 1-1 R 1-2 , R 1-16 substituted C 1 -C 7 alkyl, or unsubstituted or R 1-21 substituted "hetero atom is boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-1-1 , R 1-1-2 and R 1-1-3 are independently a C 1 -C 7 alkyl group or a C 6 -C 10 aryl group.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-1-1 and R 1-1-2 are independently C 1 -C 7 alkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen, or an unsubstituted or C 6 -C 10 aryl-substituted C 1 -C 7 alkyl group.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • All R 1-1 and R 1-2 are independently hydrogen, or an unsubstituted or C 6 -C 10 aryl-substituted C 1 -C 7 alkyl group.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, Or, NR 1-4-1 R 1-4-2 ;
  • R 1-4-1 and R 1-4-2 are independently C 1 -C 7 alkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-16 and R 1-21 are independently halogen, cyano, C 1 -C 7 alkyl, unsubstituted or R 1-16-7 substituted C 3 -C 7 cycloalkyl, unsubstituted or
  • R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 , R 1-16-6 and R 1-16-7 are independently hydrogen or C 1 ⁇ C 7 alkyl;
  • R 1-16-5 are independently a hydroxyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C 3 of a heteroatom number of 1 to 4" C 7 heterocycloalkyl", halogenated "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 - C 7 having 1 to 4 hetero atoms Heterocycloalkyl", -NR 1-16- 5-1 R 1-16-5-2 or -OR 1-16-5-3 ;
  • R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen An unsubstituted or hydroxy C 1 -C 7 alkyl group, a C 2 -C 7 alkynyl group, or a C 3 -C 7 cycloalkyl group.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 and R 1-16-6 are independently hydrogen or C 1 -C 7 alkyl;
  • R 1-16-5 are independently a hydroxyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C 3 of a heteroatom number of 1 to 4" C 7 heterocycloalkyl", halogenated "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 - C 7 having 1 to 4 hetero atoms Heterocycloalkyl", -NR 1-16- 5-1 R 1-16-5-2 or -OR 1-16-5-3 ;
  • R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen An unsubstituted or hydroxy C 1 -C 7 alkyl group, a C 2 -C 7 alkynyl group, or a C 3 -C 7 cycloalkyl group.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-16-1 , R 1-16-2 , R 1-16-4 and R 1-16-6 are independently hydrogen or C 1 -C 7 alkyl;
  • R 1-16-5 are independently a hydroxyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C 3 of a heteroatom number of 1 to 4" C 7 heterocycloalkyl", Or -NR 1-16-5-1 R 1-16-5-2 ;
  • R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen, unsubstituted or hydroxy C 1 a C 7 alkyl group, a C 2 -C 7 alkynyl group, or a C 3 -C 7 cycloalkyl group.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • All R 1-16-3 and R 1-16-6 are independently C 1 -C 7 alkyl; all R 1-16-5 are independently All R 1-16-5-4 and R 1-16-5-5 are independently C 1 -C 7 alkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • All R 1-16-6 are independently C 1 -C 7 alkyl; all R 1-16-5 are independently All R 1-16-5-4 and R 1-16-5-5 are independently C 1 -C 7 alkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1 is any of the following groups: hydrogen, amino, methyl, ethyl, n-propyl, isopropyl, 2-hydroxyethyl, 2-methoxyethyl, 2-methylaminoethyl, 2-Dimethylaminoethyl, cyanomethyl, cyano, acetyl, 2-propenyl, 2-propynyl, dimethylamino, 2-fluoroethyl, 2,2,2-trifluoro Ethyl, methoxyl, methylsulfonyl, 2,2,2-trifluoroacetyl, cyclobutyl, cyclopropylmethyl, cyclopropyl, diethylamino, di-n-propylamino, dimethyl Aminomethyl, methoxy, hydroxy, carboxymethyl,
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • n and n are independently 0, 1, or 2, and m+n is 2 or 3;
  • Y is N or CH
  • R 1-1-1 , R 1-1-2 and R 1-1-3 are independently C 1 -C 7 alkyl or C 6 -C 10 aryl;
  • R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, Or, NR 1-4-1 R 1-4-2 ;
  • R 1-4-1 and R 1-4-2 are independently C 1 -C 7 alkyl
  • R 1-16 and R 1-21 are independently halogen, cyano, C 1 -C 7 alkyl, unsubstituted or R 1-16-7 substituted C 3 -C 7 cycloalkyl, unsubstituted or
  • R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 , R 1-16-6 and R 1-16-7 are independently hydrogen or C 1 ⁇ C 7 alkyl;
  • R 1-16-5 are independently a hydroxyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C 3 of a heteroatom number of 1 to 4" C 7 heterocycloalkyl", halogenated "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 - C 7 having 1 to 4 hetero atoms Heterocycloalkyl", -NR 1-16- 5-1 R 1-16-5-2 or -OR 1-16-5-3 ;
  • R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen An unsubstituted or hydroxy C 1 -C 7 alkyl group, a C 2 -C 7 alkynyl group, or a C 3 -C 7 cycloalkyl group;
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • n and n are independently 0, 1, or 2, and m+n is 2 or 3;
  • Y is N or CH
  • R 1-1-1 and R 1-1-2 are independently C 1 -C 7 alkyl
  • R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, Or, NR 1-4-1 R 1-4-2 ;
  • R 1-4-1 and R 1-4-2 are independently C 1 -C 7 alkyl
  • R 1-16-1 , R 1-16-2 , R 1-16-3 , R 1-16-4 and R 1-16-6 are independently hydrogen or C 1 -C 7 alkyl;
  • R 1-16-5 are independently a hydroxyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C 3 of a heteroatom number of 1 to 4" C 7 heterocycloalkyl", halogenated "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 - C 7 having 1 to 4 hetero atoms Heterocycloalkyl", -NR 1-16- 5-1 R 1-16-5-2 or -OR 1-16-5-3 ;
  • R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-3 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen An unsubstituted or hydroxy C 1 -C 7 alkyl group, a C 2 -C 7 alkynyl group, or a C 3 -C 7 cycloalkyl group;
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • Y is N or CH
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen, or an unsubstituted or C 6 -C 10 aryl substituted C 1 -C 7 alkyl group;
  • R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 2 -C 7 alkynyl, C 1 -C 7 alkoxy, Or, NR 1-4-1 R 1-4-2 ;
  • R 1-4-1 and R 1-4-2 are independently C 1 -C 7 alkyl
  • R 1-16-1 , R 1-16-2 , R 1-16-4 and R 1-16-6 are independently hydrogen or C 1 -C 7 alkyl;
  • R 1-16-5 are independently a hydroxyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and C 3 of a heteroatom number of 1 to 4" C 7 heterocycloalkyl", Or -NR 1-16-5-1 R 1-16-5-2 ;
  • R 1-16-5-1 , R 1-16-5-2 , R 1-16-5-4 and R 1-16-5-5 are independently hydrogen, unsubstituted or hydroxy C 1 -C 7 alkyl, C 2 -C 7 alkynyl, or C 3 -C 7 cycloalkyl;
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • n 1;
  • Y is N or CH
  • R 1 is -NR 1-1 R 1-2 , R 1-16 substituted C 1 -C 7 alkyl, or unsubstituted or R 1-21 substituted "hetero atom is boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms";
  • All R 1-16-3 and R 1-16-6 are independently C 1 -C 7 alkyl; all R 1-16-5 are independently All R 1-16-5-4 and R 1-16-5-5 are independently C 1 -C 7 alkyl;
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • n 1;
  • Y is N or CH
  • R 1 is -NR 1-1 R 1-2 , R 1-16 substituted C 1 -C 7 alkyl, or unsubstituted or R 1-21 substituted "hetero atom is boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms";
  • All R 1-16-3 and R 1-16-6 are independently C 1 -C 7 alkyl; all R 1-16-5 are independently All R 1-16-5-4 and R 1-16-5-5 are independently C 1 -C 7 alkyl;
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • n 1;
  • Y is N or CH
  • R 1 is -NR 1-1 R 1-2 , R 1-16 substituted C 1 -C 7 alkyl, or unsubstituted or R 1-21 substituted "hetero atom is boron, silicon, oxygen, sulfur, One or more of selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms";
  • R 1-1 and R 1-2 are independently hydrogen, or unsubstituted or C 6 -C 10 aryl substituted C 1 -C 7 alkyl;
  • All R 1-16-6 are independently C 1 -C 7 alkyl; all R 1-16-5 are independently All R 1-16-5-4 and R 1-16-5-5 are independently C 1 -C 7 alkyl;
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n and n are independently 0, 1, 2 or 3, and m+n is 2, 3 or 4 ⁇ for example, "m is 0, n is 2", “m is 2, n is 0", “m is 1, n is 1", “m is 1, n is 2", or "m is 2, n is 1"; for another example, m + n is 2 or 3 ⁇ ;
  • Y is N or CH
  • One or more, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms ⁇ wherein the number of R 1-21 is one or more [for example, 2, 3 or 4 , when R 1-21 is present, the R 1-21 is the same or different; the "hetero atom” is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus.
  • hetero atom is nitrogen, the number of hetero atoms of 1 or 2 of C 3 ⁇ C 5 heterocycloalkyl ", and for example," heteroatom Is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to Y through a nitrogen atom", for example ⁇ , unsubstituted or R 1-22 substituted C 6 -C 10 aryl ⁇ wherein the number of R 1-22 is one or more [eg 2, 3 or 4], when there are multiple R 1-22 , the R 1-22 is the same or different ⁇ , unsubstituted or R 1-23 substituted "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms" ⁇ wherein the number of R 1-23
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen, C 1 -C 7 alkyl ⁇ for example C 1 -C 4 alkyl, for example methyl, ethyl, n-propyl, Isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl, ethyl, n-propyl or isopropyl ⁇ , C 2 -C 7 alkenyl, C 2 -C 7 Alkynyl group, C 3 -C 7 cycloalkyl group, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C having 1 to 4 hetero atoms 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C having 1 to 4 hetero
  • All R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1-10 are independently hydroxy, C 1 -C 7 alkyl ⁇ eg C 1 -C 4 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, further methyl, halo substituted C 1 to C 7 alkyl ⁇ wherein the number of halogens is one or more [for example, 2, 3 or 4], and when a plurality of halogens are present, the halogens are the same or different; a 1 -C 7 alkyl group such as a C 1 -C 4 alkyl group, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl
  • All R 1-4-1 and R 1-4-2 are independently hydrogen, C 1 -C 7 alkyl ⁇ eg C 1 -C 4 alkyl, for example methyl, ethyl, n-propyl, iso a propyl group, a n-butyl group, an isobutyl group, a sec-butyl group or a tert-butyl group, for example, a methyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 to C 10 An aryl group or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1
  • R 1-11 , R 1-12 , R 1-13 , R 1-14 and R 1-15 are independently H, cyano, hydroxy, C 1 -C 7 alkoxy, unsubstituted or R 1 1-11-1 substituted C 1 -C 7 alkyl ⁇ wherein the number of R 1-11-1 is one or more [for example, 2, 3 or 4], when a plurality of R 1-11 are present When -1 , the R 1-11-1 is the same or different ⁇ , the C 3 -C 7 cycloalkyl group, "the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus.
  • a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms a C 6 -C 10 aryl group, or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus.
  • a hetero atom is boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus.
  • C 1 -C 7 heteroaryl having 1 to 4 hetero atoms One or more, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms";
  • All R 1-11-1 are independently halogen, hydroxy, cyano, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkane, C 3 -C 7 naphthenic a C 1 -C 7 heterocycloalkyl group, a C 6 -C 10 aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ⁇ 4 C 1 -C 7 heteroaryl" or C 1 -C 7 alkoxy;
  • All R 1-16 , R 1-17 , R 1-18 , R 1-19 , R 1-20 , R 1-21 , R 1-22 , R 1-23 , R 1-24 and R 1- 25 is independently halogen ⁇ e.g., fluorine, chlorine, bromine or iodine, for example, fluorine ⁇ , nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, a C 1 -C 7 alkyl group (for example, trimethylsilyl), a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus.
  • halogen ⁇ e.g., fluorine, chlorine, bromine or iodine, for example, fluorine ⁇ , nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl
  • a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms (for example, "a C 3 -C 5 heterocycloalkyl group having a hetero atom is nitrogen and having 1 to 2 hetero atoms", for example, "The hetero atom is nitrogen, a C 3 -C 5 heterocycloalkyl group having 1 to 2 hetero atoms, and a heterocycloalkyl group is bonded to another group such as a C 1 -C 7 alkyl group through a nitrogen atom",
  • a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 1 -C 7 heteroatoms having 1 to 4 heteroatoms
  • All R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen, C 1 -C 7 alkyl ⁇ eg C 1 -C 4 alkyl Further, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl ⁇ , C 2 -C 7 alkenyl, C 2 - C 7 alkynyl, C 3 -C 7 cycloalkyl, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 having 1 to 4 hetero atoms -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 C 1 -
  • All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms" ⁇ eg "heteroatoms are boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen, and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, and which is bonded to a carbonyl group through a nitrogen atom, and The atom is one or more of oxygen, sulfur and nitrogen, a C 3 -C 7 heterocycloalkyl group having 1 to 2 hetero atoms, and which is bonded to the carbonyl group through
  • All R 1-16-5-1 , R 1-16-5-2 and R 1-16-5-3 are independently hydrogen, unsubstituted or R 1-16-5-1-1 substituted C 1 ⁇ C 7 alkyl ⁇ wherein the number of R 1-16-5-1-1 is one or more [for example, 2, 3 or 4], when there are a plurality of R 1-16-5-1 When -1 , the R 1-16-5-1-1 is the same or different; the "C 1 -C 7 alkyl" is, for example, a C 1 -C 4 alkyl group, for example, a methyl group, an ethyl group, N-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl or ethyl ⁇ , C 2 -C 7 alkenyl, C 2 -C 7 alkynyl ⁇ for example a C 2 -C 4 alkynyl group, for example, a 2-propynyl
  • C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms C 6 -C 10 aryl or "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen And one or more of phosphorus and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • All R 1-16-5-1-1 are independently halogen, hydroxy, cyano, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, C 1 to C 7 alkylsilyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more of them, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • z 0, 1 or 2;
  • All R 2 are independently halogen, hydroxy, cyano, amino, unsubstituted or R 2-1 substituted C 1 -C 7 alkyl ⁇ wherein the number of R 2-1 is one or more [eg 2 , 3 or 4], when a plurality of R 2-1 are present, the R 2-1 is the same or different ⁇ , unsubstituted or R 2-2 substituted C 2 -C 8 alkenyl ⁇ where The number of R 2-2 is one or more [for example, 2, 3 or 4], and when a plurality of R 2-2 are present, the R 2-2 is the same or different ⁇ , unsubstituted or R 2-3 substituted C 2 -C 7 alkynyl ⁇ wherein the number of R 2-3 is one or more [for example, 2, 3 or 4], when a plurality of R 2-3 are present, R 2-3 is the same or different ⁇ , unsubstituted or R 2-4 substituted C 1 -C 7 alkyl group ⁇ wherein the number of R 2-4 is one or more
  • One or more of the number of phosphorus heteroatoms is 1 to 4 of C 1 ⁇ C 7 heteroaryl " ⁇ wherein, R 2-6 is the number of one or more [e.g. 2, 3 or 4], when a plurality of R 2-6 are present, the R 2-6 is the same or different ⁇ , a C 3 -C 7 cycloalkyl group, or an unsubstituted or R 2-7 substituted C 1 -C 7 alkoxy ⁇ wherein the number of R 2-7 is one or more [eg 2, 3 or 4], when a plurality of R 2-7 are present, the R 2-7 is the same or different ⁇ ;
  • both R 2 are hydroxyl groups and are attached to the same carbon atom, which means that two R 2 together with the carbon atom to which they are attached form a carbonyl group ⁇
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 , R 2-6 and R 2-7 are independently halogen, nitro, cyano, C 1 ⁇ C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, oxygen, sulfur , one or more of selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group, "a hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", C 1 -C 7 alkoxy group, C 1 -C 7 Alkyl fluorenyl, -NR 2-1-1 R 2-1-21-2
  • R 2-1-1 , R 2-1-2 , R 2-1-3 and R 2-1-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ⁇ 4 C 1 -C 7 heteroaryl groups";
  • All R 2-1-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • two R 2 linkages together form an unsubstituted or R 2-8 substituted C 3 -C 7 cycloalkyl group on the same carbon atom ⁇ wherein the number of R 2-8 is one or more [eg 2 , 3 or 4], when a plurality of R 2-8 are present, the R 2-8 is the same or different ⁇ , or the unsubstituted or R 2-9 substituted C 1 -C 7 heterocycloalkyl Wherein the number of R 2-9 is one or more [eg 2, 3 or 4], and when a plurality of R 2-9 are present, the R 2-9 is the same or different ⁇ ;
  • R 2-8 and R 2-9 are independently halogen, cyano, fluorenyl, hydroxy, amino, C 1 -C 7 alkoxy or C 1 -C 7 alkanoyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n and n are independently 0, 1, 2 or 3, and m+n is 2 or 3.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n and n are independently 0, 1, 2 or 3, and m+n is 3 ⁇ for example, m is 2, n is 1 ⁇ .
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • Y is N.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • Y is CH.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1 is unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, unsubstituted or R 1-20 substituted C 3 -C 7 cycloalkyl, or unsubstituted or R 1-21 substituted"
  • the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 3 to C 7 heterocycloalkyl group having 1 to 4 hetero atoms.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1 is -NR 1-1 R 1-2 , unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, or unsubstituted or R 1-21 substituted "hetero atom is boron, silicon, oxygen , one or more of sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms";
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 7 alkyl
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1 is an unsubstituted or R 1-16 substituted C 1 -C 7 alkyl group, or an unsubstituted or R 1-20 substituted C 3 -C 7 cycloalkyl group;
  • R 1-16 and R 1-20 are independently C 3 -C 7 cycloalkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1 is unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, -NR 1-1 R 1-2 , or "heteroatoms are among boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more kinds of C 3 -C 7 heterocycloalkyl groups having 1 to 4 hetero atoms.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen or C 1 -C 7 alkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • All R 1-1 and R 1-2 are independently hydrogen or C 1 -C 7 alkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 2 -C 7 alkynyl or NR 1-4-1 R 1-4-2 ;
  • R 1-4-1 and R 1-4-2 are independently C 1 -C 7 alkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 1 -C 7 alkoxy or NR 1-4-1 R 1 -4-2 ;
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen or C 1 -C 7 alkyl;
  • R 1-16-5 are independently "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having 1 to 4 hetero atoms.
  • Heterocycloalkyl or -NR 1-16-5-1 R 1-16-5-2 ;
  • R 1-16-5-1 and R 1-16-5-2 are independently hydrogen, unsubstituted or R 1-16-5-1-1 substituted C 1 -C 7 alkyl, C 2 ⁇ C 7 alkynyl or C 3 -C 7 cycloalkyl;
  • All R 1-16-5-1-1 are independently hydroxy.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-16-1 and R 1-16-2 are independently C 1 -C 7 alkyl
  • All R 1-16-5 are independently "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having 1 to 4 hetero atoms. Heterocycloalkyl", or -NR 1-16-5-1 R 1-16-5-2 ;
  • R 1-16-5-1 and R 1-16-5-2 are independently hydrogen, unsubstituted or R 1-16-5-1-1 substituted C 1 -C 7 alkyl, C 2 ⁇ C 7 alkynyl or C 3 -C 7 cycloalkyl;
  • All R 1-16-5-1-1 are independently hydroxy.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen or C 1 -C 7 alkyl;
  • R 1-16-5 are independently "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having 1 to 4 hetero atoms.
  • Heterocycloalkyl or -NR 1-16-5-1 R 1-16-5-2 ;
  • R 1-16-5-1 and R 1-16-5-2 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkynyl or C 3 -C 7 cycloalkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • n and n are independently 0, 1, 2 or 3, and m+n is 2 or 3;
  • Y is N or CH
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen or C 1 -C 7 alkyl
  • R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 2 -C 7 alkynyl or NR 1-4-1 R 1-4-2 ;
  • R 1-4-1 and R 1-4-2 are independently C 1 -C 7 alkyl
  • R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen or C 1 -C 7 alkyl;
  • R 1-16-5 are independently "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having 1 to 4 hetero atoms.
  • Heterocycloalkyl or -NR 1-16-5-1 R 1-16-5-2 ;
  • R 1-16-5-1 and R 1-16-5-2 are independently hydrogen, unsubstituted or R 1-16-5-1-1 substituted C 1 -C 7 alkyl, C 2 ⁇ C 7 alkynyl or C 3 -C 7 cycloalkyl;
  • All R 1-16-5-1-1 are independently a hydroxyl group
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • n and n are independently 0, 1, 2 or 3, and m+n is 2 or 3;
  • Y is N or CH
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen or C 1 -C 7 alkyl
  • R 1-4 and R 1-7 are independently C 1 -C 7 alkyl, halogen-substituted C 1 -C 7 alkyl, C 1 -C 7 alkoxy, or NR 1-4-1 R 1-4-2 ;
  • R 1-4-1 and R 1-4-2 are independently C 1 -C 7 alkyl
  • R 1-16-1 and R 1-16-2 are independently hydrogen or C 1 -C 7 alkyl
  • R 1-16-5 are independently "heteroatoms are one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 having 1 to 4 hetero atoms.
  • Heterocycloalkyl or -NR 1-16-5-1 R 1-16-5-2 ;
  • R 1-16-5-1 and R 1-16-5-2 are independently hydrogen, unsubstituted or R 1-16-5-1-1 substituted C 1 -C 7 alkyl, C 2 ⁇ C 7 alkynyl or C 3 -C 7 cycloalkyl;
  • All R 1-16-5-1-1 are independently a hydroxyl group
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • n and n are independently 0, 1, 2 or 3, and m+n is 3 ⁇ for example, m is 2, n is 1 ⁇ ;
  • Y is N
  • R 1 is unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, unsubstituted or R 1-20 substituted C 3 -C 7 cycloalkyl or unsubstituted or R 1-21 substituted "hetero"
  • the atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 to C 7 heterocycloalkyl having 1 to 4 hetero atoms;
  • R 1-16 , R 1-20 and R 1-21 are independently halogen, nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl , C 1 -C 7 alkylsilyl, C 3 -C 7 cycloalkyl, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 - 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms 1 to 4 C 1 -C 7 heteroaryl", C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, -NR 1-16-1 R 1-16-2 , -OR 1 -16-3 , -SR 1-16-4 or
  • All R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ⁇ 4 C 1 -C 7 heteroaryl groups";
  • All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, and halogenated "heteroatoms are boron," One or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl, "hetero atom” Is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", -NR 1-16-5-1 R 1-16-5-2
  • R 1-16-5-1 , R 1-16-5-2 and R 1-16-5-3 are independently hydrogen, unsubstituted or R 1-16-5-1-1 substituted C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatom is boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, C 6 -C 10 aryl or "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and One or more of phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • All R 1-16-5-1-1 are independently halogen, hydroxy, cyano, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, C 1 to C 7 alkylsilyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more of them, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X is CH
  • n and n are independently 0, 1, 2 or 3, and m+n is 3 ⁇ for example, m is 2, n is 1 ⁇ ;
  • Y is CH
  • R 1 is -NR 1-1 R 1-2 , unsubstituted or R 1-16 substituted C 1 -C 7 alkyl, or unsubstituted or R 1-21 substituted "hetero atom is boron, silicon, oxygen , one or more of sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms";
  • R 1-1 and R 1-2 are independently hydrogen or C 1 -C 7 alkyl
  • All R 1-21 are independently halogen, nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and a C 3 -C 7 heterocyclic ring having 1 to 4 hetero atoms.
  • All R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ⁇ 4 C 1 -C 7 heteroaryl groups";
  • All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, and halogenated "heteroatoms are boron," One or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl, "hetero atom” Is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", -NR 1-16-5-1 R 1-16-5-2
  • R 1-16-5-1 , R 1-16-5-2 and R 1-16-5-3 are independently hydrogen, unsubstituted or R 1-16-5-1-1 substituted C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatom is boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, C 6 -C 10 aryl or "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and One or more of phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • All R 1-16-5-1-1 are independently halogen, hydroxy, cyano, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, C 1 to C 7 alkylsilyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more of them, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X can be CH
  • n+n can be 2 or 3;
  • Y can be CH or N
  • All R 1-1 and R 1-2 may independently be hydrogen, C 1 -C 7 alkyl or C 3 -C 7 cycloalkyl;
  • R 1-4 , R 1-5 and R 1-6 are independently C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkyne a group, a C 1 -C 7 alkoxy group, or NR 1-4-1 R 1-4-2 ;
  • All R 1-4-1 and R 1-4-2 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 ring
  • An alkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms";
  • R 1-11 is H
  • R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen, C 3 -C 7 cycloalkyl or C 1 -C 7 alkyl ;
  • All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl, " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms", -NR 1-16-5 -1 R 1-16-5-2 or OR 1-16-5-3 ;
  • R 1-16-5-1 , R 1-16-5-2 and R 1-16-5-3 are independently hydrogen, unsubstituted or R 1-16-5-1-1 substituted C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatom is boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, C 6 -C 10 aryl or "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and One or more of phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • All R 1-16-5-1-1 are independently halogen, hydroxy, cyano, amino, C 1 -C 7 alkyl, C 1 -C 7 alkoxy, C 1 -C 7 alkanoyl, C 1 to C 7 alkylsilyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl, "heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus One or more of them, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group or "a hetero atom is boron, silicon, oxygen, sulfur, selenium, One or more of nitrogen and phosphorus, a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X can be CH
  • Y can be N
  • R 1-1 and R 1-2 may independently be a C 1 -C 7 alkyl group
  • R 1-4 is independently C 1 -C 7 alkyl or C 2 -C 7 alkynyl
  • R 1-16 are independently cyano, -NR 1-16-1 R 1-16-2 , -OR 1-16-3 or C 3 -C 7 cycloalkyl;
  • R 1-16-1 , R 1-16-2 and R 1-16-3 are independently hydrogen or C 1 -C 7 alkyl
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X can be CH
  • Y can be C
  • R 1-1 and R 1-2 may independently be a C 1 -C 7 alkyl group
  • R 1-4 is independently C 1 -C 7 alkyl or C 2 -C 7 alkynyl
  • All R 1-16 are independently cyano, -NR 1-16-1 R 1-16-2 , -OR 1-16-3 , or , heteroatoms are boron, silicon, oxygen, sulfur, selenium, nitrogen And one or more of phosphorus and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms;
  • R 1-16-1 , R 1-16-2 and R 1-16-3 are independently hydrogen or C 1 -C 7 alkyl
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n and n are independently 0, 1, 2 or 3, and m+n is 2, 3 or 4 ⁇ for example, "m is 0, n is 2", “m is 2, n is 0", “m is 1, n is 1", “m is 1, n is 2", or "m is 2, n is 1"; for another example, m + n is 2 or 3 ⁇ ;
  • Y is N or CH
  • R 1-19 substituted or unsubstituted C 1 -C 7 alkyl silicon ⁇ wherein the number of R 1-19 is one or more [eg 2, 3 or 4], when there are multiple R When 1-19 , the R 1-19 is the same or different ⁇ , R 1-20 is substituted or unsubstituted C 3 -C 7 cycloalkyl ⁇ wherein the number of R 1-20 is one or more [for example] 2, 3 or 4], the time when a plurality of R 1-20, the R 1- 20 are the same or different ⁇ , R 1-21 substituted or unsubstituted "hetero atom is boron, silicon, oxygen , one or more of sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms" ⁇ wherein the number of R 1-21 is one or more [eg 2, 3 or 4], when a plurality of R 1-21 are present, said R 1-21 is the same or different ⁇ , R 1-22 is substituted
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen, C 1 -C 7 alkyl ⁇ for example C 1 -C 4 alkyl, for example methyl, ethyl, n-propyl, isopropyl a base, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl ⁇ , C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 cycloalkyl,"
  • the hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms, and C 6 to C 10 aromatic Or "heteroatom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1-10 are independently hydroxy, C 1 -C 7 alkyl ⁇ eg C 1 ⁇ C 4 alkyl, for example methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example methyl ⁇ , halogen, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl ⁇ eg C 2 -C 4 alkynyl, for example 2-propynyl or 1-propynyl ⁇ , C 3 -C 7 cycloalkyl, "hetero atom is boron , one or more of silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl, "he
  • All R 1-4-1 and R 1-4-2 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 ring
  • An alkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms
  • C 6 ⁇ C 10 aryl or “hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 —C 7 heteroaryl group having 1 to 4 hetero atoms”;
  • R 1-11 , R 1-12 , R 1-13 , R 1-14 and R 1-15 are independently H, cyano, hydroxy, C 1 -C 7 alkoxy, R 1-11-1 Or unsubstituted C 1 -C 7 alkyl ⁇ wherein the number of R 1-11-1 is one or more [for example, 2, 3 or 4], when a plurality of R 1-11-1 are present , R 1-11-1 is the same or different ⁇ , C 3 -C 7 cycloalkyl, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, miscellaneous a C 3 -C 7 heterocycloalkyl group having 1 to 4 atoms, a C 6 -C 10 aryl group, or "a hetero atom is one of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. Or a plurality of C 1 -C 7 heteroaryl groups having a hetero atom number of 1 to 4"
  • All R 1-11-1 are independently halogen, hydroxy, cyano, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkane, C 3 -C 7 naphthenic a C 1 -C 7 heterocycloalkyl group, a C 6 -C 10 aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ⁇ 4 C 1 -C 7 heteroaryl" or C 1 -C 7 alkoxy;
  • All R 1-16 , R 1-17 , R 1-18 , R 1-19 , R 1-20 , R 1-21 , R 1-22 , R 1-23 , R 1-24 and R 1- 25 independently is halogen, nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 a cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms", C 6 to C 10 aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms" , C 1 -C 7 alkoxy, C 1 -C
  • All R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen, C 1 -C 7 alkyl ⁇ eg C 1 -C 4 alkyl Further, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl or tert-butyl, for example, methyl ⁇ , C 2 -C 7 alkenyl, C 2 - C 7 alkynyl, C 3 -C 7 cycloalkyl, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and C 3 having 1 to 4 hetero atoms -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 to 4 C 1 -
  • All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • z 0, 1 or 2;
  • All R 2 are independently halogen, hydroxy, cyano, amino, R 2-1 substituted or unsubstituted C 1 -C 7 alkyl ⁇ wherein the number of R 2-1 is one or more [eg 2 , 3 or 4], when a plurality of R 2-1 are present, the R 2-1 is the same or different ⁇ , R 2-2 is substituted or unsubstituted C 2 -C 8 alkenyl ⁇ where R 2 The number of -2 is one or more [for example, 2, 3 or 4], when there are a plurality of R 2-2 , the R 2-2 is the same or different ⁇ , R 2-3 is substituted or Unsubstituted C 2 -C 7 alkynyl ⁇ wherein the number of R 2-3 is one or more [eg 2, 3 or 4], when a plurality of R 2-3 are present, the R 2-3 identical or different ⁇ , R 2-4 substituted or unsubstituted C 1 -C 7 alkyl silicon ⁇ wherein the number of R 2-4 is one or
  • R 2-6 when there is When R 2-6 , R 2-6 is the same or different ⁇ , or R 2-7 is substituted or unsubstituted C 1 -C 7 alkoxy ⁇ wherein the number of R 2-7 is one Or a plurality [for example, 2, 3 or 4], when there are a plurality of R 2-7 , the R 2-7 is the same or different ⁇ ;
  • both R 2 are hydroxyl groups and are attached to the same carbon atom, which means that two R 2 together with the carbon atom to which they are attached form a carbonyl group ⁇
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 , R 2-6 and R 2-7 are independently halogen, nitro, cyano, C 1 ⁇ C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, oxygen, sulfur , one or more of selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group, "a hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", C 1 -C 7 alkoxy group, C 1 -C 7 Alkyl fluorenyl, -NR 2-1-1 R 2-1-21-2
  • R 2-1-1 , R 2-1-2 , R 2-1-3 and R 2-1-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ⁇ 4 C 1 -C 7 heteroaryl groups";
  • All R 2-1-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • two R 2 linkages together form the R 2-8 substituted or unsubstituted C 3 -C 7 cycloalkyl group on the same carbon atom ⁇ wherein the number of R 2-8 is one or more [eg 2, 3 or 4], when a plurality of R 2-8 are present, the R 2-8 is the same or different ⁇ , or R 2-9 is substituted or unsubstituted C 1 -C 7 heterocycloalkyl ⁇ , the number of R 2-9 is one or more [eg 2, 3 or 4], when there are a plurality of R 2-9 , the R 2-9 is the same or different ⁇ ;
  • R 2-8 and R 2-9 are independently halogen, cyano, fluorenyl, hydroxy, amino, C 1 -C 7 alkoxy or C 1 -C 7 alkanoyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X can be CH.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n+n can be 2 or 3.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n can be 2.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n can be 1.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n can be 0.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n can be 2.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n can be 1.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • Y can be N.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-1 and R 1-2 may independently be hydrogen, a C 1 -C 7 alkyl group or a C 3 -C 7 cycloalkyl group, or may independently be a C 1 -C 7 alkyl group.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-4 , R 1-5 and R 1-6 are independently C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 7 alkenyl or C 2 -C 7 alkynyl; Further, it may independently be a C 1 -C 7 alkyl group or a C 2 -C 7 alkynyl group.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-11 is H.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • R 1-16 , R 1-17 , R 1-18 and R 1-20 are independently cyano, -NR 1-16-1 R 1-16-2 or -OR 1-16-3 ;
  • R 1-16-1 , R 1-16-2 and R 1-16-3 are independently hydrogen, C 3 -C 7 cycloalkyl or C 1 -C 7 alkyl; independently hydrogen Or C 1 -C 7 alkyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • n and n are independently 0, 1, 2 or 3, and m+n is 2, 3 or 4 ⁇ for example, "m is 0, n is 2", “m is 2, n is 0", “m is 1, n is 1", “m is 1, n is 2", or "m is 2, n is 1"; for another example, m + n is 2 or 3 ⁇ ;
  • Y is N or CH
  • R 1- 22 is one or more [eg 2, 3 or 4], when a plurality of R 1-22 are present, said R 1-22 is the same or different ⁇
  • R 1-23 is substituted or unsubstituted "The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 1 -C 7 heteroaryl" ⁇ wherein R 1-23 is one or more [eg 2, 3 or 4], when a plurality of R 1-23 are present, said R 1-23 is the same or different ⁇
  • R 1-24 is substituted or unsubstituted C 1 -C 7 alkoxy ⁇ wherein the number of R 1-24 is one or more [for example, 2, 3 or 4 ], when there are multiple R From 1 to 24 , the R 1-24 is the same or different ⁇ , or the R 1-25 is substituted or unsubstituted C 1 -
  • R 1-1 , R 1-2 and R 1-3 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 naphthenic
  • the "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 - a C 10 aryl group or "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 , R 1-9 and R 1-10 are independently hydroxy, C 1 -C 7 alkyl, halogen, C 2 to C 7 alkenyl group, C 2 -C 7 alkynyl group, C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 atoms, a C 6 -C 10 aryl group, and "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. , a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms, or NR 1-4-1 R 1-4-2 ;
  • All R 1-4-1 and R 1-4-2 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 3 -C 7 ring
  • An alkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms
  • C 6 ⁇ C 10 aryl or “hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 —C 7 heteroaryl group having 1 to 4 hetero atoms”;
  • R 1-11 , R 1-12 , R 1-13 , R 1-14 and R 1-15 are independently H, cyano, hydroxy, C 1 -C 7 alkoxy, R 1-11-1 Or unsubstituted C 1 -C 7 alkyl ⁇ wherein the number of R 1-11-1 is one or more [for example, 2, 3 or 4], when a plurality of R 1-11-1 are present , R 1-11-1 is the same or different ⁇ , C 3 -C 7 cycloalkyl, "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, miscellaneous a C 3 -C 7 heterocycloalkyl group having 1 to 4 atoms, a C 6 -C 10 aryl group, or "a hetero atom is one of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus. Or a plurality of C 1 -C 7 heteroaryl groups having a hetero atom number of 1 to 4"
  • All R 1-11-1 are independently halogen, hydroxy, cyano, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkane, C 3 -C 7 naphthenic a C 1 -C 7 heterocycloalkyl group, a C 6 -C 10 aryl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1 ⁇ 4 C 1 -C 7 heteroaryl" or C 1 -C 7 alkoxy;
  • All R 1-16 , R 1-17 , R 1-18 , R 1-19 , R 1-20 , R 1-21 , R 1-22 , R 1-23 , R 1-24 and R 1- 25 independently is halogen, nitro, cyano, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 a cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen, and phosphorus, and a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms", C 6 to C 10 aryl, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms" , C 1 -C 7 alkoxy, C 1 -C
  • All R 1-16-1 , R 1-16-2 , R 1-16-3 and R 1-16-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ⁇ 4 C 1 -C 7 heteroaryl groups";
  • All R 1-16-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • z 0, 1 or 2;
  • All R 2 are independently halogen, hydroxy, cyano, amino, R 2-1 substituted or unsubstituted C 1 -C 7 alkyl ⁇ wherein the number of R 2-1 is one or more [eg 2 , 3 or 4], when a plurality of R 2-1 are present, the R 2-1 is the same or different ⁇ , R 2-2 is substituted or unsubstituted C 2 -C 8 alkenyl ⁇ where R 2 The number of -2 is one or more [for example, 2, 3 or 4], when there are a plurality of R 2-2 , the R 2-2 is the same or different ⁇ , R 2-3 is substituted or Unsubstituted C 2 -C 7 alkynyl ⁇ wherein the number of R 2-3 is one or more [eg 2, 3 or 4], when a plurality of R 2-3 are present, the R 2-3 identical or different ⁇ , R 2-4 substituted or unsubstituted C 1 -C 7 alkyl silicon ⁇ wherein the number of R 2-4 is one or
  • R 2-6 when there is When R 2-6 , R 2-6 is the same or different ⁇ , or R 2-7 is substituted or unsubstituted C 1 -C 7 alkoxy ⁇ wherein the number of R 2-7 is one Or a plurality [for example, 2, 3 or 4], when there are a plurality of R 2-7 , the R 2-7 is the same or different ⁇ ;
  • R 2-1 , R 2-2 , R 2-3 , R 2-4 , R 2-5 , R 2-6 and R 2-7 are independently halogen, nitro, cyano, C 1 ⁇ C 7 alkyl, C 2 -C 7 alkenyl, C 2 -C 7 alkynyl, C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, "hetero atom is boron, silicon, oxygen, sulfur , one or more of selenium, nitrogen and phosphorus, a C 3 -C 7 heterocycloalkyl group having 1 to 4 hetero atoms, a C 6 -C 10 aryl group, "a hetero atom is boron, silicon, One or more of oxygen, sulfur, selenium, nitrogen and phosphorus, C 1 -C 7 heteroaryl having 1 to 4 hetero atoms", C 1 -C 7 alkoxy group, C 1 -C 7 Alkyl fluorenyl, -NR 2-1-1 R 2-1-21-2
  • R 2-1-1 , R 2-1-2 , R 2-1-3 and R 2-1-4 are independently hydrogen, C 1 -C 7 alkyl, C 2 -C 7 alkenyl, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of hetero atoms is 1 to 4 C 3 -C 7 heterocycloalkyl", C 6 -C 10 aryl or "hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and the number of heteroatoms is 1. ⁇ 4 C 1 -C 7 heteroaryl groups";
  • All R 2-1-5 are independently a hydroxyl group, a C 1 -C 7 alkyl group, a C 2 -C 7 alkenyl group, a C 2 -C 7 alkynyl group, a C 3 -C 7 cycloalkyl group, "a hetero atom is One or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, C 3 -C 7 heterocycloalkyl having 1 to 4 hetero atoms", C 6 -C 10 aryl or " The hetero atom is one or more of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus, and a C 1 -C 7 heteroaryl group having 1 to 4 hetero atoms";
  • two R 2 linkages together form the R 2-8 substituted or unsubstituted C 3 -C 7 cycloalkyl group on the same carbon atom ⁇ wherein the number of R 2-8 is one or more [eg 2, 3 or 4], when a plurality of R 2-8 are present, the R 2-8 is the same or different ⁇ , or R 2-9 is substituted or unsubstituted C 1 -C 7 heterocycloalkyl ⁇ , the number of R 2-9 is one or more [eg 2, 3 or 4], when there are a plurality of R 2-9 , the R 2-9 is the same or different ⁇ ;
  • R 2-8 and R 2-9 are independently halogen, cyano, fluorenyl, hydroxy, amino, C 1 -C 7 alkoxy or C 1 -C 7 alkanoyl.
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X can be CH
  • n+n can be 2 or 3;
  • Y can be CH or N
  • R 1-1 and R 1-2 may independently be hydrogen, C 1 -C 7 alkyl or C 3 -C 7 cycloalkyl;
  • R 1-4 , R 1-5 and R 1-6 are independently C 1 -C 7 alkyl, C 3 -C 7 cycloalkyl, C 2 -C 7 alkenyl or C 2 -C 7 alkynyl;
  • R 1-11 is H
  • R 1-16 , R 1-17 , R 1-18 and R 1-20 are independently cyano, -NR 1-16-1 R 1-16-2 or -OR 1-16-3 ;
  • R 1-16-1 , R 1-16-2 and R 1-16-3 are independently hydrogen, C 3 -C 7 cycloalkyl or C 1 -C 7 alkyl;
  • the compound I its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate
  • each group in its metabolite or its prodrug can be as follows (uncommented definition as described above):
  • X can be CH
  • Y can be N
  • R 1-1 and R 1-2 may independently be a C 1 -C 7 alkyl group
  • R 1-4 is independently C 1 -C 7 alkyl or C 2 -C 7 alkynyl
  • All R 1-16 are independently cyano, -NR 1-16-1 R 1-16-2 or -OR 1-16-3 ;
  • R 1-16-1 , R 1-16-2 and R 1-16-3 are independently hydrogen or C 1 -C 7 alkyl
  • the compound I in its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, In its metabolite or its prodrug, the compound I is any of the following compounds:
  • the compounds of the present invention can be prepared using at least the methods described below, but are not limited to the reagents and solvents in the reaction conditions below.
  • the invention also provides a preparation method of the above compound I, which is any of the following methods:
  • the method comprises the steps of: oxidizing compound 1A to obtain compound 1B, and substituting to obtain compound 1D, and deprotecting to obtain compound 1E;
  • the PG in the compound represented by the formula 1C may be various conventional amino protecting groups in the art, preferably Boc, for the purpose of When reacting with compound 1B, some of the reactive groups (such as amino groups) on the reaction are not involved in the reaction;
  • the conditions for the removal of the protecting group may be conventional removal conditions of various protecting groups in the art, such as conditions of the hydrolysis reaction, conditions of the amine hydrolysis reaction, conditions of the hydrogenation reaction, and the like;
  • the reaction of removing the protecting group may further comprise a post-treatment operation; the method and conditions of the post-treatment may be conventional methods and conditions for post-treatment of such reactions in the art.
  • the reaction system is washed, dried, filtered, and the solvent is evaporated to dryness, followed by column chromatography, or the reaction system is distilled off, washed, and filtered; or the reaction system is distilled off.
  • the conditions of the method for reacting in each step in the reaction route can be carried out according to the conventional conditions of the methods of the reactions in the art;
  • the method comprises the steps of: oxidizing compound 1A to obtain compound 1B, and reacting with 2A to obtain compound 2B;
  • the method for producing the compound of the formula I includes the following steps: in an organic solvent (for example, 1, In the presence of a reducing agent such as sodium triacetoxyborohydride and/or sodium cyanoborohydride in one or more of 2-dichloroethane, dichloromethane, methanol and dioxane
  • a reducing agent such as sodium triacetoxyborohydride and/or sodium cyanoborohydride in one or more of 2-dichloroethane, dichloromethane, methanol and dioxane
  • the conditions of the reductive amination reaction can be the conditions conventional for such reactions in the field;
  • the preparation method of the compound of the formula I includes the following steps: in an organic solvent (for example, one or more of methanol, dichloromethane, acetonitrile and DMF) in the presence of a base such as potassium carbonate, cesium carbonate, N,N-diisopropylethylamine or triethylamine,
  • an organic solvent for example, one or more of methanol, dichloromethane, acetonitrile and DMF
  • a base such as potassium carbonate, cesium carbonate, N,N-diisopropylethylamine or triethylamine
  • the compound 1E is subjected to a substitution reaction with R 1 -X 1 to obtain a compound I; the conditions of the substitution reaction may be conventional conditions in the reaction of the field; and the X
  • the process for the preparation of the compound of formula I comprises the steps of: in an organic solvent such as one or more of 1,4-dioxane, dichloromethane and DMF. , in the presence of a condensing agent (such as DMAP and EDCI), compound 1E, The condensation reaction is carried out to obtain the compound I; the conditions of the condensation reaction can be the conditions conventional for such reactions in the field;
  • the invention also provides a compound of formula 1C, 1D or 2A:
  • the present invention also provides a compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, and a solvent thereof, as described above
  • a compound, a metabolite thereof or a prodrug thereof for the preparation of a kinase (e.g., WEE1 kinase) inhibitor e.g., WEE1 kinase
  • the present invention also provides a compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, and a solvent thereof, as described above.
  • a compound, a metabolite thereof or a prodrug thereof for the preparation of a medicament for the treatment and/or prevention of a disease associated with WEE1 kinase.
  • the disease associated with WEE1 kinase such as cancer.
  • the cancer such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , ovarian cancer, villus epithelial cancer, endometrial cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, nephroblastoma, skin cancer, malignant melanoma, neurogenic Cell tumor, osteosarcoma, Ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or Hodgkin's lymphoma, and for example, breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic
  • the present invention also provides a compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, and a solvent thereof, as described above.
  • a compound, a metabolite thereof or a prodrug thereof for the preparation of a medicament for the treatment and/or prevention of cancer.
  • the cancer such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , ovarian cancer, villus epithelial cancer, endometrial cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, nephroblastoma, skin cancer, malignant melanoma, neurogenic Cell tumor, osteosarcoma, Ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or Hodgkin's lymphoma, and for example, breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable compound thereof as described above Accepted salts, solvates thereof, metabolites thereof or prodrugs thereof, and pharmaceutical excipient(s).
  • the present invention provides a combination comprising the compound I as described above, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, and a pharmaceutically acceptable salt thereof , its solvate, its metabolites or their prodrugs and anticancer drugs.
  • the anticancer drug can be a conventional anticancer drug in the art, such as an anticancer alkylating agent, an anticancer metabolic antagonist, an anticancer antibiotic, a plant-derived anticancer agent, and an anticancer platinum.
  • the anticancer alkylating agent can be a conventional anticancer alkylating agent in the art, such as nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, milfir, busulfan, two One or more of bromomannitol, carbazone, thiotepa, remustine, nimustine, temozolomide, and carmustine.
  • the anticancer metabolic antagonist can be a conventional anticancer metabolic antagonist in the art, such as methotrexate, 6-mercaptopurine nucleoside, guanidine, 5-fluorouracil, tegafur, deoxyfluoride
  • a conventional anticancer metabolic antagonist such as methotrexate, 6-mercaptopurine nucleoside, guanidine, 5-fluorouracil, tegafur, deoxyfluoride
  • One or more of glycosides, carmofur, cytarabine, sodium cytarabine octadecyl phosphate, enesitabine, S-1, gemcitabine, fludarabine, and pemetrexed disodium Further, for example, 5-fluorouracil.
  • the anticancer antibiotic may be a conventional anticancer antibiotic in the field, such as actinomycin D, doxorubicin, daunorubicin, neocarcin, bleomycin, and pilomycin.
  • actinomycin D doxorubicin
  • daunorubicin daunorubicin
  • neocarcin bleomycin
  • pilomycin pilomycin.
  • mitomycin C arubicin
  • pirarubicin pirarubicin
  • epirubicin net statin
  • idarubicin sirolimus
  • valrubicin a conventional anticancer antibiotic in the field
  • the plant-derived anticancer agent can be a conventional plant-derived anticancer agent in the art, such as vincristine, vinblastine, vindesine, etoposide, sobutazox, docetaxel, One or more of paclitaxel and vinorelbine.
  • the anti-cancer platinum coordination compound may be one or more of conventional anti-cancer platinum coordination compounds such as cisplatin, carboplatin, nedaplatin and oxaliplatin.
  • the anticancer camptothecin derivative may be one or more of conventional anticancer camptothecin derivatives in the art, such as irinotecan, topotecan, and camptothecin.
  • the anticancer tyrosine kinase inhibitor may be a conventional anticancer tyrosine kinase inhibitor in the art, such as one or more of gefitinib, imatinib and erlotinib. .
  • the monoclonal antibody may be a monoclonal antibody conventional in the art, such as one or more of cetuximab, bevacizumab, rituximab, alemtuzumab and trastuzumab. .
  • the interferon may be a conventional interferon in the art, such as one of interferon alpha, interferon alpha-2a, interferon alpha-2b, interferon beta, interferon gamma-1a, and interferon gamma-nl. Or a variety.
  • the biological response modifier may be a conventional biological response modifier in the art, such as one or more of Yunzhi polysaccharide, lentinan, cilostam, sapylin, and umbrel.
  • the components of the combination may be used simultaneously or separately (eg, sequentially); when the components of the combination are used simultaneously, the components of the combination may be uniformly mixed (ie, the components mixture).
  • the components of the combination may be prepared as a single pharmaceutical composition for simultaneous use, or the components may be separately formed into a single separate pharmaceutical composition (for example, in the form of a kit) of these individual independent pharmaceutical compositions. Can be used simultaneously or separately (for example, sequentially).
  • the invention also provides the use of the above combinations in the manufacture of a medicament for the prevention and/or treatment of cancer.
  • the cancer such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , ovarian cancer, villus epithelial cancer, endometrial cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, nephroblastoma, skin cancer, malignant melanoma, neurogenic Cell tumor, osteosarcoma, Ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or Hodgkin's lymphoma, and for example, breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin
  • the above compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvent The compound, its metabolite or its prodrug, and the anticancer drug described above may be administered simultaneously or separately (for example, sequentially).
  • the present invention also provides the above compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvate, its metabolism
  • the cancer such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , ovarian cancer, villus epithelial cancer, endometrial cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, nephroblastoma, skin cancer, malignant melanoma, neurogenic Cell tumor, osteosarcoma, Ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or Hodgkin's lymphoma, and for example, breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin
  • the above compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvent The compound, its metabolite or its prodrug, and the anticancer drug described above may be administered simultaneously or separately (for example, sequentially).
  • the present invention also provides the above anticancer drug, which is prepared for "and the above compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmacy
  • an acceptable salt, a solvate thereof, a metabolite thereof, or a prodrug thereof, in a medicament for preventing and/or treating cancer is prepared for "and the above compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmacy.
  • the cancer such as brain cancer, head and neck cancer, esophageal cancer, thyroid cancer, small cell carcinoma, non-small cell cancer, breast cancer, lung cancer, stomach cancer, gallbladder-cholangiocarcinoma, liver cancer, pancreatic cancer, colon cancer, rectal cancer , ovarian cancer, villus epithelial cancer, endometrial cancer, cervical cancer, renal pelvis-ureteral cancer, bladder cancer, prostate cancer, penile cancer, testicular cancer, embryonal cancer, nephroblastoma, skin cancer, malignant melanoma, neurogenic Cell tumor, osteosarcoma, Ewing's tumor, soft tissue tumor, acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, or Hodgkin's lymphoma, and for example, breast cancer, lung cancer, pancreatic cancer, colon cancer, ovarian cancer, Acute leukemia, chronic lymphocytic leukemia, chronic myelogenous leukemia, Hodgkin
  • the above compound I, its enantiomer, its diastereomer, its tautomer, its crystal form, its pharmaceutically acceptable salt, its solvent The compound, its metabolite or its prodrug, and the anticancer drug described above may be administered simultaneously or separately (for example, sequentially).
  • the invention also provides a pharmaceutical composition comprising a combination of the above and a pharmaceutical excipient(s).
  • the pharmaceutical composition may consist of the combination and the pharmaceutical excipient.
  • the present invention also provides a combination kit comprising a pharmaceutical composition A and a pharmaceutical composition B;
  • the pharmaceutical composition A includes the above compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, and a solvate thereof. , a metabolite thereof or a prodrug thereof, and (one or more) pharmaceutical excipients;
  • the pharmaceutical composition B includes the above-mentioned anticancer drug and the pharmaceutically acceptable excipient(s).
  • the combination kit can be composed of the pharmaceutical composition A and the pharmaceutical composition B described.
  • the pharmaceutical composition A may be the above compound I, an enantiomer thereof, a diastereomer thereof, a tautomer thereof, a crystal form thereof, a pharmaceutically acceptable salt thereof, a solvate thereof , its metabolites or their prodrugs, and, pharmaceutical excipients;
  • the pharmaceutical composition B may be composed of the above-mentioned anticancer drug and medicinal adjuvant.
  • Each of the pharmaceutical compositions in the combination kit can be used simultaneously or separately (e.g., sequentially).
  • the reagents and starting materials used in the present invention are commercially available.
  • halogen means fluoro, chloro, bromo or iodo.
  • alkyl refers to a saturated monovalent hydrocarbon radical straight or branched, having one to twelve carbon atoms (e.g., C 1 -C 6 alkyl, and C 1 -C 4 alkyl, for example).
  • alkyl groups include, but are not limited to, methyl, ethyl, 1-propyl, 2-propyl, 1-butyl, 2-methyl-1-butyl, 2-butyl, 2-methyl-2 -propyl, 1-pentyl, 2-pentyl, 3-pentyl, 2-methyl-2-butyl, 3-methyl-2-butyl, 3-methyl-1-butyl, 2 -methyl-1-butyl, 1-hexyl, 2-hexyl, 3-hexyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl , 3-methyl-3-pentyl, 2-methyl-3-pentyl, 2,3-dimethyl-2-butyl, 3,3-di
  • alkenyl refers to a straight or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms having at least one unsaturated position, ie, a carbon-carbon sp 2 double bond (eg, a C 2 -C 6 alkenyl group, For example, C 2 -C 4 alkenyl), and includes groups having "cis” and “trans” orientations or "E” and "Z” orientations.
  • Examples thereof include, but are not limited to, vinyl, allyl, 1-cyclopent-1-enyl, 1-cyclopent-2-enyl, 1-cyclopent-3-enyl, 5-hexenyl, 1 - cyclohex-1-enyl, 1-cyclohex-2-enyl, and 1-cyclohex-3-enyl.
  • alkynyl refers to a straight or branched chain monovalent hydrocarbon radical of two to twelve carbon atoms having at least one unsaturated position, ie, a carbon-carbon sp triple bond (eg, a C 2 -C 6 alkynyl group, such as C. 2 -C 4 alkynyl). Examples thereof include, but are not limited to, ethynyl and propynyl.
  • alkylsilyl refers to an alkyl group attached through a silicon bridge; the alkyl group defined above; C 1 -C 7 alkyl refers to silicon Wherein R A , R B and R C are independently C 1 -C 7 alkyl.
  • cycloalkyl means a non-aromatic saturated cyclic hydrocarbon radicals (e.g., C 3 -C 6 cycloalkyl) a monovalent three to twenty carbon atoms.
  • monocyclic carbon ring radicals include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl, cyclodecyl, cycloundecyl and cyclic. Dodecyl.
  • cycloalkyl also includes polycyclic (eg, bicyclic and tricyclic) cycloalkyl structures, and bicyclic carbon rings having 7 to 12 atoms may be arranged, for example, as bicyclo [4, 5], [5, 5 , [5,6] or [6,6] systems, or arranged as bridged ring systems such as bis[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]decane.
  • polycyclic eg, bicyclic and tricyclic
  • bicyclic carbon rings having 7 to 12 atoms may be arranged, for example, as bicyclo [4, 5], [5, 5 , [5,6] or [6,6] systems, or arranged as bridged ring systems such as bis[2.2.1]heptane, bicyclo[2.2.2]octane and bicyclo[3.2.2]decane.
  • heterocycloalkyl refers to a saturated carbocyclic group having from 3 to 12 ring atoms, wherein at least one of the ring atoms is a heteroatom independently selected from the group consisting of boron, silicon, oxygen, sulfur, selenium, nitrogen and phosphorus. The remaining ring atoms are C.
  • the group may be a carbon group or a hetero atom group (ie, it may be C-attached or N-attached as long as it is possible).
  • heterocyclic groups include, but are not limited to, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, morpholinyl, 4-thiomorpholinyl, thio Ethoxyalkyl and piperazinyl.
  • the spiro portion and the bridge portion are also included within the scope of this definition.
  • a group derived from tetrahydropyrrole may be tetrahydropyrrole-1-yl (N-attached) or tetrahydropyrrol-3-yl (C-attached).
  • aryl refers to any stable monocyclic or bicyclic carbon ring which may be up to 7 atoms in each ring, at least one of which is an aromatic ring.
  • Examples of the above aryl unit include phenyl, naphthyl, tetrahydronaphthyl, indanyl, biphenyl, phenanthryl, anthryl or acenaphthyl. It will be understood that in the case where the aryl substituent is a bicyclic substituent and one of the rings is a non-aromatic ring, the linkage is carried out through an aromatic ring.
  • heteroaryl refers to a stable monocyclic or bicyclic ring up to 7 atoms in each ring, wherein at least one ring is an aromatic ring and contains from 1 to 4 selected from the group consisting of boron, silicon, oxygen, sulfur, selenium, and nitrogen. And phosphorus heteroatoms.
  • Heteroaryl groups within the scope of this definition include, but are not limited to, acridinyl, oxazolyl, porphyrin, quinoxalinyl, pyrazolyl, indolyl, benzotriazolyl, furyl, thienyl , benzothienyl, benzofuranyl, quinolyl, isoquinolyl, oxazolyl, isoxazolyl, indolyl, pyrazinyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, Tetrahydroquinoline.
  • Heteroaryl is also understood to include any nitrogen-containing heteroaryl N-oxide derivative.
  • heteroaryl substituent is a bicyclic substituent and one ring is a non-aromatic ring or does not contain a hetero atom
  • linkage is carried out separately through an aromatic ring.
  • the heteroaryl-heterocyclic ring, bicyclic heteroaryl ring system can be fused in a fused form.
  • N, S, B, P or Se is optionally substituted by one or more oxygen atoms to obtain groups like NO, SO, SO 2 , BOH, PO, PO 2 , SeO, and the N atom may be quaternized.
  • a heteroaryl group can be attached to the main structure at any heteroatom or carbon atom to form a stable compound.
  • the heteroaryl group can be a monovalent group or a divalent group, ie a heteroarylene group.
  • alkoxy refers to an alkyl group attached through an oxygen bridge; the alkyl group is as defined above.
  • alkyl fluorenyl refers to an alkyl group attached through a sulphur bridge; the alkyl group is as defined above.
  • the term "pharmaceutically acceptable salt” refers to a salt formed from a suitable non-toxic organic acid, inorganic acid, organic base or inorganic base with Compound I which retains the biological activity of Compound I.
  • the organic acid may be various organic acids which can be salted in the art, preferably methanesulfonic acid, p-toluenesulfonic acid, maleic acid, fumaric acid, citric acid, tartaric acid, malic acid, lactic acid, formic acid, acetic acid. And one or more of propionic acid, trifluoroacetic acid, oxalic acid, succinic acid, benzoic acid, isethionic acid, naphthalenesulfonic acid and salicylic acid.
  • the inorganic acid may be any of various inorganic acids which are conventionally salt-formable in the art, preferably one or more of hydrochloric acid, sulfuric acid and phosphoric acid.
  • the organic base may be various organic bases which can be salted in the art, preferably one or more of pyridines, imidazoles, pyrazines, anthracenes, porphyrins, tertiary amines and anilines. kind.
  • the tertiary amine organic base is preferably triethylamine and/or N,N-diisopropylethylamine.
  • the aniline organic base is preferably N,N-dimethylaniline.
  • the pyridine organic base is preferably one or more of pyridine, picoline, 4-dimethylaminopyridine and 2-methyl-5-ethylpyridine.
  • the inorganic base may be various inorganic bases which can be salted in the art, preferably alkali metal hydride, alkali metal hydroxide, alkali metal alkoxide, potassium carbonate, sodium carbonate, lithium carbonate or cesium carbonate.
  • alkali metal hydride is preferably sodium hydride and/or potassium hydride.
  • the alkali metal hydroxide is preferably one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide.
  • the alkali metal alkoxide is preferably one or more of sodium methoxide, sodium ethoxide, potassium t-butoxide and sodium t-butoxide.
  • solvate refers to a substance formed by the compound I with a suitable solvent.
  • the solvent is, for example, water or an organic solvent.
  • component refers to a component of the combination of the invention, ie, compound I, its enantiomer, its diastereomer, its tautomer, its crystalline form, and its pharmaceutically acceptable a salt, a solvate thereof, a metabolite thereof or a prodrug thereof, or an anticancer drug.
  • pharmaceutical excipient refers to those excipients that are widely used in the field of pharmaceutical production.
  • the excipients are primarily used to provide a safe, stable, and functional pharmaceutical composition, and may also provide means for the subject to be dissolved at the desired rate after administration, or to promote the subject's activity after administration of the composition.
  • the ingredients are effectively absorbed.
  • the pharmaceutical excipient can be an inert filler or provide a function, such as stabilizing the overall pH of the composition or preventing degradation of the active ingredients of the composition.
  • the pharmaceutical excipient may include one or more of the following excipients: binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
  • excipients binder, suspending agent, emulsifier, diluent, filler, granulating agent, adhesive, disintegrant, lubricant, anti-adhesion Agents, glidants, wetting agents, gelling agents, absorption delaying agents, dissolution inhibitors, reinforcing agents, adsorbents, buffers, chelating agents, preservatives, colorants, flavoring agents, and sweeteners.
  • active ingredient means the active ingredient in the pharmaceutical composition or combination kit of the present invention, ie, Compound I, its enantiomer, its diastereomer, its tautomer, and its crystal form.
  • the positive progress of the present invention is that the compound of the present invention has a better inhibitory activity against WEE1 kinase.
  • the structures of all compounds of the invention can be identified by nuclear magnetic resonance ( 1 H NMR) and/or mass spectrometry (MS).
  • the 1 H NMR chemical shift ( ⁇ ) was recorded in PPM (10 -6 ).
  • NMR was performed on a Bruker AVANCE-400 spectrometer.
  • LC-MS was determined by an Agilent 1200 HPLC/6120 mass spectrometer.
  • the thin layer silica gel plate is a Liangchen silicon source HSGF254 or a Qingdao GF254 silica gel plate.
  • Column chromatography generally uses Yantai Yellow Sea 200-300 mesh silica gel as a carrier.
  • the compound of formula I-14-a is N-[2-[6-[[2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]- 3-oxo-pyrazolo[3,4-d]pyrimidin-6-yl]amino]-3,4-dihydro-1H-isoquinolin-2-yl]ethyl]-N-methyl - tert-Butyl carbamate (150 mg, 0.24 mmol).
  • LC-MS: m/z: (M+H) + 615.4.
  • reaction solution is concentrated, diluted with water, filtered, and dried to give compound 6-[(2-acetyl-3,4-dihydro-1H-isoquinolin-6-yl)amino group as shown in formula I-21. ]-2-allyl-1-[6-(1-hydroxy-1-methyl-ethyl)-2-pyridyl]pyrazolo[3,4-d]pyrimidin-3-one (40 mg, 0.085 mmol).
  • 6-Bromo-3,4-dihydronaphthalene-2(1H)-one (1.8 g, 8 mmol) (as shown in formula I-44-a) and ammonium acetate (6.2 g, 81 mmol) were added to 80 ml In methanol, stir at room temperature for 2 h. Then sodium cyanoborohydride (600 mg, 0.984 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time.
  • LC-MS: m/z: (M+H) + 226.
  • 6-Bromo-1,2,3,4-tetrahydronaphthalen-2-amine (900 mg, 3.98 mmol) (as a compound of formula I-44-b) was dissolved in 10 ml of 37% formaldehyde and 16 ml of formic acid. Heat to reflux for 4 h. The solvent was evaporated to dryness. EtOAc was evaporated. The obtained crude product was obtained as a brown oil (yield: 800 mg). The yield was 79%.
  • LC-MS: m/z: (M+H) + 254.
  • N,N-Dimethyl-5-nitroindane-2-amine 60 mg, 0.29 mmol
  • compound as shown in formula I-57-b was dissolved in 5 ml of methanol and 50 mg (0.76 mmol) was added.
  • N2,N2-dimethylindole-2,5-diamine such as the compound of formula I-57-c
  • 14 mg (0.11 mmol) of DIPEA stirred at room temperature for 4 days, the reaction solution was washed with water and the organic layer was passed.
  • N,N-Dimethyl-6-nitroindane-1-amine 500 mg, 2.42 mmol
  • 476 mg (7.27 mmol) was added.
  • 6-Bromo-3,4-dihydronaphthalene-2(1H)-one (0.7 g, 3 mmol) (as the compound of formula I-59-a) and ammonium acetate (2.4 g, 31 mmol) were added to 20 ml In methanol, stir at room temperature for 2 h. Then sodium cyanoborohydride (230 mg, 3.77 mmol) was added and stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure, and then 20 ml of water was added, and the pH was adjusted to acid with 1 mol/L hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time.
  • LC-MS: m/z: (M+H) + 226.
  • 6-Bromo-3,4-dihydronaphthalene-2(1H)-one 400 mg, 1.78 mmol (as compound of formula I-61-a) was dissolved in 18 mL of methanol then added (1368 mg, 17.8) Ethyl ammonium acetate was stirred at room temperature for 2 h, then (120 mg, 1.91 mmol) sodium cyanoborohydride. The reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time.
  • LC-MS: m/z: (M+H) + 226.0, 228.0.
  • 6-Bromo-1,2,3,4-tetrahydronaphthalen-2-amine 200 mg, 0.84 mmol
  • sodium cyanoborohydride 280 mg, 4.46 mmol
  • Dissolved in 10 ml of methanol added with 0.5 mL of propionaldehyde, and stirred at room temperature for 16 h at room temperature.
  • the reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time.
  • LC-MS: m/z: (M+H) + 310.1, 3121.
  • 6-Amino-1,4-dihydronaphthalene-1(2H)-1 (148.9 mmol) (as the compound of formula I-62-a) was dissolved in dichloromethane (200 mL), and N was added to the reaction mixture. N-diisopropylethylamine (446.7 mmol), the reaction solution was cooled to 0 ° C, acetyl chloride (223.3 mmol) was slowly added to the reaction mixture, and the reaction mixture was stirred at room temperature for 12 hours.
  • N-(5-oxo-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (25 mmol) (as a compound of formula I-62-b) is dissolved in 1,1- Dimethoxy-N,N-dimethylmethylamine (60 mL) was heated to reflux and stirred for 18 h. The reaction mixture was evaporated to dryness crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystals crystal
  • EtOAc Hydronaphthalen-2-yl)amino)-1-(3-(2-hydroxypropan-2-yl)phenyl)-1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidine- 3-ketone (as compound of formula I-62) (31 mg, 10.8%) as a white solid.
  • 6-Bromo-3,4-dihydronaphthalene-2(1H)-one 400 mg, 1.78 mmol
  • ammonium acetate 1368 mg
  • sodium cyanoborohydride 120 mg, 1.91 mmol
  • the reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time.
  • 6-Bromo-2-methoxy-1,2,3,4-tetrahydronaphthalene (340 mg, 1.41 mmol) (as shown in formula I-64-c), benzophenone imine (300 mg) , 1.66 mmol), sodium tert-butoxide (220 mg, 2.29 mmol), Pd 2 (dba) 3 (45 mg, 0.05 mmol), BINAP (90 mg, 0.14 mmol) was added to 20 ml of toluene, ventilated three times in argon, then Heat to 110 degrees overnight.
  • N-(6-Methoxy-5,6,7,8-tetrahydronaphthalen-2-yl)-1,1-benzophenone imine 450 mg, 1.3 mmol
  • 6-Acetylamino-1,2,3,4-tetrahydro-1-naphthalenone (2000 mg, 9.8406 mmol) (as shown in formula 1-66-a) was dissolved in toluene (40 mL), then B was added Ethyl aldehyde (2 equiv., 19.681 mmol, 50 mass%) (as shown in formula I-66-b), magnesium sulfate (5 equiv., 49.203 mmol) and p-toluenesulfonic acid (0.1 equiv., 0.98406 mmol) . The reaction was heated to 120 ° C and stirred for 12 hours. After adding 20 ml of water, the mixture was evaporated.
  • E Ethyl (E)-2-(6-acetamido-1-oxo-3,4-dihydronaphthalen-2-(1H)-methylene) acetate (2000 mg, 6.961 mmol) (eg The compound of formula I-66-c) was dissolved in ethanol (20 mL), then sulfuric acid solution (1 mL, 70 mass%) and Pd/C (200 mg, 10 mass%) were added. The reaction was stirred at room temperature for 12 hours under a hydrogen atmosphere. Filter and adjust the pH of the filtrate to 7-8 with saturated sodium bicarbonate solution. The solution was extracted with EtOAc (2 ⁇ 20 mL).
  • Ethyl-2-(6-acetamide-1,2,3,4-dihydronaphthalen-2-yl)acetate (700 mg, 2.436 mmol) (as compound of formula I-66-d) Dissolved in ethanol (20 mL) solution, then added sulfuric acid solution (2 mL, 70 mass%). The reaction was heated to reflux and stirred for 12 hours. The mixture was extracted with ethyl acetate (2 ⁇ 2 mL), EtOAc (EtOAc m. 99%.
  • the reaction was quenched with 1N aqueous HCl and pH was adjusted to 6-7, and then a large white solid was precipitated and filtered to give a white solid, which was rinsed twice with petroleum ether (5 ml).
  • 6-Bromo-3,4-dihydronaphthalene-2(1H)-one (855 mg, 3.8 mmol) (as shown in formula I-74-a) and (400 mg, 5.6 mmol) pyrrolidine were dissolved in 20 mL Dichloromethane was then added (1.6 g, 7.6 mmol) of sodium borohydride, and the mixture was stirred at 65 ° C overnight. Quenched with 5 ml of water, washed with saturated aqueous sodium sulfate and brine, dried over anhydrous sodium sulfate The solution was freed from solidified ethyl acetate. Filtration gave 1 g of an off-white solid. Yield: 83%.
  • LC-MS: m/z: [M+1] + 280.
  • 6-Bromo-3,4-dihydronaphthalene-2(1H)-one (900 mg, 4 mmol) (as the compound of formula I-75-a), azetidine hydrochloride (750 mg, 8 mmol) and 20 ml of water was added to 60 mL of methanol, then (1.31 g, 16 mmol) of sodium acetate was added, and the mixture was stirred at room temperature under nitrogen for 1 h.
  • 1-(6-Bromo-1,2,3,4-tetrahydronaphthalen-2-yl)azetidine 0.7 g, 2.63 mmol (as a compound of formula I-75-b), Benzophenone imine (530 mg, 2.92 mmol), sodium tert-butoxide (410 mg, 4.27 mmol), Pd 2 (dba) 3 (80 mg, 0.087 mmol), BINAP (165 mg, 0.265 mmol) was added to 35 ml of toluene. The gas was ventilated three times with argon and then heated to 110 degrees overnight.
  • 6-Bromo-3,4-dihydronaphthalene-2(1H)-one (1 g, 4.44 mmol) (as compound of formula I-76-a), piperidine (760 mg, 8.93 mmol) and p-toluene Sulfonic acid (90 mg, 0.52 mmol) was added to 40 mL of toluene, and a water separator was placed on the reaction flask, and stirred at 155 ° C overnight.
  • 6-(piperidin-1-yl)-5,6,7,8-tetrahydronaphthalen-2-amine 130 mg, 0.564 mmol was added (as shown in Formula I-76-d).
  • Compound 0.2 ml of trifluoroacetic acid and 5 ml of dimethyl sulfoxide, stirred at 60 degrees for 24 h.
  • 6-Nitro-1,2,3,4-tetrahydroisoquinoline hydrochloride (215 mg, 1 mmol) (as shown in formula I-87-a) and N,N-diisopropyl B
  • the amine (0.2 ml) was added to 15 ml of dichloromethane and stirred until clear.
  • 1-methyl-piperidin-4-one (170 mg, 1.5 mmol), sodium borohydride (422 mg, 2 mmol) and 0.3 mL of acetic acid were added and stirred at room temperature for 40 h.
  • N-(5-oxo-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (59 mmol) (as a compound of formula I-103-a) was dissolved in toluene (200 mL) , placed in a sealed tube, and added ethyl glyoxylate (118 mmol), p-toluenesulfonic acid (5.9 mmol) and magnesium sulfate (395 mmol) to the reaction mixture, and the reaction mixture was heated to 120 ° C, and the reaction solution was stirred for 16 hours. . The reaction liquid was filtered, and the filtrate was evaporated to dryness to purified crystals. Oxo-3,4-dihydronaphthalene-2(1H)-methylene) acetate (9.5 g, 56%), yellow solid.
  • LC-MS: m/z: [M+1] + 288.
  • N-(6-(2-Hydroxyethyl)-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (12 mmol) (as shown in formula I-103-d) Dissolved in dichloromethane (30 mL), and added triethylamine (46 mmol), N,N-dimethylpyridin-4-amine (5.8 mmol) and p-toluenesulfonyl chloride (23 mmol) to the reaction mixture. Stir under 16 hours. 1N Hydrochloric acid (200 mL) was added to the reaction mixture, and the mixture was evaporated.
  • N-(6-(2-Methoxyethyl)-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (1.01 mmol) (as in Formula I-103-f)
  • the compound shown was dissolved in ethanol (10 mL), concentrated hydrochloric acid (10 mL) was added, and the mixture was warmed to reflux and stirred for 16 hours.
  • 6-Bromo-3,4-dihydronaphthalene-2(1H)-one 400 mg, 1.78 mmol
  • 18 mL of methanol then ammonium acetate 1368 mg
  • sodium cyanoborohydride 120 mg, 1.91 mmol
  • the reaction solution was concentrated under reduced pressure, and then 30 ml of water was added, and the pH was adjusted to acid with 1 mol/L of hydrochloric acid, and extracted twice with 30 ml of dichloromethane each time.
  • 6-Bromo-2-(pyrrolidin-3-yl)-1,2,3,4-tetrahydroisoquinoline (600 mg, 2.1 mmol) (as compound of formula I-114-c), 37 Aqueous aqueous formaldehyde (1 ml) and sodium borohydride (900 mg, 4.24 mmol) were added to 35 ml of methanol and stirred at room temperature overnight.
  • N-(6-(2-morpholinoethyl)-5-,6-,7-,8-tetrahydronaphthalen-2-yl)acetamide (0.76 mmol) (as shown in formula I-117-b)
  • the compound was dissolved in ethanol (10 mL), sodium hydroxide (10 mL, 10 mol/L) was added to the reaction mixture, and the mixture was stirred and refluxed for 18 hours.
  • the reaction mixture was separated with water and ethyl acetate.
  • EtOAc EtOAc m. -,6-,7-,8-tetrahydronaphthalen-2-amine (152 mg, 76.7%), gray solid.
  • LC-MS: m/z: [M+1] + 261.
  • the reaction solution was evaporated to dryness, and the obtained sulfoxide intermediate was dissolved in dimethyl sulfoxide (10 mL), and 6-(2-morpholinethyl)-5-,6-,7-, 8-tetrahydronaphthalene- 2-Amine (such as the compound of formula I-117-c) (0.31 mmol) and trifluoroacetic acid (0.5 mL), and the mixture was stirred and stirred at 60 ° C for 16 hours.
  • N-Benzyl-6-((diphenylmethylene)amino)-N-ethyl-1,2,3,4-tetrahydronaphthalen-2-amine 72 mg, 0.16 mmol (as in formula I-
  • the compound shown by 119-d was dissolved in 10 ml of methanol, and then sodium acetate trihydrate (66 mg, 0.48 mmol) and hydroxylamine hydrochloride (25 mg, 0.36 mmol) were added, and the mixture was heated to 60 ° for 6 hours. The reaction mixture was concentrated with EtOAc EtOAc m.
  • LC-MS: m/z: (M+H) + 2821.
  • Test compounds were screened on WEE1 kinase at an ATP concentration of Km using an ELISA method. Three compounds were screened on the WEE1 kinase to evaluate the kinase inhibitory activity of the test compound. During the test, the initial concentration of the test compound was selected to be 100 nM, and each compound was selected to have 6 gradient dilution concentrations, and the gradient dilution factor was 4 times. Two replicate wells per concentration were used for detection, and MK-1775 was used as a standard control.
  • WEE1 purchased from Carna Biosciences, Inc., Cat. No.: 05-177; dimethyl sulfoxide, purchased from Sigma-Aldrich, Cat. No. D8418; ATP, purchased from Sigma-Aldrich, Cat. No. A7699; DTT solution, purchased from Sigma- Aldrich, Cat. No. 43816; protein tyrosine kinase (PTK)substrate(poly–Glu-Tyr), purchased from Sigma-Aldrich, Cat. No. P4476; P-Tyr (PY99), purchased from Santa Cruz, Cat. No.: sc-7020; Anti -mouse IgG HRP-linked Antibody, purchased from Santa Cruz, Cat.
  • PTK protein tyrosine kinase
  • TMB liquid Substrate System purchased from Sigma-Aldrich, Cat. No. T0440; Costar Stripwell Microplate No Lid 1 ⁇ 8 Flat Bottom, Certified High Binding, purchased from Sigma - Aldrich, Cat. No. 42592; 96-well compound plate available from Thermo Scientific, Cat. No. 267245.
  • Coating substrate 1) Take appropriate volume of substrate tyrosine kinase (PTK) substitute (poly–Glu-Tyr), dilute 10 times with PBS, and dilute the concentration from 250 mg/mL to 25 mg/mL. . Add to a high adsorption 96-well plate at 125 ⁇ L per well. Place the coating in an incubator at 37 ° C overnight. 2) After 24 hours, the 96-well plate was taken out, the liquid in the 96-well plate was drained, washed 3 times with washing buffer, and the incubator was inverted and dried for 2 hours at 37 °C.
  • PTK substrate tyrosine kinase
  • Enzyme reaction stage 1) WEE1 kinase and ATP were separately prepared into a 2 ⁇ enzyme solution and a 4 ⁇ ATP solution using 1 ⁇ reaction buffer. In this screening, the final concentration of WEE1 kinase was: 0.15 ng/ ⁇ L, and the final concentration of ATP was: 12 ⁇ M; 2) 20 ⁇ L of 2 enzyme solution was added to the high-adsorption 96-well plate; 3) 96-well to high adsorption 10 ⁇ L of 4 ⁇ ATP solution was added to the plate, and 10 ⁇ L of 1 ⁇ reaction buffer was added to the ATP-control empty; 4) The plate was placed in a HERAEUS Multifuge X1R centrifuge and centrifuged at 2000 rpm for 20 s, and then left at room temperature for 60 min.
  • Reaction termination stage 1) Pour off the reaction solution in the plate, add 200 ⁇ L washing buffer to each well, wash 5 times; add primary anti-P-Tyr (PY99) (dilution ratio 1:2000), 100 ⁇ L per well, room temperature 30 min . 2) Pour off the primary antibody in the plate, add 200 ⁇ L of washing buffer to each well, wash 5 times; add anti-mouse IgG HRP-linked Antibody (diluted 1:2000), 100 ⁇ L per well, room temperature for 30 min. 3) Pour off the secondary antibody in the plate, wash 5 times with washing buffer, add TMB, 100 ⁇ L per well, and develop color for 10 to 30 minutes, depending on the color depth. The reaction was stopped with 1 N sulfuric acid before reading.
  • the compound inhibits COLO 205 cell line in vitro
  • the inhibitory effect of the compound on the proliferation of the p53-deficient cell line COLO 205 was examined by Luminescence ATP Detection method.
  • Four compounds were screened on the cell line to evaluate the inhibitory activity of the test compound on proliferation of the cell line in vitro. During the detection, the initial concentration of the test compound was selected as 10 ⁇ M, 9 gradient dilution concentrations were selected, and the gradient dilution multiple was 3 times. Two replicate wells per concentration were used for detection, and MK-1775 was used as a standard control.
  • COLO 205 human colon cancer cell, purchased from the Chinese Academy of Sciences cell bank, catalog number: TCHu102; ATPlite 1step Single Addition Luminescence ATP Detection Assay system, purchased from PerkinElemer, catalog number: 6016739; RPMI 1640, purchased from GIBCO, article number: A10491-01; Strep/pen, purchased from GIBCO, article number: 15240-062; fetal bovine serum FBS, purchased from GIBCO, article number: 10099-141; 96-well black bottom-permeable cell culture plate, purchased from Corning, Cat. No.: 3603; 96-well compound plate , purchased from Thermo Scientific, article number: 267245.
  • Cell culture and inoculation Take normal cultured cells, and digest and disperse them under the exponential growth state, adjust the cell density to 8.8 ⁇ 10 3 cells/mL, and inoculate 90 ⁇ L per well in 96-well cell culture plates; inoculation is completed. The microplate was then placed at 37 ° C under 5% CO 2 ;
  • the microplate was taken out of the incubator and equilibrated at room temperature for 30 min. 100 ⁇ l of room temperature equilibrated ATPlite reaction solution was added to each well, and shaken at 1300 rpm for 2 min at room temperature. Then, the microplate was placed in a HERAEUS Multifuge X1R centrifuge and centrifuged at 2000 rpm for 1 min; after equilibration at room temperature for 10 min, the fluorescence signal value was measured on EnVisionTM.

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Abstract

本发明公开了一种吡唑酮并嘧啶类化合物、其制备方法及应用。本发明提供了一种如式I所示的吡唑酮并嘧啶类化合物、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，该化合物对WEE1激酶的抑制活性较佳。

Description

一种吡唑酮并嘧啶类化合物、其制备方法及应用
本申请要求申请日为2017年11月20日的中国专利申请CN201711159964.0的优先权。本申请要求申请日为2018年8月23日的中国专利申请CN201810968776.0的优先权。本申请引用上述中国专利申请的全文。
技术领域
本发明涉及一种吡唑酮并嘧啶类化合物、其制备方法及应用。
背景技术
细胞周期与DNA损伤修复过程密切相关。细胞周期是指细胞分裂所经历的整个过程，分为细胞分裂间期(interphase)与分裂期(mitotic phase，M)两个阶段。细胞周期检验点(checkpoint)是调控细胞周期的一个关键点，主要作用是保证周期中每一事件能按时和有序完成，并且调节细胞状态与外界环境相适应。细胞主要的检验点有：1)G 1/S检验点：在哺乳动物中称作R(restriction)点，控制细胞由静止的G 1期进入DNA合成期；2)S期检验点：DNA复制是否完成；3)G 2/M检验点：是调节细胞进入分裂期的控制点；4)中-后期检验点：也称纺锤体组装检验点，如果着丝点没有正确的连接到纺锤体上，就会引起细胞周期的中断。如果细胞分裂周期某些过程存在异常如DNA损伤，检验点会及时感应并且启动修复。P53蛋白是调控G 1检验点的重要蛋白，DNA受损伤时，阻止细胞进入S期，激活DNA修复机制，对于维护细胞基因组的完整性至关重要。但由于肿瘤细胞往往存在P53突变，使得G1检验点缺陷，故在P53突变的细胞中细胞分裂周期调控依赖G 2/M检验点。WEE1激酶是一种细胞周期调节蛋白，能调控细胞周期蛋白依赖性激酶1(cyclin-dependent kinase 1，CDK1)的磷酸化状态，从而调节CDK1与细胞周期蛋白B(cyclinB)复合物的活性从而实现对细胞周期的调控，且对DNA损伤检查点具有重要的调节作用。WEE1是G 2/M期阻滞的关键基因，起着重要的监测作用，在一些癌症中过表达，抑制或下调WEE1激酶均能引发有丝分裂灾难，因此WEE1激酶抑制剂在抗癌治疗中有关键作用，目前已成为抗癌剂的研发热点。
国际专利申请WO2010098367、WO2010067886、WO2008115742、WO2008115738、WO2007126122、WO2007126128、WO2004007499等公开了部分小分子WEE1激酶抑制剂，但目前尚未有小分子WEE1激酶抑制剂上市，本领域还需要开发新的抗癌活性好、安全性高的WEE1激酶抑制剂。
发明内容
本发明所要解决的技术问题是现有的化合物对WEE1激酶的抑制活性较差，故而，本发明提供了一种吡唑酮并嘧啶类化合物、其制备方法及应用，该化合物对WEE1激酶的抑制活性较佳。
本发明提供了一种如式I所示的吡唑酮并嘧啶类化合物、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体；
Figure PCTCN2018116352-appb-000001
其中，X为N或CH；
m和n独立地为0、1、2或3，且m+n为2、3或4{例如，m+n为2或3；又例如，“m为0、n为2”、“m为2、n为0”、“m为1、n为1”、“m为1、n为2”、或者、“m为2、n为1”}；
Y为N或CH；
R 1为H、卤素、巯基、硝基、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-C(＝NR 1-11)R 1- 5、-S(＝O)R 1-6、-S(＝O) 2R 1-7、-S(＝NR 1-12)R 1-8、-S(＝NR 1-13)(＝NR 1-14)R 1-9、-S(＝O)(＝NR 1-15)R 1- 10、未取代或R 1-16取代的C 1～C 7烷基{其中，R 1-16的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-16时，所述的R 1-16相同或不同；所述的“C 1～C 7烷基”例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基、乙基、正丙基或异丙基}、未取代或R 1-17取代的C 2～C 7烯基{其中，R 1-17的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-17时，所述的R 1-17相同或不同；其中，所述的“C 2～C 7烯基”例如C 2～C 4烯基，又例如2-丙烯基}、未取代或R 1-18取代的C 2～C 8炔基{其中，R 1-18的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-18时，所述的R 1-18相同或不同；其中，所述的“C 2～C 7炔基”例如C 2～C 4炔基，又例如2-丙炔基}、未取代或R 1-19取代的C 1～C 7烷硅基{其中，R 1-19的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-19时，所述的R 1-19相同或不同}、未取代或R 1-20取代的C 3～C 7 环烷基{其中，R 1-20的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-20时，所述的R 1-20相同或不同；所述的“C 3～C 7环烷基”例如环丙基、环丁基、环戊基或环己基，又例如环丁基}、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”{其中，R 1-21的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-21时，所述的R 1-21相同或不同；所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”例如“杂原子为氮和/或氧，杂原子数为1～2个的C 3～C 5杂环烷基”，又例如“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”或“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”。所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”例如“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与Y连接”或“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与Y连接”。所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与Y连接”例如
Figure PCTCN2018116352-appb-000002
所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与Y连接”例如
Figure PCTCN2018116352-appb-000003
所述的“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”例如
Figure PCTCN2018116352-appb-000004
}、未取代或R 1-22取代的C 6～C 10芳基{其中，R 1-22的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1- 22时，所述的R 1-22相同或不同}、未取代或R 1-23取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”{其中，R 1-23的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-23时，所述的R 1-23相同或不同}、未取代或R 1-24取代的C 1～C 7烷氧基{其中，R 1-24的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-24时，所述的R 1-24相同或不同}、或者、未取代或R 1-25取代的C 1～C 7烷巯基{其中，R 1-25的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-25时，所述的R 1-25相同或不同}；
所有的R 1-1、R 1-2和R 1-3独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、未取代或R 1-1-3取代的C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基 或叔丁基，又例如甲基、乙基、正丙基或异丙基}、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-1-1、R 1-1-2和R 1-1-3独立地为C 1～C 7烷基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9和R 1-10独立地为羟基、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基}、卤素取代的C 1～C 7烷基{其中，卤素的个数为一个或多个[例如2个、3个或4个]，当存在多个卤素时，所述的卤素相同或不同；所述的“卤素”独立地为氟、氯、溴或碘；所述的“C 1～C 7烷基”例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基；所述的“卤素取代的C 1～C 7烷基”例如三氟甲基}、卤素、C 2～C 7烯基、C 2～C 7炔基{例如C 2～C 4炔基，又例如2-丙炔基或1-丙炔基}、C 3～C 7环烷基、C 1～C 7烷氧基{例如C 1～C 4烷氧基，又例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，又例如甲氧基}、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为氢、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基}、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-11、R 1-12、R 1-13、R 1-14和R 1-15独立地为H、氰基、羟基、C 1～C 7烷氧基、未取代或R 1-11-1取代的C 1～C 7烷基{其中，R 1-11-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-11-1时，所述的R 1-11-1相同或不同；所述的“C 1～C 7烷基”例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基}、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、或者、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种 或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-11-1独立地为卤素、羟基、氰基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、C 1～C 7杂环烷基、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”或C 1～C 7烷氧基；
所有的R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24和R 1-25独立地为卤素{例如氟、氯、溴或碘，又例如氟}、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基{例如三甲基硅基}、未取代或R 1-16-7取代的C 3～C 7环烷基、未取代或R 1- 16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”{其中，R 1-16-6的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-16-6时，所述的R 1-16-6相同或不同；所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”例如“杂原子为氮和/或氧，杂原子数为1～2个的C 3～C 5杂环烷基”，又例如“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”、“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”或
Figure PCTCN2018116352-appb-000005
所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”例如“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与其他基团[例如C 1～C 7烷基]连接”或者“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与其他基团[例如C 1～C 7烷基]连接”。所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与其他基团连接”例如
Figure PCTCN2018116352-appb-000006
所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与其他基团连接”例如
Figure PCTCN2018116352-appb-000007
所述的“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”例如
Figure PCTCN2018116352-appb-000008
}、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷 中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4、R 1-16-6和R 1-16-7独立地为氢、羟基、卤素、氰基、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基}、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”{例如“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基，且其通过氮原子与羰基连接”，又例如“杂原子为氧、硫和氮中的一种或多种，杂原子数为1～2个的C 3～C 7杂环烷基，且其通过氮原子与羰基连接”，还例如
Figure PCTCN2018116352-appb-000009
}、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”{其中，所述的“卤素”独立地为氟、氯或溴；所述的卤素的个数为一个或多个[例如2个、3个或4个]，当存在多个卤素时，所述的卤素相同或不同；所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”例如“杂原子为氮，杂原子数为1～2个的C 3～C 7杂环烷基，且其通过氮原子与羰基连接”。所述的“卤代的杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”例如
Figure PCTCN2018116352-appb-000010
}、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、
Figure PCTCN2018116352-appb-000011
-NR 1-16-5-1R 1-16-5-2或-OR 1-16-5-3；
所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或R 1-16-5-1- 1取代的C 1～C 7烷基{其中，R 1-16-5-1-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-16-5-1-1时，所述的R 1-16-5-1-1相同或不同；所述的“C 1～C 7烷基”例如C 1～C 4烷基， 又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基或乙基}、C 2～C 7烯基、C 2～C 7炔基{例如C 2～C 4炔基，又例如2-丙炔基或1-丙炔基}、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5-1-1独立地为卤素、羟基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷巯基、C 1～C 7烷硅基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
z为0、1或2；
所有的R 2独立地为卤素、羟基、氰基、氨基、未取代或R 2-1取代的C 1～C 7烷基{其中，R 2-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-1时，所述的R 2-1相同或不同}、未取代或R 2-2取代的C 2～C 8烯基{其中，R 2-2的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-2时，所述的R 2-2相同或不同}、未取代或R 2-3取代的C 2～C 7炔基{其中，R 2-3的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-3时，所述的R 2-3相同或不同}、未取代或R 2-4取代的C 1～C 7烷硅基{其中，R 2-4的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-4时，所述的R 2-4相同或不同}、未取代或R 2-5取代的C 6～C 10芳基{其中，R 2-5的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-5时，所述的R 2-5相同或不同}、未取代或R 2-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”{其中，R 2-6的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-6时，所述的R 2-6相同或不同}、C 3～C 7环烷基、或者、未取代或R 2-7取代的C 1～C 7烷氧基{其中，R 2-7的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-7时，所述的R 2-7相同或不同}；
{当z为2、两个R 2均为羟基且连接在同一碳原子上时，其表示两个R 2与它们所连接的碳原子共同形成羰基}
所有的R 2-1、R 2-2、R 2-3、R 2-4、R 2-5、R 2-6和R 2-7独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 2-1-1R 2-1-2、-OR 2-1-3、-SR 2-1-4或-(C＝O)R 2-1-5；
所有的R 2-1-1、R 2-1-2、R 2-1-3和R 2-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 2-1-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
或者，两个R 2连接在同一碳原子上共同形成未取代或R 2-8取代的C 3～C 7环烷基{其中，R 2-8的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-8时，所述的R 2-8相同或不同}、或者、未取代或R 2-9取代的C 1～C 7杂环烷基{其中，R 2-9的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-9时，所述的R 2-9相同或不同；所述的“C 1～C 7杂环烷基”例如“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”}；
所有的R 2-8和R 2-9独立地为卤素、氰基、巯基、羟基、氨基、C 1～C 7烷氧基或C 1～C 7烷巯基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m和n独立地为0、1、2或3，且m+n为2或3。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m和n独立地为0、1、2或3，且m+n为3。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m和n独立地为1或2，且m+n为3。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
“m为2、n为1”或者“m为1、n为2”。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
Y为N。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
Y为N，且R 1中与Y相连的原子不为N。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
Y为CH。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1为H、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 8炔基、C 3～C 7环烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1为-NR 1-1R 1-2、R 1-16取代的C 1～C 7烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定 义可如下所述(未注释的定义如前任一所述)：
所有的R 1-1、R 1-2和R 1-3独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、或、未取代或R 1-1-3取代的C 1～C 7烷基；
所有的R 1-1-1、R 1-1-2和R 1-1-3独立地为C 1～C 7烷基或C 6～C 10芳基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-1、R 1-2和R 1-3独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；
所有的R 1-1-1和R 1-1-2独立地为C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-1、R 1-2和R 1-3独立地为氢、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-1和R 1-2独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；所有的R 1-1-1和R 1-1-2独立地为C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-1和R 1-2独立地为氢、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 2～C 7炔基、C 1～C 7烷氧基、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定 义可如下所述(未注释的定义如前任一所述)：
所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、未取代或R 1-16-7取代的C 3～C 7环烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16- 5；
所有的R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4、R 1-16-6和R 1-16-7独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
Figure PCTCN2018116352-appb-000012
-NR 1-16- 5-1R 1-16-5-2或-OR 1-16-5-3；
所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、C 3～C 7环烷基、未取代或R 1- 16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4和R 1-16-6独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
Figure PCTCN2018116352-appb-000013
-NR 1-16- 5-1R 1-16-5-2或-OR 1-16-5-3；
所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、C 3～C 7环烷基、未取代或R 1- 16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-4和R 1-16-6独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
Figure PCTCN2018116352-appb-000014
或-NR 1-16-5-1R 1-16-5-2；
所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-16和R 1-21独立地为C 1～C 7烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-OR 1-16-3或-(C＝O)R 1-16-5；
所有的R 1-16-3和R 1-16-6独立地为C 1～C 7烷基；所有的R 1-16-5独立地为
Figure PCTCN2018116352-appb-000015
所有的R 1-16-5-4和R 1-16-5-5独立地为C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-16和R 1-21独立地为C 1～C 7烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”或-(C＝O)R 1- 16-5；
所有的R 1-16-6独立地为C 1～C 7烷基；所有的R 1-16-5独立地为
Figure PCTCN2018116352-appb-000016
所有的R 1-16-5-4和R 1-16-5-5独立地为C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定 义可如下所述(未注释的定义如前任一所述)：
R 1为下述任一基团：氢、氨基、甲基、乙基、正丙基、异丙基、2-羟基乙基、2-甲氧基乙基、2-甲基氨基乙基、2-二甲基氨基乙基、氰基甲基、氰基、乙酰基、2-丙烯基、2-丙炔基、二甲基氨基、2-氟乙基、2,2,2-三氟乙基、甲氧酰基、甲砜基、2,2,2-三氟乙酰基、环丁基、环丙基甲基、环丙基、二乙基氨基、二正丙基氨基、二甲基氨基甲基、甲氧基、羟基、羧甲基、
Figure PCTCN2018116352-appb-000017
Figure PCTCN2018116352-appb-000018
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
m和n独立地为0、1或2，且m+n为2或3；
Y为N或CH；
R 1为H、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 8炔基、C 3～C 7环烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷 基”；
所有的R 1-1、R 1-2和R 1-3独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、或、未取代或R 1-1-3取代的C 1～C 7烷基；
所有的R 1-1-1、R 1-1-2和R 1-1-3独立地为C 1～C 7烷基或C 6～C 10芳基；
所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 2～C 7炔基、C 1～C 7烷氧基、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基；
所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、未取代或R 1-16-7取代的C 3～C 7环烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16- 5；
所有的R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4、R 1-16-6和R 1-16-7独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
Figure PCTCN2018116352-appb-000019
-NR 1-16- 5-1R 1-16-5-2或-OR 1-16-5-3；
所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
m和n独立地为0、1或2，且m+n为2或3；
Y为N或CH；
R 1为H、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 8炔基、C 3～C 7环烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1、R 1-2和R 1-3独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、或、未取代或C 6～C 10芳基 取代的C 1～C 7烷基；
所有的R 1-1-1和R 1-1-2独立地为C 1～C 7烷基；
所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 2～C 7炔基、C 1～C 7烷氧基、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基；
所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、C 3～C 7环烷基、未取代或R 1- 16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4和R 1-16-6独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
Figure PCTCN2018116352-appb-000020
-NR 1-16- 5-1R 1-16-5-2或-OR 1-16-5-3；
所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
“m为1，n为2”或者“m为2，n为1”；
Y为N或CH；
R 1为H、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 8炔基、C 3～C 7环烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1、R 1-2和R 1-3独立地为氢、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；
所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 2～C 7炔基、C 1～C 7烷氧基、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基；
所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、C 3～C 7环烷基、未取代或R 1- 16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-4和R 1-16-6独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
Figure PCTCN2018116352-appb-000021
或-NR 1-16-5-1R 1-16-5-2；
所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
m为2，n为1；
Y为N或CH；
R 1为-NR 1-1R 1-2、R 1-16取代的C 1～C 7烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1和R 1-2独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、或、未取代或R 1-1-3取代的C 1～C 7烷基；所有的R 1-1-1、R 1-1-2和R 1-1-3独立地为C 1～C 7烷基或C 6～C 10芳基；
所有的R 1-16和R 1-21独立地为C 1～C 7烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-OR 1-16-3或-(C＝O)R 1-16-5；
所有的R 1-16-3和R 1-16-6独立地为C 1～C 7烷基；所有的R 1-16-5独立地为
Figure PCTCN2018116352-appb-000022
所有的R 1-16-5-4和R 1-16-5-5独立地为C 1～C 7烷基；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
m为2，n为1；
Y为N或CH；
R 1为-NR 1-1R 1-2、R 1-16取代的C 1～C 7烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1和R 1-2独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；所有的R 1-1-1和R 1-1-2独立地为C 1～C 7烷基；
所有的R 1-16和R 1-21独立地为C 1～C 7烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-OR 1-16-3或-(C＝O)R 1-16-5；
所有的R 1-16-3和R 1-16-6独立地为C 1～C 7烷基；所有的R 1-16-5独立地为
Figure PCTCN2018116352-appb-000023
所有的R 1-16-5-4和R 1-16-5-5独立地为C 1～C 7烷基；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
m为2，n为1；
Y为N或CH；
R 1为-NR 1-1R 1-2、R 1-16取代的C 1～C 7烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1和R 1-2独立地为氢、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；
所有的R 1-16和R 1-21独立地为C 1～C 7烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”或-(C＝O)R 1- 16-5；
所有的R 1-16-6独立地为C 1～C 7烷基；所有的R 1-16-5独立地为
Figure PCTCN2018116352-appb-000024
所有的R 1-16-5-4和R 1-16-5-5独立地为C 1～C 7烷基；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
Figure PCTCN2018116352-appb-000025
其中，X为N或CH；
m和n独立地为0、1、2或3，且m+n为2、3或4{例如，“m为0、n为2”、“m为2、n为0”、“m为1、n为1”、“m为1、n为2”、或者、“m为2、n为1”；又例如，m+n为2或3}；
Y为N或CH；
R 1为H、卤素、巯基、硝基、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-C(＝NR 1-11)R 1- 5、-S(＝O)R 1-6、-S(＝O) 2R 1-7、-S(＝NR 1-12)R 1-8、-S(＝NR 1-13)(＝NR 1-14)R 1-9、-S(＝O)(＝NR 1-15)R 1- 10、未取代或R 1-16取代的C 1～C 7烷基{其中，R 1-16的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-16时，所述的R 1-16相同或不同；所述的“C 1～C 7烷基”例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基、乙基、正丙基或异丙基}、未取代或R 1-17取代的C 2～C 7烯基{其中，R 1-17的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-17时，所述的R 1-17相同或不同；其中，所述的“C 2～C 7烯基”例如C 2～C 4烯基，又例如2-丙烯基}、未取代或R 1-18取代的C 2～C 8炔基{其中，R 1-18的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-18时，所述的R 1-18相同或不同；其中，所述的“C 2～C 7炔基”例如C 2～C 4炔基，又例如2-丙炔基}、未取代或R 1-19取代的C 1～C 7烷硅基{其中，R 1-19的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-19时，所述的R 1-19相同或不同}、未取代或R 1-20取代的C 3～C 7环烷基{其中，R 1-20的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-20时，所述的R 1-20相同或不同；所述的“C 3～C 7环烷基”例如环丙基、环丁基、环戊基或环己基，又例如环丁基}、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”{其中，R 1-21的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-21时，所述的R 1-21相同或不同；所述的“杂原子为硼、 硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”例如“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”，又例如“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与Y连接”，还例如
Figure PCTCN2018116352-appb-000026
Figure PCTCN2018116352-appb-000027
}、未取代或R 1-22取代的C 6～C 10芳基{其中，R 1-22的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-22时，所述的R 1-22相同或不同}、未取代或R 1-23取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”{其中，R 1-23的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-23时，所述的R 1-23相同或不同}、未取代或R 1-24取代的C 1～C 7烷氧基{其中，R 1-24的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-24时，所述的R 1-24相同或不同}、或者、未取代或R 1-25取代的C 1～C 7烷巯基{其中，R 1-25的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-25时，所述的R 1-25相同或不同}；
所有的R 1-1、R 1-2和R 1-3独立地为氢、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基、乙基、正丙基或异丙基}、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9和R 1-10独立地为羟基、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基}、卤素取代的C 1～C 7烷基{其中，卤素的个数为一个或多个[例如2个、3个或4个]，当存在多个卤素时，所述的卤素相同或不同；所述的“C 1～C 7烷基”例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基；所述的“卤素取代的C 1～C 7烷基”例如三氟甲基}、卤素、C 2～C 7烯基、C 2～C 7炔基{例如C 2～C 4炔基，又例如2-丙炔基或1-丙炔基}、C 3～C 7环烷基、C 1～C 7烷氧基{例如C 1～C 4烷氧基，又例如甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基，又例如甲氧基}、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为氢、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、 正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基}、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-11、R 1-12、R 1-13、R 1-14和R 1-15独立地为H、氰基、羟基、C 1～C 7烷氧基、未取代或R 1-11-1取代的C 1～C 7烷基{其中，R 1-11-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-11-1时，所述的R 1-11-1相同或不同}、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、或者、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-11-1独立地为卤素、羟基、氰基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、C 1～C 7杂环烷基、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”或C 1～C 7烷氧基；
所有的R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24和R 1-25独立地为卤素{例如氟、氯、溴或碘，又例如氟}、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基{例如三甲基硅基}、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”{例如“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”，又例如“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与其他基团，例如C 1～C 7烷基，连接”，还例如
Figure PCTCN2018116352-appb-000028
Figure PCTCN2018116352-appb-000029
}、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 1-16-1R 1-16-2、-OR 1- 16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基}、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂 环烷基”{例如“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基，且其通过氮原子与羰基连接”，又例如“杂原子为氧、硫和氮中的一种或多种，杂原子数为1～2个的C 3～C 7杂环烷基，且其通过氮原子与羰基连接”，还例如
Figure PCTCN2018116352-appb-000030
}、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”{其中，所述的卤素的个数为一个或多个[例如2个、3个或4个]，当存在多个卤素时，所述的卤素相同或不同；所述的“卤素”独立地为氟、氯或溴；所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”例如“杂原子为氮，杂原子数为1～2个的C 3～C 7杂环烷基，且其通过氮原子与羰基连接”；所述的“卤代的杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”例如
Figure PCTCN2018116352-appb-000031
}、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、-NR 1-16-5-1R 1-16-5- 2或-OR 1-16-5-3；
所有的R 1-16-5-1、R 1-16-5-2和R 1-16-5-3独立地为氢、未取代或R 1-16-5-1-1取代的C 1～C 7烷基{其中，R 1-16-5-1-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-16-5-1-1时，所述的R 1-16-5-1-1相同或不同；所述的“C 1～C 7烷基”例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基或乙基}、C 2～C 7烯基、C 2～C 7炔基{例如C 2～C 4炔基，又例如2-丙炔基或1-丙炔基}、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5-1-1独立地为卤素、羟基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷巯基、C 1～C 7烷硅基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
z为0、1或2；
所有的R 2独立地为卤素、羟基、氰基、氨基、未取代或R 2-1取代的C 1～C 7烷基{其中，R 2-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-1时，所述的R 2-1相同或不同}、未取代或R 2-2取代的C 2～C 8烯基{其中，R 2-2的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-2时，所述的R 2-2相同或不同}、未取代或R 2-3取代的C 2～C 7炔基{其中，R 2-3的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-3时，所述的R 2-3相同或不同}、未取代或R 2-4取代的C 1～C 7烷硅基{其中，R 2-4的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-4时，所述的R 2-4相同或不同}、未取代或R 2-5取代的C 6～C 10芳基{其中，R 2-5的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-5时，所述的R 2-5相同或不同}、未取代或R 2-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”{其中，R 2-6的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-6时，所述的R 2-6相同或不同}、C 3～C 7环烷基、或者、未取代或R 2-7取代的C 1～C 7烷氧基{其中，R 2-7的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-7时，所述的R 2-7相同或不同}；
{当z为2、两个R 2均为羟基且连接在同一碳原子上时，其表示两个R 2与它们所连接的碳原子共同形成羰基}
所有的R 2-1、R 2-2、R 2-3、R 2-4、R 2-5、R 2-6和R 2-7独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 2-1-1R 2-1-2、-OR 2-1-3、-SR 2-1-4或-(C＝O)R 2-1-5；
所有的R 2-1-1、R 2-1-2、R 2-1-3和R 2-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 2-1-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
或者，两个R 2连接在同一碳原子上共同形成未取代或R 2-8取代的C 3～C 7环烷基{其中，R 2-8的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-8时，所述的R 2-8相同或不同}、或者、未取代或R 2-9取代的C 1～C 7杂环烷基{其中，R 2-9的个数为一个或多 个[例如2个、3个或4个]，当存在多个R 2-9时，所述的R 2-9相同或不同}；
所有的R 2-8和R 2-9独立地为卤素、氰基、巯基、羟基、氨基、C 1～C 7烷氧基或C 1～C 7烷巯基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m和n独立地为0、1、2或3，且m+n为2或3。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m和n独立地为0、1、2或3，且m+n为3{例如m为2、n为1}。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
Y为N。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
Y为CH。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1为H、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的C 1～C 7烷基、C 3～C 7环烷基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定 义可如下所述(未注释的定义如前任一所述)：
R 1为氢、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的C 1～C 7烷基、C 3～C 7环烷基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1为未取代或R 1-16取代的C 1～C 7烷基、未取代或R 1-20取代的C 3～C 7环烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1为-NR 1-1R 1-2、未取代或R 1-16取代的C 1～C 7烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1和R 1-2独立地为氢或C 1～C 7烷基；
所有的R 1-16独立地为C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1为未取代或R 1-16取代的C 1～C 7烷基、或、未取代或R 1-20取代的C 3～C 7环烷基；
所有的R 1-16和R 1-20独立地为C 3～C 7环烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1为未取代或R 1-16取代的C 1～C 7烷基、-NR 1-1R 1-2、或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构 体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-1、R 1-2和R 1-3独立地为氢或C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-1和R 1-2独立地为氢或C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 1～C 7烷氧基、C 2～C 7炔基或NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 1～C 7烷氧基或NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-16独立地为卤素、氰基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”或-NR 1-16-5-1R 1-16-5-2；
所有的R 1-16-5-1和R 1-16-5-2独立地为氢、未取代或R 1-16-5-1-1取代的C 1～C 7烷基、C 2～C 7炔基或C 3～C 7环烷基；
所有的R 1-16-5-1-1独立地为羟基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-16独立地为卤素、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂环烷基”、-NR 1-16-1R 1-16-2或-(C＝O)R 1-16-5；
所有的R 1-16-1和R 1-16-2独立地为C 1～C 7烷基；
所有的R 1-16-5独立地为“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、或、-NR 1-16-5-1R 1-16-5-2；
所有的R 1-16-5-1和R 1-16-5-2独立地为氢、未取代或R 1-16-5-1-1取代的C 1～C 7烷基、C 2～C 7炔基或C 3～C 7环烷基；
所有的R 1-16-5-1-1独立地为羟基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
所有的R 1-16独立地为C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”或-NR 1-16-5-1R 1-16-5-2；
所有的R 1-16-5-1和R 1-16-5-2独立地为氢、C 1～C 7烷基、C 2～C 7炔基或C 3～C 7环烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
m和n独立地为0、1、2或3，且m+n为2或3；
Y为N或CH；
R 1为H、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的C 1～C 7烷基、C 3～C 7环烷基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1、R 1-2和R 1-3独立地为氢或C 1～C 7烷基；
所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 1～C 7烷氧基、C 2～C 7炔基或NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基；
所有的R 1-16独立地为卤素、氰基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”或-NR 1-16-5-1R 1-16-5-2；
所有的R 1-16-5-1和R 1-16-5-2独立地为氢、未取代或R 1-16-5-1-1取代的C 1～C 7烷基、C 2～C 7炔基或C 3～C 7环烷基；
所有的R 1-16-5-1-1独立地为羟基；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
m和n独立地为0、1、2或3，且m+n为2或3；
Y为N或CH；
R 1为氢、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的C 1～C 7烷基、C 3～C 7环烷基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1、R 1-2和R 1-3独立地为氢或C 1～C 7烷基；
所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 1～C 7烷氧基、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基；
所有的R 1-16独立地为卤素、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂环烷基”、-NR 1-16-1R 1-16-2或-(C＝O)R 1-16-5；
所有的R 1-16-1和R 1-16-2独立地为氢或C 1～C 7烷基；
所有的R 1-16-5独立地为“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”或-NR 1-16-5-1R 1-16-5-2；
所有的R 1-16-5-1和R 1-16-5-2独立地为氢、未取代或R 1-16-5-1-1取代的C 1～C 7烷基、C 2～C 7炔基或C 3～C 7环烷基；
所有的R 1-16-5-1-1独立地为羟基；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
m和n独立地为0、1、2或3，且m+n为3{例如m为2、n为1}；
Y为N；
R 1为未取代或R 1-16取代的C 1～C 7烷基、未取代或R 1-20取代的C 3～C 7环烷基或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-16、R 1-20和R 1-21独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为 1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、-NR 1-16-5-1R 1-16-5-2或-OR 1-16-5-3；
所有的R 1-16-5-1、R 1-16-5-2和R 1-16-5-3独立地为氢、未取代或R 1-16-5-1-1取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5-1-1独立地为卤素、羟基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷巯基、C 1～C 7烷硅基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X为CH；
m和n独立地为0、1、2或3，且m+n为3{例如m为2、n为1}；
Y为CH；
R 1为-NR 1-1R 1-2、未取代或R 1-16取代的C 1～C 7烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1和R 1-2独立地为氢或C 1～C 7烷基；
所有的R 1-16独立地为C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-21独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7 炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、-NR 1-16-5-1R 1-16-5-2或-OR 1-16-5-3；
所有的R 1-16-5-1、R 1-16-5-2和R 1-16-5-3独立地为氢、未取代或R 1-16-5-1-1取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5-1-1独立地为卤素、羟基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷巯基、C 1～C 7烷硅基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
z为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X可为CH；
m+n可为2或3；
Y可为CH或N；
R 1可为H、氰基、硝基、-NR 1-1R 1-2、-C(＝O)R 1-4、-C(＝NR 1-11)R 1-5、-S(＝O)R 1-6、未取代或R 1-16取代的C 1～C 7烷基、未取代或R 1-17取代的C 2～C 7烯基、未取代或R 1-18取代的C 2～C 7炔基、未取代或R 1-20取代的C 3～C 7环烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
所有的R 1-1和R 1-2可独立地为氢、C 1～C 7烷基或C 3～C 7环烷基；
所有的R 1-4、R 1-5和R 1-6独立地为C 1～C 7烷基、C 3～C 7环烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷氧基、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
R 1-11为H；
所有的R 1-16、R 1-17、R 1-18、R 1-20和R 1-21独立地为氰基、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢、C 3～C 7环烷基或C 1～C 7烷基；
所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、-NR 1-16-5-1R 1-16-5-2或OR 1-16-5-3；
所有的R 1-16-5-1、R 1-16-5-2和R 1-16-5-3独立地为氢、未取代或R 1-16-5-1-1取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5-1-1独立地为卤素、羟基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷巯基、C 1～C 7烷硅基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
z可为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X可为CH；
“m为2、n为0”、“m为0、n为2”“m为1、n为1”、或者“m为2、n为1”；
Y可为N；
R 1可为H、氰基、-NR 1-1R 1-2、-C(＝O)R 1-4、R 1-16取代或未取代C 1～C 7烷基、C 2～C 7烯基、或、C 2～C 7炔基、R 1-20取代或未取代C 3～C 7环烷基；
R 1-1和R 1-2可独立地为C 1～C 7烷基；
R 1-4独立地为C 1～C 7烷基或C 2～C 7炔基；
所有的R 1-16独立地为氰基、-NR 1-16-1R 1-16-2、-OR 1-16-3或C 3～C 7环烷基；
所有的R 1-16-1、R 1-16-2和R 1-16-3独立地为氢或C 1～C 7烷基；
z可为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X可为CH；
“m为2、n为0”、“m为0、n为2”“m为1、n为1”、或者“m为2、n为1”；
Y可为C；
R 1可为H、氰基、-NR 1-1R 1-2、-C(＝O)R 1-4、未取代或R 1-16取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、未取代或R 1-20取代的C 3～C 7环烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基；
R 1-1和R 1-2可独立地为C 1～C 7烷基；
R 1-4独立地为C 1～C 7烷基或C 2～C 7炔基；
所有的R 1-16独立地为氰基、-NR 1-16-1R 1-16-2、-OR 1-16-3、或、杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基；
所有的R 1-16-1、R 1-16-2和R 1-16-3独立地为氢或C 1～C 7烷基；
z可为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
Figure PCTCN2018116352-appb-000032
其中，X为N或CH；
m和n独立地为0、1、2或3，且m+n为2、3或4{例如，“m为0、n为2”、“m为 2、n为0”、“m为1、n为1”、“m为1、n为2”、或者、“m为2、n为1”；又例如，m+n为2或3}；
Y为N或CH；
R 1为H、卤素、巯基、硝基、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-C(＝NR 1-11)R 1- 5、-S(＝O)R 1-6、-S(＝O) 2R 1-7、-S(＝NR 1-12)R 1-8、-S(＝NR 1-13)(＝NR 1-14)R 1-9、-S(＝O)(＝NR 1-15)R 1- 10、R 1-16取代或未取代C 1～C 7烷基{其中，R 1-16的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-16时，所述的R 1-16相同或不同；所述的“C 1～C 7烷基”例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基、乙基、正丙基或异丙基}、R 1-17取代或未取代C 2～C 7烯基{其中，R 1-17的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-17时，所述的R 1-17相同或不同；其中，所述的“C 2～C 7烯基”例如C 2～C 4烯基，又例如2-丙烯基}、R 1-18取代或未取代C 2～C 8炔基{其中，R 1-18的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-18时，所述的R 1-18相同或不同；其中，所述的“C 2～C 7炔基”例如C 2～C 4炔基，又例如2-丙炔基}、R 1-19取代或未取代C 1～C 7烷硅基{其中，R 1-19的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-19时，所述的R 1-19相同或不同}、R 1-20取代或未取代C 3～C 7环烷基{其中，R 1-20的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-20时，所述的R 1- 20相同或不同}、R 1-21取代或未取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”{其中，R 1-21的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-21时，所述的R 1-21相同或不同}、R 1-22取代或未取代C 6～C 10芳基{其中，R 1-22的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-22时，所述的R 1-22相同或不同}、R 1-23取代或未取代“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”{其中，R 1-23的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-23时，所述的R 1-23相同或不同}、R 1-24取代或未取代C 1～C 7烷氧基{其中，R 1-24的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-24时，所述的R 1-24相同或不同}、或者、R 1-25取代或未取代C 1～C 7烷巯基{其中，R 1-25的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-25时，所述的R 1-25相同或不同}；
R 1-1、R 1-2和R 1-3独立地为氢、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基}、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中 的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9和R 1-10独立地为羟基、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基}、卤素、C 2～C 7烯基、C 2～C 7炔基{例如C 2～C 4炔基，又例如2-丙炔基或1-丙炔基}、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
R 1-11、R 1-12、R 1-13、R 1-14和R 1-15独立地为H、氰基、羟基、C 1～C 7烷氧基、R 1-11-1取代或未取代C 1～C 7烷基{其中，R 1-11-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-11-1时，所述的R 1-11-1相同或不同}、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、或者、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-11-1独立地为卤素、羟基、氰基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、C 1～C 7杂环烷基、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”或C 1～C 7烷氧基；
所有的R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24和R 1-25独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢、C 1～C 7烷基{例如C 1～C 4烷基，又例如甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基，又例如甲基}、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
z为0、1或2；
所有的R 2独立地为卤素、羟基、氰基、氨基、R 2-1取代或未取代C 1～C 7烷基{其中，R 2-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-1时，所述的R 2-1相同或不同}、R 2-2取代或未取代C 2～C 8烯基{其中，R 2-2的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-2时，所述的R 2-2相同或不同}、R 2-3取代或未取代C 2～C 7炔基{其中，R 2-3的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-3时，所述的R 2-3相同或不同}、R 2-4取代或未取代C 1～C 7烷硅基{其中，R 2-4的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-4时，所述的R 2-4相同或不同}、R 2-5取代或未取代C 6～C 10芳基{其中，R 2-5的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-5时，所述的R 2-5相同或不同}、R 2-6取代或未取代“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”{其中，R 2-6的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-6时，所述的R 2-6相同或不同}、或者、R 2-7取代或未取代C 1～C 7烷氧基{其中，R 2-7的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-7时，所述的R 2-7相同或不同}；
{当z为2、两个R 2均为羟基且连接在同一碳原子上时，其表示两个R 2与它们所连接的碳原子共同形成羰基}
所有的R 2-1、R 2-2、R 2-3、R 2-4、R 2-5、R 2-6和R 2-7独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 2-1-1R 2-1-2、-OR 2-1-3、-SR 2-1-4或-(C＝O)R 2-1-5；
所有的R 2-1-1、R 2-1-2、R 2-1-3和R 2-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 2-1-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂 环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
或者，两个R 2连接在同一碳原子上共同形成R 2-8取代或未取代C 3～C 7环烷基{其中，R 2-8的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-8时，所述的R 2-8相同或不同}、或者、R 2-9取代或未取代C 1～C 7杂环烷基{其中，R 2-9的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-9时，所述的R 2-9相同或不同}；
所有的R 2-8和R 2-9独立地为卤素、氰基、巯基、羟基、氨基、C 1～C 7烷氧基或C 1～C 7烷巯基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X可为CH。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m+n可为2或3。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m可为0、n可为2。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m可为1、n可为1。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m可为2、n可为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m可为1、n可为2。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
m可为2、n可为1。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
Y可为N。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1可为H、氰基、硝基、-NR 1-1R 1-2、-C(＝O)R 1-4、-C(＝NR 1-11)R 1-5、-S(＝O)R 1-6、R 1-16取代或未取代C 1～C 7烷基、R 1-17取代或未取代C 2～C 7烯基、R 1-18取代或未取代C 2～C 7炔基、或、R 1-20取代或未取代C 3～C 7环烷基，又可为H、氰基、-NR 1-1R 1-2、-C(＝O)R 1-4、R 1- 16取代或未取代C 1～C 7烷基、C 2～C 7烯基、或、C 2～C 7炔基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1-1和R 1-2可独立地为氢、C 1～C 7烷基或C 3～C 7环烷基，又可独立地为C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1-4、R 1-5和R 1-6独立地为C 1～C 7烷基、C 3～C 7环烷基、C 2～C 7烯基或C 2～C 7炔基；又可独立地为C 1～C 7烷基或C 2～C 7炔基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
R 1-11为H。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定 义可如下所述(未注释的定义如前任一所述)：
所有的R 1-16、R 1-17、R 1-18和R 1-20独立地为氰基、-NR 1-16-1R 1-16-2或-OR 1-16-3；
所有的R 1-16-1、R 1-16-2和R 1-16-3独立地为氢、C 3～C 7环烷基或C 1～C 7烷基；又可独立地为氢或C 1～C 7烷基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
z可为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
其中，X为CH；
m和n独立地为0、1、2或3，且m+n为2、3或4{例如，“m为0、n为2”、“m为2、n为0”、“m为1、n为1”、“m为1、n为2”、或者、“m为2、n为1”；又例如，m+n为2或3}；
Y为N或CH；
R 1为H、卤素、巯基、硝基、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-C(＝NR 1-11)R 1- 5、-S(＝O)R 1-6、-S(＝O) 2R 1-7、-S(＝NR 1-12)R 1-8、-S(＝NR 1-13)(＝NR 1-14)R 1-9、-S(＝O)(＝NR 1-15)R 1- 10、R 1-16取代或未取代C 1～C 7烷基{其中，R 1-16的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-16时，所述的R 1-16相同或不同}、R 1-17取代或未取代C 2～C 7烯基{其中，R 1-17的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-17时，所述的R 1- 17相同或不同}、R 1-18取代或未取代C 2～C 8炔基{其中，R 1-18的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-18时，所述的R 1-18相同或不同}、R 1-19取代或未取代C 1～C 7烷硅基{其中，R 1-19的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1- 19时，所述的R 1-19相同或不同}、R 1-20取代或未取代C 3～C 7环烷基{其中，R 1-20的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-20时，所述的R 1-20相同或不同}、R 1- 21取代或未取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”{其中，R 1-21的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-21时，所述的R 1-21相同或不同}、R 1-22取代或未取代C 6～C 10芳基{其中，R 1- 22的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-22时，所述的R 1-22相同或不同}、R 1-23取代或未取代“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种， 杂原子数为1～4个的C 1～C 7杂芳基”{其中，R 1-23的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-23时，所述的R 1-23相同或不同}、R 1-24取代或未取代C 1～C 7烷氧基{其中，R 1-24的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-24时，所述的R 1-24相同或不同}、或者、R 1-25取代或未取代C 1～C 7烷巯基{其中，R 1-25的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-25时，所述的R 1-25相同或不同}；
R 1-1、R 1-2和R 1-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9和R 1-10独立地为羟基、C 1～C 7烷基、卤素、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、或、NR 1-4-1R 1-4-2；
所有的R 1-4-1和R 1-4-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
R 1-11、R 1-12、R 1-13、R 1-14和R 1-15独立地为H、氰基、羟基、C 1～C 7烷氧基、R 1-11-1取代或未取代C 1～C 7烷基{其中，R 1-11-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 1-11-1时，所述的R 1-11-1相同或不同}、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、或者、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-11-1独立地为卤素、羟基、氰基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、C 1～C 7杂环烷基、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”或C 1～C 7烷氧基；
所有的R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24和R 1-25独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 1-16-1R 1-16-2、-OR 1-16-3、 -SR 1-16-4或-(C＝O)R 1-16-5；
所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
z为0、1或2；
所有的R 2独立地为卤素、羟基、氰基、氨基、R 2-1取代或未取代C 1～C 7烷基{其中，R 2-1的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-1时，所述的R 2-1相同或不同}、R 2-2取代或未取代C 2～C 8烯基{其中，R 2-2的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-2时，所述的R 2-2相同或不同}、R 2-3取代或未取代C 2～C 7炔基{其中，R 2-3的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-3时，所述的R 2-3相同或不同}、R 2-4取代或未取代C 1～C 7烷硅基{其中，R 2-4的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-4时，所述的R 2-4相同或不同}、R 2-5取代或未取代C 6～C 10芳基{其中，R 2-5的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-5时，所述的R 2-5相同或不同}、R 2-6取代或未取代“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”{其中，R 2-6的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-6时，所述的R 2-6相同或不同}、或者、R 2-7取代或未取代C 1～C 7烷氧基{其中，R 2-7的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-7时，所述的R 2-7相同或不同}；
所有的R 2-1、R 2-2、R 2-3、R 2-4、R 2-5、R 2-6和R 2-7独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 2-1-1R 2-1-2、-OR 2-1-3、-SR 2-1-4或-(C＝O)R 2-1-5；
所有的R 2-1-1、R 2-1-2、R 2-1-3和R 2-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中 的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
所有的R 2-1-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
或者，两个R 2连接在同一碳原子上共同形成R 2-8取代或未取代C 3～C 7环烷基{其中，R 2-8的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-8时，所述的R 2-8相同或不同}、或者、R 2-9取代或未取代C 1～C 7杂环烷基{其中，R 2-9的个数为一个或多个[例如2个、3个或4个]，当存在多个R 2-9时，所述的R 2-9相同或不同}；
所有的R 2-8和R 2-9独立地为卤素、氰基、巯基、羟基、氨基、C 1～C 7烷氧基或C 1～C 7烷巯基。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X可为CH；
m+n可为2或3；
Y可为CH或N；
R 1可为H、氰基、硝基、-NR 1-1R 1-2、-C(＝O)R 1-4、-C(＝NR 1-11)R 1-5、-S(＝O)R 1-6、R 1-16取代或未取代C 1～C 7烷基、R 1-17取代或未取代C 2～C 7烯基、R 1-18取代或未取代C 2～C 7炔基、或、R 1-20取代或未取代C 3～C 7环烷基；
R 1-1和R 1-2可独立地为氢、C 1～C 7烷基或C 3～C 7环烷基；
R 1-4、R 1-5和R 1-6独立地为C 1～C 7烷基、C 3～C 7环烷基、C 2～C 7烯基或C 2～C 7炔基；
R 1-11为H；
所有的R 1-16、R 1-17、R 1-18和R 1-20独立地为氰基、-NR 1-16-1R 1-16-2或-OR 1-16-3；
所有的R 1-16-1、R 1-16-2和R 1-16-3独立地为氢、C 3～C 7环烷基或C 1～C 7烷基；
z可为0。
在某一技术方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体中各基团的定义可如下所述(未注释的定义如前任一所述)：
X可为CH；
“m为2、n为0”、“m为1、n为1”、或者、“m为2、n为1”；
Y可为N；
R 1可为H、氰基、-NR 1-1R 1-2、-C(＝O)R 1-4、R 1-16取代或未取代C 1～C 7烷基、C 2～C 7烯基、或、C 2～C 7炔基；
R 1-1和R 1-2可独立地为C 1～C 7烷基；
R 1-4独立地为C 1～C 7烷基或C 2～C 7炔基；
所有的R 1-16独立地为氰基、-NR 1-16-1R 1-16-2或-OR 1-16-3；
所有的R 1-16-1、R 1-16-2和R 1-16-3独立地为氢或C 1～C 7烷基；
z可为0。
在某一方案中，所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体里，所述的化合物I为如下任一化合物：
Figure PCTCN2018116352-appb-000033
Figure PCTCN2018116352-appb-000034
Figure PCTCN2018116352-appb-000035
Figure PCTCN2018116352-appb-000036
Figure PCTCN2018116352-appb-000037
通常，可以使用至少如下所述的方法制备本发明化合物，但并不限于下述反应条件中的试剂和溶剂。
本发明还提供了一种上述的化合物I的制备方法，其为如下任一方法：
方法一：
其包括下述步骤：化合物1A经氧化，得到化合物1B，取代后得到化合物1D，脱保护得到化合物1E即可；
Figure PCTCN2018116352-appb-000038
其中，Y为N。所述的m、n、z和R 2的定义均同前所述；反应路线中的各步骤的条件均可以为本领域该类反应的常规条件。
所述的式1C所示的化合物中的PG可为本领域各种常规的氨基保护基，优选Boc，其目的是在
Figure PCTCN2018116352-appb-000039
与化合物1B进行反应时，使其上的某些活泼基团(例如氨基)不参与反应；
所述的脱除保护基的反应的条件可为本领域各种保护基的常规脱除条件，如水解反应的条件、胺解反应的条件、氢化反应的条件等；
所述的脱除保护基的反应在结束后，较佳地，还可进一步包含后处理的操作；所述的后处理的方法和条件可为本领域此类反应后处理常规的方法和条件，较佳地为：将反应体系进行洗涤、干燥、过滤、蒸干溶剂，然后柱层析，即可；或者，将反应体系蒸除溶剂、洗涤、过滤，即可；或者，将反应体系蒸除溶剂、薄层层析，即可；
其中，反应路线中的各步骤反应的方法的条件均可以按照本领域这些反应的方法的常规条件进行；
方法二：
其包括下述步骤：化合物1A经氧化，得到化合物1B，与2A反应后得到化合物2B即可；
Figure PCTCN2018116352-appb-000040
其中，所述的m、n、z、Y、R 1和R 2的定义均同前所述；反应路线中的各步骤的条件均可以为本领域该类反应的常规条件。
方法三：
当R 1为未取代或R 1-16取代的C 1～C 7烷基、未取代或R 1-17取代的C 2～C 7烯基、未取代或R 1-18取代的C 2～C 8炔基、或、未取代或R 1-20取代的C 3～C 7环烷基时，所述的式I所示的化合物的制备方法包括下述步骤：在有机溶剂(例如1,2-二氯乙烷、二氯甲烷、甲醇和二氧六环中的一种或多种)中，在还原剂(例如三乙酰氧基硼氢化钠和/或氰基硼氢化钠)的存在下，将化合物1E与R 1-CHO进行还原胺化反应，得到化合物I即可；所述的还原胺化反应的条件可为本领域该类反应常规的条件；
Figure PCTCN2018116352-appb-000041
其中，Y为N，所述的R 1’-CH 2-等同于R 1。所述的m、n、z、R 1、R 2的定义均同前所述；反应路线中的各步骤的条件均可以为本领域该类反应的常规条件。
方法四：
当R 1为未取代或R 1-16取代的C 1～C 7烷基、未取代或R 1-17取代的C 2～C 7烯基、未取代或R 1-18取代的C 2～C 8炔基、未取代或R 1-20取代的C 3～C 7环烷基、氰基或乙酰基时，所述的式I所示的化合物的制备方法包括下述步骤：在有机溶剂(例如甲醇、二氯甲烷、乙腈和DMF中的一种或多种)中，在碱(例如碳酸钾、碳酸铯、N,N-二异丙基乙胺或三乙胺)的存在下，将化合物1E与R 1-X 1进行取代反应，得到化合物I即可；所述的取代反应的条件可为本领域该类反应常规的条件；所述的X 1为卤素(例如氯或溴)；
Figure PCTCN2018116352-appb-000042
其中，Y为N。所述的m、n、z、R 1、R 2的定义均同前所述；反应路线中的各步骤的条件均可以为本领域该类反应的常规条件。
方法五：
当R 1为-C(＝O)R 1-4，且R 1-4为C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基或C 3～C 7环烷基时，所述的式I所示的化合物的制备方法包括下述步骤：在有机溶剂(例如1,4-二氧六环、二氯甲烷和DMF中的一种或多种)中，在缩合剂(例如DMAP和EDCI)的存在下，将化合物1E，与
Figure PCTCN2018116352-appb-000043
进行缩合反应，得到化合物I即可；所述的缩合反应的条件可为本领域该类反应常规的条件；
Figure PCTCN2018116352-appb-000044
其中，Y为N。所述的m、n、z、R 1、R 2的定义均同前所述；反应路线中的各步骤的条件均可以为本领域该类反应的常规条件。
本发明还提供了一种如式1C、1D或2A所示的化合物：
Figure PCTCN2018116352-appb-000045
其中，PG、m、n、z、Y、R 1和R 2的定义均同上所述。
本发明还提供了一种如上所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体在制备激酶(例如WEE1激酶)抑制剂中的应用。
本发明还提供了一种如上所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体在制备药物中的应用，所述的药物用于治疗和/或预防与WEE1激酶有关的疾病。
所述的与WEE1激酶有关的疾病例如癌症。所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、宫颈癌、肾盂-输尿管癌、膀胱癌、前列腺癌、阴茎癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌。
本发明还提供了一种如上所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体在制备药物中的应用，所述的药物用于治疗和/或预防癌症。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、宫颈癌、肾盂-输尿管癌、膀胱癌、前列腺癌、阴茎癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、 何杰金氏淋巴瘤，还例如结肠癌或卵巢癌。
本发明还提供了一种药物组合物，其包含如上所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，和，(一种或多种)药用辅料。
本发明提供了一种组合，其包含如上所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体和抗癌药物。
所述的抗癌药物可为本领域中常规的抗癌药物，例如抗癌性烷基化剂、抗癌性代谢拮抗剂、抗癌性抗生素、来源于植物的抗癌剂、抗癌性铂配位化合物、抗癌性喜树碱衍生物、抗癌性酪氨酸激酶抑制剂、单克隆抗体、干扰素、生物反应调节物、米托蒽醌、L-天冬酰胺酶、丙卡巴肼、达卡巴嗪、羟基脲、喷司他丁、维甲酸、阿法赛特、阿法达贝汀、阿那曲唑、依西美坦、比卡鲁胺、亮丙瑞林、氟他胺、氟维司群、哌加他尼钠、地尼白介素2、阿地白介素、促甲状腺素α、三氧化二砷、硼替佐米、卡培他滨和戈舍瑞林中的一种或多种，又例如抗癌性代谢拮抗剂。
所述的抗癌性烷基化剂可为本领域常规的抗癌性烷基化剂，例如氮芥N-氧化物、环磷酰胺、异环磷酰胺、米尔法兰、白消安、二溴甘露醇、卡巴醌、塞替派、雷莫司汀、尼莫司汀、替莫唑胺和卡莫司汀中的一种或多种。
所述的抗癌性代谢拮抗剂可为本领域常规的抗癌性代谢拮抗剂，例如甲氨蝶呤、6-巯基嘌呤核苷、巯嘌呤、5-氟尿嘧啶、替加氟、去氧氟尿苷、卡莫氟、阿糖胞苷、阿糖胞苷十八烷基磷酸钠、依诺他滨、S-1、吉西他滨、氟达拉滨和培美曲塞二钠中的一种或多种，又例如5-氟尿嘧啶。
所述的抗癌性抗生素可为本领域常规的抗癌性抗生素，例如放线菌素D、多柔比星、柔红霉素、新制癌菌素、博来霉素、培洛霉素、丝裂霉素C、阿柔比星、吡柔比星、表柔比星、净司他丁斯酯、伊达比星、西罗莫司和戊柔比星中的一种或多种。
所述的来源于植物的抗癌剂可为本领域常规的来源于植物的抗癌剂，例如长春新碱、长春碱、长春地辛、足叶乙苷、索布佐生、多西他赛、紫杉醇和长春瑞滨中的一种或多种。
所述的抗癌性铂配位化合物可为本领域常规的抗癌性铂配位化合物，例如顺铂、卡铂、奈达铂和奥沙利铂中的一种或多种。
所述的抗癌性喜树碱衍生物可为本领域常规的抗癌性喜树碱衍生物，例如伊立替康、托泊替康和喜树碱中的一种或多种。
所述的抗癌性酪氨酸激酶抑制剂可为本领域常规的抗癌性酪氨酸激酶抑制剂，例如吉非替尼、伊马替尼和埃罗替尼中的一种或多种。
所述的单克隆抗体可为本领域常规的单克隆抗体，例如西妥昔单抗、贝伐单抗、利妥昔单抗、阿仑单抗和曲妥单抗中的一种或多种。
所述的干扰素可为本领域常规的干扰素，例如干扰素α、干扰素α-2a、干扰素α-2b、干扰素β、干扰素γ-1a和干扰素γ-n1中的一种或多种。
所述的生物反应调节物可为本领域常规的生物反应调节物，例如云芝多糖、香菇多糖、西佐喃、沙培林和乌苯美司中的一种或多种。
所述组合中的各组分可同时使用或分开使用(例如顺序使用)；当所述组合中的各组分同时使用时，所述组合中的各组分可均匀混合(即各组分的混合物)。
所述组合中的各组分可以制备成一个单一的药物组合物同时使用，也可以将各组分分别制成单个独立的药物组合物(例如以套装的形式)，这些单个独立的药物组合物可同时使用或分开使用(例如顺序使用)。
本发明还提供了上述的组合在制备用于预防和/或治疗癌症的药物中的应用。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、宫颈癌、肾盂-输尿管癌、膀胱癌、前列腺癌、阴茎癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌。
在本发明所述的应用中，上述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，和，上述的抗癌药物可以同时或者分开施用(例如顺序施用)。
本发明还提供了上述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，在制备用于“和上述的抗癌药物联合”预防和/或治疗癌症的药物中的应用。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、宫颈癌、肾盂-输尿管癌、膀胱癌、前列腺癌、阴茎癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性 白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌。
在本发明所述的应用中，上述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，和，上述的抗癌药物可以同时或者分开施用(例如顺序施用)。
本发明还提供了上述的抗癌药物，在制备用于“和上述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体联合”预防和/或治疗癌症的药物中的应用。
所述的癌症例如脑癌、头颈部癌、食道癌、甲状腺癌、小细胞癌、非小细胞癌、乳腺癌、肺癌、胃癌、胆囊-胆管癌、肝癌、胰腺癌、结肠癌、直肠癌、卵巢癌、绒毛上皮癌、子宫体癌、宫颈癌、肾盂-输尿管癌、膀胱癌、前列腺癌、阴茎癌、睾丸癌、胚胎性癌、肾母细胞瘤、皮肤癌、恶性黑色素瘤、成神经细胞瘤、骨肉瘤、尤文瘤、软组织瘤、急性白血病、慢性淋巴性白血病、慢性骨髓性白血病、或、何杰金氏淋巴瘤，又例如乳腺癌、肺癌、胰腺癌、结肠癌、卵巢癌、急性白血病、慢性淋巴性白血病、慢性骨髓型白血病、何杰金氏淋巴瘤，还例如结肠癌或卵巢癌。
在本发明所述的应用中，上述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，和，上述的抗癌药物可以同时或者分开施用(例如顺序施用)。
本发明还提供了一种药物组合物，其包含上述的组合和(一种或多种)药用辅料。
所述药物组合物可由所述组合和所述药用辅料组成。
本发明还提供了一种组合药盒，其包含药物组合物A和药物组合物B；
所述的药物组合物A包括上述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，和，(一种或多种)药用辅料；
所述的药物组合物B包括上述的抗癌药物和(一种或多种)药用辅料。
所述的组合药盒可由所述的药物组合物A和所述的药物组合物B组成。
所述的药物组合物A可由上述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，和，药用辅料组成；
所述的药物组合物B可由上述的抗癌药物和药用辅料组成。
所述组合药盒中的各个药物组合物可以同时使用或分开使用(例如顺序使用)。
在不违背领域常识的基础上，上述各优选条件，可任意组合，即得本发明各较佳实例。
本发明所用试剂和原料均市售可得。
除非另有说明，在本发明说明书和权利要求书中出现的以下术语具有下述含义：
术语“卤素”是指氟、氯、溴或碘。
术语“烷基”是指具有一个到十二个碳原子的饱和的直链或支链的一价烃基(例如C 1-C 6烷基，又例如C 1-C 4烷基)。烷基的实例包括但不仅限于甲基、乙基、1-丙基、2-丙基、1-丁基、2-甲基-1-丁基、2-丁基、2-甲基-2-丙基、1-戊基、2-戊基、3-戊基、2-甲基-2-丁基、3-甲基-2-丁基、3-甲基-1-丁基、2-甲基-1-丁基、1-己基、2-己基、3-己基、2-甲基-2-戊基、3-甲基-2-戊基、4-甲基-2-戊基、3-甲基-3-戊基、2-甲基-3-戊基、2,3-二甲基-2-丁基、3,3-二甲基-2-丁基、1-庚基和1-辛基。
术语“烯基”是指具有至少一个不饱和位置即碳-碳sp 2双键的二到十二个碳原子的直链或支链的一价烃基(例如C 2-C 6烯基，又例如C 2-C 4烯基)，并且包括具有“顺式”和“反式”取向或者“E”和“Z”取向的基团。其实例包括但不仅限于乙烯基、烯丙基、1-环戊-1-烯基、1-环戊-2-烯基、1-环戊-3-烯基、5-己烯基、1-环己-1-烯基、1-环己-2-烯基、和1-环己-3-烯基。
术语“炔基”是指具有至少一个不饱和位置即碳-碳sp三键的二到十二个碳原子的直链或支链的单价烃基(例如C 2-C 6炔基，又例如C 2-C 4炔基)。其实例包括但不仅限于乙炔基和丙炔基。
术语“烷硅基”是指通过硅桥连接的烷基；所述的烷基的定义同上；C 1-C 7烷硅基是指
Figure PCTCN2018116352-appb-000046
其中R A、R B和R C独立地为C 1-C 7烷基。
术语“环烷基”是指具有三到二十个碳原子的单价的非芳香族的饱和的环烃原子团(例如C 3-C 6环烷基)。单环的碳环原子团的实例包括但不仅限于环丙基、环丁基、环戊基、环己基、环庚基、环辛基、环壬基、环癸基、环十一烷基和环十二烷基。术语“环烷基”还包括多环的(例如，二环和三环)环烷基结构，具有7到12个原子的双环碳环可以布置为例如双环[4,5]、[5,5]、[5,6]或[6,6]系统，或布置为桥接环系统例如双[2.2.1]庚烷、双环[2.2.2]辛烷和双环[3.2.2]壬烷。
术语“杂环烷基”是指具有3到12个环原子的饱和的碳环基团，其中至少一个环原子为独立地选自硼、硅、氧、硫、硒、氮和磷的杂原子，其余的环原子为C。该基团可为 碳基团或杂原子基团(也即其可为C-连接的或N-连接的，只要其是可能的即可)。杂环基的实例包括但不仅限于吡咯烷基、四氢呋喃基、四氢噻吩基、四氢吡喃基、四氢噻喃基、哌啶基、吗啉基、4-硫代吗啉基、噻恶烷基和哌嗪基。螺环部分及桥环部分也被包括在该定义的范围内。例如，由四氢吡咯衍生的基团可为四氢吡咯-1-基(N-连接的)或四氢吡咯-3-基(C-连接的)。例如是3-7元环的单环(1-6个碳原子和选自N，O，P，B，Si，S和Se的1-3个杂原子，在此N，B、P或Se任选地被一个或多个氧原子所取代得到像NO，BOH，PO，PO 2，SeO的基团；N可以任选地季铵化；S原子可以任选地被一个或多个氧原子或氮原子所取代得到像SO、SO 2、S(＝O)(＝NR a),S(＝NR b)或S(＝NR c) 2的基团，同时，R a、R b和R c独立地为氰基、C 1～C 7烷基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 6～C 10芳基或C 1～C 7烷氧基；同时，-CH 2-基团可以任选地被-C(＝O)-、-C(＝S)-或-C(＝NR d)-替代，R d独立地为氰基、C 1～C 7烷基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 6～C 10芳基或C 1～C 7烷氧基；当所述的环为三元环时，其中只有一个杂原子)、或、7-10个原子组成的双环(4-9个碳原子和选自N，O，P，B，Si，S的1-3个杂原子，在此N，S、B或P任选地被一个或多个氧原子所取代得到像NO，BOH，SO，SO 2，PO，PO 2，SeO的基团，同时，-CH 2-基团可以任选地被-C(＝O)-替代)。视结构而定，杂环基可为单价基团或二价基团，即亚杂环基。
术语“芳基”是指任何稳定的在各环中可高达7个原子的单环或者双环碳环，其中至少一个环是芳香环。上述芳基单元的实例包括苯基、萘基、四氢萘基、2,3-二氢化茚基、联苯基、菲基、蒽基或者苊基(acenaphthyl)。可以理解，在芳基取代基是二环取代基，且其中一个环是非芳香环的情况中，连接是通过芳环进行的。
术语“杂芳基”是指各环中可高达7个原子的稳定单环或者二环，其中至少一个环是芳香环并且含有1-4个选自硼、硅、氧、硫、硒、氮和磷的杂原子。在此定义范围内的杂芳基包括但不限于：吖啶基、咔唑基、噌啉基、喹喔啉基、吡唑基、吲哚基、苯并三唑基、呋喃基、噻吩基、苯并噻吩基、苯并呋喃基、喹啉基、异喹啉基、噁唑基、异噁唑基、吲哚基、吡嗪基、哒嗪基、吡啶基、嘧啶基、吡咯基、四氢喹啉。“杂芳基”还应当理解为包括任何含氮杂芳基的N-氧化物衍生物。在其中杂芳基取代基是二环取代基并且一个环是非芳香环或者不包含杂原子的情况下，可以理解，连接分别通过芳环进行。杂芳环 并芳环、双环杂芳环体系可以以稠合的形式成环。其中，N、S、B、P或Se任选地被一个或多个氧原子所取代得到像NO、SO、SO 2、BOH、PO、PO 2、SeO的基团，N原子可以季铵化。杂芳基可以在任何杂原子或者碳原子上连接到主结构上从而形成稳定的化合物。视结构而定，杂芳基可为单价基团或二价基团，即亚杂芳基。
术语“烷氧基”是指通过氧桥连接的烷基；所述的烷基的定义同上。
术语“烷巯基”是指通过硫桥连接的烷基；所述的烷基的定义同上。
术语“药学上可接受的盐”是指由适宜的非毒性有机酸、无机酸、有机碱或无机碱与化合物I形成的盐，其保留化合物I的生物活性。所述的有机酸可为本领域常规的能成盐的各种有机酸，优选甲磺酸、对甲苯磺酸、马来酸、富马酸、柠檬酸、酒石酸、苹果酸、乳酸、甲酸、乙酸、丙酸、三氟乙酸、草酸、丁二酸、苯甲酸、羟乙基磺酸、萘磺酸和水杨酸中的一种或多种。所述的无机酸可为本领域常规的能成盐的各种无机酸，优选盐酸、硫酸和磷酸中的一种或多种。所述的有机碱可为本领域常规的能成盐的各种有机碱，优选吡啶类、咪唑类、吡嗪类、吲哚类、嘌啉类、叔胺类和苯胺类中的一种或多种。所述的叔胺类有机碱优选三乙胺和/或N,N-二异丙基乙胺。所述的苯胺类有机碱优选N,N-二甲基苯胺。所述的吡啶类有机碱优选吡啶、甲基吡啶、4-二甲氨基吡啶和2-甲基-5-乙基吡啶中的一种或多种。所述的无机碱可为本领域常规的能成盐的各种无机碱，优选碱金属氢化物、碱金属的氢氧化物、碱金属的烷氧化物、碳酸钾、碳酸钠、碳酸锂、碳酸铯、碳酸氢钾和碳酸氢钠中的一种或多种。所述的碱金属氢化物优选氢化钠和/或氢化钾。所述的碱金属的氢氧化物优选氢氧化钠、氢氧化钾和氢氧化锂中的一种或多种。所述的碱金属的烷氧化物优选甲醇钠、乙醇钠、叔丁醇钾和叔丁醇钠中的一种或多种。
术语“溶剂化物”是指化合物I与适宜的溶剂形成的物质。所述的溶剂例如为水或有机溶剂。
术语“组分”是指本发明组合中的组分，即化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，或者抗癌药物。
术语“药用辅料”是指药物生产领域中广泛采用的那些辅料。辅料主要用于提供一个安全、稳定和功能性的药物组合物，还可以提供方法，使受试者接受给药后活性成分以所期望速率溶出，或促进受试者接受组合物给药后活性成分得到有效吸收。所述的药用辅料可以是惰性填充剂，或者提供某种功能，例如稳定该组合物的整体pH值或防止组合物活性成分的降解。所述的药用辅料可以包括下列辅料中的一种或多种：粘合剂、助悬剂、乳化剂、稀释剂、填充剂、成粒剂、胶粘剂、崩解剂、润滑剂、抗粘着剂、助流剂、 润湿剂、胶凝剂、吸收延迟剂、溶解抑制剂、增强剂、吸附剂、缓冲剂、螯合剂、防腐剂、着色剂、矫味剂和甜味剂。
术语“活性成分”是指本发明药物组合物或组合药盒中的活性成分，即化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，抗癌药物，或者，它们所形成的上述组合。
本发明的积极进步效果在于：本发明的化合物对WEE1激酶的抑制活性较佳。
具体实施方式
下面通过实施例的方式进一步说明本发明，但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法，按照常规方法和条件，或按照商品说明书选择。
本发明所有化合物的结构可通过核磁共振( 1H NMR)和/或质谱检测(MS)鉴定。 1H NMR化学位移(δ)以PPM记录(10 -6)。NMR通过Bruker AVANCE-400光谱仪进行。
LC-MS由Agilent 1200HPLC/6120质谱仪测定。
薄层硅胶板是良臣硅源HSGF254或青岛GF254硅胶板。柱层析一般使用烟台黄海200-300目硅胶作为载体。
实施例1
Figure PCTCN2018116352-appb-000047
第一步:
将2-烯丙基-1-[6-(1-羟基-1-甲基–乙基)-2-吡啶基]-6-甲硫基吡唑并[3,4-d]嘧啶-3-酮(270mg，0.75mmol)(如式1A所示的化合物)和4-氯过氧苯甲酸(143mg,0.83mmol)溶解到甲苯(20ml)中，室温搅拌1小时，然后加入N,N-二异丙基乙胺(291mg,2.26mmol)和6-氨基-3,4-二氢-1H-异喹啉-2-羧酸叔丁酯(243mg,0.98mmol)(如式2所示的化合物)，继续室温搅拌16小时，反应液浓缩，经硅胶柱层析(石油醚/乙酸乙酯＝100％到50％)纯化得如式I-1-a所示化合物叔丁基6–[[2-烯丙基-1-[6-(1-羟基-1-甲基–乙基)-2-吡啶基]-3-氧代-吡唑并[3,4-d]嘧啶-6-基]氨基]-3,4-二氢-1H-异喹啉-2-羧酸乙酯(270mg，0.48mmol)。LC-MS:m/z:(M+H) +＝558.3， 1H NMR(400MHz,CDCl 3)δ8.88(s,1H),7.91(t,J＝7.9Hz,1H),7.85 –7.70(m,2H),7.63–7.47(m,1H),7.42(d,J＝7.6Hz,1H),7.37(s,1H),7.11(d,J＝8.3Hz,1H),5.73(dq,J＝10.2,6.1Hz,1H),5.08(d,J＝10.1Hz,1H),4.96(d,J＝17.0Hz,1H),4.79(d,J＝6.2Hz,2H),4.59(s,2H),3.70(d,J＝4.5Hz,2H),2.86(t,J＝5.5Hz,2H),1.62(s,6H),1.53(s,9H)。
第二步：
将叔丁基6-[[2-烯丙基-1-[6-(1-羟基-1-甲基–乙基)-2-吡啶基]-3-氧代-吡唑并[3,4-d]嘧啶-6-基]氨基]-3,4-二氢-1H-异喹啉-2-羧酸乙酯(250mg,0.45mmol)(如式I-1-a所示的化合物)溶于二氯甲烷(10ml)中，加入盐酸的二氧六环溶液(2ml,4M)，室温搅拌16小时，过滤，滤液浓缩干燥得如式I-1所示化合物2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(200mg,0.44mmol)。LC-MS:m/z:(M+H) +＝458.2， 1H NMR(400MHz,DMSO-d 6)δ10.37(s,1H),9.48(s,2H),8.96–8.90(m,1H),8.08(t,J＝7.9Hz,1H),7.80(d,J＝7.8Hz,2H),7.66(d,J＝7.6Hz,1H),7.51(d,J＝8.3Hz,1H),7.19(d,J＝8.4Hz,1H),5.69(qd,J＝11.1,5.7Hz,1H),5.02(d,J＝10.4Hz,1H),4.84(d,J＝17.0Hz,1H),4.72(d,J＝5.6Hz,2H),4.23(s,4H),3.39(d,J＝5.0Hz,2H),3.04(t,J＝6.0Hz,2H),1.49(s,6H)。
实施例2
Figure PCTCN2018116352-appb-000048
将2-烯丙基-1-[6-(1-羟基-1-甲基–乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(40mg,0.087mmol)(如式I-1所示的化合物)溶解到甲醇(5ml)中，然后加入甲醛的水溶液(0.1ml,40％)和三乙酰基硼氢化钠(46mg,0.22mmol)，室温搅拌4小时。反应液浓缩，用二氯甲烷和甲醇的混合液(10/1,20ml)溶解，饱和碳酸氢钠洗两次，有机层经无水硫酸钠干燥后，过滤，浓缩得如式I-2所示的化合物2-烯丙基-1-[6-(1-羟基-1-甲基–乙基)-2-吡啶基]-6-[(2-甲基-3,4-二氢-1H-异喹啉-6-基)氨基]吡唑并[3,4-d]嘧啶-3-酮(40mg,0.085mmol)。LC-MS:m/z:(M+H) +＝472.3, 1H NMR(400MHz,DMSO-d 6)δ10.23(s,1H),8.89(s,1H),8.05(t,J＝7.9Hz,1H),7.80(d,J＝8.0Hz,1H),7.66(m,2H),7.40(d,J＝7.6Hz,1H),7.01(d,J＝8.3Hz,1H),5.75–5.63(m,1H),5.35(s,1H),5.02(d,J＝10.2Hz,1H),4.84(d,J＝17.5Hz,1H),4.72(d,J＝5.8Hz,2H),3.46(s,2H),2.84(t,J＝5.5Hz,2H),2.62(t,J＝5.8Hz,2H),2.36(s,3H),1.49(s,6H)。
实施例5
Figure PCTCN2018116352-appb-000049
将2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(40mg,0.087mmol)(如式I-1所示的化合物)溶解到二氯甲烷(5ml)中，然后加入丙酮(0.1ml，40％)和三乙酰基硼氢化钠(46mg,0.22mmol)，升温至回流并搅拌48小时。反应液浓缩，经硅胶柱层析(二氯甲烷/甲醇＝100％到10％，然后二氯甲烷/甲醇/氨甲醇溶液＝100/10/1.5)纯化得如式I-5所示的化合物2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-[(2-异丙基-3,4-二氢-1H-异喹啉-6-基)氨基]吡唑并[3,4-d]嘧啶-3-酮(30mg,0.06mmol)。LC-MS:m/z:(M+H) +＝496.2, 1H NMR(400MHz,MeOD-d 4)δ8.87(s,1H),8.05(t,J＝7.8Hz,1H),7.86–7.76(m,2H),7.70(d,J＝7.8Hz,1H),7.51(d,J＝7.6Hz,1H),7.18(d,J＝8.5Hz,1H),5.74(dq,J＝11.0,6.2Hz,1H),5.06(d,J＝10.1Hz,1H),4.95(s,1H),4.84(d,J＝6.1Hz,2H),4.26(s,2H),3.58–3.49(m,1H),3.42(t,J＝5.8Hz,2H),3.16(t,J＝5.8Hz,2H),1.60(s,6H),1.42(d,J＝6.6Hz,6H)。
实施例11
Figure PCTCN2018116352-appb-000050
将2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(40mg,0.087mmol)(如式I-1所示的化合物)溶解到二氯甲烷(5ml)和甲醇(5ml)混合溶剂中，然后加入2-溴乙醇(43mg，0.34mmol)和碳酸钾(72mg,0.52mmol)，60℃搅拌16小时。反应液浓缩，经薄层层析硅胶制备板(二氯甲烷:甲醇＝10:1)纯化得如式I-11所示的化合物(18mg,0.036mmol)。收率41％。LC-MS:m/z:(M+H) +＝502.3, 1H NMR(400MHz,MeOD-d 4)δ8.84(s,1H),8.00(t,J＝7.9Hz,1H),7.85–7.79(m,1H),7.70–7.60(m,2H),7.38(dd,J＝8.3,2.0Hz,1H),7.05(d,J＝8.4Hz,1H),5.72(ddt,J＝16.3,10.2,6.1Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.96–4.89(m,1H),4.85(s,2H),3.83(s,2H),3.80(s,2H),2.97(s,4H),2.82(s,2H),1.59(s,6H)。
实施例12
Figure PCTCN2018116352-appb-000051
将2-烯丙基-1-[6-(1-羟基-1-甲基–乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(40mg,0.087mmol)(如式I-1所示的化合物)溶解到N，N-二甲基甲酰胺(5ml)中，然后加入2-溴乙基甲基醚(48mg，0.34mmol)和碳酸钾(72mg,0.52mmol),75℃搅拌16小时。反应液浓缩，经薄层层析硅胶制备板(二氯甲烷:甲醇＝10:1)纯化得如式I-12所示的化合物(8mg,0.016mmol)。收率18％。LC-MS:m/z:(M+H) +＝516.3, 1H NMR(400MHz,MeOD-d 4)δ8.84(s,1H),8.03(t,J＝7.9Hz,1H),7.81(d,J＝7.9Hz,1H),7.68(d,J＝7.7Hz,1H),7.63(s,1H),7.38(d,J＝8.4Hz,1H),7.04(d,J＝8.4Hz,1H),5.80–5.66(m,1H),5.06(d,J＝10.2Hz,1H),4.95(d,J＝1.1Hz,1H),4.83(s,2H),3.75(s,2H),3.68(t,J＝5.5Hz,2H),3.41(s,3H),2.94(dd,J＝12.2,4.8Hz,4H),2.83(t,J＝5.6Hz,2H),1.60(s,6H)。
实施例14
Figure PCTCN2018116352-appb-000052
第一步:
将2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(110mg,0.24mmol)(如式I-1所示的化合物)和N-Boc-甲氨基乙醛(83mg，0.48mmol)(如式3所示的化合物)溶解到甲醇(5ml)中，室温搅拌1小时，然后加入三乙酰氧基硼氢化钠(127mg,0.60mmol)，继续室温搅拌16小时，反应液浓缩得如式I-14-a所示化合物N-[2-[6-[[2-烯丙基-1-[6-(1-羟基-1-甲基–乙基)-2-吡啶基]-3-氧代-吡唑并[3,4-d]嘧啶-6-基]氨基]-3,4-二氢-1H-异喹啉-2-基]乙基]-N-甲基–氨基甲酸叔丁酯(150mg，0.24mmol)。LC-MS:m/z:(M+H) +＝615.4。
第二步：
将N-[2-[6-[[2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-3-氧代-吡唑并[3,4-d]嘧啶 -6-基]氨基]-3,4-二氢-1H-异喹啉-2-基]乙基]-N-甲基–氨基甲酸叔丁酯(140mg，0.23mmol)(如式I-14-a所示的化合物)溶于盐酸的水溶液(6ml，2M)，室温搅拌16小时，加碳酸氢钠饱和水溶液调PH值为7，用二氯甲烷和甲醇的混合溶液(DCM/CH 3OH＝10/1)萃取，有机层经无水硫酸钠干燥，过滤，滤液浓缩干燥得如式I-14所示化合物2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-[[2-[2-(甲基氨基)乙基]-3,4-二氢-1H-异喹啉-6-基]氨基]吡唑并[3,4-d]嘧啶-3-酮(90mg，0.17mmol)。LC-MS:m/z:(M+H) +＝515.3, 1H NMR(400MHz,DMSO-d 6)δ10.26(s,1H),8.90(s,1H),8.05(t,J＝7.9Hz,1H),7.80(d,J＝8.1Hz,1H),7.67(m,2H),7.39(d,J＝8.5Hz,1H),7.02(d,J＝8.4Hz,1H),5.69(dq,J＝11.7,6.1Hz,1H),5.37(s,1H),5.01(d,J＝10.1Hz,1H),4.84(d,J＝17.2Hz,1H),4.72(d,J＝5.6Hz,2H),3.54(s,2H),2.83(t,J＝5.2Hz,2H),2.70(t,J＝6.0Hz,4H),2.57(t,J＝6.3Hz,2H),2.34(s,3H),1.48(s,6H)。
实施例15
Figure PCTCN2018116352-appb-000053
将2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-[[2-[2-(甲基氨基)乙基]-3,4-二氢-1H-异喹啉-6-基]氨基]吡唑并[3,4-d]嘧啶-3-酮(40mg,0.116mmol)(如式I-14所示的化合物)溶解到甲醇(5ml)中，然后加入甲醛的水溶液(0.1ml，40％)和三乙酰氧基硼氢化钠(61mg，0.30mmol)，室温搅拌4小时。反应液浓缩，用二氯甲烷和甲醇的混合液(10/1,20ml)溶解，饱和碳酸氢钠洗两次，有机层经无水硫酸钠干燥，柱层析(硅胶，UV254，DCM/CH 3OH＝100％到10％，然后DCM/CH 3OH/NH 3.CH 3OH＝100/10/1.5)纯化得如式I-15所示化合物2-烯丙基-6-[[2-(2-二甲氨基乙基)-3,4-二氢-1H-异喹啉-6-基]氨基]-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]吡唑并[3,4-d]嘧啶-3-酮(30mg,0.057mmol)。LC-MS:m/z:(M+H) +＝529.2, 1H NMR(400MHz,DMSO-d 6)δ10.35–10.16(m,1H),8.92–8.86(m,1H),8.07–8.01(m,1H),7.82–7.76(m,1H),7.74–7.63(m,2H),7.45–7.37(m,1H),7.05–7.00(m,1H),5.74–5.64(m,1H),5.36(s,1H),5.05–4.98(m,1H),4.88–4.80(m,1H),4.75–4.67(m,2H),3.63–3.58(m,2H),2.87–2.81(m,2H),2.78–2.69(m,4H),2.69–2.63(m,2H),2.44–2.32(m,6H),1.52–1.44(m,6H)。
实施例21
Figure PCTCN2018116352-appb-000054
将2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(40mg,0.087mmol)(如式I-1所示的化合物)溶解到二氯甲烷(5ml)和DMF(1ml)中，然后加入乙酰氯(6.8mg，0.087mmol)和三乙胺(17.7mg，0.175mmol)，室温搅拌16小时。反应液浓缩，用水稀释后，过滤，固体经干燥得如式I-21所示的化合物6-[(2-乙酰基-3,4-二氢-1H-异喹啉-6-基)氨基]-2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]吡唑并[3,4-d]嘧啶-3-酮(40mg,0.085mmol)。LC-MS:m/z:(M+H)+＝500.3, 1H NMR(400MHz,DMSO-d 6)δ10.29(s,1H),8.90(s,1H),8.11–8.02(m,1H),7.82–7.73(m,2H),7.65(d,J＝7.5Hz,1H),7.46(t,J＝8.1Hz,1H),7.15(d,J＝8.2Hz,1H),5.74–5.62(m,1H),5.35(s,1H),5.01(dd,J＝10.3,1.3Hz,1H),4.83(dd,J＝17.3,1.3Hz,1H),4.71(d,J＝7.7Hz,2H),4.61(s,1H),4.56(s,1H),3.68(t,J＝5.8Hz,2H),2.87(t,J＝6.2Hz,1H),2.76(t,J＝6.5Hz,1H),2.11(d,J＝4.5Hz,3H),1.48(s,6H)。
实施例28
Figure PCTCN2018116352-appb-000055
将2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(30mg,0.066mmol)(如式I-1所示的化合物)溶解到N，N-二甲基甲酰胺(5ml)中，然后加入3-溴丙烯(8mg，0.66mmol)和碳酸钾(14mg，0.1mmol)，室温搅拌16小时。反应液浓缩，经薄层层析硅胶制备板(二氯甲烷:甲醇＝10:1)纯化得如式I-28所示的化合物(5mg,0.016mmol)。收率15％。 1H NMR(400MHz,MeOD-d 4)δ8.84(s,1H),8.03(t,J＝7.9Hz,1H),7.81(d,J＝7.9Hz,1H),7.69(d,J＝7.7Hz,2H),7.41(dd,J＝8.3,1.8Hz,1H),7.06(d,J＝8.4Hz,1H),6.10–5.93(m,1H),5.73(ddd,J＝17.0,6.1,4.1Hz,1H),5.42(dd,J＝23.2,5.8Hz,2H),5.05(dd,J＝10.2,1.1Hz,1H),4.98–4.92(m,1H),4.84(d,J＝6.1Hz,2H),3.84(s,2H),3.43(d,J＝6.8Hz,2H),3.02(s,4H),1.60(s,6H).LC-MS:m/z:(M+H) +＝498.3。
实施例37
Figure PCTCN2018116352-appb-000056
第一步:
将2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-甲硫基吡唑并[3,4-d]嘧啶-3-酮(如式1A所示的化合物)(100mg，0.28mmol)和4-氯过氧苯甲酸(53mg，0.31mmol)溶解到甲苯(20ml)中，室温搅拌1小时，然后加入2-氨基-7,8-二氢-5H-1,6-二氮杂萘-6-羧酸叔丁酯(243mg,0.98mmol)，升温至100℃并搅拌16小时，反应液浓缩，经硅胶柱层析(石油醚/乙酸乙酯＝100％到0％)纯化然后经制备液相纯化得如式I-6-a所示化合物叔丁基2-[[2-烯丙基-1-[6-(1-羟基-1-甲基–乙基)-2-吡啶基]-3-氧代-吡唑并[3,4-d]嘧啶-6-基]氨基]-7,8-二氢-5H-1,6-二氮杂萘-6-羧酸乙酯(28mg，0.05mmol)。LC-MS:m/z:(M+H) +＝559.3。
第二步：
将叔丁基2-[[2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-3-氧代-吡唑并[3,4-d]嘧啶-6-基]氨基]-7,8-二氢-5H-1,6-二氮杂萘-6-羧酸乙酯(28mg，0.05mmol)(如式I-37-a所示的化合物)溶于二氯甲烷(10ml)中，加入盐酸的二氧六环溶液(2ml,4M)，室温搅拌16小时,过滤,滤液浓缩干燥得如式I-6所示化合物2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-(5,6,7,8-四氢-1,6-二氮杂萘-2-基氨基)吡唑并[3,4-d]嘧啶-3-酮(200mg，0.44mmol)。 1H NMR(400MHz,MeOD-d 4)δ9.28(s,1H),8.11(t,J＝7.0Hz,2H),7.82(d,J＝7.4Hz,2H),7.43(d,J＝8.9Hz,1H),5.76(dq,J＝11.2,6.5Hz,1H),5.07(d,J＝9.5Hz,1H),4.95(s,1H),4.90(d,J＝8.0Hz,2H),4.50(s,2H),3.74(s,2H),3.49(s,2H),1.59(s,6H).LC-MS:m/z:(M+H) +＝459.2。
实施例44
Figure PCTCN2018116352-appb-000057
第一步：
将6-溴-3,4-二氢萘-2(1H)-酮(1.8g,8mmol)(如式I-44-a所示的化合物)和醋酸铵(6.2g,81mmol)加入到80ml的甲醇中，室温搅拌2h。然后加入氰基硼氢化钠(600mg,0.984mmol)，室温搅拌过夜。反应液减压浓缩后加入30ml水，并用1mol/L的盐酸将pH值调至酸性，每次用30ml的二氯甲烷萃取两次。水相用1mol/L的氢氧化钠溶液将pH值调至碱(pH＝10-11)。每次用40ml的二氯甲烷萃取三次。有机相用30ml饱和食盐水进行洗涤，用无水硫酸钠干燥后浓缩,所得粗品直接用于下一步。得到红棕色液体900mg，收率50％。LC-MS:m/z:(M+H) +＝226。
第二步：
将6-溴-1,2,3,4-四氢萘-2-胺(900mg,3.98mmol)(如式I-44-b所示的化合物)溶解到10ml37％的甲醛和16ml甲酸中,加热回流4h。减压蒸干溶剂，所得粗产物溶于30ml水，然后加入饱和的碳酸氢钠溶液将pH值调至碱性,用120ml二氯甲烷分两次萃取,有机层用无水硫酸钠干燥,浓缩,所得粗品为棕色油状物800mg,直接用于下一步反应。收率79％。LC-MS:m/z:(M+H) +＝254。
第三步：
将6-溴-N,N-二甲基-1,2,3,4-四氢萘-2-胺(600mg,2.36mmol)(如式I-44-c所示的化合物),二苯甲酮亚胺(470mg,2.594mmol),叔丁醇钠(480mg,5mmol)，Pd 2(dba) 3(70mg,0.0765mmol),BINAP(150mg,0.241mmol)加入到30ml甲苯中,在氩气换气三次，然后加热到120度过夜。反应液浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-10％),得到棕色油状物600mg，收率71％。LC-MS:m/z:(M+H) +＝355。
第四步：
将6-((二苯亚甲基)氨基)-N,N-二甲基-1,2,3,4-四氢萘-2-胺(如式I-44-d所示的化合物)(600mg,1.693mmol)溶于30ml甲醇中，然后加入醋酸钠(560mg,6.83mmol)和盐酸羟胺(350mg,5.04mmol)，加热到60度反应3小时。反应液过滤浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-20％),得到棕色固体300mg，收率93％。LC-MS:m/z:(M+H) +＝191。
第五步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(如式1A所示的化合物)(72mg,0.2mmol)在15ml甲苯的溶液中加入间氯过氧苯甲酸(50mg，0.22mmol),所得溶液室温搅拌1h得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(如式1B所示的化合物)的甲苯溶液。在上述所得溶液中加入N，N-二甲基-1,2,3,4-四氢萘-2,6-二胺(如式I-44-e所示 的化合物)(40mg,0.21mmol)和0.5mlN,N-二异丙基乙胺,室温搅拌过夜，然后室温放置16天。减压浓缩，所得粗产物先用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％),然后再用高效液相制备得到如式I-44所示的化合物10mg，白色固体，收率9％。LC-MS:m/z:(M+H) +＝500, 1H NMR(400MHz,MeOD-d 4)δ8.81(s,1H),8.54(s,1H),8.02(t,J＝7.9Hz,1H),7.80(d,J＝8.0Hz,1H),7.69(d,J＝7.7Hz,1H),7.62(s,1H),7.39(d,J＝7.9Hz,1H),7.11(d,J＝8.3Hz,1H),5.73(ddd,J＝17.0,6.0,4.2Hz,1H),5.05(d,J＝9.2Hz,1H),4.94(d,1H),4.83(d,J＝6.0Hz,2H),3.59(s,1H),3.19(d,J＝12.3Hz,1H),3.07–2.87(m,9H),2.35(m,1H),1.92(m,1H),1.60(s,6H)。
实施例49
Figure PCTCN2018116352-appb-000058
将2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(20mg,0.044mmol)(如式I-1所示的化合物)分散到二氯甲烷(5ml)中，然后加入丁炔酸(3.7mg,0.44mmol)、EDCI(17mg,0.088mmol)、4-二甲氨基吡啶(1mg，0.008mmol)，室温搅拌16小时。反应液浓缩，经薄层层析硅胶制备板(二氯甲烷：甲醇＝10：1)纯化得如式I-49所示的化合物(6mg,0.011mmol)。收率26％。LC-MS:m/z:(M+H) +＝524.3, 1H NMR(400MHz,MeOD-d 4)δ8.86(s,1H),8.11–7.98(m,1H),7.82(d,J＝8.1Hz,1H),7.70(s,2H),7.48(d,J＝8.4Hz,1H),7.21–7.08(m,1H),5.74(ddt,J＝16.3,10.2,6.1Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.94(d,J＝1.3Hz,1H),4.92(s,1H),4.84(d,J＝6.1Hz,2H),4.70(s,1H),4.06(t,J＝5.9Hz,1H),3.84(t,J＝6.1Hz,1H),2.92(dt,J＝24.8,5.9Hz,2H),2.11(s,3H),1.60(s,6H)。
实施例54
Figure PCTCN2018116352-appb-000059
将2-烯丙基-1-[6-(1-羟基-1-甲基–乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(40mg,0.087mmol)(如式I-1所示的化合物)溶解到甲醇(6ml)中， 然后加入环丁酮(9.2mg，0.131mmol)和三乙酰基硼氢化钠(37mg，0.175mmol)，室温搅拌4小时。反应液浓缩，用二氯甲烷和甲醇的混合液(10/1,20ml)溶解，饱和碳酸氢钠洗两次，有机层经无水硫酸钠干燥后，过滤，浓缩所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到目标化合物如式I-54所示的化合物(12mg,0.023mmol)，收率27％。LC-MS:m/z:(M+H) +＝512.3, 1H NMR(400MHz,MeOD)δ8.86(s,1H),8.03(t,J＝7.9Hz,1H),7.81(d,J＝7.6Hz,1H),7.75–7.62(m,2H),7.44(dd,J＝8.3,1.9Hz,1H),7.10(d,J＝8.4Hz,1H),5.81–5.65(m,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.92(dd,J＝17.1,1.2Hz,1H),4.83(s,2H),3.80(s,2H),3.29(d,J＝7.8Hz,0H),2.99(dt,J＝11.7,6.1Hz,4H),2.36–2.23(m,1H),2.13(dd,J＝15.4,6.1Hz,1H),1.92–1.80(m,1H)。
实施例55
Figure PCTCN2018116352-appb-000060
将2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-(1,2,3,4-四氢异喹啉-6-基氨基)吡唑并[3,4-D]嘧啶-3-酮(40mg,0.087mmol)(如式I-1所示的化合物)溶解到甲醇(6ml)中，然后加入环丙甲醛(9.2mg，0.131mmol)和三乙酰基硼氢化钠(37mg，0.175mmol)，室温搅拌4小时。反应液浓缩，用二氯甲烷和甲醇的混合液(10/1,20ml)溶解，饱和碳酸氢钠洗两次，有机层经无水硫酸钠干燥后，过滤，浓缩所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到目标化合物如式I-55所示的化合物(14mg,0.023mmol)，收率31％。1H NMR(400MHz,MeOD)δ8.85(s,1H),8.03(t,J＝7.9Hz,1H),7.81(d,J＝7.5Hz,1H),7.75–7.59(m,2H),7.39(dd,J＝8.3,1.9Hz,1H),7.06(d,J＝8.4Hz,1H),5.74(ddt,J＝16.4,10.3,6.1Hz,1H),5.05(dd,J＝10.2,1.2Hz,1H),4.92(dd,J＝17.1,1.3Hz,1H),4.83(s,2H),3.80(s,2H),2.97(d,J＝4.0Hz,4H),2.55(d,J＝6.7Hz,2H),1.70–1.49(m,6H),1.04(dd,J＝13.2,6.4Hz,1H),0.71–0.58(m,2H),0.27(q,J＝4.7Hz,2H).LC-MS:m/z:(M+H) +＝512.3。
实施例56
Figure PCTCN2018116352-appb-000061
第一步：
将6-硝基-1,2,3,4-四氢异喹啉盐酸盐(100mg,0.47mmol)(如式I-55-a所示的化合物)溶于10mL甲醇中,然后加入1-乙氧基-1-三甲硅氧基环丙烷(98mg,0.56mmol)和氰基硼氢化钠(29mg,0.46mmol)，60℃搅拌反应16h。反应结束后减压浓缩，所得粗产物用柱层析法分离纯化(乙酸乙酯:石油醚＝0-15％)，得到目标化合物,56mg，黄色固体，收率46％。 1H NMR(400MHz,CDCl 3)δ8.00(d,J＝7.5Hz,2H),7.21(d,J＝8.5Hz,1H),3.91(s,2H),3.01(s,4H),1.87(s,1H),0.61(d,J＝6.0Hz,4H).LC-MS:m/z:(M+H) +＝219.1。
第二步：
将2-环丙基-6-硝基-1,2,3,4-四氢异喹啉(56mg,0.26mmol)(如式I-55-b所示的化合物)和钯碳(10mg)溶于10ml甲醇中,氢气球下室温室温搅拌反应4h。反应结束后硅藻土过滤，得到黄色固体(48mg,0.26mmol)直接用于下一步，收率100％。LC-MS:m/z:(M+H) +＝189.1。
第三步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(86mg,0.24mmol)(如式1A所示的化合物)在10ml甲醇的溶液中加入间氯过氧苯甲酸(65mg,0.29mmol)，所得溶液室温搅拌3h得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(如式1B所示的化合物)的二氯甲烷溶液。在上述所得溶液中加入2-环丙基-1,2,3,4-四异喹啉-6-胺(48mg,0.26mmol)(如式I-55-c所示的化合物)和0.13ml N,N-二异丙基乙胺，室温搅拌18h。减压浓缩，所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到I-56所示目标化合物12mg，黄色固体，收率10％。LC-MS:m/z:(M+H) +＝498.3, 1H NMR(400MHz,CDCl 3)δ8.88(s,1H),7.91(s,1H),7.81(s,1H),7.65(s,1H),7.52(s,1H),7.39(d,J＝7.8Hz,1H),7.30(s,1H),7.05(d,J＝7.2Hz,1H),5.72(s,1H),5.07(d,J＝9.5Hz,1H),4.96(d,J＝17.8Hz,1H),4.78(s,2H),3.92(s,3H),3.03(d,J＝36.6Hz,4H),1.98(s,1H),1.28(s,6H),0.65(s,4H)。
实施例57
Figure PCTCN2018116352-appb-000062
第一步:
5-硝基茚-2-酮(280mg,1.58mmol)(如式I-57-a所示的化合物)溶解到5ml甲醇中,加入2ml(2M的甲醇溶液)二甲胺，室温搅拌约2小时后加入298mg(4.74mmol)的氰基硼氢化钠，继续室温搅拌16小时，浓缩，用2N的盐酸水溶液溶解，二氯甲烷萃取，水层用2N的氢氧化钠水溶液调节PH＝8，用二氯甲烷萃取，二氯甲烷层用无水硫酸钠干燥后，经过滤，浓缩得如式I-57-b所示化合物N,N-二甲基-5-硝基二氢化茚-2-胺60mg，产率18％，茶色固体。LC-MS:m/z:[M+1] +＝207.1
第二步：
N,N-二甲基-5-硝基二氢化茚-2-胺(60mg,0.29mmol)(如式I-57-b所示的化合物)溶解到5ml甲醇中，加入50mg(0.76mmol)锌粉，然后加入2ml饱和氯化铵水溶液，室温搅拌约2小时后，浓缩，加入5ml 2N盐酸水溶液，用二氯甲烷萃取，水层再用2N的氢氧化铵水溶液调节PH值到8，然后用二氯甲烷萃取，二氯甲烷层经无水硫酸钠干燥，过滤，浓缩得如式I-57-c所示化合物N2，N2-二甲基茚-2,5-二胺50mg，产率97％，茶色固体。LC-MS:m/z:[M+1] +＝177.2
第三步：
2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-甲硫基吡唑并[3,4-d]嘧啶-3-酮(20mg0.056mmol)(如式1A所示的化合物)溶解到10ml二氯甲烷中，加入10.6mg(0.062mmol)间氯过氧苯甲酸，室温搅拌约1小时，然后加入10mg(0.056mmol)N2，N2-二甲基茚-2,5-二胺(如式I-57-c所示的化合物)和14mg(0.11mmol)DIPEA，室温搅拌4天后，反应液用水洗，有机层经无水硫酸钠干燥，浓缩，柱层析(硅胶，UV，石油醚/乙酸乙酯＝100％到40％)纯化得如式I-57所示化合物2-烯丙基-6-[[2-(二甲基氨基)茚满-5-基]氨基]-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]吡唑并[3,4-d]嘧啶-3-酮15mg，产率55％，黄色固体。LC-MS:m/z:[M+1] +＝486.2,1H NMR(400MHz,MeOD)δ8.85(s,1H),8.46(s, 1H),8.03(t,J＝7.9Hz,1H),7.80(d,J＝8.4Hz,1H),7.75(s,1H),7.69(d,J＝7.7Hz,1H),7.49(dd,J＝8.2,1.8Hz,1H),7.23(d,J＝8.2Hz,1H),5.73(ddt,J＝16.3,10.2,6.1Hz,1H),5.05(dd,J＝10.2,1.2Hz,1H),4.92(dd,J＝17.1,1.3Hz,1H),4.83(d,J＝6.1Hz,2H),4.03(p,J＝7.8Hz,1H),3.40(dt,J＝15.8,7.8Hz,2H),3.17(td,J＝15.0,7.5Hz,2H),2.88(s,6H),1.59(s,6H).
实施例58
Figure PCTCN2018116352-appb-000063
第一步:
6-硝基茚-1-酮(1g,5.64mmol)(如式I-58-a所示的化合物)溶解到10ml甲醇中，加入2ml(2M的甲醇溶液)二甲胺，室温搅拌约2小时后加入1.06g(16.9mmol)的氰基硼氢化钠，在微波条件下升温至100摄氏度并搅拌1小时，浓缩，用2N的盐酸水溶液溶解，二氯甲烷萃取，水层用2N的氢氧化钠水溶液调节PH＝8，用二氯甲烷萃取，二氯甲烷层用无水硫酸钠干燥后，经过滤，浓缩得如式I-58-2所示化合物N，N-二甲基-6-硝基二氢化茚-1-胺500mg，产率43％，棕色油状物。LC-MS:m/z:[M+1] +＝207.1。
第二步：
N，N-二甲基-6-硝基二氢化茚-1-胺(500mg,2.42mmol)(如式I-58-b所示的化合物)溶解到30ml甲醇中，加入476mg(7.27mmol)锌粉，然后加入5ml饱和氯化铵水溶液，室温搅拌约2小时后，浓缩，加入5ml 2N盐酸水溶液，用二氯甲烷萃取，水层再用2N的氢氧化铵水溶液调节PH值到8，然后用二氯甲烷萃取，二氯甲烷层经无水硫酸钠干燥，过滤，浓缩得如式I-58-c所示化合物N1，N1-二甲基茚-1,6-二胺420mg，产率100％，黄色油状物。LC-MS:m/z:[M+1] +＝177.2
第三步：
2-烯丙基-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]-6-甲硫基吡唑并[3,4-d]嘧啶-3-酮(60mg,0.17mmol)(如式1A所示的化合物)溶解到20ml二氯甲烷中，加入32mg(0.18mmol)间氯过氧苯甲酸，室温搅拌约1小时，然后加入N1，N1-二甲基茚-1,6-二胺(30mg, 0.17mmol)(如式I-58-c所示的化合物)和(65mg,0.50mmol)DIPEA，室温搅拌4天后，反应液用水洗，有机层经无水硫酸钠干燥，浓缩，经高效液相制备纯化后再经薄层色谱纯化(二氯甲烷/甲醇＝10/1)纯化得如式I-58所示化合物2-烯丙基-6-[[3-(二甲基氨基)茚满-5-基]氨基]-1-[6-(1-羟基-1-甲基-乙基)-2-吡啶基]吡唑并[3,4-d]嘧啶-3-酮4mg，产率5％，黄色固体。LC-MS:m/z:[M+1] +＝486.2,1H NMR(400MHz,MeOD)δ8.88–8.83(m,1H),8.02–7.96(m,1H),7.83–7.78(m,1H),7.76–7.71(m,1H),7.70–7.65(m,1H),7.64–7.59(m,1H),7.28–7.22(m,1H),5.79–5.67(m,1H),5.08–5.02(m,1H),4.96–4.89(m,1H),4.83–4.80(m,2H),4.51–4.44(m,1H),3.06–2.96(m,1H),2.93–2.83(m,1H),2.37(s,6H),2.25(dd,J＝13.8,6.7Hz,2H),1.59(s,6H).
实施例59
Figure PCTCN2018116352-appb-000064
第一步：
将6-溴-3,4-二氢萘-2(1H)-酮(0.7g,3mmol)(如式I-59-a所示的化合物)和醋酸铵(2.4g,31mmol)加入到20ml的甲醇中，室温搅拌2h。然后加入氰基硼氢化钠(230mg,3.77mmol)，室温搅拌过夜。反应液减压浓缩后加入20ml水，并用1mol/L的盐酸将PH值调至酸性，每次用30ml的二氯甲烷萃取两次。水相用2mol/L的氢氧化钠溶液将PH值调至碱(PH＝10-11)。每次用40ml的二氯甲烷萃取三次。有机相用30ml饱和食盐水进行洗涤，用无水硫酸钠干燥后浓缩,所得粗品直接用于下一步。得到红棕色液体300mg，收率40％。LC-MS:m/z:(M+H) +＝226。
第二步：
将6-溴-1,2,3,4-四氢萘-2-胺(300mg,1.33mmol)(如式I-59-b所示的化合物)、0.65mlN,N-二异丙基乙胺和叔丁氧基羰基叔丁基碳酸酯(400mg,1.83mmol),室温搅拌过夜。 减压蒸干溶剂，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-15％),得白色固体400mg。收率92％。LC-MS:m/z:(M+Na) +＝348。
第三步：
将(6-溴-1,2,3,4-四氢萘-2-基)氨基甲酸叔丁酯(600mg,2.36mmol)(如式I-59-c所示的化合物),二苯甲酮亚胺(270mg,1.49mmol),叔丁醇钠(145mg,1.51mmol),Pd 2(dba) 3(30mg,0.033mmol),BINAP(35mg,0.056mmol)加入到20ml甲苯中,在氩气换气三次，然后加热到110度过夜。反应液浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-10％),得到棕色油状物170mg，收率40％。LC-MS:m/z:(M+H) +＝427。
第四步：
将(6–((二苯基亚甲基)氨基)-1,2,3,4-四氢萘-2-基)氨基甲酸叔丁酯(170mg,0.4mmol)(如式I-59-d所示的化合物)溶于20ml甲醇中，然后加入醋酸钠(110mg,1.34mmol)和盐酸羟胺(60mg,0.86mmol)，加热到60度反应过夜。反应液过滤浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-20％),得到无色油状物90mg，收率86％。LC-MS:m/z:(M-55) +＝207。
第五步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(107mg,0.3mmol)(如式1A所示的化合物)在15ml甲苯的溶液中加入间氯过氧苯甲酸(76mg,0.34mmol),所得溶液室温搅拌1h得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮。此溶液直接用于下一步反应。LC-MS:m/z:(M+H) +＝374。
在上述所得溶液中加入(6-氨基-1,2,3,4-四氢萘-2-基)氨基甲酸叔丁酯(90mg,0.34mmol)(如式I-59-e所示的化合物)和1ml N,N-二异丙基乙胺,室温搅拌过夜。减压浓缩，所得粗产物用薄层层析法纯化{甲醇:(二氯甲烷:乙酸乙酯＝2:1)＝1:10)},得到白色固体110mg，收率64％。LC-MS:m/z:(M+H) +＝572。
第六步：
将(6-((2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-3-氧代-2,3-二氢-1H-吡唑[3,4]叔丁基-d]嘧啶-6-基)氨基)-1,2,3,4-四氢-萘-2-基)氨基甲酸(110mg,0.19mmol)(如式I-59-f所示的化合物)溶解到5ml二氯甲烷和2ml甲醇组成的混合溶剂里，加入10ml的4mol/L的盐酸二氧六环，室温搅拌2h。减压浓缩后加入30ml甲醇和二氯甲烷组成的混合溶剂(甲醇:二氯甲烷＝10:1)和10ml饱和的碳酸钠水溶液，室温搅拌20min，有机层干燥浓缩后过柱纯化{甲醇:(二氯甲烷:乙酸乙酯＝2:1)＝0-20％)},得到40mg白色固体，收率44％。 LC-MS:m/z:(M+H) +＝472,1H NMR(400MHz,CDCl3:MeOD＝2:1)δ8.85(d,J＝4.9Hz,1H),7.93(dd,J＝10.3,5.5Hz,1H),7.80(d,J＝8.0Hz,1H),7.57(d,J＝7.7Hz,1H),7.53(s,1H),7.38–7.31(m,1H),7.06(d,J＝8.3Hz,1H),5.70(dq,J＝10.4,6.0Hz,1H),5.05(d,J＝10.2Hz,1H),4.93(d,J＝17.1Hz,1H),4.82(d,J＝5.9Hz,2H),3.28–3.16(m,1H),3.03(dd,J＝15.9,4.6Hz,1H),2.91(dd,J＝7.7,4.8Hz,2H),2.60(dd,J＝15.6,9.6Hz,1H),2.10(d,J＝9.5Hz,1H),1.74–1.63(m,1H),1.61(d,J＝4.8Hz,6H).
实施例60
Figure PCTCN2018116352-appb-000065
将2-烯丙基-6-[(6-氨基-5,6,7,8-四氢萘啶-2-基)胺]-1-[6-(2-羟基丙基-2-基)吡啶-2-基]-1,2-二氢-3H-吡唑并[3,4-D]嘧啶-3-酮(20mg,0.042mmol)(如式I-59所示的化合物)溶解到甲醇(6ml)中，然后加入40％乙醛溶液(1mL)和三乙酰基硼氢化钠(45mg,0.212mmol)，室温搅拌4小时。反应液浓缩，用二氯甲烷和甲醇的混合液(10/1,20ml)溶解，饱和碳酸氢钠洗两次，有机层经无水硫酸钠干燥后，过滤，浓缩所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到目标化合物如式I-60所示的化合物(4mg,0.008mmol)，收率18％。LC-MS:m/z:(M+H) +＝528.3, 1H NMR(400MHz,MeOD)δ8.83(s,1H),8.01(t,J＝7.9Hz,1H),7.81(d,J＝7.8Hz,1H),7.68(d,J＝7.7Hz,1H),7.56(s,1H),7.34(d,J＝8.2Hz,1H),7.06(d,J＝8.3Hz,1H),5.73(ddt,J＝16.3,10.2,6.1Hz,1H),5.10–5.02(m,1H),4.92(dd,J＝17.1,1.2Hz,1H),4.82(s,2H),3.14(d,J＝10.8Hz,0H),2.92(dt,J＝16.3,14.4Hz,1H),2.79(t,J＝12.2Hz,5H),2.17(d,J＝10.2Hz,0H),1.70(dd,J＝11.7,6.5Hz,0H),1.60(s,6H),1.17(t,J＝7.2Hz,6H)。
实施例61
Figure PCTCN2018116352-appb-000066
第一步：
将6-溴-3,4-二氢萘-2(1H)-酮(400mg,1.78mmol)(如式I-61-a所示的化合物)溶于18mL甲醇中,然后加入(1368mg,17.8mmol)乙酸铵，室温搅拌2h后加入(120mg,1.91mmol)氰基硼氢化钠，室温搅拌反应16h。反应液减压浓缩后加入30ml水，并用1mol/L的盐酸将pH值调至酸性，每次用30ml的二氯甲烷萃取两次。水相用1mol/L的氢氧化钠溶液将pH值调至碱(pH＝10-11)。每次用40ml的二氯甲烷萃取三次。有机相用30ml饱和食盐水进行洗涤，用无水硫酸钠干燥后浓缩,所得粗品直接用于下一步。得到红棕色油状物(如式I-61-b所示化合物)(200mg,0.84mmol)，收率50％。LC-MS:m/z:(M+H) +＝226.0，228.0。
第二步：
将6-溴-1,2,3,4-四氢萘-2-胺(200mg,0.84mmol)(如式I-61-b所示的化合物)和氰基硼氢化钠(280mg,4.46mmol)溶于10ml甲醇中,加入0.5mL丙醛，室温室温搅拌反应16h。反应液减压浓缩后加入30ml水，并用1mol/L的盐酸将pH值调至酸性，每次用30ml的二氯甲烷萃取两次。水相用1mol/L的氢氧化钠溶液将pH值调至碱(pH＝10-11)。每次用40ml的二氯甲烷萃取三次。有机相用30ml饱和食盐水进行洗涤，用无水硫酸钠干燥后浓缩,所得粗品直接用于下一步。得到红棕色油状物(190mg,0.61mmol)(如式I-61-c所示化合物)，收率69％。LC-MS:m/z:(M+H) +＝310.1,312.1。
第三步：
将6-溴-N,N-二甲基-1,2,3,4-四氢萘-2-胺(190mg,0.61mmol)(如式I-61-c所示的化合物),二苯甲酮亚胺(122mg,0.67mmol),叔丁醇钠(118mg,1.22mmol)，Pd 2(dba) 3(28mg,0.03mmol),BINAP(38mg,0.06mmol)加入到10ml甲苯中,在氩气换气三次，然后加热到100℃反应18h。反应液浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-10％),得到棕色油状物(220mg,0.54mmol)(如式I-61-d所示化合物)，收率87％。LC-MS:m/z:(M+H) +＝411.3。
第四步：
将6-((二苯亚甲基)氨基)-N,N-二丙基-1,2,3,4-四氢萘-2-胺(220mg,0.54mmol)(如式I-61-d所示的化合物)溶于10ml甲醇中，然后加入醋酸钠三水合物(220mg,1.62mmol)和盐酸羟胺(82mg,1.18mmol)，加热到60度反应5小时。反应液过滤浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-20％),得到棕色油状物(130mg,0.53mmol)(如式I-61-e所示化合物)，收率98％。LC-MS:m/z:(M+H) +＝247.2, 1H NMR(400MHz,CDCl 3)δ6.91(d,J＝8.2Hz,1H),6.54(dd,J＝8.2,2.1Hz,1H),6.46(s,1H),3.62(s,1H),3.24–3.02(m,4H),2.92–2.85(m,2H),2.57(d,J＝9.7Hz,1H),2.13–1.82(m,8H),1.03(t,J＝7.3Hz,6H)。
第五步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(72mg,0.2mmol)(如式1A所示化合物)在15ml甲苯的溶液中加入间氯过氧苯甲酸(50mg，0.22mmol),所得溶液室温搅拌1h得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮的甲苯溶液。在上述所得溶液中加入N，N-二丙基-1,2,3,4-四氢萘-2,6-二胺(65mg,0.27mmol)(如式I-61-e所示化合物)和0.1ml N,N-二异丙基乙胺,室温搅拌18h。减压浓缩，所得粗产物先用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到I-61所示目标化合物(如式I-61所示化合物)45mg，黄色固体，收率40％。LC-MS:m/z:(M+H) +＝556.3, 1H NMR(400MHz,CDCl 3)δ8.87(s,1H),7.90(t,J＝7.8Hz,1H),7.82(d,J＝8.1Hz,1H),7.49(s,1H),7.45(s,1H),7.39(d,J＝7.6Hz,1H),7.27(s,1H),7.09(d,J＝8.3Hz,1H),5.72(ddd,J＝16.4,11.3,5.0Hz,1H),5.07(d,J＝10.2Hz,1H),4.96(d,J＝17.1Hz,1H),4.78(d,J＝6.2Hz,2H),3.91(s,1H),3.06(s,1H),2.87(d,J＝30.3Hz,4H),2.57(s,4H),2.13(s,2H),1.61(s,6H),1.57(s,4H),0.94(t,J＝7.3Hz,6H)。
实施例62
Figure PCTCN2018116352-appb-000067
第一步：
将6-氨基-1,4-二氢萘-1(2H)-1(148.9mmol)(如式I-62-a所示化合物)溶于二氯甲烷(200mL)，向反应液中加入N,N-二异丙基乙胺(446.7mmol)，将反应液冷却至0℃，相反应液中缓慢加入乙酰氯(223.3mmol)，反应液室温下搅拌12小时。将反应液蒸干得粗品，粗品用乙酸乙酯洗涤，过滤，滤饼为目标化合物N-(5-氧-5-,6-,7-,8-四氢萘-2-基)乙酰胺(如式I-62-b所示化合物)(26.5g)，收率:87.6％，灰色固体。LC-MS:m/z:[M+1] +＝204。
第二步：
将N-(5-氧-5-,6-,7-,8-四氢萘-2-基)乙酰胺(25mmol)(如式I-62-b所示化合物)溶于1,1-二甲氧基-N，N-二甲基甲胺(60mL)，将反应液加热至回流，搅拌18小时。将反应液蒸干得粗品，粗品用乙酸乙酯洗涤，过滤，滤饼为目标化合物(E)-N-(6-((二甲氨基)亚甲基)-5-氧代-5-,6-,7-,8-四氢萘-2-基)乙酰胺(如式I-62-c所示化合物)(5.8g,91％)，灰色固体。LC-MS:m/z:[M+1] +＝259。
第三步：
将(E)-N-(6-((二甲氨基)亚甲基)-5-氧代-5-,6-,7-,8-四氢萘-2-基)乙酰胺(3.96mmol)(如式I-62-c所示化合物)溶于甲醇(15mL)，加入钯碳(500mg)和浓盐酸(1mL)，将反应液加热至回流，搅拌24小时。将反应液用饱和碳酸钾水溶液调pH＝9，过滤，滤液用乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，柱层析纯化(二氯甲烷/甲醇＝20/1)的目标化合物6-((二甲氨基)甲基)-5-,6-,7-,8-四氢萘-2-胺(如式I-62-d所示化合物)(150mg,19％)，黄色油状物。LC-MS:m/z:[M+1] +＝205。
第四步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3，4-D]嘧啶-3-酮(0.56mmol)(如式1A所示化合物)溶于1,2-二氯乙烷(10mL)，加入间氯过氧苯甲酸(0.62mmol)，反应液室温下搅拌0.5小时，向反应液中加入6-((二甲氨基)甲基)-5-,6-,7-,8-四氢萘-2-胺(0.56mmol)(如式I-62-d所示化合物)和N,N-二异丙基乙胺(1.68mmol)，将反应液加热至70℃，搅拌16小时。将反应液蒸干得粗品，粗品制备TLC板纯化得目标化合物2-烯丙基-6-((6-((二甲氨基)甲基)-5-,6-,7-,8-四氢萘-2-基)氨基)-1-(3-(2-羟基丙烷-2-基)苯基)-1,2-二氢-3H-吡唑并[3,4-D]嘧啶-3-酮(如式I-62所示化合物)(31mg,10.8％),白色固体。LC-MS:m/z:[M+1] +＝514。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.93–7.81(m,2H),7.47(s,1H),7.40–7.36(m,1H),7.26(dd,J＝8.2,2.2Hz,1H),7.09(d,J＝8.2Hz,1H),5.73(ddt,J＝16.4,10.2,6.2Hz,1H),5.01(ddd,J＝18.3,13.6,1.2Hz,2H),4.78(d,J＝6.2Hz,2H),3.91(s,1H),2.96(dd,J＝16.7,4.8Hz,1H),2.86(dd,J＝7.8,4.3 Hz,2H),2.44(dd,J＝16.2,10.4Hz,1H),2.31(s,8H),2.01(s,2H),1.61(s,6H).
实施例63
Figure PCTCN2018116352-appb-000068
第一步：
将6-溴-3,4-二氢萘-2(1H)-酮(400mg,1.78mmol)(如式I-63-a所示化合物)溶于18mL甲醇中,然后加入乙酸铵(1368mg,17.8mmol)，室温搅拌2h后加入氰基硼氢化钠(120mg,1.91mmol)，室温搅拌反应16h。反应液减压浓缩后加入30ml水，并用1mol/L的盐酸将pH值调至酸性，每次用30ml的二氯甲烷萃取两次。水相用1mol/L的氢氧化钠溶液将pH值调至碱(pH＝10-11)。每次用40ml的二氯甲烷萃取三次。有机相用30ml饱和食盐水进行洗涤，用无水硫酸钠干燥后浓缩,所得粗品直接用于下一步。得到红棕色油状物(如式I-63-2所示化合物)(150mg,0.84mmol)，收率37％。LC-MS:m/z:(M+H) +＝226.0，228.0。
第二步：
将6-溴-1,2,3,4-四氢萘-2-胺(150mg,0.67mmol)(如式I-63-b所示化合物)和氰基硼氢化钠(209mg,3.3mmol)溶于10ml甲醇中,加入0.5mL丙酮，室温室温搅拌反应16h。反应液减压浓缩后加入30ml水，并用1mol/L的盐酸将pH值调至酸性，每次用30ml的二氯甲烷萃取两次。水相用1mol/L的氢氧化钠溶液将pH值调至碱(pH＝10-11)。每次用40ml的二氯甲烷萃取三次。有机相用30ml饱和食盐水进行洗涤，用无水硫酸钠干燥后浓缩,所得粗品直接用于下一步。得到红棕色油状物(170mg,0.55mmol)(如式I-63-c所示化合物)，收率83％。LC-MS:m/z:(M+H) +＝268.1,270.1。
第三步：
将6-溴-N-异丙基-1,2,3,4-四氢萘-2-胺(170mg,0.5mmol)(如式I-63-c所示化合物)和Boc 2O(137mg,0.55mmol)溶于10ml二氯甲烷中,加入0.16mL N,N-二异丙基乙胺，室温至40℃搅拌反应16h。反应结束后减压浓缩，所得粗产物用柱层析法分离纯化(乙酸乙酯:石油醚＝0-10％)得到目标化合物(如式I-63-d所示化合物)176mg，黄色固体，收率76％。 LC-MS:m/z:(M+H) +＝368.1,370.1。
第四步：
将(6-溴-1,2,3,4-四氢萘胺-2-基)(异丙基)碳酸叔丁酯(176mg,0.48mmol)(如式I-63-d所示化合物),二苯甲酮亚胺(94mg,0.52mmol),叔丁醇钠(91mg,0.95mmol)，Pd 2(dba) 3(22mg,0.02mmol),BINAP(30mg,0.05mmol)加入到10ml甲苯中,在氩气换气三次，然后加热到100℃反应18h。反应液浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-10％),得到黄色固体(如式I-63-e所示化合物)(180mg,0.38mmol)，收率81％。LC-MS:m/z:(M+H) +＝469.3。
第五步：
将(6-((二苯亚甲基)氨基)-1,2,3,4-四氢萘胺-2-基)(异丙基)碳酸叔丁酯(180mg,0.38mmol)(如式I-63-e所示化合物)溶于10ml甲醇中，然后加入醋酸钠三水合物(157mg,1.15mmol)和盐酸羟胺(82mg,0.85mmol)，加热到60度反应5小时。反应液过滤浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-20％),得到黄色固体(如式I-63-f所示化合物)(102mg,0.34mmol)，收率87％。 1H NMR(400MHz,CDCl 3)δ6.91(d,J＝8.1Hz,1H),6.59(dd,J＝8.1,2.2Hz,1H),6.55(s,1H),3.15(s,1H),2.95–2.76(m,2H),2.66(d,J＝11.0Hz,1H),2.18(dt,J＝44.1,12.4Hz,2H),1.83(d,J＝10.1Hz,1H),1.50(s,9H),1.26(d,J＝16.4Hz,6H).LC-MS:m/z:(M+H) +＝305.3。
第六步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(如式1A所示化合物)(108mg,0.3mmol)在15ml甲苯的溶液中加入间氯过氧苯甲酸(82mg，0.47mmol),所得溶液室温搅拌1h得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮的甲苯溶液(如式1B所示化合物)。在上述所得溶液中加入(6-氨基-1,2,3,4-四氢萘胺-2-基)(异丙基)碳酸叔丁酯(102mg,0.33mmol)(如式I-63-g所示化合物)和0.16ml N,N-二异丙基乙胺,室温搅拌18h。减压浓缩，所得粗产物先用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到目标化合物(如式I-63-g所示化合物)85mg，黄色固体，收率46％。LC-MS:m/z:(M+H) +＝614.3。
第七步：
将(6-((2-烯丙基-1-(6-(2-羟基异丙基-2-基)吡啶-2-基)-3-酮-2,3-二氢-1H-吡唑并[3,4-d]嘧啶-6-基)氨基)-1,2,3,4-四氢萘胺-2-基)(异丙基)碳酸叔丁酯(85mg,0.3mmol)(如式I-63-g所示化合物)溶于10ml二氯甲烷中，加入4N氯化氢二氧六环溶液0.5mL,室温搅拌4h。减压浓缩，所得粗产物先用水溶解，二氯甲烷萃取。取水层用2N NaOH溶液调至pH＝10，过滤得到I-63所示目标化合物(如式I-63所示化合物)70mg，黄色固体，收率98％。LC- MS:m/z:(M+H) +＝514.3, 1H NMR(400MHz,CDCl 3)δ8.87(s,1H),7.90(t,J＝7.8Hz,1H),7.82(d,J＝8.0Hz,1H),7.47(s,1H),7.39(d,J＝7.6Hz,1H),7.32–7.29(m,1H),7.07(d,J＝8.3Hz,1H),5.84–5.64(m,1H),5.06(d,J＝10.2Hz,1H),4.95(d,J＝17.1Hz,1H),4.78(d,J＝6.2Hz,2H),3.94(s,1H),3.25–2.99(m,3H),2.90(s,2H),2.70–2.56(m,1H),2.12(s,1H),1.61(s,6H),1.16(d,J＝6.1Hz,6H)。
实施例64
Figure PCTCN2018116352-appb-000069
第一步：
将6-溴-3,4-二氢萘-2(1H)-酮(0.5g,2.22mmol)(如式I-64-a所示的化合物)加入到15ml的甲醇中，在冰浴下加入硼氢化钠(100mg,2.65mmol)，室温搅拌1h。反应液减压浓缩后加入10ml饱和的氯化铵水溶液，每次用15ml的乙酸乙酯萃取三次。合并的有机相用无水硫酸钠干燥后浓缩,所得粗品过柱纯化(乙酸乙酯:石油醚＝0-50％)。得到无色液体380mg，收率75％。LC-MS:m/z:(M+Na) +＝249。
第二步：
将粉末状的氢氧化钾(470mg,8.39mmol)和6-溴-1,2,3,4-四氢萘-2-醇(380mg,1.67mmol)(如式I-64-b所示的化合物)加入到7ml无水二甲亚砜中,室温搅拌15min。然后加入碘甲烷(700mg,4.93mmol),室温搅拌过夜。反应液中加入20ml饱和食盐水，二氯甲烷萃取三次(3*20ml)。有机层水洗三遍(3*15ml)，减压蒸干溶剂，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-10％),得无色油状物340mg。收率84％。LC-MS:m/z:(M+Na) +＝263。
第三步：
将6-溴-2-甲氧基-1,2,3,4-四氢化萘(340mg,1.41mmol)(如式I-64-c所示的化合物),二苯甲酮亚胺(300mg,1.66mmol),叔丁醇钠(220mg,2.29mmol),Pd 2(dba) 3(45mg,0.05mmol),BINAP(90mg,0.14mmol)加入到20ml甲苯中,在氩气换气三次，然后加热到110度过夜。反应液浓缩，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-30％),得到棕色油状物450mg，收率93％。1H NMR(400MHz,CDCl3)δ7.77–7.71(m,2H),7.47(t,J＝7.2Hz,1H),7.41(t,J＝7.4Hz,2H),7.33–7.29(m,3H),7.15(dd,J＝7.3,2.2Hz,2H),6.84(d,J＝8.0Hz,1H), 6.54(s,1H),6.45(dd,J＝8.0,2.0Hz,1H),3.60(m,1H),3.42(s,3H),3.00(dd,J＝16.3,4.9Hz,1H),2.78(dt,J＝16.9,5.7Hz,1H),2.65(m,2H),2.04(m,1H),1.80–1.68(m,1H).
第四步：
将N-(6-甲氧基-5,6,7,8-四氢萘-2-基)-1,1-二苯甲酮亚胺(450mg,1.3mmol)(如式I-64-d所示的化合物)溶于20ml甲醇中，然后加入醋酸钠(340mg,4.15mmol)和盐酸羟胺(210mg,3mmol)，加热到60度反应过夜。反应液过滤浓缩，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-30％),得到白色固体220mg，收率94％。LC-MS:m/z:(M+H) +＝178。
第五步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(107mg,0.3mmol)(如式1A所示的化合物)在25ml甲苯的溶液中加入间氯过氧苯甲酸(76mg，0.34mmol),所得溶液室温搅拌1h得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮。此溶液直接用于下一步反应。LC-MS:m/z:(M+H) +＝374。
在上述所得溶液中加入6-甲氧基-5,6,7,8-四氢萘-2-胺(55mg,0.31mmol)(如式I-64-e所示的化合物)和1ml N,N-二异丙基乙胺,室温搅拌过夜。减压浓缩，所得粗产物先过柱纯化{甲醇:(二氯甲烷:乙酸乙酯＝2:1)＝1:15}，然后用薄层层析法分离纯化{甲醇:(二氯甲烷:乙酸乙酯＝2:1)＝0-15％)},得到白色固体25mg，收率17％。LC-MS:m/z:(M+H) +＝487，1H NMR(400MHz,DMSO)δ10.18(s,1H),8.87(s,1H),8.02(t,J＝7.9Hz,1H),7.78(d,J＝8.0Hz,1H),7.64(d,J＝7.7Hz,2H),7.41–7.33(m,1H),7.02(d,J＝8.3Hz,1H),5.75–5.60(m,1H),5.32(s,1H),5.00(dd,J＝10.3,1.2Hz,1H),4.83(dd,J＝17.1,1.3Hz,1H),4.70(d,J＝5.9Hz,2H),3.64(m,1H),3.32(s,3H),2.97(dd,J＝16.4,4.5Hz,1H),2.88–2.59(m,3H),2.08–1.96(m,1H),1.83–1.68(m,1H),1.47(s,6H).。
实施例65
Figure PCTCN2018116352-appb-000070
第一步：
将6-溴-3,4-二氢萘-2(1H)-酮(0.6g,2.66mmol)(如式I-64-a所示的化合物)加入到15ml的甲醇中，在冰浴下加入硼氢化钠(110mg,2.91mmol)，室温搅拌1h。反应液减压浓缩后加入10ml饱和的氯化铵水溶液，每次用15ml的乙酸乙酯萃取三次。合并的有机相用无水硫酸钠干燥后浓缩,所得粗品过柱纯化(乙酸乙酯:石油醚＝0-50％)。得到无色液体460mg，收率75％。LC-MS:m/z:(M-OH) +＝209。
第二步：
将咪唑(330mg,4.85mmol)和6-溴-1,2,3,4-四氢萘-2-醇(440mg,1.94mmol)(如式I-64-b所示的化合物)加入到5ml的N,N-二甲基甲酰胺中,然后加入叔丁基二甲基氯硅烷(360mg,2.39mmol),室温搅拌过夜。反应液中加入30ml乙酸乙酯。有机层水洗两遍(2*15ml)，饱和食盐水洗一遍(15ml),减压蒸干溶剂，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-10％),得无色油状物540mg。收率81％。1H NMR(400MHz,CDCl3)δ7.23–7.18(m,2H),6.91(d,J＝8.0Hz,1H),4.14–4.01(m,1H),2.97–2.83(m,2H),2.80–2.60(m,2H),1.98–1.85(m,1H),1.84–1.68(m,1H),0.92–0.84(m,9H),0.14–0.02(m,6H)。
第三步：
将((6-溴-1,2,3,4-四氢萘-2-基)氧基)(叔丁基)二甲基硅烷(540mg,1.58mmol)(如式I-65-c所示的化合物),二苯甲酮亚胺(330mg,1.82mmol),叔丁醇钠(240mg,2.5mmol),Pd 2(dba) 3(45mg,0.05mmol),BINAP(95mg,0.15mmol)加入到20ml甲苯中,在氩气换气三次，然后加热到110度过夜。反应液浓缩，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-30％),得到棕色油状物600mg，收率85％。
第四步：
将N-[2-[叔丁基(二甲基)甲硅烷基]氧四氢萘-6-基]-1,1-二苯基-甲亚胺(600mg,1.36mmol)(如式I-65-d所示的化合物)溶于30ml甲醇中，然后加入醋酸钠(340mg,4.15mmol)和盐酸羟胺(210mg,3mmol)，加热到60度反应2h。反应液过滤浓缩，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-30％),得到白色固体350mg，收率92％。LC-MS:m/z:(M+H) +＝278。
第五步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(120mg,0.33mmol)(如式1A所示的化合物)在25ml甲苯的溶液中加入间氯过氧苯甲酸(85mg，0.38mmol),所得溶液室温搅拌1h。在上述所得溶液中加入6-((叔丁基二甲基硅烷基)氧基)-5,6,7,8-四氢萘-2-胺(100mg,0.36mmol)(如式I-64-e所示的化合物)和1ml  N,N-二异丙基乙胺,室温搅拌过夜。减压浓缩，所得粗产物先过柱纯化{甲醇:(二氯甲烷:乙酸乙酯＝2:1)＝1:15}，然后用薄层层析法分离纯化{甲醇:(二氯甲烷:乙酸乙酯＝2:1)＝0-15％)},得到白色固体110mg，收率55％。LC-MS:m/z:(M+H) +＝587。
第六步：
将2-烯丙基-6-((6-((叔丁基二甲基硅烷基)氧基)-5,6,7,8-四氢萘-2-基)氨基)-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(100mg,0.17mmol)(如式I-65-f所示的化合物)和1ml四正丁基氟化铵(1mol/L in THF)加入到5ml四氢呋喃中，35度搅拌过夜。减压浓缩，所得粗产物先过柱纯化{甲醇:(二氯甲烷:乙酸乙酯＝2:1)＝0-20％}，然后用高效液相制备得到白色固体28mg，收率34％。LC-MS:m/z:(M+H) +＝473。1H NMR(400MHz,DMSO)δ10.16(s,1H),8.86(s,1H),8.02(t,J＝7.9Hz,1H),7.78(d,J＝7.8Hz,1H),7.64(dd,J＝7.7,0.6Hz,1H),7.60(s,1H),7.36(dd,J＝8.3,1.9Hz,1H),7.00(d,J＝8.3Hz,1H),5.67(ddt,J＝16.2,10.3,5.9Hz,1H),5.32(s,1H),5.00(dd,J＝10.3,1.3Hz,1H),4.83(dd,J＝17.1,1.4Hz,1H),4.76(s,1H),4.70(d,J＝5.9Hz,2H),3.91(s,1H),2.86(ddd,J＝16.6,13.7,5.1Hz,2H),2.79–2.66(m,1H),2.56(dd,J＝16.1,8.1Hz,1H),1.98–1.88(m,1H),1.65(ddd,J＝12.5,9.0,3.4Hz,1H),1.47(s,6H).
实施例66
Figure PCTCN2018116352-appb-000071
第一步:
6-乙酰氨基-1,2,3,4-四氢-1-萘酮(2000mg,9.8406mmol)(如式1-66-a所示的化合物)溶于甲苯(40mL)中，然后加入乙醛酸乙酯(2equiv.,19.681mmol,50mass％)(如式I-66-b所示),硫酸镁(5equiv.,49.203mmol)及对甲基苯磺酸(0.1equiv.,0.98406mmol)。反应加热至120℃搅拌12小时。加水20ml萃灭，用乙酸乙酯萃取2x20ml，合并有机相用盐水洗1x20ml,用无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经正相硅胶柱分离纯化(洗脱液EA/PE＝0％至60％，12CV)得到目标化合物(如式I-66-c所示的化合物)2.0g，黄色固体，收率61％。LC-MS:m/z:(M+H) +＝288.0.
第二步:
将乙基(E)-2-(6-乙酰胺基-1-氧-3,4-二氢萘酮-2(1氢)-亚甲基)乙酸酯(2000mg,6.961 mmol)(如式I-66-c所示的化合物)溶于乙醇(20mL)中，然后加入硫酸溶液(1mL,70mass％)和Pd/C(200mg,10mass％)。反应在氢气氛围下室温搅拌12小时。过滤，并用饱和碳酸氢钠溶液调整滤液pH值至7-8。溶液用乙酸乙酯萃取2x20ml，合并有机相用盐水洗1x20ml,用无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经正相硅胶柱分离纯化(洗脱液EA/PE＝8％至60％，12CV)得到目标化合物(如式I-66-d所示的化合物)0.7g,黄色固体，收率36％。1H NMR(400MHz,MeOD)δ7.27(s,1H),7.23(dd,J＝8.2,2.2Hz,1H),6.98(d,J＝8.2Hz,1H),4.11(t,J＝7.1Hz,2H),2.87(d,J＝4.5Hz,1H),2.81(dd,J＝8.2,4.3Hz,2H),2.44(dd,J＝15.8,10.1Hz,1H),2.38(d,J＝7.1Hz,2H),2.20(d,J＝7.8Hz,1H),2.11(s,3H),2.01–1.90(m,1H),1.47(dd,J＝12.8,10.8Hz,1H),1.29(t,J＝5.1Hz,3H).
第三步:
将乙基-2-(6-乙酰胺-1,2,3,4-二氢萘-2-基)乙酸酯(700mg,2.436mmol)(如式I-66-d所示的化合物)溶于乙醇(20mL)溶液中，然后加入硫酸溶液(2mL,70mass％)。反应加热至回流并搅拌12小时。用乙酸乙酯萃取2x20ml，合并有机相用盐水洗1x20ml，用无水硫酸钠干燥，过滤，浓缩得到目标化合物(如式I-66-e所示的化合物)0.56g，棕色油状物，收率99％。 1H NMR(400MHz,MeOD)δ6.79(d,J＝8.0Hz,1H),6.57–6.44(m,2H),4.21–4.11(m,2H),2.80–2.66(m,3H),2.44–2.27(m,3H),2.16(dddd,J＝14.9,10.4,4.7,2.9Hz,1H),1.96–1.86(m,1H),1.49–1.37(m,1H),1.35–1.21(m,3H).
第四步:
2-烯丙基-1-[6-(1-羟-1-甲基-乙基)-2-吡啶]-6-甲硫-吡唑[3,4-d]嘧啶-3-酮(70mg,0.1959mmol)(如式1A所示的化合物)溶于二氯乙烷(2mL)，然后加入mCPBA(1.3equiv.,0.2546mmol,77mass％)。反应在室温下搅拌2小时。之后，加入DIPEA(3equiv.,0.5876mmol)及乙基2-(6-胺-1,2,3,4-四氢萘-2-基)乙酸酯(如式I-66-e所示的化合物)(3equiv.,0.5876mmol,)。反应在室温下搅拌12小时。加饱和亚硫酸氢钠20ml萃灭，用二氯甲烷萃取2x20ml，合并有机相用盐水洗1x20ml，用无水硫酸钠干燥，过滤，浓缩得到粗产品。粗产品经Pre-HPLC分离纯化(洗脱液乙腈/水(甲酸0.1％)＝30％至60％)得到目标化合物(如式I-66所示的化合物)25mg，白色固体，收率23.5％。1H NMR(400MHz,DMSO)δ10.19(s,1H),8.87(s,1H),8.03(t,J＝7.9Hz,1H),7.78(d,J＝8.0Hz,1H),7.63(d,J＝7.7Hz,2H),7.36(d,J＝8.1Hz,1H),7.00(d,J＝8.4Hz,1H),5.67(dd,J＝17.1,10.3Hz,1H),5.33(s,1H),5.00(dd,J＝10.3,1.3Hz,1H),4.83(dd,J＝17.1,1.3Hz,1H),4.70(d,J＝5.8Hz,2H),4.11(q,J＝7.1Hz,2H),2.80(dd,J＝16.0,4.2Hz,3H),2.44-2.38(m,3H),2.11(s,1H),1.90(s,1H),1.47(s,6H),1.45-1.35(m,1H)1.22(t,J＝7.1Hz,3H).LC-MS:m/z:(M+H) +＝543。
实施例67
Figure PCTCN2018116352-appb-000072
将2-(6-((2-烯丙基-1-(6-(2-羟丙烷-2-基)吡啶-2-基)-3-氧-2,3-二氢-1H-吡唑[3,4-d]嘧啶-6-基)胺)-1,2,3,4-四氢萘-2-基)乙酸酯(520mg,0.9583mmol)(如式I-66所示的化合物)溶于甲醇(5ml)与四氢呋喃(5ml)混合溶剂中，然后加氢氧化锂水溶液(1mol/L,5ml)。反应在加热至50°50℃搅拌2小时。反应用1N盐酸萃灭并使反应液pH值调至6-7，在此过程中大量白色固体析出，过滤得到白色固体，并用石油醚5ml淋洗2遍得产品。该产品经Pre-HPLC进一步精制(条件为乙腈/水(0.1％甲酸)＝30％-60％12CV)得到目标化合物(如式I-67所示的化合物)400mg,白色固体，收率81.1％。1H NMR(400MHz,DMSO)δ10.21(s,1H),8.87(s,1H),8.03(t,J＝7.9Hz,1H),7.78(d,J＝7.9Hz,0H),7.64(d,J＝7.5Hz,2H),7.35(d,J＝7.9Hz,1H),7.01(d,J＝8.4Hz,1H),5.67(dd,J＝17.1,10.3Hz,1H),5.34(s,1H),5.00(d,J＝10.2Hz,1H),4.82(d,J＝17.1Hz,1H),4.70(d,J＝5.9Hz,1H),2.81(dd,J＝21.9,4.6Hz,3H),2.39(dd,J＝16.6,10.4Hz,1H),2.29(d,J＝7.0Hz,2H),2.08(s,1H),1.92(s,1H),1.58–1.32(m,7H).LC-MS:m/z:(M+H) +＝515。
实施例68
Figure PCTCN2018116352-appb-000073
将乙基2-(6-((2-烯丙基-1-(6-(2-羟丙烷-2-基)吡啶-2-基)-3-氧-2,3-二氢-1H-吡唑[3,4-d]嘧啶-6-基)胺)-1,2,3,4-四氢萘-2-基)乙酸(40mg,0.07773mmol)(如式I-67所示的化合物)溶于DMF(2ml)中，然后加入HATU(1equiv.,0.07773mmol)和DIPEA(2equiv.,0.1555mmol)，最后加入乙胺(2equive.,0.1555mmol)。反应在室温下搅拌12小时。加水20ml萃灭，并用乙酸乙酯20ml萃取两遍。有机层用盐水20ml洗两遍，用硫酸钠干燥，过滤，浓缩得到粗产口。该粗产品经Pre-HPLC进一步精制(条件为乙腈/水(0.1％甲酸)＝30％-60％12CV)得到目标(如式I-68所示的化合物)18mg,白色固体,收率41.5％)。NMR(400MHz,DMSO)δ10.20(s,1H),8.87(s,1H),8.03(t,J＝7.9Hz,0H),7.85(t,J＝5.3Hz,1H),7.78(d,J＝7.9Hz,1H),7.63(d,J＝7.5Hz,2H),7.35(d,J＝8.5Hz,1H),7.00(d,J＝8.4Hz,1H),5.67(ddd,J＝23.0,10.3,5.9Hz,1H),5.34(s,1H),5.00(d,J＝10.3Hz,1H),4.90–4.76(m,1H), 4.70(d,J＝5.8Hz,2H),3.16–3.04(m,2H),2.74(dd,J＝23.4,14.8Hz,3H),2.43–2.30(m,1H),2.10(d,J＝12.8Hz,2H),1.88(d,J＝12.7Hz,1H),1.47(s,6H),1.38(s,1H),1.04(t,J＝7.2Hz,3GH).LC-MS:m/z:(M+H) +＝542。
实施例69
Figure PCTCN2018116352-appb-000074
采用同上化合物乙基2-(6-((2-烯丙基-1-(6-(2-羟丙烷-2-基)吡啶-2-基)-3-氧-2,3-二氢-1H-吡唑[3,4-d]嘧啶-6-基)胺)-1,2,3,4-四氢萘-2-基)乙酰胺(如式I-67所示的化合物)相同的方法制得目标化合物18mg，白色固体，收率41.5％。1H NMR(400MHz,DMSO)δ10.19(s,1H),8.91–8.84(m,1H),8.03(t,J＝7.9Hz,1H),7.87(s,1H),7.78(d,J＝7.9Hz,1H),7.64(d,J＝7.7Hz,2H),7.35(d,J＝9.6Hz,1H),6.99(d,J＝8.3Hz,1H),5.67(dd,J＝16.9,10.2Hz,1H),5.37–5.32(m,1H),5.00(d,J＝11.4Hz,1H),4.82(d,J＝17.2Hz,1H),4.73–4.65(m,2H),3.42(dd,J＝11.8,6.1Hz,2H),3.16(d,J＝5.7Hz,2H),2.81–2.67(m,3H),2.42–2.28(m,3H),2.14(s,2H),2.14-2.05(m,1H),1.87(s,1H),1.44(t,J＝18.7Hz,6H),1.45-1.30(m,1H).LC-MS:m/z:(M+H) +＝558。
实施例70
Figure PCTCN2018116352-appb-000075
采用同上化合物乙基2-(6-((2-烯丙基-1-(6-(2-羟丙烷-2-基)吡啶-2-基)-3-氧-2,3-二氢-1H-吡唑[3,4-d]嘧啶-6-基)胺)-1,2,3,4-四氢萘-2-基)乙酰胺(如式I-67所示的化合物)相同的方法制得目标化合物(如式I-70所示的化合物)20mg，白色固体，收率46.7％。1H NMR(400MHz,DMSO)δ10.20(s,1H),8.87(s,1H),8.03(t,J＝7.9Hz,1H),7.93(d,J＝3.8Hz,1H),7.78(d,J＝8.0Hz,1H),7.64(d,J＝7.6Hz,2H),7.35(d,J＝8.1Hz,1H),7.00(d,J＝8.1Hz,1H),5.73–5.62(m,1H),5.34(s,1H),5.00(d,J＝10.3Hz,1H),4.82(d,J＝18.6Hz,1H),4.70(d,J＝5.9Hz,2H),2.76(s,3H),2.69–2.61(m,1H),2.32(d,J＝10.5Hz,3H),2.2-2.09(m,1H),2.09(s,2H),1.85(s,1H),1.47(s,6H),1.37(s,1H),0.62(dd,J＝7.0,2.1Hz,2H),0.40(dd,J＝8.4,5.8Hz,2H).LC-MS:m/z:(M+H) +＝554。
实施例71
Figure PCTCN2018116352-appb-000076
采用同上化合物乙基2-(6-((2-烯丙基-1-(6-(2-羟丙烷-2-基)吡啶-2-基)-3-氧-2,3-二氢-1H-吡唑[3,4-d]嘧啶-6-基)胺)-1,2,3,4-四氢萘-2-基)乙酰胺(如式I-67所示的化合物)相同的方法制得目标化合物(如式I-71所示)15mg，白色固体，收率35.0％。1H NMR(400MHz,DMSO)δ10.20(s,1H),8.87(s,1H),8.33(s,1H),8.03(t,J＝7.9Hz,1H),7.78(d,J＝8.1Hz,1H),7.64(d,J＝7.6Hz,2H),7.35(d,J＝8.2Hz,1H),6.99(d,J＝8.6Hz,1H),5.67(dd,J＝16.9,10.4Hz,1H),5.33(s,1H),5.00(d,J＝10.3Hz,1H),4.83(d,J＝17.1Hz,1H),4.70(d,J＝5.4Hz,2H),3.89(d,J＝5.2Hz,2H),3.12(t,J＝2.5Hz,1H),2.82–2.66(m,3H),2.42–2.29(m,3H),2.2-2.1(m,3H),1.87(s,1H),1.43(s,6H),1.45-1.31(m,1H).LC-MS:m/z:(M+H) +＝552。
实施例72
Figure PCTCN2018116352-appb-000077
采用同上化合物乙基2-(6-((2-烯丙基-1-(6-(2-羟丙烷-2-基)吡啶-2-基)-3-氧-2,3-二氢-1H-吡唑[3,4-d]嘧啶-6-基)胺)-1,2,3,4-四氢萘-2-基)乙酰胺(如式I-67所示的化合物)相同的方法制得目标化合物15mg，白色固体，收率31.1％。1H NMR(400MHz,DMSO)δ10.20(s,1H),8.87(s,1H),8.02(t,J＝7.9Hz,1H),7.78(d,J＝7.9Hz,1H),7.63(d,J＝7.7Hz,2H),7.35(d,J＝8.4Hz,1H),6.99(d,J＝8.4Hz,1H),5.75–5.59(m,1H),5.34(s,1H),5.00(d,J＝10.4Hz,1H),4.82(d,J＝17.0Hz,1H),4.70(d,J＝5.6Hz,2H),4.33(s,4H),3.41(d,J＝5.8Hz,4H),2.79(d,J＝17.1Hz,3H),2.44–2.31(m,3H),2.08(s,1H),1.89(s,1H),1.85–1.65(m,4H),1.47(s,6H),1.45-1.35(m,1H)..LC-MS:m/z:(M+H) +＝624。
实施例73
Figure PCTCN2018116352-appb-000078
采用同上化合物乙基2-(6-((2-烯丙基-1-(6-(2-羟丙烷-2-基)吡啶-2-基)-3-氧-2,3-二氢-1H-吡唑[3,4-d]嘧啶-6-基)胺)-1,2,3,4-四氢萘-2-基)乙酰胺(如式I-67所示的化合物)相同的方法制得目标(如式I-73所示的化合物)化合物15mg，白色固体，收率31.2％。1H NMR(400MHz,DMSO)δ10.20(s,1H),8.87(s,1H),8.03(t,J＝7.9Hz,1H),7.78(d,J＝8.2Hz,1H),7.63(d,J＝7.6Hz,2H),7.35(d,J＝8.3Hz,1H),7.00(d,J＝8.4Hz,1H),5.73–5.62(m,1H),5.34(s,1H),5.00(d,J＝10.7Hz,1H),4.82(d,J＝16.9Hz,1H),4.70(d,J＝5.8Hz,2H),3.60(s,4H),2.89–2.72(m,3H),2.46–2.33(m,3H),2.13(s,1H),1.97(d,J＝32.9Hz,3H),1.47(s,6H),1.45-1.35(m,1H).LC-MS:m/z:(M+H) +＝618。
实施例74
Figure PCTCN2018116352-appb-000079
第一步:
将6-溴-3,4-二氢萘-2(1H)-酮(855mg,3.8mmol)(如式I-74-a所示的化合物)和(400mg,5.6mmol)吡咯烷溶于20mL二氯甲烷中，然后加入(1.6g,7.6mmol)醋酸硼氢化钠，65℃封管搅拌过夜。用5ml水淬灭,依次用饱和的碳酸钠水溶液和饱和的食盐水洗涤,无水硫酸钠干燥后减压浓缩得粗品，将粗品溶于20ml乙酸乙酯中,滴加4M盐酸二氧六环溶液直至无固体从乙酸乙酯中析出。过滤得到灰白色固体1g，收率:83％。LC-MS:m/z:[M+1] +＝280。
第二步:
将1-(6-溴-1,2,3,4-四氢萘-2-基)吡咯烷盐酸盐(1g,3.16mmol)(如式I-74-b所示的化合物),二苯甲酮亚胺(620mg,3.4mmol),叔丁醇钠(450mg,4.69mmol),Pd 2(dba) 3(100mg,0.11mmol),BINAP(150mg,0.241mmol)加入到20ml甲苯中,在氩气换气三次，然后加热到 110度过夜。反应液浓缩，所得粗产物过柱纯化(7M氨甲醇:二氯甲烷＝0-20％),得到棕色油状物1g，收率83％。LC-MS:m/z:(M+H) +＝381。
第三步:
将1,1-二苯基-N-(6-(吡咯烷-1-基)-5,6,7,8-四氢萘-2-基)甲亚胺(1g,2.63mmol)(如式I-74-c所示的化合物)溶于30ml甲醇中，然后加入醋酸钠(0.7g,8.5mmol)和盐酸羟胺(370mg,5.32mmol)，加热到60度反应过夜。反应液过滤浓缩，所得粗产物过柱纯化(7M氨甲醇:二氯甲烷＝0-20％),得到棕色固体220mg，收率38％。LC-MS:m/z:(M+H) +＝217。
第四步:
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(120mg,0.336mmol)(如式1A所示的化合物)在15ml甲苯的溶液中加入间氯过氧苯甲酸(82mg,0.367mmol),所得溶液室温搅拌2h得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮。此溶液直接用于下一步反应。
在10ml二氯甲烷中加入6-(吡咯烷-1-基)-5,6,7,8-四氢萘-2-胺(100mg,0.46mmol)(如式I-74-d所示的化合物)和0.5mlN,N-二异丙基乙胺,搅拌至溶液澄清,然后加入到上述所得的甲苯溶液中,室温搅拌40h。减压浓缩，所得粗产物先用薄层层析法分离纯化{7M氨甲醇:(二氯甲烷:乙酸乙酯＝5:1)＝1:12},然后再用高效液相制备得到白色固体16mg，收率7％。LC-MS:m/z:(M+H) +＝526， 1H NMR(400MHz,MeOD)δ8.85(s,1H),8.40(s,2H),8.14(s,1H),7.92(t,J＝7.7Hz,1H),7.77(d,J＝8.0Hz,1H),7.54–7.32(m,3H),7.08(d,J＝7.9Hz,1H),5.81–5.62(m,1H),5.07(d,J＝10.0Hz,1H),4.95(d,J＝16.9Hz,1H),4.77(d,J＝5.5Hz,2H),3.37(m,5H),3.19(d,J＝7.6Hz,2H),2.95(m,2H),2.37(s,1H),2.13(s,5H),1.62(s,6H).
实施例75
Figure PCTCN2018116352-appb-000080
第一步:
将6-溴-3,4-二氢萘-2(1H)-酮(900mg,4mmol)(如式I-75-a所示的化合物)、盐酸氮杂环 丁烷(750mg,8mmol)和20ml水加入到60mL甲醇中，然后加入(1.31g,16mmol)乙酸钠,氮气保护下室温搅拌1h。
将(1.5g,16mmol)乙酸和(500mg,8.2mmol)氰基硼氢化钠加入到上述反应物中,氮气保护下室温搅拌过夜。后减压浓缩，加入20ml饱和的碳酸钠水溶液,用二氯甲烷萃取三次(3*30ml),有机相无水硫酸钠干燥后减压浓缩得粗品，粗品过柱纯化{7M氨甲醇:(二氯甲烷:EA＝2:1)＝0-15％}，得到棕色油状物700mg收率：65％。LC-MS:m/z:[M+1] +＝266。
第二步：
将1-(6-溴-1,2,3,4-四氢萘-2-基)氮杂环丁烷(0.7g,2.63mmol)(如式I-75-b所示的化合物),二苯甲酮亚胺(530mg,2.92mmol),叔丁醇钠(410mg,4.27mmol),Pd 2(dba) 3(80mg,0.087mmol),BINAP(165mg,0.265mmol)加入到35ml甲苯中,用氩气换气三次，然后加热到110度过夜。反应液浓缩，所得粗产物过柱纯化{7M氨甲醇:(二氯甲烷:EA＝2:1)＝0-10％},得到棕色油状物0.85g，收率88％。LC-MS:m/z:(M+H) +＝367。
第三步：
将1,1-二苯基-N-(6-(氮杂环丁烷-1-基)-5,6,7,8-四氢萘-2-基)甲亚胺(1g,2.53mmol)(如式I-75-c所示的化合物)溶于40ml甲醇中，然后加入醋酸钠(0.61g,7.44mmol)和盐酸羟胺(340mg,4.89mmol)，加热到60度反应过夜。反应液过滤浓缩，所得粗产物过柱纯化(7M氨甲醇:二氯甲烷＝0-10％),得到棕色固体450mg，收率95％。LC-MS:m/z:(M+H) +＝203。
第四步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(150mg,0.42mmol)(如式1A所示的化合物)在25ml甲苯的溶液中加入间氯过氧苯甲酸(110mg,0.49mmol),所得溶液室温搅拌2h得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮。
将上述反应液浓缩后加入6-(氮杂环丁烷-1-基)-5,6,7,8-四氢萘-2-胺(100mg,0.49mmol)(如式I-75-d所示的化合物),0.2ml三氟乙酸和5ml二甲基亚砜，60度搅拌24h。
往上述反应液中加入10ml饱和的碳酸钠水溶液和25ml水，用二氯甲烷萃取三次(3*20ml),合并有机相，分别用20ml水和20ml饱和的氯化钠溶液洗涤，无水硫酸钠干燥后浓缩得粗品，所得粗产物先过柱纯化{3M氨甲醇:(二氯甲烷:乙酸乙酯＝1:1)＝0-15％},然后再用高效液相制备得到棕色固体100mg，收率39％。LC-MS:m/z:(M+H) +＝512，1H NMR(400MHz,CDCl3)δ8.84(s,1H),8.51(s,1H),8.03(s,1H),7.89(t,J＝7.9Hz,1H),7.76(d,J＝7.6Hz,1H),7.44(s,1H),7.41(d,J＝7.6Hz,1H),7.32(dd,J＝8.3,2.1Hz,1H),7.03(d,J＝8.3Hz,1H),5.71(ddt,J＝16.4,10.2,6.2Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.94(dd, J＝17.1,1.2Hz,1H),4.76(d,J＝6.2Hz,2H),4.01(t,J＝7.8Hz,4H),3.19–3.06(m,1H),3.06–2.75(m,4H),2.48(p,J＝7.5Hz,2H),2.13(d,J＝10.0Hz,1H),1.93–1.75(m,1H),1.61(s,6H).
实施例76
Figure PCTCN2018116352-appb-000081
第一步：
将6-溴-3,4-二氢萘-2(1H)-酮(1g,4.44mmol)(如式I-76-a所示的化合物),哌啶(760mg,8.93mmol)和对甲苯磺酸(90mg,0.52mmol)加入到40mL甲苯中，反应烧瓶上固定一个分水器，155℃搅拌回流过夜。
将反应中的溶剂甲苯减压蒸除后加入40ml甲醇,在冰浴下缓慢加入(0.85g,23mmol)硼氢化钠，移除冰浴室温搅拌2h。减压浓缩，加入40ml乙酸乙酯和30ml 1mol/L的盐酸，有机层用1mol/L的盐酸洗涤两次(2*20ml),用5mol/L的氢氧化钠将合并后的酸性溶液碱化,二氯甲烷萃取三次(3*30ml),有机相无水硫酸钠干燥后减压浓缩得粗品900mg棕色油状物，粗品直接用于下一步，收率：70％。LC-MS:m/z:[M+1] +＝294。
第二步：
将1-(6-溴-1,2,3,4-四氢萘-2-基)哌啶(0.9g,3.06mmol)(如式I-76-b所示的化合物),二苯甲酮亚胺(620mg,3.42mmol),叔丁醇钠(470mg,4.89mmol),Pd 2(dba) 3(90mg,0.1mmol),BINAP(190mg,0.3mmol)加入到35ml甲苯中,用氩气换气三次，然后加热到110度过夜。反应液浓缩，所得粗产物过柱纯化(7M氨甲醇:二氯甲烷＝0-10％),得到棕色油状物1g，收率82.8％。LC-MS:m/z:(M+H) +＝395。
第三步：
将1,1-二苯基-N-(6-(哌啶-1-基)-5,6,7,8-四氢萘-2-基)甲亚胺(1g,2.53mmol)(如式I-76-c所示的化合物)溶于40ml甲醇中，然后加入醋酸钠(1g,12.2mmol)和盐酸羟胺(360mg,5.18mmol)，加热到60度反应过夜。反应液过滤浓缩，所得粗产物过柱纯化(7M氨甲醇:二氯甲烷＝0-20％),得到棕色固体500mg，收率90％。LC-MS:m/z:(M+H) +＝231。
第四步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(179mg,0.5mmol)(如式1A所示的化合物)在35ml甲苯的溶液中加入间氯过氧苯甲酸(122mg,0.546mmol),所得溶液室温搅拌2h得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮。
将上述反应液浓缩后加入6-(哌啶-1-基)-5,6,7,8-四氢萘-2-胺(130mg,0.564mmol)(如式I-76-d所示的化合物),0.2ml三氟乙酸和5ml二甲基亚砜，60度搅拌24h。往上述反应液中加入10ml饱和的碳酸钠水溶液和25ml水，用二氯甲烷萃取三次(3*20ml),合并有机相，分别用20ml水和20ml饱和的氯化钠溶液洗涤，无水硫酸钠干燥后浓缩得粗品，所得粗产物先过柱纯化{3M氨甲醇:(二氯甲烷:乙酸乙酯＝1:1)＝0-15％},然后再用高效液相制备得到棕色固体130mg，收率41％。LC-MS:m/z:(M+H) +＝540， 1H NMR(400MHz,CDCl 3)δ8.84(s,1H),8.56(s,1H),7.96(s,1H),7.90(t,J＝7.9Hz,1H),7.77(d,J＝8.0Hz,1H),7.48(s,1H),7.42(d,J＝7.6Hz,1H),7.31(dd,J＝8.4,2.0Hz,1H),7.06(d,J＝8.3Hz,1H),5.71(ddt,J＝16.4,10.2,6.2Hz,1H),5.11–5.02(dd,J＝10.2,1.1Hz,1H),4.94(dd,J＝17.1,1.1Hz,1H),4.77(d,J＝6.1Hz,2H),3.54(m,1H),3.04(m,8H),2.41(d,J＝11.9Hz,1H),1.99(s,4H),1.87(m,1H),1.63(d,8H).
实施例82
Figure PCTCN2018116352-appb-000082
第一步：
将(E)-N-(6-((二甲氨基)亚甲基)-5-氧代-5-，6-，7-，8-四氢萘-2-基)乙酰胺(4.6mmol)(如式I-82-a所示的化合物)溶于乙醇(20mL)，向反应液中加入哌啶(14mmol)，将反应液加热至回流，反应液搅拌16小时。将反应液蒸干得粗品，粗品用乙酸乙酯洗涤，过滤，滤饼为目标化合物(E)-N-(5-氧代-6-(哌啶-1-亚甲基)-5-，6-，7-，8-四氢萘-2-基)乙酰胺(950mg，69％)，灰色固体。1H NMR(400MHz,CDCl3)δ7.98(d,J＝8.4Hz,1H),7.73(s,1H),7.65(d,J＝29.8Hz,2H),7.16(d,J＝8.3Hz,1H),3.47(s,4H),2.90-2.76(m,4H),2.21(s,3H),1.67(s,6H).
第二步：
将(E)-N-(5-氧代-6-(哌啶-1-亚甲基)-5-，6-，7-，8-四氢萘-2-基)乙酰胺(3.18mmol)(如式I-82-b所示的化合物)溶于无水甲醇(20mL)，向反应液中加入Pd/C(300mg)和浓硫酸(0.5mL)，将反应液在氢气中加热至回流，搅拌18小时。用饱和碳酸钠溶液将反应液调pH＝9，过滤去掉Pd/C，将反应液蒸干，用水和乙酸乙酯分层，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，粗品将反应液蒸干得粗品，粗品用乙酸乙酯洗涤，过滤，柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)得目标化合物6-(哌啶-1-甲基)-5-，6-，7-，8-四氢萘-2-胺(250mg，32.1％)，黄色油状物。LC-MS:m/z:[M+1] +＝245。
第三步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3，4-D]嘧啶-3-酮(0.56mmol)(如式1A所示的化合物)溶于甲苯(15mL)，加入间氯过氧苯甲酸(0.62mmol)，反应液室温下搅拌0.5小时，将反应液蒸干，所得亚砜中间体溶于二甲亚砜(10mL)，加入6-(哌啶-1-甲基)-5-,6-,7-,8-四氢萘-2-胺(0.67mmol)(如式I-82-c所示的化合物)和三氟乙酸(0.5mL)，将反应液加热至60℃下搅拌16小时。反应液用饱和碳酸钠溶液调pH＝9，加入水(50mL)乙酸乙酯(50mL)，分层，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，柱层析纯化(二氯甲烷/甲醇＝20/1)的目标化合物2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-((6-(哌啶-1-甲基)-5,6,7,8-四氢萘-2-基)氨基)-1,2-二氢3H-吡唑[3,4-d]嘧啶-3-酮(182.4mg,58.9％)，灰色固体。LC-MS:m/z:[M+1] +＝554。1H NMR(400MHz,CDCl3)δ8.86(s,1H),7.95-7.70(m,3H),7.46(s,1H),7.41-7.35(m,1H),7.24(dd,J＝8.2,2.1Hz,1H),7.08(d,J＝8.3Hz,1H),5.72(dd,J＝17.0,10.3Hz,1H),5.06(dd,J＝10.2,1.0Hz,1H),4.95(dd,J＝17.1,1.1Hz,1H),4.78(d,J＝6.2Hz,2H),3.99(s,1H),2.90(d,J＝4.6Hz,1H),2.84(dd,J＝8.0,4.2Hz,2H),2.43(dd,J＝15.5,10.4Hz,4H),2.32(d,J＝6.9Hz,2H),2.09-1.98(m,3H),1.68-1.58(m,10H),1.53-1.40(m,3H).
实施例87
Figure PCTCN2018116352-appb-000083
第一步：
将6-硝基-1,2,3,4-四氢异喹啉盐酸盐(215mg,1mmol)(如式I-87-a所示的化合物)和 N,N-二异丙基乙胺(0.2ml)加入到15ml的二氯甲烷中,搅拌至澄清。然后加入1-甲基-哌啶-4-酮(170mg,1.5mmol),醋酸硼氢化钠(422mg,2mmol)和0.3ml乙酸，室温搅拌40h。将反应液浓缩过柱{3mol/L氨甲醇:(二氯甲烷:乙酸乙酯＝5:1)＝0-15％},得到棕色目标产物185mg。收率:67％。LC-MS：m/z:[M+1] +＝276。
第二步：
将2-(1-甲基哌啶-4-基)-6-硝基-1,2,3,4-四氢异喹(180mg,0.65mmol)(如式I-87-b所示的化合物)和瑞尼镍(0.2g)加入到30ml乙醇中，然后向溶液中慢慢滴加水合肼(0.5ml),滴加完毕后室温搅拌2h。将反应液过滤浓缩得粗品150mg，直接用于下一步。收率:93％。LC-MS:m/z:[M+1] +＝246。
第三步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(如式1A所示的化合物)(160mg,0.45mmol)在15ml甲苯的溶液中加入间氯过氧苯甲酸(110mg,0.49mmol),所得溶液室温搅拌2h。
将上述反应液浓缩后加入2-(1-甲基哌啶-4-基)-1,2,3,4-四氢异喹啉-6-胺(150mg,0.61mmol)(如式I-87-c所示的化合物),0.2ml三氟乙酸和5ml二甲基亚砜，60度搅拌24h。往上述反应液中加入10ml饱和的碳酸钠水溶液和15ml水，用二氯甲烷萃取三次(3*20ml),合并有机相，分别用20ml水和20ml饱和的氯化钠溶液洗涤，无水硫酸钠干燥后浓缩得粗品，所得粗产物先用薄层层析板分离一次{3M氨甲醇:(二氯甲烷:乙酸乙酯＝1:1)＝1:10},然后再用高效液相制备得到黄色固体110mg，收率44％。LC-MS:m/z:(M+H) +＝555， 1H NMR(400MHz,MeOD)δ8.84(s,1H),8.37(s,2H),8.02(t,J＝7.9Hz,1H),7.81(d,J＝7.6Hz,1H),7.73–7.65(m,2H),7.42(d,J＝8.2Hz,1H),7.08(d,J＝8.4Hz,1H),5.73(ddt,J＝16.3,10.2,6.1Hz,1H),5.05(dd,J＝10.2,1.2Hz,1H),4.94(d,J＝J＝17.0,1.3Hz,1H),4.83(d,J＝6.1Hz,2H),3.98(s,2H),3.54(d,J＝12.5Hz,2H),3.12(t,J＝5.9Hz,2H),3.00(m,5H),2.82(s,3H),2.27(d,J＝12.6Hz,2H),1.99(dd,J＝22.9,11.1Hz,2H),1.60(s,6H).
实施例88
Figure PCTCN2018116352-appb-000084
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-((1,2,3,4-四氢异喹啉-6-基)氨基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(100mg,0.22mmol)(如式I-88-a所示的化合物),四氢-4H-吡喃-4-酮(100mg,1mmol)和乙酸钠(60mg,0.44mmol)加入到30ml的甲醇中。然后加入氰基硼氢化钠(110mg,1.75mmol)，室温搅拌48h。将反应液浓缩过柱{3mol/L氨甲醇:(二氯甲烷:乙酸乙酯＝5:1)＝0-15％},得到白色目标产物70mg。收率:59％。LC-MS:m/z:(M+H) +＝542，1H NMR(400MHz,CDCl3:MeOH＝3:1)δ8.85(s,1H),7.93(t,J＝7.9Hz,1H),7.79(d,J＝8.0Hz,1H),7.58(s,1H),7.54(d,J＝7.7Hz,1H),7.35(d,J＝8.3Hz,1H),7.04(d,J＝8.4Hz,1H),5.69(dq,J＝10.3,6.1Hz,1H),5.05(d,J＝10.2Hz,1H),4.92(d,J＝17.1Hz,1H),4.81(d,J＝5.9Hz,2H),4.16–4.03(m,2H),3.81(s,2H),3.47(t,J＝11.5Hz,2H),2.92(d,J＝4.4Hz,4H),2.72(dd,J＝15.4,7.3Hz,1H),1.93(d,J＝11.6Hz,2H),1.72(qd,J＝12.3,4.4Hz,2H),1.60(s,6H).
实施例103
Figure PCTCN2018116352-appb-000085
第一步：
将N-(5-氧-5-,6-,7-,8-四氢萘-2-基)乙酰胺(59mmol)(如式I-103-a所示的化合物)溶于甲苯(200mL)，置于封管中，向反应液中加入乙醛酸乙酯(118mmol)，对甲苯磺酸 (5.9mmol)和硫酸镁(395mmol)，将反应液加热至120℃，反应液搅拌16小时。将反应液过滤，滤液蒸干得粗品，粗品柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)得目标化合物乙基(E)-2(6-乙酰氨基-1-氧代-3，4-二氢萘-2(1H)-亚甲基)乙酸酯(9.5g,56％)，黄色固体。LC-MS:m/z:[M+1] +＝288。
第二步：
将乙基(E)-2(6-乙酰氨基-1-氧代-3,4-二氢萘-2(1H)-亚甲基)乙酸酯(31mmol)(如式I-103-b所示的化合物)溶于甲醇(100mL)，向反应液中加入Pd/C(900mg)和浓硫酸(1.0mL)，将反应液在氢气中搅拌18小时。用饱和碳酸钠溶液将反应液调pH＝9，过滤去掉Pd/C，将反应液蒸干，用水和乙酸乙酯分层，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，粗品将反应液蒸干得粗品，粗品用乙酸乙酯洗涤，过滤，柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)得目标化合物6-(哌啶-1-甲基)-5-，6-，7-，8-四氢萘-2-胺(4.0g，46.0％)，白色固体。LC-MS:m/z:[M+1] +＝276。
第三步：
将6-(哌啶-1-甲基)-5-,6-,7-,8-四氢萘-2-胺(如式I-103-c所示的化合物)(15.0mmol)溶于四氢呋喃(50mL)，将反应液氮气保护下冷却至0℃，加入四氢锂铝(29mmol)，加完后反应液室温下搅拌4小时。反应液用饱和氯化铵淬灭，反应液用乙酸乙酯萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)的目标化合物N-(6–(2-羟乙基)-5-,6-,7-,8-四氢萘-2-基)乙酰胺(2.70g,80.0％)，白色固体。LC-MS：m/z:[M+1] +＝234。
第四步：
将N-(6-(2-羟乙基)-5-,6-,7-,8-四氢萘-2-基)乙酰胺(12mmol)(如式I-103-d所示的化合物)溶于二氯甲烷(30mL)，向反应液中加入三乙胺(46mmol)，N，N-二甲基吡啶-4-胺(5.8mmol)和对甲苯磺酰氯(23mmol)，反应液室温下搅拌16小时。相反应中加入1N盐酸(200mL)，二氯甲烷萃取，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，柱层析纯化(石油醚/乙酸乙酯＝100/0-30/70)的目标化合物2-(6-乙酰氨基-1,2,3,4-四氢萘-2-基)4-甲基苯磺酸乙酯(2.40g,54.0％)，白色固体。LC-MS:m/z:[M+1] +＝388。
第五步：
将2-(6-乙酰氨基-1,2，3，4-四氢萘-2-基)4-甲基苯磺酸乙酯(1.03mmol)(如式I-103-e所示的化合物)溶于甲醇(10mL),加入甲醇钠(2.07mmol)，反应液加热至50℃，搅拌16小时。将反应液蒸干，柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)的目标化合物N-(6-(2-甲氧基乙基)-5-,6-,7-,8-四氢萘-2-基)乙酰胺(250mg,97.93％)，黄色油状物。LC-MS:m/ z:[M+1] +＝248。
第六步：
将N-(6-(2-甲氧基乙基)-5-，6-，7-，8-四氢萘-2-基)乙酰胺(1.01mmol)(如式I-103-f所示的化合物)溶于乙醇(10mL)，加入浓盐酸(10mL)，将反应液加热至回流，搅拌16小时。将反应液蒸干，得到粗品目标化合物6-(2-甲氧基乙基)-5-,6-,7-,8-四氢萘-2-胺(160mg,77.09％)，灰色固体。LC-MS:m/z:[M+1] +＝206。
第七步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6–(甲硫基)-1,2-二氢-3H-吡唑并[3，4-D]嘧啶-3-酮(如式1A所示的化合物)(0.28mmol)溶于甲苯(15mL)，加入间氯过氧苯甲酸(0.31mmol)，反应液室温下搅拌0.5小时，将反应液蒸干，所得亚砜中间体溶于二甲亚砜(10mL)，加入6-(哌啶-1-甲基)-5-，6-,7-,8-四氢萘-2-胺(0.34mmol)(如式I-103-g所示的化合物)和三氟乙酸(0.5mL)，将反应液加热至60℃下搅拌16小时。反应液用饱和碳酸钠溶液调pH＝9，加入水(50mL)乙酸乙酯(50mL)，分层，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，液相制备纯化得目标化合物2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-((6-(2-甲氧基乙基)-5,6,7,8-四氢萘-2-基)氨基)-1,2-二氢3H-吡唑[3,4-d]嘧啶-3-酮(32mg,22.22％)，灰色固体。LC-MS:m/z:[M+1] +＝515。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.81(t,J＝38.9Hz,3H),7.53-7.36(m,2H),7.07(s,1H),5.72(s,1H),5.02(dd,J＝42.8,13.2Hz,2H),4.80(s,2H),3.55(t,J＝6.3Hz,2H),3.42-3.36(m,3H),2.89(d,J＝21.4Hz,3H),2.53-2.39(m,1H),1.96(d,J＝26.2Hz,4H),1.75-1.66(m,3H),1.61(s,6H).
实施例114
Figure PCTCN2018116352-appb-000086
第一步：
将6-硝基-1,2,3,4-四氢异喹啉盐酸盐(214mg,1mmol)(如式I-114-a所示的化合物),3-氧代氮杂环丁烷-1-羧酸叔丁酯(190mg,1.1mmol),醋酸硼氢化钠(422mg,2mmol)和N,N-二异丙基乙胺(0.5ml)加入到15ml的二氯甲烷中，在封管中外温70度搅拌过夜。将反应液浓缩过柱(乙酸乙酯:石油醚＝0-50％),得到浅黄色目标产物300mg。收率:90％。LC-MS:m/z:[M+1] +＝334。
第二步：
将3-(6-硝基-3,4-二氢异喹啉-2(1H)-基)氮杂环丁烷-1-羧酸叔丁酯(300mg,0.9mmol)(如式I-114-b所示的化合物)和3ml三氟乙酸依次加入到3ml二氯甲烷中,室温搅拌过夜。反应液浓缩后加入10ml 7mol/L的氨甲醇，然后浓缩得粗品200mg，直接用于下一步。收率:95％。LC-MS:m/z:[M+1] +＝234。
第三步：
将2-(氮杂环丁烷-3-基)-6-硝基-1,2,3,4-四氢异喹啉(180mg,0.77mmol)(如式I-114-c所示的化合物)，37％的甲醛水溶液(0.2ml)和醋酸硼氢化钠(340mg,1.6mmol)加入到15ml的甲醇中，室温搅拌过夜。反应液浓缩后加入20ml二氯甲烷和2ml甲醇，用5ml饱和的碳酸钠溶液进行洗涤，无水硫酸钠干燥后浓缩过柱(7mol/L的氨甲醇:二氯甲烷＝0-20％)，得到175mg白色固体。收率:91％。LC-MS:m/z:[M+1] +＝248。
第四步：
将2-(1-甲基氮杂-3-基)-6-硝基-1,2,3,4-四氢异喹啉(170mg,0.69mmol)(如式I-114-d所示的化合物)和瑞尼镍(0.2g)加入到30ml乙醇中，然后向溶液中慢慢滴加水合肼(0.5ml),滴加完毕后室温搅拌2h。将反应液过滤浓缩得粗品。收率:93％。LC-MS:m/z:[M+1] +＝218。
第五步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(140mg,0.39mmol)(如式1A所示的化合物)在15ml甲苯的溶液中加入间氯过氧苯甲酸(100mg,0.45mmol),所得溶液室温搅拌2h。
将上述反应液浓缩后加入2-(1-甲基氮杂-3-基)-1,2,3,4-四氢异喹啉-6-胺(90mg,0.41mmol)(如式I-114-e所示的化合物),0.2ml三氟乙酸和5ml二甲基亚砜，60度搅拌24h。往上述反应液中加入10ml饱和的碳酸钠水溶液和15ml水，用二氯甲烷萃取三次(3*20ml),合并有机相，分别用20ml水和20ml饱和的氯化钠溶液洗涤，无水硫酸钠干燥后浓缩得粗品，所得粗产物先用薄层层析板分离一次{3M氨甲醇:(二氯甲烷:乙酸乙酯＝1:1)＝0-15％},然后再用高效液相制备得到黄色固体65mg，收率31％。LC-MS:m/z: (M+H) +＝527， 1H NMR(400MHz,CDCl 3)δ8.84(s,1H),8.42(s,1H),7.92(t,J＝8.1Hz,1H),7.78(d,J＝8.0Hz,1H),7.64–7.54(m,2H),7.39(dd,J＝8.2,2.0Hz,1H),7.01(d,J＝8.1Hz,1H),5.76–5.61(m,1H),5.04(dd,J＝10.2,1.1Hz Hz,1H),4.91(dd,J＝17.0,1.2Hz,1H),4.82(d,J＝6.2Hz,2H),4.42–4.32(m,2H),3.87–3.76(m,2H),3.54(m,3H),2.94(t,J＝5.8Hz,2H),2.88(s,3H),2.68(t,J＝5.9Hz,2H),1.59(s,6H).
实施例115
Figure PCTCN2018116352-appb-000087
第一步：
将6-溴-3,4-二氢萘-2(1H)-酮(400mg,1.78mmol)(如式I-115-a所示的化合物)溶于18mL甲醇中,然后加入乙酸铵(1368mg,17.8mmol)，室温搅拌2h后加入氰基硼氢化钠(120mg,1.91mmol)，室温搅拌反应16h。反应液减压浓缩后加入30ml水，并用1mol/L的盐酸将pH值调至酸性，每次用30ml的二氯甲烷萃取两次。水相用1mol/L的氢氧化钠溶液将pH值调至碱(pH＝10-11)。每次用40ml的二氯甲烷萃取三次。有机相用30ml饱和食盐水进行洗涤，用无水硫酸钠干燥后浓缩,所得粗品直接用于下一步。得到红棕色油状物(197mg,0.87mmol)，收率48％。LC-MS:m/z:(M+H) +＝226.0，228.0。
第二步：
将6-溴-1,2,3,4-四氢萘-2-胺(97mg,0.43mmol)(如式I-115-b所示的化合物)溶于10ml二氯甲烷中，加入碳酸钠(182mg,1.72mmol)，室温室温搅拌反应18h。反应液减压浓缩后加入30ml水，每次用30ml的二氯甲烷萃取两次。合并有机层浓缩，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-33％)，得到棕色油状物(90mg,0.30mmol)，收率71％。LC-MS:m/z:(M+H) +＝297.1,299.1。
第三步：
将3-(6-溴-1,2,3,4-四氢萘-2-基)-1,1-二甲基脲(90mg,0.30mmol)(如式I-115-c所示的化合物),二苯甲酮亚胺(60mg,0.33mmol),叔丁醇钠(58mg,0.60mmol), Pd 2(dba) 3(14mg,0.015mmol),BINAP(19mg,0.03mmol)加入到10ml甲苯中,在氩气换气三次，然后加热到100℃反应16h。反应液浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-10％),得到棕色油状物(76mg,0.19mmol)，收率63％。LC-MS:m/z:(M+H) +＝398.3。
第四步：
将3-(6-((二苯亚甲基)氨基-1,2,3,4-四氢萘-2-基)-1,1-二甲基脲(76mg,0.19mmol)(如式I-115-d所示的化合物)溶于10ml甲醇中，然后加入醋酸钠三水合物(78mg,0.57mmol)和盐酸羟胺(29mg,0.42mmol)，加热到60度反应6小时。反应液过滤浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-20％),得到棕色油状物(44mg,0.19mmol)，收率99％。LC-MS:m/z:(M+H) +＝234.2。
第五步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(70mg,0.2mmol)(如式1A所示的化合物)在15ml甲苯的溶液中加入间氯过氧苯甲酸(48mg，0.22mmol),所得溶液室温搅拌1h后蒸除溶剂后得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮粗品。在上述所得溶液中加入二甲亚砜5mL，三氟乙酸1mL，3-(6-氨基-1,2,3,4-四氢萘-2-基)-1,1-二甲基脲(44mg,0.19mmol)(如式I-115-e所示的化合物)，60度搅拌24h。减压浓缩，所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到目标化合物31mg，黄色固体，收率30％。LC-MS:m/z:(M+H) +＝543.3, 1H NMR(400MHz,DMSO)δ10.21(s,1H),8.88(s,1H),8.03(t,J＝7.9Hz,1H),7.78(d,J＝8.0Hz,1H),7.64(d,J＝7.7Hz,2H),7.36(d,J＝7.4Hz,1H),7.01(d,J＝8.3Hz,1H),6.11(d,J＝7.5Hz,1H),5.67(ddd,J＝16.4,10.9,6.1Hz,1H),5.00(d,J＝10.5Hz,1H),4.82(d,J＝17.5Hz,1H),4.70(d,J＝5.7Hz,2H),3.80(s,1H),2.89(dd,J＝16.4,4.6Hz,2H),2.81(s,6H),2.69–2.52(m,2H),2.04–1.94(m,1H),1.71–1.56(m,1H),1.47(s,6H)。
实施例116
Figure PCTCN2018116352-appb-000088
第一步：
将6-溴-1,2,3,4-四氢异喹啉(740mg,3.49mmol)(如式I-114-a所示的化合物),3-氧代吡咯烷-1-羧酸叔丁酯(1g,5.4mmol),醋酸硼氢化钠(1.5g,7.1mmol)和乙酸(0.2ml)加入到35ml的二氯甲烷中，室温搅拌过夜。有机层用20ml的饱和碳酸钠溶液洗涤,无水硫酸钠干燥浓缩,然后过柱纯化(二氯甲烷:三乙胺＝100:1),得到棕色固体850mg。收率:64％。LC-MS:m/z:[M+1] +＝381。
第二步：
将3-(6-溴-3,4-二氢异喹啉-2(1H)-基)吡咯烷-1-羧酸叔丁酯(850mg,2.2mmol)(如式I-114-b所示的化合物)和5ml三氟乙酸依次加入到5ml二氯甲烷中,室温搅拌过夜。反应液浓缩后加入50ml二氯甲烷和5ml甲醇，用10ml饱和的碳酸钠溶液洗涤,无水硫酸钠干燥后浓缩得粗品棕色油状物600mg，直接用于下一步。收率:95％。LC-MS:m/z:[M+1] +＝281。
第三步：
将6-溴-2-(吡咯烷-3-基)-1,2,3,4-四氢异喹啉(600mg,2.1mmol)(如式I-114-c所示的化合物)，37％的甲醛水溶液(1ml)和醋酸硼氢化钠(900mg,4.24mmol)加入到35ml的甲醇中，室温搅拌过夜。反应液浓缩后加入20ml二氯甲烷和2ml甲醇，用5ml饱和的碳酸钠溶液进行洗涤，无水硫酸钠干燥后浓缩过柱(7mol/L的氨甲醇:二氯甲烷＝0-15％),得到530mg棕色油状物。收率:84％。LC-MS:m/z:[M+1] +＝295。
第四步：
将6-溴-2-(1-甲基吡咯烷-3-基)-1,2,3,4-四氢异喹啉(530mg 1.8mmol)(如式I-114-d所示的化合物),二苯甲酮亚胺360mg(2mmol),叔丁醇钠260mg(2.7mmol),Pd 2(dba) 365mg(0.07mmol),BINAP(115mg,0.185mmol)加入到35ml甲苯中,在氩气换气三次，然后加热到110度过夜。反应液浓缩，所得粗产物过柱纯化[7M氨甲醇:(二氯甲烷:乙 酸乙酯＝2:1)＝0-10％],得到棕色油状物540mg，收率76％。LC-MS:m/z:[M+1] +＝396。
第五步：
将N-(2-(1-甲基吡咯烷-3-基)-1,2,3,4-四氢异喹啉-6-基)-1,1-二苯甲酮亚胺(540mg,1.365mmol)(如式I-114-e所示的化合物)溶于40ml甲醇中，然后加入醋酸钠0.56g(6.83mmol)和盐酸羟胺(190mg,2.73mmol)，加热到60度反应过夜。反应液过滤浓缩，所得粗产物过柱纯化(7M氨甲醇:二氯甲烷＝0-15％),得到棕色油状物260mg，收率82％。LC-MS:m/z:[M+1] +＝232。
第六步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(155mg,0.43mmol)(如式1A所示的化合物)在15ml甲苯的溶液中加入间氯过氧苯甲酸(106mg,0.47mmol),所得溶液室温搅拌2h。
将上述反应液浓缩后加入2-(1-甲基吡咯烷-3-基)-1,2,3,4-四氢异喹啉-6-胺(130mg,0.56mmol)(如式I-114-f所示的化合物),0.2ml三氟乙酸和5ml二甲基亚砜，60度搅拌24h。往上述反应液中加入10ml饱和的碳酸钠水溶液和15ml水，用二氯甲烷萃取三次(3*20ml),合并有机相，分别用20ml水和20ml饱和的氯化钠溶液洗涤，无水硫酸钠干燥后浓缩得粗品，所得粗产物用薄层层析板分离两次{7M氨甲醇:(二氯甲烷:乙酸乙酯＝2:1)＝1:9},得到白色固体160mg，收率68％。LC-MS:m/z:(M+H) +＝541,1H NMR(400MHz,MeOD)δ8.84(s,1H),8.02(t,J＝7.9Hz,1H),7.81(d,J＝7.9Hz,1H),7.68(d,J＝7.7Hz,1H),7.63(s,1H),7.36(d,J＝8.2Hz,1H),7.03(d,J＝8.4Hz,1H),5.73(ddt,J＝16.4,10.3,6.1Hz,1H),5.05(dd,J＝10.2,1.1Hz,1H),4.90-4.94(d,J＝17.0,1.2Hz,,1H),4.84(d,J＝6.1Hz,2H),3.72–3.60(m,2H),3.12(m,2H),2.97–2.83(m,4H),2.74(m,1H),2.55(dd,J＝16.5,9.1Hz,1H),2.50–2.39(m,4H),2.18(m,1H),1.92(m,1H),1.60(s,6H).
实施例117
Figure PCTCN2018116352-appb-000089
第一步：
将2-(6-乙酰氨基-1,2，3，4-四氢萘-2-基)4-甲基苯磺酸乙酯(1.03mmol)(如式I-117-a所示的化合物)溶于乙腈(10mL)，向反应液中加入吗啡啉(3.10mmol)和碳酸钾(4.13mmol)，将反应液加热至50℃，反应液搅拌16小时。将反应液过滤，滤液蒸干得粗品，粗品柱层析纯化(石油醚/乙酸乙酯＝100/0-50/50)得目标化合物N-(6-(2-吗啉乙基)-5-,6-,7-,8-四氢萘-2-基)乙酰胺(230mg,73.7％)，白色固体。LC-MS:m/z:[M+1] +＝303。
第二步：
将N-(6-(2-吗啉乙基)-5-，6-，7-，8-四氢萘-2-基)乙酰胺(0.76mmol)(如式I-117-b所示的化合物)溶于乙醇(10mL)，向反应液中加入氢氧化钠(10mL,10mol/L)，将反应液加热至回流搅拌18小时。反应液用水和乙酸乙酯分层，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，粗品将反应液蒸干得粗品目标化合物6-(2-吗啉乙基)-5-,6-,7-,8-四氢萘-2-胺(152mg，76.7％)，灰色固体。LC-MS:m/z:[M+1] +＝261。
第三步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-D]嘧啶-3-酮(0.28mmol)(如式1A所示的化合物)溶于甲苯(15mL)，加入3-氯过氧苯甲酸(0.31mmol)，反应液室温下搅拌0.5小时，将反应液蒸干，所得亚砜中间体溶于二甲亚砜(10mL)，加入6-(2-吗啉乙基)-5-,6-,7-,8-四氢萘-2-胺(如式I-117-c所示的化合物)(0.31mmol)和三氟乙酸(0.5mL)，将反应液加热至60℃下搅拌16小时。反应液用饱和碳酸钠溶液调pH＝9，加入水(50mL)乙酸乙酯(50mL)，分层，有机相饱和食盐水洗涤，无水硫酸钠干燥，过滤，蒸干，液相制备纯化得目标化合物2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(6-(2-吗啉乙基)-5-,6-,7-,8-四氢萘-2-基)氨基-1,2-二氢-3H-吡唑并[3,4-D]嘧啶-3-酮(68mg,42.6％)，白色固体。LC-MS:m/z:[M+H] +＝570。1H NMR(400MHz,CDCl3)δ8.87(s,1H),7.93-7.80(m,2H),7.49-7.35(m,2H),7.26(d,J＝2.2Hz,1H),7.05(d,J＝8.3Hz,1H),5.72(d,J＝6.7Hz,1H),5.01(ddd,J＝18.2,13.6,1.0Hz,2H),4.78(d,J＝6.2Hz,2H),3.80(s,2H),2.85(dd,J＝8.4,4.4Hz,2H),2.70-2.39(m,4H),2.00(d,J＝12.2Hz,1H),1.83(s,1H),1.64(d,J＝19.4Hz,4H),1.54-1.42(m,1H).
实施例119
Figure PCTCN2018116352-appb-000090
第一步：
将6-溴-3,4-二氢萘-2(1H)-酮(200mg,0.89mmol)(如式I-119-a所示的化合物)溶于10mL二氯甲烷中,然后加入苄胺(0.14ml,1.33mmol)和三乙酰基硼氢化钠(753mg,3.55mmol)，室温搅拌反应16h。反应液减压浓缩后加入30ml水，每次用30ml的二氯甲烷萃取两次。合并有机层浓缩，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-33％)，得到棕色油状物(140mg,0.44mmol)，收率50％。LC-MS:m/z:(M+H) +＝316.0，318.0。
第二步：
将N-苄基-6-溴-1,2,3,4-四氢萘-2-胺(140mg,0.44mmol)(如式I-119-b所示的化合物)溶于10ml甲醇中，然后加入乙醛(0.1ml)和氰基硼氢化钠(140mg,2.22mmol)，室温室温搅拌反应18h。反应液减压浓缩后加入30ml水，每次用30ml的二氯甲烷萃取两次。合并有机层浓缩，所得粗产物过柱纯化(乙酸乙酯:石油醚＝0-33％)，得到棕色油状物(102mg,0.30mmol)，收率67％。LC-MS:m/z:(M+H) +＝344.1,346.1。
第三步：
将N-苄基-6-溴-N-乙基-1,2,3,4-四氢萘-2-胺(102mg,0.30mmol)(如式I-119-c所示的化合物),二苯甲酮亚胺(58mg,0.32mmol),叔丁醇钠(56mg,0.60mmol),Pd 2(dba) 3(13mg,0.015mmol),BINAP(18mg,0.03mmol)加入到10ml甲苯中,氩气换气三次，然后加热到100℃反应16h。反应液浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-10％),得到棕色油状物(72mg,0.16mmol),收率54％。LC-MS:m/z:(M+H) +＝445.3。
第四步：
将N-苄基-6-((二苯亚甲基)氨基)-N-乙基-1,2,3,4-四氢萘-2-胺(72mg,0.16mmol)(如式I-119-d所示的化合物)溶于10ml甲醇中，然后加入醋酸钠三水合物(66mg,0.48mmol)和盐酸羟胺(25mg,0.36mmol)，加热到60度反应6小时。反应液过滤浓缩，所得粗产物过柱纯化(甲醇:二氯甲烷＝0-20％),得到棕色油状物(45mg,0.16mmol)，收率99％。LC-MS:m/z: (M+H) +＝281.2。
第五步：
将2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲硫基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮(53mg,0.15mmol)(如式1A所示的化合物)在15ml二氯甲烷的溶液中加入间氯过氧苯甲酸(37mg,0.16mmol),所得溶液室温搅拌1h后蒸除溶剂后得到2-烯丙基-1-(6-(2-羟基丙烷-2-基)吡啶-2-基)-6-(甲基亚磺酰基)-1,2-二氢-3H-吡唑并[3,4-d]嘧啶-3-酮的二氯甲烷溶液。在上述所得溶液中加入DIPEA(0.08ml)，N2-苄基-N2-乙基-1,2,3,4-四氢萘-2,6-二甲基胺(如式I-119-e所示的化合物)(44mg,0.19mmol)，60度搅拌24h。减压浓缩，所得粗产物用薄层层析法分离纯化(7M氨甲醇:二氯甲烷＝0-10％)得到目标化合物51mg，黄色固体，收率58％。LC-MS:m/z:(M+H) +＝590.4, 1H NMR(400MHz,MeOD)δ8.79(s,1H),7.98(t,J＝7.9Hz,1H),7.79(d,J＝8.0Hz,1H),7.67(d,J＝7.7Hz,1H),7.52(s,1H),7.40(d,J＝7.1Hz,2H),7.35–7.20(m,4H),7.02(d,J＝8.3Hz,1H),5.80–5.65(m,1H),5.04(dd,J＝10.2,1.1Hz,1H),4.92(dd,J＝17.1,1.3Hz,1H),4.83(d,J＝6.0Hz,2H),3.77(s,2H),3.08(s,1H),2.84(dt,J＝11.9,10.6Hz,4H),2.77–2.65(m,2H),2.14(d,J＝10.0Hz,1H),1.71(dd,J＝11.9,5.5Hz,1H),1.60(s,6H),1.09(t,J＝7.1Hz,3H)。
参照上述实施例，制备出表1所示的化合物，其结构表征见下：
表1 实施例列表
Figure PCTCN2018116352-appb-000091
Figure PCTCN2018116352-appb-000092
Figure PCTCN2018116352-appb-000093
Figure PCTCN2018116352-appb-000094
Figure PCTCN2018116352-appb-000095
Figure PCTCN2018116352-appb-000096
Figure PCTCN2018116352-appb-000097
Figure PCTCN2018116352-appb-000098
Figure PCTCN2018116352-appb-000099
Figure PCTCN2018116352-appb-000100
效果实施例1
一、化合物对WEE1激酶体外抑制作用
测试方法：
采用ELISA方法，在ATP浓度为Km情况下在WEE1激酶上对受试化合物进行筛选。在WEE1激酶上进行了3个化合物的筛选，以评价受试化合物的激酶抑制活性。检测过程中，受试化合物初始浓度均选择为100nM，各化合物均选择6个梯度稀释浓度，梯度稀释倍数为4倍，每浓度2个复孔进行检测，采用MK-1775作为标准对照。
WEE1，购自CarnaBiosciences,Inc.，货号：05-177；二甲基亚砜，购自Sigma-Aldrich，货号：D8418；ATP，购自Sigma-Aldrich，货号：A7699；DTT溶液，购自Sigma-Aldrich，货号：43816；protein tyrosine kinase(PTK)substrate(poly–Glu-Tyr)，购自Sigma-Aldrich，货号：P4476；P-Tyr(PY99)，购自Santa Cruz，货号：sc-7020；Anti-mouse IgG HRP-linked Antibody，购自Santa Cruz，货号：7076S；TMB liquid Substrate System，购自Sigma-Aldrich，货号：T0440；Costar Stripwell Microplate No Lid 1×8 Flat Bottom，Certified High Binding，购自Sigma-Aldrich，货号：42592；96孔化合物板，购自Thermo Scientific，货号：267245。
测试步骤：
1、包被底物：1)取适当体积的底物储存液protein tyrosine kinase(PTK)substrate(poly–Glu-Tyr)，用PBS稀释10倍，将浓度从250mg/mL的稀释为25mg/mL。加入到高吸附96孔板中，每孔125μL。放置到37℃孵育箱过夜包被。2)24h后，取出96孔板，倒掉96孔板中的液体，用washing buffer清洗3次，37℃孵育箱倒置烘干2h。
2、化合物的配制与转移：1)化合物稀释：取10mM的受试化合物储存液，在96孔 化合物板中，用DMSO将化合物分多步稀释，获得为初始浓度100×的化合物，之后再以此浓度化合物为第一个浓度，采用DMSO进行4倍梯度稀释，共稀释6个浓度；之后分别取2μL的梯度稀释液加入48μL的1×反应缓冲液中，配制成4×化合物备用；2)4×化合物的转移：从上步配置的96孔化合物板中转移10μL的4×化合物进入烘干的高吸附96孔板中；无化合物对照孔和ATP-对照孔中加入10μL的如下液体：2μL的DMSO加入48μL的1×反应缓冲液。
3、酶反应阶段：1)采用1×反应缓冲液将WEE1激酶、ATP分别配制成2×的酶溶液和4×的ATP溶液。其中在本次筛选中，WEE1激酶的终浓度为：0.15ng/μL，ATP终浓度为：12μM；2)向高吸附96孔板中加入20μL的2的酶溶液；3)向高吸附96孔板中加入10μL的4×ATP溶液，ATP-对照空加入10μL1×反应缓冲液；4)将板放于HERAEUS Multifuge X1R离心机中2000rpm离心20s后，放置于室温反应60min。
4、反应终止阶段：1)倒掉板中的反应液，每孔加入200μL washing buffer，清洗5遍；加入一抗P-Tyr(PY99)(稀释比例1：2000)，每孔100μL，室温30min。2)倒掉板中的一抗，每孔加入200μL washing buffer，清洗5遍；加入二抗Anti-mouse IgG HRP-linked Antibody(稀释比例1：2000)，每孔100μL，室温30min。3)倒掉板中的二抗，用washing buffer洗5遍，加入TMB，每孔100μL，显色10～30min，视颜色深浅而定。读数前用1N硫酸终止反应。
5、检测与数据处理：1)于ThermoScientific MultiScan GO上读取波长450nM处的光吸收，同时在650nM处读取背景。2)采用Graphpad Prism 5.0对数据进行Log(inhibitor)vs.response-Variable slope(four parameters)曲线拟合，计算相应的IC50(half maximal inhibitory concentration)。
二、化合物对COLO 205细胞株体外抑制作用
测试方法：
采用Luminescence ATP Detection方法，检测化合物对p53缺失细胞株COLO 205增殖的抑制作用。在细胞株上进行了4个化合物的筛选，以评价受试化合物对该细胞株体外增殖的抑制活性。检测过程中，受试化合物初始浓度选择为10μM，选择9个梯度稀释浓度，梯度稀释倍数为3倍，每浓度2个复孔进行检测，采用MK-1775作为标准对照。
COLO 205，人结肠癌细胞，购自中科院细胞库，目录号：TCHu102；ATPlite 1step Single Addition Luminescence ATP Detection Assay system，购自PerkinElemer，货号：6016739；RPMI 1640，购自GIBCO，货号：A10491-01；Strep/pen，购自GIBCO，货号：15240-062；胎牛血清FBS，购自GIBCO，货号：10099-141；96孔黑色底透细胞培养板， 购自Corning，货号：3603；96孔化合物板，购自Thermo Scientific，货号：267245。
测试步骤：
1、细胞培养与接种：取正常培养的细胞，在其指数生长状态下，消化分散后，调整细胞密度至8.8×10 3cells/mL，每孔90μL接种于96孔细胞培养板中；接种完成后将微孔板放置于37℃，5％的CO 2的条件下培养；
2、加药处理细胞：从培养箱中取出微孔板，向微孔板中的每个孔中各加入10×化合物，每孔加入10μL，其中每个给药浓度2个复孔，每个化合物共9个给药浓度。根据不同的细胞株，各化合物的起始浓度有所不同，完成后将微孔板放置于37℃，5％的CO 2的条件下培养72h；
3、数据的采集：将微孔板从培养箱中取出，室温平衡30min。于每孔中加入100μl室温平衡后的ATPlite反应液，1300rpm室温震荡2min，之后将微孔板放置于HERAEUS Multifuge X1R离心机中2000rpm离心1min；室温平衡10min后，于EnVisionTM上测定荧光信号值。
4、按下列公式对化合物的体外抑制活性进行计算：
细胞增殖抑制率：抑制率(％)＝(信号值对照－信号值给药)/信号值对照×100％。并根据各浓度的抑制率，采用LOGIT法计算50％抑制浓度(50％inhibitory concentration，IC 50)。细胞存活率计算：Cell viability(％)＝信号值给药/信号值对照×100％。采用Graphpad Prism 5.0对各浓度下的荧光信号值进行Log(inhibitor)vs.response-Variable slope(four parameters)曲线拟合，计算相应的IC 50(half maximal inhibitory concentration)。
三、化合物对5-FU处理的COLO 205细胞株体外抑制作用
测试方法：
本报告采用Luminescence ATP Detection方法，检测化合物对5-FU处理的p53缺失细胞株COLO 205增殖的抑制作用。在细胞株上进行了4个化合物的筛选，以评价受试化合物与5-FU联用后对该细胞株体外增殖的抑制活性。检测过程中，5-FU初始浓度选择为100μM，选择9个梯度稀释浓度，梯度稀释倍数为3倍，每浓度2个复孔进行检测，受试化合物采用300nM与100nM两个浓度分别于9个浓度的5-FU联合作用。MK-1775作为标准对照。
COLO 205，人结肠癌细胞，购自中科院细胞库，目录号：TCHu102；ATPlite 1step Single Addition Luminescence ATP Detection Assay system，购自PerkinElemer，货号：6016739；RPMI 1640，购自GIBCO，货号：A10491-01；Strep/pen，购自GIBCO，货号：15240-062；胎牛血清FBS，购自GIBCO，货号：10099-141；96孔黑色底透细胞培养板， 购自Corning，货号：3603；96孔化合物板，购自Thermo Scientific，货号：267245；
测试步骤：
1、细胞培养与接种：取正常培养的细胞，在其指数生长状态下，消化分散后，调整细胞密度至8.8×10 3cells/mL，每孔90μL接种于96孔细胞培养板中；接种完成后将微孔板放置于37℃，5％的CO 2的条件下培养；
2、加药处理细胞：从培养箱中取出微孔板，向微孔板中的每个孔中各加入10×5-FU，每孔加入10μL，其中每个给药浓度2个复孔，每个化合物共9个给药浓度对照加入含有相同比例溶媒DMSO的培养基，完成后将微孔板放置于37℃，5％的CO 2的条件下培养72h；
3、加药处理细胞：从培养箱中取出微孔板，向微孔板中的9个梯度5-FU处理的细胞以及对照孔中均加入3300nM或者1100nM化合物(11×化合物)，每孔加入10μL，完成后将微孔板放置于37℃，5％的CO 2的条件下培养72h；
4、数据的采集：将微孔板从培养箱中取出，室温平衡30min。于每孔中加入100μL室温平衡后的ATPlite反应液，1300rpm室温震荡2min，之后将微孔板放置于HERAEUS Multifuge X1R离心机中2000rpm离心1min；室温平衡10min后，于EnVisionTM上测定荧光信号值。
5、按下列公式对化合物的体外抑制活性进行计算：
细胞增殖抑制率：抑制率(％)＝(信号值对照－信号值给药)/信号值对照×100％。并根据各浓度的抑制率，采用LOGIT法计算50％抑制浓度(50％inhibitory concentration，IC 50)。细胞存活率计算：Cell viability(％)＝信号值给药/信号值对照×100％。采用Graphpad Prism 5.0对各浓度下的荧光信号值进行Log(inhibitor)vs.response-Variable slope(four parameters)曲线拟合，计算相应的IC 50(half maximal inhibitory concentration)。
四、测试结果数据。
测试中使用的对照样品结构见表2。
表2 对照样品结构
Figure PCTCN2018116352-appb-000101
测试结果详见表3。
表3 WEE1酶抑制活性和细胞抑制活性测试结果
Figure PCTCN2018116352-appb-000102
Figure PCTCN2018116352-appb-000103
Figure PCTCN2018116352-appb-000104
Figure PCTCN2018116352-appb-000105
虽然以上描述了本发明的具体实施方式，但是本领域的技术人员应当理解，这些仅是举例说明，在不背离本发明的原理和实质的前提下，可以对这些实施方式做出多种变更或修改。因此，本发明的保护范围由所附权利要求书限定。

Claims (26)

  1. 一种如式I所示的吡唑酮并嘧啶类化合物、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，
    Figure PCTCN2018116352-appb-100001
    其中，X为N或CH；
    m和n独立地为0、1、2或3，且m+n为2、3或4；
    Y为N或CH；
    R 1为H、卤素、巯基、硝基、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-C(＝NR 1-11)R 1- 5、-S(＝O)R 1-6、-S(＝O) 2R 1-7、-S(＝NR 1-12)R 1-8、-S(＝NR 1-13)(＝NR 1-14)R 1-9、-S(＝O)(＝NR 1-15)R 1- 10、未取代或R 1-16取代的C 1～C 7烷基、未取代或R 1-17取代的C 2～C 7烯基、未取代或R 1-18取代的C 2～C 8炔基、未取代或R 1-19取代的C 1～C 7烷硅基、未取代或R 1-20取代的C 3～C 7环烷基、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、未取代或R 1-22取代的C 6～C 10芳基、未取代或R 1- 23取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、未取代或R 1-24取代的C 1～C 7烷氧基、或者、未取代或R 1-25取代的C 1～C 7烷巯基；
    所有的R 1-1、R 1-2和R 1-3独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、未取代或R 1-1-3取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-1-1、R 1-1-2和R 1-1-3独立地为C 1～C 7烷基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9和R 1-10独立地为羟基、C 1～C 7烷基、卤素取代的C 1～C 7烷基、卤素、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、C 1～C 7烷氧基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、或、NR 1-4-1R 1-4-2；
    所有的R 1-4-1和R 1-4-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-11、R 1-12、R 1-13、R 1-14和R 1-15独立地为H、氰基、羟基、C 1～C 7烷氧基、未取代或R 1-11-1取代的C 1～C 7烷基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、或者、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-11-1独立地为卤素、羟基、氰基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、C 1～C 7杂环烷基、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”或C 1～C 7烷氧基；
    所有的R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24和R 1-25独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、未取代或R 1-16- 7取代的C 3～C 7环烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
    所有的R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4、R 1-16-6和R 1-16-7独立地为氢、羟基、卤素、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一 种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、
    Figure PCTCN2018116352-appb-100002
    -NR 1-16-5-1R 1-16-5-2或-OR 1-16-5-3；
    所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或R 1-16-5-1- 1取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-16-5-1-1独立地为卤素、羟基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷巯基、C 1～C 7烷硅基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    z为0、1或2；
    所有的R 2独立地为卤素、羟基、氰基、氨基、未取代或R 2-1取代的C 1～C 7烷基、未取代或R 2-2取代的C 2～C 8烯基、未取代或R 2-3取代的C 2～C 7炔基、未取代或R 2-4取代的C 1～C 7烷硅基、未取代或R 2-5取代的C 6～C 10芳基、未取代或R 2-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 3～C 7环烷基、或者、未取代或R 2-7取代的C 1～C 7烷氧基；
    所有的R 2-1、R 2-2、R 2-3、R 2-4、R 2-5、R 2-6和R 2-7独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 2-1-1R 2-1-2、-OR 2-1-3、-SR 2-1-4或-(C＝O)R 2-1-5；
    所有的R 2-1-1、R 2-1-2、R 2-1-3和R 2-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 2-1-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原 子数为1～4个的C 1～C 7杂芳基”；
    或者，两个R 2连接在同一碳原子上共同形成未取代或R 2-8取代的C 3～C 7环烷基、或者、未取代或R 2-9取代的C 1～C 7杂环烷基；
    所有的R 2-8和R 2-9独立地为卤素、氰基、巯基、羟基、氨基、C 1～C 7烷氧基或C 1～C 7烷巯基。
  2. 一种如权利要求1所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，当R 1为R 1-16取代的C 1～C 7烷基时，所述的R 1-16的个数为一个或多个，当存在多个R 1-16时，所述的R 1-16相同或不同；
    和/或，当R 1为未取代或R 1-16取代的C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 4烷基；
    和/或，当R 1为R 1-17取代的C 2～C 7烯基时，所述的R 1-17的个数为一个或多个，当存在多个R 1-17时，所述的R 1-17相同或不同；
    和/或，当R 1为未取代或R 1-17取代的C 2～C 7烯基时，所述的C 2～C 7烯基为C 2～C 4烯基；
    和/或，当R 1为R 1-18取代的C 2～C 8炔基时，所述的R 1-18的个数为一个或多个，当存在多个R 1-18时，所述的R 1-18相同或不同；
    和/或，当R 1为未取代或R 1-18取代的C 2～C 8炔基时，所述的C 2～C 8炔基为C 2～C 4炔基；
    和/或，当R 1为R 1-19取代的C 1～C 7烷硅基时，所述的R 1-19的个数为一个或多个，当存在多个R 1-19时，所述的R 1-19相同或不同；
    和/或，当R 1为R 1-20取代的C 3～C 7环烷基时，所述的R 1-20的个数为一个或多个，当存在多个R 1-20时，所述的R 1-20相同或不同；
    和/或，当R 1为未取代或R 1-20取代的C 3～C 7环烷基时，所述的C 3～C 7环烷基为环丙基、环丁基、环戊基或环己基；
    和/或，当R 1为R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的R 1-21的个数为一个或多个，当存在多个R 1-21时，所述的R 1-21相同或不同；
    和/或，当R 1为未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为 氮和/或氧，杂原子数为1～2个的C 3～C 5杂环烷基”；
    和/或，当R 1为R 1-22取代的C 6～C 10芳基时，所述的R 1-22的个数为一个或多个，当存在多个R 1-22时，所述的R 1-22相同或不同；
    和/或，当R 1为R 1-23取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”时，所述的R 1-23的个数为一个或多个，当存在多个R 1-23时，所述的R 1-23相同或不同；
    和/或，当R 1为R 1-24取代的C 1～C 7烷氧基时，所述的R 1-24的个数为一个或多个，当存在多个R 1-24时，所述的R 1-24相同或不同；
    和/或，当R 1为R 1-25取代的C 1～C 7烷巯基时，所述的R 1-25的个数为一个或多个，当存在多个R 1-25时，所述的R 1-25相同或不同；
    和/或，当R 1-1、R 1-2或R 1-3为未取代或R 1-1-3取代的C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 4烷基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 4烷基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为卤素取代的C 1～C 7烷基时，所述的卤素的个数为一个或多个，当存在多个卤素时，所述的卤素相同或不同；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为卤素取代的C 1～C 7烷基时，所述的“卤素”独立地为氟、氯、溴或碘；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为卤素取代的C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 4烷基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为C 2～C 7炔基时，所述的C 2～C 7炔基为C 2～C 4炔基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为C 1～C 7烷氧基时，所述的C 1～C 7烷氧基为C 1～C 4烷氧基；
    和/或，当R 1-4-1或R 1-4-2为C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 4烷基；
    和/或，当R 1-11、R 1-12、R 1-13、R 1-14或R 1-15为R 1-11-1取代的C 1～C 7烷基时，所述的R 1- 11-1的个数为一个或多个，当存在多个R 1-11-1时，所述的R 1-11-1相同或不同；
    和/或，当R 1-11、R 1-12、R 1-13、R 1-14或R 1-15为未取代或R 1-11-1取代的C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 4烷基；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为卤素时，所述的卤素为氟、氯、溴或碘；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为C 1～C 7烷硅基时，所述的C 1～C 7烷硅基为三甲基硅基；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为R 1-16- 6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的R 1-16-6的个数为一个或多个，当存在多个R 1-16-6时，所述的R 1-16-6相同或不同；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮和/或氧，杂原子数为1～2个的C 3～C 5杂环烷基”；
    和/或，当R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4、R 1-16-6或R 1-16-7为C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 4烷基；
    和/或，当R 1-16-5为“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基，且其通过氮原子与羰基连接”；
    和/或，当R 1-16-5为卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的卤素的个数为一个或多个，当存在多个卤素时，所述的卤素相同或不同；
    和/或，当R 1-16-5为卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“卤素”独立地为氟、氯或溴；
    和/或，当R 1-16-5为卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 7杂环烷基，且其通过氮原子与羰基连接”；
    和/或，当R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4或R 1-16-5-5为R 1-16-5-1-1取代的C 1～C 7烷基时，所述的R 1-16-5-1-1的个数为一个或多个，当存在多个R 1-16-5-1-1时，所述的R 1-16-5-1-1相同或不同；
    和/或，当R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4或R 1-16-5-5为未取代或R 1-16-5-1-1取代的 C 1～C 7烷基时，所述的C 1～C 7烷基为C 1～C 4烷基；
    和/或，当R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4或R 1-16-5-5为C 2～C 7炔基时，所述的C 2～C 7炔基为C 2～C 4炔基。
  3. 一种如权利要求2所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，当R 1为R 1-16取代的C 1～C 7烷基、且所述的R 1-16的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1为未取代或R 1-16取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，当R 1为R 1-17取代的C 2～C 7烯基、且所述的R 1-17的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1为未取代或R 1-17取代的C 2～C 7烯基时，所述的C 2～C 7烯基为2-丙烯基；
    和/或，当R 1为R 1-18取代的C 2～C 8炔基、且所述的R 1-18的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1为未取代或R 1-18取代的C 2～C 8炔基时，所述的C 2～C 8炔基为2-丙炔基；
    和/或，当R 1为R 1-19取代的C 1～C 7烷硅基、且所述的R 1-19的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1为R 1-20取代的C 3～C 7环烷基、且所述的R 1-20的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1为未取代或R 1-20取代的C 3～C 7环烷基时，所述的C 3～C 7环烷基为环丁基；
    和/或，当R 1为R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、且所述的R 1-21的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1为未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”或“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”；
    和/或，当R 1为R 1-22取代的C 6～C 10芳基、且所述的R 1-22的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1为R 1-23取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、且所述的R 1-23的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1为R 1-24取代的C 1～C 7烷氧基、且所述的R 1-24的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1为R 1-25取代的C 1～C 7烷巯基、且所述的R 1-25的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1-1、R 1-2或R 1-3为未取代或R 1-1-3取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为卤素取代的C 1～C 7烷基时、且所述的卤素的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为卤素取代的C 1～C 7烷基时，所述的“卤素”独立地为氟、氯、溴或碘；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为卤素取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为C 2～C 7炔基时，所述的C 2～C 7炔基为2-丙炔基或1-丙炔基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为C 1～C 7烷氧基时，所述的C 1～C 7烷氧基为甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基或叔丁氧基；
    和/或，当R 1-4-1或R 1-4-2为C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，当R 1-11、R 1-12、R 1-13、R 1-14或R 1-15为R 1-11-1取代的C 1～C 7烷基、且所述的R 1- 11-1的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1-11、R 1-12、R 1-13、R 1-14或R 1-15为未取代或R 1-11-1取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为卤素时，所述的卤素为氟；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为R 1-16- 6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、且所述的R 1-16-6的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”、“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”或
    Figure PCTCN2018116352-appb-100003
    和/或，当R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4、R 1-16-6或R 1-16-7为C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，当R 1-16-5为“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为
    Figure PCTCN2018116352-appb-100004
    和/或，当R 1-16-5为卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、且所述的R 1-16-5的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1-16-5为卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“卤素”独立地为氟；
    和/或，当R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4或R 1-16-5-5为R 1-16-5-1-1取代的C 1～C 7烷基、且所述的R 1-16-5-1-1的个数为多个时，所述的多个为2个、3个或4个；
    和/或，当R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4或R 1-16-5-5为未取代或R 1-16-5-1-1取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基、异丙基、正丁基、异丁基、仲丁基或叔丁基；
    和/或，当R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4或R 1-16-5-5为C 2～C 7炔基时，所述的C 2～C 7炔基为2-丙炔基或1-丙炔基。
  4. 一种如权利要求3所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物 前体，其特征在于，当R 1为未取代或R 1-16取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基或异丙基；
    和/或，当R 1为未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”时，所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与Y连接”或“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与Y连接”；
    和/或，当R 1为未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”时，所述的“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”为
    Figure PCTCN2018116352-appb-100005
    和/或，当R 1-1、R 1-2或R 1-3为未取代或R 1-1-3取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基、乙基、正丙基或异丙基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为C 1～C 7烷基时，所述的C 1～C 7烷基为甲基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为卤素取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基；
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为C 1～C 7烷氧基时，所述的C 1～C 7烷氧基为甲氧基；
    和/或，当R 1-4-1或R 1-4-2为C 1～C 7烷基时，所述的C 1～C 7烷基为甲基；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”时，所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与其他基团连接”或者“杂 原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与其他基团连接”；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”时，所述的“杂原子为氧，杂原子数为1～2个的C 3～C 5杂环烷基”为
    Figure PCTCN2018116352-appb-100006
    和/或，当R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4、R 1-16-6或R 1-16-7为C 1～C 7烷基时，所述的C 1～C 7烷基为甲基；
    和/或，当R 1-16-5为卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”时，所述的“卤代的杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为
    Figure PCTCN2018116352-appb-100007
    和/或，当R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4或R 1-16-5-5为未取代或R 1-16-5-1-1取代的C 1～C 7烷基时，所述的C 1～C 7烷基为甲基或乙基。
  5. 一种如权利要求4所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，当R 1为未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”、“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与Y连接”时，所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与Y连接”为
    Figure PCTCN2018116352-appb-100008
    和/或，当R 1为未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和 磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”、“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与Y连接”时，所述的“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与Y连接”为
    Figure PCTCN2018116352-appb-100009
    和/或，当R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9或R 1-10为卤素取代的C 1～C 7烷基时，所述的卤素取代的C 1～C 7烷基为三氟甲基；
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”、“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与其他基团连接”时，“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过氮原子与其他基团连接”为
    Figure PCTCN2018116352-appb-100010
    Figure PCTCN2018116352-appb-100011
    和/或，当R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24或R 1-25为未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”、“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基”为“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与其他基团连接”时，“杂原子为氮，杂原子数为1～2个的C 3～C 5杂环烷基，且杂环烷基通过碳原子与其他基团连接”为
    Figure PCTCN2018116352-appb-100012
    Figure PCTCN2018116352-appb-100013
  6. 一种如权利要求5所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，R 1为下述任一基团：氢、氨基、甲基、乙基、正丙基、异丙基、2-羟基乙基、2-甲氧基乙基、2-甲基氨基乙基、2-二甲基氨基乙基、氰基甲基、氰基、乙酰基、2-丙烯基、2-丙炔基、二甲基氨基、2-氟乙基、2,2,2-三氟乙基、甲氧酰基、甲砜基、2,2,2-三氟乙酰基、环丁基、环丙基甲基、环丙基、二乙基氨基、二正丙基氨基、二甲基氨基甲基、甲氧基、羟基、羧甲基、
    Figure PCTCN2018116352-appb-100014
    Figure PCTCN2018116352-appb-100015
  7. 一种如权利要求1所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，X为CH；
    和/或，m和n独立地为0、1、2或3，且m+n为2或3；
    和/或，Y为N；
    和/或，R 1为H、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 8炔基、C 3～C 7环烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
    和/或，所有的R 1-1、R 1-2和R 1-3独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、或、未取代或R 1- 1-3取代的C 1～C 7烷基；所有的R 1-1-1、R 1-1-2和R 1-1-3独立地为C 1～C 7烷基或C 6～C 10芳基；
    和/或，所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 2～C 7炔基、C 1～C 7烷氧基、或、NR 1-4-1R 1-4-2；所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基；
    和/或，所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、未取代或R 1-16-7取代的C 3～C 7环烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；所有的R 1-16-1、R 1-16-2、R 1-16-3、R 1-16-4、R 1-16-6和R 1-16-7独立地为氢或C 1～C 7烷基；所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
    Figure PCTCN2018116352-appb-100016
    -NR 1- 16-5-1R 1-16-5-2或-OR 1-16-5-3；所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基；
    和/或，z为0。
  8. 一种如权利要求7所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，m和n独立地为0、1、2或3，且m+n为3；
    和/或，Y为N，且R 1中与Y相连的原子不为N；
    和/或，R 1为-NR 1-1R 1-2、R 1-16取代的C 1～C 7烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
    和/或，所有的R 1-1、R 1-2和R 1-3独立地为氢、-C(＝O)NR 1-1-1R 1-1-2、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；所有的R 1-1-1和R 1-1-2独立地为C 1～C 7烷基；
    和/或，所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、C 3～C 7环烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；所有的R 1- 16-1、R 1-16-2、R 1-16-3、R 1-16-4和R 1-16-6独立地为氢或C 1～C 7烷基；所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
    Figure PCTCN2018116352-appb-100017
    -NR 1-16-5-1R 1-16-5-2或-OR 1-16-5-3；所有的R 1- 16-5-1、R 1-16-5-2、R 1-16-5-3、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基。
  9. 一种如权利要求8所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，m和n独立地为1或2，且m+n为3；
    和/或，所有的R 1-1、R 1-2和R 1-3独立地为氢、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；
    和/或，所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、C 3～C 7环烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-SR 1-16-4或-(C＝O)R 1-16-5；所有的R 1-16-1、R 1- 16-2、R 1-16-4和R 1-16-6独立地为氢或C 1～C 7烷基；所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
    Figure PCTCN2018116352-appb-100018
    或-NR 1-16-5-1R 1-16-5-2；所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基。
  10. 一种如权利要求9所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，“m为2、n为1”或者“m为1、n为2”；
    和/或，所有的R 1-1和R 1-2独立地为氢、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；
    和/或，所有的R 1-16和R 1-21独立地为C 1～C 7烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”或-(C＝O)R 1-16-5；所有的R 1-16-6独立地为C 1～C 7烷基；所有的R 1-16-5独立地为
    Figure PCTCN2018116352-appb-100019
    所有的R 1-16-5-4和R 1-16-5-5独立地为C 1～C 7烷基。
  11. 一种如权利要求1所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，X为CH；
    “m为1，n为2”或者“m为2，n为1”；
    Y为N或CH；
    R 1为H、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-S(＝O) 2R 1-7、未取代或R 1-16取代的 C 1～C 7烷基、C 2～C 7烯基、C 2～C 8炔基、C 3～C 7环烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
    所有的R 1-1、R 1-2和R 1-3独立地为氢、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；
    所有的R 1-4和R 1-7独立地为C 1～C 7烷基、卤素取代的C 1～C 7烷基、C 2～C 7炔基、C 1～C 7烷氧基、或、NR 1-4-1R 1-4-2；
    所有的R 1-4-1和R 1-4-2独立地为C 1～C 7烷基；
    所有的R 1-16和R 1-21独立地为卤素、氰基、C 1～C 7烷基、C 3～C 7环烷基、未取代或R 1- 16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、-NR 1-16-1R 1-16-2、-SR 1-16-4或-(C＝O)R 1-16-5；
    所有的R 1-16-1、R 1-16-2、R 1-16-4和R 1-16-6独立地为氢或C 1～C 7烷基；
    所有的R 1-16-5独立地为羟基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、
    Figure PCTCN2018116352-appb-100020
    或-NR 1-16-5-1R 1-16-5-2；
    所有的R 1-16-5-1、R 1-16-5-2、R 1-16-5-4和R 1-16-5-5独立地为氢、未取代或羟代的C 1～C 7烷基、C 2～C 7炔基、或、C 3～C 7环烷基；
    z为0。
  12. 一种如权利要求1所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，X为CH；
    m为2，n为1；
    Y为N或CH；
    R 1为-NR 1-1R 1-2、R 1-16取代的C 1～C 7烷基、或、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”；
    所有的R 1-1和R 1-2独立地为氢、或、未取代或C 6～C 10芳基取代的C 1～C 7烷基；
    所有的R 1-16和R 1-21独立地为C 1～C 7烷基、未取代或R 1-16-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”或-(C＝O)R 1- 16-5；
    所有的R 1-16-6独立地为C 1～C 7烷基；所有的R 1-16-5独立地为
    Figure PCTCN2018116352-appb-100021
    所有的 R 1-16-5-4和R 1-16-5-5独立地为C 1～C 7烷基；
    z为0。
  13. 一种如权利要求1所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，X为N或CH；
    m和n独立地为0、1、2或3，且m+n为2、3或4；
    Y为N或CH；
    R 1为H、卤素、巯基、硝基、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-C(＝NR 1-11)R 1- 5、-S(＝O)R 1-6、-S(＝O) 2R 1-7、-S(＝NR 1-12)R 1-8、-S(＝NR 1-13)(＝NR 1-14)R 1-9、-S(＝O)(＝NR 1-15)R 1- 10、未取代或R 1-16取代的C 1～C 7烷基、未取代或R 1-17取代的C 2～C 7烯基、未取代或R 1-18取代的C 2～C 8炔基、未取代或R 1-19取代的C 1～C 7烷硅基、未取代或R 1-20取代的C 3～C 7环烷基、未取代或R 1-21取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、未取代或R 1-22取代的C 6～C 10芳基、未取代或R 1- 23取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、未取代或R 1-24取代的C 1～C 7烷氧基、或者、未取代或R 1-25取代的C 1～C 7烷巯基；
    所有的R 1-1、R 1-2和R 1-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9和R 1-10独立地为羟基、C 1～C 7烷基、卤素取代的C 1～C 7烷基、卤素、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、C 1～C 7烷氧基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、或、NR 1-4-1R 1-4-2；
    所有的R 1-4-1和R 1-4-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-11、R 1-12、R 1-13、R 1-14和R 1-15独立地为H、氰基、羟基、C 1～C 7烷氧基、未取代或R 1-11-1取代的C 1～C 7烷基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷 中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、或者、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-11-1独立地为卤素、羟基、氰基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、C 1～C 7杂环烷基、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”或C 1～C 7烷氧基；
    所有的R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24和R 1-25独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
    所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、卤代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、-NR 1-16-5-1R 1-16-5-2或-OR 1-16-5-3；
    所有的R 1-16-5-1、R 1-16-5-2和R 1-16-5-3独立地为氢、未取代或R 1-16-5-1-1取代的C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-16-5-1-1独立地为卤素、羟基、氰基、氨基、C 1～C 7烷基、C 1～C 7烷氧基、C 1～C 7烷巯基、C 1～C 7烷硅基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    z为0、1或2；
    所有的R 2独立地为卤素、羟基、氰基、氨基、未取代或R 2-1取代的C 1～C 7烷基、未 取代或R 2-2取代的C 2～C 8烯基、未取代或R 2-3取代的C 2～C 7炔基、未取代或R 2-4取代的C 1～C 7烷硅基、未取代或R 2-5取代的C 6～C 10芳基、未取代或R 2-6取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 3～C 7环烷基、或者、未取代或R 2-7取代的C 1～C 7烷氧基；
    所有的R 2-1、R 2-2、R 2-3、R 2-4、R 2-5、R 2-6和R 2-7独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 2-1-1R 2-1-2、-OR 2-1-3、-SR 2-1-4或-(C＝O)R 2-1-5；
    所有的R 2-1-1、R 2-1-2、R 2-1-3和R 2-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 2-1-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    或者，两个R 2连接在同一碳原子上共同形成未取代或R 2-8取代的C 3～C 7环烷基、或者、未取代或R 2-9取代的C 1～C 7杂环烷基；
    所有的R 2-8和R 2-9独立地为卤素、氰基、巯基、羟基、氨基、C 1～C 7烷氧基或C 1～C 7烷巯基。
  14. 一种如权利要求1所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，X为N或CH；
    m和n独立地为0、1、2或3，且m+n为2、3或4；
    Y为N或CH；
    R 1为H、卤素、巯基、硝基、氰基、-NR 1-1R 1-2、-OR 1-3、-C(＝O)R 1-4、-C(＝NR 1-11)R 1- 5、-S(＝O)R 1-6、-S(＝O) 2R 1-7、-S(＝NR 1-12)R 1-8、-S(＝NR 1-13)(＝NR 1-14)R 1-9、-S(＝O)(＝NR 1-15)R 1- 10、R 1-16取代或未取代C 1～C 7烷基、R 1-17取代或未取代C 2～C 7烯基、R 1-18取代或未取代C 2～C 8炔基、R 1-19取代或未取代C 1～C 7烷硅基、R 1-20取代或未取代C 3～C 7环烷基、R 1-21取代或未取代的“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4 个的C 3～C 7杂环烷基”、R 1-22取代或未取代C 6～C 10芳基、R 1-23取代或未取代“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、R 1- 24取代或未取代C 1～C 7烷氧基、或者、R 1-25取代或未取代C 1～C 7烷巯基；
    R 1-1、R 1-2和R 1-3独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    R 1-4、R 1-5、R 1-6、R 1-7、R 1-8、R 1-9和R 1-10独立地为羟基、C 1～C 7烷基、卤素、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、或、NR 1-4-1R 1-4-2；
    所有的R 1-4-1和R 1-4-2独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    R 1-11、R 1-12、R 1-13、R 1-14和R 1-15独立地为H、氰基、羟基、C 1～C 7烷氧基、R 1-11-1取代或未取代C 1～C 7烷基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、或者、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-11-1独立地为卤素、羟基、氰基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、C 1～C 7杂环烷基、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”或C 1～C 7烷氧基；
    所有的R 1-16、R 1-17、R 1-18、R 1-19、R 1-20、R 1-21、R 1-22、R 1-23、R 1-24和R 1-25独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 1-16-1R 1-16-2、-OR 1-16-3、-SR 1-16-4或-(C＝O)R 1-16-5；
    所有的R 1-16-1、R 1-16-2、R 1-16-3和R 1-16-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷 中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 1-16-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    z为0、1或2；
    所有的R 2独立地为卤素、羟基、氰基、氨基、R 2-1取代或未取代C 1～C 7烷基、R 2-2取代或未取代C 2～C 8烯基、R 2-3取代或未取代C 2～C 7炔基、R 2-4取代或未取代C 1～C 7烷硅基、R 2-5取代或未取代C 6～C 10芳基、R 2-6取代或未取代“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、或者、R 2-7取代或未取代C 1～C 7烷氧基；
    所有的R 2-1、R 2-2、R 2-3、R 2-4、R 2-5、R 2-6和R 2-7独立地为卤素、硝基、氰基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 1～C 7烷硅基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”、C 1～C 7烷氧基、C 1～C 7烷巯基、-NR 2-1-1R 2-1-2、-OR 2-1-3、-SR 2-1-4或-(C＝O)R 2-1-5；
    所有的R 2-1-1、R 2-1-2、R 2-1-3和R 2-1-4独立地为氢、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    所有的R 2-1-5独立地为羟基、C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基、C 3～C 7环烷基、“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 3～C 7杂环烷基”、C 6～C 10芳基或“杂原子为硼、硅、氧、硫、硒、氮和磷中的一种或多种，杂原子数为1～4个的C 1～C 7杂芳基”；
    或者，两个R 2连接在同一碳原子上共同形成R 2-8取代或未取代C 3～C 7环烷基、或者、R 2-9取代或未取代C 1～C 7杂环烷基；
    所有的R 2-8和R 2-9独立地为卤素、氰基、巯基、羟基、氨基、C 1～C 7烷氧基或C 1～C 7烷巯基。
  15. 一种如权利要求1所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，X为CH；
    “m为2、n为0”、“m为1、n为1”、或者、“m为2、n为1”；
    Y为N；
    R 1为H、氰基、-NR 1-1R 1-2、-C(＝O)R 1-4、R 1-16取代或未取代C 1～C 7烷基、C 2～C 7烯基、或、C 2～C 7炔基；
    R 1-1和R 1-2独立地为C 1～C 7烷基；
    R 1-4独立地为C 1～C 7烷基或C 2～C 7炔基；
    所有的R 1-16独立地为氰基、-NR 1-16-1R 1-16-2或-OR 1-16-3；
    所有的R 1-16-1、R 1-16-2和R 1-16-3独立地为氢或C 1～C 7烷基；
    z为0。
  16. 一种如权利要求1所述的吡唑酮并嘧啶类化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，其特征在于，所述的化合物I为如下任一化合物：
    Figure PCTCN2018116352-appb-100022
    Figure PCTCN2018116352-appb-100023
    Figure PCTCN2018116352-appb-100024
    Figure PCTCN2018116352-appb-100025
    Figure PCTCN2018116352-appb-100026
  17. 一种如权利要求1～16中至少一项所述的化合物I的制备方法，其特征在于，其为如下任一方法：
    方法一：
    其包括下述步骤：化合物1A经氧化，得到化合物1B，取代后得到化合物1D，脱保护得到化合物1E即可；
    Figure PCTCN2018116352-appb-100027
    其中，PG为氨基保护基；
    方法二：
    其包括下述步骤：化合物1A经氧化，得到化合物1B，与2A反应后得到化合物2B即可；
    Figure PCTCN2018116352-appb-100028
    方法三：
    当R 1为未取代或R 1-16取代的C 1～C 7烷基、未取代或R 1-17取代的C 2～C 7烯基、未取代或R 1-18取代的C 2～C 8炔基、或、未取代或R 1-20取代的C 3～C 7环烷基时，其包括下述步骤：在有机溶剂中，在还原剂的存在下，将化合物1E与R 1-CHO进行还原胺化反应，得到化合物I即可；
    Figure PCTCN2018116352-appb-100029
    其中，Y为N，所述的R 1’-CH 2-等同于R 1；
    方法四：
    当R 1为未取代或R 1-16取代的C 1～C 7烷基、未取代或R 1-17取代的C 2～C 7烯基、未取代或R 1-18取代的C 2～C 8炔基、未取代或R 1-20取代的C 3～C 7环烷基、氰基或乙酰基时，其包括下述步骤：在有机溶剂中，在碱的存在下，将化合物1E与R 1-X 1进行取代反应，得到化合物I即可；
    Figure PCTCN2018116352-appb-100030
    其中，所述的X 1为卤素；Y为N；
    方法五：
    当R 1为-C(＝O)R 1-4，且R 1-4为C 1～C 7烷基、C 2～C 7烯基、C 2～C 7炔基或C 3～C 7环烷基时，其包括下述步骤：在有机溶剂中，在缩合剂的存在下，将化合物1E，与
    Figure PCTCN2018116352-appb-100031
    进行缩合反应，得到化合物I即可；
    Figure PCTCN2018116352-appb-100032
    其中，Y为N。
  18. 一种如式1C、1D或2A所示的化合物：
    Figure PCTCN2018116352-appb-100033
    其中，PG、m、n、z、Y、R 1和R 2的定义如权利要求1～17中至少一项所述。
  19. 一种如权利要求1～16中至少一项所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体在制备药物或激酶抑制剂中的应用；
    所述的药物用于治疗和/或预防与WEE1激酶有关的疾病，或者，所述的药物用于治疗和/或预防癌症。
  20. 一种药物组合物，其包含如权利要求1～16中至少一项所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，和，药用辅料。
  21. 一种组合，其包含如权利要求1～16中至少一项所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，和，抗癌药物。
  22. 一种如权利要求21所述的组合在制备药物中的应用，所述的药物用于治疗和/或预防癌症。
  23. 一种如权利要求1～16中至少一项所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体在制备药物中的应用，所述的药物用于“和如权利要求21所述的抗癌药物联合”治疗和/或预防癌症。
  24. 一种如权利要求21所述的抗癌药物在制备药物中的应用，所述的药物用于“和联合如权利要求1～16中至少一项所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体”治疗和/或预防癌症。
  25. 一种药物组合物，其包含如权利要求21所述的组合和药用辅料。
  26. 一种组合药盒，其包含药物组合物A和药物组合物B；
    所述的药物组合物A包括如权利要求1～16中至少一项所述的化合物I、其对映异构体、其非对映异构体、其互变异构体、其晶型、其药学上可接受的盐、其溶剂化物、其代谢产物或其药物前体，和，药用辅料；
    所述的药物组合物B包括如权利要求21所述的抗癌药物和药用辅料。
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