WO2023061434A1 - Utilisation d'un composé tricyclique - Google Patents

Utilisation d'un composé tricyclique Download PDF

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WO2023061434A1
WO2023061434A1 PCT/CN2022/125057 CN2022125057W WO2023061434A1 WO 2023061434 A1 WO2023061434 A1 WO 2023061434A1 CN 2022125057 W CN2022125057 W CN 2022125057W WO 2023061434 A1 WO2023061434 A1 WO 2023061434A1
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mutation
egfr
compound
pharmaceutically acceptable
acceptable salt
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PCT/CN2022/125057
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Chinese (zh)
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郑善松
郑庆梅
王梅
邓伟
杨莹莹
张臣伟
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齐鲁制药有限公司
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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
    • 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
    • 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
    • C07D487/02—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 two hetero rings
    • C07D487/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00

Definitions

  • the present invention provides a use of a tricyclic compound or a pharmaceutically acceptable salt thereof in treating cancer mediated by EGFR, FGFR2, KIT, ALK and/or ROS1 mutations.
  • EGFR the epidermal growth factor receptor
  • the EGFR signaling pathway plays an important role in physiological processes such as cell growth, proliferation and differentiation.
  • EGFR mutation is also the most common type of mutation in NSCLC patients, especially in Asian populations, accounting for 40% to 50%. Therefore, EGFR has always been one of the hottest targets in the field of drug development.
  • the EGFR inhibitors on the market are divided into the first, second and third generations.
  • the first generation is reversible targeted drugs, targeting L858R mutation and Del19 mutation, such as gefitinib, erlotinib, and icotinib.
  • the second generation is irreversible targeted drugs, such as afatinib and dacomitinib.
  • the first and second generation targeted drugs are effective, most patients will develop drug resistance after 1-2 years of drug use.
  • 50% of drug resistance is related to T790M mutation.
  • the third-generation EGFR-targeted drug osimertinib can overcome the tumor resistance caused by the T790M mutation and bring better survival benefits to more lung cancer patients.
  • the third-generation targeted drugs will inevitably produce drug resistance, and the reasons for drug resistance include further C797S mutation, G724S mutation, L792H mutation, E709K mutation, and EGFR amplification.
  • drug resistance include further C797S mutation, G724S mutation, L792H mutation, E709K mutation, and EGFR amplification.
  • Fibroblast growth factor and its receptor drive important developmental signaling pathways affecting cell proliferation, migration and survival. Aberrant FGF signaling plays a role in many cancers.
  • the FGFR family consists of FGFR1, FGFR2, FGFR3 and FGFR4.
  • FGFRs are tyrosine kinases that are activated in a subset of tumors by gene amplification, mutation, or chromosomal translocations or rearrangements. Amplification of FGFR1 occurs in squamous cell lung cancer and estrogen receptor-positive breast cancer.
  • FGFR2 is also amplified in gastric and breast cancers.
  • FGFR mutations have been observed in endometrial cancer and FGFR3 mutations in bladder cancer.
  • the encoded product of c-KIT is a transmembrane receptor protein with tyrosine kinase activity and a molecular weight of 145 kilodaltons. It has five immunoglobulin G-like domains in the extracellular region, so it belongs to Member of the type III tyrosine kinase superfamily. Under physiological conditions, a small amount of c-KIT is expressed in mast cells, stem cells, sperm cells and intestinal Cajal cells.
  • stem cell factor a ligand of c-KIT
  • the c-KIT molecule undergoes homodimerization, resulting in the Y568 and Y570 tyrosine Autophosphorylation of acid residues, which in turn leads to phosphorylation of tyrosine residues in many substrate proteins in cells, and activation of multiple signal transduction pathways related to cell proliferation, including Jak-Stat3/Stat5 pathway, Src kinase, Ras-MEK-Erk1/2 and PI3K-AKT pathways, thereby enabling cell proliferation.
  • GIST gastrointestinal stromal tumor
  • Gene fusion is a chimeric gene formed by connecting the coding regions of two or more genes end to end and placed under the control of the same set of regulatory sequences (including promoters, enhancers, ribosome binding sequences, terminators, etc.).
  • a fusion of the echinoderm microtubule-binding protein 4 (EML4) gene and the anaplastic lymphoma kinase (ALK) gene has been found in NSCLC.
  • EML4-ALK fusion gene is a cancer-promoting gene mutation that occurs in non-small cell lung cancer, accounting for 4-5% of the incidence of non-small cell lung cancer.
  • EML4-ALK leads to abnormal expression of tyrosine kinases, causing malignant transformation of cells.
  • the incidence of SLC34A2-ROS1 fusion gene in NSCLC is about 1.0%-3.4%, and the incidence in EGFR/KRAS/ALK negative population can reach 5.7%.
  • the pathological type is mainly adenocarcinoma.
  • SLC34A2-ROS1 gene fusion occurs, the extracellular region is lost, and the transmembrane and intracellular tyrosine kinase regions are retained.
  • the fusion sites mainly occur in exons 32, 34, 35, and 36 of the ROS1 gene.
  • ROS1 receptor tyrosine kinase is involved in the activation of multiple downstream signal transduction pathways, including RAS-MAPK/ERK, PI3K/AKT/mTOR, JAK/STAT3, PLC/IP3 and SHP2/VAV3 pathways, thereby regulating the growth and proliferation of tumor cells , cell cycle, differentiation, metastasis and migration.
  • ROS1 gene and ALK gene are homology between ROS1 gene and ALK gene in the sequence of tyrosine kinase region, and the homology between them is as high as 77% in the ATP binding site of the kinase catalytic region.
  • ROS1 fusion gene provides a new method for individualized treatment of lung cancer It is of great significance for clinical practice to clarify the positive rate of ROS1 fusion gene in lung adenocarcinoma.
  • the Del19/T790M/C797S mutation has good kinase inhibitory activity and cell anti-proliferation activity, and the molecule has good anti-tumor activity and tolerance in mouse models. In order to improve the clinical value of this compound, it is of great significance to develop more uses of it.
  • the invention provides a use of a tricyclic compound or a pharmaceutically acceptable salt thereof in preparing a medicine for treating cancer mediated by EGFR, FGFR2, KIT, ALK and/or ROS1 mutations.
  • the present invention provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer mediated by EGFR mutation, and the type of EGFR mutation is Del19 mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer mediated by EGFR mutation, and the type of EGFR mutation is L858R mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer mediated by EGFR mutation, and the type of EGFR mutation is T790M mutation without C797S mutation.
  • the T790M mutation without the C797S mutation described in the above uses is selected from one or a combination of the following: L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation Mutation, E709K/T790M/L858R triple mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in preparing a medicine for treating cancer mediated by EGFR mutation, and the type of EGFR mutation is Del19/C797S double mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in preparing a medicine for treating cancer mediated by EGFR mutation, and the type of EGFR mutation is L858R/C797S double mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer mediated by EGFR amplification.
  • the above-mentioned EGFR amplification is the amplification of Del19/T790M/C797S triple mutation, L858R/T790M/D537H triple mutation and V674L/E746_A750del/T790M triple mutation EGFR amplification.
  • the above-mentioned EGFR amplification is EGFR amplification accompanied by Del19/T790M/C797S triple mutation, EGFR amplification accompanied by L858R/T790M/D537H triple mutation or accompanied by V674L/E746_A750del/T790M triple mutation EGFR amplification.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in preparing a medicine for treating cancer mediated by EGFR mutation, and the type of EGFR mutation is exon 20 insertion mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicine for treating cancer mediated by EGFR mutation or amplification, and the type of EGFR mutation is selected from one or any combination of the following: Del19 mutation, L858R mutation, L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation, Del19/C797S double mutation, L858R/C797S double mutation, 20 outside Exon mutation; EGFR amplification selected from Del19/T790M/C797S triple mutation, L858R/T790M/D537H triple mutation, V674L/E746_A750del/T790M triple mutation EGFR amplification.
  • the present invention also provides the use of a compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer mediated by EGFR mutation or amplification, wherein the type of EGFR mutation is selected from one or any combination of the following : Del19 mutation, L858R mutation, L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation, Del19/C797S double mutation, L858R/C797S double mutation, 20 Exon mutation; the EGFR amplification is selected from one or any combination of the following: EGFR amplification accompanied by Del19/T790M/C797S triple mutation, L858R/T790M/D537H triple mutation or V674L/E746_A750del/T790M triple mutation .
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer with high expression of FGFR2.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating cancer with C-KIT mutation, and the type of C-KIT mutation is V560G mutation and/or D816Y mutation and/or D816H mutation and/or V559 and V560 amino acid deletion mutation and/or D816V mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in preparing a medicine for treating cancer mediated by EML4-ALK fusion protein.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer mediated by EML4-ALK fusion protein L1196M mutation and/or F1174L mutation and/or L1196M/L1198F double mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in preparing a medicine for treating cancer mediated by SLC34A2-ROS1 fusion protein.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the preparation of a drug for treating cancer mediated by the D2033N mutation of the SLC34A2-ROS1 fusion protein.
  • the pharmaceutically acceptable salt of the compound (A) in any of the above uses is hydrochloride.
  • the pharmaceutically acceptable salt of the compound (A) in any of the above uses is monohydrochloride.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EGFR mutation, and the type of EGFR mutation is Del19 mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EGFR mutation, and the type of EGFR mutation is L858R mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EGFR mutation, and the type of EGFR mutation is T790M mutation without C797S mutation.
  • the T790M mutation without the C797S mutation described in the above uses is selected from one or a combination of the following: L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation Mutation, E709K/T790M/L858R triple mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EGFR mutation, and the type of EGFR mutation is Del19/C797S double mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EGFR mutation, and the type of EGFR mutation is L858R/C797S double mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EGFR amplification.
  • the EGFR amplification described in the above uses is the amplification of Del19/T790M/C797S triple mutation, L858R/T790M/D537H triple mutation and V674L/E746_A750del/T790M triple mutation EGFR amplification.
  • the EGFR amplification in the above use is EGFR amplification accompanied by Del19/T790M/C797S triple mutation, L858R/T790M/D537H triple mutation or V674L/E746_A750del/T790M triple mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EGFR mutation, and the type of EGFR mutation is exon 20 insertion mutation.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EGFR mutation or amplification, and the type of EGFR mutation is selected from one or any combination of the following: Del19 mutation, L858R mutation, L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation, Del19/C797S double mutation, L858R/C797S double mutation, exon 20 mutation ; EGFR amplification is selected from the amplification of Del19/T790M/C797S triple mutation, L858R/T790M/D537H triple mutation, V674L/E746_A750del/T790M triple mutation EGFR.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EGFR mutation or amplification, wherein the type of EGFR mutation is selected from one or any combination of the following: Del19 mutation , L858R mutation, L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation, Del19/C797S double mutation, L858R/C797S double mutation, exon 20 Mutation; the EGFR amplification is selected from one or any combination of the following: EGFR amplification accompanied by Del19/T790M/C797S triple mutation, L858R/T790M/D537H triple mutation or V674L/E746_A750del/T790M triple mutation.
  • the present invention also provides a method for treating cancer mediated by EGFR mutation or amplification, which comprises administering a compound of formula (A) or a pharmaceutically acceptable salt thereof to a patient, wherein the type of EGFR mutation is selected from one or any of the following Combination: Del19 mutation, L858R mutation, L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation, Del19/C797S double mutation, L858R/C797S double mutation, Exon 20 mutation; the EGFR amplification is selected from one or any combination of the following: EGFR amplification accompanied by Del19/T790M/C797S triple mutation, L858R/T790M/D537H triple mutation or V674L/E746_A750del/T790M triple mutation increase.
  • the present invention also provides the compound of formula (A) for preparing the above-mentioned Del19 mutation, L858R mutation, L858R/T790M double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation, Del19 Application in EGFR mutation regulators of /C797S double mutation, L858R/C797S double mutation and exon 20 mutation.
  • the above-mentioned EGFR mutation regulator is used as an inhibitor of the above-mentioned mutation of EGFR.
  • the present invention also provides the use of the compound of formula (A) in preparing regulators for EGFR amplification of the above-mentioned Del19/T790M/C797S triple mutation, the above-mentioned L858R/T790M/D537H triple mutation or the above-mentioned V674L/E746_A750del/T790M triple mutation.
  • the cancer in any of the above uses is lung cancer.
  • the cancer in any of the above uses is non-small cell lung cancer.
  • the cancer in any of the above uses is treatment-naive non-small cell lung cancer.
  • the cancer in any of the above uses is non-small cell lung cancer that develops drug resistance after receiving EGFR inhibitor therapy in the past.
  • the aforementioned EGFR inhibitors include first-generation EGFR inhibitors, second-generation or third-generation EGFR inhibitors.
  • the above-mentioned first-generation EGFR inhibitors include gefitinib, icotinib, and erlotinib.
  • the above-mentioned second-generation EGFR inhibitors include afatinib and dacomitinib.
  • the aforementioned third-generation EGFR inhibitor includes osimertinib.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancers with high FGFR2 expression.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer with C-KIT mutation, and the type of C-KIT mutation is V560G mutation and/or D816Y mutation and/or D816H mutation and /or 559 and 560 amino acid deletion mutations and/or D816V mutations.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by EML-ALK fusion protein.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancers mediated by L1196M mutation and/or F1174L mutation and/or L1196M/L1198F double mutation of EML4-ALK fusion protein.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by SLC34A2-ROS1 fusion protein.
  • the present invention also provides the use of the compound of formula (A) or a pharmaceutically acceptable salt thereof in the treatment of cancer mediated by the D2033N mutation of the SLC34A2-ROS1 fusion protein.
  • the present invention also provides a method for treating the above-mentioned cancer with high FGFR2 expression, the above-mentioned cancer with C-KIT mutation, the above-mentioned cancer mediated by EML-ALK fusion protein, and the above-mentioned cancer mediated by SLC34A2-ROS1 fusion protein, which comprises administering to patients A compound of formula (A) or a pharmaceutically acceptable salt thereof.
  • the present invention also provides the use of the compound of formula (A) in preparing regulators of the above-mentioned FGFR2, the above-mentioned C-KIT mutation, the above-mentioned EML-ALK fusion protein, and the above-mentioned SLC34A2-ROS1.
  • the aforementioned modulators are inhibitors.
  • the pharmaceutically acceptable salt of the compound of formula (A) in any of the above uses is hydrochloride.
  • the pharmaceutically acceptable salt of the compound of formula (A) in any of the above uses is monohydrochloride.
  • the compound of formula (A) of the present invention not only has good activity against L858R/T790M/C797S triple mutation and Del19/T790M/C797S triple mutation, but also has good activity against L858R or Del19 single mutation, exon 20 insertion mutation, L858R/T790M or L858R/C797S or Del19/C797S double mutation, Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation and Del19/T790M/C797S triple mutation accompanied by EGFR amplification, L858R/ The T790M/D537H triple mutation and the V674L/E746_A750del/T790M triple mutation also have good in vitro kinase or cell anti-proliferation activities, and the compound has shown a strong anti-proliferative activity in the mouse models of
  • the compound of formula (A) of the present invention is effective against high expression of FGFR2, C-KIT V560G mutation, C-KIT D816Y mutation, C-KIT D816H mutation, C-KIT V559 and V560 amino acid deletion mutation, C-KIT D816V mutation , EML4-ALK fusion protein mutation, EML4-ALK fusion protein L1196M or F1174L mutation or L1196M/L1198F double mutation, SLC34A2-ROS1 fusion protein mutation, SLC34A2-ROS1 fusion protein D2033N mutation cell lines all have good anti-proliferation activity.
  • pharmaceutically acceptable salt refers to derivatives prepared from the compounds of the present invention with relatively non-toxic acids or bases. These salts can be prepared during compound synthesis, isolation, purification, or alone by reacting the free form of the purified compound with an appropriate acid or base.
  • the compound contains relatively acidic functional groups, it can react with alkali metal, alkaline earth metal hydroxide or organic amine to obtain base addition salts, including cations based on alkali metals and alkaline earth metals and non-toxic ammonium, quaternary ammonium and amine cations, Salts of amino acids and the like are also contemplated.
  • the compound contains a relatively basic functional group, it reacts with an organic acid or an inorganic acid to form an acid addition salt.
  • the EGFR mutation-mediated tumor or cancer refers to the cancer driver mutation (driver mutation) of EGFR that can be detected in these tumors or cancer patients, including but not limited to Del19 mutation, L858R mutation, T790M mutation , 20 exon insertion mutation (Exon 20ins), C797S and other mutations.
  • the Del19 mutation refers to the deletion of some bases in exon 19, resulting in a non-frameshift partial amino acid deletion
  • L858R refers to the change of amino acid 858 from L to R due to a missense mutation of the base
  • T790M refers to the change of amino acid 790 from T to M due to the missense mutation of the base in the gene
  • the exon 20 insertion (Exon 20ins) mutation refers to the in-frame duplication/ Insertion mutation
  • C797S mutation refers to the mutation of cysteine residue at position 797 to serine.
  • the EGFR mutations include not only the above-mentioned single mutants of EGFR, but also compound mutants of T790M, Del19, L858R, Exon 20ins, C797S and other sites freely combined, including but not limited to the L858R/T790M double mutation , Del19/G724S/T790M triple mutation, L858R/T790M/L792H triple mutation, E709K/T790M/L858R triple mutation, Del19/C797S double mutation, L858R/C797S double mutation, etc.
  • the EGFR amplification refers to the increase of the copy number of EGFR gene or the high-level expression of protein. It can occur on mutant cells as well as on EGFR receptor cells without the mutation (wild type).
  • Figure 1 is the animal tumor growth curve in the in vivo pharmacodynamic study of EGFR Del19/C797S mutation.
  • Fig. 2 is a graph of animal body weight in the in vivo pharmacodynamic study of EGFR Del19/C797S mutation.
  • Figure 3 is the animal tumor growth curve in the in vivo pharmacodynamic study of EGFR L858R mutation.
  • Fig. 4 is the animal body weight curve in the in vivo pharmacodynamic study of EGFR L858R mutation.
  • Figure 5 is a graph of animal tumor growth curves in the in vivo pharmacodynamic study of EGFR Del19 mutation.
  • Figure 6 is a graph of animal body weights in the in vivo pharmacodynamic study of EGFR Del19 mutation.
  • Figure 7 is the animal tumor growth curve in the PDX model study of Osimertinib-resistant human lung cancer.
  • Fig. 8 is a graph of animal body weight in the PDX model study of Osimertinib-resistant human lung cancer.
  • Figure 9 is a graph of animal tumor growth curves in the in vivo pharmacodynamic study of EGFR L858R/C797S mutation.
  • Fig. 10 is a curve diagram of animal body weight in the in vivo pharmacodynamic study of EGFR L858R/C797S mutation.
  • Figure 11 is the animal tumor growth curve in the in vivo pharmacodynamic study of EGFR L858R/T790M mutation.
  • Figure 12 is a graph of animal body weights in the in vivo pharmacodynamic study of the EGFR L858R/T790M mutation.
  • 6-Aminoquinoxaline (10 g, 68.89 mmol) was dissolved in concentrated sulfuric acid (20 mL). At 0° C., potassium nitrate (9.054 g, 89.55 mmol) was added in portions to the reaction solution and stirring was continued at this temperature for 30 minutes. After LCMS monitoring showed that the starting material disappeared, the reaction solution was poured into ice water (100 g). Its pH was adjusted to 8 with 1M aqueous sodium hydroxide solution. The mixture was extracted with ethyl acetate (200 mL x 2 times), and the organic phases were combined.
  • Embodiment 2 biological test evaluation:
  • TR-FRET fluorescence resonance energy transfer
  • EGFR, EGFR Del19, EGFR L858R, EGFR L858R/T790M, EGFR L858R/C797S, EGFR ex19del/C797S recombinases were purchased from Signalchem.
  • HTRF KinEASE-TK kit was purchased from Cisbio.
  • DTT, MnCl2, and MgCl2 were purchased from Sigma.
  • ATP was purchased from Promega.
  • a microplate reader detects the 615nm and 665nm fluorescence signal values of each well.
  • the CellTiter-Glo method was used to test the inhibitory effect of compound A on the proliferation of A431 cells, and the concentration IC 50 at which the compound inhibited half of the cell growth was obtained.
  • A431 cells were purchased from ATCC.
  • DMEM medium fetal bovine serum (FBS), and Penicillin-Streptomycin were purchased from GIBCO.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • A431 cells were seeded in a 384-well culture plate at a density of 800 cells per well, 30 ⁇ l per well, and placed in a cell culture incubator for 24 hours (37° C., 5% CO 2 ).
  • Envision microplate reader detects chemiluminescent signal.
  • the CellTiter-Glo method was used to test the inhibitory effect of compound A on the proliferation of NCI-H3255 (EGFR L858R mutation) cells, and the concentration IC 50 of compound A inhibiting half of the cell growth was obtained.
  • NCI-H3255 cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • FBS fetal bovine serum
  • Penicillin-Streptomycin purchased from GIBCO.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • Envision microplate reader detects chemiluminescent signal.
  • the CellTiter-Glo method was used to test the inhibitory effect of compound A on PC-9 (EGFR Del19 mutation) cell proliferation, and the concentration IC 50 of the compound inhibiting half of the cell growth was obtained.
  • PC-9 cells were purchased from European Collection of Authenticated Cell Cultures.
  • FBS fetal bovine serum
  • Penicillin-Streptomycin purchased from GIBCO.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • Envision microplate reader detects chemiluminescent signal.
  • the CellTiter-Glo method was used to test the inhibitory effect of compound A on the proliferation of NCI-H1975 (EGFR L858R/T790M mutation) cells, and the concentration IC 50 of compound A inhibiting half of the cell growth was obtained.
  • NCI-H1975 cells were from ATCC.
  • FBS fetal bovine serum
  • Penicillin-Streptomycin purchased from GIBCO.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • Envision microplate reader detects chemiluminescent signal.
  • the CellTiter-Glo method was used to test the inhibitory effect of compound A on the proliferation of HCC827 (EGFR Del mutation) cells, and the concentration IC 50 of compound A inhibiting half of the cell growth was obtained.
  • HCC827 cells were purchased from ATCC.
  • FBS fetal bovine serum
  • Penicillin-Streptomycin purchased from GIBCO.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • Envision microplate reader detects chemiluminescent signal.
  • the CellTiter-Glo method was used to test the inhibitory effect of compound A on the proliferation of Ba/F3 EGFR-Del19/G724S/T790M and Ba/F3 EGFR-E709K/T790M/L858R and Ba/F3 EGFR-L858R/T790M/L792H cells. And the concentration IC 50 of compound A inhibiting half of the cell growth was obtained.
  • Ba/F3 EGFR-Del19/G724S/T790M cells were from Kangyuan Biotech (Beijing) Co., Ltd.
  • Ba/F3 EGFR-E709K/T790M/L858R cells were from Kangyuan Biotech (Beijing) Co., Ltd.
  • Ba/F3 EGFR-L858R/T790M/L792H cells were from Kangyuan Biotech (Beijing) Co., Ltd.
  • FBS fetal bovine serum
  • CellTiter-Glo reagent was purchased from Promega Company.
  • the CellTiter-Glo method was used to test the inhibitory effect of compound A on the proliferation of Ba/F3 (EGFR-Del19/C797S) and Ba/F3 (EGFR-L858R/C797S) cells, and the concentration of compound A that inhibited half of the cell growth was obtained IC50 .
  • Ba/F3 EGFR-Del19/C797S cells were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3 EGFR-L858R/C797S cells were from Kangyuan Biotech (Beijing) Co., Ltd.
  • FBS fetal bovine serum
  • CellTiter-Glo reagent was purchased from Promega Company.
  • Envision microplate reader detects chemiluminescent signal.
  • the CellTiter-Glo method was used to test the inhibitory effect of compound A on the proliferation of NCI-H716 (highly expressed FGFR2) cells, and the concentration IC 50 of the compound inhibiting half of the cell growth was obtained.
  • NCI-H716 cells were purchased from ATCC.
  • FBS fetal bovine serum
  • Penicillin-Streptomycin purchased from GIBCO.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • Envision microplate reader detects chemiluminescent signal.
  • the method of CellTiter-Glo was used to test the effect of compound A on Ba/F3 C-KIT-V560G, Ba/F3 C-KIT-D816Y, Ba/F3 C-KIT-D816H, Ba/F3 C-KIT-Del(V559- V560), Ba/F3 C-KIT-D816V, NCI-H3122(EML4-ALK), Ba/F3-EML4-ALK-L1196M, Ba/F3 EML4-ALK-F1174L, Ba/F3-EML4-ALK-L1196M/ Inhibitory effect of L1198F, Ba/F3 SLC34A2/ROS1, Ba/F3 SLC34A2-ROS1-D2033N cell proliferation, and the concentration IC 50 of compound A inhibiting half of cell growth was obtained.
  • Ba/F3 C-KIT-V560G cells were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3 C-KIT-D816Y cells were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3 C-KIT-D816H cells were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3 C-KIT-Del (V559V560) cells were from Kangyuan Biotech (Beijing) Co., Ltd.
  • Ba/F3 C-KIT-D816V cells were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • NCI-H3122 (EML4-ALK) cells were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3-EML4-ALK-L1196M cells were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3 EML4-ALK-F1174L cells were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3-EML4-ALK-L1196M/L1198F cells were from Kangyuan Biotech (Beijing) Co., Ltd.
  • Ba/F3 SLC34A2/ROS1 cells were from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3 SLC34A2-ROS1-D2033N cells were from Kangyuan Biotech (Beijing) Co., Ltd.
  • FBS fetal bovine serum
  • CellTiter-Glo reagent was purchased from Promega Company.
  • compound A of the present invention is effective against NCI-H3255 L858R EGFR mutation, PC9 Del19 EGFR mutation, HCC827 Del19 EGFR mutation, NCI-H1975 L858R/T790M EGFR mutation, Ba/F3 (Del19/G724S/ T790M) EGFR triple mutant cell line, Ba/F3 (L858R/T790M/L792H) EGFR triple mutant cell line, Ba/F3 (E709K/T790M/L858R) EGFR triple mutant cell line, Ba/F3 (Del19/C797S) EGFR double mutant cell line Mutant cell lines and Ba/F3 (L858R/C797S) EGFR double mutant cell lines, NCI-H716 (FGFR2), Ba/F3 C-KIT-V560G, Ba/F3 C-KIT-D816Y, Ba/F3 C-KIT-
  • the CellTiter-Glo method was used to test the inhibitory effect of compound A on the proliferation of osimertinib-resistant PDO (Patient Derived Tumor Organoids), and the concentration IC 50 of compound A inhibiting half of the cell growth was obtained.
  • CellTiter-Glo reagent was purchased from Promega Company.
  • NU/NU mice female, SPF grade, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • Ba/F3 EGFR Del19/C797S cells were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3 EGFR Del19/C797S cells were cultured in RPMI1640 medium containing 10% fetal bovine serum at 37°C in a 5% carbon dioxide incubator, and cells in the exponential growth phase were collected for inoculation.
  • mice with moderate tumor volume were selected and randomly divided into 4 groups according to the tumor volume: G1: vehicle control group, G2: compound A (15mg/kg), G3 : Compound A (30 mg/kg) and G4: Compound A (65 mg/kg), 8 rats/group.
  • the drug was administered, and the volume of the drug was 10 mL/kg, and the drug was administered orally (po); the drug was weighed once a day, and the drug was administered continuously for 14 days; the tumor diameter was measured twice a week.
  • TGI tumor growth inhibition rate
  • mice During the experiment, the living conditions of the mice were closely observed, including appearance signs, general behavioral activities, mental state, food intake, respiratory state, feces and urine properties, injection site and other toxic manifestations.
  • mice were euthanized, and the animal corpses were stored in a freezer and handed over to a qualified medical waste disposal unit for disposal.
  • NOD SCID mice female, SPF grade, were purchased from Beijing Huafukang Biotechnology Co., Ltd.
  • NCI-H3255 (L858R) cells were purchased from Nanjing Kebai Biotechnology Co., Ltd.
  • NCI-H3255 tumor cells were cultured in RPMI-1640 medium containing inactivated 10% fetal bovine serum in an incubator at 37°C and 5% CO 2 . Tumor cells in logarithmic growth phase were used for inoculation of tumors in vivo.
  • NCI-H3255 tumor cells resuspended in serum-free RPMI-1640 culture medium at a concentration of 1 ⁇ 10 7 /100 ⁇ L were inoculated subcutaneously on the right flank of experimental animals, and the day of inoculation was set as day 0.
  • mice with moderate tumor volume were selected and randomly divided into 3 groups according to the tumor volume: G1: vehicle control group, G2: compound A (15mg/kg) and G3: Compound A (60mg/kg), 8 rats/group.
  • the drug was administered, and the volume of the drug was 10 mL/kg, and the drug was administered orally (po); the drug was administered once a day by weight, and the drug was administered continuously for 22 days; the tumor diameter was measured twice a week.
  • TGI tumor growth inhibition rate
  • mice During the experiment, the living conditions of the mice were closely observed, including appearance signs, general behavioral activities, mental state, food intake, respiratory state, feces and urine properties, injection site and other toxic manifestations.
  • mice were euthanized, and the animal corpses were stored in a freezer and handed over to a qualified medical waste disposal unit for disposal.
  • CB-17 SCID mice female, SPF grade, were purchased from Beijing Huafukang Biotechnology Co., Ltd.
  • PC-9 (Del19) cells were purchased from European Collection of Authenticated Cell Cultures.
  • PC-9 (Del19) tumor cells resuspended in serum-free RPMI-1640 culture medium at a concentration of 5 ⁇ 10 6 /100 uL were inoculated subcutaneously on the right flank of the experimental animal, and the day of inoculation was set as day 0.
  • mice with moderate tumor volume were selected and randomly divided into 4 groups according to the tumor volume: G1: vehicle control group, G2: Gefitinib (gefitinib, 100 mg/kg ), G3: Compound A (15 mg/kg) and G4: Compound A (45/60 mg/kg), 5 rats/group.
  • Animals were grouped and started to be dosed with a volume of 10 mL/kg, administered orally (po); the dose was weighed once a day for 21 consecutive days; the tumor diameter was measured twice a week.
  • TGI tumor growth inhibition rate
  • mice During the experiment, the living conditions of the mice were closely observed, including appearance signs, general behavioral activities, mental state, food intake, respiratory state, feces and urine properties, injection site and other toxic manifestations.
  • mice were euthanized, and the animal corpses were stored in a freezer and handed over to a qualified medical waste disposal unit for disposal.
  • NU/NU mice female, SPF grade, were purchased from Zhejiang Weitong Lihua Experimental Animal Technology Co., Ltd.
  • LD1-0025-200717 human lung cancer tissue, 54-year-old male patient, clinical diagnosis: left upper lung primary bronchial lung cancer, adenocarcinoma; EGFR triple mutation, 19del&T790M&C797S; Osimertinib resistance; PDX pathological diagnosis: poorly-moderately differentiated adenocarcinoma cancer. Passed to FP2+5 generation for this efficacy test.
  • the LD1-0025-200717 tumor tissue was evenly cut into a tumor mass of about 3mm ⁇ 3mm ⁇ 3mm (about 50-90mg) and inoculated subcutaneously on the right side of NU/NU mice. Post-inoculation mice were then observed and tumor growth monitored.
  • Animals were grouped into groups and administered on the same day, with a volume of 10 mL/kg, administered orally (po); administered once a day by weight, for 21 consecutive days; tumor diameter was measured twice a week.
  • TGI tumor growth inhibition rate
  • mice During the experiment, the living conditions of the mice were closely observed, including appearance signs, general behavioral activities, mental state, food intake, respiratory state, feces and urine properties, injection site and other toxic manifestations.
  • mice were euthanized, and the animal corpses were stored in a freezer and handed over to a qualified medical waste disposal unit for disposal.
  • NU/NU mice female, SPF grade, were purchased from Beijing Weitong Lihua Experimental Animal Technology Co., Ltd.
  • Ba/F3 EGFR L858R/C797S cells were purchased from Kangyuan Bochuang Biotechnology (Beijing) Co., Ltd.
  • Ba/F3 EGFR L858R/C797S cells were inoculated subcutaneously in the right axilla of NU/NU mice at 2 ⁇ 10 6 cells/0.1 mL, and the day of inoculation was set as day 0.
  • G1 Vehicle
  • G2 Osimertinib (10mg/kg)
  • G3 Compound A (15mg/kg)
  • G4 Compound A (30mg /kg)
  • G5 Compound A (65mg/kg), 7 rats/group.
  • the drug was administered, and the volume of the drug was 10 mL/kg, and the drug was administered orally (po); the drug was weighed once a day, and the drug was administered continuously for 14 days; the tumor diameter was measured twice a week.
  • TGI tumor growth inhibition rate
  • mice During the experiment, the living conditions of the mice were closely observed, including appearance signs, general behavioral activities, mental state, food intake, respiratory state, feces and urine properties, injection site and other toxic manifestations.
  • mice were euthanized, and the animal corpses were stored in a freezer and handed over to a qualified medical waste disposal unit for disposal.
  • H1975 cells were purchased from ATCC.
  • PBS containing 5 ⁇ 106 H1975 cells (final volume: 100uL) was inoculated subcutaneously in the axilla of the right forelimb of each mouse.
  • group administration began.
  • the drug was administered, and the volume of the drug was 10 mL/kg, and the drug was administered orally (po); the drug was weighed once a day, and the drug was administered continuously for 21 days; the diameter of the tumor was measured twice a week.
  • TGI tumor growth inhibition rate
  • mice Closely observe the living conditions of the mice during the experiment, including appearance signs, general behavioral activities, mental state, feeding situation, respiratory state, feces and urine properties, injection site and other toxic manifestations.
  • mice were euthanized, and the animal corpses were stored in a freezer and handed over to a qualified medical waste disposal unit for disposal.

Abstract

La présente invention concerne l'utilisation d'un composé représenté par la formule (A) ou d'un sel pharmaceutiquement acceptable de celui-ci dans la préparation de médicaments pour le traitement du cancer médié par les mutations EGFR, FGFR2, KIT, ALK et/ou ROS1. Le composé présente une activité inhibitrice évidente contre le cancer médié par ces types de mutations.
PCT/CN2022/125057 2021-10-14 2022-10-13 Utilisation d'un composé tricyclique WO2023061434A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046405A1 (fr) * 2022-09-01 2024-03-07 齐鲁制药有限公司 Utilisation d'inhibiteur de kinase egfr

Citations (4)

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Publication number Priority date Publication date Assignee Title
CN101535276A (zh) * 2006-10-23 2009-09-16 赛福伦公司 作为ALK和c-MET抑制剂的2，4-二氨基嘧啶稠合双环衍生物
CN101616895A (zh) * 2006-12-08 2009-12-30 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
WO2020216371A1 (fr) * 2019-04-26 2020-10-29 江苏先声药业有限公司 Inhibiteur d'egfr et son utilisation
WO2021208918A1 (fr) * 2020-04-14 2021-10-21 齐鲁制药有限公司 Composés tricycliques servant d'inhibiteurs d'egfr

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101535276A (zh) * 2006-10-23 2009-09-16 赛福伦公司 作为ALK和c-MET抑制剂的2，4-二氨基嘧啶稠合双环衍生物
CN101616895A (zh) * 2006-12-08 2009-12-30 Irm责任有限公司 作为蛋白激酶抑制剂的化合物和组合物
WO2020216371A1 (fr) * 2019-04-26 2020-10-29 江苏先声药业有限公司 Inhibiteur d'egfr et son utilisation
WO2021208918A1 (fr) * 2020-04-14 2021-10-21 齐鲁制药有限公司 Composés tricycliques servant d'inhibiteurs d'egfr

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024046405A1 (fr) * 2022-09-01 2024-03-07 齐鲁制药有限公司 Utilisation d'inhibiteur de kinase egfr

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