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WO2023246869A1 - 治疗肿瘤的药物组合及用途 - Google Patents

治疗肿瘤的药物组合及用途 Download PDF

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Publication number
WO2023246869A1
WO2023246869A1 PCT/CN2023/101720 CN2023101720W WO2023246869A1 WO 2023246869 A1 WO2023246869 A1 WO 2023246869A1 CN 2023101720 W CN2023101720 W CN 2023101720W WO 2023246869 A1 WO2023246869 A1 WO 2023246869A1
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Prior art keywords
cancer
pharmaceutically acceptable
tumor
acceptable salt
growth factor
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PCT/CN2023/101720
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English (en)
French (fr)
Inventor
张宝袁
刘学彬
高家明
张平
庞然
王在琪
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Inxmed Nanjing Co Ltd
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Inxmed Nanjing Co Ltd
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Priority to JP2024575581A priority Critical patent/JP2025520715A/ja
Priority to CN202380045932.5A priority patent/CN119343139A/zh
Priority to EP23826514.4A priority patent/EP4545080A1/en
Priority to US18/387,180 priority patent/US11986477B2/en
Publication of WO2023246869A1 publication Critical patent/WO2023246869A1/zh
Anticipated expiration legal-status Critical
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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
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further 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
    • A61K31/495—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
    • A61K31/517—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with carbocyclic ring systems, e.g. quinazoline, perimidine
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the invention belongs to the field of medicinal chemistry. Specifically, the present invention relates to the treatment of tumors by using the focal adhesion kinase (Focal Adhesive Kinase, FAK) inhibitor IN10018 in combination with other anti-tumor drugs.
  • focal adhesion kinase Fecal Adhesive Kinase, FAK
  • Targeted drugs currently on the market for tumor EGFR mutations include: first-generation icotinib, gefitinib, and erlotinib targeting exon 19 and 21 mutations; second-generation drugs targeting exon 8 , afatinib with exon 20 mutations, and third-generation osimertinib (also called AZD9291 in this article) targeting T790M mutations, Almonertinib and Alflutinib .
  • Targeted drugs targeting ALK mutations include: first-generation targeted drugs crizotinib, second-generation targeted drugs ceritinib, alectinib, brigatinib and The third-generation targeted drug lorlatinib, etc.
  • resistance to these targeted drugs mostly appears about 1 year after treatment. Overcoming resistance to targeted drugs or delaying resistance is the main goal of anti-tumor drug development.
  • Yet another aspect of the present disclosure provides a pharmaceutical combination product of IN0018, or a pharmaceutically acceptable salt thereof, and an epidermal growth factor receptor tyrosine kinase inhibitor for use in treating tumors in a subject.
  • Yet another aspect of the present disclosure provides a method of treating tumors, the method comprising administering a therapeutically effective amount of IN0018 or a pharmaceutically acceptable salt thereof and an epidermal growth factor receptor tyrosine kinase inhibitor to a subject in need thereof.
  • kit or pharmaceutically acceptable composition which includes: (a) IN0018 or a pharmaceutically acceptable salt thereof; and (b) epidermal growth factor receptor tyrosine kinase inhibition agent.
  • Yet another aspect of the present disclosure provides the use of IN0018 or a pharmaceutically acceptable salt thereof and an epidermal growth factor receptor tyrosine kinase inhibitor in the preparation of a combination drug for treating tumors.
  • Yet another aspect of the present disclosure provides the use of an epidermal growth factor receptor tyrosine kinase inhibitor in the preparation of a drug for treating tumors in combination with IN0018 or a pharmaceutically acceptable salt thereof.
  • Another aspect of the present disclosure provides a method of treating tumors, the method comprising administering to a subject in need thereof a therapeutically effective amount of IN0018 or a pharmaceutically acceptable salt thereof and an epidermal growth factor receptor tyrosine kinase inhibitor.
  • Yet another aspect of the present disclosure provides a pharmaceutical combination product of IN0018, or a pharmaceutically acceptable salt thereof, and an epidermal growth factor receptor tyrosine kinase inhibitor for use in treating tumors in a subject in need thereof.
  • the epidermal growth factor receptor tyrosine kinase inhibitor is Gefitinib, Erlotinib, Icotinib, Afatinib, Crizotinib, Osimertinib, AZD9291, Almonertinib, Alflutinib, EA1045, JBJ-25-02 , BLU945, BLU701, TQB3804, BBT-176, ES-072, BPI-361175, CH7233163 or pharmaceutically acceptable salts thereof, preferably Osimertinib, Almonertinib, Alflutinib or pharmaceutically acceptable salts thereof.
  • the IN0018 or a pharmaceutically acceptable salt thereof and the epidermal growth factor receptor tyrosine kinase inhibitor are administered to the subject simultaneously or sequentially.
  • Figure 1 shows a white light microscope photo of the cells taken after the lung cancer KPL cells in Example 1 were incubated with drugs for 48 hours.
  • Figure 3 shows a white light microscope photo of the cells taken after the lung cancer KPL cells in Example 2 were incubated with drugs for 48 hours.
  • Figure 5 shows a white light microscope photo of the cells taken after the lung cancer KPL cells in Example 3 were incubated with drugs for 48 hours.
  • Figure 6 shows the percentage of annexin V-positive KPL cells after 48 hours of incubation of lung cancer KPL cells with drugs in Example 3.
  • Figure 7 shows changes in tumor growth in tumor-bearing mice after administration of different test substances in the BALB/c mouse homograft tumor model of mouse colon cancer CT-26 in Example 4.
  • Figure 8 shows the changes in body weight of CT-26 tumor-bearing mice after administration of different test substances in Example 4.
  • Figure 9 shows the tumor growth curve of mice after administration of different test substances in Example 5.
  • the data points represent the average tumor volume within the group, and the error bars represent the standard error (SEM).
  • Figure 12 shows the synergistic killing effect of AZD9291 at different doses on non-small cell lung cancer cells HCC827 when combined with 3 ⁇ M IN10018 and 5 ⁇ M IN10018 for 48 hours in Example 6.
  • Figure 13 shows the detection of cell apoptosis in HCC827 cells treated with 0.3nM AZD9291 and 3 ⁇ M IN10018 in Example 6 for 48 hours.
  • the CAS number of Gefitinib is 184475-35-2; the CAS number of Erlotinib is 183321-74-6; the CAS number of Icotinib is 610798-31- 7; Afatinib (Afatinib), CAS number is 850140-72-6; Crizotinib (Crizotinib), CAS number is 877399-52-5; Osimertinib (AZD9291), CAS number is 1421373 -65-0; Almonertinib, CAS number is 1899921-05-1; Alflutinib, also known as Furmonertinib, CAS number is 1869057-83-9; EAI045, CAS number is 1942114-09-1; JBJ-04-125-02, CAS number is 2060610-53-7; BLU945, CAS number is 2660250-10-0; BLU701 is Blueprint Medicines Corp.
  • “Simultaneous or sequential administration” in this application refers to two or more drugs administered simultaneously or at a certain time interval within one administration cycle (for example, within 4 weeks, within 3 weeks, within 2 weeks, within 1 week, or within 24 hours). Administered sequentially, the methods of drug administration (such as oral, intravenous, intramuscular or subcutaneous administration, etc.) may be the same or different, and the administration frequency/period of two or more drugs may be the same or different. When the treatment methods, products or uses of the present disclosure involve two drugs, the two drugs can be administered separately at the same time or at certain intervals.
  • treatment refers to the administration of one or more pharmaceutical substances to a subject suffering from a disease or having symptoms of said disease in order to cure, alleviate, alleviate, alter, treat, ameliorate, ameliorate or affect said disease.
  • Disease or symptoms of said disease In some embodiments, the disease is tumor or cancer.
  • tumor refers to abnormal lesions formed by the body's abnormal growth caused by various tumorigenic factors. Cells in local tissues lose normal control of their growth at the genetic level, resulting in abnormal proliferation of their clonal types. Examples include, but are not limited to: bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer).
  • the term "subject” or “subject” refers to mammals and non-mammals.
  • Mammal means any member of the class Mammalia, which includes, but is not limited to: humans; non-human primates, such as chimpanzees and other ape and monkey species; farm animals, such as cattle, horses, sheep, goats, and pigs; Domestic animals, such as rabbits, dogs, and cats; laboratory animals, including rodents, such as rats, mice, and guinea pigs; etc. Examples of non-mammals include, but are not limited to, birds.
  • the term "subject” does not identify a specific age or gender. In some embodiments, the subject is a human.
  • pharmaceutically acceptable means nontoxic, biologically tolerable, and suitable for administration to a subject.
  • pharmaceutically acceptable salts refers to nontoxic, biologically tolerable acid addition salts suitable for administration to a subject, including, but not limited to, acid addition salts with inorganic acids. , such as hydrochlorides, hydrobromides, carbonates, bicarbonates, phosphates, sulfates, sulfites, nitrates, etc.; and acid addition salts formed with organic acids, such as formates, acetates, etc.
  • composition means that it must be chemically and/or toxicologically compatible with the other ingredients including the formulation, and/or with the subject to be treated therewith.
  • therapeutically effective amount refers to an amount generally sufficient to produce a beneficial therapeutic effect in a subject. Conventional influencing factors (e.g., mode of administration, pharmacokinetics of the compound, severity and course of disease, subject's medical history, subject's health condition, subject degree of response to drugs, etc.) to determine the therapeutically effective dose of the present invention.
  • inhibitor refers to a decrease in the baseline activity of a biological activity or process.
  • the kit includes (i) IN10018, or a pharmaceutically acceptable salt thereof; and (ii) instructions for using IN10018, or a pharmaceutically acceptable salt thereof, and epidermal growth factor receptor Tyrosine kinase inhibitors are used to treat tumors in subjects.
  • the kit includes (i) an epidermal growth factor receptor tyrosine kinase inhibitor; and (ii) instructions for using IN10018, or a pharmaceutically acceptable salt thereof, and epidermal growth factor Receptor tyrosine kinase inhibitors to treat tumors in subjects.
  • kits may include a first container including at least one dose of a drug including IN10018 or a pharmaceutically acceptable salt thereof, a second container including at least one dose of epidermal growth factor, and a package insert.
  • a receptor tyrosine kinase inhibitor, and the package insert includes instructions for using the drug to treat the subject's tumor.
  • the first container and the second container may contain the same or different shapes (eg, vials, syringes, and bottles) and/or materials (eg, plastic or glass). Kits may also include other materials that may aid in administering the medication, such as diluents, filters, IV bags and tubing, needles, and syringes.
  • IN10018 or its pharmaceutically acceptable salt and epidermal growth factor receptor tyrosine kinase inhibitor can be administered in a suitable manner, such as oral, intravenous, intramuscular or subcutaneous administration.
  • the drug may be administered orally with a pharmaceutically acceptable carrier such as an inert diluent or an absorbable edible carrier. They can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or can be mixed directly with the patient's food.
  • a pharmaceutically acceptable carrier such as an inert diluent or an absorbable edible carrier. They can be enclosed in hard- or soft-shell gelatin capsules, compressed into tablets, or can be mixed directly with the patient's food.
  • the drug may be combined with one or more excipients and used in the form of ingestible tablets, buccal tablets, lozenges, capsules, elixirs, suspensions, syrups, or wafers. Tablets, lozenges, pills, capsules, etc.
  • a binder such as tragacanth, acacia, corn starch or gelatin
  • an excipient such as dicalcium phosphate
  • a disintegrant such as corn starch, potato starch , alginic acid, etc.
  • lubricants such as magnesium stearate
  • sweeteners such as sucrose, fructose, lactose or aspartame; or flavoring agents.
  • solutions of the drug may be prepared in water, optionally mixed with a nontoxic surfactant.
  • Exemplary pharmaceutical dosage forms for injection or infusion include sterile aqueous solutions, dispersions, or sterile powders containing the active ingredient suitable for the extemporaneous preparation of sterile injection or infusion solutions or dispersions. Regardless, the final dosage form should be sterile, fluid, and stable under the conditions of manufacture and storage.
  • Sterile injectable solutions can be prepared by incorporating the required amount of the drug in an appropriate solvent with various other ingredients required from above, followed by filtered sterilization.
  • the preferred methods of preparation may be vacuum drying and freeze-drying techniques, which produce a powder of the active ingredient plus any other desired ingredients present after previous sterile filtration.
  • the amounts of IN10018, or a pharmaceutically acceptable salt thereof, and the epidermal growth factor receptor tyrosine kinase inhibitor required for treatment may vary not only with the particular agent selected, but also with the route of administration, the nature of the disease being treated, and vary in nature as well as the age and condition of the patient and can ultimately be determined at the discretion of the attending physician or clinician. In general, however, dosages may range from about 0.1 to about 50 mg/kg of body weight per day.
  • IN10018 is administered as a free base in adults at a dose of 5 mg/day to 100 mg/day, for example, 20 mg/day.
  • the epidermal growth factor receptor tyrosine kinase inhibitor is administered in a dosage range of 2-500 mg per day in adults.
  • Osimertinib or a pharmaceutically acceptable salt thereof is administered in adults at a dose of 2-500 mg, for example, 80 mg per day, based on Osimertinib;
  • Almonertinib or a pharmaceutically acceptable salt thereof is administered in adults.
  • Almonertinib is administered at a dose of 2 to 250 mg, for example 110 mg per day, as Almonertinib;
  • Alflutinib or a pharmaceutically acceptable salt thereof is administered as Alflutinib at a dose of 2 to 250 mg, for example 80 mg per day, in adults.
  • the present disclosure also discloses the following:
  • IN10018 or a pharmaceutically acceptable salt thereof and an epidermal growth factor receptor tyrosine kinase inhibitor in the preparation of a medicament for treating tumors in a subject, the structure of IN10018 is as follows:
  • a pharmaceutical combination product of IN10018 or a pharmaceutically acceptable salt thereof and an epidermal growth factor receptor tyrosine kinase inhibitor, which is used to treat tumors in a subject, and the structure of IN10018 is as follows:
  • a method of treating tumors comprising administering to a subject in need a therapeutically effective amount of IN10018 or a pharmaceutically acceptable salt thereof and an epidermal growth factor receptor tyrosine kinase inhibitor, the structure of IN10018 being as follows:
  • epidermal growth factor receptor tyrosine kinase inhibitor is Gefitinib (gefitinib), Erlotinib (erlotinib).
  • Icotinib Icotinib
  • Afatinib Afatinib
  • Crizotinib Cyclotinib
  • Osimertinib Osimertinib (AZD9291), Almonertinib (Ametinib), Alflutinib (Eflutinib) , also known as Furmonertinib (Fumetinib), EA1045, JBJ-25-02, BLU945, BLU701, TQB3804, BBT-176, ES-072, BPI-361175, CH7233163 or pharmaceutically acceptable salts thereof, preferably Osimertinib, Almonertinib, Alflutinib or pharmaceutically acceptable salts thereof.
  • the tumor is selected from the group consisting of bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), and esophageal cancer.
  • kits or pharmaceutically acceptable composition comprising:
  • kit or composition of any one of embodiments 8-9 for use as a medicament 10.
  • a method of treating tumors in a subject comprising administering the compounds of the kit or composition according to any one of embodiments 8-11 to the subject simultaneously or sequentially.
  • a method of treating tumors in a subject comprising administering to the subject a therapeutically effective amount of IN10018 or a pharmaceutically acceptable salt thereof and an epidermal growth factor receptor tyrosine kinase inhibitor; said The structure of IN10018 is as follows:
  • the epidermal growth factor receptor tyrosine kinase inhibitor is Gefitinib, Erlotinib, Icotinib ), Afatinib, Crizotinib, Osimertinib, AZD9291, Almonertinib, Alflutinib, also known as Furmonertinib )), EA1045, JBJ-25-02, BLU945, BLU701, TQB3804, BBT-176, ES-072, BPI-361175, CH7233163 or pharmaceutically acceptable salts thereof, preferably Osimertinib, Almonertinib, Alflutinib or pharmaceutically acceptable salts thereof Acceptable salt.
  • the tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer Cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma , Sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, Ovarian cancer, salivary gland cancer, metastases from spindle cell carcinoma, anaplastic large cell lymph
  • epidermal growth factor receptor tyrosine kinase inhibitor is Gefitinib, Erlotinib, Icotinib ), Afatinib, Crizotinib, Osimertinib, AZD9291, Almonertinib, Alflutinib, also known as Furmonertinib )), EA1045, JBJ-25-02, BLU945, BLU701, TQB3804, BBT-176, ES-072, BPI-361175, CH7233163 or pharmaceutically acceptable salts thereof, preferably Osimertinib, Almonertinib, Alflutinib or pharmaceutically acceptable salts thereof Acceptable salt.
  • the tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer Cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma , Sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, Ovarian cancer, salivary gland cancer, metastases from spindle cell carcinoma, anaplastic large cell
  • an epidermal growth factor receptor tyrosine kinase inhibitor in the preparation of a medicament for treating tumors in a subject, wherein the epidermal growth factor receptor tyrosine kinase inhibitor and IN10018 or a pharmaceutically acceptable
  • the structure of IN10018 is as follows:
  • the epidermal growth factor receptor tyrosine kinase inhibitor is Gefitinib (gefitinib), Erlotinib (erlotinib), Icotinib (icotinib), Afatinib (Afatinib), Crizotinib (Crizotinib), Osimertinib (AZD9291), Almonertinib (Ametinib), Alflutinib (Fumetinib, Furmonertinib, Aflutinib), EA1045, JBJ-25-02, BLU945, BLU701, TQB3804, BBT-176, ES-072, BPI-361175, CH7233163 or pharmaceutically acceptable salts thereof, preferably Osimertinib, Almonertinib, Alflutinib or pharmaceutically acceptable salts thereof.
  • the tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer Cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma , Sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, Ovarian cancer, salivary gland cancer, metastases from spindle cell carcinoma, anaplastic large cell
  • IN10018 or a pharmaceutically acceptable salt thereof in the preparation of a drug for the treatment of tumors in combination with an epidermal growth factor receptor tyrosine kinase inhibitor; the structure of IN10018 is as follows:
  • epidermal growth factor receptor tyrosine kinase inhibitor is Gefitinib (gefitinib), Erlotinib (erlotinib), Icotinib (Erlotinib).
  • tumor is bladder cancer, breast cancer, cervical cancer, colon cancer (including colorectal cancer), esophageal cancer, esophageal squamous cell carcinoma, head and neck cancer Cancer, liver cancer, lung cancer (including small cell lung cancer and non-small cell lung cancer), melanoma, myeloma, rhabdomyosarcoma, inflammatory myofibroblastic tumor, neuroblastoma, pancreatic cancer, prostate cancer, kidney cancer, renal cell carcinoma , Sarcoma (including osteosarcoma), skin cancer (including squamous cell carcinoma), gastric cancer, testicular cancer, thyroid cancer, uterine cancer, mesothelioma, cholangiocarcinoma, leiomyosarcoma, liposarcoma, nasopharyngeal cancer, neuroendocrine cancer, Ovarian cancer, salivary gland cancer, metastases from spindle cell carcinoma, anaplastic large
  • KPL cells (Institute of Cell Science, Chinese Academy of Sciences) were cultured with RPMI 1640 (Shanghai Yuanpei, classification number: L210KJ, batch number: F210916) + 10% FBS (Gibco, classification number: 10099-141c, batch number: 2158737cp), and passaged twice.
  • four groups were set up. The first group was the negative control group and culture medium was added. The second group was IN10018 at a concentration of 10 ⁇ M. The third group was Almonertinib at a concentration of 4.7 ⁇ M. The fourth group was IN10018 and Almonertinib.
  • the combination group is IN10018 (10 ⁇ M) and Almonertinib (4.7 ⁇ M). Mix the drugs and incubate in a 5% CO2 incubator at 37°C for 48 hours.
  • Example 4 Study on the in vivo anti-tumor efficacy of AZD9291 in colon cancer CT-26 cell BALB/c mouse subcutaneous allograft tumor model
  • Light cycle 12 hours of light, 12 hours of no light
  • Cage Made of polycarbonate, volume 300mm ⁇ 180mm ⁇ 150mm.
  • the bedding material is corn cobs and is changed twice a week.
  • Drinking water Experimental animals can drink sterilized water freely.
  • Animal identification Experimental animals are identified with ear tags.
  • Dosage regimen of test substances on CT-26 mouse xenograft tumor model Note: 1. Number of mice in each group; 2. Administration volume: Based on the mouse body weight of 10 mL/kg, if the body weight drops by more than 15%, the animal will stop administration; wait until the body weight recovers to a 10% decrease before resuming administration.
  • Routine examinations include observing tumor growth and the effects of drug treatment on the daily behavioral performance of the animals, such as behavioral activities, food and water intake (visual inspection only), weight changes, appearance signs or other abnormal conditions.
  • the number of animal deaths and side effects within the group were recorded based on the number of animals in each group.
  • the animal's health condition continues to deteriorate, or the tumor volume exceeds 3,000mm 3 , or it has severe disease or pain, it must be euthanized. If the following conditions occur, the veterinarian will be notified and euthanasia will be implemented: obvious weight loss, weight loss of more than 20%; unable to freely eat and drink; the average tumor volume in the control group reaches 2,000mm 3 , and the experiment will be terminated.
  • the animals showed the following clinical manifestations and continued to worsen: piloerection, arched back, white ears, nose, eyes or feet, rapid breathing, convulsions, continuous diarrhea, dehydration, slow movement and vocalization.
  • Tumor diameter was measured with vernier calipers three times a week.
  • TGI (%) [1-(Average tumor volume of a certain administration group-Average tumor volume of the administration group at the beginning of treatment)/(Average tumor volume of the solvent control group-Average tumor volume of the solvent control group at the beginning of treatment)] ⁇ 100%.
  • the tumor volume in the control group was 1546.6 ⁇ 1038.8mm 3 .
  • the experiment was conducted in accordance with the dosage regimen. During the experiment, the animals were observed for eating, drinking and other activities every day, and the animal weight was recorded three times a week. The animal weight curve is shown in Figure 8. During the entire dosing cycle, the animals in each group showed no significant weight loss and were in good condition.
  • Example 5 Study on the in vivo anti-tumor efficacy of AZD9291 and IN10018 in human non-small cell lung cancer HCC827 cell BALB/c-nude mouse subcutaneous xenograft tumor model
  • Human non-small cell lung cancer cells HCC827 (sourced from Shanghai Cell Bank, product number: TCHu153) were maintained and passaged by Nanjing Yunqiao Purui Biotechnology Co., Ltd.
  • the cells were cultured in monolayer in vitro, and the culture conditions were RPMI-1640 medium + 10% FBS, 37°C, and 5% CO2 .
  • 0.1 mL of cell suspension containing 5 ⁇ 10 6 cells was inoculated subcutaneously into the right back of each mouse. When the tumor volume reached about ⁇ 147 mm 3 (on the 16th day after cell inoculation), the tumors were randomly grouped and administered according to the tumor volume. The grouping information is shown in Table 5.
  • the tumors were divided into groups based on tumor volume.
  • the average tumor volume in the group was approximately 147 mm 3 .
  • the control group was euthanized on the 48th day after vaccination, that is, the 32nd day after group administration; the AZD9291 high-dose (3mg/kg) and the combination group related to the IN10018 25mg/kg group were euthanized in the control group.
  • the 53rd day after vaccination that is, on the 37th day after group administration, the entire experiment was completed by euthanasia.
  • the AZD9291 (3mg/kg), IN10018 (25mg/kg) and AZD9291+IN10018 (3+25mg/kg) groups continued to be administered and observed until the 37th day. .
  • the tumor volumes of the AZD9291 (3mg/kg) and IN10018 (25mg/kg) single drug groups were 17.0 ⁇ 6.7mm 3 and 69.6 ⁇ 46.6mm 3 respectively.
  • the tumor volume in the AZD9291+IN10018 (3+25mg/kg) two-drug combination group was 5.8 ⁇ 6.5mm 3 .
  • Table 5-2 Evaluation of the anti-tumor effect of test substances on the BALB/c-nude mouse transplant tumor model of human non-small cell lung cancer HCC827 cells (based on the data on the 37th day after group administration) Note: 1. Calculated based on the number of days after group administration, the data is the mean ⁇ standard deviation (mean ⁇ SD); 2.*: p ⁇ 0.05, **: p ⁇ 0.01, vs.AZD9291+IN10018(3+25mg/kg), t-test, Mann Whitney test
  • the experiment was conducted in accordance with the dosage regimen. During the experiment, the animals were observed for eating, drinking and other activities every day, and the animal weight was recorded three times a week. After 28 days of group administration, the average weight of the control group changed from 20.0g on the day of group administration (Day0) to 19.4g, with a weight growth rate of -3.3%; the average weight of the IN10018 (25mg/kg) treatment group changed from Day0 The weight change rate from 21.3g to 20.7g on Day28 was -2.6%;
  • the average weight of the AZD9291 (3mg/kg) and IN10018 (25mg/kg) single drug groups changed from 19.9g and 21.3g on Day0 to 19.4g and 20.3g on Day37, respectively.
  • the weight change rates were respectively -2.2% and -4.5%; the average weight of the AZD9291+IN10018 (3+25mg/kg) group changed from 20.0g on Day0 to 19.5g on Day37, with a weight change rate of -2.3%.
  • the tumor volume of the AZD9291+IN10018 (3+25mg/kg) two-drug combination group has always been smaller than that of the AZD9291 (3mg/kg) and IN10018 (25mg/kg) single-drug treatment groups, and is consistent with There are also statistical differences between the two monotherapy groups, showing that the combination of AZD9291+IN10018 (3+25mg/kg) has a better effect on inhibiting tumor growth.
  • Anti-calreticulin antibody Recombinant Alexa 647 Fluorescent Anti-Calreticulin (anti-calreticulin) antibody (Abcam, ab196159), FAK antibody (CST, 3285S), Phospho-eIF2 ⁇ (Ser51) (CST, 3398), eif2 ⁇ (CST, 5324), DDIT3 (HUABIO, ET1703-05), HRP-labeled Alpha tubulin ( ⁇ -tubulin) antibody (Proteintech, HRP-66031).
  • a 96-well cell plate was laid with 5000 HCC827 cells/well, and 24 hours later a fixed concentration of IN10018 combined with different concentrations of AZD9291 was added.
  • the concentrations of IN10018 are 3 ⁇ M and 5 ⁇ M; the highest concentration of AZD9291 is 1 ⁇ M, and a total of 9 concentrations are set by 3-fold concentration gradient dilution.
  • 10 ⁇ L of CCK8 solution was added to each well.
  • a microplate reader was used to set the absorbance wavelength to 450 nm for reading. The values read were compared to the DMSO control group and plotted using Graphpad 8.0. See attached figure 12 for details.

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Abstract

本公开涉及IN10018和表皮生长因子受体酪氨酸激酶抑制剂联合治疗肿瘤。

Description

治疗肿瘤的药物组合及用途 技术领域
本发明属于药物化学领域。具体地，本发明涉及粘着斑激酶(Focal Adhesive Kinase,FAK)抑制剂IN10018与其它抗肿瘤药物联用治疗肿瘤。
背景技术
EGFR，中文名为表皮生长因子受体(Epidermal Growth Factor Receptor，EGFR)。EGFR基因负责编码并制造一种称为表皮生长因子受体的受体蛋白。EGFR受体蛋白是一种跨膜蛋白，其分为三部分：蛋白的一端位于细胞外，一部分位于细胞膜，另一端则位于细胞内。这允许EGFR受体与细胞外的其他蛋白(称为配体)结合，帮助细胞接收信号并对其刺激作出反应。而受体与配体的结合如同钥匙与锁，因此它们都有特定的结合“伙伴”。当EGFR与配体结合时，它会附着于另一个位于附近的EGFR受体并形成复合物(二聚体)，从而进入激活状态，并激活细胞内的信号传导途径。EGFR突变主要发生在18～21号外显子，其中19号外显子的缺失突变和21号外显子的L858R点突变是最常见的突变类型，占所有突变类型的90％。当EGFR发生致病性基因突变时，EGFR受体蛋白便会处于持续激活状态，这导致细胞持续接收增生和生存的信号，造成细胞过度生长及存活(不能正常凋亡)，导致肿瘤的形成。
目前上市针对肿瘤EGFR突变的靶向药物包括：一代针对19、21外显子突变的埃克替尼(icotinib)、吉非替尼(gefitinib)、厄洛替尼(erlotinib)；二代针对8、20号外显子突变的阿法替尼(afatinib)及三代针对T790M突变的奥希替尼(osimertinib，在本文中也称作AZD9291)、阿美替尼(Almonertinib)及艾氟替尼(Alflutinib)。针对ALK突变的靶向药物包括：一代靶向药物克唑替尼(crizotinib)，二代靶向药色瑞替尼(ceritinib)、艾乐替尼(alectinib)、布格替尼(brigatinib)及三代的靶向药物劳拉替尼(lorlatinib)等。但这些靶向药物耐药性多出现于用药后1年左右。克服靶向药物的耐药性，或推迟耐药时间是抗肿瘤药物研发的主要目标。
发明内容
本公开一方面提供了IN0018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂在制备用于在对象中治疗肿瘤的药物中的用途，所述IN10018结构如下：
本公开又一方面提供了IN0018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂的药物组合产品，其用于在对象中治疗肿瘤。
本公开又一方面提供了一种治疗肿瘤的方法，该方法包括向有需要的对象施用治疗有效量的IN0018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂。
本公开又一方面提供了一种试剂盒或药学上可接受的组合物，其包括：(a)IN0018或其药学上可接受的盐；和(b)表皮生长因子受体酪氨酸激酶抑制剂。
本公开又一方面提供了IN0018或其药学上可接受的盐与表皮生长因子受体酪氨酸激酶抑制剂在制备用于治疗肿瘤的联用药物中的用途。
本公开又一方面提供了IN0018或其药学上可接受的盐在制备用于与表皮生长因子受体酪氨酸激酶抑制剂治疗肿瘤的联用药物中的用途。
本公开又一方面提供了表皮生长因子受体酪氨酸激酶抑制剂在制备用于与IN0018或其药学上可接受的盐治疗肿瘤的联用药物中的用途。
本公开又一方面提供了一种试剂盒，其包括：IN0018或其药学上可接受的盐；和说明书，该说明书指出该IN0018或其药学上可接受的盐可用于与表皮生长因子受体酪氨酸激酶抑制剂联合治疗肿瘤。
本公开又一方面提供了一种试剂盒，其包括：表皮生长因子受体酪氨酸激酶抑制剂；和说明书，该说明书指出该表皮生长因子受体酪氨酸激酶抑制剂可用于与IN0018或其药学上可接受的盐联合治疗肿瘤。
本公开另一方面提供了一种治疗肿瘤的方法，该方法包括向有需要的对象施用治疗有效量的IN0018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂。
本公开又一方面提供了IN0018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂的药物组合产品，其用于在有需要的对象中治疗肿瘤。
可选的，所述IN10018药学上可接受的盐为IN10018酒石酸盐。
可选的，所述表皮生长因子受体酪氨酸激酶抑制剂为Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(艾氟替尼，又名Furmonertinib(伏美替尼))、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐，优选为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
所述Gefitinib(吉非替尼)，CAS号为184475-35-2；Erlotinib(厄洛替尼)CAS号为183321-74-6；Icotinib(埃克替尼)，CAS号为610798-31-7；Afatinib(阿法替尼)，CAS号为850140-72-6；Crizotinib(克唑替尼)，CAS号为877399-52-5；Osimertinib(奥希替尼，AZD9291)，CAS号为1421373-65-0；Almonertinib(阿美替尼)，CAS号为1899921-05-1；Alflutinib (艾氟替尼，又名Furmonertinib(伏美替尼))，CAS号为1869057-83-9；EAI045，CAS号为1942114-09-1；JBJ-04-125-02，CAS号为2060610-53-7；BLU945，CAS号为2660250-10-0；BLU701是缆图药业公司(Blueprint Medicines Corp)和再鼎医药联合开发；TQB3804，CAS号为2267329-76-8；BBT-176是毕利吉生物科技股份有限公司开发；ES-072是由博生医药开发；BPI-361175是由贝达药业研发；CH7233163是由中外制药株式会社开发。
可选的，所述IN0018或其药学上可接受的盐和所述表皮生长因子受体酪氨酸激酶抑制剂被同时或依次施用于所述对象。
可选的，所述肿瘤选自膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选的，其中所述肿瘤为肺癌、乳腺癌、神经胶质瘤食管癌、头颈癌或结直肠癌；优选的，所述肿瘤为肺癌或结直肠癌。
附图说明
为了更清楚地说明本公开实施例的技术方案，下面将对实施例的附图作简单地介绍，显而易见地，下面描述中的附图仅仅涉及本公开的一些实施例，而非对本发明的限制。
图1显示了实施例1肺癌KPL细胞与药物孵育48小时后，拍摄细胞的白光显微镜照片。
图2显示了实施例1肺癌KPL细胞与药物孵育48小时后，annexin V阳性KPL细胞的百分比。
图3显示了实施例2肺癌KPL细胞与药物孵育48小时后，拍摄细胞的白光显微镜照片。
图4显示了实施例2肺癌KPL细胞与药物孵育48小时后，annexin V阳性KPL细胞的百分比。
图5显示了实施例3肺癌KPL细胞与药物孵育48小时后，拍摄细胞的白光显微镜照片。
图6显示了实施例3肺癌KPL细胞与药物孵育48小时后，annexin V阳性KPL细胞的百分比。
图7显示了实施例4小鼠结肠癌CT-26的BALB/c小鼠同种移植瘤模型中荷瘤鼠在给予不同受试物后的肿瘤生长的变化。
图8显示了实施例4给予不同受试物后CT-26荷瘤小鼠体重变化情况。
图9显示了实施例5给予不同受试物后小鼠肿瘤生长曲线，数据点代表组内平均肿瘤体积，误差线代表标准误(SEM)。
图10显示实施例5实验终点各治疗组肿瘤数据，数据点代表组内每只动物的肿瘤体积，误差线代表标准误(SEM)。
图11显示实施例5给予不同受试物后小鼠体重变化情况，数据点代表组内平均体重，误差线代表标准误(SEM)。
图12显示实施例6中不同剂量下AZD9291分别与3μM IN10018和5μM IN10018合用48小时对非小细胞肺癌细胞HCC827的杀伤协同作用。
图13显示实施例6中0.3nM AZD9291与3μM IN10018合用处理HCC827细胞48小时后检测细胞凋亡。
具体实施方式
为使本公开实施例的目的、技术方案和优点更加清楚，下面将结合本公开实施例的附图，对本公开实施例的技术方案进行清楚、完整地描述。显然，所描述的实施例是本公开的一部分实施例，而不是全部的实施例。基于所描述的本公开的实施例，本领域普通技术人员在无需创造性劳动的前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明可在不偏离本发明基本属性的情况下以其它具体形式来实施。应该理解的是，在不冲突的前提下，本发明的任一和所有实施方案都可与任一其它实施方案或多个其它实施方案中的技术特征进行组合以得到另外的实施方案。本发明包括这样的组合得到的另外的实施方案。
本公开中提及的所有出版物和专利在此通过引用以它们的全部内容纳入本公开。如果通过引用纳入的任何出版物和专利中使用的用途或术语与本公开中使用的用途或术语冲突，那么以本公开的用途和术语为准。
本文所用的章节标题仅用于组织文章的目的，而不应被解释为对所述主题的限制。
除非另有规定，本文使用的所有技术术语和科学术语具有要求保护主题所属领域的通常含义。倘若对于某术语存在多个定义，则以本文定义为准。
除了在工作实施例中或另外指出之外，在说明书和权利要求中陈述的定量性质例如剂量的所有数字应理解为在所有情况中被术语“约”修饰。还应理解的是，本申请列举的任何数字范围意在包括该范围内的所有的子范围和该范围或子范围的各个端点的任何组合。
本公开中使用的“包括”、“含有”或者“包含”等类似的词语意指出现该词前面的要素涵盖出现在该词后面列举的要素及其等同，而不排除未记载的要素。本文所用的术语“含有”或“包括(包含)”可以是开放式、半封闭式和封闭式的。换言之，所述术语也包括“基本上由…组成”、或“由…组成”。
定义
本申请中所用的下列术语和符号具有如下所述的含义，其所处的上下文中另有说明的除外。
本文所用术语“表皮生长因子受体酪氨酸激酶抑制剂”是可选择性地、有效地抑制表皮生长因子受体酪氨酸激酶的药剂。所述表皮生长因子受体酪氨酸激酶抑制剂的实例包括但不限于Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(艾氟替尼，又名Furmonertinib(伏美替尼))、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐。在一些实施方案中，所述表皮生长因子受体酪氨酸激酶抑制剂为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
所述Gefitinib(吉非替尼)，CAS号为184475-35-2；Erlotinib(厄洛替尼)CAS号为183321-74-6；Icotinib(埃克替尼)，CAS号为610798-31-7；Afatinib(阿法替尼)，CAS号为850140-72-6；Crizotinib(克唑替尼)，CAS号为877399-52-5；Osimertinib(奥希替尼，AZD9291)，CAS号为1421373-65-0；Almonertinib(阿美替尼)，CAS号为1899921-05-1；Alflutinib(艾氟替尼，又名Furmonertinib(伏美替尼))，CAS号为1869057-83-9；EAI045，CAS号为1942114-09-1；JBJ-04-125-02，CAS号为2060610-53-7；BLU945，CAS号为2660250-10-0；BLU701是缆图药业公司(Blueprint Medicines Corp)和再鼎医药联合开发；TQB3804，CAS号为2267329-76-8；BBT-176是毕利吉生物科技股份有限公司开发；ES-072是由博生医药开发；BPI-361175是由贝达药业研发；CH7233163是由中外制药株式会社开发。
本文所用的“药物组合”或者“药物组合产品”既可以指采用一个剂量单位形式的固定组合(例如所有药物活性成分以一种剂型存在)或者成套药盒以组合施用的产品的情形，也可以指一种药物与指示该药物可与另外的一种或多种药物联合使用的说明书的组合情形。
本文所用的“联合治疗”或者“联用药物”是指一种药物与另外的一种或多种药物联合使用来治疗疾病，既包括一种药物与另外的一种或多种药物的组合的情形，也包括一种药物与指示该药物可与另外的一种或多种药物联合使用的说明书的组合情形。
“同时或依次施用”在本申请中是指一个给药周期内(例如4周内、3周内、2周内、1周内或24小时以内)两种以上的药物同时或以一定时间间隔先后施用，药物施用的方式(例如口服、静脉、肌肉或皮下施用等)可以相同或不同，两种以上的药物的给药频率/周期可以相同或不同。当本公开的治疗方法、产品或用途涉及两种药物时，两种药物可同时或以一定时间间隔分别单独施用。
本文所用的术语“治疗”是指给患有疾病或者具有所述疾病的症状的对象施用一种或多种药物物质，用以治愈、缓解、减轻、改变、医治、改善、改进或影响所述疾病或者所述疾病的症状。在一些实施方案中，所述疾病是肿瘤或者癌症。
本文所用的术语“肿瘤”是指机体在各种致瘤因素的作用下，局部组织的细胞在基因水平上失去对其生长的正常调控，从而导致其克隆型异常增生而形成的异常病变。实施例包括，但不限于：膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤，神经胶质瘤以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选的，其中所述肿瘤为肺癌、乳腺癌、神经胶质瘤食管癌、头颈癌或结肠癌；优选的，所述肿瘤为肺癌或结肠癌。
本文所用的术语“对象”或“受试者”是指哺乳动物和非哺乳动物。哺乳动物是指哺乳类的任何成员，其包括但不限于：人；非人灵长类动物，如黑猩猩及其它猿类和猴类物种；农场动物，如牛、马、绵羊、山羊和猪；家畜，如兔、狗和猫；实验室动物，包括啮齿类动物，如大鼠、小鼠和豚鼠；等等。非哺乳动物的例子包括但不限于鸟等。术语“对象”并不限定特定的年龄或性别。在一些实施方案中，对象是人。
本文所用的术语“药学上可接受的”指的是无毒的、生物学上可耐受的，适合给对象施用的。
本文所用的术语“药学上可接受的盐”指的是无毒的、生物学上可耐受的适合给对象施用的酸加成盐，包括但不限于：与无机酸形成的酸加成盐，例如盐酸盐、氢溴酸盐、碳酸盐、碳酸氢盐、磷酸盐、硫酸盐、亚硫酸盐、硝酸盐等；以及与有机酸形成的酸加成盐，例如甲酸盐、乙酸盐、苹果酸盐、马来酸盐、富马酸盐、酒石酸盐、琥珀酸盐、柠檬酸盐、乳酸盐、甲磺酸盐、对甲苯磺酸盐、2-羟基乙磺酸盐、苯甲酸盐、水杨酸盐、硬脂酸盐和与式HOOC-(CH2)n-COOH(其中n是0-4)的链烷二羧酸形成的盐等。
此外，药学上可接受的酸加成盐可以按照由碱性化合物制备酸加成盐的常规操作通过将游离碱溶于合适的溶剂并用酸处理该溶液来得到。本领域技术人员无需过多实验即可确定各种可用来制备无毒的药学上可接受的酸加成盐的合成方法。在一些实施例中，IN10018药学上可接受的盐为酒石酸盐。
本文所用的术语“药学上可接受的组合物”是指必须在化学和/或毒理学上与包括制剂的其他成分相容，和/或与接受其治疗的对象相容。本文所用的术语“治疗有效量”是指通常足以对对象产生有益治疗效果的量。可以通过常规方法(例如建模、剂量递增研究或临床试验)结合常规影响因素(例如给药方式、化合物的药代动力学、疾病的严重程度和病程、对象的病史、对象的健康状况、对象对药物的响应程度等)来确定本发明的治疗有效量。
本文所用的术语“抑制”是指生物活动或过程的基线活性的降低。
本文所用的术语“试剂盒”是指用于盛放检测化学成分、药物残留、病毒种类等化学试剂的盒子。本发明所述试剂盒可以是包括(i)IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂中的一种或二种；以及(ii)说明书，所述说明书指出可使用IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂来在对象中治疗肿瘤。在一种实施方案中，试剂盒包括(i)IN10018或其药学上可接受的盐；以及(ii)说明书，所述说明书指出可使用IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂来在对象中治疗肿瘤。在一种实施方案中，试剂盒包括(i)表皮生长因子受体酪氨酸激酶抑制剂；以及(ii)说明书，所述说明书指出可使用IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂来在对象中治疗肿瘤。在一种实施方案中，试剂盒包括(i)IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂；以及(ii)说明书，所述说明书指出可使用IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂来在对象中治疗肿瘤。
试剂盒的化合物可以包含在分开的容器中。可选地，两种或更多种化合物包含在同一容器中。例如，试剂盒可以包括第一容器、第二容器和包装插页，其中第一容器包括至少一个剂量的包括IN10018或其药学上可接受的盐的药物，第二容器包括至少一个剂量的表皮生长因子受体酪氨酸激酶抑制剂，且所述包装插页包括使用药物治疗对象的肿瘤的说明。第一容器和第二容器可以包含相同或不同形状(例如，小瓶、注射器和瓶)和/或材料(例如，塑料或玻璃)。试剂盒还可以包括可以有助于施用药物的其他材料，如稀释剂、过滤器、IV袋和管线、针和注射器。
给予受试者的IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂的精确量将取决于各种因素，例如给定的药物或化合物，药物制剂，给药途径，疾病类型，病症，所治疗的受试者或宿主的身份等，但是仍然可以由本领域技术人员常规确定。例如，确定有效量还取决于细胞增殖的程度，严重性和类型。技术人员将能够根据这些和其他因素确定合适的剂量。
IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂可选择合适的方式例如口服、静脉、肌肉或皮下施用给药。
例如，口服给药时，可以将药物与药学上可接受的载体例如惰性稀释剂或可吸收的食用载体一起口服给药。它们可以封装在硬壳或软壳明胶胶囊中，可以压制成片剂，或者可以直接与患者的食物混合。例如，药物可以与一种或多种赋形剂组合，并以可摄取的片剂，口腔片剂，锭剂，胶囊，酏剂，悬浮液，糖浆或糯米纸囊剂等形式使用。片剂，锭剂，丸剂，胶囊剂等可进一步包括：粘合剂，例如黄芪胶，阿拉伯胶，玉米淀粉或明胶；赋形剂，如磷酸二钙；崩解剂，例如玉米淀粉，马铃薯淀粉，海藻酸等；润滑剂，例如硬脂酸镁；或甜味剂，例如蔗糖，果糖，乳糖或阿斯巴甜；或调味剂。
例如，输注或注射静脉内或腹膜内给药时，药物的溶液可以在水中制备，任选地与无毒的表面活性剂混合。
用于注射或输注的示例性药物剂型包括：无菌水溶液，分散液，或包含活性成分的无菌粉末，该无菌粉末适合于临时制备无菌注射或输注溶液或分散液。无论如何，最终剂型在生产和储存条件下均应无菌，流动且稳定。
无菌注射溶液可以通过将所需量的药物与所需的上述各种其他成分掺入适当的溶剂中，然后过滤灭菌来制备。对于用于制备无菌注射溶液的无菌粉末，优选的制备方法可以是真空干燥和冷冻干燥技术，其可以产生活性成分加上先前无菌过滤后存在的任何其他所需成分的粉末。
用于治疗所需的IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂的量不仅可以随所选择的特定试剂而变化，还可以随给药途径，所治疗疾病的性质以及患者的年龄和状况而变化，并且最终可以由主治医师或临床医生自行决定。然而，一般而言，剂量可以在每天约0.1至约50mg/kg体重的范围内。
在一些实施方案中，IN10018或其药学上可接受盐以成年人中5mg/天-100mg/天，例如20mg/天的剂量施用，所述剂量以游离碱计。
所述表皮生长因子受体酪氨酸激酶抑制剂以成年人中每天2-500mg的剂量范围施用。在一种具体的实施方式中，Osimertinib或其药学上可接受盐以成年人中每天2-500mg，例如80mg的剂量施用，所述剂量Osimertinib计；Almonertinib或其药学上可接受盐以成年人中每天2-250mg，例如110mg的剂量施用，所述剂量以Almonertinib计；Alflutinib或其药学上可接受盐以成年人中每天2-250mg，例如80mg的剂量施用，所述剂量以Alflutinib计。
本文所用的未具体定义的技术和科学术语具有本发明所属领域的技术人员通常理解的含义。
在一些实施方案中，本公开还公开了以下：
1.IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂在制备用于在对象中治疗肿瘤的药物中的用途，所述IN10018结构如下：
2.IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂的药物组合产品，其用于在对象中治疗肿瘤，所述IN10018结构如下：
3.一种治疗肿瘤的方法，该方法包括向有需要的对象施用治疗有效量的IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂，所述IN10018结构如下：
4.如实施方案1-3任一项所述的用途、药物组合产品或者方法，其中所述IN10018药学上可接受的盐为酒石酸盐。
5.如实施方案1-4任一项所述的用途、药物组合产品或者方法，其中所述表皮生长因子受体酪氨酸激酶抑制剂为Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(艾氟替尼，又名Furmonertinib(伏美替尼))、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐，优选为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
6.如实施方案1-5任一项所述的用途、药物组合产品或者方法，其中所述IN10018或其药学上可接受的盐和所述表皮生长因子受体酪氨酸激酶抑制剂被同时或依次施用于所述对象。
7.如实施方案1-6任一项所述的用途、药物组合产品或者方法，其中所述肿瘤为选自膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选的，其中所述肿瘤为肺癌、乳腺癌、神经胶质瘤食管癌、头颈癌或结肠癌；优选的，其中所述肿瘤为肺癌或结肠癌。
8.一种试剂盒或药学上可接受的组合物，其包括：
(a)IN10018或其药学上可接受的盐；和
(b)表皮生长因子受体酪氨酸激酶抑制剂，
所述IN10018结构如下：
9.如实施方案8所述的试剂盒或组合物，其中所述表皮生长因子受体酪氨酸激酶抑制剂为Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(艾氟替尼，又名Furmonertinib(伏美替尼))、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐，优选为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
10.如实施方案8-9任一项所述的试剂盒或组合物，其用作药物。
11.如实施方案8-10任一项所述的试剂盒或组合物，所述IN10018药学上可接受的盐为酒石酸盐。
12.一种在对象中治疗肿瘤的方法，其中所述方法包括将根据实施方案8-11任一项所述的试剂盒或组合物中的化合物同时或依次施用至所述对象。
13.如实施方案12所述的方法，所述肿瘤为选自膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选的，其中所述肿瘤为肺癌、乳腺癌、神经胶质瘤食管癌、头颈癌或结肠癌；优选的，其中所述肿瘤为肺癌或结肠癌。
14.一种在对象中治疗肿瘤的方法，其中所述方法包括向所述对象施用治疗有效量的IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂；所述IN10018结构如下：
15.如实施方案14所述的方法，其中所述IN10018其药学上可接受的盐是IN10018酒石酸盐。
16.如实施方案14或15所述的方法，其中所述表皮生长因子受体酪氨酸激酶抑制剂为Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(艾氟替尼，又名Furmonertinib(伏美替尼))、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐，优选为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
17.如实施方案14-16任一项所述的方法，其中所述IN10018或其药学上可接受的盐和所述表皮生长因子受体酪氨酸激酶抑制剂被同时或依次施用于所述对象。
18.如实施方案14-17任一项所述的方法，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选的，其中所述肿瘤为肺癌、乳腺癌、神经胶质瘤食管癌、头颈癌或结肠癌；优选的，其中所述肿瘤为肺癌或结肠癌。
19.IN10018或其药学上可接受的盐在制备用于在对象中治疗肿瘤的药物中的用途，其中将所述IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂施用于所述对象，所述IN10018结构如下：
20.如实施方案19所述的用途，其中所述IN10018药学上可接受的盐是IN10018酒石酸盐。
21.如实施方案19或20所述的用途，其中所述表皮生长因子受体酪氨酸激酶抑制剂为Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(艾氟替尼，又名Furmonertinib(伏美替尼))、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐，优选为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
22.如实施方案19-21任一项所述的用途，其中所述IN10018或其药学上可接受的盐和所述表皮生长因子受体酪氨酸激酶抑制剂被同时或依次施用于所述对象。
23.如实施方案19-22任一项所述的用途，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤，神经胶质瘤以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选的，其中所述肿瘤为肺癌、乳腺癌、神经胶质瘤食管癌、头颈癌或结直肠癌；优选的，其中所述肿瘤为肺癌或结肠癌。
24.表皮生长因子受体酪氨酸激酶抑制剂在制备用于在对象中治疗肿瘤的药物中的用途，其中将所述表皮生长因子受体酪氨酸激酶抑制剂和IN10018或其药学上可接受的盐施用于所述对象，所述IN10018结构如下：
25.如实施方案24所述的用途，其中所述表皮生长因子受体酪氨酸激酶抑制剂为Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(伏美替尼、Furmonertinib、艾氟替尼)、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐，优选为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
26.如实施方案24或25所述的用途，其中所述IN10018其药学上可接受的盐是IN10018酒石酸盐。
27.如实施方案24-26任一项所述的用途，其中所述IN10018或其药学上可接受的盐和所述表皮生长因子受体酪氨酸激酶抑制剂被同时或依次施用于所述对象。
28.如实施方案24-27任一项所述的用途，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤，神经胶质瘤以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选的，其中所述肿瘤为肺癌、乳腺癌、神经胶质瘤食管癌、头颈癌或结肠癌；优选的，其中所述肿瘤为肺癌或结肠癌。
29.IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂在制备用于联合治疗肿瘤的药物中的用途；所述IN10018结构如下：
30.IN10018或其药学上可接受的盐在制备用于与表皮生长因子受体酪氨酸激酶抑制剂联合治疗肿瘤的药物中的用途；所述IN10018结构如下：
31.表皮生长因子受体酪氨酸激酶抑制剂在制备用于与IN10018或其药学上可接受的盐联合治疗肿瘤的药物中的用途；所述IN10018结构如下：
32.如实施方案29-31任一项所述的用途，其中所述IN10018或其药学上可接受的盐是IN10018酒石酸盐，
33.如实施方案29-32任一项所述的用途，其中所述表皮生长因子受体酪氨酸激酶抑制剂为Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(伏美替尼、Furmonertinib、艾氟替尼)、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐，优选为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
34.如实施方案29-33任一项所述的用途，其中所述IN10018或其药学上可接受的盐和所述表皮生长因子受体酪氨酸激酶抑制剂被同时或依次施用于所述对象。
35.如实施方案29-34任一项所述的用途，其中所述肿瘤为膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤，神经胶质瘤以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选的，其中所述肿瘤为肺癌、乳腺癌、神经胶质瘤食管癌、头颈癌或结肠癌；优选的，其中所述肿瘤为肺癌或结肠癌。
实施例
提供下面的实施例以进一步阐述本发明。应理解，这些实施例仅用于举例说明本发明，而不用于限制本发明的范围。
下列实施例中未注明具体条件的实验方法均可以按照这类反应的常规条件进行或者按照制造厂商所建议的条件进行。
以下实施例中所用的实验材料和试剂如无特别说明均可从市售渠道获得。
实施例中所用的缩写含义如下：

实施例1：IN10018和AZD9291在肺癌KPL细胞中的研究
KPL细胞(中科院细胞所)用RPMI 1640(上海元培，分类号:L210KJ,批号:F210916)+10％FBS(Gibco，分类号:10099-141c,批号:2158737cp)培养，传代两次，当细胞状况良好时，将培养液放置在24孔板中。细胞铺展24小时后，设四组，第一组为阴性对照组，加入培养基，第二组为IN10018，浓度为10μM，第三组为AZD9291，浓度为10μM，第四组为IN10018和AZD9291联用组，分别为IN10018(10μM)和AZD9291(10μM)。将药物混合，并在37℃的5％CO2培养箱中培养48小时。
药物作用48h后，对细胞进行显微镜观察和拍照，并保存照片。然后收集细胞进行流动分析，并用流动缓冲液(PBS+2％FBS)洗涤细胞两次，将0.5μl共轭GRP94多克隆抗体(Proteintech，分类号：CL488-14700，批号：21006579)添加到每个孔中，混合，在4℃且避光的条件下孵育20min。20min后，用流动缓冲液(PBS+2％FBS)清洗细胞两次。然后在流式细胞仪上进行分析。
显微镜下观察细胞，AZD9291单药组和两药联合组细胞状态较差，两药联合组最差，细胞死亡较多，而阴性对照组和IN10018组细胞状态较好。详见图1和图2。
实施例2：IN10018和Almonertinib在肺癌KPL细胞中的研究
KPL细胞(中科院细胞所)用RPMI 1640(上海元培，分类号:L210KJ, 批号:F210916)+10％FBS(Gibco，分类号:10099-141c,批号:2158737cp)培养，传代两次，当细胞状况良好时，将培养液放置在24孔板中。细胞铺展24小时后，设四组，第一组为阴性对照组，加入培养基，第二组为IN10018，浓度为10μM，第三组为Almonertinib，浓度为4.7μM，第四组为IN10018和Almonertinib联用组，分别为IN10018(10μM)和Almonertinib(4.7μM)。将药物混合，并在37℃的5％CO2培养箱中培养48小时。
药物作用48h后，对细胞进行显微镜观察和拍照，并保存照片。然后收集细胞进行流动分析，并用流动缓冲液(PBS+2％FBS)洗涤细胞两次，将0.5ul共轭GRP94多克隆抗体(Proteintech，分类号：CL488-14700，批号：21006579)添加到每个孔中，混合，在4℃且避光的条件下孵育20min。20min后，用流动缓冲液(PBS+2％FBS)清洗细胞两次。然后在流式细胞仪上进行分析。
显微镜下观察细胞，Almonertinib单药组和两药联合组细胞状态较差，两药联合组最差，细胞死亡较多，而阴性对照组和IN10018组细胞状态较好。详见图3和图4。
实施例3：IN10018和Alflutinib在肺癌KPL细胞中的研究
KPL细胞(中科院细胞所)用RPMI 1640(上海元培，分类号:L210KJ,批号:F210916)+10％FBS(Gibco，分类号:10099-141c,批号:2158737cp)培养，传代两次，当细胞状况良好时，将培养液放置在24孔板中。细胞铺展24小时后，设四组，第一组为阴性对照组，加入培养基，第二组为IN10018，浓度为10μM，第三组为Alflutinib，浓度为4.7μM，第四组为IN10018和Alflutinib联用组，分别为IN10018(10μM)和Alflutinib(4.7μM)。将药物混合，并在37℃的5％CO2培养箱中培养48小时。
药物作用48h后，对细胞进行显微镜观察和拍照，并保存照片。然后收集细胞进行流动分析，并用流动缓冲液(PBS+2％FBS)洗涤细胞两次，将0.5ul共轭GRP94多克隆抗体(Proteintech，分类号：CL488-14700，批号：21006579)添加到每个孔中，混合，在4℃且避光的条件下孵育20min。20min后，用流动缓冲液(PBS+2％FBS)清洗细胞两次。然后在流式细胞仪上进行分析。
显微镜下观察细胞，Alflutinib单药组和两药联合组细胞状态较差，两药联合组最差，细胞死亡较多，而阴性对照组和IN10018组细胞状态较好。详见图5和图6。
实施例4：AZD9291在结肠癌CT-26细胞BALB/c小鼠皮下同种移植瘤模型中的体内抗肿瘤药效研究
实验材料：
小鼠：6-8周龄的雌性BALB/c小鼠购自上海斯莱克实验动物有限责任公司。动物到达后在实验环境适应性饲养后开始实验。动物在SPF级动物房以IVC(独立送风系统)笼具饲养(每笼5只)。所有笼具、垫料及饮水在使用前均需灭菌。所有实验人员在动物房操作时应穿着防护服和乳胶手套。笼具、饲料及饮水每周更换两次。饲养环境及光照情况如下：
温度：20-26℃
湿度：40-70％
光照周期：12小时光照，12小时无光照
笼具：以聚碳酸酯制成，体积300mm×180mm×150mm。垫料为玉米芯，每周更换两次。
食物：实验动物在整个实验阶段中可自由进食(辐照灭菌，干颗粒状食物)。
饮水：实验动物可自由饮用灭菌水。
笼具标识：每笼动物信息卡应注明笼内动物数目，性别，品系，接收日期，给药方案，实验编号，组别以及实验开始日期。
动物标识：实验动物以耳标进行标识。
化合物信息见表1
表1.化合物信息
结肠癌细胞CT-26(来源南京科佰生物科技有限公司，货号：CBP60043)由应世生物科技(南京)有限公司维持传代。细胞体外单层培养，培养条件为RPMI-1640培养基中加10％胎牛血清，37℃5％CO2培养箱中培养。一周两到三次用胰酶-EDTA进行常规消化处理传代。当细胞处于指数生长期，饱和度为80％-90％时，收取细胞，计数后接种。
细胞接种及分组
将0.1mL含有3×105个细胞的细胞悬液皮下接种于每只小鼠的右后背。当肿瘤体积达到～59mm3时(细胞接种后第12天)，根据肿瘤体积进行随机分组给药，分组信息见表2。
表2.受试物对CT-26小鼠移植瘤模型的给药方案

注：1.每组小鼠数目；
2.给药体积：根据小鼠体重10mL/kg，如果体重下降超过15％，动物停止给
药；待体重恢复至降低10％，再恢复给药。
受试物的配制
详见表3
表3.受试物配置方法
实验动物日常观察
每天监测动物的健康状况及死亡情况，例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动，摄食摄水量(仅目测)，体重变化，外观体征或其它不正常情况。基于各组动物数量记录了组内动物死亡数和副作用。
实验终止
若动物健康状况持续恶化，或瘤体积超过3,000mm3，或有严重疾病，或疼痛，须处以安乐死。有以下情况者，通知兽医并处以安乐死：明显消瘦，体重降低大于20％；不能自由取食和饮水；对照组瘤体积平均值达到2,000mm3，实验终止。动物出现以下临床表现且持续恶化：立毛，弓背，耳、鼻、眼或足色发白，呼吸仓促，抽搐，连续腹泻，脱水，行动迟缓，发声。
肿瘤测量和实验指标
用游标卡尺测量肿瘤直径，每周测量3次。肿瘤体积的计算公式为：V＝0.5×a×b2，a和b分别表示肿瘤的长径和短径。
参照分组后第一天的肿瘤体积，根据以下公式计算肿瘤生长抑制率TGI(％)。TGI(％)＝[1-(某给药组的平均瘤体积-该给药组开始治疗时平均瘤体积)/(溶剂对照组的平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100％。
统计分析
统计分析基于试验结束时肿瘤体积和肿瘤重量运用Prism Graphpad软件进行分析。多组间比较，采用Two-way ANOVA，Fisher’s LSD test法检验进行分析。P<0.05认为有显著性差异。
实验结果
受试物AZD9291与IN10018联用在CT-26小鼠结肠癌细胞BALB/c小鼠皮下同种移植瘤模型中的体内药效。细胞接种后，每天观察肿瘤生长情况，接种后第11天根据肿瘤体积进行分组，入组平均肿瘤体积约为38mm3。由于肿瘤负荷，对照组在接种后的第26天，即分组给药之后的第15天安乐死，整个实验结束。
分组给药后第15天，对照组的肿瘤体积为1546.6±1038.8mm3。IN10018(25mg/kg)、AZD9291(20mg/kg)和AZD9291+IN10018(20+25mg/kg)各治疗组的肿瘤体积分别为1766.9±732.5mm3,1046.3±407.8mm3和540.4±218.0mm3，详见表4。综合肿瘤体积与对照组进行比较，IN10018(25mg/kg)、AZD9291(20mg/kg)和AZD9291+IN10018(20+25mg/kg)组的抑瘤率TGI分别为-14.5％(p＝0.3079)，33.2％(p＝0.0216)和66.6％(p<0.0001)。详见表4。综合瘤体积与AZD9291+IN10018(20+25mg/kg)联用组相比较，进行统计学分析，对照组，IN10018(25mpk)单药和AZD9291(20mpk)单药各组的P值分别为p<0.0001，p<0.0001和p＝0.0202。各剂量组在不同时间段的肿瘤体积如图7所示。
表4受试物对小鼠结肠癌CT-26细胞的BALB/c小鼠移植瘤模型的抑瘤效果评价(基于分组给药后第15天数据)

注：1.按照分组给药后的天数来计算，数据为平均值±标准误差。
2.*：p<0.05，****：p<0.0001，vs.对照组，Two-way ANOVA。
3.*：p<0.05，****：p<0.0001，vs.AZD9291+IN10018(20+25mg/kg)组，Two-way 
ANOVA。
实验按照给药方案进行，实验过程中，每天观察动物摄食饮水等活动，每周记录3次动物体重，动物体重曲线见图8。在整个给药周期中，各组组动物体重均无明显下降且状态良好。
结论
与空白对照组相比，AZD9291(20mg/kg)和AZD9291+IN10018(20+25mg/kg)组均有明显肿瘤生长抑制作用，和对照组相比都有统计学差异。综合整个给药周期，AZD9291+IN10018(20+25mg/kg)组相对于IN10018(25mg/kg)组和AZD9291(20mg/kg)组的肿瘤体积一直都更小，并且和这两组相比均具有统计学差异，其相对于IN10018(25mg/kg)和AZD9291(20mg/kg)单药组，具有更好的抑制肿瘤生长的效果。同时，动物体重变化良好，整个给药周期的活动、饮水进食以及精神状况也未发现异常，说明动物对AZD9291+IN10018(20+25mg/kg)两药联用耐受。
实施例5：AZD9291和IN10018在人非小细胞肺癌HCC827细胞BALB/c-nude小鼠皮下异种移植瘤模型中的体内抗肿瘤药效研究
实验材料






实验方法与步骤
人非小细胞肺癌细胞HCC827(来源上海细胞库，货号：TCHu153)由南京云桥璞瑞生物科技有限公司维持传代。细胞体外单层培养，培养条件为RPMI-1640培养基+10％FBS，37℃，5％CO2中培养。一周两到三次用胰酶-EDTA进行常规消化处理传代。当细胞处于指数生长期，饱和度为80％-90％时，收取细胞，计数后接种。将0.1mL含有5×106个细胞的细胞悬液皮下接种于每只小鼠的右后背。当肿瘤体积达到～147mm3左右时(细胞接种后的第16天)，根据肿瘤体积进行随机分组并给药，分组信息见表5。
表5.体内药效实验动物分组及给药方案

注：1.N为每组小鼠数目
2.给药体积根据小鼠体重为10mL/kg，如果体重下降超过15％，动物停止给药；待体重恢复至降
低10％，再恢复给药
实验动物日常观察
实验动物的使用及福利遵照AAALAC的规定执行。每天监测动物的健康状况及死亡情况，例行检查包括观察肿瘤生长和药物治疗对动物日常行为表现的影响如行为活动、摄食摄水量(仅目测)、体重变化、外观体征或其它不正常情况。基于各组动物数量记录了组内动物死亡数和副作用。
实验终止
若动物健康状况持续恶化，或瘤体积超过3,000mm3，或有严重疾病，或疼痛，须处以安乐死。有以下情况者，通知兽医并处以安乐死：明显消瘦，体重降低大于20％；不能自由取食和饮水；对照组瘤体积平均值达到2,000mm3，实验终止。动物出现以下临床表现且持续恶化：立毛，弓背，耳、鼻、眼或足色发白，呼吸仓促，抽搐，连续腹泻，脱水，行动迟缓，发声。
肿瘤测量和实验指标
实验指标是考察肿瘤生长是否被抑制、延缓或治愈。用游标卡尺测量肿瘤直径，每周测量3次。肿瘤体积的计算公式为：V＝0.5×a×b2，a和b分别表示肿瘤的长径和短径。
化合物的抑瘤疗效用TGI(％)评价，反映肿瘤生长抑制率。参照分组后第一天的肿瘤体积，根据以下公式计算肿瘤生长抑制率TGI(％)。TGI(％)＝[1-(某给药组的平均瘤体积-该给药组开始时平均瘤体积)/(溶剂对照组的平均瘤体积-溶剂对照组开始治疗时平均瘤体积)]×100％。
统计分析
统计分析基于试验结束时肿瘤体积运用Prism Graphpad软件进行分析。多组间比较，采用Two-way ANOVA，Fisher’s LSD test法检验进行分析，P<0.05认为有显著性差异。两组之间比较，采用t-test，Mann Whitney test法检验进行分析，P<0.05认为有显著性差异。
实验结果
细胞接种后，每天观察肿瘤生长情况，接种后第16天根据肿瘤体积进行分组，入组平均肿瘤体积约为147mm3。由于肿瘤负荷，对照组在接种后的第48天，即分组给药之后的第32天安乐死；AZD9291高剂量(3mg/kg)以及和IN10018 25mg/kg组别相关的联用组在对照组在接种后的第53天，即分组给药之后的第37天安乐死整个实验结束。
分组给药后第32天，对照组的肿瘤体积为1805.6±722.8mm3。AZD9291(3mg/kg)、IN10018(25mg/kg)和AZD9291+IN10018(3+25mg/kg)各治疗组的肿瘤体积分别为20.3±4.7mm3,79.2±51.8mm3和9.0±7.0mm3。综合肿瘤体积与对照组进行比较，AZD9291(3mg/kg)、IN10018(25mg/kg)和AZD9291+IN10018(3+25mg/kg)组的抑瘤率TGI分别为107.7％(p<0.0001)，104.1％(p<0.0001)和108.4％(p<0.0001)。详见表5-1。各剂量组在不同时间段的肿瘤体积如图9所示。
分组给药后第32天，对照组肿瘤体积过大进行安乐死，AZD9291(3mg/kg)、IN10018(25mg/kg)和AZD9291+IN10018(3+25mg/kg)组继续给药观察至第37天。结合分组给药后第37天的肿瘤体积的数据，AZD9291(3mg/kg)和IN10018(25mg/kg)单药组的肿瘤体积分别为17.0±6.7mm3和69.6±46.6mm3。AZD9291+IN10018(3+25mg/kg)两药联用组的肿瘤体积为5.8±6.5mm3。综合肿瘤体积与AZD9291+IN10018(3+25mg/kg)两药联用组进行比较，AZD9291(3mg/kg)和IN10018(25mg/kg)各单药组的P值分别是p＝0.0317和p＝0.0079，均具有统计学差异。详见表5-2。各剂量组在不同时间段的肿瘤体积如图9所示。各剂量组在实验终点的肿瘤体积如图10所示。
表5-1受试物对人非小细胞肺癌HCC827细胞的BALB/c-nude小鼠移植瘤模型的抑瘤效果评价(基于分组给药后第32天数据)

注：
1.按照分组给药后的天数来计算，数据为平均值±标准差(mean±SD)；
2.****：p<0.0001，vs.对照组，Two-way ANOVA；
表5-2受试物对人非小细胞肺癌HCC827细胞的BALB/c-nude小鼠移植瘤模型的抑瘤效果评价(基于分组给药后第37天数据)

注：
1.按照分组给药后的天数来计算，数据为平均值±标准差(mean±SD)；
2.*：p<0.05，**：p<0.01，vs.AZD9291+IN10018(3+25mg/kg)，t-test，Mann Whitney test
实验按照给药方案进行，实验过程中，每天观察动物摄食饮水等活动，每周记录3次动物体重。分组给药28天之后，对照组的平均体重从分组给药当天(Day0)的20.0g，变化至19.4g，体重增长率为-3.3％；IN10018(25mg/kg)治疗组的平均体重从Day0的21.3g变化至Day28的20.7g体重变化率为-2.6％；
分组给药37天之后，AZD9291(3mg/kg)和IN10018(25mg/kg)单药组的平均体重分别从Day0的19.9g和21.3g变化至Day37的19.4g和20.3g，体重变化率分别为-2.2％和-4.5％；AZD9291+IN10018(3+25mg/kg)组的平均体重从Day0的20.0g变化至Day37的19.5g，体重变化率为-2.3％。
在整个给药周期中，各组组动物体重均无明显下降且状态良好。详见表5-3。AZD9291(3mg/kg)和IN10018联用的相关组别在不同时间段的体重变化以及变化率如图11。
表5-3.受试物对人非小细胞肺癌HCC827细胞的BALB/c-nude小鼠移植瘤模型的体重变化评价(基于分组给药后第28/37天数据)

注：
1.按照分组给药后的天数来计算，第0天的动物存活数目/第15天的动物存活数目；
2.数据为平均值±标准差(mean±SD)；
3.体重变化率＝[1-(Wt-W0)/W0]*100％。
实验结论
与空白对照组相比，AZD9291(3mg/kg)、IN10018(25mg/kg)和AZD9291+IN10018(3+25mg/kg)组均有明显肿瘤生长抑制作用，和对照组相比都有统计学差异。综合整个给药周期，AZD9291+IN10018(3+25mg/kg)两药联用组相对于AZD9291(3mg/kg)和IN10018(25mg/kg)单药治疗组的肿瘤体积一直都更小，且和该两个单药治疗组相比也均有统计学差异，显示出AZD9291+IN10018(3+25mg/kg)两药联用组具有更好的抑制肿瘤生长的效果。
实施例6：IN10018联合AZD-9291产生协同肿瘤杀伤作用
体外实验检测AZD9291在肺癌细胞HCC827中的杀伤曲线并确定IC50值。探索不同剂量AZD-9291分别与3μM IN10018和5μM IN10018合用检测细胞毒作用。同时利用流式细胞仪，采用Annexin V染色检测药物单用与合用细胞凋亡反应。
实验抗体：重组Alexa 647荧光Anti-Calreticulin(抗-钙网蛋白)抗体(Abcam，ab196159)，FAK抗体(CST，3285S)，Phospho-eIF2α(Ser51)(CST，3398)，eif2α(CST,5324)，DDIT3(HUABIO，ET1703-05)，HRP标记Alpha tubulin(α-微管蛋白)抗体(Proteintech，HRP-66031)。
1、IN10018联合AZD9291产生协同肿瘤杀伤作用
以5000个HCC827细胞/孔铺设96孔细胞板，24小时后加入定浓度的IN10018联合不同浓度的AZD9291。IN10018的浓度为3μM和5μM；AZD9291最高浓度为1μM以3倍浓度梯度稀释共设9个浓度。药物与细胞共同孵育72小时后每孔加入10μL CCK8溶液，于37℃5％二氧化碳孵箱孵育2小时后，使用酶标仪设定吸光度波长为450nm进行读值。读取的数值与DMSO对照组进行比较并使用Graphpad 8.0进行绘图。详见附图12。
2、IN10018联合AZD9291促进细胞凋亡
使用0.3nM AZD9291与3μM IN10018联合处理HCC827细胞，48小时后收取细胞使用Annexin V试剂盒进行细胞染色并使用流式细胞仪进行检测。统计细胞早期和晚期凋亡数值与DMSO对照组进行比较并使用Graphpad8.0进行绘图。详见附图13。结果显示合用组与单药组比较，早期及晚期凋亡均被显著的增强了。
通过引用将本发明中所提及的所有参考文献均完整合并入本文，就如同每一篇文献均单独列出一样。应理解，在阅读了本发明的公开内容之后，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入本申请所附权利要求书所限定的范围内。
本申请要求于2022年6月24日递交的中国专利申请第202210730136.2号的优先权，在此全文引用上述中国专利申请公开的内容以作为本申请的一部分。

Claims (11)

  1. IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂在制备用于在对象中治疗肿瘤的药物中的用途，所述IN10018结构如下：
  2. IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂的药物组合产品，其用于在对象中治疗肿瘤，所述IN10018结构如下：
  3. 一种治疗肿瘤的方法，该方法包括向有需要的对象同时或依次施用治疗有效量的IN10018或其药学上可接受的盐和表皮生长因子受体酪氨酸激酶抑制剂，所述IN10018结构如下：
  4. 如权利要求1-3任一项所述的用途、药物组合产品或者方法，其中所述IN10018药学上可接受的盐为酒石酸盐。
  5. 如权利要求1-4任一项所述的用途、药物组合产品或者方法，其中所述表皮生长因子受体酪氨酸激酶抑制剂为Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(艾氟替尼，又名Furmonertinib(伏美替尼))、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐，优选为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
  6. 如权利要求1-5任一项所述的用途、药物组合产品或者方法，其中所述IN10018或其药学上可接受的盐和所述表皮生长因子受体酪氨酸激酶抑制剂被同时或依次施用于所述对象。
  7. 如权利要求1-6任一项所述的用途、药物组合产品或者方法，其中所述肿瘤为选自膀胱癌、乳腺癌、子宫颈癌、结肠癌(包括结直肠癌)、食管癌、食管鳞状细胞癌、头颈癌、肝癌、肺癌(包括小细胞肺癌和非小细胞肺癌)、黑色素瘤、骨髓瘤、横纹肌肉瘤、炎性肌纤维母细胞瘤、成神经细胞瘤、胰腺癌、前列腺癌、肾癌、肾细胞癌、肉瘤(包括骨肉瘤)、皮肤癌(包括鳞状细胞癌)、胃癌、睾丸癌、甲状腺癌、子宫癌、间皮瘤、胆管癌、平滑肌肉瘤、脂肪肉瘤、鼻咽癌、神经内分泌癌、卵巢癌、唾液腺癌、梭形细胞癌引起的转移瘤、间变性大细胞淋巴瘤、甲状腺未分化癌、非霍奇金淋巴瘤、霍奇金淋巴瘤、神经胶质瘤以及恶性血液病，例如急性髓细胞性白血病(AML)、急性淋巴细胞白血病(ALL)、弥漫性大B细胞淋巴瘤(DLBCL)、滤泡性淋巴瘤(FL)、慢性淋巴细胞性白血病(CLL)、慢性粒细胞白血病(CML)；优选的，其中所述肿瘤为肺癌、乳腺癌、神经胶质瘤食管癌、头颈癌或结肠癌；优选的，所述肿瘤为肺癌或结肠癌。
  8. 一种试剂盒或药学上可接受的组合物，其包括：
    (a)IN10018或其药学上可接受的盐；和
    (b)表皮生长因子受体酪氨酸激酶抑制剂，
    所述IN10018结构如下：
  9. 如权利要求8所述的试剂盒或组合物，其中所述表皮生长因子受体酪氨酸激酶抑制剂为Gefitinib(吉非替尼)、Erlotinib(厄洛替尼)、Icotinib(埃克替尼)、Afatinib(阿法替尼)、Crizotinib(克唑替尼)、Osimertinib(奥希替尼，AZD9291)、Almonertinib(阿美替尼)、Alflutinib(艾氟替尼，又名Furmonertinib(伏美替尼))、EA1045、JBJ-25-02、BLU945、BLU701、TQB3804、BBT-176、ES-072、BPI-361175、CH7233163或其药学上可接受的盐，优选为Osimertinib、Almonertinib、Alflutinib或其药学上可接受的盐。
  10. 如权利要求8-9任一项所述的试剂盒或组合物，其用作药物。
  11. 如权利要求8-10任一项所述的试剂盒或组合物，所述IN10018药学上可接受的盐为酒石酸盐。
PCT/CN2023/101720 2022-06-24 2023-06-21 治疗肿瘤的药物组合及用途 Ceased WO2023246869A1 (zh)

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