CN115484955A

CN115484955A - Aminopyridine derivatives for the treatment of disorders of MET gene abnormality

Info

Publication number: CN115484955A
Application number: CN202180030830.7A
Authority: CN
Inventors: 张喜全; 王训强; 于鼎; 苏楠; 汪荣亮; 唐晓闻; 李鑫; 刘雯雯
Original assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Current assignee: Chia Tai Tianqing Pharmaceutical Group Co Ltd
Priority date: 2020-04-30
Filing date: 2021-04-30
Publication date: 2022-12-16
Also published as: WO2021219137A1

Abstract

The present application relates to aminopyridine derivatives useful for treating diseases with MET gene abnormalities. In particular, the application relates to the use of substituted 2-aminopyridine derivatives for the treatment of non-small cell lung cancer with MET gene abnormality and gastric cancer with MET gene abnormality. The 2-aminopyridine derivative is, for example, compound I or a pharmaceutically acceptable salt thereof, having the chemical name 5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -4' -methoxy-6 ' - ((S) -2-methylpiperazin-1-yl) -3,3' -bipyridin-6-amine.

Description

Aminopyridine derivatives for the treatment of disorders of MET gene abnormality

Cross Reference to Related Applications

This application claims the benefit and priority of the chinese patent application No. 202010366117.7 filed on 30.04.2020 by the national intellectual property office of the people's republic of china, the entire contents of which are hereby incorporated by reference in their entirety.

Technical Field

The present application belongs to the field of medicine, and in particular, it relates to the use of substituted 2-aminopyridine derivatives in the treatment of diseases with MET gene abnormality.

Background

The MET protooncogene is present in the long arm of human chromosome 7, the protein product is the c-MET tyrosine kinase receptor, and the MET gene is expressed both in embryonic and adult stages. The ligand of c-MET is hepatocyte-derived growth factor (HGF), and the binding of HGF and c-MET promotes proliferation, migration, differentiation and morphological changes of cells. The HGF/c-MET signaling pathway is subject to complex, high degree of regulation, playing an important role in cell proliferation, differentiation and motility. c-MET is combined with HGF to activate a plurality of downstream channels such as PI3K/Ak/mTOR, ras-MAPK and the like, so that the drug resistance phenomenon is caused; meanwhile, c-MET can be combined with HER3 to form a heterodimer so as to activate a downstream pathway.

The HGF/c-MET signal channel is abnormal by the following three mechanisms: 1. gene aspects include gene rearrangement, activating mutations, and gene amplification; 2. overexpression of c-MET protein due to transcriptional upregulation; 3. sustained activation of c-MET proteins is enabled by ligand-dependent autocrine or paracrine mechanisms.

The MET gene amplification comprises two different modes of overall amplification and regional amplification. The overall amplification is caused by the increase of the number of chromosome 7, is often accompanied by the amplification of other genes, and the MET gene amplification in the form is not considered to cause tumorigenesis and drug resistance at present; the mode of regional amplification, i.e. independent copy number of the MET gene, is increased.

In addition to MET gene amplification, exon 14 skipping mutations are currently considered to be important independent driver mutations in NSCLC (non-small cell lung cancer). The current clinical pathological characteristics research shows that the MET gene 14 exon skipping mutation mostly occurs in NSCLC, and lung sarcomatoid carcinoma and adenocarcinoma are the most common. The MET gene exon 14 skipping mutant population is older and has more smoking history. Therefore, the development of targeted drugs for treating MET gene abnormal diseases is necessary. And the analysis and research on the drug resistance mechanism of the drug have important guiding significance for the subsequent development of the drug and the subsequent medication of patients.

Summary of The Invention

In a first aspect, the application provides the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease with abnormal MET gene,

in a second aspect, the application provides a method of treating a disease with MET gene abnormality, comprising administering to a patient in need thereof a therapeutically effective amount of compound I or a pharmaceutically acceptable salt thereof.

In a third aspect, the present application provides a pharmaceutical composition for treating a disease with abnormal MET gene, comprising 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) instructions for treating a disease in which the MET gene is aberrant.

In a fifth aspect, the present application provides compound I or a pharmaceutically acceptable salt thereof for use in the treatment of a disease in which the MET gene is aberrant.

In a sixth aspect, the present application provides the use of compound I, or a pharmaceutically acceptable salt thereof, in the treatment of a disease in which the MET gene is aberrant.

Detailed Description

MET gene abnormalities described herein include, but are not limited to, MET gene amplification, MET gene rearrangement, MET gene mutation, and/or c-MET overexpression. Wherein the MET gene amplification includes but is not limited to primary MET gene amplification and acquired drug resistant MET gene amplification. The MET gene mutation includes, but is not limited to, exon 14 mutation, such as exon 14 skipping mutation.

In some embodiments of the present application, there is provided the use of compound I or a pharmaceutically acceptable salt thereof for treating a disease of MET gene amplification. In some embodiments, uses for treating diseases of MET gene rearrangement are provided. In some embodiments, uses for treating diseases in which MET gene is mutated are provided. In some embodiments, uses for treating diseases in which c-MET is overexpressed are provided. In some embodiments, there is provided a method for treating a cancer having a biological activity selected from the group consisting of: use of a disease in which two or more MET genes are abnormal in MET gene amplification, MET gene rearrangement, MET gene mutation, and c-MET overexpression. In some embodiments of the present application, the above-described treatment is achieved by administering a therapeutically effective amount of said compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need thereof.

In some embodiments of the present application, there is provided use for treating a disease in which a primary MET gene is amplified. In some embodiments, uses are provided for treating diseases of acquired drug resistant MET gene amplification. In some embodiments, uses for treating diseases in which the MET gene is globally amplified are provided. In some embodiments, there is provided a use for treating a disease in which a MET gene region is amplified. In some embodiments, MET gene amplification refers to an average gene copy number of ≧ 5 and/or a MET/CEP-7 copy number ratio (ratio of MET copy number to chromosome 7 centromere number) of ≧ 2. In some embodiments of the present application, the above treatment is achieved by administering said compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need thereof.

In some embodiments of the present application, there is provided a use for treating a disease in which MET gene exon 14 is mutated. In some embodiments, there is provided a use for treating a disease with exon 14 skipping mutation of the MET gene. In some embodiments of the present application, the above treatment is achieved by administering said compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need thereof.

In some embodiments of the present application, the disorder in which MET gene is aberrant is a disorder in which at least one chemotherapeutic drug and/or targeted drug treatment fails. In some embodiments, the disorder in which MET gene is aberrant is a disorder in which MET gene has previously received at least one chemotherapeutic and/or targeted drug.

In some embodiments, the disease in which MET gene is abnormal is selected from non-small cell lung cancer in which MET gene is abnormal or gastric cancer in which MET gene is abnormal.

In some embodiments of the present application, there is provided a use for treating non-small cell lung cancer with MET gene abnormality. In some 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 embodiments, the non-small cell lung cancer is a pulmonary sarcomatoid carcinoma. In some embodiments, the non-small cell lung cancer is squamous carcinoma. In some embodiments of the present application, the above treatment is achieved by administering said compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need thereof. In some embodiments, the non-small cell lung cancer is one that has failed treatment with at least one chemotherapeutic and/or targeted drug. In some embodiments, the non-small cell lung cancer is one that has failed treatment with at least one or two chemotherapeutic agents. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that has not previously been treated systemically.

In some embodiments of the present application, the present application provides a use of compound I or a pharmaceutically acceptable salt thereof for the manufacture of a medicament for the treatment of non-small cell lung cancer with chemotherapeutic drugs and/or MET gene abnormalities that target drug resistance. In some embodiments, there is provided a use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for treating non-small cell lung cancer that has failed chemotherapy and/or targeted drug therapy.

In some embodiments of the present application, there is provided the use of compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof for the treatment of gastric cancer. In some embodiments, the gastric cancer is gastric cancer with MET gene abnormality. In some embodiments, the above treatment is achieved by administering said compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof to a subject in need thereof. In some embodiments, the present application provides the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of gastric cancer with chemotherapeutic drugs and/or MET gene abnormalities that target drug resistance. In some embodiments, there is provided the use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of gastric cancer that has failed chemotherapy and/or targeted drug therapy for MET gene abnormalities.

In a second aspect, the present application provides a method of treating a disease with abnormal MET gene, comprising administering to a subject in need thereof a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof,

in some embodiments of the present application, the MET gene abnormality is selected from the group consisting of: one or more of MET gene amplification, MET gene rearrangement, MET gene mutation, and c-MET overexpression. In some embodiments, the MET gene mutation is a MET gene exon 14 skipping mutation. In some embodiments, MET gene amplification refers to an average gene copy number of ≧ 5 and/or a MET/CEP-7 copy number ratio of ≧ 2.

In certain embodiments of the present application, 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 non-small cell lung cancer of undefined type; 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 is a sarcomatoid lung cancer; in some embodiments, the non-small cell lung cancer is squamous carcinoma.

In certain embodiments of the present application, the subject has locally advanced, and/or advanced (e.g., stage IIIB/IV) and/or metastatic non-small cell lung cancer; wherein metastatic non-small cell lung cancer includes but is not limited to focal single metastasis, disseminated metastasis and diffuse metastasis; the metastatic lesions include, but are not limited to, lymph nodes, pleura, bone, brain, pericardium, adrenal gland, and liver. In some embodiments, the non-small cell lung cancer is brain metastatic non-small cell lung cancer. In some embodiments, the subject has relapsed non-small cell lung cancer including, but not limited to, intrabronchial blocked non-small cell lung cancer, resectable relapsed non-small cell lung cancer, mediastinal lymph node relapsed non-small cell lung cancer, superior Vena Cava (SVC) blocked non-small cell lung cancer, severely hemoptysed non-small cell lung cancer. In some embodiments, the subject is a non-small cell lung cancer patient who has previously failed at least one chemotherapeutic and/or targeted drug therapy. In some embodiments, the subject is a non-small cell lung cancer patient that has progressed or relapsed after prior treatment with at least one chemotherapeutic and/or targeted drug. In some embodiments, the subject is a non-small cell lung cancer patient that has not previously received systemic treatment.

In some embodiments of the present application, the non-small cell lung cancer is MET gene mutated non-small cell lung cancer; in some embodiments, the genetic mutation is an exon 14 skipping mutation. In some embodiments, the non-small cell lung cancer is MET gene-amplified non-small cell lung cancer; in some embodiments, the MET gene amplification means an average gene copy number of 5 or more and/or a MET/CEP-7 copy number ratio of 2 or more. In some embodiments, the non-small cell lung cancer is c-MET overexpressing non-small cell lung cancer.

In certain embodiments of the present application, the subject has locally advanced, and/or advanced (e.g., stage IIIB/IV) and/or metastatic gastric cancer; wherein metastatic gastric cancer includes, but is not limited to, focal hematogenous metastasis, peritoneal colonization metastasis, and lymphatic metastasis; the metastatic lesions include, but are not limited to, lung, lymph node, pleura, bone, brain, pericardium, adrenal gland, liver, and pancreas. In some embodiments, the subject has recurrent gastric cancer. In some embodiments, the subject is a gastric cancer patient who has previously failed at least one chemotherapeutic and/or targeted drug therapy. In some embodiments, the subject is a patient with gastric cancer that has progressed or relapsed after prior treatment with at least one chemotherapeutic and/or targeted drug. In some embodiments, the subject is a patient with gastric cancer who has not previously received systemic treatment. In some embodiments of the present application, the gastric cancer is gastric cancer with a MET gene mutation; in some embodiments, the genetic mutation is an exon 14 skipping mutation. In some embodiments, the gastric cancer is a MET gene-amplified gastric cancer; in some embodiments, the MET gene amplification means that the average gene copy number is 5 or more and/or the MET/CEP-7 copy number ratio is 2 or more. In some embodiments, the gastric cancer is gastric cancer with c-MET protein overexpression.

The method of administration can be determined comprehensively on the basis of the activity, toxicity of the drug, tolerance of the patient, and the like. Preferably, compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered as a daily continuous dose. The daily continuous administration may be about the same time as the morning and evening of each day. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered for one treatment cycle every 14 to 42 days; preferably, 21 days is one 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 thereof, or a pharmaceutical composition thereof, is administered once or more times per day. Preferably, compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered twice daily during the dosing period.

In some embodiments of the present application, compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered on a daily basis, one dosing cycle every 28 days, with compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof being administered twice daily within the dosing cycle. In some embodiments, compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered at about the same time each day, 28 days being one dosing cycle, and compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is administered twice daily within the dosing cycle.

In certain specific embodiments of the present application, compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered orally at a dose of 800mg per day, in two doses, for a cycle of 28 days.

In certain specific embodiments of the present application, compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered orally at a dose of 1000mg per day, in two doses, for a cycle of 28 days.

In certain specific embodiments of the present application, compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered orally at a dose of 1200mg per day, in two administrations over a 28 day cycle.

In certain specific embodiments of the present application, compound I or a pharmaceutically acceptable salt thereof or a pharmaceutical composition thereof is administered orally at a dose of 1600mg per day, in two doses, over a 28 day cycle.

In some embodiments of the present application, the radiation therapy may be administered simultaneously or sequentially with a therapeutically effective amount of compound I, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, to a patient in need thereof.

In some embodiments, the present application provides a pharmaceutical composition for treating MET gene-amplified non-small cell lung cancer, comprising compound I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier; in some embodiments, the present application also provides a pharmaceutical composition for treating MET gene mutated non-small cell lung cancer, comprising compound I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier; in some embodiments, the present application also provides a pharmaceutical composition for treating c-MET overexpressed non-small cell lung cancer, comprising 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 locally advanced, and/or advanced (e.g., stage IIIB/IV) and/or metastatic and/or relapsed non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that has progressed or relapsed after prior treatment with at least one chemotherapeutic and/or targeted drug. In some embodiments, the non-small cell lung cancer is a non-small cell lung cancer that has not previously been treated systemically. In some embodiments, the non-small cell lung cancer is non-squamous; 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 is a sarcomatoid lung cancer. In some embodiments, the non-small cell lung cancer is squamous carcinoma.

In some embodiments, the present application provides a pharmaceutical composition for treating MET gene-amplified gastric cancer, comprising compound I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier; in some embodiments, the present application provides a pharmaceutical composition for treating gastric cancer with MET gene mutation, comprising compound I or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier; in some embodiments, the present application provides a pharmaceutical composition for treating gastric cancer in which c-MET protein is overexpressed, comprising compound I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier.

In some embodiments of the present application, the pharmaceutical composition includes, but is not limited to, pharmaceutical compositions suitable for oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical, subcutaneous, intralipid, intraarticular, intraperitoneal, and intrathecal administration. In some embodiments, the pharmaceutical composition is a formulation suitable for oral administration, including tablets, capsules, powders, granules, pills, pastes, powders, and the like, preferably tablets and capsules.

In some embodiments of the present application, the pharmaceutical composition comprises 50 mg to 2000 mg of compound I or a pharmaceutically acceptable salt thereof; in some embodiments, the pharmaceutical composition comprises 100 mg to 1600mg of compound I or a pharmaceutically acceptable salt thereof; in some embodiments, the pharmaceutical composition comprises 100 mg to 1200mg of compound I or a pharmaceutically acceptable salt thereof; in some embodiments, the pharmaceutical composition comprises 100 mg to 1000mg of compound I or a pharmaceutically acceptable salt thereof; in some embodiments, the pharmaceutical composition comprises 100 mg to 800mg 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, 125mg, 150 mg, 200mg, 250 mg, 300 mg, 350 mg, 375 mg, 400 mg, 450 mg, 500 mg, 600mg, 675 mg, 700 mg, 800mg, 900 mg, 1000mg, 1100 mg, 1200mg of compound I or a pharmaceutically acceptable salt thereof.

In some embodiments of the present application, there is provided a pharmaceutical composition formulated in unit dosage form for the treatment of a disease in which MET gene is aberrant; the pharmaceutical composition further comprises at least one pharmaceutically acceptable carrier. In some embodiments, the pharmaceutical composition in unit dosage form contains 50 mg to 1200mg of compound I or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition in unit dosage form contains 300 mg to 600mg 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 600mg to 1200mg 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 200mg of compound I or a pharmaceutically acceptable salt thereof, more preferably 125mg to 175 mg of compound I or a pharmaceutically acceptable salt thereof. In some particular embodiments, the pharmaceutical composition in unit dosage form contains 50 mg, 100 mg, 125mg, 150 mg, 175 mg, 200mg of compound I or a pharmaceutically acceptable salt thereof. For example, with respect to tablets or capsules, a "pharmaceutical composition in unit dose form" means each tablet or each capsule.

The present application also provides a kit comprising (a) at least one unit dose of an orally suitable formulation comprising compound I or a pharmaceutically acceptable salt thereof and (b) instructions for treating a disease in which MET gene is aberrant. In some particular embodiments, a kit is provided comprising (a) at least one unit dose of a tablet or capsule comprising compound I or a pharmaceutically acceptable salt thereof and (b) instructions for treating a disease with MET gene abnormality. In some particular embodiments, a kit is provided comprising (a) at least one unit dose of a tablet or capsule comprising compound I or a pharmaceutically acceptable salt thereof and (b) instructions for treating non-small cell lung cancer with MET gene abnormality. In some particular embodiments, a kit is provided comprising (a) at least one unit dose of a tablet or capsule comprising compound I or a pharmaceutically acceptable salt thereof and (b) instructions for treating gastric cancer with MET gene abnormality. In some embodiments, the MET gene abnormality comprises one or more of MET gene amplification, MET gene rearrangement, MET gene mutation, c-MET overexpression. By "unit dose" is meant a pharmaceutical composition packaged in a single package for ease of administration, e.g., each tablet or capsule.

Compound I or a pharmaceutically acceptable salt thereof

Compound I of the present application has the chemical name 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 its free base form, as well as in the form of its salts, hydrates, and prodrugs, which convert in vivo to the free base form of compound I. For example, pharmaceutically acceptable salts of compound I are within the scope of the present application, which salts can be produced from various organic and inorganic acids according to methods well known in the art.

In some embodiments herein, a pharmaceutically acceptable salt of compound I herein refers to a salt of compound I with a pharmaceutically acceptable acid, wherein the pharmaceutically acceptable acid is 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. In some embodiments, the pharmaceutically acceptable acid is selected from the group consisting of 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 pharmaceutically acceptable acid in the salt is 1. In some embodiments, the pharmaceutically acceptable salt of compound I is the citrate salt of compound I. In some embodiments, the pharmaceutically acceptable acid is citric acid, and the molar ratio of compound I to citric acid is 1.

In some embodiments of the present application, compound I is administered as the citrate salt of compound I. In some embodiments, compound I is administered as the mono-citrate salt of compound I. In some embodiments, compound I is administered as the citrate salt of compound I. In some embodiments, the compound I is administered as a crystalline form of the citrate salt of compound I. In some embodiments, the compound I is administered as an amorphous form of the citrate salt.

Compound I or a pharmaceutically acceptable salt thereof may be administered by a variety of routes including, but not limited to, a route selected from: oral, parenteral, intraperitoneal, intravenous, intraarterial, transdermal, sublingual, intramuscular, rectal, transbuccal, intranasal, inhalation, vaginal, intraocular, topical administration, subcutaneous, intraadipogenic, intraarticular, intraperitoneal, and intrathecal. In some particular embodiments, administration is by oral administration.

The amount of compound I or a pharmaceutically acceptable salt thereof administered may be determined according to the severity of the disease, the response to 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 administered is from 100 mg to 2000 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 150 mg to 1950 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 200mg to 1900 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is from 300 mg to 1800 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is 450 mg to 1750 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is 500 mg to 1650 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is 750 mg to 1500 mg. In some embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is 900 mg to 1350 mg. In some embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 1050 mg to 1250 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is 200 mg. In some particular embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 400 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is 600 mg. In some particular embodiments, the daily dose of compound I or a pharmaceutically acceptable salt thereof administered is 800 mg. In some particular embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 1000 mg. In some particular embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 1200 mg. In some particular embodiments, the daily dose of compound I, or a pharmaceutically acceptable salt thereof, administered is 1600 mg.

Compound I or a pharmaceutically acceptable salt thereof may be administered one or more times per day. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered twice daily. In some embodiments, compound I or a pharmaceutically acceptable salt thereof is administered twice daily in the form of an oral solid formulation.

Non-small cell lung cancer

In the present application, the non-small cell lung cancer is classified according to histology, and includes, but is not limited to, adenocarcinoma, squamous cell carcinoma, large cell carcinoma or non-small cell lung cancer with undefined type; according to clinical stage, including but not limited to locally advanced, and/or advanced (e.g., stage IIIB/IV) and/or metastatic non-small cell lung cancer. Metastatic non-small cell lung cancer including but not limited to focal single metastasis, disseminated metastasis and diffuse metastasis; the metastatic lesions include, but are not limited to, lymph nodes, pleura, bone, brain, pericardium, adrenal gland, and liver. In some embodiments, the non-small cell lung cancer is brain metastatic non-small cell lung cancer. In some embodiments, the non-small cell lung cancer is recurrent non-small cell lung cancer, including, but not limited to, intrabronchial blocked non-small cell lung cancer, resectable recurrent non-small cell lung cancer, mediastinal lymph node recurrent non-small cell lung cancer, superior Vena Cava (SVC) blocked non-small cell lung cancer, severe hemoptytic non-small cell lung cancer.

Stomach cancer

In the present application, the gastric cancer, based on histological classification, includes, but is not limited to, adenocarcinoma, adenosquamous carcinoma, squamous carcinoma and carcinoid, wherein gastric adenocarcinoma includes, but is not limited to, papillary carcinoma, tubular adenocarcinoma, poorly differentiated adenocarcinoma, mucinous adenocarcinoma and signet ring cell carcinoma, based on tissue structure. Gastric cancer includes, but is not limited to, highly differentiated gastric cancer, moderately differentiated gastric cancer and poorly differentiated gastric cancer according to the degree of cell differentiation. Gastric cancers include, but are not limited to, carcinoma of the fundus cardia, corpus gastris, and antrum gastris, depending on the classification of the site of incidence. Depending on the clinical stage, including but not limited to locally advanced, and/or advanced (e.g., stage IIIB/IV) and/or metastatic gastric cancer. Metastatic gastric cancer includes, but is not limited to, focal hematogenous metastasis, peritoneal graft metastasis, and lymphatic metastasis; the metastatic lesions include, but are not limited to, lung, lymph node, pleura, bone, brain, pericardium, adrenal gland, liver, and pancreas.

Chemotherapy medicine

In the present application, the chemotherapeutic drug includes, but is not limited to, one or more of alkylating agents, podophyllum, camptothecin, taxus, antimetabolites, and antibiotic antineoplastic drugs. Examples that may be cited include, but are not limited to, platinum drugs (e.g., oxaliplatin, cisplatin, carboplatin, miboplatin, nedaplatin, dicycloplatin (dicycloplatin)), fluoropyrimidine derivatives (e.g., gemcitabine, capecitabine, fluorouracil, difurofluorouracil, doxifluridine, tegafur, carmofur, trifluridine), taxanes (e.g., paclitaxel, albumin-bound paclitaxel, paclitaxel liposomes, and docetaxel), camptothecins (e.g., camptothecin, hydroxycamptothecin, irinotecan, topotecan), vinblastines (vinorelbine, vincristine, vindesine, vinfuvinflunine (vinflunine)), pemetrexed, etoposide, irinotecan, mitomycin, ifosfamide, azacitidine, amrubicin, methotrexate, benzene, epirubicin, doxorubicin, temozolomide, LCL-161, KML-001, pacitabine, saproline (saprolin), tresultrin (octreotoxin), treulin (e), tremulin hydrochloride, tremulin, and one or two or three of them.

Targeted drugs

In the present application, the targeted drug includes, but is not limited to, tyrosine kinase inhibitors including, but not limited to, ALK inhibitors, EGFR inhibitors, VEGFR inhibitors, FGFR inhibitors, PDGFR inhibitors; in some embodiments, the targeted drugs include, but are not limited to, small molecule targeted drugs and antibodies; examples that may be cited include, but are not limited to, icotinib, aletinib (aletinib), crizotinib (Crizotinib), ceritinib (Ceritinib), bugatitinib (Brigatinib), cabozantinib (Cabozantinib), reritinib (SAF-189 s), enzatinib (X-396), loratinib (loretinib), and bevacizumab. In some typical embodiments, the targeted drug is erlotinib, crizotinib, enzatinib, loratinib, reritinib, 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.

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

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

"patient," "subject," or "subject" are used interchangeably and refer to a mammal, preferably a human.

By "pharmaceutically acceptable" is meant that it is used to prepare pharmaceutical compositions that are generally safe, non-toxic, and neither biologically nor otherwise undesirable, and include that they are acceptable for human pharmaceutical use.

"pharmaceutically acceptable salts" include, but are not limited to, acid addition salts formed with inorganic acids such as sulfuric, carbonic, nitric, hydrochloric, hydrobromic, hydroiodic, phosphoric, metaphosphoric, and the like; 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, maleic acid, tartaric acid, oxalic acid, fumaric acid, acrylic acid, crotonic acid, oleic acid, linoleic acid and the like.

By "therapeutically effective amount" is meant an amount of a compound that, when administered to a subject, e.g., a human, for the treatment of a disease, is sufficient to effect treatment for the disease.

By "treatment" is meant any administration of a therapeutically effective amount of a compound and includes:

(1) Inhibiting the disease (i.e., arresting the further development of the pathology and/or symptomatology) in a human experiencing or exhibiting the pathology or symptomatology of the disease, or

(2) Ameliorating the disease (i.e., reversing the pathology and/or symptomatology) in a human experiencing or exhibiting the pathology or symptomatology of the disease.

"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 disease control rate, including CR + PR + SD; these terms have meanings well known in the art, for example, as described in reference to the therapeutic efficacy assessment criteria for solid tumors (RECIST), version 1.1.

"treatment failure" includes intolerance of toxic side effects, disease progression during treatment, or relapse after treatment is complete; wherein intolerance includes, but is not limited to, hematologic toxicity up to grade IV (platelet lowering grade III and above), and non-hematologic toxicity up to grade III or above.

"c-MET overexpression" and "c-MET overexpression" are synonymous and used interchangeably.

"PFS (progression free survival) refers to the time from first drug enrollment to disease progression or death (on first-present basis).

"OS (overall survival)" means the time from first dose to full-blown death. Subjects who survived the last visit had OS scored as data loss at the time of the last visit. Subjects who were missed their OS counted as data loss by the time of last confirmed survival before the missed visit.

By "DOR (duration of disease remission)" is meant the time from the first recording of objective tumor remission (CR or PR) to the first recording of objective tumor progression or death for any reason, whichever occurs first.

"CNS-PFS (intracranial progression-free survival)" refers to the time from the start of enrollment to the first demonstration of intracranial progression in a baseline brain transfer subject.

"CNS-DCR (intracranial disease control rate)" means the proportion of subjects with complete remission, partial remission, and stable intracranial disease compared to subjects with target focal brain metastases at baseline.

"CNS-ORR (intracranial objective remission rate)" refers to the proportion of subjects with target focal brain metastases at baseline with complete intracranial remission, partial intracranial remission.

"CNS-TTP (to time of progression of intracranial disease)" means the time from the start of enrollment to the first appearance of progression of intracranial disease, including subjects with and without brain metastasis at baseline.

Examples

The present application is further illustrated below with reference to specific examples. It should be understood that these examples are only for illustrating the present application and are not intended to limit the scope of the present application.

Example 1- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -4' -methoxy-6 ' - ((S) -2-methylpiperazin-1-yl) -3,3' -bipyridin-6-amine (Compound I) citrate (Compound I citrate)

The title compound can be prepared by reference to WO2016015676 "preparation of salt of pharmaceutically acceptable acid of compound of formula I".

Example 2 capsules containing 5- ((R) -1- (2, 6-dichloro-3-fluorophenyl) ethoxy) -4' -methoxy-6 ' - ((S) -2-methylpiperazin-1-yl) -3,3' -bipyridin-6-amine citrate (citrate salt of Compound I)

Uniformly mixing citrate of the compound I with microcrystalline cellulose, croscarmellose sodium and silicon dioxide; magnesium stearate is then added to the above mixture, mixed, dry granulated, and filled into capsules.

Capsules containing other amounts of compound I citrate can be prepared with reference to the same proportions and formulations described above.

Example 3

A certain number of cells (SNU-5) in logarithmic growth phase were inoculated into 96-well culture plates, and cultured for 72 hours with different concentrations of drugs. After the drug action is finished, MTT working solution is added into each hole, after 4 hours, the triple solution is dissolved, the temperature is kept overnight at 37 ℃, the OD value is measured by adopting an enzyme-labeling instrument at the wavelength of 570nm and 690nm the next day, and the OD is used ₅₇₀ -OD ₆₉₀ As the final OD value. The cell growth inhibition rate was calculated by the following formula:

inhibition rate = (OD value) _{Control well} OD value _{Medicine feeding hole} ) the/OD values are plotted against wells × 100%

Calculating half inhibitory concentration IC according to each concentration inhibition rate ₅₀ The value is obtained.

TABLE 1 SNU-5 gastric cancer cell proliferation inhibition results of C-MET high expression by citrate of Compound I

Inhibition rate	Citrate salt of Compound I
IC ₅₀ (nM)	179.3±2.5

Example 4

Inoculating 100ul Hs746T cells into a 96-well plate, incubating for 24h, taking 100uM citrate of the compound I, diluting by 4 times, feeding for 72h at 9 concentrations, adding CCK-8 reagent, incubating for 1-6h, measuring absorbance at 450nm, and calculating IC ₅₀ The value is obtained.

TABLE 2 inhibition of Met-14 jump mutant Hs746T gastric cancer cell proliferation by citrate of Compound I

Inhibition rate	Citrate salt of Compound I
IC ₅₀ (nM)	0.24

Example 5

In subjects who were histologically or cytologically confirmed to be non-small cell lung cancer (NSCLC) and who were stage IIIB-IV (judged according to the international association for the study of lung cancer and the american joint committee for cancer classification, 8 th edition), and who were assessed to be abnormal in MET gene status, one treatment cycle every 28 days, citrate capsules of compound I prepared in example 2 were administered with an initial daily dose of 1200mg (administered twice a day in the morning and evening, 600mg each), a regimen of continuous daily administration, either fasting at approximately the same time in the morning and evening or with meals, patients who received at least 1 treatment cycle were evaluated for efficacy, and clinical studies of safety and efficacy were conducted with Objective Remission Rate (ORR) as the primary efficacy endpoint, and intracranial disease control rate (CNS), total survival (total survival), DOR (duration of disease remission), CNS-PFS (non-progression), CNS-DCR (intracranial disease control rate), CNS-to-brain (TTP), and CNS-to-brain disease progression (TTP) as the secondary efficacy endpoints. The subjects are over 18 years old, unlimited in nature, have an ECOG score of 0-1, and are expected to have a survival time of greater than 12 weeks; according to RECIST v.1.1 standard, there is at least one measurable target lesion (brain lesion is not the only lesion).

The dosage administered can be adjusted as follows, if desired:

first Down-regulated daily dose	1000mg BID
Second Down-regulated daily dose	800mg BID

MET gene status assessment

For mutation, amplification and overexpression of the MET gene in NSCLC patients, corresponding detection methods comprise a direct sequencing method, real-time fluorescent quantitative PCR (RTFQ-PCR), FISH and IHC, and people who benefit from the application of the c-MET inhibitor are necessarily screened by analyzing the MET gene and the c-MET protein.

The direct sequencing method has high accuracy in detecting the MET gene mutation, and other potential exon mutation sites can be detected without determining the specific position of the MET gene mutation site; RTFQ-PCR and FISH can be used for MET gene amplification detection, the detection speed of the RTFQ-PCR is higher, but the quality requirement on genome DNA fragments is higher, and the quality of the genome DNA fragments obtained by the existing extraction method is poorer, so that the FISH application is wider compared with the RTFQ-PCR and the FISH. 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), and the evaluation standard can be based on two aspects: (1) the fluorescent probe ratio of MET/CEP 7; (2) the copy number of the gene of each cell and the proportion of the positive cells in the total cells. IHC can be used for detecting the overexpression condition of the c-MET protein.

Examples MET gene abnormalities in clinical trials include exon 14 skipping mutations of the MET gene, MET gene amplification (including 2: average gene copy number. Gtoreq.5 and/or MET/CEP-7 copy number. Gtoreq.2).

Preliminary results show efficacy in NSCLC patients where the efficacy of MET gene abnormalities can be assessed.

Example 5-1

Male, age 81, clinical diagnosis: in stage IV of lung adenocarcinoma, mediastinal lymph node metastasis and diplocardia metastasis, no chemotherapy history exists, and gene detection indicates exon 14 skipping mutation of MET gene.

600mg of compound I citrate capsules prepared in example 2 are initially taken 2 times daily and orally, continuously daily, approximately the same time each day, with two recommended intervals of 10-12 hours, either on an empty stomach or with meals, for 1 treatment cycle every 28 days.

CT scans before compound I citrate capsules showed that the sum of measurable target lesion diameters was 55mm, CT scans were performed periodically after dosing, and after one cycle of treatment, the sum of target lesion diameters decreased to 37.5mm, and the efficacy was evaluated as PR, which decreased by more than 30%. After 3 and 5 cycles of treatment, the sum of the diameters of the target lesions is reduced to 31.2mm and 31.1mm, and the curative effect is evaluated as PR. During treatment, overall tolerability was good.

Example 5-2

Male, age 79, puncture, pathological diagnosis suggestion: non-small cell lung cancer, adenocarcinoma. And (3) clinical diagnosis: primary right lung adenocarcinoma, lymph node metastasis, no distant metastasis. Gene detection suggests MET gene amplification with no history of chemotherapy.

Subsequently, 600mg of compound I citrate capsules prepared in example 2 were administered orally 2 times daily for 1 treatment cycle every 28 days with a continuous daily dose approximately the same time in the morning and evening, with two recommended intervals of 10-12 hours, and with an empty stomach or with meals.

CT scans showed a measurable sum of target lesion diameters of 27.7mm before compound I citrate capsules were administered, and CT scans were performed periodically after dosing, with the sum of target lesion diameters decreasing to 17.7mm after one cycle of treatment, with a reduction in efficacy rating of PR of over 30%. After 3 and 5 cycles of treatment, the sum of the diameters of the target lesions decreased to 15.4mm and 14.4mm, and the efficacy was evaluated as PR. During treatment, overall tolerability was good.

Examples 5 to 3

Male, 72 years old, puncture, pathological diagnosis prompt: non-small cell lung cancer, poorly differentiated adenocarcinoma. And (3) clinical diagnosis: stage iv lung adenocarcinoma, mediastinal lymph node metastasis. Gene detection suggests that the MET gene 14 exon skipping mutation has no chemotherapy history.

CT scans showed that the sum of measurable target lesion diameters was 111.2mm before administration of citrate capsules of compound I, and CT scans were performed periodically after administration, and after one cycle of treatment, the sum of target lesion diameters decreased to 71.2mm, and the efficacy was evaluated as PR, which decreased by more than 30%. After 3 cycles of treatment, the target lesion diameter dropped to 70.8mm and the efficacy was evaluated as PR, with the patient still on treatment. During treatment, overall tolerability was good.

Examples 5 to 4

Male, age 85, clinical diagnosis: non-small cell lung cancer, left lung malignant tumor pleural metastasis (adenocarcinoma, stage IV, KPS score 90 points), gene detection suggests MET gene exon 14 skipping mutation.

Prior to enrollment, patients received 125mg po qd of icotinib (1 month of treatment, no efficacy assessment); and bevacizumab thoracic cavity infusion therapy (no efficacy assessment).

Subsequently, 600mg of a citrate capsule of compound I prepared in example 2 was administered orally 2 times daily for 2 consecutive daily administrations in the morning and evening, with two intervals of 10-12 hours recommended, orally on an empty stomach or with meals, for 1 treatment cycle every 28 days.

CT scans before administration of citrate capsules of compound I showed that the sum of measurable target lesion diameters was 34.7mm, CT scans were performed periodically after administration, and after one cycle of treatment, the sum of target lesion diameters decreased to 21.2mm, and the efficacy was evaluated as PR, which decreased by more than 30%. After 3 and 5 cycles of treatment, the sum of the target lesion diameters dropped to 18mm and the efficacy was evaluated as PR, with the patient still on treatment. During treatment, overall tolerability was good.

Claims

Use of compound I or a pharmaceutically acceptable salt thereof in the manufacture of a medicament for the treatment of a disease in which the MET gene is abnormal,
a method of treating a disease with MET gene abnormality, comprising administering to a patient in need thereof a therapeutically effective amount of Compound I or a pharmaceutically acceptable salt thereof,
a pharmaceutical composition for treating a disease with abnormal MET gene, comprising Compound I, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable carrier,
a kit comprising (a) at least one unit dose of a pharmaceutical composition comprising Compound I, or a pharmaceutically acceptable salt thereof, and (b) instructions for treating a disease with MET gene abnormality,
the use of compound I or a pharmaceutically acceptable salt thereof in the treatment of a disease in which the MET gene is abnormal,
the use according to claim 1 or 5, the method according to claim 2, the pharmaceutical composition according to claim 3 or the kit according to claim 4, wherein the disease with abnormal MET gene is non-small cell lung cancer with abnormal MET gene or gastric cancer with abnormal MET gene.
The use according to claim 1, 5 or 6, the method according to claim 2 or 6, the pharmaceutical composition according to claim 3 or 6 or the kit according to claim 4 or 6, wherein the MET gene abnormality is selected from MET gene amplification, MET gene rearrangement, MET gene mutation and/or c-MET overexpression.
The use according to any one of claims 1 and 5-7, the method of claim 2,6 or 7, the pharmaceutical composition of claim 3, 6 or 7 or the kit of claim 4, 6 or 7, wherein the disease with abnormal MET gene is a disease with abnormal MET gene in which treatment with at least one chemotherapeutic drug and/or targeted drug fails.
The use according to any one of claims 1 and 5 to 8, the method according to any one of claims 2 and 6 to 8, the pharmaceutical composition according to any one of claims 3 and 6 to 8 or the kit according to any one of claims 4 and 6 to 8, wherein the disease with abnormal MET gene is non-small cell lung cancer with abnormal MET gene that fails at least one chemotherapeutic drug and/or targeted drug therapy or non-small cell lung cancer that progresses or recurs after first receiving at least one chemotherapeutic drug and/or targeted drug therapy, or gastric cancer with abnormal MET gene that fails at least one chemotherapeutic drug and/or targeted drug therapy or gastric cancer with abnormal MET gene that is at least one chemotherapeutic drug and/or targeted drug resistant.
The use according to any one of claims 1 and 5-9, the method of any one of claims 2 and 6-9, the pharmaceutical composition of any one of claims 3 and 6-9, or the kit of any one of claims 4 and 6-9, wherein the pharmaceutically acceptable salt of compound I is a salt of compound I with any of the following acids: 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 use according to any one of claims 1 and 5-10, the method of any one of claims 2 and 6-10, the pharmaceutical composition of any one of claims 3 and 6-10, or the kit of any one of claims 4 and 6-10, wherein the pharmaceutically acceptable salt of compound I is citrate.
The use according to any one of claims 1 and 5-11, the method of any one of claims 2 and 6-11, the pharmaceutical composition of any one of claims 3 and 6-11, or the kit of any one of claims 4 and 6-11, wherein the compound I or the pharmaceutically acceptable salt thereof is administered in a daily dose selected from the group consisting of 100 mg to 2000 mg, 150 mg to 1950 mg, 200mg 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, 200mg, 400 mg, 600mg, 800mg, 1000mg, 1200mg, or 1600 mg.
The use according to any one of claims 1 and 5 to 12, the method according to any one of claims 2 and 6 to 12, the pharmaceutical composition according to any one of claims 3 and 6 to 12 or the kit according to any one of claims 4 and 6 to 12, wherein compound I or the pharmaceutically acceptable salt thereof is administered on a daily basis.