[go: up one dir, main page]

WO2024008048A1 - Nouveau composé pyridohétérocyclique substitué par pyrimidine ou triazine - Google Patents

Nouveau composé pyridohétérocyclique substitué par pyrimidine ou triazine Download PDF

Info

Publication number
WO2024008048A1
WO2024008048A1 PCT/CN2023/105583 CN2023105583W WO2024008048A1 WO 2024008048 A1 WO2024008048 A1 WO 2024008048A1 CN 2023105583 W CN2023105583 W CN 2023105583W WO 2024008048 A1 WO2024008048 A1 WO 2024008048A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
alkoxy
group
cycloalkyl
amino
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/CN2023/105583
Other languages
English (en)
Chinese (zh)
Inventor
张龙
牛张明
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Mindrank Ai Ltd
Original Assignee
Mindrank Ai Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Mindrank Ai Ltd filed Critical Mindrank Ai Ltd
Publication of WO2024008048A1 publication Critical patent/WO2024008048A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • 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. Specifically disclosed are the compounds represented by the formula (I) or their pharmaceutically acceptable salts, solvates, hydrates, isotope substitutions or isomers thereof.
  • the structural compound of formula (I) has a strong inhibitory effect on EGFR mutation targets, especially on the activity of mutant proteins such as EGFR19Del-T790M-C797S, EGFRL858R-T790M-C797S, EGFR19Del-C797S, EGFRL858R-C797S, and EGFR-C797S. , can be used to prepare drugs for preventing or treating diseases related to EGFR mutation signaling pathways (such as cancer, immune diseases, etc.).
  • diseases related to EGFR mutation signaling pathways 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 heterodimers with several other major members of the same family, such as erbB2, erbB3, or erbB4.
  • the formation of these dimers can lead to the phosphorylation of key tyrosine residues in EGFR-expressing cells, thereby activating many intracellular downstream signaling pathways, leading to cell proliferation, survival, and resistance to apoptosis.
  • Disorders in the EGFR signal transduction pathway 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 mutations and deletions are one of the most important causes of non-small cell lung cancer.
  • EGFR mutations found in NSCLC tumors are exon 19 (del 19) deletions, L858R mutations, and single missense mutations in exon 21. These changes cause 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 mechanism of resistance to first- and second-generation EGFR-TKIs is due to secondary mutations in the gene, such as the T790M mutation, which occurs in about 50% to 70% of patients. This secondary mutation reduces the affinity of first- and second-generation drugs for the target protein, resulting in drug resistance and leading to tumor recurrence or disease progression.
  • Third-generation EGFR TKI osimertinib It has been developed to treat tumors with or without T790M mutations in dell9 or L858R gene mutations in patients with primary EGFR mutation-positive NSCFC. 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 will still develop resistance to this drug, leading to disease progression.
  • One of the main causes of drug resistance is the mutation of C797 in exon 20 of EGFR (C797S).
  • the EGFR dell9/L858R-T790M-C797S cis mutation usually occurs in patients after osimertinib treatment and is called a "triple mutation".
  • the first, second or third generation EGFR inhibitors are no longer effective.
  • most of the compounds of the present invention have extremely high selectivity for EGFR-wt. It is expected that they can not only solve drug resistance, but also solve the problems of existing clinical applications. Toxicity issues of EGFR inhibitors.
  • some representative compounds also have good brain penetration capabilities and are more suitable for the prevention or treatment of EGFR mutant tumors and tumors with brain metastasis. Further research is ongoing.
  • the object of the present invention is to provide new compounds represented by formula (I) or pharmaceutically acceptable salts, solvates, isomers and isotopic substitutions thereof:
  • A is a 3-20-membered cyclic structure, and the cyclic structure can be any single ring, bicyclic, tricyclic, bridged ring or spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure can be any Contains 0 to more heteroatoms, and the heteroatoms are randomly selected from O, S or N;
  • X 0 , 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 alkyne 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 0 can be the same or different, and is optionally selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 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 together can form a 3-10 membered cyclic structure.
  • the cyclic structure can be any saturated, unsaturated or aromatic structure, and the cyclic structure can optionally contain 0 to more heteroatoms, so The heteroatoms mentioned above are arbitrarily selected from O, S or N;
  • Each R 1 may be the same or different, and is any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogen Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R 1 Optimally, it can be further optionally substituted by 1 to more substituents, and the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, and alkynyl.
  • R 1 can form a 3-10-membered cyclic structure together with the directly connected carbon thereof.
  • the cyclic structure can be any single ring, bicyclic ring or bridged ring containing 0 to more unsaturated bonds. Or a spiro ring; and the cyclic structure may optionally contain 0 to more heteroatoms, and the heteroatoms may be selected from O, S or N;
  • Each R 2 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl group, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono and other groups; and the hydrogen on R 2 can optionally be further optionally substituted by 1 to more substituents, The substituents are optionally 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, alkyl sulfone, alkyl
  • Each R 3 can be the same or different, and is any independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halo 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, phosphonoyl ;
  • R 5 is arbitrarily 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 5 can be optional Further substituted by 1 to more substituents, the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkyl Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alky
  • R 6 and R 7 are each 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 together with the directly connected carbons form a 3-10 member cyclic structure, and the cyclic structure
  • the structure can be any monocyclic, bicyclic, bridged or spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure can be arbitrarily containing 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 isomer thereof has the structure of formula (IA):
  • X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • X 9 is independently selected from C, C(R 0 ) or N;
  • X 10 is independently selected from O, S, SO, SO 2 , C(R 6 R 7 ) or NR 3 ;
  • Z is independently selected from O or NR 3 ;
  • Each R 0 can be the same or different, and is optionally selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro;
  • Each R 1 may be the same or different, and is any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogen Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R 1 Optimally, it can be further optionally substituted by 1 to more substituents, and the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, and alkynyl.
  • R 1 can form a 3-10-membered cyclic structure together with the directly connected carbon thereof.
  • the cyclic structure can be any single ring, bicyclic ring or bridged ring containing 0 to more unsaturated bonds. Or a spiro ring; and the cyclic structure may optionally contain 0 to more heteroatoms, and the heteroatoms may be selected from O, S or N;
  • Each R 2 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl group, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono and other groups; and the hydrogen on R 2 can optionally be further optionally substituted by 1 to more substituents, The substituents are optionally 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, alkyl sulfone, alkyl
  • Each R 3 can be the same or different, and is any independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halo 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, phosphonoyl ;
  • R 5 is arbitrarily 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 5 can be optional Further substituted by 1 to more substituents, the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkyl Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alky
  • R 6 and R 7 are each 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 together with the directly connected carbons form a 3-10 member cyclic structure, and the cyclic structure
  • the structure can be any monocyclic, bicyclic, bridged or spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure can be arbitrarily containing 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 isomer thereof has the structure of formula (IB):
  • X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • X 9 is independently selected from C, C(R 0 ) or N;
  • X 10 is independently selected from O, S, SO, SO 2 , C(R 6 R 7 ) or NR 3 ;
  • Each R 0 can be the same or different, and is optionally selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro;
  • Each R 1 may be the same or different, and is any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogen Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R 1 Optimally, it can be further optionally substituted by 1 to more substituents, and the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, and alkynyl.
  • R 1 can form a 3-10-membered cyclic structure together with the directly connected carbon thereof.
  • the cyclic structure can be any single ring, bicyclic ring or bridged ring containing 0 to more unsaturated bonds. Or a spiro ring; and the cyclic structure may optionally contain 0 to more heteroatoms, and the heteroatoms may be selected from O, S or N;
  • Each R 2 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl group, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono and other groups; and the hydrogen on R 2 can optionally be further optionally substituted by 1 to more substituents, The substituents are optionally 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, alkyl sulfone, alkyl
  • Each R 3 can be the same or different, and is any independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halo 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, phosphonoyl ;
  • R 5 is arbitrarily 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 5 can be optional Further substituted by 1 to more substituents, the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkyl Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alky
  • R 6 and R 7 are each 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 together with the directly connected carbons form a 3-10 member cyclic structure, and the cyclic structure
  • the structure can be any monocyclic, bicyclic, bridged or spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure can be arbitrarily containing 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 isomer thereof has the structure of formula (IC):
  • X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • X 9 is independently selected from C, C(R 0 ) or N;
  • X 10 is independently selected from O, S, SO, SO 2 , C(R 6 R 7 ) or NR 3 ;
  • Each R 0 can be the same or different, and is optionally selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro;
  • Each R 1 may be the same or different, and is any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogen Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R 1 Optimally, it can be further optionally substituted by 1 to more substituents, and the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, and alkynyl.
  • R 1 can form a 3-10-membered cyclic structure together with the directly connected carbon thereof.
  • the cyclic structure can be any single ring, bicyclic ring or bridged ring containing 0 to more unsaturated bonds. Or a spiro ring; and the cyclic structure may optionally contain 0 to more heteroatoms, and the heteroatoms may be selected from O, S or N;
  • Each R 2 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl group, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono and other groups; and the hydrogen on R 2 can optionally be further optionally substituted by 1 to more substituents, The substituents are optionally 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, alkyl sulfone, alkyl
  • Each R 3 can be the same or different, and is any independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halo 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, phosphonoyl ;
  • R 5 is arbitrarily 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 5 can be optional Further substituted by 1 to more substituents, the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkyl Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alky
  • R 6 and R 7 are each 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 together with the directly connected carbons form a 3-10 member cyclic structure, and the cyclic structure
  • the structure can be any monocyclic, bicyclic, bridged or spirocyclic ring containing 0 to more unsaturated bonds; and the The cyclic structure can optionally contain 0 to more heteroatoms, and the heteroatoms are optionally 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 isomer thereof has the structure of formula (ID):
  • X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • X 9 is independently selected from C, C(R 0 ) or N;
  • X 10 is independently selected from O, S, SO, SO 2 , C(R 6 R 7 ) or NR 3 ;
  • Each R 0 can be the same or different, and is optionally selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro;
  • Each R 1 may be the same or different, and is any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogen Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R 1 Optimally, it can be further optionally substituted by 1 to more substituents, and the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, and alkynyl.
  • R 1 can form a 3-10-membered cyclic structure together with the directly connected carbon thereof.
  • the cyclic structure can be any single ring, bicyclic ring or bridged ring containing 0 to more unsaturated bonds. Or a spiro ring; and the cyclic structure may optionally contain 0 to more heteroatoms, and the heteroatoms may be selected from O, S or N;
  • Each R 2 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl group, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono and other groups; and the hydrogen on R 2 can optionally be further optionally substituted by 1 to more substituents, The substituents are optionally 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, alkyl sulfone, alkyl
  • Each R 3 can be the same or different, and is any independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halo 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, phosphonoyl ;
  • R 5 is arbitrarily 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 5 can be optional Further substituted by 1 to more substituents, the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkyl Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alky
  • R 6 and R 7 are each 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 together with the directly connected carbons form a 3-10 member cyclic structure, and the cyclic structure
  • the structure can be any monocyclic, bicyclic, bridged or spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure can be arbitrarily containing 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 isomer thereof has the structure of formula (IF):
  • X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N;
  • X 9 is independently selected from C, C(R 0 ) or N;
  • X 10 is independently selected from O, S, SO, SO 2 , C(R 6 R 7 ) or NR 3 ;
  • Z is independently selected from absence, O or NR 3 ;
  • Each R 0 can be the same or different, and is optionally selected from H, deuterium, halogen, C1-6 alkyl, halogenated C1-6 alkyl, deuterated C1-6 alkyl, heterocyclyl, cycloalkyl, hetero Cycloalkyl, amino, alkenyl, hydroxyl, cyano, nitro;
  • Each R 1 may be the same or different, and is any independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkoxy, halogen Substituted C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocyclyl, heterocycloalkyl, heterocycloalkoxy, cycloalkoxy and other groups; and the hydrogen on R 1 Optimally, it can be further optionally substituted by 1 to more substituents, and the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, and alkynyl.
  • R 1 can form a 3-10-membered cyclic structure together with the directly connected carbon thereof.
  • the cyclic structure can be any single ring, bicyclic ring or bridged ring containing 0 to more unsaturated bonds. Or a spiro ring; and the cyclic structure may optionally contain 0 to more heteroatoms, and the heteroatoms may be selected from O, S or N;
  • Each R 2 can be the same or different, and is any independently selected from H, deuterium, halogen, C1-6 alkyl, haloC1-6 alkyl, deuterated C1-6 alkyl, cycloalkyl, heterocycloalkyl group, amino, alkenyl, cyano, cyanoalkyl, nitro, acyl, sulfonyl, phosphono and other groups; and the hydrogen on R 2 can optionally be further optionally substituted by 1 to more substituents, The substituents are optionally 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, alkyl sulfone, alkyl
  • Each R 3 can be the same or different, and is any independently selected from H, deuterium, hydroxyl, C1-6 alkyl, halo 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, phosphonoyl ;
  • R 5 is arbitrarily 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 5 can be optional Further substituted by 1 to more substituents, the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkyl Oxygen, halogenated C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, Heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy,
  • R 6 and R 7 are each 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 together with the directly connected carbons form a 3-10 member cyclic structure, and the cyclic structure
  • the structure can be any monocyclic, bicyclic, bridged or spirocyclic ring containing 0 to more unsaturated bonds; and the cyclic structure can be arbitrarily containing 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.
  • X 3 , X 7 and X 8 are each independently selected from C(R 0 ) or N; preferably C(R 0 );
  • X 9 is independently selected from C, C(R 0 ) or N; preferably N;
  • R 5 is arbitrarily 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 5 can be optional Further substituted by 1 to more substituents, the substituents are independently selected from hydrogen, deuterium, tritium, halogen, hydroxyl, amino, nitro, C1-6 alkyl, alkenyl, alkynyl, C1-6 alkyl Oxygen, halo C1-6 alkoxy, deuterated C1-6 alkoxy, cycloalkyl, heterocycloalkyl, heterocyclyl, heterocycloalkoxy, cycloalkoxy, alkyla
  • the above-mentioned compound or its pharmaceutically acceptable salt, or its isomer or isotope substitution is selected from compounds with structures as listed in the examples of the present invention.
  • Another object of the present invention is to provide the use of the above-mentioned compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers in the preparation of drugs for preventing or treating diseases caused by EGFR mutations. .
  • Another object of the present invention is to provide the use of the above-mentioned compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers in the preparation of drugs for preventing or treating diseases caused by EGFR mutations. .
  • Another object of the present invention is to provide the above-mentioned compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers for preparation and use in preventing or treating EGFR mutations, especially triple EGFR mutants ( dell9/L858R-T790M-C797S) mutations or diseases caused by signaling pathways related to EGFR mutations.
  • Another object of the present invention is to provide the above compounds, their pharmaceutically acceptable salts, solvates or hydrates and their isotopes or isomers for preparation and use in preventing or treating EGFR mutations or signaling pathways related to EGFR mutations, such as Inhibitors of ROS1, BRAF, c-MET, EGFR/HER2, KRAS/MEK, PIK3CA, FDFR, DDR2 and/or VEGFR, PI3K, CDKs, PARP, etc., or with cytotoxins, immune target modulators PD-1/PD -Application in combination therapeutic drugs such as L1.
  • the combination therapeutic drug at least contains one or more compounds of the present invention, their pharmaceutically acceptable salts, solvates or hydrates and isotopes or isomers thereof.
  • C1-6 is selected from the group consisting of C 1 , C 2 , C 3 , C 4 , C 5 or C 6 , the number indicating the number of carbon atoms in the group.
  • the term "pharmaceutically acceptable” refers to those compounds, materials, compositions and/or dosage forms which, within the scope of sound medical judgment, are suitable for use in contact with human and animal tissue. , without undue toxicity, irritation, allergic reactions, or other problems or complications, commensurate with a reasonable benefit/risk ratio.
  • salts refers to salts of compounds of the present invention prepared from compounds having specific substituents found in the present invention and relatively non-toxic acids or bases.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of base in pure 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 acid in neat solution or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include inorganic acid salts including, for example, hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, bicarbonate, phosphoric acid, monohydrogen phosphate, dihydrogen phosphate, sulfuric acid, Hydrogen sulfate, hydriodic acid, phosphorous acid, etc.; and organic acid salts, including acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, Similar acids such as fumaric acid, lactic acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid; also include salts of amino acids (such as arginine, etc.) , as well as salts of organic acids such as glucuronic acid (see Berge et al., "Pharmaceutic
  • the neutral form of the compound is regenerated by contacting the salt with a base or acid in a conventional manner and isolating the parent compound.
  • the parent form of a compound differs from its various salt forms in certain physical properties, such as solubility in polar solvents.
  • “Pharmaceutically acceptable salts” as used herein belong to derivatives of the compounds of the present invention, wherein the parent compound is modified by salt formation with an acid or salt with a base.
  • pharmaceutically acceptable salts include, but are not limited to, inorganic or organic acid salts of bases such as amines, alkali metal or organic salts of acid radicals such as carboxylic acids, and the like.
  • Pharmaceutically acceptable salts include conventional nontoxic salts or quaternary ammonium salts of the parent compound, such as salts formed with nontoxic inorganic or organic acids.
  • nontoxic salts include, but are not limited to, those derived from inorganic acids 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, dodecyl sulfonic acid, maleic acid, malic acid, mandelic acid, methane sulfonic acid, nitric acid, oxalic acid, Pamoic acid, pantothenic acid, phenylacetic acid,
  • the pharmaceutically acceptable salts of the present invention can be synthesized by conventional chemical methods from parent compounds containing acid groups or bases.
  • 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 the two.
  • non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol or acetonitrile are preferred.
  • the compounds provided by the invention also exist in prodrug forms.
  • Prodrugs of the compounds described herein readily undergo chemical changes under physiological conditions to transform into the compounds of the present invention.
  • prodrugs can be converted to compounds of the invention by chemical or biochemical methods in the in vivo environment.
  • Certain compounds of the present invention may exist in unsolvated or solvated forms, including hydrated forms. In general, solvated and unsolvated forms are equivalent to each other and are included within the scope of the present invention. Certain compounds of the present invention may exist in polycrystalline or amorphous forms.
  • Certain compounds of the present invention may have asymmetric carbon atoms (optical centers) or double bonds. Racemates, diastereomers, geometric isomers and individual isomers are all included within the scope of the invention.
  • the compounds of the present invention may exist in specific 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 racemic mixtures thereof and other mixtures, such as enantiomeric 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 the 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 auxiliaries, in which the resulting diastereomeric mixture is separated and the auxiliary group is cleaved to provide pure desired enantiomer.
  • diastereomeric salts are formed with a suitable optically active acid or base, and then the diastereomeric salts are formed by step-by-step procedures well known in the art. Diastereomers are resolved by crystallization or chromatography, and the pure enantiomers are recovered. Furthermore, the separation of enantiomers and diastereomers is usually accomplished by the use of chromatography using chiral stationary phases, optionally combined with chemical derivatization methods (e.g., generation of amino groups from amines). formate).
  • the compounds of the present invention may contain unnatural proportions of atomic isotopes on one or more of the atoms that make up the compound.
  • Radioactive isotope labeled compounds such as tritium ( 3 H), iodine-125 ( 125 I) or C-14 ( 14 C). All variations in the 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 that can deliver 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 matrices include suspending agents, viscosifiers, transdermal penetration enhancers, etc. Their preparations are well known to those skilled in the field of cosmetics or topical medicine. For additional information on vectors, please refer to 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 for formulating an effective pharmaceutical composition.
  • the term "effective amount” or “therapeutically effective amount” with respect to a drug or pharmacologically active agent refers to a non-toxic amount of the drug or agent sufficient to achieve the desired effect.
  • the "effective amount” of an active substance in the composition refers to the amount required to achieve the desired effect when combined with another active substance in the composition.
  • the determination of the effective amount varies from person to person, depends on the age and general condition of the recipient, and also depends on the specific active substance. The appropriate effective amount in individual cases can be determined by those skilled in the art based on routine experiments.
  • active ingredient refers to a chemical entity that is effective in treating a target disorder, disease, or condition.
  • substituted means that any one or more hydrogen atoms on a specific atom are replaced by a substituent, including deuterium and hydrogen variants, as long as the valence state of the specific atom is normal and the substituted compound is stable .
  • two hydrogen atoms are substituted.
  • Ketone substitution does not occur on aromatic groups.
  • optionally substituted means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents may be arbitrary on the basis of chemical achievability.
  • any variable e.g., R
  • its definition in each instance is independent.
  • said group may optionally be substituted by up to two R's, with independent options for R in each case.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • substituents and/or variants thereof are permitted only if such combinations result in stable compounds.
  • Alkyl and heteroalkyl radicals (including those commonly known as alkylene, alkenyl, heteroalkylene, heteroalkenyl, alkynyl, cycloalkyl, heterocycloalkyl, cycloalkenyl and heterocycloalkenyl
  • 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, thioalkyl 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 for each of these groups.
  • R' and R'' are attached to the same nitrogen atom, they can combine with that nitrogen atom to form a 5-, 6- or 7- -Metal rings.
  • -NR'R is intended to include, but is not limited to, 1-pyrrolidinyl and 4-morpholinyl.
  • alkyl is intended to include carbon Groups composed of atoms bonded to non-hydrogen groups, such as haloalkyl groups (such as -CF 3 , -CH 2 CF 3 ) and acyl groups (such as -C(O)CH 3 , -C(O)CF 3 , - C(O)CH 2 OCH 3 , etc.).
  • Two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the general formula -TC(O)-(CRR')qU-, where T and U are independently selected From -NR-, -O-, CRR'- or a single bond, q is an integer from 0 to 3.
  • two substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally substituted with substituents of the general formula -A(CH2)rB-, where A and B are independently selected.
  • r is 1 to 4 integer.
  • one single bond in the new ring thus formed can be replaced by a double bond.
  • substituents on adjacent atoms of the aryl or heteroaryl ring may be optionally replaced by substituents of the general formula -A(CH2)rB-, where s and d are each 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.
  • halogen or halogen by itself or as part of another substituent means a fluorine, chlorine, bromine or iodine atom.
  • haloalkyl is intended to include both monohaloalkyl and polyhaloalkyl groups.
  • halo(C 1 -C 4 )alkyl is intended to include, but is not limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like wait.
  • haloalkyl groups 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 connected through an oxygen bridge.
  • C 1-6 alkoxy groups include C 1 , C 2 , C 3 , C 4 , C 5 and C 6 alkoxy groups.
  • alkoxy 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 cyclic 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 a straight or branched configuration in which one or more carbon-carbon double bonds are present at any stable point on the chain, such as vinyl and propenyl.
  • 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.
  • Cycle means substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl.
  • the so-called rings include fused rings.
  • the number of atoms in a ring is usually defined as the ring membership.
  • a "5- to 7-membered ring” means 5 to 7 atoms arranged around it. Unless otherwise specified, the ring optionally contains 1 to 3 heteroatoms.
  • 5- to 7-membered ring includes, for example, phenylpyridine and piperidinyl; on the other hand, the term “5- to 7-membered heterocycloalkyl ring” includes pyridinyl and piperidinyl, but does not include phenyl.
  • ring also includes ring systems containing at least one ring, each of which independently meets the above definition.
  • heterocycle or “heterocyclyl” means a stable monocyclic or bicyclic or bicyclic heterocycle, which may be saturated, partially unsaturated or unsaturated (aromatic), which contains 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 may optionally be oxidized (i.e., NO and S(O)p).
  • Nitrogen atoms may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined herein).
  • the heterocycle can be attached to any pendant heteroatom or carbon atom to form a stable structure.
  • the heterocycles described herein may be substituted at the carbon or nitrogen position 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 embodiment 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 5, 6, 7-membered monocyclic or bicyclic aromatic ring or a 7, 8, 9 or 10-membered bicyclic heterocyclyl, It contains carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S.
  • Nitrogen atoms may be substituted or unsubstituted (i.e., N or NR, where R is H or other substituents already defined herein).
  • Nitrogen and sulfur heteroatoms may optionally be oxidized (i.e., 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 (i.e., C, O, N, or S) connect 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 appear on the bridge.
  • heterocyclic compounds include, but are not limited to: acridinyl, anovanyl, benzimidazolyl, benzofuryl, benzmercaptofuryl, benzmercaptophenyl, benzoxazolyl, benzox Zozolinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl, 4aH-carbazolyl, Carboline, chromanyl, chromene, cinnolinyldecahydroquinolyl, 2H,6H-1,5,2-dithiazinyl, dihydrofura[2,3-b] Tetrahydrofuryl, furanyl, furanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indo
  • hydrocarbyl or its sub-concepts (such as alkyl, alkenyl, alkynyl, phenyl, etc.) by itself or as part of another substituent means straight-chain, branched or cyclic.
  • Hydrocarbon radicals or combinations thereof may be fully saturated, mono- or polyunsaturated, may be mono-, disubstituted or poly-substituted, may include divalent or polyvalent radicals, have a specified number of carbon atoms (such as C 1 -C 10 table showing 1 to 10 carbons).
  • Hydrocarbon groups include but are not limited to aliphatic hydrocarbon groups and aromatic hydrocarbon groups.
  • the aliphatic hydrocarbon groups include chain and cyclic ones, specifically including but not limited to alkyl, alkenyl, and alkynyl groups.
  • the aromatic hydrocarbon groups include but are not limited to 6-12 membered ones.
  • the term "alkyl” refers to a linear or branched chain radical or a combination thereof, which may be fully saturated, mono- or polyunsaturated, and may include divalent and polyvalent 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) Methyl, cyclopropylmethyl, and homologues or isomers of n-pentyl, n-hexyl, n-heptyl, n-octyl and other atomic groups.
  • Unsaturated alkyl groups have 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 homologues and isomers conformation.
  • heteroalkyl or its sub-concepts (such as heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.) by itself or in combination with another term means stable linear, branched chain A cyclic or cyclic hydrocarbon group or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • heteroalkyl by itself or in combination with another term refers to a stable linear, branched chain hydrocarbon radical or combination thereof, consisting of a certain number of carbon atoms and at least one heteroatom.
  • the heteroatoms are selected from B, O, N and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatoms are optionally quaternized.
  • Heteroatoms B, O, N, and S can be located at any internal position of the heteroalkyl group (except where the hydrocarbyl group is attached to the rest of the molecule).
  • Up to two heteroatoms can be consecutive, for example -CH2- NH- OCH3 .
  • alkoxy alkylamino
  • alkylthio thioalkoxy
  • cycloalkyl Unless otherwise specified, the terms “cycloalkyl”, “heterocycloalkyl”, “cycloalkyl” or their subtitles (such as aryl, heteroaryl, arylheteroyl, cycloalkyl, heterocycloalkyl, cycloalkyl, etc.) Alkane heteroyl, cycloalkenyl, heterocycloalkenyl, cycloalkene heteroyl, cycloalkynyl, heterocycloalkynyl, cycloalkynyl heteroyl, etc.) by themselves or in combination with other terms respectively represent cyclized “hydrocarbyl", “ "Heteroalkyl” or “heterocarbyl”.
  • heteroalkyl or heterocycloalkyl groups eg, heteroalkyl, heterocycloalkyl
  • the heteroatom may occupy the position where 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 or "aromatic ring” refers to: It should be understood that it preferably represents a monovalent aromatic or partially aromatic monocyclic or bicyclic ring (such as fused ring, bridged ring, spiro ring) with 6 to 20 carbon atoms. ) or a tricyclic hydrocarbon ring, which may be a single aromatic ring or a polyaromatic ring fused together, preferably "C 6-14 aryl".
  • C 6-14 aryl is understood to mean preferably a monovalent or partially aromatic monocyclic, bicyclic or Tricyclic hydrocarbon rings (“C 6-14 aryl”), especially rings with 6 carbon atoms (“C 6 aryl”), such as phenyl; or biphenyl, or with 9 carbon atoms a ring (“C 9 aryl”), such as indanyl or indenyl, or a ring having 10 carbon atoms (“C 10 aryl”), such as tetrahydronaphthyl, dihydronaphthyl or naphthyl, Either a ring with 13 carbon atoms (“C 13 aryl”), such as fluorenyl, or a ring with 14 carbon atoms (“C 14 aryl”), such as anthracenyl.
  • C 6-20 aryl group When the C 6-20 aryl group is substituted, it may be mono- or poly-substituted. Moreover, there is no restriction on the substitution
  • spiro ring refers to a ring system in which two rings share one ring atom, which may contain an aliphatic ring, a heterocyclic ring, an aromatic ring or a heteroaromatic ring as described above.
  • cyclic ring refers to a ring system in which two rings share two ring-forming atoms, which may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as mentioned above.
  • bridged ring refers to a ring system in which two rings share more than three ring-forming atoms, which may contain aliphatic rings, heterocyclic rings, aromatic rings or heteroaromatic rings as mentioned above.
  • heteroaryl refers to an aryl group (or ring) containing one to four heteroatoms.
  • the heteroatoms are selected from B, N, O, and S, wherein the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized.
  • a heteroaryl group 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-isoxazolyl 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-indo
  • aryl when used in conjunction with other terms (eg, aryloxy, arylthio, aralkyl) includes 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 where a carbon atom (e.g., methylene) has been replaced by, e.g., oxygen
  • alkyl groups replaced by atoms such as phenoxymethyl, 2-pyridyloxymethyl 3-(1-naphthyloxy)propyl, etc.
  • leaving group refers to a functional group or atom that can be replaced by another functional group or atom through a substitution reaction, such as an affinity substitution reaction.
  • representative leaving groups include triflate; chlorine, bromine, iodine; sulfonate groups such as mesylate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate Ester, etc.; acyloxy group, such as acetoxy group, trifluoroacetoxy group, etc.
  • 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 compound, and its preparation route is as follows:
  • Z represents a boric acid or borate ester group or active hydrogen
  • G represents a protecting group
  • other substituents have the definitions described in the present invention.
  • Z represents a boric acid or borate ester group or active hydrogen, and other substituents have the definitions described in the present invention.
  • 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 many methods known in the art of organic synthesis.
  • Embodiments of the present invention may use the methods described below to Synthesis, as well as synthetic methods known in the field of organic synthetic chemistry, or improved methods based on them.
  • Preferred methods include, but are not limited to, the methods described below.
  • reaction liquid was heated to 100°C under nitrogen protection and reacted for 5 hours.
  • (2R,3S)-1-diphenylmethyl-2-methylazetidin-3-yl methanesulfonate (6.20g, 18.73mmol) was dissolved in acetonitrile (60mL and water). (10 mL) of the mixed solution, add sodium methyl mercaptide (2.62 g, 37.46 mmol). After the addition is completed, the resulting reaction solution is heated to 70°C and stirred for 16 hours. The reaction is completed, and the reaction solution is concentrated under reduced pressure.
  • (2R, 3S)-1-diphenylmethyl-2-methyl-3-(methylthio)azetidine (6.20g, 21.90mmol) was dissolved in tetrahydrofuran (40mL), To a mixed solution of ethanol (40 mL) and water (40 mL), potassium peroxymonosulfonate (20.86 g, 33.92 mmol) was added. After the addition was completed, the resulting reaction solution was stirred at room temperature for 2 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure.
  • reaction liquid is heated to 100°C and stirred for 16 hours under nitrogen protection.
  • the crude product was passed through reversed-phase flash chromatography (chromatography 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 in 20 minutes; detector: 254nm) for further purification.
  • reaction liquid is heated to 100°C under nitrogen protection and stirred for 16 hours.
  • the crude product was passed through reversed-phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 ⁇ m, 40 g; mobile phase A: water containing 0.1% ammonia; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 20 minutes 30% B-80% B; detection wavelength: 254nm) is further purified.
  • 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfinyl)azetidin-1-yl) is dissolved in the solution.
  • isoquinoline (30 mg, 0.09 mmol) in dioxane (5 mL)
  • 3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoro-3-methylpiperidine was added -4-ol (25 mg, 0.11 mmol), cesium carbonate (88 mg, 0.27 mmol) and methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'- Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6 mg, 0.007 mmol).
  • 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfinyl)azetidin-1-yl) is dissolved in the solution.
  • 2-((3S,4R)-3-fluoro-4-methoxy-3-methylpiperidin-1-yl was added )pyrimidin-4-amine (26 mg, 0.11 mmol), cesium carbonate (88 mg, 0.27 mmol) and methanesulfonate (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6 '-Triisopropyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6 mg, 0.007 mmol).
  • the crude product was passed through reversed-phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40 ⁇ m, 40 g; mobile phase A: water containing 0.1% ammonia; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 20 minutes 30% B-80% B; detection wavelength: 254nm) is further purified.
  • reaction liquid is protected by nitrogen gas.
  • the temperature was raised to 100°C and stirred for 16 hours.
  • reaction solution was quenched with water (30 mL), extracted with ethyl acetate (50 mL ⁇ 2), dried over anhydrous sodium sulfate, filtered, and concentrated.
  • the residue was subjected to reversed-phase flash chromatography (chromatographic conditions: column: spherical C18, 20-40um, 40g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 40mL/ min; gradient: 50% B-70% B in 15 minutes; detector: 254nm) purification, when the mobile B content reaches 63%, collect the fractions containing the product, and then concentrate under reduced pressure to obtain 2-((S)-4 -(4-((5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfonyl)azetidin-1-yl)isoquinoline-3- base)amino)pyrimidin-2-yl
  • 3-chloro-5-isopropyl-8-((2R,3S)-2-methyl-3-(methylsulfinyl)azetidin-1-yl) is dissolved in the solution.
  • isoquinoline (30 mg, 0.09 mmol) in dioxane (5 mL)
  • (3S, 4R)-1-(4-aminopyrimidin-2-yl)-3-fluoropiperidin-4-ol 23 mg, 0.11 mmol
  • cesium carbonate 88 mg, 0.27 mmol
  • methanesulfonic acid (2-dicyclohexylphosphine)-3,6-dimethoxy-2',4',6'-triisopropyl- 1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) (6 mg, 0.007 mmol).
  • reaction liquid is heated to 100°C under nitrogen protection and stirred for 16 hours. hour.
  • the crude product was subjected to reversed-phase 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: 40% B-95% B, within 20 minutes; detector: 254nm) is further purified.
  • the crude product was passed by reversed-phase flash chromatography (chromatography conditions: column: spherical C18,20- 40 ⁇ m, 40g; mobile phase A: water containing 0.1% ammonia; mobile phase B: acetonitrile; flow rate: 40mL/min; gradient: 40%B-95%B in 20 minutes; detection wavelength: 254nm) Purification: when the mobile phase When the B content reaches 47%, collect the fractions containing the product, and then concentrate under reduced pressure to obtain N-(2-((3S, 4R)-3-fluoro-4-methoxypiperidin-1-yl)pyrimidine-4- base)-5-isopropyl-8-(3-(methylsulfinyl)azetidin-1-yl)isoquinolin-3-amine) (70 mg, 0.14 mmol, yield: 61.9% ).
  • the crude product is passed through reversed phase 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: 30% B-80% B in 20 minutes; Detector: 254nm) for further purification.
  • reversed phase 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: 30% B-80% B in 20 minutes; Detector: 254nm
  • the crude product was purified by reversed-phase flash chromatography (column: spherical C18, 20-40 ⁇ m, 40 g; mobile phase A: aqueous solution containing 0.1% ammonia; mobile phase B: acetonitrile; flow rate: 40 mL/min; gradient: 40% in 20 minutes B-95%B; detector: 254nm) purification, when the mobile phase B content reaches 45%, collect the fractions containing the product, and then concentrate under reduced pressure to obtain N-(2-((3S, 4R)-3-fluoro- 4-Methoxy-3-methylpiperidin-1-yl)pyrimidin-4-yl)-5-isopropyl-8-(3-(methylsulfinyl)azetidine-1- (34.87 mg, 0.066 mmol, yield: 31.9%), retention time: 1.611 min. LCMS m/z: 527.3[M+H] + .
  • the resulting reaction liquid is heated to 100°C and stirred for 16 hours under the protection of nitrogen gas.
  • the crude product was purified by reversed-phase flash chromatography (chromatography conditions: column: spherical C18, 20-40 ⁇ m, 40 g; mobile phase A: pure water containing 0.1% NH 3 ⁇ H 2 O; mobile phase B: acetonitrile; flow rate: 40 mL/ min; gradient: 30% B-80% B in 15 minutes; detector: 254nm) for further purification.
  • Biochemical analysis of EGFR enzyme activity inhibitory activity Biochemical analysis of EGFR enzyme activity inhibitory activity:
  • the EGFR inhibitory effect of the compounds of the invention was determined in a biochemical assay: EGFR enzyme phosphorylation of 2.5 micromoles of 5-FAMEEPLYWSFPAKKK-CONFh was measured in the presence of adenosine-5'-triphosphate (ATP) and different concentrations of the test compound. Activity of peptide substrate (FL-Peptide 22, PerkinElmer, 760366).
  • EGFR enzyme fluorescently labeled substrate peptide, ATP and test compound were mixed in 100mM 2-[4-(2-hydroxyethyl)piperazin-l-yl]ethanesulfonic acid (HEPES), pH 7.5, 10mM MgCl 2 , 0.015% Brij-35, 1mM dithiothreitol (DTT) and 1.0% dimethyl sulfoxide (DMSO) to initiate the kinase reaction. Assays were performed at 1.0mM ATP or ATP Km of EGFR enzyme.
  • HEPES 2-[4-(2-hydroxyethyl)piperazin-l-yl]ethanesulfonic acid
  • DTT dithiothreitol
  • DMSO dimethyl sulfoxide
  • EGFR enzyme activity was monitored using the Perkin-Elmer electrophoretic migration transfer technology platform (caliper shift detection method), in which the phosphorylated peptide (product) and substrate were separated and measured by electrophoresis. According to the compound The logarithm of the concentration and the points plotted as percent activity.
  • the enzyme phenotypes of EGFR analyzed were as follows: EGFRWT; EGFR(L858R T790M C797S); EGFR(d746-750)T790M C797S; EGFR L858R; EGFR(d746-750); EGFR( D770_N77 IinsNPG T790M); EGFR (D770_N771 insNPG).
  • the compound to be tested is diluted with 2.5% DMSO 1 ⁇ enzyme buffer, starting from 1uM, diluted 4 times, and 10 concentration gradients.
  • the ER of the compound well is marked as ER compound
  • the ER of the vehicle control well is marked as ER vehicle
  • the ER of the blank control well is marked as ER blank .
  • the inhibition rate is calculated using the following formula:
  • Inhibition rate (ER vehicle -ER compound )/(ER vehicle -ER blank ) ⁇ 100%
  • the inhibition rate was plotted and analyzed using GraphPad Prism 6 (version 6.01), and IC 50 was calculated.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un nouveau composé pyrimidohétérocyclique substitué, qui peut être utilisé en tant qu'inhibiteur de cible de mutation EGFR. L'invention concerne en particulier un composé représenté par la structure dans la formule (I) ou des sels, solvates, hydrates, substitutions d'isotopes ou isomères pharmaceutiquement acceptables de celui-ci. Le composé a un effet d'affinité sur des cibles de mutation EGFR, et a en particulier un effet inhibiteur puissant sur l'activité de protéines mutantes telles que EGFR19Del-T790M-C797S, EGFRL858R-T790M-C797S, EGFR19Del-C797S, EGFRL858R-C797S, EGFR-C797S, etc. Le composé peut être utilisé pour préparer des médicaments ou des sondes moléculaires pour prévenir ou traiter des maladies associées à des voies de signalisation de mutation EGFR (telles que le cancer, des maladies immunitaires, etc.).
PCT/CN2023/105583 2022-07-04 2023-07-03 Nouveau composé pyridohétérocyclique substitué par pyrimidine ou triazine Ceased WO2024008048A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210786970.3 2022-07-04
CN202210786970 2022-07-04

Publications (1)

Publication Number Publication Date
WO2024008048A1 true WO2024008048A1 (fr) 2024-01-11

Family

ID=89454393

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/105583 Ceased WO2024008048A1 (fr) 2022-07-04 2023-07-03 Nouveau composé pyridohétérocyclique substitué par pyrimidine ou triazine

Country Status (1)

Country Link
WO (1) WO2024008048A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024152986A1 (fr) * 2023-01-18 2024-07-25 北京鞍石生物科技有限责任公司 Composé amino hétéroaryle, son procédé de préparation et son utilisation
WO2024238574A1 (fr) * 2023-05-15 2024-11-21 Aleksia Therapeutics, Inc. Composés inhibiteurs de cdk

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014210354A1 (fr) * 2013-06-28 2014-12-31 Genentech, Inc. Composés d'azaindazole en tant qu'inhibiteurs de la t790m contenant des mutants de l'egfr
WO2016070816A1 (fr) * 2014-11-05 2016-05-12 上海页岩科技有限公司 Composés pyrimidine ou pyridine, leur procédé de préparation et leurs utilisations pharmaceutiques
WO2021133809A1 (fr) * 2019-12-23 2021-07-01 Blueprint Medicines Corporation Inhibiteurs de formes mutantes de l'egfr
WO2022271612A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs hétérocycliques d'egfr destinés à être utilisés dans le traitement du cancer
WO2022271630A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs de l'egfr
CN115650958A (zh) * 2022-10-14 2023-01-31 中国药科大学 2-氨基嘧啶类化合物及其制备方法、用途和药物组合物
WO2023025320A1 (fr) * 2021-08-27 2023-03-02 上海翰森生物医药科技有限公司 Inhibiteur de dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation
WO2023070114A2 (fr) * 2021-10-22 2023-04-27 Terremoto Biosciences, Inc. Modificateurs covalents de lysine réversibles de l'egfr et leurs utilisations
WO2023071998A1 (fr) * 2021-10-26 2023-05-04 杭州德睿智药科技有限公司 Nouveau composé pyrido ou pyrido hétérocyclique à substitution triazine
CN116262741A (zh) * 2021-12-14 2023-06-16 杭州紫晶医药科技有限公司 作为突变型egfr抑制剂的化合物
WO2023134266A1 (fr) * 2022-01-17 2023-07-20 苏州浦合医药科技有限公司 Composé pyrimidine substitué par 2-pipéridyle ou 2-pyrazolyle servant d'inhibiteur d'egfr
CN116554150A (zh) * 2022-12-30 2023-08-08 苏州浦合医药科技有限公司 第四代egfr抑制剂

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014210354A1 (fr) * 2013-06-28 2014-12-31 Genentech, Inc. Composés d'azaindazole en tant qu'inhibiteurs de la t790m contenant des mutants de l'egfr
WO2016070816A1 (fr) * 2014-11-05 2016-05-12 上海页岩科技有限公司 Composés pyrimidine ou pyridine, leur procédé de préparation et leurs utilisations pharmaceutiques
WO2021133809A1 (fr) * 2019-12-23 2021-07-01 Blueprint Medicines Corporation Inhibiteurs de formes mutantes de l'egfr
WO2022271612A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs hétérocycliques d'egfr destinés à être utilisés dans le traitement du cancer
WO2022271630A1 (fr) * 2021-06-22 2022-12-29 Blueprint Medicines Corporation Inhibiteurs de l'egfr
WO2023025320A1 (fr) * 2021-08-27 2023-03-02 上海翰森生物医药科技有限公司 Inhibiteur de dérivé hétérocyclique contenant de l'azote, son procédé de préparation et son utilisation
WO2023070114A2 (fr) * 2021-10-22 2023-04-27 Terremoto Biosciences, Inc. Modificateurs covalents de lysine réversibles de l'egfr et leurs utilisations
WO2023071998A1 (fr) * 2021-10-26 2023-05-04 杭州德睿智药科技有限公司 Nouveau composé pyrido ou pyrido hétérocyclique à substitution triazine
CN116262741A (zh) * 2021-12-14 2023-06-16 杭州紫晶医药科技有限公司 作为突变型egfr抑制剂的化合物
WO2023134266A1 (fr) * 2022-01-17 2023-07-20 苏州浦合医药科技有限公司 Composé pyrimidine substitué par 2-pipéridyle ou 2-pyrazolyle servant d'inhibiteur d'egfr
CN115650958A (zh) * 2022-10-14 2023-01-31 中国药科大学 2-氨基嘧啶类化合物及其制备方法、用途和药物组合物
CN116554150A (zh) * 2022-12-30 2023-08-08 苏州浦合医药科技有限公司 第四代egfr抑制剂

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
BRYAN, K. C. ET AL.: "Discovery of a Noncovalent, Mutant-Selective Epidermal Growth Factor Receptor Inhibitor", J. MED. CHEM., vol. 59, no. 19, 26 August 2016 (2016-08-26), XP055497250, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.6b00995 *
MEREDITH, S. E. ET AL.: "Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer", J. MED. CHEM., vol. 65, no. 14, 15 July 2022 (2022-07-15), XP055959499, ISSN: 0022-2623, DOI: 10.1021/acs.jmedchem.2c00704 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024152986A1 (fr) * 2023-01-18 2024-07-25 北京鞍石生物科技有限责任公司 Composé amino hétéroaryle, son procédé de préparation et son utilisation
WO2024238574A1 (fr) * 2023-05-15 2024-11-21 Aleksia Therapeutics, Inc. Composés inhibiteurs de cdk

Similar Documents

Publication Publication Date Title
CN111153901B (zh) 一类含氮稠杂环类shp2抑制剂化合物、制备方法和用途
CA2984586C (fr) Compose aryl-pyrimidine tricyclique ou a cycle fusionne utilise comme inhibiteur de kinase
TWI791511B (zh) 細胞凋亡誘導劑
ES2936627T3 (es) Compuesto de pirazina-2(1H)-cetona como inhibidor de FGFR
BR112020001124A2 (pt) composto ou o sal farmaceuticamente aceitável do mesmo, composição farmacêutica, uso do composto ou do sal farmaceuticamente aceitável do mesmo e método para tratamento de câncer
WO2021018009A1 (fr) Inhibiteur d'egfr, composition et procédé de préparation correspondant
CN108026102A (zh) 可用于治疗与kit和pdgfr相关的病症的化合物
CN105461711B (zh) 作为PI3K抑制剂的吡啶并[1,2-a]嘧啶酮类似物
WO2024008048A1 (fr) Nouveau composé pyridohétérocyclique substitué par pyrimidine ou triazine
CN108069959A (zh) 一种含氮杂环类化合物、其制备方法、药物组合物及应用
WO2024002024A1 (fr) Composés tricycliques et leurs utilisations
WO2020215998A1 (fr) Composé hétérocyclique à cinq chaînons à base de pyrimido et son utilisation en tant qu'inhibiteur d'idh2 mutant
WO2021115335A1 (fr) Composé utile en tant qu'inhibiteur de la kinase 9 dépendante de la cycline et son utilisation
WO2023071998A1 (fr) Nouveau composé pyrido ou pyrido hétérocyclique à substitution triazine
WO2021197467A1 (fr) Composé antitumoral multicible, son procédé de préparation et son utilisation
CN103936762B (zh) 吗啉并喹啉类化合物，其制备方法和用途
CN111556869A (zh) 作为csf-1r抑制剂的杂环化合物及其应用
CN118119625A (zh) 具有mat2a抑制活性的嘧啶-2(1h)-酮并二环类化合物及其用途
TW201904969A (zh) Ｃｋ２抑制劑，其組成物及方法
KR20210139378A (ko) 피롤아미드피리돈계 화합물, 제조방법 및 용도
WO2024067744A1 (fr) Quinazoline substituée hétérocyclique, son procédé de préparation et son utilisation
CN116102533A (zh) 一种芳杂环类化合物及其应用
WO2020200154A1 (fr) Classe de n-hétérocycles fusionnés par du thiophène, procédé de préparation et utilisation
KR20190077085A (ko) Fgfr4 억제제, 이의 제조 방법 및 응용
EP3498715A1 (fr) Composé du virus anti-hcmv

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23834815

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 23834815

Country of ref document: EP

Kind code of ref document: A1