WO2019096322A1 - Composé de pyrazolone-pyrimidine, son procédé de préparation et son application - Google Patents

Composé de pyrazolone-pyrimidine, son procédé de préparation et son application 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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group
nitrogen
substituted
alkyl
oxygen
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PCT/CN2018/116352
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Chinese (zh)
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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
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    • 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
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    • 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

La présente invention concerne un composé de pyrazolone-pyrimidine, son procédé de préparation et une application correspondante. La présente invention concerne un composé de pyrazolone-pyrimidine tel que représenté par la formule (I), et un énantiomère, un diastéréoisomère, un tautomère, une forme cristalline, un sel pharmaceutiquement acceptable, un solvate, un métabolite ou un promédicament de celui-ci. Le composé a une activité d'inhibition élevée pour la kinase WEE1.
PCT/CN2018/116352 2017-11-20 2018-11-20 Composé de pyrazolone-pyrimidine, son procédé de préparation et son application WO2019096322A1 (fr)

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US10793561B2 (en) 2017-07-18 2020-10-06 Nuvation Bio Inc. 1,8-naphthyridinone compounds and uses thereof
US10807994B2 (en) 2017-10-09 2020-10-20 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
WO2021098813A1 (fr) * 2019-11-22 2021-05-27 南京明德新药研发有限公司 Composés spiro pyrimidopyrrole et leurs dérivés en tant qu'inhibiteurs de la protéine dna-pk
US11028058B2 (en) 2017-07-18 2021-06-08 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
US11254670B2 (en) 2019-01-18 2022-02-22 Nuvation Bio Inc. 1,8-naphthyridinone compounds and uses thereof
US11261192B2 (en) 2018-03-09 2022-03-01 Recurium Ip Holdings, Llc Substituted 1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidin-3-ones
US11299493B2 (en) 2017-10-09 2022-04-12 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US11306071B2 (en) 2019-01-18 2022-04-19 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
US11332473B2 (en) 2019-04-09 2022-05-17 Nuvation Bio Inc. Substituted pyrazolo[3,4-d]pyrimidines as Wee1 inhibitors
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors

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KR102549484B1 (ko) * 2020-12-08 2023-06-29 한국화학연구원 피라졸로피리미딘 설폰아마이드 유도체 및 이를 유효성분으로 포함하는 암 관련 질환의 예방 또는 치료용 약학적 조성물
CN117222648A (zh) * 2021-04-30 2023-12-12 微境生物医药科技(上海)有限公司 作为Wee-1抑制剂的稠环化合物及其制备方法和用途
CN117751122A (zh) * 2021-08-11 2024-03-22 微境生物医药科技(上海)有限公司 作为Wee-1抑制剂的1,2-二氢-3H-吡唑[3,4-d]嘧啶-3-酮化合物
WO2023045942A1 (fr) * 2021-09-22 2023-03-30 微境生物医药科技(上海)有限公司 Composé 1,2-dihydro-3h-pyrazole[3,4-d]pyrimidin-3-one servant d'inhibiteur de wee-1
CN113735863A (zh) * 2021-09-29 2021-12-03 武汉九州钰民医药科技有限公司 Wee1抑制剂adavosertib的制备工艺

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US10793561B2 (en) 2017-07-18 2020-10-06 Nuvation Bio Inc. 1,8-naphthyridinone compounds and uses thereof
US11028058B2 (en) 2017-07-18 2021-06-08 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
US10807994B2 (en) 2017-10-09 2020-10-20 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US11299493B2 (en) 2017-10-09 2022-04-12 Nuvation Bio Inc. Heterocyclic compounds and uses thereof
US11261192B2 (en) 2018-03-09 2022-03-01 Recurium Ip Holdings, Llc Substituted 1,2-dihydro-3H-pyrazolo[3,4-D]pyrimidin-3-ones
US11254670B2 (en) 2019-01-18 2022-02-22 Nuvation Bio Inc. 1,8-naphthyridinone compounds and uses thereof
US11306071B2 (en) 2019-01-18 2022-04-19 Nuvation Bio Inc. Heterocyclic compounds as adenosine antagonists
US11332473B2 (en) 2019-04-09 2022-05-17 Nuvation Bio Inc. Substituted pyrazolo[3,4-d]pyrimidines as Wee1 inhibitors
WO2021098813A1 (fr) * 2019-11-22 2021-05-27 南京明德新药研发有限公司 Composés spiro pyrimidopyrrole et leurs dérivés en tant qu'inhibiteurs de la protéine dna-pk
TWI768550B (zh) * 2019-11-22 2022-06-21 大陸商南京明德新藥研發有限公司 作為dna-pk抑制劑的嘧啶并吡咯類螺環化合物及其衍生物
US12084453B2 (en) 2021-12-10 2024-09-10 Incyte Corporation Bicyclic amines as CDK12 inhibitors

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