WO2022117051A1 - Composé macrocyclique, son procédé de préparation et son utilisation - Google Patents

Composé macrocyclique, son procédé de préparation et son utilisation Download PDF

Info

Publication number
WO2022117051A1
WO2022117051A1 PCT/CN2021/135154 CN2021135154W WO2022117051A1 WO 2022117051 A1 WO2022117051 A1 WO 2022117051A1 CN 2021135154 W CN2021135154 W CN 2021135154W WO 2022117051 A1 WO2022117051 A1 WO 2022117051A1
Authority
WO
WIPO (PCT)
Prior art keywords
alkyl
amino
cycloalkyl
alkoxy
group
Prior art date
Application number
PCT/CN2021/135154
Other languages
English (en)
Chinese (zh)
Inventor
张培龙
李功
兰文丽
薛宝玉
Original Assignee
北京鞍石生物科技有限责任公司
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 北京鞍石生物科技有限责任公司 filed Critical 北京鞍石生物科技有限责任公司
Publication of WO2022117051A1 publication Critical patent/WO2022117051A1/fr

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains four or more hetero rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D498/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D513/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00
    • C07D513/22—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for in groups C07D463/00, C07D477/00 or C07D499/00 - C07D507/00 in which the condensed system contains four or more hetero rings

Definitions

  • the present invention relates to macrocyclic compounds and their preparation methods and applications, in particular to compounds that inhibit, regulate and/or regulate the signal transduction of EGFR kinases, their preparation methods, pharmaceutical compositions containing them and their applications.
  • Protein kinases are enzymatic components of signaling pathways that catalyze the transfer of terminal phosphates from ATP to the hydroxyl groups of tyrosine, serine and/or threonine residues of proteins. Therefore, compounds that inhibit protein kinase function are valuable tools for assessing the physiological consequences of protein kinase activity.
  • Overexpression or inappropriate expression of normal or mutant protein kinases in mammals has been the subject of extensive research and has been demonstrated in many diseases, including diabetes, angiogenesis, psoriasis, restenosis, eye disease, schizophrenia, It plays an important role in the development of rheumatoid arthritis, atherosclerosis, cardiovascular disease and cancer. Protein kinase inhibitors have particular utility in the treatment of human and animal diseases.
  • EGFR is a member of the ErbB receptor family of receptor tyrosine kinases. When EGFR binds to its ligand EGF extracellularly, the receptor undergoes homo- or heterodimerization and autophosphorylation, activating downstream cascade signaling pathways, and ultimately promoting cell growth, proliferation, and division.
  • Overexpression (upregulation) or overactivity of EGFR has been shown to be associated with many cancers, including head and neck, ovarian, cervical, bladder, esophageal, gastric, breast, endometrial, colorectal, non- Small cell lung cancer, and glioblastoma.
  • EGFR as an oncogene has given rise to targeted therapy against EGFR small molecule inhibitors.
  • NSCLC non-small cell lung cancer
  • side effects such as rash and diarrhea, and after one year of use, the patient develops drug resistance.
  • Clinical data show that about 50% of patients with acquired resistance originate from the T790M (exon 20 position 790 threonine is replaced by methionine) mutant.
  • Second-generation inhibitors such as afatinib and dacomitinib have stronger binding activity to EGFR, but have poor selectivity for the T790M mutant, and cannot reach effective concentrations in vivo at tolerable doses.
  • the third-generation inhibitor osimertinib can be used as a second-line treatment for patients with T790M mutation after first- and second-generation therapy, or as a first-line treatment for patients with EGFR-sensitive mutations who have not been treated with EGFR-TKIs. After 9.9-18.9 months of treatment with the EGFR inhibitor osimertinib, resistance mutation C797S (C797S mutation at position 797 of exon 20) was inevitable.
  • Thress KS first reported that 40% of patients with T790M mutation who took osimertinib developed C797S resistance mutation. In addition, Lee JY et al. also reported that 24% of patients with T790M mutation developed C797S resistance after taking osimertinib. The Papadimitrakopoulou V.A. analysis of 73 patients with disease progression on osimertinib in the AURA3 clinical trial found that 15% of patients developed the C797S resistance mutation.
  • osimertinib also showed superior efficacy as first-line treatment compared with the standard treatment of first-generation EGFR inhibitors (gefitinib or erlotinib), in which 91 patients took osimertinib
  • the present invention provides a macrocyclic compound, which can overcome both EGFR C797S mutation and EGFR T790M mutation, and has high selectivity.
  • the present invention is achieved through the following technical solutions.
  • the present invention provides a compound having the structure shown in the following formula I:
  • Ring A and Ring B are each independently a 6-10 membered monocyclic aromatic ring or a bicyclic aromatic ring, a 5-10 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S, or Bicyclic heteroaromatic ring, or 5-10 membered monocyclic heterocycle or bicyclic heterocycle containing 1-4 heteroatoms independently selected from N, O and S, the 6-10 membered monocyclic aromatic ring or Bicyclic aromatic rings, 5-10 membered monocyclic heteroaromatic or bicyclic heteroaromatic rings containing 1-4 heteroatoms independently selected from N, O and S, or containing 1-4 heteroatoms independently selected from N,
  • the 5-10 membered monocyclic or bicyclic heterocycle of the O and S heteroatoms may be optionally substituted with one or more substituents independently selected from the group consisting of: C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, halogenated C 1-6
  • Ring D is a 6-10-membered monocyclic aromatic ring or a bicyclic aromatic ring, a 5-10-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S heteroatoms, 5-10 membered monocyclic heterocycle or bicyclic heterocycle, or C 5-7 cycloalkane containing 1-4 heteroatoms independently selected from N, O and S heteroatoms;
  • R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
  • R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged or spirocyclic heterocyclyl-C 0-3 alkyl, amino group containing 1-3 heteroatoms independently selected from N, O or S heteroatoms , C 1-6 alkyl-amino, C 3-6 cycloalkyl-amino, two (C 1-6 alkyl)-amino, C 1-6 alkoxy-C 1-6 alkyl-amino, 4 -6-membered heterocyclyl-C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl-amino, hydrogen atom, halogen, hydroxyl, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl , hydroxy-C 1-6 alk
  • R3 together with any atom on Ring D other than the atom to which R3 is attached alternatively, R3 and R6 together with the attached atom optionally form a heterocycle consisting of 3-10 atoms
  • the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S and the heterocyclic ring is optionally further selected from one or more C 1-6 alkyl groups, halogens, 6-10-membered aryl groups, including 5-10-membered heteroaryl groups containing 1-3 heteroatoms independently selected from N, O or S, 5-10-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O or S , halogenated C 1-6 alkyl, hydroxyl, cyano, halogen, C 1-6 alkoxy, 4-6 membered heterocyclyl alkyl, C 1-6 alkylamino and bis(C 1-6 alkane base) is substituted with amino;
  • the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
  • R7 is or C 1-6 alkyl C(O);
  • Y 1 , Y 2 and Y 3 are each independently a chemical bond, O, NR 8 , S, S(O) 2 , CR 8 R 16 , carbonyl, -amino-acyl, -acyl-amino, -O(CO)- or -(CO)O-;
  • M is a chemical bond, -C 1-6 alkyl- substituted or unsubstituted by one or more R m , -C 3-6 cycloalkyl- substituted or unsubstituted by one or more R m , One or more R m substituted or unsubstituted -C 3-6 cycloalkyl-C 1-6 alkyl-, one or more R m substituted or unsubstituted -C 1-6 alkyl- Amino-C 1-6 alkyl-, substituted or unsubstituted by one or more R m -4-7 membered heterocyclyl- containing 1-2 heteroatoms independently selected from N, O and S heteroatoms-, -4-7 membered heterocyclyl-C 1-6 alkyl- containing 1-2 heteroatoms independently selected from N, O and S heteroatoms substituted or unsubstituted by one or more R m ;
  • R 8 is a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or 5-7 containing 1-2 heteroatoms independently selected from N, O and S and optionally substituted by oxo membered heterocyclic group;
  • R 9 and R 10 are independently a hydrogen atom, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, or heterocyclylalkyl;
  • R 11 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 Alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, including 1-3 independently selected from N, 4-10-membered heterocyclic group of O or S heteroatom, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1 -6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, including 1- 3 4-10 membered heterocyclyl groups independently selected from N, O or S heteroatoms may be optionally substituted with one or more groups independently selected from the group consisting
  • R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a 4-10-membered heterocyclic ring containing 1-3 heteroatoms independently selected from N, O or S.
  • R 12 and R 13 together with N in NR 12 R 13 form a 4-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S, the C 1-6 alkane group, C 3-7 cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, or R 12 and R 13 together with N in NR 12 R 13
  • Forming a 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S may be optionally substituted with one or more substituents independently selected from the group: C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3 -6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, oxo, C C
  • R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
  • R 16 is a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group, or a C 3-6 cycloalkoxy group;
  • R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
  • R a and R b together with the attached carbon atoms form a ring
  • R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy.
  • Ring E is a 4-7 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or 1-5 heteroatoms independently selected from N, O or S 5-10-membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle, the 4-7-membered saturated or partially unsaturated heterocycle and 5-10-membered bridged or spirocyclic saturated or partially unsaturated heterocycle can be any is independently replaced by one or more Rm ;
  • Ring G is a 4-7 membered saturated or partially unsaturated heterocycle, C3-6 cycloalkane, 6-10 membered monocyclic aromatic ring or bicyclic containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Aromatic ring, or a 5-10-membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle containing 1-5 heteroatoms independently selected from N, O or S, the 4-7 membered saturated or partially unsaturated heterocycle Ring, C 3-6 cycloalkane, 6-10 membered monocyclic aromatic ring or bicyclic aromatic ring, 5-10 membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle may be optionally independently replaced by one or more R replaced by m ;
  • R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3- 6 cycloalkyl, C 3-6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino -C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl -Amino-C 1-6 alkyl, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl) -amino, C 3-6 cycloalkyl-amino, C
  • q and t are each independently 0, 1, 2 or 3;
  • w 1, 2 or 3;
  • X is O, S, CR 17 R 18 , NR 17 , CO or S(O) 2 ;
  • R 17 is hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-6 alkoxy-C 1 -6 alkyl, halogenated C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl-carbonyl or C 1-6 alkyl-sulfone;
  • R 18 is hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkane group, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkyl-amino
  • Z is N, O, S, CO, S(O) 2 , -amino-acyl, -acyl-amino, -O(CO)-, -(CO)O-, CR 19 , C 3-7 cycloalkyl or 3-7 membered heterocyclyl, the C 3-7 cycloalkyl and 3-7 membered heterocyclyl may be optionally independently substituted with one or more R 18 ;
  • R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2 or 3.
  • Ring A and Ring B are each independently a benzene ring, or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S, the benzene ring Or the 5-6 membered heteroaromatic ring may be optionally substituted with one or more substituents independently selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen Substituted C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkane Oxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, C 1-6 alkyl
  • ring A and ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, Isothiazoles, said benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole and isothiazole may be optionally combined with one or more Substituted independently from the following substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycl
  • Ring D is a benzene ring, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N,O and S, containing 1-2 heteroatoms independently selected from N,O and 5-7 membered heterocycle or cyclohexyl ring of S heteroatom;
  • ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, pyrazole, imidazole or cyclohexane.
  • one of R 1 , R 2 , R 4 and R 5 is a warhead group, and when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 , When R 2 is a warhead group, R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a war head group, R 1 , R 2 and R 5 are each independently R 6 ; or when When R 5 is a warhead group, R 1 , R 2 and R 4 are each independently R 6 ;
  • R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged ring or spirocyclic heterocyclyl-C 0-3 alkyl, hydrogen containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Atom, halogen, hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy base-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino-C 1-6 alkyl, di(C 1-6 6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino-C 1-6 alkyl, C 1-6 alkoxy, bis(C 1-6 alkyl)-amino-C
  • the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
  • Y 1 , Y 2 and Y 3 are each independently a chemical bond, O or NR 8 ;
  • R 8 is a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
  • R 9 and R 10 are independently a hydrogen atom, halogen or cyano
  • R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or R 12 and R 13 together with N in NR 12 R 13 form 1-3 independently A 4-7 membered heterocycle selected from N, O or S heteroatoms, the C 1-6 alkyl, C 3-6 cycloalkyl and formed containing 1-3 independently selected from N, O or S
  • the 4-7 membered heterocycle of the heteroatom may be optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, C 1-6 alkyl-amino, bis(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, 3-7 membered heterocyclyl and C 1-6 alkyl-carbonyl containing N, O or S heteroatom
  • R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
  • R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
  • R a and R b together with the attached carbon atoms form a ring
  • R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy;
  • Ring E is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or a 7-10 membered heteroatom containing 1-5 heteroatoms independently selected from N, O or S Bridged or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, 7-10 membered bridged or spiro saturated heterocycle may be optionally independently substituted by one or more Rm ;
  • Ring G is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, a C 3-6 cycloalkane, or contains 1-5 heteroatoms independently selected from N, O or S
  • the heteroatom 7-10 membered bridged ring or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, C 3-6 cycloalkane, 7-10 membered bridged ring or spiro saturated heterocycle can be optionally independently replaced by one or more R m ;
  • R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy base-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, halogen, hydroxyl, cyano, Amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkane base-OC(O)- or C 3-6 cycloalkyl-OC(O)-;
  • q and t are each independently 0, 1, 2 or 3;
  • w 1, 2 or 3;
  • one of R 1 , R 2 , R 4 and R 5 is a warhead group, and when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 when R 2 is a warhead group, R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a war head group, R 1 , R 2 and R 5 are each independently R 6 ; or When R 5 is a warhead group, R 1 , R 2 and R 4 are each independently R 6 ;
  • R 3 and R 6 are each independently a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethyl Oxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxy Methyl, N,N,N'-trimethylethylenediaminomethyl, N,N-dimethylethylenediaminomethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinyl Methyl, piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 4-(3-methoxyacridin-1-yl)piperidin-1-ylmethyl, piperidine Azin-1-ylmethyl, 4-methylpiperazin-1
  • the warhead groups are:
  • X is O or S
  • Z is N, O, S, -amino-acyl, -acyl-amino, or CR 19 ;
  • R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
  • Z is N, O or CR 19 ;
  • R 19 is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl.
  • Ring A and Ring B are each independently a benzene ring, or a 5-6-membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S, said benzene ring or a 5-6-membered heteroaromatic ring
  • the ring may be optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-6 alkyl , C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 Alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino , C 1-6 alkyl
  • Ring D is a benzene ring, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N, O and S, a 5-membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S 7-membered heterocycle or cyclohexane;
  • R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
  • R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged ring or spirocyclic heterocyclyl-C 0-3 alkyl, hydrogen containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Atom, halogen, hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy base-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino-C 1-6 alkyl, di(C 1-6 6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino-C 1-6 alkyl, C 1-6 alkoxy, bis(C 1-6 alkyl)-amino-C
  • the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
  • Y 1 , Y 2 and Y 3 are each independently a chemical bond, O or NR 8 ;
  • R 8 is a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
  • R 9 and R 10 are independently a hydrogen atom, halogen or cyano
  • R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or R 12 and R 13 together with N in NR 12 R 13 form 1-3 independently A 4-7 membered heterocycle selected from N, O or S heteroatoms, the C 1-6 alkyl, C 3-6 cycloalkyl and formed containing 1-3 independently selected from N, O or S
  • the 4-7 membered heterocycle of the heteroatom may be optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, C 1-6 alkyl-amino, bis(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, 3-7 membered heterocyclyl and C 1-6 alkyl-carbonyl containing N, O or S heteroatom
  • R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
  • R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
  • R a and R b together with the attached carbon atoms form a ring
  • R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy;
  • Ring E is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or a 7-10 membered heteroatom containing 1-5 heteroatoms independently selected from N, O or S Bridged or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, 7-10 membered bridged or spiro saturated heterocycle may be optionally independently substituted by one or more Rm ;
  • Ring G is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, a C 3-6 cycloalkane, or contains 1-5 heteroatoms independently selected from N, O or S
  • the heteroatom 7-10 membered bridged ring or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, C 3-6 cycloalkane, 7-10 membered bridged ring or spiro saturated heterocycle can be optionally independently replaced by one or more R m ;
  • R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy base-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, halogen, hydroxyl, cyano, Amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkane base-OC(O)- and C 3-6 cycloalkyl-OC(O)-;
  • q and t are each independently 0, 1, 2 or 3;
  • w 1, 2 or 3;
  • X is O or S
  • Z is N, O, S, -amino-acyl, -acyl-amino, or CR 19 ;
  • R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2 or 3.
  • Ring A and Ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, isothiazole, and the benzene ring , pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole and isothiazole may be optionally replaced by one or more substituents independently selected from the following Substituted: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, hal
  • Ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, pyrazole, imidazole or hexane;
  • R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
  • R 3 and R 6 are each independently a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethyl Oxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxy Methyl, N,N,N'-trimethylethylenediaminomethyl, N,N-dimethylethylenediaminomethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinyl Methyl, piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 4-(3-methoxyacridin-1-yl)piperidin-1-ylmethyl, piperidine Azin-1-ylmethyl, 4-methylpiperazin-1
  • the warhead groups are:
  • X is O or S
  • Z is N, O or CR 19 ;
  • R 19 is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl;
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2 or 3.
  • Ring A and Ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, imidazole, oxazole, isoxazole, thiazole, isothiazole, said benzene, pyridine, pyrimidine, pyridazine , pyrazine, pyrazole, imidazole, oxazole, isoxazole, thiazole and isothiazole may be optionally substituted with one or more substituents independently selected from the group consisting of methyl, ethyl, isopropyl , vinyl, ethynyl, fluoroethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl, methoxy, ethoxy, cyclopropoxy, methoxymethyl, methoxy Ethyl, hydroxyethyl, hydroxypropyl,
  • Ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine or piperazine;
  • R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
  • R3 and R6 are independently hydrogen atom, fluorine, chlorine, bromine, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl group, ethoxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylamino Ethoxymethyl, N,N,N'-trimethylethylenediaminomethyl, N,N-dimethylethylenediaminomethyl, pyrrolidinylmethyl, morpholinomethyl, nitrogen heterocycle Butylmethyl, piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 4-(3-methoxyacridin-1-yl)piperidin-1-ylmethyl base, piperazin-1-ylmethyl, 4-methylpiperazin-1-ylmethyl, 4-acety
  • the warhead groups are:
  • X is O or S
  • Z is N, O or CR 19 ;
  • R 19 is independently a hydrogen atom, methyl, ethyl or cyclopropyl
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2 or 3.
  • the compound shown in formula I is selected from the following compounds:
  • the present application provides a pharmaceutical composition
  • a pharmaceutical composition comprising the above-mentioned compound and a pharmaceutically acceptable carrier or excipient; preferably, the pharmaceutical composition is a tablet, capsule, pill, granule, powder, suppository, Injections, solutions, suspensions, ointments, patches, lotions, drops, liniments or sprays.
  • the present application provides the use of the above-mentioned compounds and/or pharmaceutical compositions in the preparation of antitumor drugs.
  • the antineoplastic drug is used for the following conditions: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovary cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, Cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.
  • the tumor is a malignant tumor carrying EGFR gene mutation; preferably, the EGFR gene mutation is selected from one of: Del19EGFR gene mutation, L858R EGFR gene mutation, T790M EGFR gene mutation and C797S EGFR gene mutation or more.
  • the present application provides a method for treating a tumor in a patient in need thereof, comprising administering to the patient a therapeutically effective amount of the above-mentioned compound or pharmaceutical composition, the patient is preferably a mammal, and the mammal is preferably a human .
  • modes of administration include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal.
  • the tumor comprises: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovarian cancer, cervical cancer, Pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, bile duct cancer, intrauterine cancer Membranous carcinoma, multiple myeloma, or mesothelioma.
  • the application provides a method for preparing a compound of formula I, the method comprising the following reaction steps:
  • the alkali used under alkaline conditions in step (1) is selected from potassium carbonate;
  • the base used in the hydrolysis in step (5) is selected from lithium hydroxide.
  • the method for preparing a compound of formula I comprises the following reaction steps:
  • the alkali used under alkaline conditions in step (1) is selected from potassium carbonate;
  • R 22 is a hydrogen atom, -Y 1 (CR a R b ) q NHR 8 , R 20 is R 22 with a protective group, halogen, an oxy group with a protective group, an amino group with a protective group, etc., R 18 , R 19 , R 21 , R 23 , R 24 and R 25 are R 6 ; when When R 2 is a warhead group, R 23 is -Y 1 (CR a R b ) q NHR 8 , R 21 is R 23 with a protective group, halogen, an oxy group with a protective group, an amino group with a protective group, etc., R 18 , R 19 , R 20 , R 22 , R 24 and R 25 are R 6 ; when When R 4 is a warhead group, R 24 is -Y 1 (CR a R b ) q NHR 8 , R 18 is R 24 with a protective group, halogen, an oxy group
  • protective groups include but are not limited to tert-butoxycarbonyl, benzyloxycarbonyl, benzyl or dimethoxybenzyl;
  • L is hydroxyl, halogen or leaving group
  • A, B, D, E, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R a , R b , R c , R d , Y 1 , Y 2 , Y 3 , Z, X, p, q, m, n, t, warhead groups are as defined above;
  • the present invention relates to compounds of formula I or a pharmaceutically acceptable salt, stereoisomer, racemate, tautomer, isotopic label, nitrogen oxide, prodrug molecule, hydrate or solvate thereof:
  • Ring A and Ring B are each independently a 6-10 membered monocyclic aromatic ring or a bicyclic aromatic ring, a 5-10 membered monocyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S, or Bicyclic heteroaromatic ring, or 5-10 membered monocyclic heterocycle or bicyclic heterocycle containing 1-4 heteroatoms independently selected from N, O and S, the 6-10 membered monocyclic aromatic ring or Bicyclic aromatic rings, 5-10 membered monocyclic heteroaromatic or bicyclic heteroaromatic rings containing 1-4 heteroatoms independently selected from N, O and S, or containing 1-4 heteroatoms independently selected from N,
  • the 5-10 membered monocyclic or bicyclic heterocycle of the O and S heteroatoms may be optionally substituted with one or more substituents independently selected from the group consisting of: C 1-6 alkyl, C 2-6 Alkenyl, C 2-6 alkynyl, halogenated C 1-6
  • Ring D is a 6-10-membered monocyclic aromatic ring or a bicyclic aromatic ring, a 5-10-membered monocyclic heteroaromatic ring or a bicyclic heteroaromatic ring containing 1-4 heteroatoms independently selected from N, O and S heteroatoms, 5-10 membered monocyclic heterocycle or bicyclic heterocycle, or C 5-7 cycloalkane containing 1-4 heteroatoms independently selected from N, O and S heteroatoms;
  • R 1 , R 2 , R 4 and R 5 is a warhead group, when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 ; when R 2 is a warhead group When R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a warhead group, R 1 , R 2 and R 5 are each independently R 6 ; or when R 5 is a warhead group , R 1 , R 2 and R 4 are each independently R 6 ;
  • R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged or spirocyclic heterocyclyl-C 0-3 alkyl, amino group containing 1-3 heteroatoms independently selected from N, O or S heteroatoms , C 1-6 alkyl-amino, C 3-6 cycloalkyl-amino, two (C 1-6 alkyl)-amino, C 1-6 alkoxy-C 1-6 alkyl-amino, 4 -6-membered heterocyclyl-C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl-amino, hydrogen atom, halogen, hydroxyl, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl , hydroxy-C 1-6 alk
  • R3 together with any atom on Ring D except the atom to which R3 is attached alternatively, R3 and R6 together with the attached atom optionally form a heterocycle consisting of 3-10 atoms
  • the heterocyclic ring contains 1-3 heteroatoms selected from N, O or S and the heterocyclic ring is optionally further selected from one or more C 1-6 alkyl groups, halogens, 6-10-membered aryl groups, including 5-10-membered heteroaryl groups containing 1-3 heteroatoms independently selected from N, O or S, 5-10-membered heterocyclic groups containing 1-3 heteroatoms independently selected from N, O or S , halogenated C 1-6 alkyl, hydroxyl, cyano, halogen, C 1-6 alkoxy, 4-6 membered heterocyclyl alkyl, C 1-6 alkylamino and bis(C 1-6 alkane base) is substituted with amino;
  • the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
  • R7 is or C 1-6 alkyl C(O);
  • Y 1 , Y 2 and Y 3 are each independently a chemical bond, O, NR 8 , S, S(O) 2 , CR 8 R 16 , carbonyl, -amino-acyl, -acyl-amino, -O(CO)- or -(CO)O-;
  • M is a chemical bond, -C 1-6 alkyl- substituted or unsubstituted by one or more R m , -C 3-6 cycloalkyl- substituted or unsubstituted by one or more R m , One or more R m substituted or unsubstituted -C 3-6 cycloalkyl-C 1-6 alkyl-, one or more R m substituted or unsubstituted -C 1-6 alkyl- Amino-C 1-6 alkyl-, substituted or unsubstituted by one or more R m -4-7 membered heterocyclyl- containing 1-2 heteroatoms independently selected from N, O and S heteroatoms-, -4-7 membered heterocyclyl-C 1-6 alkyl- containing 1-2 heteroatoms independently selected from N, O and S heteroatoms substituted or unsubstituted by one or more R m ;
  • R 8 is a hydrogen atom, C 1-6 alkyl, C 3-6 cycloalkyl, or 5-7 containing 1-2 heteroatoms independently selected from N, O and S and optionally substituted by oxo membered heterocyclic group;
  • R 9 and R 10 are independently a hydrogen atom, halogen, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, or heterocyclylalkyl;
  • R 11 is a hydrogen atom, C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 Alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, amino, C 1-6 alkylamino, di(C 1-6 alkyl)amino, including 1-3 independently selected from N, 4-10-membered heterocyclic group of O or S heteroatom, said C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1 -6 alkoxy-C 1-6 alkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkylamino, di(C 1-6 alkyl)amino, including 1- 3 4-10 membered heterocyclyl groups independently selected from N, O or S heteroatoms may be optionally substituted with one or more groups independently selected from the group consisting
  • R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-7 cycloalkyl group, a 4-10-membered heterocyclic ring containing 1-3 heteroatoms independently selected from N, O or S.
  • R 12 and R 13 together with N in NR 12 R 13 form a 4-10 membered heterocyclic group containing 1-3 heteroatoms independently selected from N, O or S, the C 1-6 alkane group, C 3-7 cycloalkyl, 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S, or R 12 and R 13 together with N in NR 12 R 13
  • Forming a 4-10 membered heterocyclyl containing 1-3 heteroatoms independently selected from N, O or S may be optionally substituted with one or more substituents independently selected from the group: C 1-6 Alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3 -6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, oxo, C C
  • R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
  • R 16 is a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, a C 1-6 alkoxy group, or a C 3-6 cycloalkoxy group;
  • R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
  • R a and R b together with the attached carbon atoms form a ring
  • R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy.
  • Ring E is a 4-7 membered saturated or partially unsaturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or 1-5 heteroatoms independently selected from N, O or S 5-10-membered bridged or spiro saturated or partially unsaturated heterocycle, the 4-7-membered saturated or partially unsaturated heterocycle and 5-10-membered bridged or spiro saturated or partially unsaturated heterocycle can be any is independently replaced by one or more Rm ;
  • Ring G is a 4-7 membered saturated or partially unsaturated heterocycle, C3-6 cycloalkane, 6-10 membered monocyclic aromatic ring or bicyclic containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Aromatic ring, or a 5-10-membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle containing 1-5 heteroatoms independently selected from N, O or S, the 4-7 membered saturated or partially unsaturated heterocycle Ring, C 3-6 cycloalkane, 6-10 membered monocyclic aromatic ring or bicyclic aromatic ring, 5-10 membered bridged ring or spirocyclic saturated or partially unsaturated heterocycle may be optionally independently replaced by one or more R replaced by m ;
  • R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3- 6 cycloalkyl, C 3-6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino -C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl -Amino-C 1-6 alkyl, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl) -amino, C 3-6 cycloalkyl-amino, C
  • q and t are each independently 0, 1, 2 or 3;
  • w 1, 2 or 3;
  • X is O, S, CR 17 R 18 , NR 17 , CO or S(O) 2 ;
  • R 17 is hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 1-6 alkoxy-C 1 -6 alkyl, halogenated C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, cyano-C 1-6 alkyl, C 1-6 alkyl-carbonyl or C 1-6 alkyl-sulfone;
  • R 18 is hydrogen atom, C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkoxy, halogenated C 3-6 cycloalkoxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkane group, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkyl-amino
  • Z is N, O, S, CO, S(O) 2 , -amino-acyl, -acyl-amino, -O(CO)-, -(CO)O-, CR 19 , C 3-7 cycloalkyl or 3-7 membered heterocyclyl, the C 3-7 cycloalkyl and 3-7 membered heterocyclyl may be optionally independently substituted with one or more R 18 ;
  • R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
  • n 0, 1, 2, 3 or 4;
  • p 0, 1, 2 or 3.
  • Ring A and Ring B are each independently a benzene ring, or a 5-6 membered heteroaromatic ring containing 1-2 heteroatoms independently selected from N, O and S, the benzene ring Or the 5-6 membered heteroaromatic ring may be optionally substituted with one or more substituents independently selected from the group consisting of: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogen Substituted C 1-6 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycloalkyl, halogenated C 3-6 cycloalkyl, C 3-6 cycloalkane Oxy, C 1-6 alkoxy-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, oxo, halogen, hydroxyl, cyano, cyano-C 1-6 alkyl, amino, C 1-6 alkyl
  • ring A and ring B are each independently a benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole, Isothiazoles, said benzene ring, pyridine, pyrimidine, pyridazine, pyrazine, pyrazole, pyrrole, thiophene, imidazole, oxazole, isoxazole, furan, thiazole and isothiazole may be optionally combined with one or more Substituted independently from the following substituents: C 1-6 alkyl, C 2-6 alkenyl, C 2-6 alkynyl, halogenated C 1-4 alkyl, C 1-6 alkoxy, halogenated C 1-6 alkoxy, C 3-6 cycl
  • Ring D is a benzene ring, a 5-6 membered heteroaromatic ring containing 1-3 heteroatoms independently selected from N,O and S, containing 1-2 heteroatoms independently selected from N,O and 5-7 membered heterocycle or cyclohexyl ring of S heteroatom;
  • ring D is a benzene ring, pyridine, pyrimidine, pyrazine, pyridazine, piperidine, piperazine, pyrazole, imidazole or cyclohexane.
  • one of R 1 , R 2 , R 4 and R 5 is a warhead group, and when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 , When R 2 is a warhead group, R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a war head group, R 1 , R 2 and R 5 are each independently R 6 ; or when When R 5 is a warhead group, R 1 , R 2 and R 4 are each independently R 6 ;
  • R 3 and R 6 are each independently a 3-11-membered monocyclic or bridged ring or spirocyclic heterocyclyl-C 0-3 alkyl, hydrogen containing 1-3 heteroatoms independently selected from N, O or S heteroatoms Atom, halogen, hydroxy, cyano, C 1-6 alkyl, halogenated C 1-6 alkyl, hydroxy-C 1-6 alkyl, hydroxy-C 1-6 alkoxy, C 1-6 alkoxy base-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino-C 1-6 alkyl, di(C 1-6 6 alkyl)-amino-C 1-6 alkoxy-C 1-6 alkyl, di(C 1-6 alkyl)-amino-C 1-6 alkyl-amino-C 1-6 alkyl, C 1-6 alkoxy, bis(C 1-6 alkyl)-amino-C
  • the warhead group is R 7 , -Y 1 (CR a R b ) q NR 7 R 8 ,
  • Y 1 , Y 2 and Y 3 are each independently a chemical bond, O or NR 8 ;
  • R 8 is a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
  • R 9 and R 10 are independently a hydrogen atom, halogen or cyano
  • R 12 and R 13 are each independently a hydrogen atom, a C 1-6 alkyl group, a C 3-6 cycloalkyl group, or R 12 and R 13 together with N in NR 12 R 13 form 1-3 independently A 4-7 membered heterocycle selected from N, O or S heteroatoms, the C 1-6 alkyl, C 3-6 cycloalkyl and formed containing 1-3 independently selected from N, O or S
  • the 4-7 membered heterocycle of the heteroatom may be optionally substituted with one or more substituents independently selected from the group consisting of C 1-6 alkyl, C 1-6 alkoxy, C 3-6 ring Alkyl, C 3-6 cycloalkoxy, halogen, hydroxyl, cyano, C 1-6 alkyl-amino, bis(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, 3-7 membered heterocyclyl and C 1-6 alkyl-carbonyl containing N, O or S heteroatom
  • R 14 and R 15 are independently a hydrogen atom, a C 1-6 alkyl group, or R 14 and R 15 together with the carbon atom to which they are attached form a C 3-6 cycloalkyl group;
  • R a , R b , R c and R d are each independently hydrogen atom, deuterium atom, halogen, hydroxyl, cyano, oxo, C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 Cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkyl-amino, C 1-6 alkyl- Amino-C 1-6 alkyl, di(C 1-6 alkyl)-amino, di (C 1-6 alkyl)-amino-C 1-6 alkyl, C 3-6 cycloalkyl-amino, 3-7-membered heterocyclyl, 3-7-membered heterocyclyl-C 1-6 alkyl, said C 1-6 alkyl, C 3-6 cycloalkyl, C 3-6 cycloalkyl-C 1-6 alkyl, C 1-6 alkoxy, C 1-6 al
  • R a and R b together with the attached carbon atoms form a ring
  • R c and R d together with the attached carbon atoms form a ring which is a C 3-6 cycloalkane or contains 1-3 independently 4-7-membered saturated or partially unsaturated heterocycles selected from N, O or S heteroatoms, said C 3-6 cycloalkanes, 4-7 members containing 1-3 heteroatoms independently selected from N, O or S heteroatoms -7-membered saturated or partially unsaturated heterocycle optionally substituted with one or more of the following groups: halogen, hydroxy, cyano, C 1-6 alkyl, C 3-6 cycloalkyl and C 1-6 alkoxy;
  • Ring E is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, or a 7-10 membered heteroatom containing 1-5 heteroatoms independently selected from N, O or S Bridged or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, 7-10 membered bridged or spiro saturated heterocycle may be optionally independently substituted by one or more Rm ;
  • Ring G is a 4-7 membered saturated heterocycle containing 1-3 heteroatoms independently selected from N, O or S, a C 3-6 cycloalkane, or contains 1-5 heteroatoms independently selected from N, O or S
  • the heteroatom 7-10 membered bridged ring or spiro saturated heterocycle, the 4-7 membered saturated heterocycle, C 3-6 cycloalkane, 7-10 membered bridged ring or spiro saturated heterocycle can be optionally independently replaced by one or more R m ;
  • R m is C 1-6 alkyl, halogenated C 1-6 alkyl, C 1-6 alkoxy, C 3-6 cycloalkyl, C 3-6 cycloalkoxy, C 1-6 alkoxy base-C 1-6 alkyl, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkyl-amino-C 1-6 alkyl, halogen, hydroxyl, cyano, Amino, oxo, C 1-6 alkyl-amino, di(C 1-6 alkyl)-amino, C 3-6 cycloalkyl-amino, C 1-6 alkyl-carbonyl, C 1-6 alkane base-OC(O)- or C 3-6 cycloalkyl-OC(O)-;
  • q and t are each independently 0, 1, 2 or 3;
  • w 1, 2 or 3;
  • one of R 1 , R 2 , R 4 and R 5 is a warhead group, and when R 1 is a warhead group, R 2 , R 4 and R 5 are each independently R 6 when R 2 is a warhead group, R 1 , R 4 and R 5 are each independently R 6 ; when R 4 is a war head group, R 1 , R 2 and R 5 are each independently R 6 ; or When R 5 is a warhead group, R 1 , R 2 and R 4 are each independently R 6 ;
  • R 3 and R 6 are each independently a hydrogen atom, halogen, methyl, ethyl, trifluoromethyl, methoxy, isopropoxy, cyano, hydroxy, hydroxymethyl, methoxymethyl, ethyl Oxymethyl, methylcarbonyl, methoxycarbonyl, 4-methylpiperazin-1-ylcarbonyl, dimethylaminomethyl, dimethylaminoethoxy, hydroxyethoxy, dimethylaminoethoxy Methyl, N,N,N'-trimethylethylenediaminomethyl, N,N-dimethylethylenediaminomethyl, pyrrolidinylmethyl, morpholinomethyl, azetidinyl Methyl, piperidinylmethyl, 4-(dimethylamino)piperidin-1-ylmethyl, 4-(3-methoxyacridin-1-yl)piperidin-1-ylmethyl, piperidine Azin-1-ylmethyl, 4-methylpiperazin-1
  • the warhead groups are:
  • X is O or S
  • Z is N, O, S, -amino-acyl, -acyl-amino, or CR 19 ;
  • R 19 is independently a hydrogen atom, a C 1-6 alkyl group or a C 3-6 cycloalkyl group
  • Z is N, O or CR 19 ;
  • R 19 is independently a hydrogen atom, methyl, ethyl, isopropyl, cyclopropyl or cyclobutyl.
  • (C ab )alkyl means any alkyl group containing "a" to "b” carbon atoms.
  • (C 1-6 )alkyl refers to an alkyl group containing from 1 to 6 carbon atoms. Said alkyl group is branched or straight chain.
  • Atoms described in the compounds of the present application include isotopes thereof, for example, hydrogen may be deuterium or tritium.
  • Alkyl means a straight or branched chain, monovalent, saturated hydrocarbon group including, but not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl , tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, and other similar groups.
  • C 1-8 alkyl groups are preferred. More preferred is C 1-6 alkyl. More preferred is C 1-4 alkyl.
  • Cycloalkyl means a saturated monocyclic, bicyclic, spirocyclic, paracyclic, or bridged cycloalkyl, possibly in combination with other groups. Cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, for example. C 3-8 cycloalkyl is preferred. More preferred is C 3-6 cycloalkyl. More preferred is C 3-4 cycloalkyl.
  • Alkenyl refers to a straight-chain, branched or cyclic hydrocarbon group containing one or more double bonds, including but not limited to vinyl, propenyl, (E)-2-methylvinyl, (Z) -2-Methylvinyl, (E)-but-2-enyl, (Z)-but-2-enyl, (E)-but-1-enyl, (Z)-but-1-ene base.
  • C 2-6 alkenyl is preferred. More preferred is C 2-4 alkenyl.
  • Alkynyl refers to a straight-chain, branched or cyclic hydrocarbon group containing one or more triple bonds, including but not limited to ethynyl, prop-1-ynyl, prop-2-ynyl, but-1 -Alkynyl, but-2-ynyl, but-3-ynyl. Preferred is C 2-6 alkynyl. More preferred is C 2-4 alkynyl.
  • Alkoxy means a straight or branched chain, monovalent, saturated alkyl group bonded to an oxygen atom, including but not limited to, for example, methoxy, ethoxy, propoxy, butoxy , isobutoxy, tert-butoxy and other similar groups.
  • C 1-8 alkoxy is preferred. More preferred is C 1-6 alkoxy. More preferred is C 1-4 alkoxy.
  • Halogen means fluorine, chlorine, bromine or iodine, preferably fluorine, chlorine and bromine.
  • Haloalkyl refers to an alkyl group, as defined herein, wherein one or more hydrogens have been replaced with the same or different halogen. Including, but not limited to, such as -CH 2 Cl, -CHF 2 , -CH 2 CF 3 , -CH 2 CCl 3 , perfluoroalkyl (eg, -CF 3 ), and the like.
  • Aryl refers to a substituted or unsubstituted monocyclic or polycyclic aromatic group including, but not limited to, eg, phenyl, naphthyl. A 6-10 membered monocyclic or bicyclic aromatic group is preferred. More preferred is phenyl or naphthyl. Most preferred is phenyl.
  • Heterocyclyl means a substituted or unsubstituted 3-10 membered non-aromatic monocyclic saturated ring system containing 1-3 heteroatoms independently selected from N, O, or S, the remaining ring atoms being carbon atoms .
  • heterocyclyl moieties include, but are not limited to: azetidinyl, oxetanyl, pyrrolidinyl, piperidinyl, piperazinyl, homopiperazinyl, oxopiperidinyl, oxo Piperazinyl, oxohomopiperazinyl, tetrahydrofuranyl, imidazolinyl, morpholinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, quinuclidinyl, thiadiazole Alkyl, dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, etc.
  • a 4- to 7-membered heterocyclic group is preferred.
  • Heteroaryl means a substituted or unsubstituted 5- or 6-membered mono-heteroaromatic ring system, or a substituted or unsubstituted 9- or 10-membered fused or bi-heteroaromatic ring system containing 1-4 independent Selected from N, O, or S heteroatoms, the remaining ring atoms are carbon atoms.
  • heteroaryl moieties include, but are not limited to: thienyl, furyl, imidazolyl, isoxazolyl, oxazolyl, pyrazolyl, pyrrolyl, thiadiazolyl, triazolyl, pyridyl, pyridazine radical, pyrimidinyl, indolyl, indazolyl, quinolyl, isoquinolyl, benzimidazolyl or benzothiazolyl.
  • “Bridged ring” refers to a polycyclic group in which any two rings share two atoms that are not directly connected, may contain one or more double bonds, but none of the rings have a fully conjugated pi electron system, and the ring atoms may be All carbon atoms may also be one or more ring atoms selected from N, O, S, SO or SO2 . 7-10 rings are preferred.
  • “Spirocycle” refers to a polycyclic group in which any two rings share carbon atoms, and may contain one or more double bonds, but none of the rings has a completely conjugated ⁇ -electron system, and the ring atoms may be all carbon atoms or One or more of the ring atoms are selected from N, O, S, SO or SO2. 5-10 rings are preferred.
  • the number of constituent rings it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic groups, preferably bicyclic, tricyclic or tetracyclic, more preferably bicyclic or tricyclic.
  • a cyclic group can bond to another group in a number of ways. If no bonding method is specified, all possible methods are included. For example, “pyridyl” includes 2-, 3-, or 4-pyridyl, and “thienyl” includes 2- or 3-thienyl.
  • “Pharmaceutically acceptable salt” refers to conventional acid addition salts or base addition salts which retain the biological effectiveness and properties of the compounds of formula I, formed from suitable non-toxic organic or inorganic acids or bases.
  • acid addition salts include those derived from inorganic acids such as hydrochloric, hydrobromic, hydroiodic, sulfuric, sulfamic, phosphoric, and nitric acids, and those derived from organic acids.
  • organic acids such as acetic acid, propionic acid, glycolic acid, oxalic acid, stearic acid, ascorbic acid, p-toluenesulfonic acid, salicylic acid, methanesulfonic acid, ethanesulfonic acid, oxalic acid, succinic acid, citric acid, maleic acid, Hydroxymaleic acid, lactic acid, fumaric acid, tartaric acid, malic acid, isethionic acid, benzenesulfonic acid, trifluoroacetic acid, mandelic acid, etc.
  • base addition salts include those derived from inorganic acids such as ammonium, calcium, iron, aluminum, sodium, potassium, zinc, magnesium, and those derived from organic acids.
  • the organic bases include salts of primary, secondary, and tertiary amines, such as trimethylamine, triethylamine, tripropylamine, diethanolamine, ethylenediamine, ethanolamine, and the like.
  • Chemical modification of pharmaceutical compounds (ie, drugs) into salts is a technique well known to pharmacists to obtain improved physical and chemical stability, hygroscopicity, fluidity, and solubility of compounds.
  • Prodrug refers to a prodrug that can be converted in vivo to the structure of the compounds involved in the present invention and their pharmaceutically acceptable salts.
  • the present application also relates to methods of preparing compounds of formula I.
  • the compounds of the present invention can be prepared by any conventional means. Suitable methods for synthesizing these compounds are provided in the Examples. In multistep synthetic routes, the order of the reactions can be adjusted in specific cases.
  • the application provides a method for preparing a compound of formula I, the method comprising the following reaction steps:
  • the alkali used under alkaline conditions in step (1) is selected from potassium carbonate;
  • the base used in the hydrolysis in step (5) is selected from lithium hydroxide.
  • the method for preparing a compound of formula I comprises the following reaction steps:
  • the alkali used under alkaline conditions in the step (1) is selected from potassium carbonate
  • R 22 is a hydrogen atom, -Y 1 (CR a R b ) q NHR 8 , R 20 is R 22 with a protective group, halogen, an oxy group with a protective group, an amino group with a protective group, etc., R 18 , R 19 , R 21 , R 23 , R 24 and R 25 are R 6 ; when When R 2 is a warhead group, R 23 is -Y 1 (CR a R b ) q NHR 8 , R 21 is R 23 with a protective group, halogen, an oxy group with a protective group, an amino group with a protective group, etc., R 18 , R 19 , R 20 , R 22 , R 24 and R 25 are R 6 ; when When R 4 is a warhead group, R 24 is -Y 1 (CR a R b ) q NHR 8 , R 18 is R 24 with a protective group, halogen, an oxy group
  • protective groups include but are not limited to tert-butoxycarbonyl, benzyloxycarbonyl, benzyl or dimethoxybenzyl;
  • L is hydroxyl, halogen or leaving group
  • A, B, D, E, G, R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 8 , R a , R b , R c , R d , Y 1 , Y 2 , Y 3 , Z, X, p, q, m, n, t, warhead groups are as defined above;
  • the present invention also provides a pharmaceutical composition
  • a pharmaceutical composition comprising the compound as an EGFR kinase inhibitor and a pharmaceutically acceptable carrier or excipient.
  • pharmaceutical composition refers to combining one or more of the compounds of the present invention, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, with other chemical ingredients, such as pharmaceutical acceptable carriers, excipients or diluents.
  • pharmaceutical acceptable carriers such as pharmaceutical acceptable carriers, excipients or diluents.
  • the purpose of a pharmaceutical composition is to facilitate the process of administration to an animal.
  • “Pharmaceutically acceptable carrier” refers to a pharmaceutically acceptable substance, ingredient or medium, such as a liquid or solid filler, diluent, excipient, solvent or potting material, which is involved in carrying out the subject matter of the present invention.
  • the compound is loaded or delivered from one location, body fluid, tissue, organ (internal or external), or body part to another location, body fluid, organ (internal or external), or body part.
  • a pharmaceutically acceptable carrier can be a vehicle, diluent, excipient or other material which is not undue toxicity or side effects and which can be used in contact with animal tissue.
  • Typical pharmaceutically acceptable carriers include sugars, starches, celluloses, maltose, tragacanth, gelatin, Ringer's solution, alginic acid, physiological saline, buffers and the like.
  • Each pharmaceutically acceptable carrier should be compatible with the other ingredients, such as to form formulations with the compounds provided in the present invention, without undue toxicity, irritation, allergic reaction, immunogenicity or other problems to living tissues or organs or complications, and a reasonable benefit-risk ratio.
  • Some pharmaceutically acceptable carrier materials include: (1) carbohydrates, such as lactose, glucose, and sucrose; (2) starches, such as cornstarch and potato starch; (3) cellulose and its derivatives, such as carboxymethyl Sodium cellulose, ethyl cellulose, cellulose acetate; (4) tragacanth powder; (5) maltose; (6) gelatin; (7) talc; (8) excipients such as cocoa butter and suppositories Waxes; (9) oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; (10) glycols such as propylene glycol; (11) polyols such as glycerol, sorbitan Alcohols, mannitol, and polyethylene glycols; (12) lipids, such as ethyl oleate, ethyl laurate; (13) agar; (14) buffers, such as magnesium hydroxide and aluminum hydroxide; (15) (16)
  • compositions may include pharmaceutically acceptable excipients to simulate physiological conditions, such as pH adjusting and buffering agents, toxicity adjusting agents, and the like, such as sodium acetate, sodium chloride, potassium chloride, calcium chloride, sodium lactate, and the like.
  • the pharmaceutical ingredients can be prepared in any suitable dosage form, such as solid dosage forms (eg, tablets, capsules, powders, granules, etc.) and liquid dosage forms (eg, aqueous solutions, emulsions, elixirs, syrups, etc.).
  • suitable dosage form such as solid dosage forms (eg, tablets, capsules, powders, granules, etc.) and liquid dosage forms (eg, aqueous solutions, emulsions, elixirs, syrups, etc.).
  • liquid dosage forms eg, aqueous solutions, emulsions, elixirs, syrups, etc.
  • the preparation methods of pharmaceutical compositions are well known and can be prepared according to conventional techniques, such as those provided in Remington, The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000).
  • the compounds or pharmaceutical compositions provided in the present invention can be formulated into dosage forms suitable for drug release and administered by injection route (eg, subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, framed intra-, intra-cardiac, intra-dermal, intra-peritoneal, transtracheal, epidermal, intra-articular, sub-capsular, sub-arachnoid, intra-spinal, intra-sternal, and/or infusion) and non-injection routes (eg, oral, enteral, Oral, nasal, intranasal, mucosal, epidermal, patch, dermal, ophthalmic, pulmonary, sublingual, rectal, vaginal or epidermal topical administration).
  • injection route eg, subcutaneous, intravenous, intramuscular, arterial, intrathecal, intracapsular, framed intra-, intra-cardiac, intra-dermal, intra-peritoneal, transtracheal, epidermal, intra-articular, sub-capsular, sub-
  • Suitable dosage forms include, but are not limited to, dosage forms for injectable use such as emulsions, solutions and suspensions, dosage forms for oral use such as tablets, capsules, pills, dragees, powders and granules, topical or transdermal formulations.
  • Dosage forms such as sprays, ointments, pastes, creams, lotions, gels, solutions, pharmaceutical patches and inhalants, and those for vaginal or rectal administration such as suppositories.
  • These dosage forms can be prepared under suitable conditions depending on the compound and suitable excipients, and the methods and techniques of preparation are well known, for example provided by Remington: In The Science and Practice of Pharmacy (Gennaro ed. 20th edition, Williams & Wilkins PA, USA) (2000) .
  • the present application provides pharmaceutical compositions comprising the above-described compounds and a pharmaceutically acceptable carrier or excipient.
  • the pharmaceutical compositions are tablets, capsules, pills, granules, powders, suppositories, injections, solutions, suspensions, ointments, patches, lotions, drops, liniments, sprays agent
  • Another aspect of the present invention provides applications of the above compounds and/or pharmaceutical compositions in the preparation of medicines and the treatment of diseases.
  • the present invention provides the use of the above-mentioned compounds and/or pharmaceutical compositions in the preparation of anti-tumor drugs.
  • the present application provides the use of the above-mentioned compounds and/or pharmaceutical compositions in the preparation of antitumor drugs.
  • the antineoplastic drug is used for the following conditions: head and neck cancer, melanoma, bladder cancer, esophageal cancer, anaplastic large cell lymphoma, renal cell carcinoma, breast cancer, colorectal cancer, ovary cancer, cervical cancer, pancreatic cancer, glioma, glioblastoma, prostate cancer, leukemia, lymphoma, non-Hodgkin lymphoma, gastric cancer, lung cancer, hepatocellular carcinoma, gastrointestinal stromal tumor, thyroid cancer, Cholangiocarcinoma, endometrial cancer, multiple myeloma, or mesothelioma.
  • the present application provides a method of treating a tumor in a patient in need thereof, comprising administering to said patient, preferably a mammal, said mammal an effective amount of a compound or pharmaceutical composition described above People are preferred.
  • modes of administration include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal.
  • the compounds or pharmaceutical compositions of the present invention may be administered into the organism by any suitable route, such as oral, intravenous, intranasal, topical, intramuscular, intradermal, transdermal, or subcutaneous routes.
  • suitable route such as oral, intravenous, intranasal, topical, intramuscular, intradermal, transdermal, or subcutaneous routes.
  • the modes of administration of the compounds or pharmaceutical compositions contemplated by the present invention include oral, mucosal, sublingual, ocular, topical, parenteral, rectal, cisternal, vaginal, peritoneal, bladder, nasal administration medicine.
  • the compounds or pharmaceutical compositions involved in the present invention can be administered simultaneously with the second active substance, so that an additive or even synergistic effect can be achieved in vivo.
  • a compound of the present invention may be combined with a second active substance in a pharmaceutical composition, either administered simultaneously in separate compositions, or administered sequentially in separate compositions.
  • Second active substances that can be administered concurrently with the compounds of the present invention for the treatment of cancer include, but are not limited to: fluorouracil, doxorubicin, daunorubicin, tamoxifen, leuprolide, goserelin, fluorouracil Tamide, Nilutamide, Finasteride, Dexamethasone, Amglutide, Amacridine, Anastrozole, Asparaginase, BCG, Bicalutamide, Bleomycin, Baixiao Camptothecin, capecitabine, carboplatin, carmustine, chlorambucil, cisplatin, cladribine, colchicine, cyclophosphamide, cyproterone, cytarabine, dacarbazine, actinomycin d, danamycin, diethylstilbestrol, diethylstilbestrol, docetaxel, doxorubicin, doxorubicin, epirubicin,
  • the compounds provided herein can be used concurrently with non-chemical methods for cancer treatment. In certain embodiments, the compounds provided herein can be administered concurrently with radiation therapy. In certain embodiments, the compounds provided by the present invention can be used in combination with surgery, tumor thermal therapy, focused ultrasound therapy, cryotherapy, or a combination of the above.
  • the compounds provided herein can be used concurrently with steroids.
  • Suitable steroids include, but are not limited to: amxicil, beclomethasone, betamethasone, budesonide, cloprednisone, clobetasol, corticosterone, cortisone, hydroxyprednisone, des Oxymethasone, Dexamethasone, Diflurasone, Diflumethasone, Diflugestin, Glycyrrhetinic Acid, Fluzacortisone, Flumethasone, Flunisolide, Fluclonide, Paclolone Acetate, Fluocinolone Acetate, Fluocetide, Fluocinolone, Fludroxolone Acetone, Flupirone Acetate, Fluprednidine Acetate, Fluprednisolone, Fluocinolone, Fluoride Propionate, Aldehydrone, Clobetasol Propionate, Hacecil, Halometasone, Hydrocortisone, Lot
  • the compounds provided herein can be used concurrently with immunotherapeutic agents.
  • immunotherapeutic agents include tumor cell multidrug resistance reversal agents (such as verapamil), rapamycin, mycophenolate mofetil, thalidomide, cyclophosphamide, cyclosporine, and monocytogenes. cloned antibodies.
  • the first step 2,2,2-trifluoro-N-(2-((2-hydroxyethyl)amino)ethyl)acetamide
  • tert-butyl (2-hydroxyethyl)(2-(2,2,2-trifluoroacetamido)ethyl)carbamate (20.4g, 0.0677mol) and methanol were successively added to a 500mL round-bottomed flask. (50 mL), water (10 mL) and potassium carbonate (5.0 g), warmed to 60 °C and stirred for 48 h.
  • 3,7-Dimethyloct-6-enoic acid (3.5 g, 20.56 mmol) was dissolved in toluene (300 mL), the temperature was raised to 50 °C, triethylamine (2.5 g, 24.67 mmol) was added, and then the stack was slowly added.
  • Diphenyl nitrophosphate (5.65g, 20.56mmol) was heated to 70°C and stirred for 12h, 2-methylbutan-2-ol (3.6g, 41.16mmol) was added, the temperature was raised to 110°C and stirred for 2h, then 2-Methylbutan-2-ol (3.6 g, 41.16 mmol) was added. The reaction mixture was stirred at 110 °C for 12 h.
  • tert-amyl (2,6-dimethylhept-5-en-1-yl)carbamate 2.5 g, 10.11 mmol
  • methanol 20 mL
  • ozone was slowly introduced into the reaction system until the reaction system became sky blue, and stirring was continued for 20 min until colorless.
  • the temperature was lowered to 0° C., sodium borohydride (0.95 g, 25.1 mmol) was slowly added, and after the addition was completed, the temperature was slowly raised to room temperature and stirred for 12 h.
  • tert-amyl (5-hydroxy-2-methylpentyl)carbamate 450 mg, 1.95 mmol
  • 4M hydrochloric acid in dioxane 10 mL
  • tert-butyl (R)-(2-hydroxypropyl) carbamate 900 mg, 5.1 mmol
  • pyridine 5 mL
  • Sulfonyl chloride 1.07g, 5.6mmol
  • the second step 2-((tert-butoxycarbonyl)amino)ethyl-1,1-dideutero 4-toluenesulfonate
  • tert-butyl(2-hydroxyethyl-2,2-dideutero)carbamate 2.5 g, 15.3 mmol
  • dichloromethane 25 mL
  • p-toluenesulfonyl chloride 4.4 g, 23.0 mmol
  • triethylamine 3.1 g, 30.6 mmol
  • 1-bromo-2-fluoro-3-nitrobenzene (5.0g, 0.03mol), 1,4-dioxane (50mL), propane- 2-alkyn-1-ylcarbamate tert-butyl ester (4.23g, 0.03mol), N,N-diisopropylethylamine (3.4g, 0.03mol), cuprous iodide (0.04g, 0.2mmol), Bistriphenylphosphonium palladium dichloride (0.64 g, 0.9 mol) and tri-tert-butylphosphine (0.15 g, 1.3 mol), warmed to 45° C. and stirred for 15 h.
  • the first step methyl 2-chloro-6-(2-hydroxyphenyl)isonicotinate
  • 2-chloro-6-(2-hydroxyphenyl)isonicotinic acid methyl ester (10 g, 0.03 mol), dioxane (100 mL), BocNH 2 (5.32 mol) were added to a 250 mL round-bottomed flask at room temperature. g, 0.04 mol), cesium carbonate (24.0 g, 0.07 mmol), Xphos (3.6 g, 0.0075 mol) and bis(dibenzylideneacetone)palladium (13.3 mg, 0.02 mmol), warmed to 85° C. and stirred for 16 h.
  • methyl 2-chloro-6-methylisonicotinate (20.0 g, 0.11 mol) was added to anisole (200 mL) at room temperature, followed by 1-methyl-5-hydroxypyrazole (21.2 g, 0.2156 mol), sodium carbonate (29.4 g, 0.237 mol) and PdCl2 (dppf) (2.36 g, 0.003 mol).
  • the first step 2-methyl-6-(1-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)isonicotine methyl ester
  • Methyl 2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinate (2.7 g, 10.9 mmol) was dissolved in a 50 mL round bottom flask at room temperature Acetonitrile (30 mL), K 2 CO 3 (2.41 g, 17.44 mmol) and SEMCl (2.91 g, 17.44 mmol) were added successively, and the mixture was stirred at room temperature for 5 h.
  • the second step 2-methyl-6-(1-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)-1H-pyrazol-4-yl)isofumine acid
  • Step 2 2-(5-(2-((tert-butoxycarbonyl)(2-((2-nitrophenyl)amino)ethyl)amino)ethoxy)-1-methyl-1H- Pyrazol-4-yl)-6-methylisonicotinic acid methyl ester
  • the third step 2-(5-(2-((2-aminophenyl)amino)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-1-methyl-1H-pyrazole-4- yl)-6-methylisonicotinic acid methyl ester
  • the fourth step 2-(5-(2-((2-(2-amino-1H-benzimidazol-1-yl)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-1-methyl yl-1H-pyrazol-4-yl)-6-methylisonicotinic acid methyl ester
  • the fifth step 2-(5-(2-((2-(2-amino-1H-benzimidazol-1-yl)ethyl)(tert-butoxycarbonyl)amino)ethoxy)-1-methyl yl-1H-pyrazol-4-yl)-6-methylisonicotinic acid
  • intermediates A2-A4 and B1-B7 were prepared using the method for the synthesis of intermediate A1 (Example 31).
  • Step 4 1-(5-Hydroxypentyl)-2-(2-methyl-6-(1-methyl-5-((2-(trimethylsilyl)ethoxy)methoxy)methoxy )-1H-pyrazol-4-yl)isonicotinamide)-1H-benzo[d]imidazole-6-carboxylate methyl ester
  • the fifth step 2-(2-(5-hydroxy-1-methyl-1H-pyrazol-4-yl)-6-methylisonicotinamide)-1-(5-hydroxypentyl)-1H- Benzo[d]imidazole-6-carboxylate methyl ester
  • Example 43 11,26 - Dimethyl-56-(( 4 -methylpiperazin- 1 - yl)methyl)-3-oxo-11H,51H-11-oxo Hetero-4,8-diaza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridyl-1(4,5)-pyrazolecycloundecyl-8 -Synthesis of tert-butyl carboxylate (Intermediate A5)
  • Intermediates A6-A11 were prepared by the method for the synthesis of intermediate A5 (Example 43) using intermediate B and nitrogen heterocyclic compound as starting materials.
  • intermediate B3 (15.0 g, 0.03 mol), 1,4-dioxane (100 mL), and (2,4-dimethoxyphenyl)methane were successively added to a 100 mL round-bottomed flask at room temperature.
  • Amine (7.5 g, 0.045 mol ), Pd2(bda)3 ( 2.75 g, 0.003 mol), BINAP (3.73 g, 0.006 mol) and sodium tert-butoxide (5.77 g, 0.06 mol), stirred at 100°C overnight.
  • the third step (E)-(2-((1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa- 4-Aza-5(2,1)-benzo[d]imidazol-2(2,4)-pyridyl- 1 (4,5)-pyrazolecycloundecan-57-yl)amino) Ethyl) tert-butyl carbamate
  • sodium cyanoborohydride (58.25 mg, 0.93 mmol) was added and stirred at room temperature overnight. After the reaction was completed, water (10 mL) was added, extracted with ethyl acetate (10 mL ⁇ 3), the organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • N-BOC-L-alanine (877 mg, 4.64 mmol) was dissolved in THF (30 mL), NMM (375 mg, 3.7 mmol) was added, the temperature was lowered to -20 °C, and isobutyl chloroformate ( 876.6 mg, 4.64 mmol), stirred at -20 °C for 1 h, then added dropwise (E)-57-amino - 11,26 - dimethyl - 52,53-dihydro - 11H, 51 H-11-oxa-4-aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridyl-1(4,5)-pyrazolecycloundecane- A solution of 3-keto (200 mg, 0.46 mmol) in THF (15 mL) and NMM (234 mg, 2.32 mmol) was stirred at room temperature overnight.
  • Example 62 (E)-(1-((1 1 ,2 6 -Dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa- 4-Aza- 5 (2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)-pyrazolecycloundecan-57-yl)amino)- Synthesis of tert-butyl 6-(dimethylamino)-1-oxohexane-2-yl)carbamate (Intermediate A24)
  • the first step (E)-(6-amino-1-((1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11 -oxa-4-aza- 5 (2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)-pyrazolcycloundecan-57-yl ) amino)-1-oxohexane-2-yl) tert-butyl carbamate
  • the second step (E)-(1-((1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa- 4-Aza- 5 (2,1)-benzo[d]imidazol-2(2,4)-pyridine-1(4,5)-pyrazolecycloundecan-57-yl)amino)- 6-(Dimethylamino)-1-oxohexane-2-yl)carbamic acid tert-butyl ester
  • the second step (E)-(2-((1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa- 4-Aza-5(2,1)-benzo[d]imidazozol-2(2,4)-pyridyl- 1 (4,5)-pyrazolecycloundecan-56-yl) tert-butyl oxy)ethyl)carbamate
  • intermediates A27-A45 were prepared using the method for the synthesis of intermediate A26 (Example 64).
  • the first step (S)-2-((tert-butoxycarbonyl)amino)-5-((2-nitrophenyl)amino)pentanoic acid
  • intermediate A47 was prepared according to the method for synthesizing intermediate A46 (Example 84).
  • the first step methyl 2-(2-(5-bromopentyl)oxy)phenyl)-6-(tert-butoxycarbonyl)amino)isonicotinate
  • Step 2 2-(2-((5-(2-Amino-1H-benzo[d]imidazol-1-yl)pentyl)oxy)phenyl)-6-((tert-butoxycarbonyl) Amino) methyl isonicotinate
  • the third step 2-(2-((5-(2-amino-1H-benzo[d]imidazol-1-yl)pentyl)oxy)phenyl)-6-((tert-butoxycarbonyl) amino)isonicotinic acid
  • dichloromethane (20 mL) was added to dilute, washed with saturated brine (10 mL ⁇ 3), the organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure.
  • intermediate A Using intermediate A as raw material, the final products 4-8, 49, 50, 55, 58, 60, 62, 67-69, 73, 74, 76-78, 80-83, 102, 109, 114, 115, 118-122, 124-126, 131-133, 135, 137-141, 147, 152, 154.
  • the final product was prepared according to the method for synthesizing the final product 10 (Example 135) using the amine obtained by the hydrolysis of Intermediate A and a commercially available acid as raw materials.
  • the first step methyl 2-methyl-6-(1-methyl-5-(3-(epoxypropan-2-yl)propoxy)-1H-pyrazol-4-yl)isonicotinate
  • Step 2 2-(5-((5-(2-Amino-1H-benzo[d]imidazol-1-yl)-4-hydroxypentyl)oxy)-1-methyl-1H-pyridine azol-4-yl)-6-methylisonicotinic acid
  • the seventh step (E)-N-(1 1 ,2 6 -dimethyl-3-oxo-5 2 ,5 3 -dihydro-1 1 H,5 1 H-11-oxa-4- Aza-5(2,1)-benzo[d]imidazole-2(2,4)-pyridyl-1(4,5)-pyrazolecycloundecan-7-yl)acrylamide
  • the HTRF KinEASE-TK kit was used to measure its activity by detecting the remaining amount of ATP after the EGFR protein kinase reaction.
  • the intensity of the luminescent signal tested was positively correlated with the amount of ATP remaining in the reaction, positively correlated with compound activity, and negatively correlated with kinase activity.
  • the enzyme buffer was diluted 5-fold with 5 mM MgCl 2 ; 1 mM DTT; 1 mM MnCl 2 in water.
  • Enzyme inhibition percentage (%) 100-(Signal compound -Signal average_PC )/(Signal average_VC -Signal average_PC ) ⁇ 100
  • Table 9 shows the inhibitory IC50 of the compounds of the present invention to EGFR L858R/T790M/C797S and EGFR Del19/T790M/C797S enzymatic activities.
  • the CellTiter-Glo TM live cell detection kit uses luciferase as the detection substance, and luciferase requires the participation of ATP in the process of luminescence.
  • Add CellTiter-Glo TM reagent to the cell culture medium measure the luminescence value, the light signal is proportional to the amount of ATP in the system, and ATP is positively correlated with the number of viable cells. Therefore, by using the CellTiter-Glo kit to detect ATP content, the proliferation of cells can be detected.
  • the celltiter-Glo (CTG) method was used to measure the compounds prepared above in tumor cell lines NCI-H1975, Ba/F 3 (EGFR-L858R/C797S/T790M), Ba/F 3 (EGFR-Del19/C797S/T790M) and A431, and the 50% inhibitory concentration IC50 was calculated.
  • Cell viability (%) (Lum test drug- Lum culture solution control )/(Lum cell control -Lum culture solution control ) ⁇ 100%.
  • Table 10 shows the IC50 of the compounds of the present invention for inhibiting proliferation of NCI-H1975, Ba/F3 (EGFR-L858R/C797S/T790M), Ba/F3 (EGFR-Del19/C797S/T790M) and A431 cell lines.
  • the compounds of the present invention have positive effects on NCI-H1975 double mutant cell line, Ba/F3 (EGFR-L858R/C797S/T790M) triple mutant cell line and Ba/F3 (EGFR-Del19/C797S/T790M) three
  • the mutant cell line has good growth inhibitory activity, and the inhibitory effect on the EGFR wild-type cell line A431 is weak, indicating that the compound of the present invention has good cell inhibitory activity and selectivity.

Landscapes

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

Abstract

L'invention concerne un composé macrocyclique, son procédé de préparation et son utilisation. Le composé macrocyclique a une structure telle que représentée par la formule I, dans laquelle A, B, D, R1, R2, R3, R4, R5, Z, X, m, n et p sont tels que définis dans la description. Le composé macrocyclique est capable de surmonter la mutation d'EGFR C797S et d'EGFR T790M et présente une sélectivité élevée.
PCT/CN2021/135154 2020-12-03 2021-12-02 Composé macrocyclique, son procédé de préparation et son utilisation WO2022117051A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202011410505.7 2020-12-03
CN202011410505 2020-12-03

Publications (1)

Publication Number Publication Date
WO2022117051A1 true WO2022117051A1 (fr) 2022-06-09

Family

ID=80228607

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2021/135154 WO2022117051A1 (fr) 2020-12-03 2021-12-02 Composé macrocyclique, son procédé de préparation et son utilisation

Country Status (2)

Country Link
CN (1) CN114057771B (fr)
WO (1) WO2022117051A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022204544A1 (fr) * 2021-03-26 2022-09-29 Theseus Pharmaceuticals, Inc. Inhibiteurs d'egfr macrocycliques pour le traitement du cancer
WO2024099395A1 (fr) * 2022-11-10 2024-05-16 Beigene, Ltd. Composés utilisés dans la dégradation de la kinase egfr

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115368378A (zh) * 2021-05-21 2022-11-22 深圳市塔吉瑞生物医药有限公司 取代的大环化合物及包含该化合物的组合物及其用途
TW202330550A (zh) * 2021-11-30 2023-08-01 大陸商正大天晴藥業集團股份有限公司 含有環烷基或鹵代烷基的化合物
CN117024443A (zh) * 2022-05-09 2023-11-10 元启(苏州)生物制药有限公司 Egfr抑制剂及其用途
WO2024016986A1 (fr) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Composé macrocyclique et composition pharmaceutique et utilisation de celui-ci
WO2024017358A1 (fr) * 2022-07-21 2024-01-25 贝达药业股份有限公司 Composé macrocyclique, composition pharmaceutique de celui-ci et son utilisation
WO2024046221A1 (fr) * 2022-09-02 2024-03-07 Dizal (Jiangsu) Pharmaceutical Co., Ltd. Inhibiteurs d'egfr et leurs utilisations

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105008371A (zh) * 2013-02-07 2015-10-28 默克专利股份公司 大环哒嗪酮衍生物
CN106536506A (zh) * 2014-03-20 2017-03-22 卡佩拉医疗公司 苯并咪唑衍生物作为erbb酪氨酸激酶抑制剂用于治疗癌症
CN110291092A (zh) * 2017-01-25 2019-09-27 特普医药公司 涉及二芳基巨环化合物的组合疗法
WO2020260252A1 (fr) * 2019-06-24 2020-12-30 Boehringer Ingelheim International Gmbh Nouveaux composés macrocycliques et leurs dérivés utilisés en tant qu'inhibiteurs d'egfr
CN113527335A (zh) * 2020-04-15 2021-10-22 南京圣和药业股份有限公司 作为egfr抑制剂的大环类化合物及其应用

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114163454A (zh) * 2020-09-11 2022-03-11 上海翰森生物医药科技有限公司 含吡啶多环类衍生物抑制剂、其制备方法和应用

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105008371A (zh) * 2013-02-07 2015-10-28 默克专利股份公司 大环哒嗪酮衍生物
CN106536506A (zh) * 2014-03-20 2017-03-22 卡佩拉医疗公司 苯并咪唑衍生物作为erbb酪氨酸激酶抑制剂用于治疗癌症
CN110291092A (zh) * 2017-01-25 2019-09-27 特普医药公司 涉及二芳基巨环化合物的组合疗法
WO2020260252A1 (fr) * 2019-06-24 2020-12-30 Boehringer Ingelheim International Gmbh Nouveaux composés macrocycliques et leurs dérivés utilisés en tant qu'inhibiteurs d'egfr
CN113527335A (zh) * 2020-04-15 2021-10-22 南京圣和药业股份有限公司 作为egfr抑制剂的大环类化合物及其应用

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022204544A1 (fr) * 2021-03-26 2022-09-29 Theseus Pharmaceuticals, Inc. Inhibiteurs d'egfr macrocycliques pour le traitement du cancer
WO2024099395A1 (fr) * 2022-11-10 2024-05-16 Beigene, Ltd. Composés utilisés dans la dégradation de la kinase egfr

Also Published As

Publication number Publication date
CN114057771A (zh) 2022-02-18
CN114057771B (zh) 2023-10-03

Similar Documents

Publication Publication Date Title
WO2022117051A1 (fr) Composé macrocyclique, son procédé de préparation et son utilisation
JP7023243B2 (ja) イソキノリン－３イル－カルボキサミドならびにその調製および使用の方法
WO2017167182A1 (fr) Inhibiteur sélectif de la kinase c-kit
JP6791979B2 (ja) 含窒素ヘテロ環化合物、製造方法、中間体、組成物及び応用
CN105175394B (zh) 具有抗癌活性的化合物
TW202144345A (zh) Ｋｒａｓ突變蛋白抑制劑
CN109790169A (zh) 具有作为usp30抑制剂活性的氰基吡咯烷衍生物
CN112552295A (zh) Kras突变蛋白抑制剂
KR102388312B1 (ko) 아미노피리미딘 화합물, 이의 제조방법 및 용도
WO2015158310A1 (fr) Inhibiteur de tyrosine kinase et ses utilisations
JP6896701B2 (ja) イミダゾリルアミド誘導体
CN105541836A (zh) 激酶抑制剂的前药形式及其在治疗中的用途
CN103421005A (zh) 具有抗肿瘤活性的乙炔衍生物
EP3181553B1 (fr) Dérivé de quinazoline, procédé pour le préparer, composition pharmaceutique et application de celle-ci
JP2021536436A (ja) キノリン誘導体から調製される新規な阻害剤
TW201348213A (zh) 喹唑啉二酮衍生物
JP2023504866A (ja) 大環構造を有するフッ素含有複素環誘導体およびその用途
CN111989332B (zh) 作为cdk抑制剂的大环化合物、其制备方法及其在医药上的应用
WO2023280237A1 (fr) Synthèse et utilisation d'agent de dégradation de phosphatase
US9126935B2 (en) Aurora kinase modulators and methods of use
CN112513041A (zh) 三环化合物
JP7190755B2 (ja) オキサジノキナゾリンおよびオキサジノキノリン系化合物、ならびに調製方法およびその使用
WO2023109751A1 (fr) Dérivé de pyrimidine ou de pyridine et son utilisation médicinale
JP2021514398A (ja) Ｅｇｆｒ阻害剤の組合せ医薬製剤およびその使用法
CN117653636B (zh) 含稠合双环类化合物的抗癌药及该化合物的制药用途

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: 21900077

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 26/09/2023)

122 Ep: pct application non-entry in european phase

Ref document number: 21900077

Country of ref document: EP

Kind code of ref document: A1