WO2021018310A1 - Aminopyridine derivatives for treatment of non-small cell lung cancer - Google Patents

Abstract

Disclosed is a use of a substituted 2-aminopyridine derivative in treatment of non-small cell lung cancer, particularly in a patient who have previously treated with at least one chemotherapeutic drug and/or targeted drug, wherein the substituted 2-aminopyridine derivative is the compound I having a chemical name of 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4'-methoxy-6'-((S)-2-methylpiperazin-1-yl)-3,3'-bipyridin-6-amine or a pharmaceutically acceptable salt thereof.

Description

Aminopyridine derivatives for the treatment of non-small cell lung cancer Technical field

This application belongs to the field of medicine. Specifically, this application relates to the use of substituted 2-aminopyridine derivatives in the treatment of non-small cell lung cancer.

Background technique

Recent molecular biology studies have shown that the cell signal transduction pathways of tyrosine kinases (Protein Tyrosine Kinases, PTKs) play an extremely important role in the formation and development of tumors. Inhibiting the activity of tyrosine kinase can reduce the activation of cell signal transduction pathways, thereby inhibiting tumor cells from inducing survival and proliferation, and achieving the effect of treating tumors.

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase, a member of the insulin receptor superfamily, and it plays an important role in the growth and development of tumor cells. ALK gene can be fused with a variety of protein genes to express ALK protein, and can also produce mutations, amplifications and other mutations. In 1997, the oncogenic ALK gene recombination on the short arm of chromosome 2 on xenogeneic large cell lymphoma was first described, and it was later found in other malignant tumors, including diffuse large B cell lymphoma and malignant histiocytosis, and It has also been found in a variety of solid tumors, including inflammatory myofibroblastoma, esophageal squamous cell carcinoma, neuroblastoma and the recently proposed non-small cell lung cancer (NSCLC).

In 2007, it was first reported that the ALK gene could form a fusion gene with the EML4 gene to encode ALK, thereby promoting lung cancer cell growth. The EML4-ALK fusion is caused by the insertion of the short arm of chromosome 2, and many variants have been found so far. After testing, all these fusion genes have biological functions, and their expression product is a chimeric tyrosine kinase, which has gradually appeared in NSCLC related research reports in 2007.

The discovery of the EML4-ALK fusion gene and the unique effects of ALK inhibitors in its subgroups have allowed NSCLC to be divided into different subtypes, such as EGFR mutants, KRAS mutants, and EML4-ALK based on different molecular pathogenesis. Gene fusion type, etc. In general patients with non-small cell lung cancer, the positive rate of EML4-ALK fusion gene is relatively low, about 3% to 7%. The EML4-ALK fusion gene is mainly found in non-smokers with lung adenocarcinoma. A study reported in 2010 showed that among Chinese lung adenocarcinoma patients, the positive rate of EML4-ALK fusion gene was significantly higher than that of European and American patients, which was 16.13%; among non-smokers with lung adenocarcinoma, the positive rate was 19.23. %; In lung adenocarcinoma lacking EGFR and KRAS mutations, the mutation rate is as high as 42.8%.

ROS1 (c-ros oncogene 1 receptor kinase, c-ros proto-oncogene 1 tyrosine kinase) is a tyrosine kinase receptor in the insulin receptor family, and a unique receptor not related to ALK. It is estimated that in NSCLC patients, the probability of ROS1 gene rearrangement is about 2%; they occur more frequently in patients with EGFR mutation negative, KRAS mutation negative and ALK gene rearrangement negative (also called triple negative).

At present, some protein kinase inhibitors have been marketed and used to treat ALK-positive non-small cell lung cancer (NSCLC), including aletinib, crizotinib, ceritinib, brigatinib, and cabozantinib , Furitinib, Ensatinib, and Loratinib. Crizotinib is an inhibitor of ALK, ROS1 and MET tyrosine kinases. The FDA approved it for the treatment of patients with metastatic NSCLC who are ALK-positive (ie, ALK gene rearrangement) or ROS1-positive (ROS1 gene rearrangement).

However, due to the development of drug resistance, patients with ALK-positive or ROS1-positive metastatic NSCLC always relapse, usually within 1 year. For example, there is currently no very effective treatment for NSCLC patients resistant to crizotinib. Therefore, there is an urgent need to develop new protein kinase inhibitors for the prevention, alleviation and/or treatment of resistant non-small cell lung cancer.

Summary of the invention

In the first aspect, this application provides a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof for preparing a drug for treating non-small cell lung cancer that a patient has previously received at least one chemotherapy drug and/or targeted drug therapy Use in.

In the second aspect, this application provides a method for treating non-small cell lung cancer, which comprises administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, said patient having previously received at least A treatment with chemotherapy drugs and/or targeted drugs.

In the third aspect, the present application provides a pharmaceutical composition for treating non-small cell lung cancer that a patient has previously received at least one chemotherapeutic drug and/or targeted drug therapy, which comprises Compound I or a pharmaceutically acceptable salt thereof, And at least one pharmaceutically acceptable carrier.

In a fourth aspect, the present application provides a kit comprising (a) at least one unit dose of a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof and (b) for treating patients who have previously received at least one Instructions for non-small cell lung cancer treated with chemotherapeutic drugs and/or targeted drugs.

Detailed description of the invention

In the first aspect, this application provides a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof for preparing a drug for treating non-small cell lung cancer that a patient has previously received at least one chemotherapy drug and/or targeted drug therapy Use in.

In some embodiments, there is provided use for treating at least one chemotherapeutic drug and/or non-small cell lung cancer that has failed targeted drug therapy; in some embodiments, use is provided for treating at least one chemotherapeutic drug and/or Or use of targeted drug treatment for non-small cell lung cancer with disease progression or recurrence; in some embodiments, use for the treatment of non-small cell lung cancer resistant to at least one chemotherapeutic drug and/or targeted drug is provided . In some embodiments, the non-small cell lung cancer is non-small cell lung cancer for which the patient has not previously received systemic treatment. In some embodiments, the non-small cell lung cancer is preferably squamous cell carcinoma; in some embodiments, the non-small cell lung cancer is non-squamous carcinoma; in some specific embodiments, the non-small cell lung cancer is glandular cancer. In some specific embodiments, the non-small cell lung cancer is invasive adenocarcinoma.

In the present application, the non-small cell lung cancer includes non-small cell lung cancer with positive gene mutation; the gene mutation includes ALK rearrangement and/or ROS1 mutation. In some embodiments, the non-small cell lung cancer is ALK (anaplastic lymphoma kinase) positive non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is ROS1 (c-ros proto-oncogene 1 tyrosine kinase) positive non-small cell lung cancer.

In some embodiments, the application provides the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-small cell lung cancer resistant to chemotherapeutic drugs and/or targeted drugs. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating chemotherapeutic drugs and/or non-small cell lung cancer that has failed targeted drug treatment. The application also provides the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ALK-positive non-small cell lung cancer resistant to chemotherapeutic drugs and/or targeted drugs. The application also provides the use of compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ROS1-positive non-small cell lung cancer resistant to chemotherapeutic drugs and/or targeted drugs.

In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer that has failed ALK inhibitor treatment; in some embodiments, Compound I or The use of its pharmaceutically acceptable salt in the preparation of a medicament for the treatment of non-small cell lung cancer resistant to ALK inhibitors. The ALK inhibitors include but are not limited to crizotinib, aletinib, color One or more of retinib, ensatinib, loratinib, and fretinib; the non-small cell lung cancer includes ALK positive and/or ROS1 positive non-small cell lung cancer. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-small cell lung cancer resistant to crizotinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ALK-positive non-small cell lung cancer resistant to crizotinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ROS1-positive non-small cell lung cancer resistant to crizotinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ALK-positive advanced non-small cell lung cancer resistant to crizotinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ALK-positive clinical stage IIIB/IV non-small cell lung cancer resistant to crizotinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ALK-positive metastatic non-small cell lung cancer that is resistant to crizotinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of crizotinib-resistant ALK-positive brain metastatic non-small cell lung cancer.

In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-small cell lung cancer resistant to Ensatinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ALK-positive non-small cell lung cancer resistant to Ensatinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ROS1-positive non-small cell lung cancer resistant to Ensatinib.

In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer resistant to loratinib. In some embodiments, provided is the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ALK-positive non-small cell lung cancer resistant to loratinib.

In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-small cell lung cancer resistant to frittinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ALK-positive non-small cell lung cancer that is resistant to Fritinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating non-small cell lung cancer resistant to pemetrexed and/or platinum drugs.

In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-small cell lung cancer resistant to crizotinib and/or ensatinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer resistant to crizotinib and/or frizotinib. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer resistant to crizotinib and/or loratinib.

In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer that has failed the treatment of at least one chemotherapeutic drug; in some embodiments, the compound is provided Use of I or a pharmaceutically acceptable salt thereof in preparing a medicament for treating non-small cell lung cancer resistant to at least one chemotherapeutic drug. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer resistant to at least two chemotherapeutic drugs.

In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-small cell lung cancer resistant to pemetrexed and/or carboplatin. In some embodiments, the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer resistant to pemetrexed and/or nedaplatin is provided. In some embodiments, the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer resistant to pemetrexed and/or bevacizumab is provided. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-small cell lung cancer resistant to paclitaxel drugs and/or platinum drugs. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for the treatment of non-small cell lung cancer resistant to paclitaxel liposomes and/or nedaplatin. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer resistant to gemcitabine and/or platinum drugs. In some embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer resistant to gemcitabine and/or cisplatin.

In the second aspect, this application provides a method for treating non-small cell lung cancer, which comprises administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, said patient having previously received at least A treatment with chemotherapy drugs and/or targeted drugs.

In certain embodiments, the patient is, for example, a patient who has been diagnosed with adenocarcinoma, squamous cell carcinoma, large cell carcinoma, or ambiguous non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is preferably squamous cell carcinoma; in some embodiments, the non-small cell lung cancer is non-squamous carcinoma; in some specific embodiments, the non-small cell lung cancer is glandular cancer. In some specific embodiments, the non-small cell lung cancer is invasive adenocarcinoma.

In certain embodiments, the patient is diagnosed as having locally advanced, and/or advanced (such as stage IIIB/IV) and/or metastatic non-small cell lung cancer; wherein metastatic non-small cell lung cancer includes but 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. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with brain metastases. In some embodiments, the patient is, for example, a patient who has been diagnosed with 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 nodes with recurrent non-small cell lung cancer. Lung cancer, superior vena cava (SVC) block non-small cell lung cancer and non-small cell lung cancer with severe hemoptysis. In some embodiments, the patient has previously received at least one chemotherapy drug and/or targeted drug treatment, and the treatment has failed. In some embodiments, the patient has previously received at least one chemotherapy drug and/or targeted drug treatment, and non-small cell lung cancer has progressed or recurred after the treatment. In some embodiments, the patient has not previously received systemic therapy.

In some embodiments of the present application, the non-small cell lung cancer is non-small cell lung cancer with positive gene mutation; the gene mutation is ALK rearrangement and/or ROS1 mutation. In some embodiments, the non-small cell lung cancer is ALK (anaplastic lymphoma kinase) positive non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is ROS1 (c-ros proto-oncogene 1 tyrosine kinase) positive non-small cell lung cancer.

On the other hand, this application provides a method for treating non-small cell lung cancer that is resistant to chemotherapeutic drugs and/or targeted drugs. In some embodiments, the application provides a method for treating non-small cell lung cancer that has failed treatment with chemotherapeutic drugs and/or targeted drugs. The application also provides a method for treating ALK-positive non-small cell lung cancer resistant to chemotherapeutic drugs and/or targeted drugs. The application also provides a method for treating ROS1-positive non-small cell lung cancer resistant to chemotherapeutic drugs and/or targeted drugs.

In some embodiments, methods of treating non-small cell lung cancer resistant to crizotinib are provided. In some embodiments, methods of treating ALK-positive non-small cell lung cancer that are resistant to crizotinib are provided. In some embodiments, a method of treating ROS1-positive non-small cell lung cancer resistant to crizotinib is provided. In some embodiments, methods for treating ALK-positive advanced non-small cell lung cancer that are resistant to crizotinib are provided. In some embodiments, a method for treating ALK-positive clinical stage IIIB/IV non-small cell lung cancer that is resistant to crizotinib is provided. In some embodiments, a method for treating ALK-positive metastatic non-small cell lung cancer that is resistant to crizotinib is provided. In some embodiments, there is provided a method for treating crizotinib-resistant ALK-positive brain metastatic non-small cell lung cancer.

In some embodiments, a method of treating non-small cell lung cancer resistant to Ensatinib is provided. In some embodiments, a method of treating ALK-positive non-small cell lung cancer that is resistant to Ensatinib is provided. In some embodiments, a method of treating ROS1-positive non-small cell lung cancer that is resistant to Ensatinib is provided.

In some embodiments, methods of treating non-small cell lung cancer resistant to loratinib are provided. In some embodiments, methods of treating ALK-positive non-small cell lung cancer that are resistant to loratinib are provided.

In some embodiments, a method of treating non-small cell lung cancer resistant to fritinib is provided. In some embodiments, a method of treating ALK-positive non-small cell lung cancer that is resistant to fritinib is provided.

In some embodiments, methods of treating non-small cell lung cancer resistant to pemetrexed and/or platinum drugs are provided. In some embodiments, methods for treating non-small cell lung cancer resistant to pemetrexed and/or carboplatin are provided. In some embodiments, methods for treating non-small cell lung cancer resistant to pemetrexed and/or nedaplatin are provided. In some embodiments, methods for treating non-small cell lung cancer resistant to pemetrexed and/or bevacizumab are provided. In some embodiments, methods for treating non-small cell lung cancer resistant to paclitaxel drugs and/or platinum drugs are provided. In some embodiments, methods for treating non-small cell lung cancer resistant to paclitaxel liposomes and/or nedaplatin are provided. In some embodiments, a method of treating non-small cell lung cancer resistant to gemcitabine and/or platinum drugs is provided. In some embodiments, methods of treating non-small cell lung cancer resistant to gemcitabine and/or cisplatin are provided.

The method of administration can be determined comprehensively according to the activity, toxicity and patient tolerance of the drug. Preferably, Compound I or a pharmaceutically acceptable salt thereof is administered in a manner of continuous administration every day. The continuous daily administration can be administered at approximately the same time in the morning and evening. In some embodiments, the period of administration of Compound I or its pharmaceutically acceptable salt is 14 to 42 days as a cycle; preferably, the period of administration is 21 days as a cycle; preferably, the The medication schedule is 35 days as a cycle; more preferably, the medication schedule is 28 days as a cycle; in some embodiments, compound I or its pharmaceutically acceptable compound is administered one or more times a day salt. Preferably, Compound I or a pharmaceutically acceptable salt thereof is administered twice a day during the administration cycle.

In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered in a continuous manner every day, the administration time course is 28 days as a cycle, and Compound I or a pharmaceutically acceptable salt thereof is administered twice a day during the administration cycle. Acceptable salt. In some embodiments, Compound I or a pharmaceutically acceptable salt thereof is administered continuously at approximately the same time every morning and evening, and the administration time course is 28 days as a cycle, and the compound is administered twice a day during the administration cycle I or a pharmaceutically acceptable salt thereof.

In certain specific embodiments, it is administered orally at a dose of 400 mg per day, preferably in two doses, more preferably at approximately the same time every morning and evening; and a 28-day cycle is used to It is administered by continuous medication every day.

In certain specific embodiments, it is administered orally at a dose of 600 mg per day, preferably in two doses, more preferably at approximately the same time each morning and evening; and a 28-day cycle is used to It is administered by continuous medication every day.

In certain specific embodiments, it is administered orally at a dose of 800 mg per day, preferably in two doses, and more preferably at approximately the same time each morning and evening; and a 28-day cycle is used to It is administered by continuous medication every day.

In certain specific embodiments, it is administered orally at a dose of 1000 mg per day, preferably in two doses, more preferably at approximately the same time each morning and evening; and a 28-day cycle, with It is administered by continuous medication every day.

In some specific embodiments, it is administered orally at a dose of 1200 mg per day, preferably divided into two doses, and more preferably administered at approximately the same time every morning and evening; and a 28-day cycle is used to It is administered by continuous medication every day.

In some specific embodiments, it is administered orally at a dose of 1600 mg per day, preferably in two doses, more preferably at approximately the same time each morning and evening; and a 28-day cycle is used to It is administered by continuous medication every day.

In some embodiments, when a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof is administered to a patient in need of treatment, radiotherapy may be administered simultaneously or sequentially.

In the third aspect, the present application provides a pharmaceutical composition for treating non-small cell lung cancer that a patient has previously received at least one chemotherapeutic drug and/or targeted drug therapy, 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 treating non-small cell lung cancer that has failed chemotherapeutic drugs and/or targeted drugs, 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 resistant to chemotherapeutic drugs and/or targeted drugs, which comprises compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Carrier. In some embodiments, the non-small cell lung cancer is ALK-positive non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is ROS1-positive non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with brain metastases. In some embodiments, the non-small cell lung cancer is relapsed non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer that has progressed or recurred after the patient has previously received at least one chemotherapy drug and/or targeted drug treatment. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer for which the patient has not previously received systemic treatment. In some embodiments, the non-small cell lung cancer is preferably squamous cell carcinoma; in some embodiments, the non-small cell lung cancer is non-squamous carcinoma; in some specific embodiments, the non-small cell lung cancer is glandular cancer. In some specific embodiments, the non-small cell lung cancer is invasive adenocarcinoma.

In some embodiments, the drug-resistant non-small cell lung cancer is non-small cell lung cancer that is resistant to crizotinib. In some embodiments, the non-small cell lung cancer is ALK-positive non-small cell lung cancer that is resistant to crizotinib. In some embodiments, the non-small cell lung cancer is ROS1-positive non-small cell lung cancer that is resistant to crizotinib. In some embodiments, the non-small cell lung cancer is ALK-positive advanced non-small cell lung cancer that is resistant to crizotinib. In some embodiments, the non-small cell lung cancer is ALK-positive clinical stage IIIB/IV non-small cell lung cancer that is resistant to crizotinib. In some embodiments, the non-small cell lung cancer is ALK-positive metastatic non-small cell lung cancer that is resistant to crizotinib. In some embodiments, the non-small cell lung cancer is crizotinib-resistant ALK-positive non-small cell lung cancer with brain metastases.

In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to Ensatinib. In some embodiments, the non-small cell lung cancer is ALK-positive non-small cell lung cancer that is resistant to Ensatinib. In some embodiments, the non-small cell lung cancer is ROS1-positive non-small cell lung cancer that is resistant to Ensatinib.

In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to loratinib. In some embodiments, the non-small cell lung cancer is ALK-positive non-small cell lung cancer resistant to loratinib. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to fritinib. In some embodiments, the non-small cell lung cancer is ALK-positive non-small cell lung cancer that is resistant to fritinib.

In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to pemetrexed and/or platinum drugs. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to pemetrexed and/or carboplatin. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to pemetrexed and/or nedaplatin. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to pemetrexed and/or bevacizumab. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to paclitaxel drugs and/or platinum drugs. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to paclitaxel liposomes and/or nedaplatin. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to gemcitabine and/or platinum drugs. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to gemcitabine and/or cisplatin.

In some embodiments of the present application, the pharmaceutical composition includes, but is not limited to, suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, intrabuccal, and intranasal , Inhalation, vaginal, intraocular, topical, subcutaneous, intra-fat, intra-articular, intraperitoneal and intrathecal pharmaceutical compositions. In some embodiments, the pharmaceutical composition is a preparation suitable for oral administration, including tablets, capsules, powders, granules, dripping pills, pastes, powders, etc., preferably tablets and capsules.

In some embodiments, 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 of the 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 drug The composition includes 100 mg to 1000 mg of Compound I or a pharmaceutically acceptable salt thereof; in some embodiments, the pharmaceutical composition includes 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 The pharmaceutical composition described 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, 1200 mg of compound I or a pharmaceutically acceptable salt thereof.

In some embodiments, there is provided a pharmaceutical composition formulated into a unit dosage form for treating non-small cell lung cancer that a patient has previously received at least one chemotherapeutic drug and/or targeted drug therapy; the pharmaceutical composition further At least one pharmaceutically acceptable carrier is included. In some embodiments, the pharmaceutical composition in unit dosage form contains 50 mg to 1200 mg of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 300 mg to 600 mg of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 400 mg to 500 mg of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 600 mg to 1200 mg of Compound I or a pharmaceutically acceptable salt thereof. In some embodiments, 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. In some specific embodiments, the pharmaceutical composition in the 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. For example, for tablets or capsules, "a pharmaceutical composition in unit dosage form" means each tablet or each capsule.

In some embodiments, the non-small cell lung cancer is advanced and/or metastatic non-small cell lung cancer. In some embodiments, the drug-resistant non-small cell lung cancer is non-small cell lung cancer that has failed chemotherapeutic drugs and/or targeted drugs; in some embodiments, the non-small cell lung cancer is ALK positive and / Or ROS1-positive non-small cell lung cancer; in some embodiments, the non-small cell lung cancer is non-small cell lung cancer that is resistant to ALK inhibitors or has failed treatment with ALK inhibitors; in some embodiments, the The non-small cell lung cancer of is ALK-positive and/or ROS1-positive non-small cell lung cancer that is resistant to ALK inhibitors or has failed treatment with ALK inhibitors; in some embodiments, the ALK inhibitors include but are not limited to crizoti One or more of Ni, Ensatinib, Loratinib, Freatinib; In some embodiments, the ALK inhibitor includes but not limited to Crizotinib, Ensatinib, One or two of lauratinib and fretinib. In some specific embodiments, the non-small cell lung cancer is ALK-positive metastatic non-small cell lung cancer that is resistant to crizotinib.

In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to pemetrexed and/or platinum drugs. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to pemetrexed and/or carboplatin. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to pemetrexed and/or nedaplatin. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to pemetrexed and/or bevacizumab. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to paclitaxel drugs and/or platinum drugs. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to paclitaxel liposomes and/or nedaplatin. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to gemcitabine and/or platinum drugs. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer resistant to gemcitabine and/or cisplatin.

In a fourth aspect, the present application provides a kit comprising (a) at least one unit dose of a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof and (b) for treating patients who have previously received at least one Instructions for non-small cell lung cancer treated with chemotherapeutic drugs and/or targeted drugs.

The application also provides a kit, which comprises (a) at least one unit dose of a formulation suitable for oral administration containing Compound I or a pharmaceutically acceptable salt thereof and (b) continuous daily administration for the treatment of patients’ previous Instructions for non-small cell lung cancer that has received at least one chemotherapy drug and/or targeted drug treatment. In some specific embodiments, 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 continuous daily administration. Instructions for treating patients with non-small cell lung cancer that have previously received at least one chemotherapy drug and/or targeted drug therapy. In some more typical embodiments, the non-small cell lung cancer that has previously received at least one chemotherapeutic drug and/or targeted drug treatment is a non-small cell lung cancer that has failed or is resistant to chemotherapeutic drugs and/or targeted drugs. Lung cancer. The "unit dosage (unit dosage or unit dosage)" refers to a pharmaceutical composition packaged in a single package, such as each tablet or capsule, for the convenience of medication.

In the fifth aspect, the application provides the use of a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof in the preparation for the treatment of ROS1-positive non-small cell lung cancer. In some specific embodiments, there is provided the use of Compound I or a pharmaceutically acceptable salt thereof to treat ROS1-positive non-small cell lung cancer in patients who have previously received chemotherapy and/or targeted drug therapy.

In a sixth aspect, a method for treating ROS1-positive non-small cell lung cancer is provided, the method comprising administering a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof to a patient in need of such treatment.

The application also provides a pharmaceutical composition for treating ROS1-positive non-small cell lung cancer, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier. The application also 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) instructions for treating ROS1-positive non-small cell lung cancer.

Compound I or a pharmaceutically acceptable salt thereof

The chemical name of compound I is 5-((R)-1-(2,6-dichloro-3-fluorophenyl)ethoxy)-4'-methoxy-6'-((S)-2 -Methylpiperazin-1-yl)-3,3'-bipyridin-6-amine, which has the following structural formula:

Compound I can be administered in the form of its free base, or in the form of its pharmaceutically acceptable salts, hydrates and prodrugs, which are converted into the free base form of Compound I in vivo. For example, a pharmaceutically acceptable salt of Compound I is within the scope of this application, and the salt can be produced from different organic acids and inorganic acids according to methods well known in the art.

In some embodiments, the pharmaceutically acceptable salt of Compound I of the present application is a salt formed by Compound I and a pharmaceutically acceptable acid 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, benzene Acetic acid, malonic acid, cinnamic acid, malic acid, maleic acid, tartaric acid, oxalic acid, fumaric acid, acrylic acid, crotonic acid, oleic acid and linoleic acid. In some embodiments, 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. In some embodiments, 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. In some embodiments, 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. In a specific embodiment of the application, the molar ratio of compound I to citric acid is 1:1.

In some embodiments, Compound I is administered in the form of the citrate salt. 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 various routes, including but not limited to routes selected from the group consisting of oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, Intramuscular, rectal, intrabuccal, intranasal, inhalation, vagina, 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 according to the severity of the disease, the response of the disease, any treatment-related toxicity, the age and health of the patient. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof is 100 mg to 2000 mg. In some embodiments, the daily dose for administration of Compound I or a pharmaceutically acceptable salt thereof is 150 mg to 1950 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 200 mg to 1900 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is 300 mg to 1800 mg. In some embodiments, the daily dose of Compound I or a pharmaceutically acceptable salt thereof is between 450 mg and 1750 mg. In some embodiments, 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. In some specific embodiments, 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 at approximately the same time every morning and evening. In some embodiments, the oral solid formulation is administered twice a day. In some embodiments, the capsules are administered orally once or twice a day.

Non-small cell lung cancer

In this application, the said non-small cell lung cancer, according to histological classification, includes but not limited to adenocarcinoma, squamous cell carcinoma, large cell carcinoma or ambiguous non-small cell lung cancer; according to the clinical stage, including but not limited to local Advanced, and/or advanced (eg 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. In some embodiments, the non-small cell lung cancer is non-small cell lung cancer with brain metastases. In some embodiments, 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 and non-small cell lung cancer with severe hemoptysis.

Chemotherapy drugs

In this application, the chemotherapeutic drugs include, but are not limited to, one or more of alkylating agents, podophyllates, camptothecins, taxanes, antimetabolites, and antibiotic antitumor drugs. Examples that can be cited include, but are not limited to, platinum drugs (such as oxaliplatin, cisplatin, carboplatin, nedaplatin, dicycloplatin), fluoropyrimidine derivatives (such as gemcitabine, capecitabine, fluorouracil, Difuroxacil, deoxyfluridine, tegafur, carmofur, trifluridine), taxanes (e.g. paclitaxel, albumin-bound paclitaxel, paclitaxel liposomes and docetaxel), Vinblastine and its derivatives (e.g. camptothecin, hydroxycamptothecin, irinotecan, topotecan), vinblastine and its derivatives (vinorelbine, vinblastine, vincristine, vindesine, vinblastine) Ning (vinflunine)), pemetrexed, etoposide, irinotecan, mitomycin, ifosfamide, cyclophosphamide, azacitidine, amrubicin, methotrexate, benda Mustine, Epirubicin, Doxorubicin, Temozolomide, LCL-161, KML-001, Sapacitabine, Plenabulin, Treosulfan, Dipiforin Hydrochloride (tipiracil One or more (for example, two or three) of hydrochloride), ticgio and encequidar.

Targeted drugs

In this application, the targeted drugs include tyrosine kinase inhibitors, and the tyrosine kinase inhibitors include but are not limited to ALK inhibitors, EGFR inhibitors, VEGFR inhibitors, FGFR inhibitors, and PDGFR inhibitors In some embodiments, the targeted drugs include but are not limited to small molecule targeted drugs and antibodies; examples that can be enumerated include but are not limited to Alectinib, Crizotinib, color Ceritinib, Brigatinib, Cabozantinib, Fritinib (SAF-189s), Ensatinib (X-396), Lorlatinib And bevacizumab. In some typical embodiments, the targeted drugs are crizotinib, ensatinib, loratinib, fretinib and bevacizumab. In some more typical embodiments, the targeted drug is crizotinib.

Herein, unless otherwise stated, the dosages and ranges provided herein are based on the molecular weight of Compound I in free base form.

Unless otherwise stated, for the purpose of this application, the following terms used in this specification and claims shall have the following meanings.

"Patient" or "individual" refers to mammals, preferably humans.

"Pharmaceutically acceptable" refers to its use in the preparation of pharmaceutical compositions, which are generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes its use in human medicine Use is acceptable.

"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.

"Therapeutically effective amount" means an amount sufficient to achieve treatment of the disease when the compound is administered to a patient or individual (for example, a human) for the treatment of the disease.

"Treatment" means any administration of a therapeutically effective amount of a compound, and includes:

(1) To inhibit the disease in the human body who is experiencing or exhibiting the pathology or symptomology of the disease (ie, to block the further development of the pathology and/or symptomology), or

(2) Improving the disease in the human body who is experiencing or showing the pathology or symptomology of the disease (ie, reversing the pathology and/or symptomology).

"CR" means complete remission, "PR" means partial remission, "PD" means disease progression, "SD" means stable disease, "ORR" means objective response rate, including CR+PR, and "DCR" means Refers to the disease control rate, including CR+PR+SD; these terms 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.

"Treatment failure" includes intolerable toxic and side effects, disease progression during treatment, or recurrence after the end of treatment; intolerable includes, but not limited to, hematological toxicity reaching level IV (platelet decline level III and above), non-hematological toxicity reaching Level III or above.

"Late" includes "local late".

"EGFR inhibitor" refers to epidermal growth factor receptor inhibitors.

"VEGFR inhibitor" refers to a vascular endothelial growth factor receptor inhibitor.

Example

The application will be further explained below in conjunction with specific embodiments. It should be understood that these embodiments are only used to exemplify the present application and not to limit the protection scope of the present application.

Example 1 5-((R)-1-(2,6-Dichloro-3-fluorophenyl)ethoxy)-4'-methoxy-6'-((S)-2-methyl Piperazin-1-yl)-3,3'-bipyridine-6-amine (Compound I) Citrate (Citrate of Compound I)

The title compound can be prepared by referring to the method in Example 2 "Preparation of pharmaceutically acceptable acid salt of 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'-bipyridine-6-amine citrate (Citrate of Compound I)

Mix the citrate of compound I with microcrystalline cellulose, croscarmellose sodium, and silicon dioxide uniformly; then add magnesium stearate to the above mixture and mix, dry granulate, and fill capsules.

For capsules containing other content of Compound I citrate, it can be prepared by referring to the same ratio and prescription as mentioned above.

Example 3

A phase I/II clinical study of dose escalation, safety and efficacy in advanced ALK-positive or ROS-1-positive NSCLC patients. Every 28 days is a treatment cycle. Patients who have received at least one treatment cycle are included in the efficacy evaluation At present, the clinical research is still continuing. As of July 12, 2019, a total of 63 patients with advanced non-small cell lung cancer were enrolled. During the dose escalation phase, the citrate capsules of Compound I were administered twice a day, and the amount of each administration (in the Free base form calculation) as shown in the table below. Preliminary results show that in NSCLC patients whose ALK-positive curative effect can be evaluated, the daily dose range of 400 mg to 1600 mg all show good anti-tumor curative effect. Among the enrolled patients, 21 patients had brain metastases, the disease control rate (DCR) accounted for 100%, and the ORR accounted for 66.67%.

Table 1 Efficacy of ALK-positive patients who have previously received at least one chemotherapy drug or targeted drug

Single dose	Evaluable cases	ORR	DCR
200mg	3	66.67%	100%
300mg	4	100%	100%
400mg	7	85.71%	100%
500mg	12	83.33%	91.67%
600mg	14	85.71%	100%
800mg	3	100%	100%

Among the enrolled patients, there were 12 subjects with a history of treatment with ALK inhibitors (including crizotinib, ensatinib, fretinib, and lauratinib) (including progression, intolerance) Accepted), after taking the drugs of this application, they can all benefit. Among them, 7 subjects have the best curative effect to achieve PR. As of July 15, 2019, there are still 7 subjects in the study, as of June 2020 On the 28th, there is still one subject under study. Table 2 shows the efficacy of patients who have been treated with ALK inhibitors in the past.

Table 2 Medication and efficacy of ALK-positive NSCLC patients

Among them, in the course of treatment, tumor inhibition rate=(minimum tumor shrinkage-baseline tumor size)/baseline tumor size*100%.

Among the enrolled patients, there are ROS1-positive NSCLC patients who have taken chemotherapy drugs (including pemetrexed, carboplatin, nedaplatin, paclitaxel liposome, gemcitabine, cisplatin), bevacizol Anti-and/or targeted small molecule drugs (such as Ensatinib) can benefit from taking the drugs of this application. As of June 28, 2020, one subject is still under study. Table 3 shows the medication and efficacy of ROS1-positive NSCLC patients.

Table 3 Medication and efficacy of ROS1-positive NSCLC patients

In terms of safety, in all dose groups, the total incidence of all grades of drug-related adverse reactions (AE) was 73.81%. The drug-related AEs with the highest incidence were vomiting (64.29%), diarrhea (59.52%), nausea (54.76%), dizziness (30.95%), elevated ALT (28.57%), fatigue (19.05%), AST Elevated (21.43%), visual impairment (21.43%), most of the related AEs are Grade I or Grade II, which can be tolerated or relieved under stopping or symptomatic treatment.

Claims (20)

1. Use of compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating non-small cell lung cancer that a patient has previously received at least one chemotherapeutic drug and/or targeted drug therapy,

   
2. A method for the treatment of non-small cell lung cancer, the treatment method comprising administering Compound I or a pharmaceutically acceptable salt thereof to a patient in need of treatment, the patient having previously received at least one chemotherapy drug and/or targeted drug treatment ,

   
3. A pharmaceutical composition for treating non-small cell lung cancer that a patient has previously received at least one chemotherapeutic drug and/or targeted drug therapy, which comprises Compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable Carrier,

   
4. A kit comprising (a) at least one unit dose of a pharmaceutical composition comprising Compound I or a pharmaceutically acceptable salt thereof and (b) for treating patients who have previously received at least one chemotherapeutic drug and/or targeted drug Instructions for treatment of non-small cell lung cancer,

   
5. The use of claim 1, the method of claim 2, the pharmaceutical composition of claim 3, or the kit of claim 4, wherein the non-small cell lung cancer is at least one chemotherapeutic drug And/or non-small cell lung cancer that failed targeted drug therapy.
6. The use of claim 1, the method of claim 2, the pharmaceutical composition of claim 3, or the kit of claim 4, wherein the non-small cell lung cancer is at least one chemotherapeutic drug And/or non-small cell lung cancer with disease progression or recurrence after targeted drug treatment.
7. The use of claim 1, the method of claim 2, the pharmaceutical composition of claim 3, or the kit of claim 4, wherein the non-small cell lung cancer is for at least one chemotherapy Drug and/or targeted drug-resistant non-small cell lung cancer.
8. The use, method, pharmaceutical composition or kit according to any one of claims 1-7, wherein the non-small cell lung cancer includes squamous cell carcinoma, non-squamous carcinoma and adenocarcinoma, preferably invasive adenocarcinoma.
9. The use, method, pharmaceutical composition or kit according to any one of claims 1-8, wherein the non-small cell lung cancer comprises gene mutation-positive non-small cell lung cancer, preferably ALK-positive non-small cell lung cancer Lung cancer and/or ROS1-positive non-small cell lung cancer.
10. The use, method, pharmaceutical composition or kit according to any one of claims 1-9, wherein the non-small cell lung cancer is ALK-positive non-small cell lung cancer.
11. The use, method, pharmaceutical composition or kit according to any one of claims 1-9, wherein the non-small cell lung cancer is ROS1-positive non-small cell lung cancer.
12. Use of compound I or a pharmaceutically acceptable salt thereof in the preparation of a medicament for treating ROS1-positive non-small cell lung cancer,

    
13. The use according to claim 12, wherein the non-small cell lung cancer is a non-small cell lung cancer that the patient has previously received at least one chemotherapeutic drug and/or targeted drug.
14. The use, method, pharmaceutical composition or kit according to any one of claims 1-11 or 13, wherein the targeted drugs include ALK inhibitors, EGFR inhibitors, VEGFR inhibitors, FGFR inhibitors, PDGFR inhibitors and antibodies; preferably ALK inhibitors, the ALK inhibitors include one of crizotinib, aletinib, ceritinib, ensatinib, loratinib and freitinib or Many kinds.
15. The use, method, pharmaceutical composition or kit according to any one of claims 1-11 or 13, wherein the chemotherapeutic drugs are alkylating agents, podophylls, camptothecins, taxans, One or more of antimetabolites and antibiotic anticancer drugs.
16. The use, method, pharmaceutical composition or kit according to any one of claims 1-11 or 13, wherein the chemotherapeutic drug and/or targeted drug is any one of the following (1) to (15) Kind or more:

    (1) Pemetrexed and platinum drugs;

    (2) Pemetrexed and carboplatin;

    (3) Pemetrexed and nedaplatin;

    (4) Pemetrexed and bevacizumab;

    (5) Paclitaxel drugs and platinum drugs;

    (6) Paclitaxel liposomes and nedaplatin;

    (7) Gemcitabine and platinum drugs;

    (8) Gemcitabine and Cisplatin;

    (9) Crizotinib;

    (10) Ensatinib;

    (11) Loratinib;

    (12) Furitinib;

    (13) Crizotinib and Ensatinib;

    (14) Crizotinib and Frizotinib;

    (15) Crizotinib and loratinib.
17. The use, method, pharmaceutical composition or kit according to any one of claims 1-16, wherein the pharmaceutically acceptable salt is a salt formed by compound I and an acid selected from the group consisting of 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, preferably sulfuric acid, hydrochloric acid, phosphoric acid, p- Toluenesulfonic acid, citric acid, methanesulfonic acid, malic acid, maleic acid, tartaric acid and fumaric acid; more preferably citrate, more preferably monocitrate and dicitrate.
18. The use, method, pharmaceutical composition or kit according to any one of claims 1-17, wherein based on the molecular weight of the compound I in free base form, the day when the compound I or a pharmaceutically acceptable salt thereof is administered The doses are 100 mg to 2000 mg, 150 mg to 1950 mg, 200 mg to 1900 mg, 300 mg to 1800 mg, 450 mg to 1750 mg, 500 mg to 1650 mg, 750 mg to 1500 mg, 900 mg to 1350 mg, 1050 mg to 1250 mg, 200 mg, 400 mg, 600 mg, 800 mg, 1000 mg, 1200 mg or 1600 mg.
19. The use, method, pharmaceutical composition or kit according to any one of claims 1-18, wherein the compound I or a pharmaceutically acceptable salt thereof is administered in a continuous manner every day, and the administration time course is 14 to 42 Day is a cycle; preferably, the medication time course is 21 days, 35 days or 28 days as a cycle.
20. The use, method, pharmaceutical composition or kit according to any one of claims 1-19, wherein the compound I or a pharmaceutically acceptable salt thereof can be administered once a day or multiple times a day, preferably Preferably, it is administered twice a day, and more preferably, it is administered at approximately the same time every morning and evening.