WO2022042755A1 - 抑制突变型egfr的化合物及其应用 - Google Patents

抑制突变型egfr的化合物及其应用 Download PDF

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WO2022042755A1
WO2022042755A1 PCT/CN2021/116076 CN2021116076W WO2022042755A1 WO 2022042755 A1 WO2022042755 A1 WO 2022042755A1 CN 2021116076 W CN2021116076 W CN 2021116076W WO 2022042755 A1 WO2022042755 A1 WO 2022042755A1
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cancer
mutations
egfr
mutant egfr
mutation
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PCT/CN2021/116076
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French (fr)
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李洪林
赵振江
刁妍妍
陈卓
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华东理工大学
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Priority to EP21860587.1A priority Critical patent/EP4205746A4/en
Priority to JP2023514146A priority patent/JP2023540491A/ja
Priority to US18/043,419 priority patent/US20230321103A1/en
Priority to KR1020237010660A priority patent/KR20240046817A/ko
Publication of WO2022042755A1 publication Critical patent/WO2022042755A1/zh

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    • 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
    • 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

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  • the present invention relates to the field of medicinal chemistry; in particular, the present invention relates to pteridone derivatives as inhibitors of mutant epidermal growth factor receptor tyrosine kinase (epidermal growth factor receptor tyrosine kinase, EGFR), especially non-classical mutant EGFR Applications.
  • mutant epidermal growth factor receptor tyrosine kinase epidermal growth factor receptor tyrosine kinase, EGFR
  • EGFR epidermal growth factor receptor tyrosine kinase
  • EGFR exon 20 insertion mutations EGFR 20ins
  • these non-canonical mutations mainly include insertion mutations and point mutations in exons 18-21, and point mutations and insertion mutations in ERBB2.
  • the object of the present invention is to provide an inhibitor of non-classical mutant EGFR and a pharmaceutical composition comprising the above-mentioned inhibitor.
  • the present invention provides the use of a compound shown in formula I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for inhibiting mutant EGFR or a medicament for treating or preventing mutant EGFR-mediated diseases:
  • the mutant EGFR comprises at least one of the following mutations: point and insertion mutations in exons 18-21 of EGFR, point and insertion mutations in ERBB2.
  • the mutant EGFR comprises:
  • Exon 20 insertion mutations and point mutations include: A763-Y764insFQEA, A763-Y764insFHEA, V769-D770insASV, V769-D770insDNP, D770-N771insNPG, D770-N771insNPH, D770-N771insSVD, D770-N771insASVDN, SVDNPinsD770- ,, P772-H773insPNP, P772-H773insPR, H773-V774insH, A763-Y764insFQEA, H773-V774insPH, H773-V774insNPH, N771-P772insH, H771-P772insN, H773-V774insAH, D770delinsGY, V774-C775insHV like, and number 20 N771-H773dup
  • ERBB2 point mutations V777L, D769Y, R896C, P1170A and insertion mutations V777-G778insCG, P780-Y781insGSP and so on.
  • the mutant EGFR contains at least one of the following mutations: G719X (X represents A, S, C, D), D761Y, A763-Y764insFQEA, A763-Y764insFHEA, V769-D770insASV, D770-N771insSVD , D770-N771insASVDN, D770-N771insG, N771-P772insSVDNP, N771-H773dupNPH, P772-H773insPNP, P772-H773insPR, H773-V774insH, A763-Y764insFQEA, H773-V774insPH, H773-V774insNPH, N771-P772insH, H771-P772insN, H773 -V774insAH, D770delinsGY, V774-C7
  • the mutant EGFR contains at least one of the following mutations: A763_Y764insFHEA, A763-Y764insFQEA, d747-749/A750P D761Y, D770-N771insNPG, D770-N771insNPG/T790M, D770GY, G719C, G719D, G719S, L861Q and ERBB's V777-G778insCG, V777L, D769Y, etc.
  • the disease is cancer.
  • the cancer is non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, glioblastoma, head and neck squamous cell carcinoma cancer, cervical cancer, esophageal cancer, liver cancer, kidney cancer, colon cancer, skin cancer, leukemia, lymphoma, stomach cancer or multiple myeloid cancer.
  • the present invention provides a compound of formula I or a pharmaceutically acceptable salt thereof for inhibiting mutant EGFR or treating or preventing mutant EGFR-mediated diseases,
  • the mutant EGFR comprises at least one of the following mutations: EGFR exons 18-21 point mutation and insertion mutation, ERBB2 point mutation and insertion mutation.
  • the mutant EGFR contains:
  • Exon 20 insertion mutations and point mutations include: A763-Y764insFQEA, A763-Y764insFHEA, V769-D770insASV, V769-D770insDNP, D770-N771insNPG, D770-N771insNPH, D770-N771insSVD, D770-N771insASVDN, SVDNPinsD770- ,, P772-H773insPNP, P772-H773insPR, H773-V774insH, A763-Y764insFQEA, H773-V774insPH, H773-V774insNPH, N771-P772insH, H771-P772insN, H773-V774insAH, D770delinsGY, V774-C775insHV like, and number 20 N771-H773dup
  • ERBB2 point mutations V777L, D769Y, R896C, P1170A and insertion mutations V777-G778insCG, P780-Y781insGSP and so on.
  • the mutant EGFR contains at least one of the following mutations: G719X (X represents A, S, C, D), D761Y, A763-Y764insFQEA, A763-Y764insFHEA, V769-D770insASV, D770-N771insSVD , D770-N771insASVDN, D770-N771insG, N771-P772insSVDNP, N771-H773dupNPH, P772-H773insPNP, P772-H773insPR, H773-V774insH, A763-Y764insFQEA, H773-V774insPH, H773-V774insNPH, N771-P772insH, H771-P772insN, H773 -V774insAH, D770delinsGY, V774-C7
  • the mutant EGFR contains at least one of the following mutations: A763_Y764insFHEA, A763-Y764insFQEA, d747-749/A750P D761Y, D770-N771insNPG, D770-N771insNPG/T790M, D770GY, G719C, G719D, G719S, L861Q and ERBB's V777-G778insCG, V777L, D769Y, etc.
  • the disease is cancer.
  • the cancer is non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, glioblastoma, head and neck squamous cell carcinoma cancer, cervical cancer, esophageal cancer, liver cancer, kidney cancer, colon cancer, skin cancer, leukemia, lymphoma, stomach cancer or multiple myeloid cancer.
  • the present invention provides a method for inhibiting mutant EGFR or treating or preventing mutant EGFR-mediated diseases, the method comprising administering a compound of formula I or a pharmaceutically acceptable salt thereof in need thereof the steps of the object,
  • the mutant EGFR comprises at least one of the following mutations: EGFR exons 18-21 point mutation and insertion mutation, ERBB2 point mutation and insertion mutation.
  • the mutant EGFR contains:
  • Exon 20 insertion mutations and point mutations include: A763-Y764insFQEA, A763-Y764insFHEA, V769-D770insASV, V769-D770insDNP, D770-N771insNPG, D770-N771insNPH, D770-N771insSVD, D770-N771insASVDN, SVDNPinsD770- ,, P772-H773insPNP, P772-H773insPR, H773-V774insH, A763-Y764insFQEA, H773-V774insPH, H773-V774insNPH, N771-P772insH, H771-P772insN, H773-V774insAH, D770delinsGY, V774-C775insHV like, and number 20 N771-H773dup
  • ERBB2 point mutations V777L, D769Y, R896C, P1170A and insertion mutations V777-G778insCG, P780-Y781insGSP and so on.
  • the mutant EGFR contains at least one of the following mutations: G719X (X represents A, S, C, D), D761Y, A763-Y764insFQEA, A763-Y764insFHEA, V769-D770insASV, D770-N771insSVD , D770-N771insASVDN, D770-N771insG, N771-P772insSVDNP, N771-H773dupNPH, P772-H773insPNP, P772-H773insPR, H773-V774insH, A763-Y764insFQEA, H773-V774insPH, H773-V774insNPH, N771-P772insH, H771-P772insN, H773 -V774insAH, D770delinsGY, V774-C7
  • the mutant EGFR contains at least one of the following mutations: A763_Y764insFHEA, A763-Y764insFQEA, d747-749/A750P D761Y, D770-N771insNPG, D770-N771insNPG/T790M, D770GY, G719C, G719D, G719S, L861Q and ERBB's V777-G778insCG, V777L, D769Y, etc.
  • the disease is cancer.
  • the cancer is non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, glioblastoma, head and neck squamous cell carcinoma cancer, cervical cancer, esophageal cancer, liver cancer, kidney cancer, colon cancer, skin cancer, leukemia, lymphoma, stomach cancer or multiple myeloid cancer.
  • Figures 1a-f show the GI50 data of compound I on the proliferation inhibition assay of stable cell lines containing different EGFR mutations, wherein compound 1 is shown as -R201 and compound TAK788 is shown as R-203.
  • EGFR inhibitors bring good news to patients with non-small cell lung cancer with classic EGFR mutation and T790M resistance mutation. However, not all patients with EGFR mutations benefit from marketed EGFR inhibitors. Studies have found that NSCLC with EGFR exon 20 insertion mutations (EGFR 20ins) has poor or ineffective targeted therapy for most EGFR inhibitors. These mutations are often classified as non-classical mutations. In the present invention, the non-classical mutations mainly include insertion mutations and point mutations in exons 18-21, and point mutations and insertion mutations in ERBB2.
  • the non-canonical mutations in exon 18 mainly showed G719X, E709X, K716A, K728A point mutations, and deletion mutations at codon 709.
  • G719X mutation is G719X in EGFR (X represents A alanine, S serine, C cysteine, etc.) mutation refers to point mutation, and G719X mutation accounts for about 3.10% of total EGFR mutations [Cancer Sci.2016,107(9) ,: 1179-1186].
  • the G719S mutation is less carcinogenic than the sensitive mutation.
  • Gefitinib can inhibit the autophosphorylation of G719S in an increased dose.
  • Gefitinib was required to inhibit the G719S mutation at higher concentrations compared to the sensitive mutation L858R.
  • the E709X point mutation is another non-canonical mutation in exon 18, and the E709X mutation accounts for about 0.30% of the total EGFR mutations.
  • patients with the E709X point mutation were highly sensitive to afatinib compared with first- or third-generation TKIs.
  • DelE709-T710insD was the most common deletion mutation at codon 709, accounting for approximately 0.30% of total EGFR mutations.
  • Non-canonical mutations in exon 19 manifested as insertion and point mutations.
  • Exon 19 insertion mutations accounted for about 0.60% of EGFR mutations, including: I744-K745insKIPVAI, K745-E746insIPVAIK, K745-E746insVPVAIK, K745-E746insTPVAIK.
  • I744-K745insKIPVAI K745-E746insIPVAIK
  • K745-E746insVPVAIK K745-E746insTPVAIK.
  • In vitro experiments showed that the exon 19 insertion mutation was sensitive to afatinib.
  • the exon 19 point mutation is mainly D761Y, and some studies suggest that its appearance may be related to EGFR-TKi resistance, but the degree of resistance is weaker than that of the exon 20 point mutation T790M. Clinical trial data are currently lacking.
  • the amino acid positions for translation of exon 20 are 762-823.
  • the glutamate Glu762 starting at the N-terminus is an important catalytic site. These include a C-helix consisting of E762-M766 amino acids and a loop consisting of A767-V774 amino acids.
  • the non-canonical mutations in exon 20 mainly include insertion and point mutations.
  • A763-Y764insFQEA V769-D770insASV, V769-D770insDNP, D770-N771insNPG, D770-N771insNPH, D770-N771insSVD, D770-N771insASVDN, D770-N771insG, N771-P772insSVDNP, N771-H773dupNPH, P772-H773insPNP, P772-H773insPR, H773-V774insH, A763-Y764insFQEA, H773-V774insPH, H773-V774insNPH, N771-P772insH, H771-P772insN, H773-V774insAH, D770delinsGY, V774-C775insHV, etc.
  • Poziotinib effectively inhibited the growth of Ba/F3 cell line with EGFR exon 20 insertion mutation. Poziotinib is stronger than Osimertinib and Afatinib. But the side effects are obvious, manifested as rash and diarrhea, and clinical trial data are lacking.
  • the main point mutations in exon 20 were: S768I, accounting for about 1.0% of the total EGFR mutations.
  • S768I mutation was more sensitive to afatinib than Osimertinib.
  • EGFR ex20ins mutations are not as sensitive to first- and second-generation EGFR-TKIs as classical mutations, but are the most common non-sensitive mutations in EGFR mutations. Therefore, the treatment of people with ex20ins mutation is a major problem faced by clinicians in clinical management.
  • the non-classical mutation in exon 21 is mainly manifested as the point mutation L861Q, which accounts for about 0.90% of the total EGFR mutations.
  • the L861Q mutation is caused by the substitution of T by A at position 2828 of exon 21, and has oncogenic activity similar to the L858R mutation. In vitro studies have found that the L861Q mutation is sensitive to osimertinib, but clinical trial data are currently lacking.
  • ERBB2 point mutations V777L, D769Y, R896C, P1170A and insertion mutations V777-G778insCG, P780-Y781insGSP and so on.
  • the compound of the present invention is a compound represented by formula I or a pharmaceutically acceptable salt thereof,
  • the compounds of the present invention can inhibit mutant EGFR, especially EGFR exon 18-21 point mutation and insertion mutation, ERBB2 point mutation and insertion mutation. Therefore, on the basis of the compound of the present invention, the present invention also provides a pharmaceutical composition, which contains a therapeutically effective amount of the compound of the present invention or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.
  • Examples of pharmaceutically acceptable salts of the compounds of the present invention include, but are not limited to, inorganic and organic acid salts such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate , fumarate, mandelate, and oxalate; and inorganic and inorganic compounds formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucamine.
  • inorganic and organic acid salts such as hydrochloride, hydrobromide, sulfate, citrate, lactate, tartrate, maleate , fumarate, mandelate, and oxalate
  • inorganic and inorganic compounds formed with bases such as sodium hydroxy, tris(hydroxymethyl)aminomethane (TRIS, tromethamine), and N-methylglucamine.
  • TriS tris(hydroxymethyl)aminomethane
  • compositions of the present invention can be formulated into formulations suitable for various routes of administration, including but not limited to being formulated for parenteral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, buccal, intrathecal, cranial In the form of intranasal, nasal or topical administration for the treatment of tumors and other diseases.
  • the amount administered is that amount effective to ameliorate or eliminate one or more conditions.
  • an effective amount is an amount sufficient to ameliorate or in some way alleviate symptoms associated with the disease.
  • Such amounts can be administered as a single dose, or can be administered according to an effective therapeutic regimen.
  • the amount administered may cure the disease, but the drug is usually given to improve the symptoms of the disease. Repeated dosing is generally required to achieve the desired symptomatic improvement.
  • the dose of the drug will be determined based on the patient's age, health and weight, the type of concurrent therapy, the frequency of therapy, and the desired therapeutic benefit.
  • the pharmaceutical formulations of the present invention can be administered to any mammal so long as they can obtain the therapeutic effects of the compounds of the present invention.
  • the most important of these mammals are humans.
  • the cancer is non-small cell lung cancer, small cell lung cancer, lung adenocarcinoma, lung squamous cell carcinoma, breast cancer, pancreatic cancer, prostate cancer, ovarian cancer, glioblastoma, head and neck squamous cell carcinoma Cancer, cervical cancer, esophageal cancer, liver cancer, kidney cancer, colon cancer, skin cancer, leukemia, lymphoma, gastric cancer, multiple myeloid cancer.
  • the pharmaceutical formulations of the present invention can be manufactured in a known manner. For example, manufactured by conventional mixing, granulating, tableting, dissolving, or freeze-drying processes.
  • solid excipients and active compounds can be combined and the mixture optionally ground. After adding suitable auxiliaries, if desired or necessary, the mixture of granules is processed to obtain tablets or dragee cores.
  • auxiliaries are in particular fillers, such as sugars such as lactose or sucrose, mannitol or sorbitol; cellulose preparations or calcium phosphates, such as tricalcium phosphate or dicalcium phosphate; and binders, such as starch pastes, including corn starch , wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.
  • fillers such as sugars such as lactose or sucrose, mannitol or sorbitol
  • cellulose preparations or calcium phosphates such as tricalcium phosphate or dicalcium phosphate
  • binders such as starch pastes, including corn starch , wheat starch, rice starch, potato starch, gelatin, tragacanth, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, or polyvinylpyrrolidone.
  • disintegrants such as the starches mentioned above, can be added, as well as carboxymethyl starch, cross-linked polyvinylpyrrolidone, agar, or alginic acid or a salt thereof, such as sodium alginate.
  • Adjuvants are especially flow conditioners and lubricants, for example, silica, talc, stearates, such as magnesium calcium stearate, stearic acid or polyethylene glycols.
  • dragee cores can be provided with a suitable coating that is resistant to gastric juices. For this purpose, concentrated sugar solutions can be used.
  • This solution may contain gum arabic, talc, polyvinylpyrrolidone, polyethylene glycol and/or titanium dioxide, a lacquer solution and a suitable organic solvent or solvent mixture.
  • suitable cellulose solutions such as cellulose acetate phthalate or hydroxypropyl methylcellulose phthalate can be used.
  • Dyestuffs or pigments may be added to the coatings of the tablets or dragee cores. For example, for identification or to characterize combinations of active ingredient doses.
  • the compound provided by the present invention is a compound with a novel structure that can inhibit mutant EGFR, especially non-classical mutant EGFR;
  • the compound provided by the present invention has excellent inhibitory activity on non-classical mutant EGFR;
  • the compounds provided by the present invention lay a foundation for the development of drugs that can inhibit EGFR mutation, especially non-classical mutant EGFR, have great industrialization and commercialization prospects and market value, and have significant economic benefits.
  • the substrate of the kinase reaction was placed in a freshly prepared reaction buffer, and the cofactors required for the kinase reaction were added, wherein the buffer ratio was: 20mM HEPES (pH 7.5), 10mM MgCl 2 , 1mM EGTA, 0.02% Brij35 , 0.02 mg/mL BSA, 0.1 mM Na 3 VO 4 , 2 mM DTT, 1% DMSO; then add the kinase to be tested and shake gently.
  • the compounds to be tested are dissolved in DMSO to the desired concentration and added to the above kinase/substrate-containing buffer using an Autosampler Echo 550.
  • 33 P-labeled ATP ( 33 P-ATP, final concentration of 0.01 ⁇ Ci/ ⁇ L) was added to the reaction system to initiate the kinase reaction, and the reaction was carried out at room temperature for 2 h.
  • the reaction was spotted on P81 ion exchange paper (Whatman #3698-915), the filtration was thoroughly washed with 0.75% phosphoric acid, and finally the radiophosphorylated substrate remaining on the filter paper was measured.
  • Kinase activity data were expressed as a percentage of the remaining kinase activity in the test samples, 10 concentration gradients were determined, curve fitting was performed using Prism4 (GraphPad software) and IC50 values were calculated.
  • TAK-788 Takeda Pharmaceutical
  • BTD Breakthrough Therapy Designation
  • FDA U.S. Food and Drug Administration
  • TAK-788 was used as a positive control in this experiment.
  • Compound I inhibited the proliferation of stable cell lines containing different EGFR mutations.
  • Ba/F3 is an interleukin-3-dependent mouse pro-B cell line, a commonly used system for studying kinases and their kinase inhibitors, because recombinant expression of some protein kinases can make Ba/F3 cells independent of According to its characteristics, the inhibition of the proliferation of Ba/F3 cells expressing different target kinases by detecting compounds can reflect the inhibitory effect of compounds on different kinase targets at the cellular level, and can be used for kinase inhibitors filter.
  • Adenosine Tri-Phosphate is an energy carrier shared by various life activities in nature, and is the smallest unit of energy storage and transfer.
  • the CellTiter-Glo TM Live Cell Assay Kit uses luciferase as the detection substance, and luciferase requires the participation of ATP to generate a light signal. Luminescence values were measured after adding CellTiter-Glo TM reagent to the cells. The light signal is proportional to the amount of ATP in the system, and ATP is positively related to the number of living cells. Therefore, by using the CellTiter-Glo kit to detect the ATP content, it can reflect the cell viability and thus the proliferation level of the cell.
  • GI50 is defined as the corresponding compound concentration when the cell proliferation rate is 50%.
  • the fitting formula in the software is as follows:
  • the GI50 of compound I on the proliferation inhibition assay of stable cell lines containing different EGFR mutations is shown in the following table:
  • Figures 1a-f show the GI50 data of compound I on the proliferation inhibition assay of stable cell lines containing different EGFR mutations, wherein compound 1 is shown as R201 and compound TAK788 is shown as R-203.

Abstract

碟啶酮系列及其或其药学上可接受的盐、前药作为EGFR非经典突变抑制剂的应用。具体而言，涉及式I所示系列化合物、含有式I系列化合物的药物组合物在制备治疗含有EGFR 20insX突变、EGFR G719X突变、ERBB2突变的疾病的药物中的用途。

Description

抑制突变型EGFR的化合物及其应用 技术领域
本发明涉及药物化学领域；具体地说，本发明涉及蝶啶酮衍生物作为突变型表皮生长因子受体酪氨酸激酶(epidermal growth factor receptor tyrosine kinase,EGFR)，特别是非经典突变EGFR的抑制剂的应用。
背景技术
随着EGFR一、二和三代抑制剂上市，给EGFR经典型敏感突变和T790M耐药突变非小细胞肺癌患者带来福音，但是并非所有EGFR突变患者都能获益。其中EGFR 20外显子插入突变(EGFR 20ins)的NSCLC对大部分EGFR抑制剂靶向治疗效果差或无效，这些突变常常归为非经典突变。这些非经典突变主要包括18-21外显子的插入突变和点突变，ERBB2的点突变和插入突变。
因此，研究开发靶向非经典突变EGFR抑制剂的药物具有重大的临床意义和应用前景。
发明内容
本发明的目的是提供非经典突变EGFR的抑制剂以及包含上述抑制剂的药物组合物。
在第一方面，本发明提供式I所示化合物或其药学上可接受的盐在制备抑制突变型EGFR的药物或治疗或预防突变型EGFR介导的疾病的药物中的用途：
Figure PCTCN2021116076-appb-000001
在具体的实施方式中，所述突变型EGFR包括至少一种以下突变：EGFR 18-21外显子点突变和插入突变，ERBB2的点突变和插入突变。
在具体的实施方式中，所述突变型EGFR含有：
18外显子G719X、E709X、K716A、K728A点突变与密码子709处缺失突变；
19号外显子插入突变I744-K745insKIPVAI、K745-E746insIPVAIK、K745-E746insVPVAIK、K745-E746insTPVAIK和点突变D761Y；
20号外显子插入突变与点突变包括：A763-Y764insFQEA、A763-Y764insFHEA、V769-D770insASV、V769-D770insDNP、D770-N771insNPG、D770-N771insNPH、D770-N771insSVD、D770-N771insASVDN、D770-N771insG、N771-P772insSVDNP、 N771-H773dupNPH、P772-H773insPNP、P772-H773insPR、H773-V774insH、A763-Y764insFQEA、H773-V774insPH、H773-V774insNPH、N771-P772insH、H771-P772insN、H773-V774insAH、D770delinsGY、V774-C775insHV等以及20号外显子点突变S768I；
21号外显子点突变L861Q；
ERBB2的点突变V777L、D769Y、R896C、P1170A和插入突变V777-G778insCG、P780-Y781insGSP等。
在具体的实施方式中，所述突变型EGFR含有至少一种以下的突变：G719X(X表示A、S、C、D)、D761Y、A763-Y764insFQEA、A763-Y764insFHEA、V769-D770insASV、D770-N771insSVD、D770-N771insASVDN、D770-N771insG、N771-P772insSVDNP、N771-H773dupNPH、P772-H773insPNP、P772-H773insPR、H773-V774insH、A763-Y764insFQEA、H773-V774insPH、H773-V774insNPH、N771-P772insH、H771-P772insN、H773-V774insAH、D770delinsGY、V774-C775insHV、L861Q、V777-G778insCG、V777L、D769Y等。
在具体的实施方式中，所述突变型EGFR含有至少一种以下突变：A763_Y764insFHEA、A763-Y764insFQEA、d747-749/A750P D761Y、D770-N771insNPG、D770-N771insNPG/T790M、D770GY、G719C、G719D、G719S、L861Q以及ERBB的V777-G778insCG、V777L、D769Y等。
在具体的实施方式中，所述疾病为癌症。
在具体的实施方式中，所述癌症为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、胰腺癌、前列腺癌、卵巢癌、神经胶质细胞瘤、头颈部鳞癌、宫颈癌、食管癌、肝癌、肾癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌或多发性骨髓癌。
在第二方面，本发明提供式I所示化合物或其药学上可接受的盐，用于抑制突变型EGFR或治疗或预防突变型EGFR介导的疾病，
Figure PCTCN2021116076-appb-000002
在优选的实施方式中，所述突变型EGFR包括至少一种以下突变：EGFR 18-21外显子点突变和插入突变，ERBB2的点突变和插入突变。
在优选的实施方式中，所述突变型EGFR含有：
18外显子G719X、E709X、K716A、K728A点突变与密码子709处缺失突变；
19号外显子插入突变I744-K745insKIPVAI、K745-E746insIPVAIK、 K745-E746insVPVAIK、K745-E746insTPVAIK和点突变D761Y；
20号外显子插入突变与点突变包括：A763-Y764insFQEA、A763-Y764insFHEA、V769-D770insASV、V769-D770insDNP、D770-N771insNPG、D770-N771insNPH、D770-N771insSVD、D770-N771insASVDN、D770-N771insG、N771-P772insSVDNP、N771-H773dupNPH、P772-H773insPNP、P772-H773insPR、H773-V774insH、A763-Y764insFQEA、H773-V774insPH、H773-V774insNPH、N771-P772insH、H771-P772insN、H773-V774insAH、D770delinsGY、V774-C775insHV等以及20号外显子点突变S768I；
21号外显子点突变L861Q；
ERBB2的点突变V777L、D769Y、R896C、P1170A和插入突变V777-G778insCG、P780-Y781insGSP等。
在优选的实施方式中，所述突变型EGFR含有至少一种以下的突变：G719X(X表示A、S、C、D)、D761Y、A763-Y764insFQEA、A763-Y764insFHEA、V769-D770insASV、D770-N771insSVD、D770-N771insASVDN、D770-N771insG、N771-P772insSVDNP、N771-H773dupNPH、P772-H773insPNP、P772-H773insPR、H773-V774insH、A763-Y764insFQEA、H773-V774insPH、H773-V774insNPH、N771-P772insH、H771-P772insN、H773-V774insAH、D770delinsGY、V774-C775insHV、L861Q、V777-G778insCG、V777L、D769Y等。
在优选的实施方式中，所述突变型EGFR含有至少一种以下突变：A763_Y764insFHEA、A763-Y764insFQEA、d747-749/A750P D761Y、D770-N771insNPG、D770-N771insNPG/T790M、D770GY、G719C、G719D、G719S、L861Q以及ERBB的V777-G778insCG、V777L、D769Y等。
在优选的实施方式中，所述疾病为癌症。
在优选的实施方式中，所述癌症为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、胰腺癌、前列腺癌、卵巢癌、神经胶质细胞瘤、头颈部鳞癌、宫颈癌、食管癌、肝癌、肾癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌或多发性骨髓癌。
在第三方面，本发明提供一种抑制突变型EGFR或治疗或预防突变型EGFR介导的疾病的方法，所述方法包括将式I所示化合物或其药学上可接受的盐给予有此需要的对象的步骤，
Figure PCTCN2021116076-appb-000003
在优选的实施方式中，所述突变型EGFR包括至少一种以下突变：EGFR 18-21外显子点突变和插入突变，ERBB2的点突变和插入突变。
在优选的实施方式中，所述突变型EGFR含有：
18外显子G719X、E709X、K716A、K728A点突变与密码子709处缺失突变；
19号外显子插入突变I744-K745insKIPVAI、K745-E746insIPVAIK、K745-E746insVPVAIK、K745-E746insTPVAIK和点突变D761Y；
20号外显子插入突变与点突变包括：A763-Y764insFQEA、A763-Y764insFHEA、V769-D770insASV、V769-D770insDNP、D770-N771insNPG、D770-N771insNPH、D770-N771insSVD、D770-N771insASVDN、D770-N771insG、N771-P772insSVDNP、N771-H773dupNPH、P772-H773insPNP、P772-H773insPR、H773-V774insH、A763-Y764insFQEA、H773-V774insPH、H773-V774insNPH、N771-P772insH、H771-P772insN、H773-V774insAH、D770delinsGY、V774-C775insHV等以及20号外显子点突变S768I；
21号外显子点突变L861Q；
ERBB2的点突变V777L、D769Y、R896C、P1170A和插入突变V777-G778insCG、P780-Y781insGSP等。
在优选的实施方式中，所述突变型EGFR含有至少一种以下的突变：G719X(X表示A、S、C、D)、D761Y、A763-Y764insFQEA、A763-Y764insFHEA、V769-D770insASV、D770-N771insSVD、D770-N771insASVDN、D770-N771insG、N771-P772insSVDNP、N771-H773dupNPH、P772-H773insPNP、P772-H773insPR、H773-V774insH、A763-Y764insFQEA、H773-V774insPH、H773-V774insNPH、N771-P772insH、H771-P772insN、H773-V774insAH、D770delinsGY、V774-C775insHV、L861Q、V777-G778insCG、V777L、D769Y等。
在优选的实施方式中，所述突变型EGFR含有至少一种以下突变：A763_Y764insFHEA、A763-Y764insFQEA、d747-749/A750P D761Y、D770-N771insNPG、D770-N771insNPG/T790M、D770GY、G719C、G719D、G719S、L861Q以及ERBB的V777-G778insCG、V777L、D769Y等。
在优选的实施方式中，所述疾病为癌症。
在优选的实施方式中，所述癌症为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、胰腺癌、前列腺癌、卵巢癌、神经胶质细胞瘤、头颈部鳞癌、宫颈癌、食管癌、肝癌、肾癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌或多发性骨髓癌。
应理解，在本发明范围内中，本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合，从而构成新的或优选的技术方案。限于篇幅，在此不再一一累述。
附图简述
图1a-f显示了化合物I对包含不同EGFR突变的稳定细胞系增殖抑制检测实验GI50数据，其中化合物1显示为-R201，化合物TAK788显示为R-203。
具体实施方式
发明人经过广泛而深入的研究，出乎意料地发现一批蝶啶酮衍生物，这些衍生物能够靶向非经典突变EGFR，从而能够作为新一代的EGFR抑制剂。在此基础上完成了本发明。
EGFR非经典突变
EGFR抑制剂为EGFR经典型敏感突变和T790M耐药突变的非小细胞肺癌患者带来福音。然而，并非所有EGFR突变患者都能从已经上市的EGFR抑制剂中获益。经研究发现，存在EGFR 20外显子插入突变(EGFR 20ins)的NSCLC对大部分EGFR抑制剂的靶向治疗效果差或无效。这些突变常常归为非经典突变。在本发明中，所述非经典突变主要包括18-21外显子的插入突变和点突变，ERBB2的点突变和插入突变。
18号外显子非经典突变主要表现G719X、E709X、K716A、K728A点突变，密码子709处缺失突变。G719X突变为EGFR中的G719X(X表示A丙氨酸，S丝氨酸，C半胱氨酸等)突变是指点突变，G719X突变约占总EGFR突变的3.10％[Cancer Sci.2016,107(9),:1179-1186]。
G719S突变致癌性较敏感突变弱，体外实验发现Gefitinib能以增加剂量的方式抑制G719S的自身磷酸化。与敏感突变L858R相比，Gefitinib需要以更高的浓度抑制G719S突变。E709X点突变为18号外显子的另一非经典突变，E709X突变约占总EGFR突变的0.30％。在体外实验中，与一代或三代TKIs相比，E709X点突变患者对Afatinib具有高度敏感性。
DelE709-T710insD是密码子709处最常见的缺失突变，约占总EGFR突变的0.30％。
19号外显子非经典突变表现为插入突变和点突变。19号外显子插入突变约占EGFR突变的0.60％，包括：I744-K745insKIPVAI、K745-E746insIPVAIK、K745-E746insVPVAIK、K745-E746insTPVAIK。体外试验均显示19号外显子插入突变对Afatinib敏感。
19号外显子点突变主要表现为D761Y，有研究认为它的出现可能与EGFR-TKi耐药相关，但耐药程度弱于20号外显子点突变T790M。目前缺乏临床试验数据。
20外显子翻译的氨基酸位点为762-823。起始于N-末端的谷氨酸Glu762为重要的催化位点。其中包括由E762-M766氨基酸构成的C-螺旋以及由A767-V774氨基酸构成的环。20号外显子非经典突变主要表现为插入突变与点突变。包括：A763-Y764insFQEA、V769-D770insASV、V769-D770insDNP、D770-N771insNPG、D770-N771insNPH、D770-N771insSVD、D770-N771insASVDN、D770-N771insG、N771-P772insSVDNP、N771-H773dupNPH、P772-H773insPNP、P772-H773insPR、H773-V774insH、A763-Y764insFQEA、H773-V774insPH、H773-V774insNPH、N771-P772insH、H771-P772insN、H773-V774insAH、D770delinsGY、V774-C775insHV等。以上突变约占总EGFR突变的5.80％。除A763-Y764insFQEA外，EGFR20号外显子插入突变对一、二代TKIs靶向治疗不敏感。 在众多的突变形式中，最为特殊的是763_764insFQEA。763_764insFQEA是目前发现ex20ins突变里的敏感突变。
至今发现有超过60种独特的EGFR ex20ins形式，在其研究中最常见的EGFR ex20ins依次为D770_N771>ASVDN、N771_P772>SVDNP和N771_H773dupNPH，约占ex20ins突变的50％。
在最新体外实验中发现，Poziotinib有效抑制了具有EGFR20号外显子插入突变的Ba/F3细胞系的生长。Poziotinib较Osimertinib、Afatinib强。但副作用明显，表现为皮疹和腹泻，缺乏临床试验数据。
20号外显子点突变主要为：S768I，约占总EGFR突变的1.0％。在体外实验中，S768I突变对Afatinib较Osimertinib更敏感。
EGFR ex20ins突变并不像经典突变那样对一二代EGFR-TKIs敏感，而是EGFR突变中最常见的非敏感突变。因而ex20ins突变的人群的治疗是目前临床医生在临床管理中面临的一大难题。
21号外显子非经典突变主要表现为点突变L861Q，约占总EGFR突变的0.90％。L861Q突变是由21号外显子第2828位点的T被A取代所致，具有类似于L858R突变的致癌活性。体外研究发现L861Q突变对于Osimertinib敏感，但目前缺少临床试验数据。
ERBB2的点突变V777L、D769Y、R896C、P1170A和插入突变V777-G778insCG、P780-Y781insGSP等。
本发明的化合物及药物组合物
本发明的化合物是式I所示化合物或其药学上可接受的盐，
Figure PCTCN2021116076-appb-000004
本发明所述化合物的制备方法可参考公开于CN108721298A中所描述的方法。
本发明的化合物可以抑制突变型EGFR，特别是EGFR 18-21外显子点突变和插入突变，ERBB2的点突变和插入突变。因此，在本发明的化合物的基础上，本发明还提供一种药物组合物，该组合物含有治疗有效量的本发明的化合物或其药学上可接受的盐，以及药学上可接受的载体或赋形剂。
本发明化合物的药学上可接受的盐的例子包括但不限于无机和有机酸盐，例如盐酸盐、氢溴酸盐、硫酸盐、柠檬酸盐、乳酸盐、酒石酸盐、马来酸盐、富马酸盐、扁桃酸盐和草酸盐；以及与碱例如钠羟基、三(羟基甲基)胺基甲烷(TRIS，胺丁三醇)和N-甲基葡糖胺形成的 无机和有机碱盐。
本发明的药物组合物可被配制成适合各种给药途径的制剂形式，包括但不限于被配制成用于肠外，皮下，静脉，肌肉，腹腔内，透皮，口腔，鞘内，颅内，鼻腔或外用途径给药的形式，用于治疗肿瘤和其他疾病。给药量是有效地改善或消除一个或多个病症的药量。对于特定疾病的治疗，有效量是足以改善或以某些方式减轻与疾病有关的症状的药量。这样的药量可作为单一剂量施用，或者可依据有效的治疗方案给药。给药量也许可治愈疾病，但是给药通常是为了改善疾病的症状。一般需要反复给药来实现所需的症状改善。药的剂量将根据病人的年龄，健康与体重，并行治疗的种类，治疗的频率，以及所需治疗效益来决定。
本发明的药物制剂可以给予任何哺乳动物，只要他们能获得本发明化合物的治疗效果。在这些哺乳动物中最为重要的是人类。
基于本发明的教导，本领域技术人员知晓本发明的化合物可用于治疗癌症。在具体的实施方式中，所述癌症为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、胰腺癌、前列腺癌、卵巢癌、神经胶质细胞瘤、头颈部鳞癌、宫颈癌、食管癌、肝癌、肾癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌、多发性骨髓癌。
本发明的药物制剂可用已知的方式制造。例如，由传统的混合，制粒，制锭，溶解，或冷冻干燥过程制造。制造口服制剂时，可结合固体辅料和活性化合物，选择性研磨混合物。如果需要或必要时加入适量助剂后，加工颗粒混合物，获得片剂或锭剂芯。
合适的辅料特别是填料，例如糖类如乳糖或蔗糖，甘露醇或山梨醇；纤维素制剂或钙磷酸盐，例如磷酸三钙或磷酸氢钙；以及粘结剂，例如淀粉糊，包括玉米淀粉，小麦淀粉，大米淀粉，马铃薯淀粉，明胶，黄芪胶，甲基纤维素，羟丙基甲基纤维素，羧甲基纤维素钠，或聚乙烯吡咯烷酮。如果需要，可增加崩解剂，比如上面提到的淀粉，以及羧甲基淀粉，交联聚乙烯吡咯烷酮，琼脂，或褐藻酸或其盐，如海藻酸钠。辅助剂特别是流动调节剂和润滑剂，例如，硅石，滑石，硬脂酸盐类，如镁硬脂酸钙，硬脂酸或聚乙二醇。如果需要，可以給锭剂核芯提供可以抵抗胃液的合适包衣。为此，可以应用浓缩糖类溶液。这个溶液可以含有阿拉伯树胶，滑石，聚乙烯吡咯烷酮，聚乙二醇和/或二氧化钛，漆溶液和合适的有机溶剂或溶剂混合物。为了制备耐胃液的包衣，可使用适当的纤维素溶液，例如醋酸纤维素邻苯二甲酸或羟丙基甲基纤维素邻苯二甲酸。可向药片或锭剂核芯的包衣加入染料或色素。例如，用于识别或为了表征活性成分剂量的组合。
本发明的优点：
1.本发明提供的化合物是一种结构全新的能够抑制突变型EGFR，特别是非经典突变型EGFR的化合物；
2.本发明提供的化合物对非经典突变型EGFR具有优异的抑制活性；
3.本发明提供的化合物为开发能抑制EGFR突变，特别是非经典突变型EGFR的药物奠定了基础，具备极大的产业化和商品化前景以及市场价值，经济效益显著。
以下结合具体实施案例对本发明的技术方案进一步描述，但以下实施案例不构成对本发明的限制，所有依据本发明的原理和技术手段采用的各种施用方法，均属于本发明范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件，或按照制造厂商所建议的条件。除非另外说明，否则百分比和份数按重量计算。
实施例1
化合物1激酶谱评价(委托测试：Reaction Biology Corporation，One Great Valley Parkway,Suite 2Malvern,PA 19355,USA.)
实验方法：
将激酶反应的底物置于新鲜配置的反应缓冲液中，并加入激酶反应所需要的辅因子，其中缓冲液配比为：20mM HEPES(pH 7.5)、10mM MgCl 2,、1mM EGTA、0.02％Brij35、0.02mg/mL BSA,0.1mM Na 3VO 4,2mM DTT、1％DMSO；之后加入待测激酶，轻轻震荡。将待测化合物溶于DMSO中，制备成所需要的浓度，并使用自动进样器Echo550将待测化合物加入到上述含激酶/底物的缓冲液中。向反应体系中加入 33P标记的ATP( 33P-ATP，终浓度为0.01μCi/μL)，以启动激酶反应，并在室温下反应2h。将反应点在P81离子交换纸上(Whatman#3698-915)，用0.75％的磷酸彻底清洗过滤，最后测量残留在滤纸上的放射性磷酸化底物。激酶活性数据表示为测试样品中剩余激酶活性的百分比，测定10个浓度梯度，使用Prism4(GraphPad软件)进行曲线拟合并计算获得IC 50值。
化合物1 EGFR突变激酶谱IC 50值(nM)：
Figure PCTCN2021116076-appb-000005
Figure PCTCN2021116076-appb-000006
空格表示未测。
化合物1系列衍生物(WO2018/192536A1)EGFR突变激酶抑制活性IC50值(nM)，评价方法同上。
Figure PCTCN2021116076-appb-000007
Figure PCTCN2021116076-appb-000008
实施例2、细胞系增殖抑制检测实验
Mobocertinib(TAK-788，武田制药)日前美国FDA已授予突破性疗法认定(BTD)药物资格，用于治疗在含铂化疗后疾病进展的具有EGFR外显子20插入突变的转移性非小细 胞肺癌患者。为了更客观评价化合物1活性，本实验采用TAK-788作为阳性对照。
1.化合物I对包含不同EGFR突变的稳定细胞系增殖抑制检测实验。
2.项目内容
通过CTG Assay检测化合物1，TAK788对不同突变类型Ba/F3EGFR细胞系增殖的抑制作用。
3.主要试剂和耗材
3.1化合物：化合物1和TAK788，为粉末。
3.2细胞列表:
Figure PCTCN2021116076-appb-000009
3.3 RPMI-1640(Gibco#C11875500CP；Lot#8120069)
3.4 FBS(Gibco#10099-141C；Lot#2145068CP)
3.5
Figure PCTCN2021116076-appb-000010
Luminescent Cell Viability Assay(Promega,Cat.No.:G7573；Lot
#0000319784)
3.7细胞培养及检测板：96 Well Assay Plate(White Plate,Clear Bottom with Lid Tissue Culture Treated Polystyrene 1/Pack,Costar 3610)
3.8 T25细胞培养瓶(BIOFIL#TCF012050)
3.9化合物配置板(Costar#3357)
4.主要实验仪器
Synergy H1多功能酶标仪(Biotek,REF:8040534；SN:500431)
5.实验原理
B a/F3是一种依赖于白介素-3的小鼠pro-B细胞系，是一种研究激酶及其激酶抑制剂的常用系统，因为重组表达一些蛋白激酶可以使Ba/F3细胞不再依赖IL-3而生长，根据其这样的特性，检测化合物对表达不同靶点激酶的B a/F3细胞增殖的抑制，可以从细胞水平反映化合物对不同激酶靶点的抑制作用，用于激酶抑制剂的筛选。
本实验采用
Figure PCTCN2021116076-appb-000011
Luminescent Cell Viability Assay检测细胞增殖，其具体原理如下：
三磷酸腺苷(Adenosine Tri-Phosphate,ATP)是自然界中各种生命活动中共用的能量载体，是能量储存和转移的最小单位。CellTiter-Glo TM活细胞检测试剂盒采用萤光素酶作为检测物，而萤光素酶需要ATP的参与才能产生光信号。向细胞中加入CellTiter-Glo TM试剂后，测量发光值。光信号和体系中ATP量成正比，而ATP又和活细胞数正相关。因此通过使 用CellTiter-Glo试剂盒检测ATP含量，可以反映出细胞的活力进而反映细胞的增殖水平。
6.实验流程
6.1细胞复苏及培养
液氮内取出细胞，37摄氏度水浴快速融化细胞，并将冻存管以1000rpm的速度离心，并弃去冻存液上清，将细胞重悬于RPMI1640+10％FBS培养基中，放置37摄氏度细胞培养箱中培养，细胞培养密度始终保持2*10e5到2*10e6/ml之间。
6.2化合物配制
1)在化合物配制板中用DMSO对化合物进行连续梯度稀释，稀释起始浓度为1或10mM,梯度稀释倍数为3。
2)准备一个新的化合物配制板，每孔加入198ul RPMI160+10％FBS培养基，从前一个梯度稀释好的化合物配制板中一一对应的转移2ul/孔的化合物至该板，并充分混匀备用，使该板内最高起始化合物浓度为1或10uM，并依梯度而下(该板为10*化合物浓度稀释板)。
6.3检测过程
1)取对数生长的细胞，离心弃培养上清，将离心下来的细胞重悬于新鲜RPMI1640培养基中，细胞密度为2*10e4/ml
2)将重悬的细胞接种到白壁透明底的96孔细胞培养板中，100ul/孔细胞悬液，接种两块培养板，放置37度细胞培养箱培养过夜
3)第二天取其中一块接种细胞的96孔板，加入100ul/孔cell titer glo检测试剂放置60分钟，读取数值，定义为G0数据
4)取另一块平行板，从之前梯度稀释好的10*化合物浓度稀释板中取11.1ul/孔化合物至该板，使得细胞检测板中化合物终浓度从0.5或1uM开始，3倍稀释9个浓度梯度，并另外设置DMSO对照孔，继续在37度细胞培养箱培养72小时
5)将化合物处理过72小时的96孔板从培养箱中取出，加入100ul/孔cell titer glo检测试剂放置60分钟，读取数值，定义为G3数据
6)根据以下公式计算每个孔对应的细胞增殖率
％Proliferation＝(待测化合物孔G3–G0平均值)/(DMSO对照孔G3平均值–G0平均值)*100
7)根据每个梯度浓度孔对应的增殖率和其浓度，利用Prism Graphpad5.0软件拟合细胞增殖的梯度曲线，并且计算化合物的GI50(GI50定义为细胞增殖率为50％时对应的化合物浓度，软件中拟合公式如下：
Y＝Bottom+(Top-Bottom)/(1+10^((LogIC50-X)*HillSlope))
7.实验结果：
化合物I对包含不同EGFR突变的稳定细胞系增殖抑制检测实验GI50如下表所示：
Figure PCTCN2021116076-appb-000012
Figure PCTCN2021116076-appb-000013
图1a-f显示了化合物I对包含不同EGFR突变的稳定细胞系增殖抑制检测实验GI50数据，其中化合物1显示为R201，化合物TAK788显示为R-203。
结论：从化合物1极其系列衍生物针对EGFR非经典突变激酶活性结果看出，化合物1具备优异的抑制活性；进一步的典型EGFR 20ins突变稳定细胞系增殖抑制活性说明，化合物1达到或优于目前大家普遍认为最有前景的EGFR 20ins激酶抑制剂TAK788。
在本发明提及的所有文献都在本申请中引用作为参考，就如同每一篇文献被单独引用作为参考那样。此外应理解，在阅读了本发明的上述讲授内容之后，本领域技术人员可以对本发明作各种改动或修改，这些等价形式同样落于本申请所附权利要求书所限定的范围。

Claims (9)

  1. 式I所示化合物或其药学上可接受的盐在制备抑制突变型EGFR的药物或治疗或预防突变型EGFR介导的疾病的药物中的用途：
    Figure PCTCN2021116076-appb-100001
  2. 如权利要求1所述的用途，其特征在于，所述突变型EGFR包括至少一种以下突变：EGFR 18-21外显子点突变和插入突变，ERBB2的点突变和插入突变。
  3. 如权利要求2所述的用途，其特征在于，所述突变型EGFR含有：
    18外显子G719X、E709X、K716A、K728A点突变与密码子709处缺失突变；
    19号外显子插入突变I744-K745insKIPVAI、K745-E746insIPVAIK、K745-E746insVPVAIK、K745-E746insTPVAIK和点突变D761Y；
    20号外显子插入突变与点突变包括：A763-Y764insFQEA、A763-Y764insFHEA、V769-D770insASV、V769-D770insDNP、D770-N771insNPG、D770-N771insNPH、D770-N771insSVD、D770-N771insASVDN、D770-N771insG、N771-P772insSVDNP、N771-H773dupNPH、P772-H773insPNP、P772-H773insPR、H773-V774insH、A763-Y764insFQEA、H773-V774insPH、H773-V774insNPH、N771-P772insH、H771-P772insN、H773-V774insAH、D770delinsGY、V774-C775insHV等以及20号外显子点突变S768I；
    21号外显子点突变L861Q；
    ERBB2的点突变V777L、D769Y、R896C、P1170A和插入突变V777-G778insCG、P780-Y781insGSP等。
  4. 如权利要求2所述的用途，其特征在于，所述突变型EGFR含有至少一种以下的突变：G719X(X表示A、S、C、D)、D761Y、A763-Y764insFQEA、A763-Y764insFHEA、V769-D770insASV、D770-N771insSVD、D770-N771insASVDN、D770-N771insG、N771-P772insSVDNP、N771-H773dupNPH、P772-H773insPNP、P772-H773insPR、H773-V774insH、A763-Y764insFQEA、H773-V774insPH、H773-V774insNPH、N771-P772insH、H771-P772insN、H773-V774insAH、D770delinsGY、V774-C775insHV、L861Q、V777-G778insCG、V777L、D769Y等。
  5. 如权利要求4所述的用途，其特征在于，所述突变型EGFR含有至少一种以下突变：A763_Y764insFHEA、A763-Y764insFQEA、d747-749/A750P D761Y、D770-N771insNPG、D770-N771insNPG/T790M、D770GY、G719C、G719D、G719S、L861Q以及ERBB的V777-G778insCG、V777L、D769Y等。
  6. 如权利要求1所述的用途，其特征在于，所述疾病为癌症。
  7. 如权利要求6所述的用途，其特征在于，所述癌症为非小细胞肺癌、小细胞肺癌、肺腺癌、肺鳞癌、乳腺癌、胰腺癌、前列腺癌、卵巢癌、神经胶质细胞瘤、头颈部鳞癌、宫颈癌、食管癌、肝癌、肾癌、结肠癌、皮肤癌、白血病、淋巴瘤、胃癌或多发性骨髓癌。
  8. 式I所示化合物或其药学上可接受的盐，用于抑制突变型EGFR或治疗或预防突变型EGFR介导的疾病，
    Figure PCTCN2021116076-appb-100002
  9. 一种抑制突变型EGFR或治疗或预防突变型EGFR介导的疾病的方法，所述方法包括将式I所示化合物或其药学上可接受的盐给予有此需要的对象的步骤，
    Figure PCTCN2021116076-appb-100003
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