WO2022033416A1 - Composé cyclique condensé utilisé en tant qu'inhibiteur d'egfr, son procédé de préparation et son utilisation - Google Patents

Composé cyclique condensé utilisé en tant qu'inhibiteur d'egfr, son procédé de préparation et son utilisation Download PDF

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WO2022033416A1
WO2022033416A1 PCT/CN2021/111447 CN2021111447W WO2022033416A1 WO 2022033416 A1 WO2022033416 A1 WO 2022033416A1 CN 2021111447 W CN2021111447 W CN 2021111447W WO 2022033416 A1 WO2022033416 A1 WO 2022033416A1
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alkyl
deuterium
substituted
cycloalkyl
membered
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Chinese (zh)
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寻国良
喻红平
陈椎
徐耀昌
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Abbisko Therapeutics Co Ltd
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Abbisko Therapeutics Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to a fused-ring compound as an EGFR inhibitor, a preparation method and application thereof.
  • Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) accounting for 85%.
  • Targets epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) translocation, ROS1 proto-oncogene receptor tyrosine kinase (ROS1) rearrangement and B-raf proto-oncogene, serine/threonine Kinase (BRAF) multitargeted therapy has been developed and clinically validated.
  • EGFR inhibition can significantly improve progression-free survival in adenocarcinoma NSCLC, whose acquired resistance mutations are subsequently targeted by third-generation inhibitors.
  • exon 20 mutations are heterogeneous and include in-frame insertions or duplications of 1-7 amino acids between amino acids 762-774 of the EGFR protein.
  • NSCLC the mutation frequency of EGFR exon 20 accounts for 4-10% of all mutations in EGFR.
  • EGFR exon 20 insertion mutations are also seen in a rare type of head and neck cancer, nasal squamous cell carcinoma (SNSCC).
  • SNSCC nasal squamous cell carcinoma
  • a structurally similar exon 20 insertion mutation was also found in HER2, another member of the receptor tyrosine kinase (RTK) EGFR family.
  • the object of the present invention is to provide a highly selective EGFR inhibitor.
  • the series of compounds of the present invention have a strong inhibitory effect on the cytological activity of EGFR exon 20 insertion, deletion or other mutation, and have high selectivity for EGFR wild type, and can be widely used in the preparation of treatment and/or prevention at least partially related to EGFR Drugs for cancers, tumors or metastatic diseases associated with exon 20 insertions, deletions or other mutations, especially for hyperproliferative diseases and cell death-inducing disorders, are expected to lead to the development of a new generation of EGFR inhibitors.
  • a first aspect of the present invention provides a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof:
  • X 1 is CR a R b , CR c or C(O);
  • X 2 is CR d Re , CR f , N or NH;
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from N, C(O), CR g , N(O) and NR h ;
  • Z 1 , Z 2 and Z 3 are each independently CR i or N;
  • L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
  • L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-10 cycloalkyl, 3-10 membered heterocyclic group, C 6-10 aryl, 5-10 membered heteroaryl, C 3-10 cycloalkyl C 1-2 alkyl, 3-12 membered heterocyclyl C 1-2 alkyl, C 6-10 aryl C 1-2 alkyl and 5 -10-membered heteroaryl C 1-2 alkyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-10 alkyl, halogen Substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl, 5-10 membered heteroaryl,
  • R a , R b , R d and R e are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 2- 10 alkenyl and C 2-10 alkynyl, or, alternatively, one of the groups of Ra and R b , R d and Re , Ra and R d each independently together with the carbon atom to which it is directly attached forms a C 3 -8 cycloalkyl or 3-8 membered heterocyclyl, the other two groups are as previously defined;
  • R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-10 alkyl, halo-substituted C 1-10 alkyl, and deuterium substituted C 1-10 alkyl, alternatively, R c and R f are directly therewith
  • the linked moieties together form a C 3-8 cycloalkyl or 3-8 membered heterocyclyl;
  • R g is selected from hydrogen, deuterium, halogen, cyano, C 1-10 alkyl, C 1-10 alkoxy, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, halogen substituted C 1 -10 alkoxy, deuterium substituted C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl and -C 0-8 alkyl-NR 4 R 5 ;
  • R is selected from hydrogen, deuterium , hydroxyl, C 1-10 alkyl, halo-substituted C 1-10 alkyl and deuterium substituted C 1-10 alkyl;
  • R j is selected from hydrogen, deuterium, C 1-10 alkyl, halo-substituted C 1-10 alkyl and deuterium substituted C 1-10 alkyl;
  • R 2 is vinyl or ethynyl, and the above groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium Substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-8 alkyl-C(O)OR 7 , -C 0-8 alkyl-C(O ) R 8 , -C 0-8 alkyl-C(O)-NR 9 R 10 and the substituents of -C 0-8 alkyl-NR 9 R 10 ;
  • R and L together with the nitrogen atom to which they are directly attached form a 4-10 membered heterocyclyl ;
  • R 4 and R 5 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6- 10 -aryl, 5-10-membered heteroaryl and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6 -10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 9 R 10 substituents;
  • Each R 6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 Aryl, 5-10 membered heteroaryl and -NR 9 R 10 , the above-mentioned groups independently optionally further selected by one or more groups selected from deuterium, halogen, hydroxyl, oxo, C 1-10 alkyl, C 1 -10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6- 10 -aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 9 R 10 ;
  • Each R 7 is independently selected from hydrogen, deuterium, C 1-10 alkyl, C 2-10 alkenyl, C 3-12 cycloalkyl, 3-12 membered heterocyclyl, C 6-10 aryl and 5-10-membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-10 alkyl, C 1-10 alkoxy , C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and substituents of -NR 9 R 10 ;
  • Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-10 alkyl, C 1-10 alkoxy, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 Cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy, 5-10-membered heterocycle Aryl, 5-10 membered heteroaryloxy and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-10 alkyl, C 1-10 alkoxy, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12 membered heterocyclyl, 3-12 membered heterocyclyloxy, C 6-10 aryl, C 6 -10 -aryloxy, 5-10-membered heteroaryl, 5
  • R 9 and R 10 is independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkoxy, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, C 3-12 -membered cycloalkyl, 3-12-membered heterocyclyl, C 6-10 -membered aryl, 5-10-membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl, the above groups are independently any is further selected by one or more selected from deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10
  • R 9 and R 10 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or a 4-10-membered heteroaryl group independently optionally further , hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-10 alkoxy base, C 3-12 cycloalkyl, C 3-12 cycloalkoxy, 3-12-membered heterocyclyl, 3-12-membered heterocyclyloxy, C 6-10 aryl, C 6-10 aryloxy , 5-10-membered heteroaryl, 5-10-membered heteroaryloxy, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl substituents;
  • n 0, 1 or 2;
  • Each r is independently 0, 1, or 2.
  • R g is selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, C 1 -4 alkoxy, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, halogen substituted C 1-4 alkoxy, deuterium substituted C 1-4 alkoxy, C 2-4 alkene group, C 2-4 alkynyl and -C 0-4 alkyl-NR 4 R 5 ;
  • R is selected from hydrogen, deuterium , hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
  • R4 and R5 are as defined in compounds of formula (I ) .
  • R a , R b , R d and Re are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl and C 2-4 alkynyl, or, R a and R b , R One of the groups of d and Re , R a and R d each independently forms a C 3-6 cycloalkyl or 3-6 membered heterocyclic group together with the carbon atom to which it is directly attached, and the other two groups are as defined above;
  • R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R c and R f are directly therewith
  • the linked moieties together form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl.
  • R j is selected from hydrogen, deuterium, C 1-4 alkyl, halogen-substituted C 1-4 alkyl base and deuterium substituted C 1-4 alkyl;
  • R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
  • L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2- 4 -alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, C 3-6 cycloalkyl, C 1-2 alkyl, 3-6 membered heterocyclyl C 1-2 alkyl, C 6-8 aryl C 1-2 alkyl and 5-8 membered heteroaryl C 1-2 alkyl, the above groups are independently optionally further One or more selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl,
  • R and L together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclyl ;
  • R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
  • the compound of formula (I) is the following compound of formula (IIa) or (IIb):
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently selected from N, C(O), CR g , N(O) and NR h ;
  • Z 1 , Z 2 and Z 3 are each independently CR i or N;
  • L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
  • L 2 is selected from C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclic group, C 6-8 aryl, 5-8 membered heteroaryl, C 3-6 cycloalkyl C 1-2 alkyl, 3-6 membered heterocyclyl C 1-2 alkyl, C 6-8 aryl C 1-2 alkyl and 5 -8-membered heteroaryl C 1-2 alkyl, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen Substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl,
  • R a , R b , R d , and R e are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium-substituted C 1-4 alkyl, or, R One of a and R b , R d and Re , Ra and R d each independently forms a C 3-6 cycloalkyl together with the carbon atom to which it is directly attached, and the other two groups are as previously defined;
  • R c and R f are each independently selected from hydrogen, deuterium, halogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R c and R f are directly therewith
  • R g is selected from hydrogen, deuterium, C 1-2 alkyl, C 1-2 alkoxy, halo-substituted C 1-2 alkyl, deuterium-substituted C 1-2 alkyl, halo-substituted C 1-2 alkoxy , deuterium substituted C 1-2 alkoxy and -C 0-2 alkyl-NR 4 R 5 ;
  • R h is each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl;
  • R i is selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 chain Alkenyl, C 2-4 alkynyl and -C 0-2 alkyl-OR 7 ;
  • R j is selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl and deuterium substituted C 1-4 alkyl;
  • R k and R p are each independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl , C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl, or, R k and R p together with the carbon atom to which they are directly attached form a C 3-6 cycloalkyl or 3-6 membered heterocyclyl;
  • Each R 1 is independently selected from hydrogen, deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -C 0 -2 alkyl-OR 7 ;
  • R 2 is vinyl or ethynyl, and the above groups are independently optionally further selected from one or more groups selected from hydrogen, deuterium, halogen, cyano, C 1-4 alkyl, halogen-substituted C 1-4 alkyl, deuterium Substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, -C 0-2 alkyl-C(O)OR 7 , -C 0-2 alkyl-C(O ) R 8 , -C 0-2 alkyl-C(O)-NR 9 R 10 and the substituents of -C 0-2 alkyl-NR 9 R 10 ;
  • R 3 and L 2 together with the nitrogen atom to which they are directly attached form a 4-8 membered nitrogen-containing heterocyclic group
  • R 4 and R 5 are each independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 6- 8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 ;
  • n 0, 1 or 2;
  • each r is independently 0, 1, or 2;
  • R 6 , R 7 , R 8 , R 9 , R 10 and r are as defined in compounds of formula (I).
  • the compound of formula (I) is the following compound of formula (IIIa 1 ) or (IIIa 2 ):
  • Y 1 is N or CH
  • each Z 1 is independently CH or N;
  • Each L 1 is independently selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
  • Each L 2 is independently selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-4 cycloalkyl, C 1-2 alkyl and 3-4 membered heterocyclyl Heterocyclyl C 1-2 alkyl groups independently optionally further C 1 substituted with one or more groups selected from deuterium, halogen, cyano, nitro, azido, C 1-4 alkyl, halogen -4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and - Replaced by the substituent of OR 7 ;
  • Ra , Rb , Rd and Re is independently selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, Tribromomethyl, monodeuteromethyl, dideuteromethyl and trideuteromethyl, alternatively, one of the groups of Ra and Rb , Rd and Re each independently together with the carbon atom to which it is directly attached form a C 3-6 cycloalkyl, another group is as previously defined;
  • Each R g is independently selected from hydrogen, deuterium and -NR 4 R 5 ;
  • Each Rj is independently selected from the group consisting of hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl , di-deuteromethyl and tri-deuteromethyl;
  • Each R k and R p is independently selected from hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, R k and R p are directly attached thereto.
  • the carbon atoms together form a C 3-6 cycloalkyl;
  • Each R 1a is independently selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and -OR 7 ;
  • Each R 1b is independently selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, and -OR 7 ;
  • Each R 2 is each independently vinyl or ethynyl, independently optionally further selected by one or more groups selected from the group consisting of hydrogen, deuterium, fluorine, chlorine, cyano, methyl, difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl, trideuteromethyl, cyclopropyl and -C 0-2 alkyl- Substituents of NR 9 R 10 are substituted;
  • Each R is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 3-4 cycloalkyl, and 3-4 membered heterocyclyl, independently optionally further substituted by one or more
  • One is selected from deuterium, fluorine, chlorine, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 chain Alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, -OR 7 and -NR 9 R 10 substituents,
  • R and L together with their directly attached nitrogen atoms form the following structure:
  • Each R4 and R5 is independently selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, mono deuteromethyl, di-deuteromethyl and tri-deuteromethyl;
  • n 0, 1 or 2;
  • R 7 , R 9 and R 10 are as defined in the compound of formula (IIa).
  • the compound of formula (I) is the compound of formula (IIIb) below:
  • Y 3 is N or N(O);
  • L1 is selected from O, S , NRj , CRkRp , OCRkRp and a bond ;
  • L 2 is selected from C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, C 3-4 cycloalkyl C 1-2 alkyl and 3-4 membered heterocyclyl C 1 -2 alkyl groups, the above groups are independently optionally further substituted by one or more groups selected from the group consisting of deuterium, halogen, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl substituted with substituents of C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and -OR 7 ;
  • Rc and Rf are each independently selected from the group consisting of hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl group, di- deuteromethyl and tri- deuteromethyl , alternatively, R and R together with the moiety to which they are directly attached form a C 3-6 cycloalkyl;
  • R g is selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl and trideuteromethyl;
  • R i is selected from hydrogen, deuterium, fluorine, chlorine and cyano;
  • R j is selected from hydrogen, deuterium, methyl, difluoromethyl, dichloromethyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, dideuteromethyl and trideuteromethyl;
  • R k and R p are each independently selected from hydrogen, C 1-4 alkyl, halo-substituted C 1-4 alkyl, and deuterium substituted C 1-4 alkyl, alternatively, the carbon atom to which R k and R p are directly attached together form a C 3-6 cycloalkyl;
  • R 1a is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium-substituted C 1-4 alkyl and -OR 7 ;
  • R 1b is selected from hydrogen, deuterium, fluorine, chlorine, bromine, cyano, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl and -OR 7 ;
  • R 2 is vinyl or ethynyl, which are independently optionally further selected from one or more groups selected from hydrogen, deuterium, fluorine, chlorine, cyano, methyl, difluoromethyl, dichloromethyl, dibromo Methyl, trifluoromethyl, trichloromethyl, tribromomethyl, deuteromethyl, di-deuteromethyl, tri-deuteromethyl, cyclopropyl and -C 0-2 alkyl-NR 9 R 10 substituted by a substituent;
  • R 3 is selected from hydrogen, deuterium, C 1-4 alkyl, C 3-4 cycloalkyl and 3-4 membered heterocyclyl, the above-mentioned groups are independently optionally further substituted by one or more selected from deuterium, fluorine, Chlorine, cyano, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-6 Substituents of cycloalkyl, 3-6 membered heterocyclyl, phenyl, -OR 7 and -NR 9 R 10 ,
  • R and L together with their directly attached nitrogen atoms form the following structure:
  • R 7 , R 9 and R 10 are as defined in the compound of formula (IIa).
  • each R 6 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl , C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 9 R 10 , the above groups are independent optionally further selected from deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy base, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heteroaryl, 5-8 membered heteroaryloxy and -NR 9 R 10 substituents;
  • Each R 7 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl and 5-8 membered heteroaryl groups, the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, cyano, C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and substituents of -NR 9 R 10 ;
  • Each R 8 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 Cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8 membered heterocycle Aryl, 5-8 membered heteroaryloxy and -NR 9 R 10 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, cyano, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6 -8 -aryloxy, 5-8-membered heteroaryl, 5-8-member
  • R 9 and R 10 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl Acyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl, the above groups are independently any is further selected from the group consisting of one or more deuterium, halogen, hydroxyl, C 1-4 alkyl, C 2-4 alkenyl, C 2-4
  • R 9 and R 10 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclic group or a 4-8 membered heteroaryl group independently optionally further substituted by one or more selected from the group consisting of deuterium, halogen, Hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 2-4 alkynyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 1-4 alkoxy , C 3-8 cycloalkyl, C 3-8 cycloalkoxy, 3-8 membered heterocyclyl, 3-8 membered heterocyclyloxy, C 6-8 aryl, C 6-8 aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl substituents.
  • the compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts include but are not limited to the following compounds:
  • the second aspect of the present invention provides a preparation method of the compound of formula (I), its stereoisomer or its pharmaceutically acceptable salt, comprising the following steps:
  • R is R 3 or an amino protecting group, the amino protecting group is tert-butoxycarbonyl or benzyl, X 1 , X 2 , Y 1 , Y 2 , Y 3 , Y 4 , Z 1 , Z 2 , Z 3 , L 1 , L 2 , R 1 , R 2 , R 3 and m are as defined in compounds of formula (I).
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also relates to the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of the treatment and/or prevention of cancers, tumors at least partially associated with EGFR exon 20 insertions, deletions or other mutations or the use of drugs in metastatic disease.
  • the present invention also relates to a compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the prevention and/or treatment of tumors, cancers and/or metastatic diseases caused by hyperproliferative and cell death-inducing disorders use in.
  • the present invention also relates to the aforementioned compounds of formula (I), their stereoisomers or their pharmaceutically acceptable salts in the preparation of the prevention and/or treatment of lung cancer, colon cancer, pancreatic cancer, head and neck cancer caused by hyperproliferation and cell death-induced disorders , breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors , urological tumor, skin tumor, sarcoma, sinus inverted papilloma or nasal sinus squamous cell carcinoma associated with the use in the drug.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use as a medicament.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of cancers associated at least in part with EGFR exon 20 insertions, deletions or other mutations , tumor or metastatic disease.
  • the present invention also relates to said compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the prevention and/or treatment of tumors, cancers and/or metastases caused by hyperproliferative and cell death-inducing disorders use of sexually transmitted diseases.
  • the present invention also relates to the compound of formula (I), a stereoisomer thereof or a pharmaceutically acceptable salt thereof, for use in the treatment and/or prevention of lung, colon, pancreatic cancer caused by hyperproliferative and cell death-induced disorders , head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, myelodysplastic syndromes, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and Use in other gynecological tumors, urological tumors, skin tumors, sarcomas, naso-inverted papilloma or nasosinus-related squamous cell carcinoma of the sinuses.
  • the present invention also relates to a method of treating and/or preventing cancer, tumor or metastatic disease associated at least in part with EGFR exon 20 insertions, deletions or other mutations, comprising administering to a patient in need thereof a therapeutically effective amount of said A compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a method of preventing and/or treating tumors, cancers and/or metastatic diseases caused by hyperproliferative and induced cell death disorders, comprising administering to a patient in need thereof a therapeutically effective amount of said formula (I) A compound, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof.
  • the present invention also relates to a treatment and/or prevention of lung cancer, colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, gastric cancer, non-small cell lung cancer, leukemia, Myelodysplastic syndromes, malignant lymphomas, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus inverted papilloma or A method of nasosinusal inverting papilloma-associated squamous cell carcinoma of the nasal cavity, comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof .
  • an EGFR inhibitor with the structure of the following formula (I). 20 Drugs for cancers, tumors or metastatic diseases associated with insertions, deletions or other mutations, especially for hyperproliferative and cell death-inducing disorders, are expected to be developed into next-generation EGFR inhibitors. On this basis, the present invention has been completed.
  • Alkyl refers to a straight-chain or branched-chain saturated aliphatic hydrocarbon group, preferably a straight-chain alkyl group and a branched-chain alkyl group comprising 1 to 10 or 1 to 6 carbon atoms or 1 to 4 carbon atoms, Including but not limited to methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, n-pentyl, 1,1-dimethylpropyl, 1, 2-dimethylpropyl, 2,2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, 1-ethyl-2-methyl propylpropyl, 1,1,2-trimethylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3- Dimethylbutyl,
  • C 1-10 alkyl refers to straight-chain alkyl groups including 1 to 10 carbon atoms and branched alkyl groups
  • C 1-4 alkyl refers to straight-chain alkyl groups including 1 to 4 carbon atoms and A branched-chain alkyl group
  • C 1-2 alkyl refers to a straight-chain alkyl group including 1 to 2 carbon atoms
  • C 0-8 alkyl refers to a straight-chain alkyl group including 0 to 8 carbon atoms and A branched-chain alkyl group
  • C 0-4 alkyl refers to a straight-chain alkyl group containing 0 to 4 carbon atoms and a branched alkyl group
  • C 0-2 alkyl refers to a group containing 0 to 4 carbon atoms straight-chain and branched-chain alkyl groups.
  • Cycloalkyl or “carbocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon means that the cyclic hydrocarbon may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings has a completely conjugated ⁇ electron system, cycloalkyl is divided into monocyclic cycloalkyl, polycyclic cycloalkyl, preferably including 3 to 12 or 3 to 8 or 3 Cycloalkyl groups of up to 6 carbon atoms, for example, "C 3-12 cycloalkyl” refers to cycloalkyl groups including 3 to 12 carbon atoms, “C 3-10 cycloalkyl” refers to cycloalkyl groups including 3 to 10 carbon atoms atomic cycloalkyl, “C 3-8 cycloalkyl” refers to a cycloalkyl group comprising 3 to 8 carbon atoms, "C 3-6
  • Monocyclic cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, Cyclooctyl etc.
  • Polycyclic cycloalkyl groups include spiro, fused and bridged cycloalkyl groups.
  • “Spirocycloalkyl” refers to polycyclic groups in which a single carbon atom (called a spiro atom) is shared between the monocyclic rings, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have Fully conjugated pi electron system. According to the number of spiro atoms shared between the rings, spirocycloalkyl groups are classified into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, and spirocycloalkyl groups include but are not limited to:
  • fused cycloalkyl refers to an all-carbon polycyclic group in which each ring in the system shares an adjacent pair of carbon atoms with other rings in the system, wherein one or more rings may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused cycloalkyl groups, fused cycloalkyl groups include but are not limited to:
  • “Bridged cycloalkyl” refers to an all-carbon polycyclic group in which any two rings share two non-directly attached carbon atoms, these may contain one or more (preferably 1, 2 or 3) double bonds, but none The ring has a fully conjugated pi electron system. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged cycloalkyl, including but not limited to:
  • the cycloalkyl ring can be fused to an aryl, heteroaryl or heterocycloalkyl ring, wherein the ring connected to the parent structure is a cycloalkyl, including but not limited to indanyl, tetrahydronaphthyl , benzocycloheptyl, etc.
  • Heterocyclyl or “heterocycle” refers to a saturated or partially unsaturated monocyclic or polycyclic cyclic hydrocarbon substituent, and the partially unsaturated cyclic hydrocarbon refers to a cyclic hydrocarbon that may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings have a fully conjugated pi-electron system, heterocyclyl wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O ) r (where r is an integer 0, 1, 2) heteroatoms excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon.
  • Heterocyclyl groups including 3 to 12 or 3 to 8 or 3 to 6 ring atoms are preferred, for example, "3-4 membered heterocyclyl” refers to a ring group containing 3 to 4 ring atoms, "3-6 "Membered heterocyclyl” refers to a ring group containing 3 to 6 ring atoms, “3-8 membered heterocyclyl” refers to a ring group containing 3 to 8 ring atoms, and “3-10 membered heterocyclyl” refers to a ring group containing 3 A ring group of up to 10 ring atoms, “3-12 membered heterocyclyl” refers to a ring group containing 3 to 12 ring atoms, and “4-6 membered heterocyclyl” refers to a ring group containing 4 to 6 ring atoms , “4-8 membered heterocyclyl” refers to a ring group containing 4 to 8 ring atoms, and "4-10 member
  • Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, oxetanyl, tetrahydrofuranyl, and the like.
  • Polycyclic heterocyclyls include spiro, fused and bridged heterocyclyls.
  • “Spiroheterocyclyl” refers to a polycyclic heterocyclic group in which a single atom (called a spiro atom) is shared between the monocyclic rings, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or a heteroatom of S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. These may contain one or more double bonds (preferably 1, 2 or 3), but none of the rings have a fully conjugated pi-electron system.
  • Spiroheterocyclyls are classified into mono-, bis-, or poly-spiroheterocyclyls according to the number of spiro atoms shared between the rings.
  • Spiroheterocyclyl groups include, but are not limited to:
  • “Fused heterocyclic group” refers to a polycyclic heterocyclic group in which each ring in the system shares an adjacent pair of atoms with other rings in the system, one or more (preferably 1, 2, 3 or 4) rings may be contains one or more (preferably 1, 2, or 3) double bonds, but none of the rings has a fully conjugated pi-electron system, wherein one or more (preferably 1, 2, 3 or 4) ring atoms are selected from A heteroatom of nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) and the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocycloalkyl groups, fused heterocyclic groups include but are not limited to:
  • Bridged heterocyclyl refers to a polycyclic heterocyclic group in which any two rings share two atoms that are not directly connected, these may contain one or more (preferably 1, 2 or 3) double bonds, but none of the rings having a fully conjugated pi-electron system in which one or more (preferably 1, 2, 3 or 4) ring atoms are selected from nitrogen, oxygen or S(O) r (where r is an integer 0, 1, 2) Heteroatoms, the remaining ring atoms are carbon. According to the number of formed rings, it can be divided into bicyclic, tricyclic, tetracyclic or polycyclic bridged heterocyclic groups, bridged heterocyclic groups include but are not limited to:
  • the heterocyclyl ring can be fused to an aryl, heteroaryl or cycloalkyl ring, wherein the ring connected to the parent structure is a heterocyclyl, including but not limited to:
  • Aryl or “aromatic ring” refers to an all-carbon monocyclic or fused polycyclic (ie, rings sharing adjacent pairs of carbon atoms) groups, polycyclic rings having a conjugated pi electron system (ie, with adjacent ring) groups for carbon atoms, preferably all-carbon aryl groups containing 6-10 or 6-8 carbons, for example, “C 6-10 aryl” refers to all-carbon aryl groups containing 6-10 carbons, “C 6-8 aryl” refers to a full carbon aryl group containing 6-8 carbons, including but not limited to phenyl and naphthyl.
  • the aryl ring can be fused to a heteroaryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is an aryl ring, including but not limited to:
  • Heteroaryl refers to a heteroaromatic system containing one or more (preferably 1, 2, 3 or 4) heteroatoms including nitrogen, oxygen and S(O)r (where r is the integer 0 , 1, 2) heteroatoms, preferably heteroaromatic systems containing 5-10 or 5-8 or 5-6 ring atoms, for example, "4-10-membered heteroaryl” means containing 4-10 ring atoms Heteroaromatic system of ring atoms, “4-8 membered heteroaryl” refers to a heteroaromatic system containing 4-8 ring atoms, “5-6 membered heteroaryl” refers to a heteroaromatic system containing 5-6 ring atoms Aromatic system, "5-8 membered heteroaryl” refers to a heteroaromatic system containing 5-8 ring atoms, "5-10 membered heteroaryl” refers to a heteroaromatic system containing 5-10 ring atoms, Including, but not limited to, furanyl,
  • Alkenyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon double bond, preferably a straight or branched chain alkenyl group containing 2-10 or 2-4 carbons
  • C 2-10 alkenyl refers to a straight-chain or branched alkenyl containing 2-10 carbons
  • C 2-4 alkenyl refers to a straight-chain or branched alkenyl containing 2-4 carbons Branched alkenyl.
  • Alkynyl means an alkyl group as defined above consisting of at least two carbon atoms and at least one carbon-carbon triple bond, preferably a straight-chain or branched-chain alkynyl group containing 2-10 or 2-4 carbons,
  • C 2-10 alkynyl refers to a straight or branched chain alkynyl group containing 2-10 carbons
  • C 2-4 alkynyl refers to a straight or branched chain containing 2-4 carbons alkynyl.
  • ethynyl 1-propynyl, 2-propynyl, 1-, 2- or 3-butynyl, and the like.
  • Alkoxy refers to -O-alkyl, where alkyl is as defined above, eg, "C 1-10 alkoxy” refers to an alkyloxy group containing 1-10 carbons, “C 1-4 "Alkoxy” refers to an alkyloxy group containing 1-4 carbons including, but not limited to, methoxy, ethoxy, propoxy, butoxy, and the like.
  • Cycloalkoxy and “cycloalkyloxy” refer to -O-cycloalkyl, wherein the definition of cycloalkyl is as described above, for example, “C 3-12 cycloalkoxy” refers to a group containing 3-12 Carbon cycloalkyloxy, “C 3-8 cycloalkoxy” refers to cycloalkyloxy containing 3-8 carbons, “C 3-6 cycloalkoxy” refers to 3-6 carbons Cycloalkyloxy, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy, and the like.
  • Heterocyclyloxy and “heterocyclyloxy” refer to -O-heterocyclyl, wherein heterocyclyl is as defined above, including but not limited to azetidinyloxy, oxetanyloxy group, azacyclopentyloxy, nitrogen, oxanyloxy and the like.
  • C 1-10 alkanoyl refers to the monovalent atomic group left after C 1-10 alkanoic acid removes the hydroxyl group, usually also expressed as "C 0-9 -C(O)-", for example, "C 1 -C (O)-” means acetyl; “C2 - C(O)-” means propionyl; “C3 - C(O)-” means butyryl or isobutyryl.
  • C 3-10 cycloalkyl C 1-2 alkyl means that the carbon atom in “C 3-10 cycloalkyl” is attached to the C 1-2 alkyl, C 3-10 cycloalkyl and C 1- 2Alkyl is as defined above.
  • 3-12-membered heterocyclyl C 1-2 alkyl means that the carbon atom in "3-12-membered heterocyclyl” is attached to C 1-2 alkyl, 3-12-membered heterocyclyl and C 1- 2Alkyl is as defined above.
  • C 6-10 aryl C 1-2 alkyl means the carbon atom in “C 6-10 aryl” is attached to C 1-2 alkyl, C 6-10 aryl and C 1-2 alkyl is defined as above.
  • 5-10-membered heteroaryl C 1-2 alkyl means that the carbon atom in "5-10-membered heteroaryl” is attached to C 1-2 alkyl, 5-10-membered heteroaryl and C 1- 2Alkyl is as defined above.
  • Halo-substituted C 1-10 alkyl refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted by fluorine, chlorine, bromine and iodine atoms, including but not limited to difluoromethyl, dichloro Methyl, dibromomethyl, trifluoromethyl, trichloromethyl, tribromomethyl, etc.
  • Halo-substituted C 1-10 alkoxy refers to a 1-10 carbon alkoxy group in which the hydrogen on the alkyl group is optionally substituted with fluorine, chlorine, bromine, or iodine atoms. Including but not limited to difluoromethoxy, dichloromethoxy, dibromomethoxy, trifluoromethoxy, trichloromethoxy, tribromomethoxy and the like.
  • Deuterium-substituted C1-10 alkyl refers to a 1-10 carbon alkyl group in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to deuteromethyl, di-deuteromethyl, tri-deuteromethyl and the like.
  • Halogen refers to fluorine, chlorine, bromine or iodine.
  • Optional or “optionally” means that the subsequently described event or circumstance may but need not occur, and the description includes instances where the event or circumstance occurs or does not occur, that is, both substituted and unsubstituted .
  • a heterocyclic group optionally substituted with an alkyl group means that an alkyl group may, but need not, be present, and the description includes the case where the heterocyclic group is substituted with an alkyl group and the case where the heterocyclic group is not substituted with an alkyl group .
  • Substituted means that one or more "hydrogen atoms" in a group are, independently of one another, substituted with the corresponding number of substituents. It goes without saying that the substituents are only in their possible chemical positions, in accordance with valence bond theory in chemistry, and those skilled in the art can determine (either experimentally or theoretically) possible or impossible without undue effort replacement. For example, amino or hydroxyl groups with free hydrogen may be unstable when combined with carbon atoms with unsaturated bonds, such as alkenes.
  • Stereoisomer its English name is stereoisomer, refers to the isomers produced by the different arrangements of atoms in the molecule in space. It can be divided into cis-trans isomers and enantiomers. It can also be divided into two categories: enantiomers and diastereomers. Stereoisomers due to rotation of a single bond are called conformational stereo-isomers, and are sometimes called rotamers. Stereoisomers caused by bond length, bond angle, double bond in the molecule, ring, etc. are called configuration stereo-isomers, and configuration isomers are divided into two categories.
  • the isomers caused by the double bond or the single bond of the ring carbon atom not being able to rotate freely are called geometric isomers, also known as cis-trans isomers, which are divided into Z, E two configurations.
  • geometric isomers also known as cis-trans isomers, which are divided into Z, E two configurations.
  • cis-2-butene and trans-2-butene are a pair of geometric isomers, and the stereoisomers with different optical properties caused by the absence of anti-axial symmetry in the molecule are called optical isomers ( optical isomer), divided into R and S configurations.
  • the "stereoisomer" may be understood to include one or more of the above-mentioned enantiomers, configurational isomers and conformational isomers unless otherwise specified.
  • “Pharmaceutically acceptable salts” as used herein refers to pharmaceutically acceptable acid addition salts, including inorganic and organic acid salts, which can be prepared by methods known in the art.
  • “Pharmaceutical composition” means a mixture containing one or more of the compounds described herein, or a physiologically/pharmaceutically acceptable salt or prodrug thereof, with other chemical components, and other components such as a physiological/pharmaceutically acceptable carrier and excipients.
  • the purpose of the pharmaceutical composition is to facilitate the administration to the organism, facilitate the absorption of the active ingredient and then exert the biological activity.
  • the structures of the compounds of the present invention are determined by nuclear magnetic resonance (NMR) or/and liquid chromatography-mass spectrometry (LC-MS). NMR chemical shifts ([delta]) are given in parts per million (ppm). NMR was measured by Bruker AVANCE-400/500 nuclear magnetic instrument, the solvent was deuterated dimethyl sulfoxide (DMSO-d 6 ), deuterated methanol (CD 3 OD) and deuterated chloroform (CDCl 3 ), internal standard For tetramethylsilane (TMS).
  • DMSO-d 6 dimethyl sulfoxide
  • CD 3 OD deuterated methanol
  • CDCl 3 deuterated chloroform
  • TMS internal standard For tetramethylsilane
  • the thin layer chromatography silica gel plate uses Yantai Huanghai HSGF254 or Qingdao GF254 silica gel plate, the specifications used for TLC are 0.15mm ⁇ 0.20mm, and the specifications used for TLC separation and purification products are 0.4mm ⁇ 0.5mm.
  • Column chromatography generally uses Yantai Huanghai silica gel 200-300 mesh silica gel as the carrier.
  • the starting materials in the examples of the present invention are known and commercially available, or can be synthesized using or according to methods known in the art.
  • the first step the synthesis of 1-fluoro-3-isothiocyano-2-methoxybenzene
  • the second step tert-butyl 5-((3-fluoro-2-methoxyphenyl)carbamoyl)-4-hydroxy-6-oxo-3,6-dihydropyridine-1(2H )-carboxylate synthesis
  • the third step synthesis of N-(3-fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-methylthioamide
  • the first step the synthesis of 3-(2-aminoethoxy) isonicotine nitrile
  • Ethanolamine (1.40 g, 23.0 mmol) was dissolved in tetrahydrofuran (40 mL), cooled to 0 °C, sodium hydrogen (920 mg, 60%, 23.0 mmol) was added in portions, the reaction was stirred at room temperature for 0.5 h, cooled to 0 °C, A solution of 3-fluoroisonicotine nitrile (2.44 g, 20.0 mmol) in tetrahydrofuran (10 mL) was added dropwise, the dropwise addition was completed, and the reaction solution was warmed to room temperature to continue the reaction for 2 hours.
  • the second step synthesis of tert-butyl (2-((4-cyanopyridin-3-yl)oxy)ethyl)carbamate
  • the third step synthesis of tert-butyl (2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)carbamate
  • tert-Butyl(2-((4-cyanopyridin-3-yl)oxy)ethyl)carbamate (2.80 g, 10.6 mmol) was dissolved in methanol (60 mL), 2 mL of ammonia was added, Raney nickel (3.0 g), the reaction system was replaced with hydrogen three times, stirred at room temperature for 18 hours, after the reaction, the reaction solution was filtered, washed with methanol five times, the filtrate was concentrated to dryness, and the residue was separated by flash silica gel column chromatography [ 0-10% methanol: dichloromethane] to give tert-butyl(2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)carbamate (1.5g, yield: 53%).
  • ESI-MS 268.0[M+1] + .
  • the fourth step tert-butyl(2-((4-(((5-((3-fluoro-2-methoxyphenyl)carbamoyl)-6-oxo-1,2, Synthesis of 3,6-tetrahydropyridin-4-yl)amino)methyl)pyridin-3-yl)oxy)ethyl)carbamate
  • N-(3-Fluoro-2-methoxyphenyl)-4-hydroxy-2-oxo-1,2,5,6-tetrahydropyridine-3-methylthioamide 500 mg, 1.69 mmol
  • tert-Butyl(2-((4-(aminomethyl)pyridin-3-yl)oxy)ethyl)carbamate 632 mg, 2.36 mmol
  • N,N-dimethylacetamide 1.5 mL
  • the reaction solution was extracted with ethyl acetate (50 mL) and saturated brine (50 mL).
  • the fifth step tert-butyl (2-((4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro Synthesis of -1H-pyrro[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)carbamate
  • the seventh step N-(2-((4-(3-((3-fluoro-2-methoxyphenyl)amino)-4-oxo-4,5,6,7-tetrahydro-1H- Synthesis of pyrrolo[3,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)acrylamide
  • Embodiments 2-33 can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of Example 1:
  • the first step tert-butyl(2-((4-(((5-((3-chloro-2-methoxyphenyl)aminomethylthioacyl)-6-oxo-1,2, Synthesis of 3,6-tetrahydropyridin-4-yl)amino)methyl)pyridin-3-yl)oxy)ethyl)(methyl)carbamate
  • Step 4 3-((3-Chloro-2-methoxyphenyl)amino)-2-(3-(2-(methylamino)ethoxy)pyridin-4-yl)-1,5- Synthesis of Dihydro-4H-pyrrolo[3,2-c]pyridin-4-one
  • the fifth step N-(2-((4-(3-((3-chloro-2-methoxyphenyl)amino)-4-oxo-4,5-dihydro-1H-pyrrolo[3 Synthesis of ,2-c]pyridin-2-yl)pyridin-3-yl)oxy)ethyl)-N-methacrylamide
  • Embodiments 35-67 can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of Example 34:
  • the cells were placed in a 96-well plate filled with drugs at a temperature of 37°C, 5% CO 2 and 95% humidity, and cultured for 72 hours, followed by CTG analysis.
  • Cell survival rate (%) (Lum test drug-Lum culture medium control)/(Lum cell control-Lum culture medium control) ⁇ 100%.
  • the series of compounds of the present invention have a strong inhibitory effect on EGFR exon 20 insertion mutation at the cellular level, and some compounds have a strong inhibitory effect on Ba/F3 EGFR-D770-N771ins_SVD and Ba/F3
  • the activity of EGFR-V769_D770insASV cells in inhibiting proliferation relative to EGFR WT (wild-type) cells has high selectivity, and the selectivity reaches more than 10 times, even more than 20 times.
  • the selectivity of the compound of the present invention has been greatly improved.
  • the selectivity of the compounds of Examples 3, 7, and 33 has been increased by more than two times compared to the positive compound, and the selectivity of the compound of Example 45 has even been improved relative to the positive compound. to more than six times.

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Abstract

L'invention concerne un composé cyclique fusionné de la structure de formule (I) utilisé en tant qu'inhibiteur d'EGFR, un procédé de préparation de celui-ci, une composition pharmaceutique le contenant, et leur utilisation dans le traitement et/ou la prévention de cancers, de tumeurs ou de maladies métastatiques qui sont au moins partiellement associées à l'insertion ou la mutation de type délétion de l'exon 20 de l'EGFR, en particulier leur utilisation dans le traitement de maladies hyperprolifératives et de troubles de la mort cellulaire induite. Chacun des substituants dans la formule (I) est le même que ceux définis dans la description.
PCT/CN2021/111447 2020-08-10 2021-08-09 Composé cyclique condensé utilisé en tant qu'inhibiteur d'egfr, son procédé de préparation et son utilisation Ceased WO2022033416A1 (fr)

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Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023183601A1 (fr) * 2022-03-24 2023-09-28 Scorpion Therapeutics, Inc. Procédés de synthèse d'inhibiteurs d'egfr
US12037346B2 (en) 2021-04-13 2024-07-16 Nuvalent, Inc. Amino-substituted heteroaryls for treating cancers with EGFR mutations
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024208315A1 (fr) * 2023-04-07 2024-10-10 中国医药研究开发中心有限公司 Composé hétérocyclique aromatique, son procédé de préparation et son utilisation médicale
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon
EP4511376A4 (fr) * 2022-04-20 2026-04-29 Celyn Therapeutics Inc Inhibiteurs d'egfr dans le traitement du cancer

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315285A (zh) * 2014-07-25 2016-02-10 上海海雁医药科技有限公司 2,4-二取代7H-吡咯并[2,3-d]嘧啶衍生物、其制法与医药上的用途
WO2019081486A1 (fr) * 2017-10-24 2019-05-02 Bayer Aktiengesellschaft Dérivés de 4h-pyrrolo[3,2-c]pyridin-4-one
CN109843858A (zh) * 2016-08-15 2019-06-04 润新生物公司 某些化学实体、组合物及方法
WO2020039060A1 (fr) * 2018-08-23 2020-02-27 Lead Discovery Center Gmbh Pyrrolo[2,3-b]pyridine substituée en position 4 en tant que modulateurs d'erbb utiles pour le traitement du cancer
WO2020216773A1 (fr) * 2019-04-24 2020-10-29 Bayer Aktiengesellschaft Composés de 4h-pyrrolo[3,2-c]pyridin-4-one
WO2020216781A1 (fr) * 2019-04-24 2020-10-29 Bayer Aktiengesellschaft Composés de 4h-pyrrolo[3,2-c]pyridin-4-one

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TN2017000329A1 (en) * 2015-01-28 2019-01-16 Bayer Pharma AG 4h-pyrrolo[3,2-c]pyridin-4-one derivatives

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105315285A (zh) * 2014-07-25 2016-02-10 上海海雁医药科技有限公司 2,4-二取代7H-吡咯并[2,3-d]嘧啶衍生物、其制法与医药上的用途
CN109843858A (zh) * 2016-08-15 2019-06-04 润新生物公司 某些化学实体、组合物及方法
WO2019081486A1 (fr) * 2017-10-24 2019-05-02 Bayer Aktiengesellschaft Dérivés de 4h-pyrrolo[3,2-c]pyridin-4-one
WO2020039060A1 (fr) * 2018-08-23 2020-02-27 Lead Discovery Center Gmbh Pyrrolo[2,3-b]pyridine substituée en position 4 en tant que modulateurs d'erbb utiles pour le traitement du cancer
WO2020216773A1 (fr) * 2019-04-24 2020-10-29 Bayer Aktiengesellschaft Composés de 4h-pyrrolo[3,2-c]pyridin-4-one
WO2020216781A1 (fr) * 2019-04-24 2020-10-29 Bayer Aktiengesellschaft Composés de 4h-pyrrolo[3,2-c]pyridin-4-one

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US12037346B2 (en) 2021-04-13 2024-07-16 Nuvalent, Inc. Amino-substituted heteroaryls for treating cancers with EGFR mutations
WO2023183601A1 (fr) * 2022-03-24 2023-09-28 Scorpion Therapeutics, Inc. Procédés de synthèse d'inhibiteurs d'egfr
EP4511376A4 (fr) * 2022-04-20 2026-04-29 Celyn Therapeutics Inc Inhibiteurs d'egfr dans le traitement du cancer
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
WO2024208315A1 (fr) * 2023-04-07 2024-10-10 中国医药研究开发中心有限公司 Composé hétérocyclique aromatique, son procédé de préparation et son utilisation médicale
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
WO2025034702A1 (fr) 2023-08-07 2025-02-13 Revolution Medicines, Inc. Rmc-6291 destiné à être utilisé dans le traitement d'une maladie ou d'un trouble lié à une protéine ras
WO2025080946A2 (fr) 2023-10-12 2025-04-17 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras
WO2025255438A1 (fr) 2024-06-07 2025-12-11 Revolution Medicines, Inc. Procédés de traitement d'une maladie ou d'un trouble lié à la protéine ras
WO2025265060A1 (fr) 2024-06-21 2025-12-26 Revolution Medicines, Inc. Compositions thérapeutiques et procédés de gestion d'effets liés au traitement
WO2026006747A1 (fr) 2024-06-28 2026-01-02 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026015825A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Utilisation d'un inhibiteur de ras pour traiter le cancer du pancréas
WO2026015801A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble liés à ras
WO2026015790A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026015796A1 (fr) 2024-07-12 2026-01-15 Revolution Medicines, Inc. Méthodes de traitement d'une maladie ou d'un trouble lié à ras
WO2026050446A1 (fr) 2024-08-29 2026-03-05 Revolution Medicines, Inc. Inhibiteurs de ras
WO2026072904A2 (fr) 2024-09-26 2026-04-02 Revolution Medicines, Inc. Compositions et méthodes de traitement du cancer du poumon

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