WO2023071998A1 - Nouveau composé pyrido ou pyrido hétérocyclique à substitution triazine - Google Patents

Nouveau composé pyrido ou pyrido hétérocyclique à substitution triazine Download PDF

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Publication number
WO2023071998A1
WO2023071998A1 PCT/CN2022/127094 CN2022127094W WO2023071998A1 WO 2023071998 A1 WO2023071998 A1 WO 2023071998A1 CN 2022127094 W CN2022127094 W CN 2022127094W WO 2023071998 A1 WO2023071998 A1 WO 2023071998A1
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alkyl
alkoxy
amino
group
cycloalkyl
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PCT/CN2022/127094
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English (en)
Chinese (zh)
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张龙
牛张明
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杭州德睿智药科技有限公司
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Publication of WO2023071998A1 publication Critical patent/WO2023071998A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • 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

Definitions

  • the invention belongs to the field of medicinal chemistry and discloses a novel pyrimidine or triazine substituted pyridoheterocyclic compound, which can be used as an EGFR mutation target inhibitor.
  • the compound of the formula (I) has a strong affinity for the EGFR mutation target, especially for the EGFR19del/L858R-T790M-C797S triple mutant protein, and can be used to prepare for the prevention or treatment of EGFR mutations (especially 19del/L858R-T790M-C797S).
  • L858R-T790M-C797S triple mutation signaling pathway-related diseases (such as cancer, immune diseases, etc.)
  • Epidermal growth factor receptor is a member of the erbB receptor family, which includes four major transmembrane protein tyrosine kinase receptor members EGFR, erbB2, erbB3 and erbB4.
  • EGFR epidermal growth factor
  • ligands such as epidermal growth factor (EGF)
  • EGFR can form homodimers on the cell membrane or form heterodimers with several other major members of the same family, such as erbB2, erbB3 or erbB4.
  • the formation of these dimers can lead to phosphorylation of key tyrosine residues in EGFR-expressing cells, thereby activating many intracellular downstream signaling pathways, resulting in cell proliferation, survival and resistance to apoptosis.
  • EGFR signal transduction pathways including increased expression of ligands and receptors, EGFR gene amplification and changes such as mutations and deletions, can promote malignant transformation of cells and play an important role in tumor cell proliferation, invasion, metastasis and angiogenesis .
  • EGFR gene mutation and deletion are one of the most important causes of non-small cell lung cancer.
  • EGFR mutations found in NSCLC tumors are exon 19 (del 19) deletion, L858R mutation, and single missense mutation in exon 21. These several changes lead to ligand-independent EGFR activation, leading to the occurrence, development and progression of tumors.
  • EGFR inhibitors have been approved for marketing, such as erlotinib, gefitinib, afatinib, osimertinib, etc.
  • first-generation drugs such as erlotinib or gefitinib
  • second-generation drugs afatinib
  • the most prominent resistance mechanism to first- and second-generation EGFR-TKIs is due to secondary mutations in genes such as T790M mutations, which occur in about 50% to 70% of patients. This secondary mutation reduces the affinity of the first- and second-generation drugs for the target protein, resulting in drug resistance and leading to tumor recurrence or disease progression.
  • the third-generation EGFR TKI—osimertinib It has been developed for the treatment of primary EGFR mutation-positive NSCFC patients with tumors with or without the T790M mutation in the dell9 or L858R gene mutation. Although the third-generation EGFR TKI osimertinib has shown good efficacy in NSCLC, unfortunately, after an average of more than 10 months of treatment, most patients still develop resistance to the drug, leading to disease progression.
  • One of the main reasons for drug resistance is the mutation of EGFR exon 20 C797 (C797S).
  • the EGFR dell9/L858R-T790M-C797S cis mutation commonly occurs in patients treated with osimertinib and is referred to as a “triple mutation” where first-, second-, or third-generation EGFR inhibitors are no longer effective.
  • triple mutation There are currently no effective therapeutics that can inhibit the triple mutant variant. Therefore, there is an urgent need to develop new EGFR inhibitors that can highly selectively inhibit the triple EGFR mutant (dell9/L858R-T790M-C797S) while having no or low activity against wild type.
  • the inventors unexpectedly found that some of the novel compounds of the formula (I) of the present invention showed a very high affinity with triple EGFR mutant (dell9/L858R-T790M-C797S) protein affinity prediction, which is expected to be used for the detection of EGFR mutant tumors treat. Further research is still ongoing.
  • the object of the present invention is to provide new compounds shown in formula (I) or pharmaceutically acceptable salts, solvates, isomers and isotope substitutions thereof:
  • a and B are 3-20-membered ring structures, and the ring structures can be arbitrarily monocyclic, bicyclic, tricyclic, bridging rings or spiro rings containing 0 to more unsaturated bonds; and the ring structures It can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N; or, X 5 , X 6 and their respective attached atoms form a hydrocarbon ring or heterocycle; or, X 2 and X 1 or X 2 and X 3 form a hydrocarbon ring or a heterocycle with their respective attached atoms;
  • Y 0 is independently selected from a single bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or - C(R 6 R 7 )-;
  • Y1 and Y2 are each independently selected from CH or N;
  • R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can constitute 3-10 membered ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms, the heteroatoms can be selected from O , S or N;
  • R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy,
  • R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic,
  • the hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally The following groups selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, unsubstituted or optionally substituted by one, two or more R 5 :
  • R is arbitrarily selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;
  • R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;
  • R and R are arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 Alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 7 and R 6 form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be any It is a monocyclic ring, a bicyclic ring, a bridged ring or a spiro ring containing 0 to more unsaturated bonds; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5.
  • the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has a structure of formula (I'):
  • a and B are 3-20-membered ring structures, and the ring structures can be arbitrarily monocyclic, bicyclic, tricyclic, bridging rings or spiro rings containing 0 to more unsaturated bonds; and the ring structures It can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • Y 0 is independently selected from a single bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or - C(R 6 R 7 )-;
  • R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can constitute 3-10 membered ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms, the heteroatoms can be selected from O , S or N;
  • R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy,
  • R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic,
  • the hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, hal
  • R is arbitrarily selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;
  • R and R are arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 Alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl; or R 7 and R 6 form a 3-10-membered ring structure together with the carbon directly connected to it, and the ring structure can be any It is a monocyclic ring, a bicyclic ring, a bridged ring or a spiro ring containing 0 to more unsaturated bonds; and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (IA):
  • A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;
  • R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can constitute 3-10 membered ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms, the heteroatoms can be selected from O , S or N;
  • R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy,
  • R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic,
  • the hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, hal
  • R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5;
  • the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IB):
  • A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;
  • Z is any independently absent, O, NH or N(R 5 );
  • R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and two adjacent X 1 and X 2 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can form 3-10 members
  • a ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N ;
  • R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy,
  • R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic,
  • the hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, hal
  • R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (IC):
  • X 0 is independently selected from -O-, -S-, -N(R 5 )-, -S(O)-, -S(O) 2 -, -C(R 6 R 7 )O-, -OC (R 6 R 7 )-or -C(R 6 R 7 )-;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;
  • R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can constitute 3-10 membered ring structure, the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms, the heteroatoms can be selected from O , S or N;
  • R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy,
  • R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic,
  • the hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, hal
  • R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (ID):
  • A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;
  • X 3 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 are each independently selected from C(R 0 ) or N;
  • Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;
  • Z is any independently absent, O, NH or N(R 5 );
  • R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can form a 3-10-membered ring structure, and the ring structure can be Any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are randomly selected from O, S or N;
  • R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy,
  • R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic,
  • the hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, hal
  • R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the formula
  • A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;
  • X 1 , X 4 , X 5 , X 6 , X 7 , X 8 , X 9 , X 10 , X 11 , X 12 are each independently selected from C(R 0 ), C(R 0 ) 2 , N(R 0 ) or N;
  • Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;
  • Z is any independently absent, O, NH or N(R 5 );
  • R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; any two adjacent X 5 , X 6 , X 7 and X 8 together with the R 0 connected thereto can form a 3-10-membered ring structure, and the ring structure can be Any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are randomly selected from O, S or N;
  • R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy,
  • R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic,
  • the hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, hal
  • R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (IF):
  • A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;
  • X 1 , X 4 , X 2 , X 3 , X 7 , X 8 , X 9 , and X 10 are each independently selected from C(R 0 ), C(R 0 ) 2 , C(R 0 ) 2 C(R 0 ) 2 , N(R 0 ), C(R 0 ) 2 N(R 0 ) or N;
  • Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;
  • Z is any independently absent, O, NH or N(R 5 );
  • R is randomly selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, alkenyl , hydroxyl, cyano, nitro; any two adjacent X 1 , X 2 or X 3 together with the R 0 attached to it can form a 3-10 membered ring structure, and the ring structure can be arbitrarily saturated , unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • R is independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, Deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy; and the hydroxyl, amino, C1-6 alkyl, alkenyl, Hydrogen on alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy Can be optionally further substituted by 1 to more substituents, the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 Alkoxy,
  • R is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, alkenyl, cyano, Cyanoalkyl, nitro, acyl, sulfonyl, phosphono; and the C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocyclic,
  • the hydrogen on the heterocycloalkyl, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono can be optionally further substituted by 1 to more substituents, and the substituents are optionally From hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, hal
  • R and R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocyclyl Cycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, nitro, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphine Acyl;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5;
  • the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (II):
  • A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;
  • X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • Y 0 is independently selected from a bond, an acetylene bond, -O-, -S-, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C (R 6 R 7 )-;
  • Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 and above
  • the connected R 0 can form a 3-10 membered ring structure together, and the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms at will, so
  • the heteroatoms mentioned above are arbitrarily selected from O, S or N;
  • Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any
  • Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents,
  • the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkyls
  • R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;
  • R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5.
  • the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IIA):
  • A is a 3-20-membered ring structure, and the ring structure can be arbitrarily monocyclic, bicyclic, tricyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can be any Contains 0 to more heteroatoms, the heteroatoms are arbitrarily selected from O, S or N;
  • X 3 , X 6 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and any two adjacent X 1 , X 2 and X 3 or any two adjacent X 5 , X 6 , X 7 and X 8 and above
  • the connected R 0 can form a 3-10 membered ring structure together, and the ring structure can be any saturated, unsaturated or aromatic structure, and the ring structure can contain 0 to more heteroatoms at will, so
  • the heteroatoms mentioned above are arbitrarily selected from O, S or N;
  • Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any
  • Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents,
  • the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkyls
  • R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5.
  • the compound or its pharmaceutically acceptable salt, isotope substitution or its isomer has the structure of formula (IIB):
  • X is any independently selected from C, C(R 0 ) or N;
  • X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;
  • Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and two adjacent X 7 and X 8 together with the connected R 0 can form a 3-10-membered ring structure, the ring
  • the structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any
  • Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents,
  • the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkyls
  • R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;
  • R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5.
  • the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IIC):
  • X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;
  • Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro;
  • Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any
  • Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents,
  • the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkyls
  • R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;
  • R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5.
  • the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IID):
  • X is any independently selected from C, C(R 0 ) or N;
  • Z is any independently O, NH or N(R 3 );
  • X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N; and when X 3 is CH, X is not N;
  • X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;
  • Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and two adjacent X 7 and X 8 together with the connected R 0 can form a 3-10-membered ring structure, the ring
  • the structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any
  • Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents,
  • the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkyls
  • R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;
  • R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5.
  • the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has a structure of formula (IIE):
  • Z is any independently O, NH or N(R 3 );
  • X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;
  • Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and two adjacent X 7 and X 8 together with the connected R 0 can form a 3-10-membered ring structure, the ring
  • the structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any
  • Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents,
  • the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkyls
  • R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;
  • R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5.
  • the compound or its pharmaceutically acceptable salt, isotopic substitution or its isomer has the structure of formula (IIF):
  • Z is any independently O, NH or N(R 3 );
  • X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • X 10 is independently selected from -O-, -S-, -SO-, -SO 2 -, -N(R 3 )-, -C(R 6 R 7 )O-, -OC(R 6 R 7 )- or -C(R 6 R 7 )-;
  • Each R can be the same or different, and is arbitrarily selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro; and two adjacent X 7 and X 8 together with the connected R 0 can form a 3-10-membered ring structure, the ring
  • the structure can be any saturated, unsaturated or aromatic structure, and the ring structure can optionally contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • Each R can be the same or different, and any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halo Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R It can be optionally further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl , C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, Alkylamino; or any
  • Each R can be the same or different, and any independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkane group, amino group, alkenyl group, cyano group, cyanoalkyl group, nitro group, acyl group, sulfonyl group, phosphono group, etc.; and the hydrogen on R2 can be optionally further substituted by 1 to more substituents,
  • the substituents are arbitrarily selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogenated C1-6 alkoxy , deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, sulfone, sulfoxide, alkyls
  • R is independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl, sulfonyl, phosphono;
  • R is independently selected from H, deuterium, halogen, hydroxyl, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, heterocycloalkyl, Amino, C1-6 alkylamino, alkenyl, alkynyl, cyano, cyanoalkyl, C1-6 alkyl acyl, halogenated C1-6 alkyl acyl; and the hydrogen on R can be the most optional Further substituted by 1 to more substituents, any of which are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkylamino;
  • the halogen is F, Cl, Br and iodine and their respective isotopes;
  • R and R is independently selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl, amino, C1-6 alkylamino group, alkenyl group, alkynyl group, nitro group, cyano group, cyanoalkyl group; or R 7 and R 6 form a 3-10 membered ring structure together with the directly connected carbon, and the ring
  • the structure can be arbitrarily monocyclic, bicyclic, bridged or spiro ring containing 0 to more unsaturated bonds; and the ring structure can arbitrarily contain 0 to more heteroatoms, and the heteroatoms are arbitrarily selected from O, S or N;
  • n and t are each independently 0, 1, 2, 3, 4 or 5;
  • n is independently 1, 2, 3, 4 or 5.
  • a or B is independently selected from a 3-10 membered heterocycle or a C3-10 hydrocarbon ring;
  • A is selected from piperidine ring, tetrahydropyrrole ring,
  • B is selected from N-hetidine rings.
  • X 1 , X 2 , and X 3 are independently selected from N or CH, and are not N at the same time; or, X 2 and X 1 or X 2 and X 3 form a
  • X 4 and X 5 are independently selected from N or CH;
  • X 6 is selected from C(R 0 ); or, X 5 , X 6 and their respective attached atoms form
  • X 7 , X 8 are independently selected from N or CH.
  • Y is selected from NH
  • Y 1 when Y 1 is CH, it is linked to Y 0 , and Y 2 is N; or, when Y 2 is CH, it is linked to Y 0 , and Y 1 is N.
  • R is selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, C3-8 cycloalkyl;
  • R is selected from H, deuterium, Cl, methyl, isopropyl, cyclopropyl.
  • R is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, hydroxy C1-6 alkyl, hydroxy C1-6 alkoxy, C3-8 cycloalkyl, C1-6 alkoxy-C1-6 alkoxy, C1-6 alkyl-amino -C1-6 alkoxy, (C1-6 alkyl) 2 -amino-C1-6 alkoxy, C1-6 alkylamino, (C1-6 alkyl) 2 -amino;
  • R is selected from H, deuterium, F, hydroxy, amino, methyl, methoxy, methylamino, hydroxymethyl, hydroxyethyl, hydroxyethoxy, deuteromethyl, deuterium Substituted methoxy, methoxy-ethoxy,
  • R is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, C1-6 alkoxy, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, C3-8 cycloalkyl,
  • R is selected from H, deuterium, F, hydroxyl, amino, methyl, methoxy;
  • R is selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkoxy, halogenated C1 -6 alkoxy, deuterated C1-6 alkoxy, C3-8 cycloalkyl, C3-8 cycloalkyloxy, C1-6 alkyl-amino-C1-6 alkyl, (C1-6 alk Base) 2 -amino-C1-6 alkyl, C1-6 alkyl-3-8 membered heterocyclic group;
  • R is selected from methyl, ethyl, isopropyl, cyclopropyl, dimethylaminoethyl, difluoromethyl, trifluoromethyl, cyclopropyloxy,
  • R and R are each independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, halogenated C1-6 alkyl, C1-6 alkane Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, C3-8 cycloalkyl, amino C1-6 alkyl;
  • R6 and R7 are each independently selected from H, methyl, aminomethyl.
  • the above-mentioned compounds or their pharmaceutically acceptable salts, or their isomers and isotope substitutions are selected from the compounds with the following structures in the examples: Compound 1 to Compound 308, Compound A1 to Compound A40.
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount of at least one of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer and isotopic substitution kind.
  • the pharmaceutical composition is formulated for administration by a route selected from the group consisting of: oral, injectable, rectal, nasal, pulmonary, topical, buccal and sublingual, vaginal, parenteral, subcutaneous, Intramuscular, intravenous, intradermal, intrathecal, and epidural.
  • the pharmaceutical composition is preferably administered orally.
  • the oral dosage form is not particularly limited, and any oral dosage form known in the art can be used, preferably including tablets, capsules, suspensions or oral solutions and other oral dosage forms known in the art.
  • the dosage standard used is, for example, 500-1500 mg/day, preferably 700-1200 mg/day, preferably 800-1000 mg/day, most preferably 1000 mg/day.
  • the medication time of the pharmaceutical composition according to the present invention can be determined according to the severity of the disease, preferably at least 1 month, for example, 1, 2, 3, 4, 5 or 6 months, the longest may be taken for life due to the needs of the disease .
  • the pharmaceutical composition may further comprise pharmaceutically acceptable excipients, which are selected from at least one of the following excipients including but not limited to: fillers, disintegrants, binders, lubricants , surfactants, flavoring agents, wetting agents, pH regulators, solubilizers or co-solvents, osmotic pressure regulators.
  • pharmaceutically acceptable excipients including but not limited to: fillers, disintegrants, binders, lubricants , surfactants, flavoring agents, wetting agents, pH regulators, solubilizers or co-solvents, osmotic pressure regulators.
  • the pharmaceutical composition may further contain one or more additional therapeutic agents.
  • Another object of the present invention is to provide the application of the above-mentioned compound, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer in the preparation of medicines for preventing or treating diseases caused by EGFR mutation .
  • Another object of the present invention is to provide the application of the above-mentioned compound, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer in the preparation of medicines for preventing or treating diseases caused by EGFR mutation .
  • Another object of the present invention is to provide the above-mentioned compound, its pharmaceutically acceptable salt, solvate or hydrate and its isotope or isomer in the preparation for the prevention or treatment of EGFR mutation, especially triple EGFR mutant ( dell9/L858R-T790M-C797S) mutation-related diseases or diseases caused by EGFR mutation-related signaling pathways.
  • Another object of the present invention is to provide the above compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers used in the preparation of prevention or treatment of EGFR mutations or signaling pathways related to EGFR mutations such as ROS1, BRAF, c-MET, EGFR/HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 and/or VEGFR, PI3K, CDKs, PARP and other inhibitors, or with cytotoxin, immune target modulator PD-1/PD -Application in combined therapeutic drugs such as L1.
  • the combined therapeutic drug at least comprises one or more compounds of the present invention, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers.
  • the present invention also provides the compounds represented by the formula (I), their pharmaceutically acceptable salts, solvates, enantiomers and isotope substitutions, and the pharmaceutical composition in the prevention or treatment of EGFR mutation-induced use in diseases.
  • the diseases caused by EGFR mutations have the above definition.
  • the present invention also provides a method for preventing or treating diseases caused by EGFR mutations, comprising administering to patients a preventive or therapeutically effective amount of the compound represented by formula (I), its pharmaceutically acceptable salt, solvate, enantiomer At least one of the conformers and isotope substitutions, or give the patient a prophylactically or therapeutically effective amount of the above-mentioned pharmaceutical composition.
  • the diseases caused by EGFR mutations have the above definition.
  • the patient is a mammal, preferably a human.
  • C1-6 is selected from a group consisting of C 1 , C 2 , C 3 , C 4 , C 5 or C 6 , and the number indicates the group with the number of carbon atoms.
  • pharmaceutically acceptable refers to those compounds, materials, compositions and/or dosage forms, which are suitable for use in contact with human and animal tissues within the scope of sound medical judgment , without undue toxicity, irritation, allergic reaction or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • pharmaceutically acceptable salt refers to a salt of a compound of the present invention, which is prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base, either neat solution or in a suitable inert solvent.
  • Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic ammonia or magnesium salts or similar salts.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the acid, either neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include salts of inorganic acids including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogenphosphate, dihydrogenphosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, such as acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid and similar acids; also salts of amino acids such as arginine and the like , and salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutical Salts", Journal of
  • the neutral form of the compound is regenerated by contacting the salt with a base or acid in the conventional manner followed by isolation of the parent compound.
  • the parent form of the compound differs from its various salt forms by certain physical properties, such as solubility in polar solvents.
  • “Pharmaceutically acceptable salt” as used herein belongs to the derivatives of the compounds of the present invention, wherein the parent compound is modified by forming a salt with an acid or a salt with a base.
  • pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of bases such as amines, alkali metal or organic salts of acid groups such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional non-toxic salts or quaternary ammonium salts of the parent compound, such as salts formed from non-toxic inorganic or organic acids.
  • non-toxic salts include, but are not limited to, those derived from inorganic and organic acids selected from the group consisting of 2-acetoxybenzoic acid, 2-hydroxyethanesulfonic acid, acetic acid, ascorbic acid, Benzenesulfonic acid, benzoic acid, bicarbonate, carbonic acid, citric acid, edetic acid, ethanedisulfonic acid, ethanesulfonic acid, fumaric acid, glucoheptose, gluconic acid, glutamic acid, glycolic acid, Hydrobromic acid, hydrochloric acid, hydroiodide, hydroxyl, hydroxynaphthalene, isethionic acid, lactic acid, lactose, dodecylsulfonic acid, maleic acid, malic acid, mandelic acid, methanesulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid, phosphoric
  • the pharmaceutically acceptable salts of the present invention can be synthesized from the parent compound containing acid groups or bases by conventional chemical methods.
  • such salts are prepared by reacting the free acid or base form of these compounds with a stoichiometric amount of the appropriate base or acid in water or an organic solvent or a mixture of both.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided herein also exist in prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to convert them to the compounds of the present invention.
  • prodrugs can be converted to the compounds of the invention by chemical or biochemical methods in an in vivo environment.
  • Certain compounds of the present invention can exist in unsolvated or solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms.
  • Certain compounds of the invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are included within the scope of the present invention.
  • the compounds of the invention may exist in particular geometric or stereoisomeric forms.
  • the present invention contemplates all such compounds, including cis and trans isomers, (-)- and (+)-enantiomers, (R)- and (S)-enantiomers, diastereomers isomers, (D)-isomers, (L)-isomers, and their racemic and other mixtures, such as enantiomerically or diastereomerically enriched mixtures, all of which are within the scope of the present invention.
  • Additional asymmetric carbon atoms may be present in substituents such as alkyl groups. All such isomers, as well as mixtures thereof, are included within the scope of the present invention.
  • Optically active (R)- and (S)-isomers as well as D and L-isomers can be prepared by chiral synthesis or chiral reagents or other conventional techniques. If one enantiomer of a compound of the invention is desired, it can be prepared by asymmetric synthesis or derivatization with chiral auxiliary agents, wherein the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • a diastereomeric salt is formed with an appropriate optically active acid or base, and then step by step known in the art Resolution of diastereomers by crystallization or chromatography followed by recovery of the pure enantiomers.
  • the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally in combination with chemical derivatization methods (e.g. amines to amino groups formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes at one or more of the atoms that constitute the compounds.
  • compounds may be labeled with radioactive isotopes such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All changes in isotopic composition of the compounds of the invention, whether radioactive or not, are included within the scope of the invention.
  • pharmaceutically acceptable carrier refers to any preparation or carrier medium capable of delivering an effective amount of the active substance of the present invention, does not interfere with the biological activity of the active substance, and has no toxic side effects on the host or patient.
  • Representative carriers include water, oil, Vegetables and minerals, cream bases, lotion bases, ointment bases, etc. These bases include suspending agents, viscosity builders, skin penetration enhancers and the like. Their formulations are well known to those skilled in the field of cosmetics or topical medicine. Additional information on carriers can be found in Remington: The Science and Practice of Pharmacy, 21st Ed., Lippincott, Williams & Wilkins (2005), the contents of which are incorporated herein by reference.
  • excipient generally refers to a carrier, diluent and/or medium required to formulate an effective pharmaceutical composition.
  • the term "effective amount” or “therapeutically effective amount” refers to a non-toxic but sufficient amount of the drug or agent to achieve the desired effect.
  • the "effective amount” of one active substance in the composition refers to the amount needed to achieve the desired effect when used in combination with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depending on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in each case can be determined by those skilled in the art according to routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating the disorder, disease or condition of interest.
  • substituted refers to the replacement of any one or more hydrogen atoms on a specified atom with a substituent, including deuterium and hydrogen variants, as long as the valence of the specified atom is normal and the substituted compound is stable .
  • Keto substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted, and unless otherwise specified, the type and number of substituents may be arbitrary on a chemically realizable basis.
  • any variable eg, R
  • its definition is independent at each occurrence.
  • said group may optionally be substituted with up to two R, with independent options for each occurrence of R.
  • substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • substituents When a bond of a substituent can cross-link two atoms in a ring, the substituent can be bonded to any atom in the ring.
  • substituent When a substituent is listed without specifying the atom through which it is bonded to a compound included in a general chemical formula but not specifically mentioned, such a substituent may be bonded through any atom thereof. Combinations of substituents and/or variations thereof are permissible only if such combinations result in stable compounds.
  • R', R", R"', R"" and R""' are each independently preferably hydrogen, Substituted or unsubstituted heteroalkyl, substituted or unsubstituted aryl (for example, aryl substituted by 1 to 3 halogens), substituted or unsubstituted alkyl, alkoxy, thioalkane Oxy group or aralkyl group.
  • each R group is independently selected, as when there are more than one R', R", R "', R"" and R""' groups.
  • R' and R" When R' and R" are attached to the same nitrogen atom, they can combine with the nitrogen atom to form a 5-, 6-, or 7- - Yuan ring.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon A group consisting of an atom bonded to a non-hydrogen group, such as a haloalkyl group (eg -CF 3 , -CH 2 CF 3 ) and an acyl group (eg -C(O)CH 3 , -C(O)CF 3 , - C(O) CH2OCH3 , etc.).
  • a haloalkyl group eg -CF 3 , -CH 2 CF 3
  • acyl group eg -C(O)CH 3 , -C(O)CF 3 , - C(O) CH2OCH3 , etc.
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may optionally be substituted with substituents of the general formula -TC(O)-(CRR')qU-, where T and U are independently selected from From -NR-, -O-, CRR'- or a single bond, q is an integer of 0 to 3.
  • two substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be substituted with substituents of the general formula -A(CH2)rB-, where A and B are independently selected from From –CRR'-, -O-, -NR-, -S-, -S(O)-, S(O) 2 -, -S(O) 2 NR'- or a single bond, r is 1 to 4 an integer of .
  • a single bond on the new ring thus formed can be replaced by a double bond.
  • substituents on adjacent atoms of an aryl or heteroaryl ring may optionally be substituted with substituents of the general formula -A(CH2)rB-, where s and d are independently An integer selected from 0 to 3, X is -O-, -NR', -S-, -S(O)-, -S(O) 2 - or -S(O) 2 NR'-.
  • the substituents R, R', R" and R"' are each independently preferably selected from hydrogen and substituted or unsubstituted (C 1 -C 6 )alkyl groups.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include monohaloalkyl and polyhaloalkyl.
  • halo(C 1 -C 4 )alkyl is intended to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl, etc. wait.
  • haloalkyl examples include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl, and pentachloroethyl.
  • Alkoxy represents the above-mentioned alkyl group having the specified number of carbon atoms attached through an oxygen bridge.
  • C 1-6 alkoxy includes C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy.
  • alkoxy groups include, but are not limited to: methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy, and S- Pentyloxy.
  • Cycloalkyl includes saturated ring groups such as cyclopropyl, cyclobutyl or cyclopentyl. 3-7 cycloalkyl includes C 3 , C 4 , C 5 , C 6 and C 7 cycloalkyl.
  • Alkenyl includes hydrocarbon chains in straight or branched configuration in which one or more carbon-carbon double bonds are present at any stable point on the chain, eg, ethenyl and propenyl.
  • halo or halogen refers to fluorine, chlorine, bromine and iodine.
  • heteroatom as used herein includes atoms other than carbon (C) and hydrogen (H), including, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum ( Al) and boron (B), etc.
  • hetero examples include atoms other than carbon (C) and hydrogen (H) and also include those of the aforementioned heteroatoms free radicals.
  • heteroatoms free radicals.
  • oxygen O
  • nitrogen N
  • sulfur S
  • silicon Si
  • germanium Ge
  • aluminum Al
  • boron B
  • Ring means a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl.
  • the so-called ring includes fused rings.
  • the number of atoms on a ring is usually defined as the number of ring members, for example, "5-7 membered ring” refers to 5-7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms.
  • 5-7 membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5-7 membered heterocycloalkyl ring” includes pyridyl and piperidinyl, but excludes phenyl.
  • ring also includes ring systems comprising at least one ring, wherein each "ring” is independently defined above.
  • heterocycle or “heterocyclyl” means a stable monocyclic or bicyclic or bicyclic heterocyclic ring, which may be saturated, partially unsaturated or unsaturated (aromatic), comprising carbon atoms and 1 , 2, 3 or 4 ring heteroatoms independently selected from N, O and S, wherein any of the above heterocycles can be fused to a benzene ring to form a bicyclic ring.
  • Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O)p).
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
  • the heterocycle can be attached to any heteroatom or pendant carbon atom to form a stable structure.
  • the heterocyclic rings described herein may be substituted at the carbon or nitrogen positions if the resulting compound is stable.
  • the nitrogen atoms in the heterocycle are optionally quaternized.
  • a preferred solution is that when the total number of S and O atoms in the heterocycle exceeds 1, these heteroatoms are not adjacent to each other. Another preferred solution is that the total number of S and O atoms in the heterocycle does not exceed 1.
  • aromatic heterocyclic group or “heteroaryl” means a stable aromatic ring of 5, 6, 7 membered monocyclic or bicyclic or 7, 8, 9 or 10 membered bicyclic heterocyclic groups, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • the nitrogen atom may be substituted or unsubstituted (ie, N or NR, where R is H or other substituents already defined herein).
  • Nitrogen and sulfur heteroatoms can optionally be oxidized (ie NO and S(O)p). It is worth noting that the total number of S and O atoms on the aromatic heterocycle does not exceed 1. Bridged rings are also included in the definition of heterocycle.
  • a bridged ring is formed when one or more atoms (ie, C, O, N, or S) link two non-adjacent carbon or nitrogen atoms.
  • Preferred bridged rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms, and a carbon-nitrogen group. It is worth noting that a bridge always converts a single ring into a triple ring. In bridged rings, substituents on the ring may also be present on the bridge.
  • heterocyclic compounds include, but are not limited to: acridinyl, aziocinyl, benzimidazolyl, benzofuryl, benzomercaptofuranyl, benzomercaptophenyl, benzoxazolyl, benzoxazolyl Azolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolyl, carbazolyl, 4aH-carbazolyl, Carbolinyl, chromanyl, chromene, cinnolinyl decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b] Tetrahydrofuryl, furyl, furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolen
  • hydrocarbyl or its subordinate concepts (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched-chain or cyclic Hydrocarbon radicals or combinations thereof, which may be fully saturated, mono- or polyunsaturated, may be mono-, di- or polysubstituted, may include divalent or polyvalent radicals, have a specified number of carbon atoms (e.g. C 1 -C 10 represents 1 to 10 carbons).
  • Hydrocarbon group includes but not limited to aliphatic hydrocarbon group and aromatic hydrocarbon group, said aliphatic hydrocarbon group includes chain and ring, specifically includes but not limited to alkyl, alkenyl, alkynyl, said aromatic hydrocarbon group includes but not limited to 6-12 members Aromatic hydrocarbon groups such as benzene, naphthalene, etc.
  • alkyl refers to straight or branched chain radicals or combinations thereof, which may be fully saturated, mono or polyunsaturated, and may include divalent and multivalent radicals.
  • saturated hydrocarbon radicals include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) Homologues or isomers of methyl, cyclopropylmethyl, and n-pentyl, n-hexyl, n-heptyl, n-octyl and other atomic groups.
  • Unsaturated alkyl has one or more double or triple bonds, examples of which include, but are not limited to, vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2-(butadienyl ), 2,4-pentadienyl, 3-(1,4-pentadienyl), ethynyl, 1- and 3-propynyl, 3-butynyl, and higher homologs and iso Construct.
  • heterohydrocarbyl or its subordinate concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term represent stable straight-chain, branched or cyclic hydrocarbon radicals or combinations thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in combination with another term means a stable straight-chain, branched-chain hydrocarbon radical or a combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • the heteroatom is selected from B, O, N, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen heteroatom is optionally quaternized.
  • the heteroatoms B, O, N and S may be located at any internal position of the heterohydrocarbyl group (other than the position where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms can be consecutive, eg -CH2 -NH- OCH3 .
  • alkoxy "alkylamino” and “alkylthio” (or thioalkoxy) are conventional expressions referring to those alkyl groups attached to the rest of the molecule through an oxygen, amino or sulfur atom, respectively. base group.
  • cycloalkyl refers to any one of the groups listed above.
  • heterocycloalkyl refers to any one of the groups listed above.
  • cyclohydrocarbyl or their subordinate concepts (such as aryl, heteroaryl, heteroaryl, cycloalkyl, heterocycloalkyl, cyclo Alkyl, cycloalkenyl, heterocycloalkenyl, cycloalkenyl, cycloalkynyl, heterocycloalkynyl, cycloalkynyl, etc.) by themselves or in combination with other terms represent respectively cyclized “hydrocarbyl", “ Heterohydrocarbyl” or “heterohydrocarbyl”.
  • heteroalkyl or heterocycloalkyl e.g., heteroalkyl, heterocycloalkyl
  • a heteroatom can occupy the position at which the heterocycle is attached to the remainder of the molecule.
  • cycloalkyl include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, and the like.
  • heterocyclyl examples include 1-(1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl, tetrahydrofurindol-3-yl, tetrahydrothiophen-2-yl, tetrahydrothiophen-3-yl, 1-piperazinyl and 2-piperazinyl.
  • aryl denotes a polyunsaturated aromatic hydrocarbon substituent, which may be monosubstituted, disubstituted or polysubstituted, which may be monocyclic or polycyclic (preferably 1 to 3 rings), They are fused together or covalently linked.
  • heteroaryl refers to an aryl group (or ring) containing one to four heteroatoms. In an illustrative example, the heteroatom is selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized, and the nitrogen atom is optionally quaternized.
  • a heteroaryl can be attached to the rest of the molecule through a heteroatom.
  • Non-limiting examples of aryl or heteroaryl include phenyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolyl, 2-pyrrolyl, 3-pyrrolyl, 3-pyrrolyl Azolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2-oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isox Azolyl, 4-isoxazolyl, 5-isoxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-furyl, 2-thienyl, 3-thiophene Base, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzothiazolyl, purinyl, 2-benzimidazolyl, 5-indolyl,
  • aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes both aryl and heteroaryl rings as defined above.
  • aralkyl is intended to include those radicals in which an aryl group is attached to an alkyl group (e.g., benzyl, phenethyl, pyridylmethyl, etc.), including wherein a carbon atom (e.g., methylene) has been replaced by, e.g., oxygen
  • alkyl groups in which atoms are substituted such as phenoxymethyl, 2-pyridyloxymethyl, 3-(1-naphthyloxy)propyl and the like.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction (eg, an affinity substitution reaction).
  • substituent groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, brosylate, tosylate esters, etc.; acyloxy groups such as acetoxy, trifluoroacetoxy, and the like.
  • compounds of formula (I) can be prepared according to the synthetic methods described in the following schemes:
  • Another object of the present invention is to provide a method for preparing the above-mentioned compound, and its preparation route is as follows:
  • Z represents boronic acid or borate ester group or active hydrogen
  • G represents a protecting group
  • other substituents are as described in claims 1-7.
  • the intermediate 2 is obtained from the coupling reaction between the starting material halogenated heterocycle and the substituted or unsubstituted heterocycle B under the action of a catalyst or the substitution reaction with active hydrogen:
  • Z represents boronic acid or borate ester group or active hydrogen, and other substituents are as described in claims 1-7.
  • the invention is now further described by way of examples.
  • the examples given below are for illustrative purposes only and do not limit the scope of this invention.
  • the compounds of the present invention can be prepared by a number of methods known in the art of organic synthesis.
  • Embodiments of the present invention may be synthesized using the methods described below, as well as synthetic methods known in the art of synthetic organic chemistry, or by modifications thereof.
  • Preferred methods include, but are not limited to, the methods described below.
  • aq represents water
  • DCM dichloromethane
  • PE represents petroleum ether
  • DMF represents N,N-dimethylformamide
  • DMSO represents dimethyl sulfoxide
  • EtOAc represents ethyl acetate
  • EtOH stands for ethanol
  • MeOH stands for methanol
  • Cbz stands for benzyloxycarbonyl, an amine protecting group
  • Boc stands for tert-butyloxycarbonyl, an amine protecting group
  • HOAc stands for acetic acid
  • Sodium rt stands for room temperature
  • THF stands for tetrahydrofuran
  • Boc 2 O stands for di-tert-butyl dicarbonate
  • TFA stands for trifluoroacetic acid
  • DIPEA stands for diisopropylethylamine
  • Pd(dppf)Cl stands for [1,1'- Bis(diphenylphosphino)ferrocene]palladium(II) dichloride
  • tert-butyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (starting material 1) (500 mg, 2.28 mmol) in N,N-dimethylformamide (5 mL) and dissolve in Sodium hydride (60% in mineral oil) (365mg, 9.12mmol) was added under ice-cooling, and after stirring for 20 minutes, iodomethane (320mg, 2.28mmol) was added under ice-cooling, heated to 25°C and stirred for 3 hours.
  • 3-chloro-5-isopropyl-8-(3-(methylsulfonylmethyl)azetidin-1-yl)isoquinoline (20mg, 0.056mmol) was dissolved in dioxo Hexacyclic (2mL), sequentially added 4-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)-1,3,5-triazin-2-amine (11mg, 0.051mmol) and cesium carbonate (36mg, 0.112mmol), and finally Brettphos Pd G3 (8mg, 0.008mmol, 0.15eq), heated to 100°C and stirred for 12 hours.
  • starting material 1 Dissolve tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (starting material 1) (500 mg, 2.28 mmol) in N,N-dimethylformamide (10 mL) and dissolve in Under ice bath, sodium hydride (60% in mineral oil) (365 mg, 9.12 mmol) was added, and after stirring for 20 minutes, deuteroiodomethane (330 mg, 2.28 mmol) was added under ice bath, and the temperature was raised to 25° C. and stirred for reaction 3 Hour.
  • starting material 1 Dissolve tert-butyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate (starting material 1) (500 mg, 2.28 mmol) in N,N-dimethylformamide (10 mL) and dissolve in Under ice bath, sodium hydride (60% in mineral oil) (365 mg, 9.12 mmol) was added, and after stirring for 20 minutes,
  • 3-chloro-5-isopropyl-8-(3-(methylsulfinylmethyl)azetidin-1-yl)isoquinoline (102mg, 0.3mmol) was dissolved in To dioxane (6mL), add 2-((3R,4S)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidin-4-amine (69mg, 0.3mmol) and cesium carbonate (195mg, 0.6mmol), and finally Brettphos Pd G3 (27mg, 0.03mmol) was added, the temperature was raised to 100°C and the reaction was stirred for 16 hours.
  • (4S, 5R)-1-(4-amino-1,3,5-triazin-2-yl)-5-fluoro-3,3-dimethylpiperidine-4- Alcohol (20mg, 0.083mmol) and 3-chloro-5-isopropyl-8-(3-((methylsulfonyl)methyl)azetidin-1-yl)isoquinoline (29mg, 0.083 mmol) in dioxane (4 mL), cesium carbonate (108 mg, 0.332 mmol) and Brettphos Pd G3 (8 mg, 0.008 mmol) were added sequentially. The temperature was raised to 100° C., and the reaction was carried out for 5 hours.
  • (3R,4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg , 0.13mmol) in dioxane solution (7mL), add 6-chloro-1-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazacyclocycline successively Butan-1-yl)-4-isopropyl-2,7-naphthyridine (50mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours.
  • (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg , 0.13mmol) in dioxane solution (7mL), successively add 6-chloro-1-((2R, 3S)-3-((ethylsulfonyl)methyl)-2-methylazacyclic Butan-1-yl)-4-isopropyl-2,7-naphthyridine (50mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours.
  • (3S, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg , 0.13mmol) in dioxane solution (7mL), sequentially add 6-chloro-1-((2R,3S)-3-((ethylsulfonyl)methyl)-2-methylazepine Cyclobutan-1-yl)-4-isopropyl-2,7-naphthyridine (50 mg, 0.13 mmol), cesium carbonate (85 mg, 0.26 mmol) and Brettphos Pd G3 (12 mg, 0.013 mmol), warming to 100 °C, react for 5 hours.
  • (3R,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg , 0.13mmol) in dioxane solution (7mL), successively add 6-chloro-1-((2R, 3S)-3-((ethylsulfonyl)methyl)-2-methylazacyclic Butan-1-yl)-4-isopropyl-2,7-naphthyridine (50mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 were heated to 100°C and reacted for 5 hours.
  • (3R,4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg ,0.13mmol) in dioxane solution (7mL), add 6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl)azetidin-1-yl)-2,7-naphthyridine (48mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours.
  • (3S, 4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg ,0.13mmol) in dioxane solution (7mL), add 6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl)azetidin-1-yl)-2,7-naphthyridine (48mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C °C, react for 5 hours.
  • (3S, 4S)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg ,0.13mmol) in dioxane solution (7mL), add 6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl)azetidin-1-yl)-2,7-naphthyridine (48mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours.
  • (3R,4R)-1-(4-amino-1,3,5-triazin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (30mg ,0.13mmol) in dioxane solution (7mL), add 6-chloro-4-isopropyl-1-((2R,3S)-2-methyl-3-((methylsulfonyl) Methyl)azetidin-1-yl)-2,7-naphthyridine (48mg, 0.13mmol), cesium carbonate (85mg, 0.26mmol) and Brettphos Pd G3 (12mg, 0.013mmol), warming to 100°C , reacted for 5 hours.
  • the resulting reaction solution was heated up to 100° C. and reacted for 5 hours.
  • the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • LC-MS [M+H] +527 .
  • the resulting reaction solution was heated to 100° C. under the protection of nitrogen and reacted for 5 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure to obtain a crude product.
  • the resulting reaction solution was heated to 100° C. under the protection of nitrogen and reacted for 5 hours.
  • the reaction solution was concentrated by rotary evaporation to obtain a crude product.
  • reaction liquid was heated to 100° C. for 5 hours. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue.
  • 3-chloro-8-(3-((ethylsulfinyl)methyl)azetidin-1-yl)-5-isopropylisoquinoline (70mg, 0.20 mmol) in dioxane solution was sequentially added (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (45mg, 0.20mmol) , cesium carbonate (130mg, 0.40mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl-1,1'- Biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (18 mg, 0.020 mmol).
  • the temperature of the obtained mixed reaction liquid was raised to 100° C. for 5 hours under the protection of nitrogen.
  • the reaction solution was concentrated to remove the solvent to obtain a residue.
  • the crude product was subjected to reverse-phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: pure water containing 0.1% NH 4 OH; mobile phase B: acetonitrile; flow rate: 80mL/min; gradient : 40% B-95% B detection wavelength: 254nm) purification within 20 minutes.
  • reaction liquid was heated to 100° C. for 5 hours under the protection of nitrogen. After the reaction was completed, the reaction solution was concentrated to remove the solvent to obtain a residue.
  • the crude product was passed through flash reverse phase column chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; flow A: pure water containing 0.1% NH 3 .H 2 O; mobile phase B: acetonitrile; flow rate: 80mL/ min; gradient: 40%B-95%B in 20 minutes; detector: 254nm) purification.
  • Peak 1 0.745min; (S)-3-chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline or (R)-3-Chloro-5-isopropyl-8-(3-((methylsulfinyl)methyl)azetidin-1-yl)isoquinoline (710mg, 2.11mmol, yield Rate: 47.3%);
  • Peak 2 1.163min.
  • reaction solution was added to a saturated aqueous solution of sodium bisulfite (20 mL), the reaction was quenched, and extracted with dichloromethane (20 mL ⁇ 3), the combined organic phases were dried over anhydrous sodium sulfate, filtered, and concentrated to obtain The residue.
  • Peak 1 2.995min; 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azacycle Butane-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl yl)azetidin-1-yl)isoquinoline (240mg, 0.68mmol, yield: 48.0%).
  • Peak 2 3.739min; 3-Chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((R)-methylsulfinyl)methyl)azacycle Butane-1-yl)isoquinoline or 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl yl)azetidin-1-yl)isoquinoline (240mg, 0.68mmol, yield: 48.0%)
  • the crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: water containing 0.1% NH 3 .H 2 O; mobile phase B: acetonitrile; flow rate: 40mL/min ; Gradient: 35% B-50% B in 15 minutes; Detector: 254 nm.) Purification.
  • Example 65 (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8-((2R, 3S)-2-methyl-3-(((R)-methyl Sulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol or 3S,4R)-3-fluoro- 1-(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(((S)-methylsulfinyl)methyl)azetidine- Synthesis of 1-yl)isoquinolin-3-yl)amino)pyrimidin-2-yl)piperidin-4-ol (Compound 65)
  • the crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: water containing 0.1% NH 3 .H 2 O; mobile phase B: acetonitrile; flow rate: 40mL/min ; Gradient: 35% B-50% B in 15 minutes; Detector: 254 nm.) Purification.
  • reaction liquid was heated up to 100° C. for 16 hours under the protection of nitrogen. The reaction is over.
  • the reaction solution was concentrated to remove the solvent to obtain a residue.
  • the crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water containing 0.1% NH 3 .H 2 O; mobile phase B: acetonitrile; flow rate: 80mL/min ; Gradient: 5% B-30% B in 20 minutes; Detector: 254 nm.) Purification.
  • the crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; mobile phase A: water containing 0.1% NH 3 .H 2 O; mobile phase B: acetonitrile; flow rate: 80mL/min ; Gradient: 5% B-30% B in 20 minutes; Detector: 254 nm.) Purification.
  • Example 70 N-(2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl- 8-((2R,3S)-2-methyl-3-((S)-methylsulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine or N-(2- ((3S, 4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)- Synthesis of 2-methyl-3-((R)-methylsulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine (compound 70)
  • Thick product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18, 20-40um, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: Within 20 minutes, 40% B-95% B; detection wavelength: 254nm) was further purified, and when the mobile phase B content reached 63%, the fraction containing the product was collected and concentrated under reduced pressure to obtain N-(2-((3S, 4R )-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-((2R,3S)-2-methyl- 3-((R)-methylsulfinyl)methyl)azacyclo-1-ylisoquinolin-3-amine or N-(2-((3S,4R)-3-fluoro-4-methyl Oxy-3-methylpiperidin-1-yl)pyrimidin
  • Thick product is passed through reverse phase flash chromatography (chromatographic condition: column: spherical C18, 20-40um, 40g; Mobile phase A: the water that contains 0.1% ammoniacal liquor; Mobile phase B: acetonitrile; Flow rate: 40mL/min; Gradient: 20 minutes 30%B-80%B; detection wavelength: 254nm) for further purification, when the content of the mobile phase reached 40%B, the fraction containing the product was collected and concentrated under reduced pressure to obtain (3S, 4R)-3-fluoro-1-(4 -((5-isopropyl-8-(3-(((S)-isopropylsulfinyl)methyl)azetidin-1-yl)isoquinolin-3-yl)amino) Pyrimidin-2-yl)-3-methylpiperidin-4-ol or (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((R )-is
  • the mobile phase B content reached 45% B
  • the fractions containing the product were collected and concentrated under reduced pressure to obtain (3R, 4S)-3-fluoro-1-(4-((5-isopropyl-8-( 3-((((R)-isopropylsulfoxide)methyl)azetidin-1-yl)isoquinolin-3-yl)amino)pyr
  • the crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; and mobile phase A: water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 80mL/ min; gradient: 5% B-30% B, within 20 minutes; detection wavelength: 254nm) purification, when the mobile phase B content reaches 20%, collect the fraction containing the product, then concentrate under reduced pressure to obtain (3S, 4R)- 1-(4-((8-(3-((((S)-(cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-isopropyliso Quinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpipe
  • Example 77 1. (3S, 4R)-1-(4-((8-(3-(((R)-(cyclopropylmethyl)sulfoxide)methyl)azetidine -1-yl)-5-isopropylisoquinolin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol or (3S,4R)-1 -(4-((8-(3-((((S)-(cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-isopropylisoquine Synthesis of Lin-3-yl)amino)pyrimidin-2-yl)-3-fluoro-3-methylpiperidin-4-ol (Compound 77)
  • the crude product was passed through reaction flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 80g; and mobile phase A: water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 80mL/ min; gradient: 5% B-30% B, within 20 minutes; detection wavelength: 254nm) purification, when the mobile phase B content reached 20%, the fractions containing the product were collected and concentrated under reduced pressure to obtain (3S, 4R)- 1-(4-((8-(3-((((R)-(cyclopropylmethyl)sulfoxide)methyl)azetidin-1-yl)-5-isopropyliso Quinolin-3-yl)amino)pyrimidin-2-yl)-3-
  • Example 78 1. N-(2-((3R,4S)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl Base-8-(3-(((S)-methylsulfinyl)methyl)azacyclo-1-yl]isoquinolin-3-amine or N-(2-((3R,4S)- 3-fluoro-4-methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(((R)-methylsulfinyl ) methyl) azacyclo-1-yl] isoquinolin-3-amine (compound 78) synthesis
  • Example 80 (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((S)-methylsulfinyl)azacyclo-1- Base) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol or (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8- (3-(((R)-methylsulfinyl) azacyclo-1-yl) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol (compound 80) synthesis
  • reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 16 hours.
  • Example 81 (3S,4R)-3-fluoro-1-(4-((5-isopropyl-8-(3-(((R)-methylsulfinyl)azacyclo-1- Base) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol or (3S, 4R)-3-fluoro-1-(4-((5-isopropyl-8- (3-(((S)-methylsulfinyl) azacyclo-1-yl) isoquinolin-3-yl) amino) pyrimidin-2-yl) piperidin-4-ol (compound 81) synthesis
  • reaction liquid was raised to 100° C. under the protection of nitrogen, and stirred for 16 hours.

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Abstract

L'invention concerne un composé pyrido hétérocyclique substitué ou un sel pharmaceutiquement acceptable, un solvate, un hydrate, une substitution d'isotope ou un isomère de celui-ci. La structure du composé est représentée dans la formule (I). Le composé de formule (I) a un effet d'affinité sur une cible de mutation d'EGFR, en particulier a un effet inhibiteur de prolifération puissant sur les cellules du cancer mutant triple EGFR19del/L858R-T790M-C797S, peut être utilisé pour préparer des médicaments ou des sondes moléculaires pour prévenir ou traiter des maladies (telles que le cancer et des maladies immunitaires) liées à la voie de signal de la mutation EGFR (notamment EGFR19del/L858R-T790M-C797S triple mutation).
PCT/CN2022/127094 2021-10-26 2022-10-24 Nouveau composé pyrido ou pyrido hétérocyclique à substitution triazine WO2023071998A1 (fr)

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WO2024008048A1 (fr) * 2022-07-04 2024-01-11 杭州德睿智药科技有限公司 Nouveau composé pyridohétérocyclique substitué par pyrimidine ou triazine

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WO2023241618A1 (fr) * 2022-06-14 2023-12-21 南京明德新药研发有限公司 Composés aminopyrimidines et leur utilisation
WO2024008048A1 (fr) * 2022-07-04 2024-01-11 杭州德睿智药科技有限公司 Nouveau composé pyridohétérocyclique substitué par pyrimidine ou triazine

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