WO2021219137A1 - 用于治疗met基因异常疾病的氨基吡啶衍生物 - Google Patents

用于治疗met基因异常疾病的氨基吡啶衍生物 Download PDF

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Publication number
WO2021219137A1
WO2021219137A1 PCT/CN2021/091584 CN2021091584W WO2021219137A1 WO 2021219137 A1 WO2021219137 A1 WO 2021219137A1 CN 2021091584 W CN2021091584 W CN 2021091584W WO 2021219137 A1 WO2021219137 A1 WO 2021219137A1
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acid
compound
pharmaceutically acceptable
met gene
acceptable salt
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PCT/CN2021/091584
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English (en)
French (fr)
Inventor
张喜全
王训强
于鼎
苏楠
汪荣亮
唐晓闻
李鑫
刘雯雯
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正大天晴药业集团股份有限公司
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Priority to CN202180030830.7A priority Critical patent/CN115484955A/zh
Publication of WO2021219137A1 publication Critical patent/WO2021219137A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/444—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring heteroatom, e.g. amrinone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings

Definitions

  • This application belongs to the field of medicine. Specifically, the application relates to the use of substituted 2-aminopyridine derivatives in the treatment of diseases with abnormal MET genes.
  • the MET proto-oncogene exists on the long arm of human chromosome 7.
  • the protein product is the c-MET tyrosine kinase receptor.
  • the MET gene is expressed in both embryonic and adult stages.
  • the ligand of c-MET is hepatocyte-derived growth factor (HGF).
  • HGF hepatocyte-derived growth factor
  • the combination of HGF and c-MET can promote cell proliferation, migration, differentiation and morphological changes.
  • the HGF/c-MET signaling pathway is complex and highly regulated, and plays an important role in cell proliferation, differentiation and movement.
  • the combination of c-MET and HGF activates PI3K/Ak/mTOR, Ras-MAPK and many other downstream pathways, leading to drug resistance.
  • c-MET can still bind to HER3 to form heterodimers and activate downstream pathways.
  • the abnormality of the HGF/c-MET signaling pathway mainly has the following three mechanisms: 1. In terms of genes, including gene rearrangement, activating mutation and gene amplification; 2. Overexpression of c-MET protein caused by transcription upregulation; 3. Passing Ligand-dependent autocrine or paracrine mechanisms make c-MET protein continuous activation.
  • MET gene amplification includes two different methods: overall amplification and regional amplification.
  • the overall amplification is caused by the increase in the number of chromosome 7, which is often accompanied by the amplification of other genes.
  • the regional amplification method means that the MET gene is independent The number of copies increased.
  • skipping mutation in exon 14 is currently considered to be an important independent driver mutation in NSCLC (non-small cell lung cancer).
  • NSCLC non-small cell lung cancer
  • Current clinical and pathological studies have shown that skipping mutations in exon 14 of the MET gene mostly occur in NSCLC, among which lung sarcomatoid carcinoma and adenocarcinoma are the most common.
  • People with skipping mutations in exon 14 of the MET gene are older and have a history of smoking. Therefore, it is very necessary to develop targeted drugs for the treatment of MET gene abnormalities. And the analysis of the drug resistance mechanism of the study has important guiding significance for the follow-up development of drugs and the follow-up medication of patients.
  • this application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diseases with abnormal MET gene,
  • the present application provides a method for treating a disease with abnormal MET gene, the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment.
  • this application provides a pharmaceutical composition for treating diseases with abnormal MET gene, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the present application provides a kit comprising (a) at least one unit dose of a pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof and (b) for the treatment of diseases with abnormal MET gene instruction of.
  • the present application provides compound I or a pharmaceutically acceptable salt thereof for the treatment of diseases with abnormal MET gene.
  • this application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the treatment of diseases with abnormal MET gene.
  • this application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of diseases with abnormal MET gene,
  • the MET gene abnormalities described in this application include but are not limited to MET gene amplification, MET gene rearrangement, MET gene mutation and/or c-MET overexpression.
  • the MET gene amplification includes, but is not limited to, primary MET gene amplification and acquired drug resistance MET gene amplification.
  • the MET gene mutations include, but are not limited to, exon 14 mutations, such as exon 14 jumping mutations.
  • the use of Compound I or a pharmaceutically acceptable salt thereof for the treatment of diseases of MET gene amplification is provided.
  • a use for treating diseases of MET gene rearrangement is provided for the treatment of diseases with mutations in the MET gene.
  • use is provided for the treatment of diseases in which c-MET is overexpressed.
  • a use for treating diseases with two or more MET gene abnormalities selected from the group consisting of: MET gene amplification, MET gene rearrangement, MET gene mutation, and c-MET overexpression.
  • the above-mentioned treatment is achieved by administering a therapeutically effective amount of the compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need.
  • a use for treating diseases of primary MET gene amplification In some embodiments, there is provided a use for the treatment of acquired drug-resistant MET gene amplification diseases. In some embodiments, use is provided for the treatment of diseases in which the MET gene is amplified in its entirety. In some embodiments, there is provided a use for treating diseases in which the MET gene region is amplified.
  • MET gene amplification refers to the average gene copy number ⁇ 5 and/or the MET/CEP-7 copy number ratio (the ratio of the MET copy number to the centromere number of chromosome 7) ⁇ 2.
  • the above-mentioned treatment is achieved by administering the compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need.
  • a use for treating diseases with mutations in exon 14 of the MET gene there is provided a use for treating diseases with mutations in exon 14 of the MET gene. In some embodiments, there is provided a use for the treatment of a disease caused by a jumping mutation in exon 14 of the MET gene. In some embodiments of the present application, the above-mentioned treatment is achieved by administering the compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need.
  • the disease with abnormal MET gene is a disease with abnormal MET gene for which at least one chemotherapeutic drug and/or targeted drug treatment fails. In some embodiments, the disease with abnormal MET gene is a disease with abnormal MET gene that has previously received at least one chemotherapeutic drug and/or targeted drug.
  • the disease with abnormal MET gene is selected from non-small cell lung cancer with abnormal MET gene or gastric cancer with abnormal MET gene.
  • the non-small cell lung cancer is non-squamous cell carcinoma.
  • the non-small cell lung cancer is adenocarcinoma.
  • the non-small cell lung cancer is invasive adenocarcinoma.
  • the non-small cell lung cancer is pulmonary sarcomatoid carcinoma.
  • the non-small cell lung cancer is squamous cell carcinoma.
  • the above-mentioned treatment is achieved by administering the compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need.
  • the non-small cell lung cancer is non-small cell lung cancer that has failed treatment with at least one chemotherapeutic drug and/or targeted drug. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that has failed treatment with at least one or two chemotherapeutic drugs. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has not previously received systemic treatment.
  • the present application provides that Compound I or a pharmaceutically acceptable salt thereof is used in the preparation of a medicament for the treatment of chemotherapeutic drugs and/or targeted drug-resistant non-small cell lung cancer with abnormal MET gene the use of.
  • Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer with abnormal MET gene that has received chemotherapeutic drugs and/or targeted drug treatment failure.
  • the use of Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof for the treatment of gastric cancer is provided.
  • the gastric cancer is gastric cancer with abnormal MET gene.
  • the above-mentioned treatment is achieved by administering the compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof to a subject in need.
  • the application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chemotherapeutic drugs and/or targeted drug-resistant gastric cancer with abnormal MET gene.
  • this application provides a method for treating diseases with abnormal MET gene, the method comprising administering to a subject in need of treatment a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof,
  • the MET gene abnormality is selected from one or more of: MET gene amplification, MET gene rearrangement, MET gene mutation, and c-MET overexpression.
  • the MET gene mutation refers to a jumping mutation in exon 14 of the MET gene.
  • MET gene amplification refers to an average gene copy number ⁇ 5 and/or a MET/CEP-7 copy number ratio ⁇ 2.
  • the subject has non-small cell lung cancer.
  • the non-small cell lung cancer includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or unspecified non-small cell lung cancer; in some specific embodiments, the non-small cell lung cancer is non-squamous carcinoma In some specific embodiments, the non-small cell lung cancer is adenocarcinoma; in some specific embodiments, the non-small cell lung cancer is invasive adenocarcinoma; in some specific embodiments, the non-small cell lung cancer The cell lung cancer is a pulmonary sarcomatoid carcinoma; in some embodiments, the non-small cell lung cancer is a squamous cell carcinoma.
  • the subject has locally advanced, and/or advanced (for example, stage IIIB/IV) and/or metastatic non-small cell lung cancer; wherein metastatic non-small cell lung cancer includes but It is not limited to single metastasis, disseminated metastasis and diffuse metastasis of the lesion; the metastatic lesions include, but are not limited to, lymph nodes, pleura, bone, brain, pericardium, adrenal glands, and liver.
  • the non-small cell lung cancer is non-small cell lung cancer with brain metastases.
  • the subject has relapsed non-small cell lung cancer
  • the relapsed non-small cell lung cancer includes, but is not limited to, non-small cell lung cancer with intrabronchial obstruction, resectable recurrent non-small cell lung cancer, mediastinum Lymph node recurrence of non-small cell lung cancer, superior vena cava (SVC) obstruction of non-small cell lung cancer, non-small cell lung cancer with severe hemoptysis.
  • the subject is a patient with non-small cell lung cancer that has previously received at least one chemotherapeutic drug and/or targeted drug treatment failure.
  • the subject is a patient with non-small cell lung cancer that has progressed or recurred after receiving at least one chemotherapeutic drug and/or targeted drug treatment. In some embodiments, the subject is a patient with non-small cell lung cancer who has not previously received systemic treatment.
  • the non-small cell lung cancer is a non-small cell lung cancer with a mutation in the MET gene; in some embodiments, the gene mutation is an exon 14 skipping mutation.
  • the non-small cell lung cancer is non-small cell lung cancer with MET gene amplification; in some embodiments, the MET gene amplification refers to an average gene copy number ⁇ 5 and/or MET/CEP -7 copy number ratio ⁇ 2.
  • the non-small cell lung cancer is non-small cell lung cancer overexpressing c-MET.
  • the subject has locally advanced, and/or advanced (for example, stage IIIB/IV) and/or metastatic gastric cancer; wherein metastatic gastric cancer includes, but is not limited to, focal blood metastasis, Peritoneal implantation and lymphatic metastasis; the metastatic lesions include but are not limited to lung, lymph node, pleura, bone, brain, pericardium, adrenal gland, liver and pancreas.
  • the subject has recurring gastric cancer.
  • the subject is a patient with gastric cancer that has previously received at least one chemotherapeutic drug and/or targeted drug treatment failure.
  • the subject is a patient who has developed or recurred gastric cancer after receiving at least one chemotherapeutic drug and/or targeted drug treatment.
  • the subject is a patient with gastric cancer who has not previously received systemic treatment.
  • the gastric cancer is gastric cancer with a mutation in the MET gene; in some embodiments, the gene mutation is an exon 14 skipping mutation.
  • the gastric cancer is gastric cancer with MET gene amplification; in some embodiments, the MET gene amplification refers to an average gene copy number ⁇ 5 and/or a MET/CEP-7 copy number ratio ⁇ 2.
  • the gastric cancer is gastric cancer in which c-MET protein is overexpressed.
  • the method of administration can be comprehensively determined according to the activity, toxicity and patient tolerance of the drug.
  • Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered in the manner of continuous administration every day.
  • the continuous daily medication can be administered at approximately the same time in the morning and evening each day.
  • every 14 to 42 days is a treatment cycle; preferably, 21 days is a treatment cycle; preferably, 35 days is One treatment cycle; more preferably, 28 days is one treatment cycle; in some embodiments, Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered one or more times a day.
  • Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered twice a day during the administration cycle.
  • Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered daily, and every 28 days is a dosing cycle, and it is administered twice a day during the dosing cycle Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof. In some embodiments, Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered at approximately the same time every morning and evening, 28 days is a dosing cycle, and Compound I or Compound I is administered twice a day during the dosing cycle. Its pharmaceutically acceptable salt or its pharmaceutical composition.
  • Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is orally administered at a dose of 800 mg per day, administered in two divided doses, with a cycle of 28 days.
  • Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is orally administered at a dose of 1000 mg per day, administered in two divided doses, with a cycle of 28 days.
  • Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is orally administered at a dose of 1200 mg per day, administered in two divided doses, with a cycle of 28 days.
  • Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is orally administered at a dose of 1600 mg per day, administered in two divided doses, with a 28-day cycle.
  • radiotherapy when a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt or pharmaceutical composition thereof is administered to a patient in need of treatment, radiotherapy may be administered simultaneously or sequentially.
  • the present application provides a pharmaceutical composition for treating diseases with abnormal MET gene, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the application provides a pharmaceutical composition for treating non-small cell lung cancer with amplified MET gene, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier
  • the application also provides a pharmaceutical composition for the treatment of non-small cell lung cancer with mutations in the MET gene, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable A carrier;
  • the application also provides a pharmaceutical composition for the treatment of non-small cell lung cancer overexpressing c-MET, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable salt Acceptable carrier.
  • the non-small cell lung cancer is locally advanced, and/or advanced (for example, stage IIIB/IV) and/or metastatic and/or recurring non-small cell lung cancer.
  • the non-small cell lung cancer is non-small cell lung cancer that has progressed or recurred after receiving at least one chemotherapeutic drug and/or targeted drug treatment.
  • the non-small cell lung cancer is non-small cell lung cancer that has not previously received systemic treatment.
  • the non-small cell lung cancer is non-squamous carcinoma; in some specific embodiments, the non-small cell lung cancer is adenocarcinoma.
  • the non-small cell lung cancer is invasive adenocarcinoma.
  • the non-small cell lung cancer is pulmonary sarcomatoid carcinoma.
  • the non-small cell lung cancer is squamous cell carcinoma.
  • the application provides a pharmaceutical composition for treating gastric cancer with amplified MET gene, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier; in some In an embodiment, the application provides a pharmaceutical composition for treating gastric cancer with mutations in the MET gene, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier; in some embodiments This application provides a pharmaceutical composition for treating gastric cancer with overexpression of c-MET protein, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition includes, but is not limited to, suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, and intranasal , Inhalation, vaginal, intraocular, topical, subcutaneous, intra-fat, intra-articular, intraperitoneal and intrathecal pharmaceutical compositions.
  • the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules.
  • the pharmaceutical composition contains 50 mg to 2000 mg of Compound I or a pharmaceutically acceptable salt thereof; in some embodiments, the pharmaceutical composition contains 100 mg to 1600 mg. Milligrams of Compound I or a pharmaceutically acceptable salt thereof; in some embodiments, the pharmaceutical composition comprises 100 mg to 1200 mg of Compound I or a pharmaceutically acceptable salt thereof; in some embodiments, the The pharmaceutical composition comprises 100 mg to 1000 mg of Compound I or a pharmaceutically acceptable salt thereof; in some embodiments, the pharmaceutical composition comprises 100 mg to 800 mg of Compound I or a pharmaceutically acceptable salt thereof In some embodiments, the pharmaceutical composition comprises 100 mg-600 mg, 100 mg-150 mg, 100 mg-125 mg of Compound I or a pharmaceutically acceptable salt thereof; in some embodiments , The pharmaceutical composition comprises 100 mg, 125 mg, 150 mg, 200 mg, 250 mg, 300 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 600 mg, 675 mg, 700 mg, 800 mg, 900 mg, 1000 mg, 1100 mg, 1
  • a pharmaceutical composition formulated into a unit dosage form for treating diseases with abnormal MET gene the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier.
  • the pharmaceutical composition in unit dosage form contains 50 mg to 1200 mg of Compound I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 300 mg to 600 mg of Compound I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 400 mg to 500 mg of Compound I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 600 mg to 1200 mg of Compound I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 75 mg to 300 mg of Compound I or a pharmaceutically acceptable salt thereof, preferably 100 mg to 200 mg of Compound I or a pharmaceutically acceptable salt thereof, More preferably, 125 mg to 175 mg of Compound I or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition in unit dosage form contains 50 mg, 100 mg, 125 mg, 150 mg, 175 mg, 200 mg of Compound I or a pharmaceutically acceptable salt thereof.
  • "a pharmaceutical composition in unit dosage form" means each tablet or each capsule.
  • the present application provides a kit comprising (a) at least one unit dose of a pharmaceutical composition containing Compound I or a pharmaceutically acceptable salt thereof and (b) for the treatment of diseases with abnormal MET gene instruction of.
  • kits comprising (a) at least one unit dose of a preparation suitable for oral administration containing Compound I or a pharmaceutically acceptable salt thereof, and (b) a preparation for treating diseases with abnormal MET gene illustrate.
  • a kit is provided, which comprises (a) at least one unit dose of a tablet or capsule containing Compound I or a pharmaceutically acceptable salt thereof and (b) for the treatment of MET gene Description of abnormal disease.
  • a kit is provided, which comprises (a) at least one unit dose of a tablet or capsule containing Compound I or a pharmaceutically acceptable salt thereof and (b) for the treatment of MET gene Description of abnormal non-small cell lung cancer.
  • a kit which comprises (a) at least one unit dose of a tablet or capsule containing Compound I or a pharmaceutically acceptable salt thereof and (b) for the treatment of MET gene Description of abnormal stomach cancer.
  • the MET gene abnormality includes one or more of MET gene amplification, MET gene rearrangement, MET gene mutation, and c-MET overexpression.
  • unit dosage unit dosage or unit dosage
  • Compound I can be administered in its free base form, or in the form of its salts, hydrates and prodrugs, which are converted to the free base form of Compound I in vivo.
  • a pharmaceutically acceptable salt of Compound I is within the scope of the present application, and the salt can be produced from different organic acids and inorganic acids according to methods well known in the art.
  • the pharmaceutically acceptable salt of Compound I in the present application refers to a salt formed by Compound I and a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid is selected from sulfuric acid, Carbonic acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, trifluoroacetic acid, lactic acid, mandelic acid, glycolic acid, p-toluenesulfonic acid, o-toluenesulfonic acid, citric acid, methanesulfonic acid, formic acid, Acetic acid, benzoic acid, phenylacetic acid, malonic acid, cinnamic acid, malic acid, maleic acid, tartaric acid, oxalic acid, fumaric acid, acrylic acid, crotonic acid, oleic acid and linoleic acid.
  • the pharmaceutically acceptable acid is selected from sulfuric acid, Carbonic acid, nitric acid, hydrochloric acid
  • the pharmaceutically acceptable acid is selected from sulfuric acid, hydrochloric acid, phosphoric acid, p-toluenesulfonic acid, citric acid, methanesulfonic acid, malic acid, maleic acid, tartaric acid, and fumaric acid.
  • the molar ratio of Compound I to the pharmaceutically acceptable acid in the salt is 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3 5 or 1:4.
  • the pharmaceutically acceptable salt of Compound I is the citrate salt of Compound I.
  • the pharmaceutically acceptable acid is citric acid, and the molar ratio of compound I to citric acid is 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3 , 1:3.5 or 1:4.
  • the administration is in the form of the citrate salt of Compound I. In some embodiments, the administration is in the form of the monocitrate salt of Compound I. In some embodiments, compound I is administered in the form of the dicitrate salt. In some embodiments, the administration is in the form of crystals of the citrate salt of Compound I. In some embodiments, the administration is in the amorphous form of the citrate salt of Compound I.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered by a variety of routes, including but not limited to routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, transbuccal, intranasal, inhaled, vaginal, intraocular, topical, subcutaneous, intra-fat, intra-articular, intraperitoneal, and intrathecal. In some specific embodiments, it is administered orally.
  • the amount of compound I or its pharmaceutically acceptable salt administered can be determined based on the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 100 mg to 2000 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 150 mg to 1950 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 200 mg to 1900 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 300 mg to 1800 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 450 mg to 1750 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 500 mg to 1650 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 750 mg to 1500 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 900 mg to 1350 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 1050 mg to 1250 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 200 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 400 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 600 mg.
  • the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 800 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 1000 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 1200 mg. In some specific embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 1600 mg.
  • Compound I or a pharmaceutically acceptable salt thereof can be administered one or more times a day. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered once a day. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered twice a day. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered twice a day in the form of an oral solid formulation.
  • the non-small cell lung cancer mentioned in the present application includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or non-small cell lung cancer that is not clearly classified according to histological classification; according to clinical staging, including but not Limited to locally advanced, and/or advanced (such as stage IIIB/IV) and/or metastatic non-small cell lung cancer.
  • Metastatic non-small cell lung cancer includes, but is not limited to, single metastasis, disseminated metastasis, and diffuse metastasis; the metastatic focus includes, but is not limited to, lymph nodes, pleura, bone, brain, pericardium, adrenal glands, and liver.
  • the non-small cell lung cancer is non-small cell lung cancer with brain metastases.
  • the non-small cell lung cancer is recurrent non-small cell lung cancer, including but not limited to non-small cell lung cancer with intrabronchial obstruction, resectable recurrent non-small cell lung cancer, and mediastinal lymph node recurrent non-small cell lung cancer , Superior vena cava (SVC) obstruction of non-small cell lung cancer, non-small cell lung cancer with severe hemoptysis.
  • SVC Superior vena cava
  • the gastric cancer includes but not limited to adenocarcinoma, adenosquamous cell carcinoma, squamous cell carcinoma and carcinoid according to histological classification.
  • gastric adenocarcinoma includes but not limited to papillary carcinoma, tubular adenocarcinoma, Poorly differentiated adenocarcinoma, mucinous adenocarcinoma, and signet ring cell carcinoma.
  • gastric cancer includes, but is not limited to, well differentiated gastric cancer, moderately differentiated gastric cancer, and poorly differentiated gastric cancer.
  • gastric cancer includes but is not limited to fundus and cardia cancer, gastric body cancer and gastric antrum cancer.
  • the clinical stage including but not limited to locally advanced, and/or advanced (for example, stage IIIB/IV) and/or metastatic gastric cancer.
  • Metastatic gastric cancer includes, but is not limited to, focal blood metastasis, peritoneal implantation, and lymphatic metastasis; the metastatic lesions include, but are not limited to, lung, lymph node, pleura, bone, brain, pericardium, adrenal gland, liver, and pancreas.
  • the chemotherapeutic drugs include but are not limited to one or more of alkylating agents, podophyllums, camptothecins, taxanes, antimetabolites, and antibiotic antitumor drugs.
  • examples that can be cited include but are not limited to platinum drugs (e.g. oxaliplatin, cisplatin, carboplatin, miplatin, nedaplatin, dicycloplatin), fluoropyrimidine derivatives (e.g. gemcitabine, capecitabine) , Fluorouracil, difurfurouracil, deoxyfluridine, tegafur, carmofur, trifluridine), taxanes (e.g.
  • camptothecins such as camptothecin, hydroxycamptothecin, irinotecan, topotecan
  • vinblastines vinorelbine, vinblastine, vincristine, vindesine, vinflunine
  • pemetrexed etoposide, irinotecan, mitomycin, ifosfamide, cyclophosphamide, azacitidine, amrubicin, methotrexate, bendamustine , Epirubicin, Adriamycin, Temozolomide, LCL-161, KML-001, Sapacitabine, Plenabulin, Treosulfan, Tipiracil Hydrochloride, One or two or three of ticgio and encequidar.
  • the targeted drugs include but are not limited to tyrosine kinase inhibitors, and the tyrosine kinase inhibitors include but are not limited to ALK inhibitors, EGFR inhibitors, VEGFR inhibitors, FGFR inhibitors, PDGFR inhibitors;
  • the targeted drugs include but are not limited to small molecule targeted drugs and antibodies; examples that can be cited include but are not limited to icotinib, alectinib, gram Zoltinib (Crizotinib), Ceritinib (Ceritinib), Uberatinib (Brigatinib), Cabozantinib (Cabozantinib), Fritinib (SAF-189s), Ensatinib (X-396) , Lorlatinib and Bevacizumab.
  • the targeted drugs are icotinib, crizotinib, ensatinib, loratinib, pentinib, and bevacizumab. In some more typical embodiments, the targeted drug is icotinib, bevacizumab or crizotinib. In some more typical embodiments, the targeted drug is crizotinib.
  • “Pharmaceutically acceptable” means that it is used to prepare a pharmaceutical composition that is generally safe, non-toxic, and neither biologically or otherwise undesirable, and includes its use in human medicine. Accepted.
  • “Pharmaceutically acceptable salts” include, but are not limited to, acid addition salts formed with inorganic acids such as sulfuric acid, carbonic acid, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, metaphosphoric acid, etc.; or with organic acids Such as trifluoroacetic acid, lactic acid, mandelic acid, glycolic acid, p-toluenesulfonic acid, o-toluenesulfonic acid, citric acid, methanesulfonic acid, formic acid, acetic acid, benzoic acid, phenylacetic acid, malonic acid, cinnamic acid, malic acid, Acid addition salts formed by maleic acid, tartaric acid, oxalic acid, fumaric acid, acrylic acid, crotonic acid, oleic acid and linoleic acid.
  • inorganic acids such as sulfuric acid, carbonic acid, nitric acid, hydrochlor
  • “Therapeutically effective amount” means an amount sufficient to achieve treatment of a disease when the compound is administered to a subject, such as a human, for the treatment of the disease.
  • Treatment means any administration of a therapeutically effective amount of a compound, and includes:
  • CR means complete remission
  • PR means partial remission
  • PD means disease progression
  • SD means stable disease
  • ORR means objective remission rate, including CR+PR
  • DCR means Refers to disease control rate, including CR+PR+SD; these terms all have the meanings well-known in the art, for example, refer to the meanings described in the RECIST Version 1.1 of the Curative Effect Evaluation Criteria for Solid Tumors (RECIST).
  • Treatment failure includes intolerable side effects, disease progression during treatment, or recurrence after the end of treatment; intolerable includes but not limited to hematological toxicity level IV (platelet drop level III and above), non-hematological toxicity level Class III or above.
  • C-MET overexpression and “c-MET overexpression” have the same meaning and can be used interchangeably.
  • PFS Progress-Free Survival
  • OS “Overall Survival)” refers to the time from the first administration of the drug to death from all causes. For subjects who were still alive at the last follow-up, their OS was counted as data censored based on the time of the last follow-up. For subjects who are lost to follow-up, their OS is counted as data censorship based on the last confirmed survival time before being lost to follow-up.
  • DOR Duration of Disease Remission
  • CNS-PFS Intracranial Progression-Free Survival
  • CNS-DCR Intracranial Disease Control Rate
  • CNS-ORR Objective Intracranial Response Rate
  • CNS-TTP Time to Intracranial Disease Progression
  • the title compound can be prepared by referring to the method of Example 2 "Preparation of the pharmaceutically acceptable acid salt of the compound of formula I" in WO2016015676.
  • Example 2 Contains 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4'-methoxy-6'-((S)-2-methyl (Piperazine-1-yl)-3,3'-bipyridin-6-amine citrate (the citrate of compound I) in capsules
  • Capsules with other contents of Compound I citrate can be prepared by referring to the same ratio and prescription as mentioned above.
  • Inhibition rate (OD value control hole- OD value dosing hole )/OD value control hole ⁇ 100%
  • the IC 50 value of the half inhibition concentration was calculated.
  • NSCLC non-small cell lung cancer
  • stage IIIB-IV accordinging to the 8th edition of the International Association for the Study of Lung Cancer and the American Joint Committee on Cancer Classification
  • MET gene status In subjects with abnormal status assessment, every 28 days is a treatment cycle, and the citrate capsule of compound I prepared in Example 2 is administered, and the starting daily dose is 1200 mg (two doses in the morning and evening, 600 mg each time) ,
  • the daily continuous dosing regimen take orally on an empty stomach or with a meal at roughly the same time every morning and evening, patients who have received at least one treatment cycle will be included in the efficacy evaluation, and the safety and effectiveness of the clinical research will be carried out.
  • the main efficacy endpoint is objective relief Rate (ORR)
  • the secondary efficacy endpoints are PFS (progression-free survival), DCR (disease control rate), OS (overall survival), DOR (duration of disease remission), CNS-PFS (intracranial progression-free survival) Stage), CNS-DCR (intracranial disease control rate), CNS-ORR (intracranial objective response rate), CNS-TTP (time to intracranial disease progression).
  • Subjects are over 18 years old, gender is not limited, ECOG score [0-1] points, estimated survival time is greater than 12 weeks; according to the RECIST v.1.1 standard, at least one measurable target lesion (brain lesion is not the only lesion) ).
  • the dosage can be adjusted as follows:
  • the corresponding detection methods include direct sequencing, real-time fluorescence quantitative PCR (RTFQ-PCR), FISH and IHC, through analysis It is necessary for the MET gene and c-MET protein to screen the beneficiaries suitable for the application of c-MET inhibitors.
  • the direct sequencing method for detecting MET gene mutations has a high degree of accuracy, and it is not necessary to know the specific location of the MET gene mutation site, and other potential exon mutation sites can be detected; RTFQ-PCR and FISH can be used for MET gene expansion. For increased detection, the former has faster detection speed, but requires higher quality of genomic DNA fragments, while the quality of genomic DNA fragments obtained by the existing extraction methods is poor. Therefore, compared with the two, FISH is more widely used.
  • the FISH method can determine the MET gene copy number (MET gene copies number, MET GCN) by detecting the ratio of fluorescent probes of MET and CEP7 (as a control).
  • the evaluation criteria can be based on two aspects: 1 MET/CEP7 fluorescent probe ratio 2The number of gene copies in each cell and the proportion of positive cells in the total cells. IHC can be used to detect the overexpression of c-MET protein.
  • the abnormality of MET gene in clinical trials includes MET gene exon 14 skipping mutation and MET gene amplification (including 2 types: average gene copy number ⁇ 5 and/or MET/CEP-7 copy number ratio ⁇ 2).
  • the citrate capsules of compound I prepared in Example 2 of 600mg were taken orally twice a day at the beginning, and were administered every day continuously at approximately the same time in the morning and evening each day.
  • the recommended interval between the two was 10-12 hours, orally on an empty stomach or with a meal. , Every 28 days is a treatment cycle.
  • CT scan showed that the sum of measurable target lesion diameters was 55mm. After administration, CT scans were performed regularly. After one cycle of treatment, the total diameter of target lesions decreased to 37.5mm. It was evaluated as PR, and it was reduced by more than 30%. After 3 and 5 cycles of treatment, the sum of the diameters of the target lesions decreased to 31.2mm and 31.1mm, and the curative effect was evaluated as PR. During the treatment, the overall tolerance was good.
  • CT scan showed that the sum of the measurable target lesion diameters was 27.7mm. After the administration, CT scans were performed regularly. After one cycle of treatment, the total diameter of the target lesions decreased to 17.7mm. The curative effect is evaluated as PR, which is reduced by more than 30%. After 3 and 5 cycles of treatment, the total diameter of the target lesions decreased to 15.4mm and 14.4mm, and the curative effect was evaluated as PR. During the treatment, the overall tolerance was good.
  • the CT scan showed that the sum of the measurable target lesion diameters was 111.2mm. After the administration, CT scans were performed regularly. After one cycle of treatment, the total diameter of the target lesions decreased to 71.2mm. The curative effect is evaluated as PR, which is reduced by more than 30%. After 3 cycles of treatment, the diameter of the target lesion was reduced to 70.8mm, the curative effect was evaluated as PR, and the patient is still undergoing treatment. During the treatment, the overall tolerance was good.
  • the patient Prior to enrollment, the patient had received 125 mg of icotinib po qd (treatment for 1 month, no efficacy evaluation); and bevacizumab thoracic perfusion therapy (no efficacy evaluation).
  • CT scan showed that the sum of measurable target lesion diameters was 34.7mm. After administration, CT scans were performed regularly. After one cycle of treatment, the total diameter of target lesions decreased to 21.2mm. , The curative effect is evaluated as PR, which is reduced by more than 30%. After 3 and 5 cycles of treatment, the total diameter of the target lesions dropped to 18mm, the curative effect was evaluated as PR, and the patient is still undergoing treatment. During the treatment, the overall tolerance was good.

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Abstract

本申请涉及用于治疗MET基因异常的疾病的氨基吡啶衍生物。具体而言，本申请涉及取代的2-氨基吡啶衍生物在治疗MET基因异常的非小细胞肺癌和MET基因异常的胃癌中的用途。2-氨基吡啶衍生物例如为化合物I或其药学上可接受的盐，其化学名称为5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺。

Description

用于治疗MET基因异常疾病的氨基吡啶衍生物
相关申请的交叉引用
本申请要求于2020年04月30日向中华人民共和国国家知识产权局提交的申请号为202010366117.7的中国发明专利申请的权益和优先权，在此将它的全部内容以援引的方式整体并入本文中。
技术领域
本申请属于医药领域，具体而言，本申请涉及取代的2-氨基吡啶衍生物在治疗MET基因异常的疾病中的用途。
背景技术
MET原癌基因存在于人类7号染色体的长臂，蛋白产物是c-MET酪氨酸激酶受体，MET基因在胚胎期和成人期均有表达。c-MET的配体是肝细胞源性生长因子(HGF)，HGF和c-MET的结合能够促进细胞的增殖、迁移、分化和形态改变。HGF/c-MET信号通路受到复杂的、高度的调节，在细胞增殖、分化和运动扮演重要作用。c-MET与HGF结合，激活PI3K/Ak/mTOR、Ras-MAPK等诸多下游通路，导致耐药现象；同时，c-MET尚可与HER3结合形成异源二聚体进而激活下游通路。
HGF/c-MET信号通路的异常主要有以下三种机制：1.在基因方面包括基因重排、激活突变和基因扩增；2.转录上调导致的c-MET蛋白的过表达；3.通过配体依赖的自分泌或旁分泌机制使得c-MET蛋白持续激活。
其中，MET基因扩增包括了整体扩增和区域扩增两种不同的方式。整体扩增是因为7号染色体数目的增多导致的，往往伴有其他基因的扩增，目前并不认为这种形式的MET基因扩增导致肿瘤发生及耐药；区域扩增方式即MET基因独立的拷贝数增加。
除MET基因扩增外，14号外显子跳跃突变目前也被认为是NSCLC(非小细胞肺癌)重要的独立驱动基因突变。目前临床病理特征的研究显示，MET基因14号外显子跳跃突变多发生于NSCLC，其中以肺肉瘤样癌和腺癌最为多见。MET基因14号外显子跳跃突变人群年龄较大并且多有吸烟史。因此，开发治疗MET基因异常疾病的靶向药物是十分必要的。并且分析研究药物的耐药机制，对于药物的后续开发以及患者的后续用药，具有重要指导意义。
发明概述
第一方面，本申请提供了化合物I或其药学上可接受的盐在制备用于治疗MET基因异常的疾病的药物中的用途，
Figure PCTCN2021091584-appb-000001
第二方面，本申请提供了一种治疗MET基因异常的疾病的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐。
第三方面，本申请提供了一种治疗MET基因异常的疾病的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。
第四方面，本申请提供了一种试剂盒，其包含(a)至少一个单位剂量的包含化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗MET基因异常的疾病的说明。
第五方面，本申请提供了用于治疗MET基因异常的疾病的化合物I或其药学上可接受的盐。
第六方面，本申请提供了化合物I或其药学上可接受的盐在治疗MET基因异常的疾病中的用途。
发明详述
第一方面，本申请提供了化合物I或其药学上可接受的盐在制备用于治疗MET基因异常的疾病的药物中的用途，
Figure PCTCN2021091584-appb-000002
本申请所述的MET基因异常，包括但不限于MET基因扩增、MET基因重排、MET基因突变和/或c-MET过表达。其中所述的MET基因扩增包括但不限于原发MET基因扩增和获得性耐药的MET基因扩增。所述的MET基因突变包括但不限于14号外显子突变，例如14号外显子跳跃突变。
在本申请的一些实施方案中，提供了化合物I或其药学上可接受的盐用于治疗MET基因扩增的疾病的用途。在一些实施方案中，提供了用于治疗MET基因重排的疾病的用途。在一些实施方案中，提供了用于治疗MET基因突变的疾病的用途。在一些实施方案中，提供了用于治疗c-MET过表达的疾病的用途。在一些实施方案中，提供了用于治疗具有选自：MET 基因扩增、MET基因重排、MET基因突变和c-MET过表达中的两种或多种MET基因异常的疾病的用途。在本申请的一些实施方案中，通过向有需要的主体给予治疗有效量的所述化合物I或其药学上可接受的盐或其药物组合物来实现上述治疗。
在本申请的一些实施方案中，提供了用于治疗原发MET基因扩增的疾病的用途。在一些实施方案中，提供了用于治疗获得性耐药的MET基因扩增的疾病的用途。在一些实施方案中，提供了用于治疗MET基因整体扩增的疾病的用途。在一些实施方案中，提供了用于治疗MET基因区域扩增的疾病的用途。在一些实施方案中，MET基因扩增是指平均基因拷贝数≥5和/或MET/CEP-7拷贝数比(MET拷贝数与7号染色体着丝粒数的比值)≥2。在本申请的一些实施方案中，通过向有需要的主体施用所述化合物I或其药学上可接受的盐或其药物组合物来实现上述治疗。
在本申请的一些实施方案中，提供了用于治疗MET基因14号外显子突变的疾病的用途。在一些实施方案中，提供了用于治疗MET基因14号外显子跳跃突变的疾病的用途。在本申请的一些实施方案中，通过向有需要的主体施用所述化合物I或其药学上可接受的盐或其药物组合物来实现上述治疗。
在本申请的一些实施方案中，所述的MET基因异常的疾病为至少一种化疗药物和/或靶向药物治疗失败的MET基因异常的疾病。在一些实施方案中，所述的MET基因异常的疾病为在先接受过至少一种化疗药物和/或靶向药物的MET基因异常的疾病。
在一些实施方案中，所述的MET基因异常的疾病选自MET基因异常的非小细胞肺癌或MET基因异常的胃癌。
在本申请的一些实施方案中，提供了用于治疗MET基因异常的非小细胞肺癌的用途。在一些实施方案中，所述非小细胞肺癌为非鳞癌。在一些具体的实施方案中，所述非小细胞肺癌为腺癌。在一些具体的实施方案中，所述非小细胞肺癌为浸润性腺癌。在一些实施方案中，所述非小细胞肺癌为肺肉瘤样癌。在一些实施方案中，所述非小细胞肺癌为鳞癌。在本申请的一些实施方案中，通过向有需要的主体给予所述化合物I或其药学上可接受的盐或其药物组合物来实现上述治疗。在一些实施方案中，所述的非小细胞肺癌为至少一种化疗药物和/或靶向药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为至少一种或两种化疗药物治疗失败的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为在先未接受过系统治疗的非小细胞肺癌。
在本申请的一些实施方案中，本申请提供了化合物I或其药学上可接受的盐在制备用于治疗化疗药物和/或靶向药物耐药的MET基因异常的非小细胞肺癌的药物中的用途。在一些实施方案中，提供了化合物I或其药学上可接受的盐在制备用于治疗接受化疗药物和/或靶向 药物治疗失败的MET基因异常的非小细胞肺癌的药物中的用途。
在本申请的一些实施方案中，提供了化合物I或其药学上可接受的盐或其药物组合物用于治疗胃癌的用途。在一些实施方案中，所述的胃癌为MET基因异常的胃癌。在一些实施方案中，通过向有需要的主体施用所述化合物I或其药学上可接受的盐或其药物组合物来实现上述治疗。在一些实施方案中，本申请提供了化合物I或其药学上可接受的盐在制备用于治疗化疗药物和/或靶向药物耐药的MET基因异常的胃癌的药物中的用途。在一些实施方案中，提供了化合物I或其药学上可接受的盐在制备用于治疗接受化疗药物和/或靶向药物治疗失败的MET基因异常的胃癌的药物中的用途。
第二方面，本申请提供了一种治疗MET基因异常的疾病的方法，所述方法包括给予需要治疗的主体治疗有效量的化合物I或其药学上可接受的盐，
Figure PCTCN2021091584-appb-000003
在本申请的一些实施方案中，所述的MET基因异常是选自：MET基因扩增、MET基因重排、MET基因突变、c-MET过表达中的一种或多种。在一些实施方案中，MET基因突变是指MET基因14号外显子跳跃突变。在一些实施方案中，MET基因扩增是指平均基因拷贝数≥5和/或MET/CEP-7拷贝数比≥2。
在本申请的某些实施方案中，所述主体患有非小细胞肺癌。所述非小细胞肺癌包括但不限于腺癌、鳞状细胞癌、大细胞癌或不明确分型的非小细胞肺癌；在一些具体的实施方案中，所述非小细胞肺癌为非鳞癌；在一些具体的实施方案中，所述非小细胞肺癌为腺癌；在一些具体的实施方案中，所述非小细胞肺癌为浸润性腺癌；在一些具体的实施方案中，所述非小细胞肺癌为肺肉瘤样癌；在一些实施方案中，所述非小细胞肺癌为鳞癌。
在本申请的某些实施方案中，所述主体患有局部晚期、和/或晚期(例如IIIB/IV期)和/或转移性的非小细胞肺癌；其中转移性的非小细胞肺癌包括但不限于病灶单个转移、播散性转移和弥漫性转移；所述转移病灶包括但不限于淋巴结、胸膜、骨、脑、心包、肾上腺和肝脏。在一些实施方案中，所述的非小细胞肺癌为脑转移的非小细胞肺癌。在一些实施方案中，所述主体患有复发的非小细胞肺癌，所述的复发的非小细胞肺癌包括但不限于支气管内阻塞的非小细胞肺癌、可切除的复发非小细胞肺癌、纵隔淋巴结复发非小细胞肺癌、上腔静脉(SVC)阻塞非小细胞肺癌、严重咯血的非小细胞肺癌。在一些实施方案中，所述主体是在先接受过 至少一种化疗药物和/或靶向药物治疗失败的非小细胞肺癌的患者。在一些实施方案中，所述主体是在先接受过至少一种化疗药物和/或靶向药物治疗后出现进展或复发的非小细胞肺癌的患者。在一些实施方案中，所述主体是在先未接受过系统治疗的非小细胞肺癌的患者。
本申请中的一些实施方案中，所述的非小细胞肺癌是MET基因突变的非小细胞肺癌；在一些实施方案中，所述的基因突变为14号外显子跳跃突变。在一些实施方案中，所述非小细胞肺癌是MET基因扩增的非小细胞肺癌；在一些实施方案中，所述的MET基因扩增是指平均基因拷贝数≥5和/或MET/CEP-7拷贝数比≥2。在一些实施方案中，所述非小细胞肺癌为c-MET过表达的非小细胞肺癌。
在本申请的某些实施方案中，所述主体患有局部晚期、和/或晚期(例如IIIB/IV期)和/或转移性的胃癌；其中转移性的胃癌包括但不限于病灶血行转移、腹膜种植转移和淋巴转移；所述转移病灶包括但不限于肺、淋巴结、胸膜、骨、脑、心包、肾上腺、肝脏和胰脏。在一些实施方案中，所述主体患有复发的胃癌。在一些实施方案中，所述主体是在先接受过至少一种化疗药物和/或靶向药物治疗失败的胃癌的患者。在一些实施方案中，所述主体是在先接受过至少一种化疗药物和/或靶向药物治疗后出现进展或复发的胃癌的患者。在一些实施方案中，所述主体是在先未接受过系统治疗的胃癌的患者。本申请中的一些实施方案中，所述的胃癌为MET基因突变的胃癌；在一些实施方案中，所述的基因突变为14号外显子跳跃突变。在一些实施方案中，所述胃癌为MET基因扩增的胃癌；在一些实施方案中，所述的MET基因扩增是指平均基因拷贝数≥5和/或MET/CEP-7拷贝数比≥2。在一些实施方案中，所述胃癌为c-MET蛋白过表达的胃癌。
给药的方法可根据药物的活性、毒性以及患者的耐受性等来综合确定。优选地，以每天连续用药的方式给予化合物I或其药学上可接受的盐或其药物组合物。所述的每天连续用药，可以为每天早晚大致相同的时间给药。在一些实施方案中，给予化合物I或其药学上可接受的盐或其药物组合物时，每14～42天为一个治疗周期；优选地，21天为一个治疗周期；优选地，35天为一个治疗周期；更优选地，28天为一个治疗周期；在一些实施方案中，每天一次或多次给予化合物I或其药学上可接受的盐或其药物组合物。优选地，在给药周期内每天两次给予化合物I或其药学上可接受的盐或其药物组合物。
在本申请的一些实施方案中，以每天用药的方式给予化合物I或其药学上可接受的盐或其药物组合物，每28天为一个给药周期，在给药周期内每天两次地给予化合物I或其药学上可接受的盐或其药物组合物。在一些实施方案中，以每天早晚大致相同的时间给予化合物I或其药学上可接受的盐或其药物组合物，28天为一个给药周期，在给药周期内每天两次给予化合物I或其药学上可接受的盐或其药物组合物。
在本申请的某些特定的实施方案中，化合物I或其药学上可接受的盐或其药物组合物以每日800mg的剂量口服给药，分两次给药，28天为一个周期。
在本申请的某些特定的实施方案中，化合物I或其药学上可接受的盐或其药物组合物以每日1000mg的剂量口服给药，分两次给药，28天为一个周期。
在本申请的某些特定的实施方案中，化合物I或其药学上可接受的盐或其药物组合物以每日1200mg的剂量口服给药，分两次给药，28天为一个周期。
在本申请的某些特定的实施方案中，化合物I或其药学上可接受的盐或其药物组合物以每日1600mg的剂量口服给药，分两次给药，28天为一个周期。
在本申请的一些实施方案中，在给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐或其药物组合物的时候，可以同时或者先后给予放疗。
第三方面，本申请提供了一种治疗MET基因异常的疾病的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。
在一些实施方案中，本申请提供了一种治疗MET基因扩增的非小细胞肺癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体；在一些实施方案中，本申请还提供了一种治疗MET基因突变的非小细胞肺癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体；在一些实施方案中，本申请还提供了一种治疗c-MET过表达的非小细胞肺癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。在一些实施方案中，所述的非小细胞肺癌为局部晚期、和/或晚期(例如IIIB/IV期)和/或转移性和/或复发的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为在先接受过至少一种化疗药物和/或靶向药物治疗后出现进展或复发的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为在先未接受过系统治疗的非小细胞肺癌。在一些实施方案中，所述非小细胞肺癌为非鳞癌；在一些具体的实施方案中，所述非小细胞肺癌为腺癌。在一些具体的实施方案中，所述非小细胞肺癌为浸润性腺癌。在一些具体的实施方案中，所述非小细胞肺癌为肺肉瘤样癌。在一些实施方案中，所述非小细胞肺癌为鳞癌。
在一些实施方案中，本申请提供了一种治疗MET基因扩增的胃癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体；在一些实施方案中，本申请提供了一种治疗MET基因突变的胃癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体；在一些实施方案中，本申请提供了一种治疗c-MET蛋白过表达的胃癌的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体。
在本申请的一些实施方案中，所述的药物组合物包括但不限于适合口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内给药的药物组合物。在一些实施方案中，所述药物组合物是适于口服的制剂，包括片剂、胶囊剂、粉剂、颗粒剂、滴丸、糊剂、散剂等，优选片剂和胶囊剂。
在本申请的一些实施方案中，所述的药物组合物包含50毫克至2000毫克的化合物I或其药学上可接受的盐；在一些实施方案中，所述的药物组合物包含100毫克至1600毫克的化合物I或其药学上可接受的盐；在一些实施方案中，所述的药物组合物包含100毫克至1200毫克的化合物I或其药学上可接受的盐；在一些实施方案中，所述的药物组合物包含100毫克至1000毫克的化合物I或其药学上可接受的盐；在一些实施方案中，所述的药物组合物包含100毫克至800毫克的化合物I或其药学上可接受的盐；在一些实施方案中，所述的药物组合物包含100毫克-600毫克、100毫克-150毫克、100毫克-125毫克的化合物I或其药学上可接受的盐；在一些实施方案中，所述的药物组合物包含100毫克、125毫克、150毫克、200毫克、250毫克、300毫克、350毫克、375毫克、400毫克、450毫克、500毫克、600毫克、675毫克、700毫克、800毫克、900毫克、1000毫克、1100毫克、1200毫克的化合物I或其药学上可接受的盐。
在本申请的一些实施方案中，提供了一种治疗MET基因异常的疾病的配制成单位剂量形式的药物组合物；所述的药物组合物进一步包含至少一种药学上可接受的载体。在一些实施方案中，该单位剂量形式的药物组合物含有50毫克至1200毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有300毫克至600毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有400毫克至500毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有600毫克至1200毫克的化合物I或其药学上可接受的盐。在一些实施方案中，该单位剂量形式的药物组合物含有75毫克至300毫克的化合物I或其药学上可接受的盐，优选100毫克至200毫克的化合物I或其药学上可接受的盐，较优选125毫克至175毫克的化合物I或其药学上可接受的盐。在一些特定的实施方案中，该单位剂量形式的药物组合物含有50毫克、100毫克、125毫克、150毫克、175毫克、200毫克的化合物I或其药学上可接受的盐。例如，对于片剂或胶囊而言，“单位剂量形式的药物组合物”意味着每片片剂或每颗胶囊。
第四方面，本申请提供了一种试剂盒，其包含(a)至少一个单位剂量的包含化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗MET基因异常的疾病的说明。
本申请还提供了一种试剂盒，其包含(a)至少一个单位剂量的包含化合物I或其药学上可接受的盐的适于口服的制剂和(b)用于治疗MET基因异常的疾病的说明。在一些特定的实施方案中，提供了一种试剂盒，其包含(a)至少一个单位剂量的包含化合物I或其药学上可接受的盐的片剂或胶囊和(b)用于治疗MET基因异常的疾病的说明。在一些特定的实施方案中，提供了一种试剂盒，其包含(a)至少一个单位剂量的包含化合物I或其药学上可接受的盐的片剂或胶囊和(b)用于治疗MET基因异常的非小细胞肺癌的说明。在一些特定的实施方案中，提供了一种试剂盒，其包含(a)至少一个单位剂量的包含化合物I或其药学上可接受的盐的片剂或胶囊和(b)用于治疗MET基因异常的胃癌的说明。在一些实施方案中，所述MET基因异常包括MET基因扩增、MET基因重排、MET基因突变、c-MET过表达中的一种或多种。所述的“单位剂量(unit dosage或unit dose)”是指为了服用的方便，包装在单个包装中的药物组合物，例如每片片剂或者胶囊。
化合物I或其药学上可接受的盐
本申请的化合物I的化学名为5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺，其具有如下的结构式：
Figure PCTCN2021091584-appb-000004
化合物I可以以它的游离碱形式给药，也可以以其盐、水合物和前药的形式给药，该前药在体内转换成化合物I的游离碱形式。例如，化合物I的药学上可接受的盐在本申请的范围内，可按照本领域公知的方法由不同的有机酸和无机酸产生所述盐。
在本申请的一些实施方案中，本申请的化合物I的药学上可接受的盐，是指化合物I与药学上可接受的酸形成的盐，其中所述药学上可接受的酸选自硫酸、碳酸、硝酸、盐酸、氢溴酸、氢碘酸、磷酸、偏磷酸、三氟乙酸、乳酸、扁桃酸、乙醇酸、对甲苯磺酸、邻甲苯磺酸、柠檬酸、甲磺酸、甲酸、乙酸、苯甲酸、苯乙酸、丙二酸、肉桂酸、苹果酸、马来酸、酒石酸、草酸、富马酸、丙烯酸、巴豆酸、油酸和亚油酸。在一些实施方案中，所述药学上可接受的酸选自硫酸、盐酸、磷酸、对甲苯磺酸、柠檬酸、甲磺酸、苹果酸、马来酸、酒石酸和富马酸。在一些实施方案中，所述盐中化合物I与药学上可接受的酸的摩尔比为1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3 5或1:4。在一些实施方案中，所述的化合物I的药学上可接受的盐为化合物I的柠檬酸盐。在一些实施方案中，所述的药学上可接受酸为柠檬酸，化合 物I与柠檬酸的摩尔比为1:0.5、1:1、1:1.5、1:2、1:2.5、1:3、1:3.5或1:4。
在本申请的一些实施方案中，以化合物I的柠檬酸盐的形式给药。在一些实施方案中，以化合物I的一柠檬酸盐的形式给药。在一些实施方案中，以化合物I的二柠檬酸盐的形式给药。在一些实施方案中，以化合物I的柠檬盐的晶体形式给药。在一些实施方案中，以化合物I的柠檬盐的无定型形式给药。
化合物I或其药学上可接受的盐可通过多种途径给药，该途径包括但不限于选自以下的途径：口服、肠胃外、腹膜内、静脉内、动脉内、透皮、舌下、肌内、直肠、透颊、鼻内、经吸入、阴道、眼内、经局部给药、皮下、脂肪内、关节内、腹膜内和鞘内。在一些特定的实施方案中，通过口服给药。
给予化合物I或其药学上可接受的盐的量可根据疾病的严重程度、疾病的响应、任何治疗相关的毒性、患者的年龄和健康状态来确定。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为100毫克至2000毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为150毫克至1950毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为200毫克至1900毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为300毫克至1800毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为450毫克至1750毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为500毫克至1650毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为750毫克至1500毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为900毫克至1350毫克。在一些实施方案中，给予化合物I或其药学上可接受的盐的日剂量为1050毫克至1250毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为200毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为400毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为600毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为800毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为1000毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为1200毫克。在一些特定的实施方案中，给予化合物I或其药学上可接受的盐的日剂量为1600毫克。
化合物I或其药学上可接受的盐可以每日施用一次或多次。在一些实施方案中，每天一次给予化合物I或其药学上可接受的盐。在一些实施方案中，每天两次给予化合物I或其药学上可接受的盐。在一些实施方案中，化合物I或其药学上可接受的盐以口服固体制剂的形式每天给药两次。
非小细胞肺癌
本申请中，所述的非小细胞肺癌，根据组织学分型，包括但不限于腺癌、鳞状细胞癌、大细胞癌或不明确分型的非小细胞肺癌；依据临床分期，包括但不限于局部晚期、和/或晚期(例如IIIB/IV期)和/或转移性的非小细胞肺癌。转移性非小细胞肺癌包括但不限于病灶单个转移、播散性转移和弥漫性转移；所述转移病灶包括但不限于淋巴结、胸膜、骨、脑、心包、肾上腺和肝脏。在一些实施方案中，所述的非小细胞肺癌为脑转移的非小细胞肺癌。在一些实施方案中，所述的非小细胞肺癌为复发的非小细胞肺癌，包括但不限于支气管内阻塞的非小细胞肺癌、可切除的复发非小细胞肺癌、纵隔淋巴结复发非小细胞肺癌、上腔静脉(SVC)阻塞非小细胞肺癌、严重咯血的非小细胞肺癌。
胃癌
本申请中，所述的胃癌，根据组织学分型，包括但不限于腺癌、腺鳞癌、鳞癌和类癌，其中根据组织结构，胃腺癌包括但不限于乳头状癌、管状腺癌、低分化腺癌、黏液腺癌和印戒细胞癌。根据细胞分化程度，胃癌包括但不限于高分化胃癌、中分化胃癌和低分化胃癌。根据发病部位分类，胃癌包括但不限于胃底贲门癌、胃体癌和胃窦癌。依据临床分期，包括但不限于局部晚期、和/或晚期(例如IIIB/IV期)和/或转移性的胃癌。转移性胃癌包括但不限于病灶血行转移、腹膜种植转移和淋巴转移；所述转移病灶包括但不限于肺、淋巴结、胸膜、骨、脑、心包、肾上腺、肝脏和胰脏。
化疗药物
本申请中，所述的化疗药物包括但不限于烷化剂、鬼臼类、喜树碱类、紫杉类、抗代谢类、抗生素类抗肿瘤药物中的一种或多种。可以列举的实例包括但不限于铂类药物(例如奥沙利铂、顺铂、卡铂、米铂、奈达铂、双环铂(dicycloplatin))、氟嘧啶衍生物(例如吉西他滨、卡培他滨、氟尿嘧啶、双呋氟尿嘧啶、去氧氟尿苷、替加氟、卡莫氟、三氟尿苷)、紫杉烷类(例如紫杉醇、白蛋白结合的紫杉醇、紫杉醇脂质体以及多西他赛)、喜树碱类(例如喜树碱、羟基喜树碱、伊立替康、拓扑替康)、长春碱类(长春瑞滨、长春碱、长春新碱、长春地辛、长春富宁(vinflunine))、培美曲塞、依托泊苷、伊立替康、丝裂霉素、异环磷酰胺、环磷酰胺、阿扎胞苷、氨柔比星、甲氨蝶呤、苯达莫司汀、表阿霉素、阿霉素、替莫唑胺、LCL-161、KML-001、Sapacitabine、普那布林(plinabulin)、曲奥舒凡(treosulfan)、地匹福林盐酸盐(tipiracil hydrochloride)、替吉奥和encequidar中的一种或两种或三种。
靶向药物
本申请中，所述的靶向药物包括但不限于酪氨酸激酶抑制剂，所述的酪氨酸激酶抑制剂包括但不限于ALK抑制剂、EGFR抑制剂、VEGFR抑制剂、FGFR抑制剂、PDGFR抑制剂； 在一些实施方案中，所述的靶向药物包括但不限于小分子靶向药物和抗体；可以列举的实例包括但不限于埃克替尼、阿来替尼(Alectinib)、克唑替尼(Crizotinib)、色瑞替尼(Ceritinib)、布加替尼(Brigatinib)、卡博替尼(Cabozantinib)、复瑞替尼(SAF-189s)、恩沙替尼(X-396)、劳拉替尼(Lorlatinib)和贝伐珠单抗。在一些典型的实施方案中，所述的靶向药物为埃克替尼、克唑替尼、恩沙替尼、劳拉替尼、复瑞替尼和贝伐珠单抗。在一些更为典型的实施方案中，所述的靶向药物为埃克替尼、贝伐珠单抗或克唑替尼。在一些更典型的实施方案中，所述的靶向药物为克唑替尼。
本文中，除非另有说明，这里提供的剂量和范围都是基于化合物I游离碱形式的分子量。
除非另有说明，为本申请的目的，本说明书和权利要求书中所用的下列术语应具有下述含义。
“患者”、“主体”或“受试者”可以互换，是指哺乳动物，优选人。
“药学上可接受的”是指其用于制备药物组合物，该药物组合物通常是安全、无毒的并且既不在生物学上或其它方面不合乎需要，并且包括其对于人类药物使用是可接受的。
“药学上可接受的盐”包括，但不限于与无机酸如硫酸、碳酸、硝酸、盐酸、氢溴酸、氢碘酸、磷酸、偏磷酸等等形成的酸加成盐；或者与有机酸如三氟乙酸、乳酸、扁桃酸、乙醇酸、对甲苯磺酸、邻甲苯磺酸、柠檬酸、甲磺酸、甲酸、乙酸、苯甲酸、苯乙酸、丙二酸、肉桂酸、苹果酸、马来酸、酒石酸、草酸、富马酸、丙烯酸、巴豆酸、油酸和亚油酸等形成的酸加成盐。
“治疗有效量”意指化合物被给予主体例如人用于治疗疾病时，足以实现对该疾病的治疗的量。
“治疗”意指治疗上有效量的化合物的任何施用，并且包括：
(1)抑制正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即，阻滞所述病理学和/或症状学的进一步发展)，或
(2)改善正经历或显示出所述疾病的病理学或症状学的人体中的该疾病(即逆转所述病理学和/或症状学)。
“CR”是指完全缓解，“PR”是指部分缓解，“PD”是指疾病进展，“SD”是指疾病稳定，“ORR”是指客观缓解率，包括CR+PR，“DCR”是指疾病控制率，包括CR+PR+SD；这些术语均具有本领域公知的含义，例如可参考实体肿瘤的疗效评价标准(RECIST)1.1版所述的含义。
“治疗失败”包括毒副作用不可耐受、治疗过程中疾病进展或治疗结束后复发；其中不可耐受包括但不限于血液学毒性达IV级(血小板下降III级及以上)、非血液学毒性达到III 级或以上。
“c-MET过表达”和“c-MET高表达”含义相同，可互换使用。
“PFS(疾病无进展生存期)”是指从首次用药入组至疾病进展或死亡(以先出现者计)的时间。
“OS(总生存期)”是指从首次用药入组至全因死亡的时间。末次随访时仍存活的受试者，其OS以末次随访时间计为数据删失。失访的受试者，其OS以失访前末次证实存活的时间计为数据删失。
“DOR(疾病缓解持续时间)”是指是指首次记录到客观肿瘤缓解(CR或PR)至首次记录到客观肿瘤进展或由于任何原因死亡(以先发生者为准)的时间。
“CNS-PFS(颅内无进展生存期)”是指基线脑转移受试者，从入组开始至首次证实颅内进展的时间。
“CNS-DCR(颅内疾病控制率)”是指内完全缓解、颅内部分缓解和颅内疾病稳定受试者占基线有靶病灶脑转移受试者的比例。
“CNS-ORR(颅内客观缓解率)”是指颅内完全缓解、颅内部分缓解占基线有靶病灶脑转移受试者的比例。
“CNS-TTP(至颅内疾病进展时间)”是指从入组开始到首次出现颅内疾病进展的时间，包括基线有脑转移和无脑转移的受试者。
实施例
下面结合具体实施例，进一步阐述本申请。应理解，这些实施例仅用于说明本申请而不用于限制本申请的保护范围。
实施例1 5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺(化合物I)柠檬酸盐(化合物I的柠檬酸盐)
Figure PCTCN2021091584-appb-000005
可参照WO2016015676中实施例2“式I化合物的药学上可接受酸的盐的制备”的方法，制备得到标题化合物。
实施例2 含有5-((R)-1-(2,6-二氯-3-氟苯基)乙氧基)-4'-甲氧基-6'-((S)-2-甲基哌嗪-1-基)-3,3'-联吡啶-6-胺柠檬酸盐(化合物I的柠檬酸盐)的胶囊
Figure PCTCN2021091584-appb-000006
将化合物I的柠檬酸盐与微晶纤维素、交联羧甲基纤维素钠、二氧化硅混合均匀；接着将硬脂酸镁加至上述混合物中混合，干法制粒，并填充胶囊。
对于其它含量的化合物I的柠檬酸盐的胶囊，可参照上述相同的比例和处方制备得到。
实施例3
接种一定数量的对数生长期细胞(SNU-5)于96孔培养板，加入不同浓度的药物培养72小时。药物作用结束后，每孔加入MTT工作液，4小时后，三联液溶解，37℃过夜，次日采用酶标仪在570nm和690nm波长测定OD值，以OD 570-OD 690作为最终OD值。以下列公式计算细胞生长抑制率：
抑制率＝(OD值 对照孔-OD值 给药孔)/OD值对照孔×100％
根据各浓度抑制率，计算半数抑制浓度IC 50值。
表1化合物I的柠檬酸盐对c-MET高表达的SNU-5胃癌细胞增殖抑制结果
抑制率 化合物I的柠檬酸盐
IC 50(nM) 179.3±2.5
实施例4
将100ul Hs746T细胞接种至96孔板中，孵育24h后，取100uM的化合物I的柠檬酸盐，4倍稀释，共9个浓度，给药72h，加入CCK-8试剂孵育1-6h，450nm测定吸光度，计算IC 50值。
表2化合物I的柠檬酸盐对Met-14跳跃突变的Hs746T胃癌细胞增殖抑制结果
抑制率 化合物I的柠檬酸盐
IC 50(nM) 0.24
实施例5
在经组织学或细胞学确诊为非小细胞肺癌(NSCLC)、并且为IIIB-IV期(根据国际肺癌研究协会和美国癌症分类联合委员会第8版判断)、且经过MET基因状态评估为MET基因状态评估异常的受试者中，每28天为一个治疗周期，给予实施例2中制备的化合物I的柠檬酸 盐胶囊，起始日剂量为1200mg(分早晚两次给药，每次600mg)，每天连续给药的方案，在每天早晚大致相同的时间空腹或随餐口服，对至少接受1个治疗周期的患者纳入疗效评价，进行安全性和有效性的临床研究，主要疗效终点为客观缓解率(ORR)，次要疗效终点为PFS(疾病无进展生存期)、DCR(疾病控制率)、OS(总生存期)、DOR(疾病缓解持续时间)、CNS-PFS(颅内无进展生存期)、CNS-DCR(颅内疾病控制率)、CNS-ORR(颅内客观缓解率)、CNS-TTP(至颅内疾病进展时间)。受试者年龄18岁以上，性别不限，ECOG评分[0-1]分，预计生存期大于12周；按照RECIST v.1.1标准，至少有一处可测量的靶病灶(脑部病灶非唯一病灶)。
视需要，给药剂量可调整如下：
第一次下调日剂量 1000mg BID
第二次下调日剂量 800mg BID
MET基因状态评估
对于NSCLC患者中可存在MET基因的突变、扩增和过表达，其相应的检测方法有直接测序法、实时荧光定量PCR(real-time fluorescence quantitative PCR,RTFQ-PCR)、FISH和IHC，通过分析MET基因和c-MET蛋白筛选出适合c-MET抑制剂应用的获益人群十分必要。
直接测序法检测MET基因突变具有高度的准确性，且不必明确MET基因突变位点所在的具体位置，可以检测出其他潜在的外显子突变位点；RTFQ-PCR和FISH均可用于MET基因扩增的检测，前者检测速度更快，但是对基因组DNA片段的质量要求较高，而现有的提取方法得到的基因组DNA片段质量较差，因此二者相比，FISH的应用更广泛。FISH法可通过检测MET和CEP7(作为对照)的荧光探针比值来判定MET基因拷贝数(MET gene copies number,MET GCN)，其评估标准可依据两个方面：①MET/CEP7的荧光探针比值；②每一个细胞的基因拷贝数量及其阳性细胞所占总细胞比例。IHC可用于检测c-MET蛋白的过表达情况。
实施例临床试验中MET基因异常包括MET基因14号外显子跳跃突变、MET基因扩增(包括2种：平均基因拷贝数≥5和/或MET/CEP-7拷贝数比≥2)。
初步结果显示，在MET基因异常的疗效可评估的NSCLC患者中，显示出疗效。
实施例5-1
男，81岁，临床诊断：肺腺癌Ⅳ期，纵隔淋巴结转移，双肺转移，无化疗史，基因检测提示MET基因14号外显子跳跃突变。
开始每日2次每次口服600mg的实施例2中制备的化合物I的柠檬酸盐胶囊，连续每天给药，每天早晚大致相同的时间，两次间隔建议10-12小时，空腹或随餐口服，每28天为1 个治疗周期。
在给予化合物I的柠檬酸盐胶囊前，CT扫描显示，可测量的靶病灶直径之和为55mm，给药后定期进行CT扫描，治疗一个周期后，靶病灶直径之和降至37.5mm，疗效评价为PR，降低超过30％。治疗3个及5个周期后，靶病灶直径之和降至31.2mm及31.1mm，疗效评价为PR。治疗期间，总体耐受性良好。
实施例5-2
男，79岁，穿刺，病理诊断提示：非小细胞肺癌，腺癌。临床诊断：原发性右肺腺癌，淋巴结转移，无远处转移。基因检测提示MET基因扩增，无化疗史。
随后开始每日2次每次口服600mg的实施例2中制备的化合物I的柠檬酸盐胶囊，连续每天给药，每天早晚大致相同的时间，两次间隔建议10-12小时，空腹或随餐口服，每28天为1个治疗周期。
在给予化合物I的柠檬酸盐胶囊前，CT扫描显示，可测量的靶病灶直径之和为27.7mm，给药后定期进行CT扫描，治疗一个周期后，靶病灶直径之和降至17.7mm，疗效评价为PR，降低超过30％。治疗3个及5个周期后，靶病灶直径之和降至15.4mm及14.4mm，疗效评价为PR。治疗期间，总体耐受性良好。
实施例5-3
男，72岁，穿刺，病理诊断提示：非小细胞肺癌，低分化腺癌。临床诊断：肺腺癌Ⅳ期，纵隔淋巴结转移。基因检测提示MET基因14号外显子跳跃突变，无化疗史。
随后开始每日2次每次口服600mg的实施例2中制备的化合物I的柠檬酸盐胶囊，连续每天给药，每天早晚大致相同的时间，两次间隔建议10-12小时，空腹或随餐口服，每28天为1个治疗周期。
在给予化合物I的柠檬酸盐胶囊前，CT扫描显示，可测量的靶病灶直径之和为111.2mm，给药后定期进行CT扫描，治疗一个周期后，靶病灶直径之和降至71.2mm，疗效评价为PR，降低超过30％。治疗3个周期后，靶病灶直径降至70.8mm，疗效评价为PR，患者仍在继续治疗中。治疗期间，总体耐受性良好。
实施例5-4
男，85岁，临床诊断：非小细胞肺癌，左肺恶性肿瘤胸膜转移(腺癌，Ⅳ期，KPS评分90分)，基因检测提示MET基因14号外显子跳跃突变。
在入组之前，患者先后接受过埃克替尼125mg po qd(治疗1个月，未进行疗效评估)；和贝伐珠单抗胸腔灌注治疗(未进行疗效评估)。
随后开始每日2次每次口服600mg的实施例2中制备的化合物I的柠檬酸盐胶囊，连续 每天给药，每天早晚大致相同的时间，两次间隔建议10-12小时，空腹或随餐口服，每28天为1个治疗周期。
在给与化合物I的柠檬酸盐胶囊前，CT扫描显示，可测量的靶病灶直径之和为34.7mm，给药后定期进行CT扫描，治疗一个周期后，靶病灶直径之和降至21.2mm，疗效评价为PR，降低超过30％。治疗3个及5个周期后，靶病灶直径之和降至18mm，疗效评价为PR，患者仍在继续治疗中。治疗期间，总体耐受性良好。

Claims (13)

  1. 化合物I或其药学上可接受的盐在制备用于治疗MET基因异常的疾病的药物中的用途，
    Figure PCTCN2021091584-appb-100001
  2. 治疗MET基因异常的疾病的方法，所述方法包括给予需要治疗的患者治疗有效量的化合物I或其药学上可接受的盐，
    Figure PCTCN2021091584-appb-100002
  3. 用于治疗MET基因异常的疾病的药物组合物，其包含化合物I或其药学上可接受的盐，以及至少一种药学上可接受的载体，
    Figure PCTCN2021091584-appb-100003
  4. 试剂盒，其包含(a)至少一个单位剂量的包含化合物I或其药学上可接受的盐的药物组合物和(b)用于治疗MET基因异常的疾病的说明，
    Figure PCTCN2021091584-appb-100004
  5. 化合物I或其药学上可接受的盐在治疗MET基因异常的疾病中的用途，
    Figure PCTCN2021091584-appb-100005
  6. 根据权利要求1或5所述的用途、权利要求2所述的方法、权利要求3所述的药物组合物或权利要求4所述的试剂盒，其中所述的MET基因异常的疾病为MET基因异常的非小细胞肺癌或MET基因异常的胃癌。
  7. 根据权利要求1、5或6所述的用途、权利要求2或6所述的方法、权利要求3或6所述的药物组合物或权利要求4或6所述的试剂盒，其中所述的MET基因异常选自MET基因 扩增、MET基因重排、MET基因突变和/或c-MET过表达。
  8. 根据权利要求1和5-7中任一项所述的用途、权利要求2、6或7所述的方法、权利要求3、6或7所述的药物组合物或权利要求4、6或7所述的试剂盒，其中所述的MET基因异常的疾病为至少一种化疗药物和/或靶向药物治疗失败的MET基因异常的疾病。
  9. 根据权利要求1和5-8中任一项所述的用途、权利要求2和6-8中任一项所述的方法、权利要求3和6-8中任一项所述的药物组合物或权利要求4和6-8中任一项所述的试剂盒，其中所述的MET基因异常的疾病为至少一种化疗药物和/或靶向药物治疗失败的MET基因异常的非小细胞肺癌或在先接受过至少一种化疗药物和/或靶向药物治疗后出现进展或复发的非小细胞肺癌，或者至少一种化疗药物和/或靶向药物治疗失败的MET基因异常的胃癌或至少一种化疗药物和/或靶向药物耐药的MET基因异常的胃癌。
  10. 根据权利要求1和5-9中任一项所述的用途、权利要求2和6-9中任一项所述的方法、权利要求3和6-9中任一项所述的药物组合物或权利要求4和6-9中任一项所述的试剂盒，其中所述化合物I的药学上可接受的盐为化合物I与任意如下酸所形成的盐：硫酸、碳酸、硝酸、盐酸、氢溴酸、氢碘酸、磷酸、偏磷酸、三氟乙酸、乳酸、扁桃酸、乙醇酸、对甲苯磺酸、邻甲苯磺酸、柠檬酸、甲磺酸、甲酸、乙酸、苯甲酸、苯乙酸、丙二酸、肉桂酸、苹果酸、马来酸、酒石酸、草酸、富马酸、丙烯酸、巴豆酸、油酸和亚油酸。
  11. 根据权利要求1和5-10中任一项所述的用途、权利要求2和6-10中任一项所述的方法、权利要求3和6-10中任一项所述的药物组合物或权利要求4和6-10中任一项所述的试剂盒，其中所述化合物I的药学上可接受的盐为柠檬酸盐。
  12. 根据权利要求1和5-11中任一项所述的用途、权利要求2和6-11中任一项所述的方法、权利要求3和6-11中任一项所述的药物组合物或权利要求4和6-11中任一项所述的试剂盒，其中给予所述化合物I或其药学上可接受的盐的日剂量选自100毫克至2000毫克、150毫克至1950毫克、200毫克至1900毫克、300毫克至1800毫克、450毫克至1750毫克、500毫克至1650毫克、750毫克至1500毫克、900毫克至1350毫克、1050毫克至1250毫克、200毫克、400毫克、600毫克、800毫克、1000毫克、1200毫克或1600毫克。
  13. 根据权利要求1和5-12中任一项所述的用途、权利要求2和6-12中任一项所述的方法、权利要求3和6-12中任一项所述的药物组合物或权利要求4和6-12中任一项所述的试剂盒，其中以每天用药的方式给予化合物I或其药学上可接受的盐。
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