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WO2022007841A1 - Inhibiteur de l'egfr, procédé de préparation associé, et application pharmaceutique associée - Google Patents

Inhibiteur de l'egfr, procédé de préparation associé, et application pharmaceutique associée Download PDF

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Publication number
WO2022007841A1
WO2022007841A1 PCT/CN2021/104977 CN2021104977W WO2022007841A1 WO 2022007841 A1 WO2022007841 A1 WO 2022007841A1 CN 2021104977 W CN2021104977 W CN 2021104977W WO 2022007841 A1 WO2022007841 A1 WO 2022007841A1
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Prior art keywords
alkyl
deuterium
membered
substituted
cycloalkyl
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English (en)
Chinese (zh)
Inventor
张鸣鸣
赵保卫
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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Priority to CN202180047548.XA priority Critical patent/CN116096372B/zh
Publication of WO2022007841A1 publication Critical patent/WO2022007841A1/fr
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/14—Ortho-condensed systems

Definitions

  • the invention belongs to the field of drug synthesis, and in particular relates to an EGFR inhibitor, a preparation method and pharmaceutical 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) multi-target therapy has been successfully developed and clinically validated.
  • Inhibitors targeting EGFR can significantly improve the progression-free survival of adenocarcinoma in NSCLC, and its acquired resistance mutations can be targeted by third-generation EGFR inhibitors.
  • Exon 20 Although classical EGFR activating mutations (exons 19 and 21) and resistance mutations (T790M) can be inhibited by existing drugs, insertional mutations in exon 20 (Exon 20) also lead to structural EGFR signaling activated and were insensitive to existing EGFR inhibitors. Exon 20 mutations are heterogeneous and include insertions or duplications of 1-7 amino acids between amino acids 762-774 of the EGFR protein. In NSCLC, the mutation frequency of EGFR exon 20 accounts for 4-10% of all mutations in EGFR. These mutations were mutually exclusive with other known oncogene driver mutations and were enriched in adenocarcinomas in women, non-smokers, Asian populations, and patients with non-small cell lung cancer.
  • 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 EGFR family.
  • the purpose of the present invention is to provide an EGFR inhibitor, its preparation method and pharmaceutical application.
  • 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 a strong inhibitory effect on the cytological activity of EGFR exon 20 insertion, deletion or other mutation.
  • EGFR wild-type has high selectivity and can be widely used in the preparation of drugs for the treatment and/or prevention of cancers, tumors or metastatic diseases at least partially associated with EGFR exon 20 insertions, deletions or other mutations, especially for the treatment of hyperproliferative disease and cell death-inducing disorders, thus promising the development of a new generation of EGFR inhibitors.
  • the first aspect of the present invention provides a compound of formula (I), a stereoisomer, a prodrug or a pharmaceutically acceptable salt thereof:
  • X is CH or N
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 1 or N;
  • R 4a and R 4b are each independently selected from hydrogen, deuterium, hydroxy, C 1-10 alkyl, halo-substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 3-12 cycloalkyl, 3 -12-membered heterocyclyl, -C(O)OR 6 , -C(O)R 7 and -C(O)NR 8 R 9 ;
  • Each R 5 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 radicals, 5-10-membered heteroaryl groups, and -NR 8 R 9 , 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 substituted by the substituents of aryloxy, 5-10-membered heteroaryl, 5-10-membered heteroaryloxy and -NR 8 R 9 ;
  • Each R 6 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 group, and 5-10-membered heteroaryl, 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 -NR 8 R 9 substituents;
  • Each R 7 is 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 heteroaryl, 5-10-membered heteroaryloxy and -NR 8 R 9 , 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 aryl substituted by the substituents of oxy, 5
  • Each R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxyl, 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, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclopropylsulfonyl, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-10 alkylamino, di-C 1-10 alkylamino and C 1-10 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C 1-10 alkyl, C 2-10 alkenyl, C 2-10 alkynyl, halogen substituted C 1
  • R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 4-10-membered heterocyclic group or 4-10-membered heteroaryl group, which is either is further selected by one or more selected from deuterium, halogen, 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, 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 Substituents of C 1-10 alkanoyl groups are substituted;
  • n 0, 1, 2, 3, or 4;
  • Each r is independently 0, 1, or 2.
  • R 5 , R 6 , R 7 , R 8 , R 9 and r are as described for the compound of formula (I).
  • R 5 , R 6 , R 7 , R 8 , R 9 and r are as described for the compound of formula (I).
  • each R 5 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkane group, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl, 5-8 membered heteroaryl and -NR 8 R 9 , the above-mentioned groups independently optionally further selected by one or more of the group consisting of deuterium, halogen, hydroxy, oxo, C 1-4 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, C 3-8 cycloalkane Oxy, 3-8-membered heterocyclyl, 3-8-membered heterocyclyloxy, C 6-8 aryl, C 6-10- aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy substituted with the substituent of -NR 8 R 9;
  • Each R 6 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 group, and 5-8-membered heteroaryl, 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 -NR 8 R 9 substituents;
  • Each R 7 is 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 heteroaryl, 5-8-membered heteroaryloxy and -NR 8 R 9 , 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 aryl substituted by the substituents of oxy, 5-8-membered
  • R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxy, 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, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C —
  • R 8 and R 9 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclyl optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, hydroxyl, C 1-4 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 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, Substituents of mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl groups.
  • the compound of formula (I) is the following compound of formula (II):
  • X is CH or N
  • Y 1 , Y 2 , Y 3 and Y 4 are each independently CR 1 or N;
  • R 4a and R 4b are each independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl, 3 -6-membered heterocyclyl and -C(O)R 7 ;
  • Each R 5 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 2-4 alkenyl, C 3-8 cycloalkyl, 3-8 membered heterocyclyl, C 6-8 aryl radicals, 5-8 membered heteroaryl groups and -NR 8 R 9 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, halogen, hydroxyl, oxo, 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 substituted by the substituents of aryloxy, 5-8-membered heteroaryl, 5-8-membered heteroaryloxy and -NR 8 R 9 ;
  • Each R 6 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 group, and 5-8-membered heteroaryl, 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 -NR 8 R 9 substituents;
  • Each R 7 is 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 heteroaryl, 5-8-membered heteroaryloxy and -NR 8 R 9 , 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 aryl substituted by the substituents of oxy, 5-8-membered
  • R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxy, 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, p-toluenesulfonyl, amino Sulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl groups, independently optionally further selected by one or more From deuterium, halogen, hydroxyl, C 1-4 alkyl, halogen substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C —
  • R 8 and R 9 are taken together with the nitrogen atom to which they are directly attached to form a 4-8 membered heterocyclyl optionally further substituted by one or more members selected from the group consisting of deuterium, halogen, hydroxyl, C 1-4 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 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, substituted by the substituents of mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;
  • n 0, 1, 2, 3, or 4;
  • Each r is independently 0, 1, or 2.
  • the compound of formula (I) is the compound of formula (III) as follows:
  • X is CH or N
  • Y 2 and Y 4 are each independently CR 1 or N;
  • R 4a and R 4b are each independently selected from hydrogen, deuterium, C 1-4 alkyl, halo-substituted C 1-4 alkyl, deuterium substituted C 1-4 alkyl, C 3-6 cycloalkyl and -C( O)R 7 ;
  • R 5 , R 6 , R 7 , R 8 , R 9 and r are as described for the compound of formula (I).
  • R 4a and R 4b are each independently selected from hydrogen, deuterium, methyl, Ethyl, propyl, isopropyl, cyclopropyl, -CHF 2 , -CF 3 , -CHD 2 , -CD 3 and -C(O)R 7 ; wherein R 7 is as described for the compound of formula (I) ;
  • R 4a is selected from hydrogen, deuterium, methyl, ethyl, propyl, isopropyl, cyclopropyl, -CHF 2, -CF 3, -CHD 2 , and -CD 3;
  • R 4b is selected from hydrogen, Deuterium and -C(O)R 7 ; wherein R 7 is as described for compounds of formula (I).
  • R 5 , R 6 , R 7 , R 8 , R 9 and r are as described for the compound of formula (I).
  • each R 5 is independently selected from hydrogen, deuterium, hydroxyl, C 1-4 alkane group, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl, 5-6 membered heteroaryl and -NR 8 R 9 independently optionally further selected from one or more Substituted by substituents of deuterium, halogen, hydroxyl, oxo, C 1-4 alkyl and C 1-4 alkoxy;
  • Each R 6 is independently selected from hydrogen, deuterium, C 1-4 alkyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, phenyl and 5-6 membered heteroaryl, the above groups are independently optionally further substituted with one or more substituents selected from the group consisting of deuterium, fluorine, chlorine, hydroxy, oxo, cyano, C 1-4 alkyl and C 1-4 alkoxy;
  • Each R 7 is selected from hydrogen, deuterium, hydroxyl, C 1-4 alkyl, C 1-4 alkoxy, C 2-4 alkenyl, C 3-8 cycloalkyl, C 3-8 cycloalkoxy group, phenyl, and -NR 8 R 9 , the above-mentioned groups are independently optionally further selected from one or more groups selected from deuterium, fluorine, chlorine, hydroxy, cyano, C 1-4 alkyl and C 1-4 alkoxy substituted by the substituent of the base;
  • Each R 8 and R 9 is independently selected from hydrogen, deuterium, hydroxy, C 1-4 alkyl, C 3-8 cycloalkyl, sulfinyl, sulfonyl, methanesulfonyl, isopropylsulfonyl, cyclo Propylsulfonyl, p-toluenesulfonyl, aminosulfonyl, dimethylaminosulfonyl, amino, mono-C 1-4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl;
  • R 8 and R 9 together with the nitrogen atom to which they are directly attached form a 4-8 membered heterocyclic group optionally further substituted by one or more members selected from the group consisting of deuterium, fluorine, chlorine, hydroxy , C 1-4 alkyl, halogen substituted C 1-10 alkyl, deuterium substituted C 1-10 alkyl, C 1-4 alkoxy, C 3-8 cycloalkyl, phenyl, amino, mono-C 1 -4 alkylamino, di-C 1-4 alkylamino and C 1-4 alkanoyl substituents.
  • the compounds of formula (I), their stereoisomers, prodrugs 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, prodrug or its pharmaceutically acceptable salt, comprising the following steps:
  • a third aspect of the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, a prodrug or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.
  • the present invention also relates to the compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof in the preparation of treatment and/or prophylaxis at least partially associated with EGFR exon 20 insertions, deletions or other mutations Use in the medicament of cancer, tumor or metastatic disease.
  • the present invention also relates to compounds of formula (I), their stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, in the preparation of the prevention and/or treatment of tumors, cancers and or metastatic diseases caused by hyperproliferative and cell death-inducing disorders use in medicines.
  • the present invention also relates to the aforementioned compounds of formula (I), their stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, in the preparation of the prevention and/or treatment of lung cancers associated at least in part with EGFR exon 20 insertions, deletions or other mutations, Colon cancer, pancreatic cancer, head and neck cancer, breast cancer, ovarian cancer, uterine cancer, stomach cancer, non-small cell lung cancer, leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, Use in endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, paranasal sinus inverted papilloma or paranasal sinus squamous cell carcinoma associated with sinus inverted papilloma.
  • the present invention also relates to said compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, for use in the treatment and/or prophylaxis of insertions, deletions or other mutations at least partially associated with EGFR exon 20 Use in associated cancer, tumor or metastatic disease.
  • the present invention also relates to said compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, for use in the prevention and/or treatment of tumors, cancers and or metastatic disease.
  • the present invention also relates to said compounds of formula (I), stereoisomers, prodrugs or pharmaceutically acceptable salts thereof, for use in the treatment and/or prophylaxis of insertions, deletions or other mutations at least partially associated with EGFR exon 20
  • 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, a prodrug 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 compound of formula (I) , its stereoisomers, prodrugs or pharmaceutically acceptable salts thereof.
  • the present invention also relates to a treatment and/or prophylaxis of lung, colon, pancreatic, head and neck, breast, ovarian, uterine, gastric, non-small cell carcinomas associated at least in part with EGFR exon 20 insertions, deletions or other mutations
  • Cell lung cancer leukemia, myelodysplastic syndrome, malignant lymphoma, head and neck tumors, thoracic tumors, gastrointestinal tumors, endocrine tumors, breast and other gynecological tumors, urological tumors, skin tumors, sarcomas, sinus inversion
  • a method of paranasal papilloma or paranasal inversion papilloma-associated squamous cell carcinoma of the paranasal sinuses comprising administering to a patient in need thereof a therapeutically effective amount of said compound of formula (I), its stereoisomers, pro- medicine or a pharmaceutically acceptable salt thereof.
  • an EGFR inhibitor with the structure of the following formula (I).
  • 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 be developed into next-generation EGFR inhibitors.
  • 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 Contains branched 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 3-8 cycloalkyl” refers to cycloalkyl groups including 3 to 8 carbon atoms Atom cycloalkyl, “C 3-6 cycloalkyl” refers to a cycloalkyl group comprising 3 to 6 carbon atoms, wherein:
  • 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 divided into single spirocycloalkyl groups, double spirocycloalkyl groups or polyspirocycloalkyl groups, including but 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 ) heteroatoms of r (wherein r is an integer of 0, 1, 2), excluding ring moieties of -OO-, -OS- or -SS-, the remaining ring atoms being carbon, preferably including 3 to 12 or 3 to Heterocyclyl groups of 8 or 3 to 6 ring atoms, for example, "3-6 membered heterocyclyl” refers to a ring group containing 3 to 6 ring atoms, and "4-8 membered heterocyclyl” refer
  • Monocyclic heterocyclyl groups include, but are not limited to, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl, homopiperazinyl, 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, 5-6 membered heteroaryl means containing 5-6 ring atoms
  • the heteroaromatic system of Not limited to furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, pyrazinyl, imidazolyl, tetrazolyl, and the like.
  • the heteroaryl ring can be fused to an aryl, heterocyclyl or cycloalkyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, including but not limited to:
  • 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 or branched alkenyl containing 2-4 carbons .
  • 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 group refers to a straight chain containing 2-10 carbon atoms or branched alkynyl group
  • C 2-4 alkynyl group refers to a straight chain containing 2-4 carbons or a branched alkynyl group.
  • 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 refers to -O-cycloalkyl, where cycloalkyl is as defined above, for example, “C 3-12 cycloalkoxy” refers to a cycloalkyloxy group containing 3-12 carbons, “C 3-8 cycloalkoxy” refers to a cycloalkyloxy group containing 3-8 carbons, including but not limited to cyclopropoxy, cyclobutoxy, cyclopentyloxy, cyclohexyloxy and the like.
  • Heterocyclyloxy refers to -O-heterocyclyl, wherein heterocyclyl is as defined above, and heterocyclyloxy, including but not limited to azetidinyloxy, oxetanyloxy, nitrogen Heterocyclopentyloxy, nitrogen, oxhexyloxy, etc.
  • C 1-10 alkanoyl refers to the monovalent atomic group remaining after C 1-10 alkyl acid removes the hydroxyl group, usually also expressed as "C 0-9 alkyl-C(O)-", for example, "C 1 alkyl -C (O) - "means acetyl;” C 2 alkyl group -C (O) - “refers propionyl;” C 3 alkyl -C (O) - “refers to butyryl or isobutyryl Acyl.
  • 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, or iodine atoms, including but not limited to difluoromethyl (-CHF 2 ), dichloromethyl (-CHCl 2 ), dibromomethyl (-CHBr 2 ), trifluoromethyl (-CF 3 ), trichloromethyl (-CCl 3 ), tribromomethyl (-CBr 3 ) 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 a deuterated methyl (-CH 2 D), two deuterium methyl (-CHD 2), trideuteromethyl (-CD 3) and the like.
  • Deuterium substituted C 1-10 alkoxy refers to 1-10 carbon alkyl groups in which the hydrogen on the alkyl group is optionally substituted with a deuterium atom. Including but not limited to mono-deuteromethoxy, di-deuteromethoxy, tri-deuteromethoxy 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, if the compound of the present invention contains a double bond, if not specified, it can be understood as containing E and/or Z form.
  • Stereoisomers with different optical properties due to the absence of anti-axial symmetry in the molecule are called optical isomers and are divided into R and S configurations.
  • the "stereoisomer" can be understood to include one or more of the above-mentioned enantiomers, configuration isomers and conformation isomers unless otherwise specified, preferably S configuration type.
  • “Pharmaceutically acceptable salts” in the present invention refer to pharmaceutically acceptable acid addition salts or base 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.
  • Example 1a and Example 1b (S)-N-(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrole Iso[2,1-a]isoquinolin-5-yl)acrylamide and (R)-N-(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[ Preparation of 5',4':4,5]pyrrolo[2,1-a]isoquinolin-5-yl)acrylamide
  • the first step the synthesis of 2-(2-bromophenyl) oxa propane
  • the second step synthesis of tert-butyl (1-(2-bromophenyl)-2-hydroxyethyl) carbamate
  • Boc 2 O 122 g, 0.56 mol was added to the aqueous solution, the reaction was stirred at room temperature for 2 hours, the resulting mixture was filtered, the filter cake was washed with water (100 mL) and methyl tert-butyl ether (3*20 mL), the filter cake was collected and dried tert-Butyl(1-(2-bromophenyl)-2-hydroxyethyl)carbamate (25.5 g, 29% yield) was obtained.
  • ESI-MS 260[M-56] + .
  • Step 7 12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a]isoquinoline-5,11 -Synthesis of diamines
  • Step 8 N-(11-Amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2,1-a] Synthesis of isoquinolin-5-yl)acrylamide
  • the ninth step (S)-N-(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2, 1-a]Isoquinolin-5-yl)acrylamide and (R)-N-(11-amino-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4 Synthesis of ':4,5]pyrrolo[2,1-a]isoquinolin-5-yl)acrylamide
  • Examples 2a ⁇ 38b can be prepared by selecting corresponding raw materials with reference to all or part of the synthetic methods of Examples 1, 1a and 1b:
  • the first step the synthesis of 2-bromo-1-(2-bromo-4-fluorophenyl) ethane-1-one
  • the seventh step tert-butyl (2-(4-amino-5-(quinolin-3-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-1-(2-bromo Synthesis of -4-fluorophenyl)ethylcarbamate methyl ester
  • Step 9 2-fluoro--N 5 - methyl-12- (quinolin-3-yl) -5,6-dihydro-pyrimido [5 ', 4': 4,5] pyrrolo [2,1 Synthesis of -a]isoquinoline-5,11-diamine
  • Step 10 N-(11-Amino-2-fluoro-12-(quinolin-3-yl)-5,6-dihydropyrimido[5',4':4,5]pyrrolo[2, Synthesis of 1-a]isoquinolin-5-yl)-N-methacrylamide
  • Embodiments 40a-45b can be prepared with reference to all or part of the synthetic methods of Examples 39, 39a and 39b to select corresponding raw materials:
  • Luminescence cell viability detection kit Promega, Cat#G7572
  • black transparent flat-bottom 96-well plate Cat#3603
  • cell line cell culture medium Cell density 1 A431 DMEM+15%FBS 5000 2 Ba/F3EGFR-D770-N771ins_SVD RPMI1640+10%FBS 3000 3 Ba/F3EGFR-V769-D770ins_ASV RPMI1640+10%FBS 3000
  • the cells were placed in a drug-filled 96-well plate 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, deletion or other mutations at the cellular level, and have certain selectivity for EGFR WT.

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Abstract

L'invention concerne un inhibiteur de l'EGFR, un procédé de préparation associé, et une application pharmaceutique de celui-ci, en particulier se rapportant à un inhibiteur de l'EGFR ayant la structure de formule (I), un procédé de préparation associé, une composition pharmaceutique le contenant, une utilisation de celui-ci en tant qu'inhibiteur de l'EGFR, et une utilisation de ceux-ci dans la préparation de médicaments pour le traitement et/ou la prévention de cancers, de tumeurs, ou des maladies métastatiques au moins partiellement associés à l'insertion, à la délétion, ou autre mutation de l'exon 20 de l'EGFR, en particulier l'utilisation de ceux-ci dans la préparation de médicaments pour le traitement et/ou la prévention de maladies hyperprolifératives et de troubles de la mort cellulaire induite. Chaque substituant dans la formule (I) a la même définition que celle donnée dans la description.
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WO2024008128A1 (fr) * 2022-07-06 2024-01-11 上海科恩泰生物医药科技有限公司 Composé de sulfoximine ayant un effet inhibiteur de fgfr, composition pharmaceutique le comprenant et utilisation associée
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
WO2024229406A1 (fr) 2023-05-04 2024-11-07 Revolution Medicines, Inc. Polythérapie pour une maladie ou un trouble lié à ras
US12209089B1 (en) * 2024-04-10 2025-01-28 King Faisal University Pyrimido[1′,6′: 1,5]pyrazolo[4,3-c] [2,7] naphthyridines as CK2 inhibitors
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
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CN110191711A (zh) * 2016-10-31 2019-08-30 大鹏药品工业株式会社 外显子20插入突变型egfr的选择性抑制剂
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Cited By (9)

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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
WO2024008128A1 (fr) * 2022-07-06 2024-01-11 上海科恩泰生物医药科技有限公司 Composé de sulfoximine ayant un effet inhibiteur de fgfr, composition pharmaceutique le comprenant et utilisation associée
WO2024206858A1 (fr) 2023-03-30 2024-10-03 Revolution Medicines, Inc. Compositions pour induire une hydrolyse de ras gtp et leurs utilisations
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
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WO2025171296A1 (fr) 2024-02-09 2025-08-14 Revolution Medicines, Inc. Inhibiteurs de ras
US12209089B1 (en) * 2024-04-10 2025-01-28 King Faisal University Pyrimido[1′,6′: 1,5]pyrazolo[4,3-c] [2,7] naphthyridines as CK2 inhibitors
WO2025240847A1 (fr) 2024-05-17 2025-11-20 Revolution Medicines, Inc. Inhibiteurs de ras

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