Application of sulfamide compound in treatment of biliary tract cancer

Abstract

The invention relates to application of a sulfamide compound in treatment of biliary tract cancer, in particular to application of a compound shown in a formula I or pharmaceutically acceptable salt thereof in treatment of biliary tract cancer. The compound as shown in the formula I or the pharmaceutically acceptable salt thereof has good safety and antitumor activity.

Description

Use of a sulfonamide compound in the treatment of bile duct cancer

[0001] This application is a divisional application of Chinese Patent Application No. 202380087017.2, filed on December 18, 2023, entitled "Use of a sulfonamide compound in the treatment of biliary tract cancer".

[0002] Cross-reference to related applications This application claims priority and benefits to patent applications No. 202211632640.5 and No. 202310971301.8, filed with the State Intellectual Property Office of the People's Republic of China on December 19, 2022 and August 2, 2023, respectively, the contents of which are incorporated herein by reference in their entirety. Technical Field

[0003] This application belongs to the field of pharmaceutical chemistry and relates to the use of a sulfonamide compound for the treatment of biliary tract cancer, specifically the use of a compound of formula I or a pharmaceutically acceptable salt thereof for the treatment of biliary tract cancer. Background Technology

[0004] IDH (isocitrate dehydrogenase) is a key enzyme in the intracellular tricarboxylic acid cycle, catalyzing the oxidative decarboxylation of isocitrate to 2-oxoglutarate (i.e., α-ketoglutarate). There are two distinct IDH subtypes: one uses NAD(+) as an electron acceptor, and the other uses NADP(+). Five IDHs have been reported, three of which are NAD(+)-dependent isocitrate dehydrogenases located in the mitochondrial matrix; the other two are NADP(+)-dependent isocitrate dehydrogenases, one located in the mitochondria and the other in the cytoplasm.

[0005] Studies have found IDH mutations in various tumors (such as gliomas, sarcomas, and acute myeloid leukemia), with the mutation sites being arginine residues located in the catalytic center (IDH1 / R132H, IDH2 / R140Q, IDH2 / R172K). In 2009, Bleeker et al. detected IDH1 mutations in 672 tumors from different sources and 84 different tumor cell lines, finding that this mutation specifically occurred in gliomas (Bleeker et al., 2009. IDH1 mutations atresidue p.R132(IDH1(R132)) occur frequently in high-grade gliomas but not in other solid tumors. Hum Mutat. 30: 7-11.). However, subsequent literature reports show that IDH1 mutations also exist in acute myeloid leukemia, prostate cancer, and paragangliomas (Green et al., 2010, Somatic mutations of IDH1 and IDH2 in the leukemic transformation of myeloproliferative neoplasms. N Engl J Med. 362: 369-370.). Bleeker et al. found that R132H accounted for 86.9% of cases with IDH1 mutations, while other types such as R132C, R132G, R132L, R132V, and R132S accounted for a smaller proportion (Bleeker et al., 2009).

[0006] WO2017162157 discloses a series of compounds that are IDH1 inhibitors, and specifically discloses compounds of formula I with the following structures: . Summary of the Invention

[0007] On the one hand, this application provides a compound of formula I or a pharmaceutically acceptable salt thereof for treating biliary tract cancer in patients. .

[0008] On the one hand, this application provides a pharmaceutical composition for treating biliary tract cancer in patients, said pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof.

[0009] On the one hand, this application provides a method for treating a patient with biliary tract cancer, comprising administering to the patient an effective amount of a compound of formula I as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0010] On the one hand, this application provides the use of the compound of formula I as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating biliary tract cancer in patients.

[0011] On the one hand, this application provides the use of the compound of formula I as described above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the treatment of patients with biliary tract cancer.

[0012] On the one hand, this application provides a pharmaceutical product for treating biliary tract cancer comprising a compound of formula I as described above or a pharmaceutically acceptable salt thereof as an active ingredient.

[0013] In some embodiments of this application, the compound of formula I or a pharmaceutically acceptable salt thereof described herein is used as a single active agent.

[0014] In some embodiments of this application, the compound of formula I described herein or a pharmaceutically acceptable salt thereof may also be used in combination with other chemotherapeutic agents.

[0015] In some embodiments of this application, the other chemotherapeutic drugs include pyrimidine antitumor drugs, fluorouracil antitumor drugs, platinum-based antitumor drugs, taxane-based antitumor drugs, tyrosine kinase inhibitors, PD-1 / PD-L1 inhibitors, camptothecin-based antitumor drugs, BRAF inhibitors, or any combination thereof.

[0016] In some of the regimens of this application, the other chemotherapeutic agents include gemcitabine; 5-fluorouracil; a combination of gemcitabine, cisplatin, and nab-paclitaxel; a combination of 5-fluorouracil and oxaliplatin; a combination of capecitabine and oxaliplatin; a combination of gemcitabine and capecitabine; a combination of gemcitabine and cisplatin; a combination of 5-fluorouracil and cisplatin; a combination of capecitabine and cisplatin; a combination of gemcitabine and oxaliplatin; a combination of gemcitabine, cisplatin, and tegafur; a combination of 5-fluorouracil and oxaliplatin; a combination of gemcitabine and nab-paclitaxel; entrectinib; larotrectinib; pembrolizumab; camrelizumab; tegafur; capecitabine; irinotecan and capecitabine; regorafenib; dabrafenib and trametinib.

[0017] In some embodiments of this application, the other chemotherapeutic drugs are fluorouracil antitumor drugs, platinum-based antitumor drugs, or combinations thereof.

[0018] In some embodiments of this application, the other chemotherapy drugs are a combination of capecitabine and oxaliplatin.

[0019] In some embodiments of this application, when the compound of formula I or a pharmaceutically acceptable salt thereof is used in combination with other chemotherapeutic agents, the administration method of the compound of formula I or a pharmaceutically acceptable salt thereof is the same as when it is used as a single active agent.

[0020] In some embodiments of this application, the Formula I compound or a pharmaceutically acceptable salt thereof described herein may be provided in the form of a pharmaceutical composition comprising a therapeutically effective amount of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0021] In some embodiments of this application, the pharmaceutical composition wherein the compound of formula I or a pharmaceutically acceptable salt thereof is in a single dose or multiple doses.

[0022] In some embodiments of this application, the pharmaceutical composition is packaged in a box that also includes instructions for treating a patient with biliary tract cancer using a compound of formula I or a pharmaceutically acceptable salt thereof.

[0023] In some embodiments of this application, the pharmaceutical composition contains 100-1200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I.

[0024] In some embodiments of this application, the pharmaceutical composition contains a compound of formula I or a pharmaceutically acceptable salt thereof, in a range of 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 700 mg, 800 mg, 900 mg, 1000 mg, or any of the above values, calculated as a compound of formula I.

[0025] In some embodiments of this application, the pharmaceutical composition contains 100-900 mg, 200-900 mg, 200-800 mg, 200-600 mg, 400-900 mg, or 400-600 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0026] In some embodiments of this application, the pharmaceutical composition contains 400-600 mg or 400-900 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0027] In some embodiments of this application, the pharmaceutical composition contains 400 mg, 600 mg, or 900 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0028] In some embodiments of this application, the pharmaceutical composition contains 400 mg or 600 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0029] In some embodiments of this application, the pharmaceutical composition contains 600 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0030] In some embodiments of this application, the pharmaceutical composition of Formula I compound or a pharmaceutically acceptable salt thereof is in single-dose or multi-dose form. In some embodiments of this application, the pharmaceutical composition of Formula I compound or a pharmaceutically acceptable salt thereof is in multi-dose form.

[0031] In some embodiments of this application, the pharmaceutical composition contains a daily dose of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0032] In some embodiments of this application, the pharmaceutical composition contains a compound of formula I or a pharmaceutically acceptable salt thereof in a once-daily dose.

[0033] In some embodiments of this application, the pharmaceutical composition contains a compound of formula I or a pharmaceutically acceptable salt thereof in a once-daily dose, and each dose is a single dose or multiple doses, usually multiple doses.

[0034] In some embodiments of this application, the pharmaceutical composition contains a compound of formula I or a pharmaceutically acceptable salt thereof in a once-daily dose, and each dose is a single dose or multiple doses, usually multiple doses, wherein the multiple doses are 400 mg, 600 mg or 900 mg; preferably the multiple doses are 400 mg or 600 mg; or preferably the multiple doses are 600 mg.

[0035] In some embodiments of this application, the pharmaceutical composition contains a single dose of 50 mg and / or 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition is in the form of a single-dose formulation and contains 50 mg and / or 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition is in the form of a single-dose formulation and contains 50 mg and / or 200 mg of a compound of formula I, or an integer multiple thereof (e.g., 100 mg, 150 mg, 400 mg) of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0036] In some embodiments of this application, the pharmaceutical composition contains 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, calculated as a single dose. Alternatively, the pharmaceutical composition is in the form of a single-dose formulation and contains 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, calculated as a single dose. Alternatively, the pharmaceutical composition is in the form of a single-dose formulation and contains 200 mg of a compound of formula I or an integer multiple thereof, calculated as a single dose, of a compound of formula I or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments of this application, the pharmaceutical composition contains a compound of formula I or a pharmaceutically acceptable salt thereof in a once-daily dose, and each dose is a single dose or multiple doses, usually multiple doses, wherein the multiple doses are 400 mg, 600 mg or 900 mg; preferably the multiple doses are 400 mg or 600 mg; or preferably the multiple doses are 600 mg; the multiple doses consist of a single dose of 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0038] In some of the treatment regimens described in this application, a treatment cycle is defined as 2-6 weeks. In some of the regimens described in this application, a treatment cycle is defined as 28 days. In some of the regimens described in this application, a treatment cycle is defined as 21 days.

[0039] In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 2.8 g to 33.6 g, calculated as a compound of formula I. In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 2.1 g to 25.2 g, calculated as a compound of formula I.

[0040] In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 5.6 g to 25.2 g, calculated as a compound of formula I. In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 4.2 g to 18.9 g, calculated as a compound of formula I.

[0041] In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 5.6 g to 16.8 g, calculated as a compound of formula I. In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 4.2 g to 12.6 g, calculated as a compound of formula I.

[0042] In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 11.2 g to 25.2 g, calculated as a compound of formula I. In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration within a single treatment cycle (e.g., a 21-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 8.4 g to 18.9 g, calculated as a compound of formula I.

[0043] In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 11.2 g to 16.8 g, calculated as a compound of formula I. In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 21-day treatment cycle), comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 8.4 g to 12.6 g, calculated as a compound of formula I.

[0044] In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 11.2 g, 16.8 g, or 25.2 g, calculated as a compound of formula I. In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 21-day treatment cycle), comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 8.4 g, 12.6 g, or 18.9 g, calculated as a compound of formula I.

[0045] In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), comprising: a pharmaceutical composition of a compound of formula I with a total dose of 11.2 g or 16.8 g, or a pharmaceutically acceptable salt thereof, based on a compound of formula I. In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 21-day treatment cycle), comprising: a pharmaceutical composition of a compound of formula I with a total dose of 8.4 g or 12.6 g, or a pharmaceutically acceptable salt thereof, based on a compound of formula I.

[0046] In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 28-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 16.8 g based on a compound of formula I. In some embodiments of this application, the pharmaceutical composition is a formulation suitable for administration over a single treatment cycle (e.g., a 21-day treatment cycle), the formulation comprising: a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof, in a total dose of 12.6 g based on a compound of formula I.

[0047] On the other hand, this application also provides a kit for treating biliary tract cancer in patients, comprising a compound of formula I as described in this application or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

[0048] On the other hand, this application also provides a method for treating biliary tract cancer in patients, comprising administering to an individual in need a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, such as administering to an individual in need a therapeutically effective amount of the pharmaceutical composition described above in this application.

[0049] On the other hand, this application also provides a therapy for treating an individual suffering from biliary tract cancer, the therapy comprising administering, to the individual alone, a therapeutically effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition, such as administering, to the individual alone, a therapeutically effective amount of the pharmaceutical composition described above in this application.

[0050] On the other hand, this application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for treating biliary tract cancer in patients, such as the use of the pharmaceutical composition described above in this application in the preparation of a medicament for treating biliary tract cancer in patients. In some embodiments of this application, the pharmaceutical composition is any of the pharmaceutical compositions described above in this application.

[0051] On the other hand, this application also provides the use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, for treating biliary tract cancer in patients, such as the use of the pharmaceutical composition described above in this application for treating biliary tract cancer in patients.

[0052] In some embodiments of this application, in the methods, therapies, or uses described, the definition of the Formula I compound or a pharmaceutically acceptable salt thereof is the same as the definition of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical compositions described above, such as content, dosage, form of presence, packaging form, etc.

[0053] In some embodiments of this application, in the methods, therapies, or uses described, the application of the Formula I compound or its pharmaceutically acceptable salt, or its pharmaceutical composition, is performed in treatment cycles of 2-6 weeks, for example, every 1 week, every 2 weeks, every 3 weeks, or every 4 weeks. Preferably, every 4 weeks is a treatment cycle. Alternatively, preferably, every 3 weeks is a treatment cycle.

[0054] In some embodiments of this application, in the methods, therapies, or uses, the amount of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a daily dose, administered by means of: administering the Formula I compound or a pharmaceutically acceptable salt thereof once daily.

[0055] In some embodiments of this application, in the methods, therapies, or uses, the content of the Formula I compound or its pharmaceutically acceptable salt in the pharmaceutical composition is a daily dose, wherein the Formula I compound or its pharmaceutically acceptable salt is administered in a single-dose or multiple-dose manner, typically in a multiple-dose manner; further, wherein the Formula I compound or its pharmaceutically acceptable salt is administered once daily in a multiple-dose manner; further, wherein the Formula I compound or its pharmaceutically acceptable salt is administered once daily continuously in a multiple-dose manner within each treatment cycle.

[0056] In some embodiments of this application, in the methods, therapies, or uses described herein, the compound of Formula I or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 100-1200 mg; or a daily dose of 100-900 mg; or a daily dose of 200-900 mg; or a daily dose of 200-800 mg; or a daily dose of 200-600 mg; or a daily dose of 400-900 mg; or a daily dose of 400-600 mg.

[0057] In some embodiments of this application, in the methods, therapies, or uses described, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 400 mg; or, a daily dose of 600 mg; or, a daily dose of 900 mg.

[0058] In some embodiments of this application, in the methods, therapies, or uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered in the following manner: a daily dose of 400 mg; or a daily dose of 600 mg.

[0059] In some embodiments of this application, in the methods, therapies, or uses, the Formula I compound or a pharmaceutically acceptable salt thereof is administered at a daily dose of 600 mg. In some embodiments of this application, in the methods, therapies, or uses, the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is administered in multiple doses, said multiple doses consisting of a pharmaceutical composition of a single dose of 50 mg and / or 200 mg of the Formula I compound or a pharmaceutically acceptable salt thereof. In some embodiments of this application, in the methods, therapies, or uses, the Formula I compound or a pharmaceutically acceptable salt thereof is administered in a continuous daily manner.

[0060] In some embodiments of this application, in the methods, therapies, or uses, the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is administered in multiple doses, said multiple doses consisting of a pharmaceutical composition of a Formula I compound or a pharmaceutically acceptable salt thereof, with a single dose of 200 mg. In some embodiments of this application, in the methods, therapies, or uses, the Formula I compound or a pharmaceutically acceptable salt thereof is administered in a continuous daily manner.

[0061] In some embodiments of this application, in the methods, therapies or uses described herein, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily in multiple doses of 400 mg or 600 mg daily.

[0062] In some embodiments of this application, in the methods, therapies, or uses described herein, a compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily in multiple doses of 600 mg; said daily dose consists of a pharmaceutical composition of a compound of formula I or a pharmaceutically acceptable salt thereof in a single dose of 200 mg.

[0063] In some embodiments of this application, in the methods, therapies, or uses described, the content of the Formula I compound or a pharmaceutically acceptable salt thereof in the pharmaceutical composition is a dose for each treatment cycle, administered by daily application of the Formula I compound or a pharmaceutically acceptable salt thereof. The Formula I compound or a pharmaceutically acceptable salt thereof is packaged in single or multiple portions (e.g., 2 portions, 3 portions, 4 portions, 7 portions, 14 portions, 21 portions, 28 portions, or more).

[0064] In some embodiments of this application, in the methods, therapies, or uses, a treatment cycle is 28 days, and the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof, administered on days 1-28 of each treatment cycle, is 2.8 g to 33.6 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is 5.6 g to 25.2 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is 5.6 g to 16.8 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is 11.2 g to 25.2 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is 11.2 g to 16.8 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 11.2 g, 16.8 g, or 25.2 g. In some embodiments, the total dose of the pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof is selected from 11.2 g or 16.8 g. In some embodiments, the total dose of the pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof is preferably 16.8 g.

[0065] In some embodiments of this application, in the methods, therapies, or uses, a treatment cycle is 21 days, and the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof, administered on days 1-21 of each treatment cycle, is 2.1 g to 25.2 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is 4.2 g to 18.9 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is 4.2 g to 12.6 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is 8.4 g to 18.9 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is 8.4 g to 12.6 g. In some embodiments, the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is selected from 8.4 g, 12.6 g, or 18.9 g. In some embodiments, the total dose of the pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof is selected from 8.4 g or 12.6 g. In some embodiments, the total dose of the pharmaceutical composition containing a compound of formula I or a pharmaceutically acceptable salt thereof is preferably 12.6 g.

[0066] In some embodiments of this application, in the methods, therapies, or uses, a treatment cycle is 28 days; the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 11.2 g, 16.8 g, or 25.2 g. In some embodiments of this application, in the methods, therapies, or uses, a treatment cycle is 21 days; the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily for 21 consecutive days, and the total dose of the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 8.4 g, 12.6 g, or 18.9 g.

[0067] In some embodiments of this application, in the methods, therapies, or uses, a treatment cycle is 28 days; the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 11.2 g or 16.8 g. In some embodiments of this application, in the methods, therapies, or uses, a treatment cycle is 21 days; the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily for 21 consecutive days, and the total dose of the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 8.4 g or 12.6 g.

[0068] In some embodiments of this application, in the methods, therapies, or uses, a treatment cycle is 28 days; the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily for 28 consecutive days, and the total dose of the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 16.8 g. In some embodiments of this application, in the methods, therapies, or uses, a treatment cycle is 21 days; the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof is administered once daily for 21 consecutive days, and the total dose of the pharmaceutical composition containing the compound of Formula I or a pharmaceutically acceptable salt thereof administered in each treatment cycle is 12.6 g.

[0069] In the protocol of this application, the above treatment cycle is repeated as long as the disease remains under control and the dosing regimen is clinically tolerable.

[0070] In the protocol of this application, the medication is administered continuously between each treatment cycle, that is, the medication is not stopped after the end of the previous treatment cycle, and the next treatment cycle continues.

[0071] Compound of Formula I or a pharmaceutically acceptable salt thereofIn some embodiments of this application, the compound of formula I described herein can be obtained by referring to the preparation methods in WO2017162157 or WO2019057142. .

[0072] The Formula I compound of this application can be administered in its free base form, or in the form of a pharmaceutically acceptable salt, hydrate, or prodrug, which is converted into the Formula I compound in vivo. For example, pharmaceutically acceptable salts of the Formula I compound within the scope of this application can be generated from various organic and inorganic acids according to methods known in the art.

[0073] As used in this application, the compound of formula I is its free base.

[0074] As used in this application, the compound of formula I is in its hydrated form, and is administered in its hydrated form, wherein each molecule of free base contains 0.5 to 3 water molecules; preferably, each molecule of free base contains 1 water molecule, as shown in the following compound of formula II: .

[0075] As used in this application, the compound of formula II is in crystalline form.

[0076] As used in this application, the compound of formula II is in amorphous solid form.

[0077] The dosages of Formula I compounds or their pharmaceutically acceptable salts mentioned in this application, unless otherwise stated, are based on the molecular weight of the Formula I compound (expressed in C1). 28 H 23 (Calculated using ClF3N5O4S).

[0078] In some embodiments of this application, the compound of formula II described herein can be obtained by referring to the preparation method in WO2019057142.

[0079] As used in this application, isomers of Formula I are also included within the scope of this application, such as racemic compounds of Formula I, enantiomers of Formula I, tautomers of Formula I, diastereomers of Formula I, or mixtures of the above isomers.

[0080] Pharmaceutical compositions of Formula I compounds or pharmaceutically acceptable salts thereof In some embodiments of this application, the Formula I compound or a pharmaceutically acceptable salt thereof is a pharmaceutical composition comprising a therapeutically effective amount of the Formula I compound or a pharmaceutically acceptable salt thereof.

[0081] In some embodiments of this application, the pharmaceutical composition contains a single dose of 50 mg or 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I. Alternatively, the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is prepared such that a unit dosage form contains 50 mg or 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I.

[0082] In some embodiments of this application, the pharmaceutical composition contains 200 mg of a single dose of a compound of formula I or a pharmaceutically acceptable salt thereof. Alternatively, the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is prepared such that each unit dosage contains 200 mg of the compound of formula I or a pharmaceutically acceptable salt thereof.

[0083] The method of administration can be determined comprehensively based on factors such as the drug's activity, toxicity, and the patient's tolerance.

[0084] In some embodiments of this application, the pharmaceutical composition includes, but is not limited to, formulations suitable for oral, parenteral, or topical administration; in some embodiments, the pharmaceutical composition is a formulation suitable for oral administration; in some embodiments, the pharmaceutical composition is a solid dosage form suitable for oral administration; and in some embodiments, the pharmaceutical composition includes, but is not limited to, tablets or capsules.

[0085] In some embodiments of this application, the pharmaceutical composition is a solid pharmaceutical composition.

[0086] In some embodiments of this application, the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is a solid pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof.

[0087] In some embodiments of this application, the pharmaceutical composition of the compound of formula I or a pharmaceutically acceptable salt thereof is a tablet containing the compound of formula I or a pharmaceutically acceptable salt thereof.

[0088] In some embodiments of this application, pharmaceutical compositions of Formula I compounds or their pharmaceutically acceptable salts may also contain pharmaceutically acceptable carriers and / or excipients.

[0089] The pharmaceutical compositions of the Formula I compounds or their pharmaceutically acceptable salts thereof can be manufactured using methods well known in the art, such as conventional mixing, dissolving, granulation, sugar-coated pill making, grinding, emulsification, freeze drying, etc.

[0090] Solid oral compositions can be prepared by conventional mixing, filling, or tableting methods. For example, they can be obtained by mixing the active compound with solid excipients, optionally milling the resulting mixture, adding other suitable excipients if necessary, and then processing the mixture into granules to obtain the core of a tablet or sugar-coated formulation. Suitable excipients include, but are not limited to, binders, diluents, disintegrants, lubricants, glidants, sweeteners, or flavoring agents.

[0091] Biliary tract cancer In this application, biliary tract cancer includes primary cancers in the hilar bile duct, common hepatic duct, and common bile duct region, including bile duct cancer, gallbladder cancer, and ampullary tumors.

[0092] In some embodiments of this application, the biliary carcinoma is biliary adenocarcinoma.

[0093] In some embodiments of this application, the biliary carcinoma is bile duct cystadenocarcinoma.

[0094] In some embodiments of this application, the biliary cancer is bile duct cancer or gallbladder cancer.

[0095] In some embodiments of this application, the biliary tract cancer is intrahepatic bile duct cancer, hilar bile duct cancer, distal bile duct cancer, or gallbladder cancer.

[0096] In some embodiments of this application, the biliary tract cancer is intrahepatic bile duct cancer, extrahepatic bile duct cancer, or gallbladder cancer.

[0097] In some embodiments of this application, the biliary cancer is bile duct cancer.

[0098] In some embodiments of this application, the cholangiocarcinoma is intrahepatic cholangiocarcinoma or extrahepatic cholangiocarcinoma.

[0099] In some embodiments of this application, the cholangiocarcinoma is intrahepatic cholangiocarcinoma. In some embodiments of this application, the intrahepatic cholangiocarcinoma comprises a mixed-type hepatocellular carcinoma cholangiocarcinoma component of >50%.

[0100] In some embodiments of this application, the cholangiocarcinoma is cholangiocarcinoma.

[0101] In some embodiments of this application, the cholangiocarcinoma is intrahepatic cholangiocarcinoma or extrahepatic cholangiocarcinoma.

[0102] In some embodiments of this application, the cholangiocarcinoma is intrahepatic cholangiocarcinoma.

[0103] In some embodiments of this application, the cholangiocarcinoma is poorly differentiated cholangiocarcinoma, moderately differentiated cholangiocarcinoma, or well differentiated cholangiocarcinoma.

[0104] In some embodiments of this application, the cholangiocarcinoma is poorly differentiated cholangiocarcinoma.

[0105] In some embodiments of this application, the cholangiocarcinoma is moderately differentiated cholangiocarcinoma.

[0106] In some embodiments of this application, the cholangiocarcinoma is poorly differentiated intrahepatic cholangiocarcinoma or moderately differentiated intrahepatic cholangiocarcinoma.

[0107] In some embodiments of this application, the cholangiocarcinoma is poorly differentiated extrahepatic cholangiocarcinoma or moderately differentiated extrahepatic cholangiocarcinoma.

[0108] In some embodiments of this application, the biliary tract cancer is biliary tract cancer with an IDH1 gene mutation.

[0109] In some embodiments of this application, the IDH1 gene mutation is an IDH1 R132 gene mutation.

[0110] In some embodiments of this application, the IDH1 gene mutation includes, but is not limited to, one or more mutations of R132C, R132G, R132H, R132L, or R132S.

[0111] In some embodiments of this application, the biliary tract cancer is advanced biliary tract cancer.

[0112] In some embodiments of this application, the biliary tract cancer is advanced biliary tract cancer with IDH1 mutation.

[0113] In some embodiments of this application, the biliary tract cancer is locally advanced, recurrent, and / or metastatic biliary tract cancer.

[0114] In some embodiments of this application, the biliary tract cancer is locally advanced, recurrent, and / or metastatic biliary tract cancer with IDH1 mutation.

[0115] In some embodiments of this application, the biliary tract cancer is locally advanced, recurrent, and / or metastatic biliary tract cancer with IDH1 mutation, and the biliary tract cancer is intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, distal cholangiocarcinoma, or gallbladder cancer. Preferably, the biliary tract cancer is intrahepatic cholangiocarcinoma.

[0116] In some embodiments of this application, the biliary tract cancer is an unresectable, advanced biliary tract cancer.

[0117] In some embodiments of this application, the biliary tract cancer is an unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer.

[0118] In some embodiments of this application, the biliary carcinoma is biliary carcinoma with at least one measurable lesion according to RECIST 1.1 criteria.

[0119] In some embodiments of this application, the biliary tract cancer is an unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer with at least one measurable lesion according to RECIST 1.1 criteria.

[0120] In some embodiments of this application, the biliary tract cancer is locally advanced, recurrent, and / or metastatic biliary tract cancer that has not previously received systemic treatment for advanced disease.

[0121] In some embodiments of this application, the biliary tract cancer is an unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer that has not previously received systemic therapy for advanced disease. In some embodiments of this application, the biliary tract cancer is an unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer with at least one measurable lesion according to RECIST 1.1 criteria that has not previously received systemic therapy for advanced disease.

[0122] In some embodiments of this application, the biliary tract cancer is biliary tract cancer that has failed previous treatment with gemcitabine, and / or fluorouracil, and / or platinum-based drugs. In some embodiments of this application, the biliary tract cancer is unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer that has failed previous treatment with gemcitabine, and / or fluorouracil, and / or platinum-based drugs. In some embodiments of this application, the biliary tract cancer is unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer that has failed previous treatment with gemcitabine, and / or fluorouracil.

[0123] In some embodiments of this application, the biliary tract cancer is locally advanced, recurrent, and / or metastatic biliary tract cancer with IDH1 mutation that has failed previous treatment with gemcitabine, and / or fluorouracil, and / or platinum-based drugs.

[0124] In some embodiments of this application, the biliary tract cancer is locally advanced, recurrent, and / or metastatic biliary tract cancer that has failed first- or second-line treatment.

[0125] In some embodiments of this application, the biliary tract cancer is unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer that has failed first- or second-line treatment. In some embodiments of this application, the biliary tract cancer is unresectable locally advanced, recurrent, and / or metastatic biliary tract cancer that has failed first- or second-line treatment and has at least one measurable lesion according to RECIST 1.1 criteria.

[0126] In some embodiments of this application, the first-line and second-line treatments include one or more of surgical treatment, radiotherapy, and drug treatment.

[0127] In some embodiments of this application, the drug treatment includes one or more of chemotherapy, targeted drug therapy, or immune checkpoint inhibitor therapy.

[0128] In some of the regimens of this application, the chemotherapy includes one or more of gemcitabine, capecitabine, fluorouracil, tegafur, platinum-based drugs, taxanes, vincristine alkaloids, doxorubicin, epirubicin, mitoxantrone, irinotecan, docetaxel, pemetrexed, raltitrexed, methotrexate, or temozolomide.

[0129] In some embodiments of this application, the chemotherapy includes one or more of gemcitabine, capecitabine, epirubicin, fluorouracil, tegafur, platinum-based drugs, and taxanes.

[0130] In some embodiments of this application, the platinum group includes cisplatin, carboplatin, nedaplatin, lobaplatin, and oxaliplatin; cisplatin and oxaliplatin are preferred.

[0131] In some embodiments of this application, the paclitaxel class includes paclitaxel, docetaxel, liposomal paclitaxel, and albumin-bound paclitaxel; albumin-bound paclitaxel is preferred.

[0132] In some embodiments of this application, the vinca alkaloids include vinca alkaloids, vincristine, vinorelbine, or vindesine.

[0133] In some of the regimens of this application, the chemotherapy includes gemcitabine and cisplatin combination therapy; or gemcitabine and oxaliplatin combination therapy; or gemcitabine and fluorouracil combination therapy; or gemcitabine and tegafur combination therapy.

[0134] In some embodiments of this application, the targeted drug therapy includes one or more of lenvatinib, apatinib, anlotinib, gefitinib, erlotinib, afatinib, imatinib, nilotinib, sunitinib, lapatinib, besutinib, vandetanib, sunitinib, erlotinib, neratinib, dasatinib, canutinib, cananetinib, dasatinib, cicatinib, sunitinib, olaparib, niraparib, bevacizumab, or recombinant human endostatin.

[0135] In some embodiments of this application, the targeted drug therapy includes one or more of lenvatinib, apatinib, olaparib, niraparib, bevacizumab, or recombinant human endostatin.

[0136] In some embodiments of this application, the immune checkpoint inhibitor includes a PD-1 inhibitor and / or a PD-L1 inhibitor, wherein the PD-1 inhibitor and / or PD-L1 inhibitor includes one or more of pembrolizumab, nivolumab, atezolizumab, acitumab, durvalumab, cimiprimab, dotalimab, camrelizumab, tislelizumab, sintilimab, toripalimab, or penamprolium.

[0137] In some embodiments of this application, the immune checkpoint inhibitor includes one or more of pembrolizumab, durvalumab, toripalimab, tislelizumab, sintilimab, or camrelizumab.

[0138] In some embodiments of this application, the drug treatment includes single-drug therapy or combination therapy with multiple drugs.

[0139] In some of the regimens of this application, the single-agent treatment includes lenvatinib, apatinib, olaparib, niraparib, pembrolizumab, durvalumab, gemcitabine, oxaliplatin, fluorouracil, sintilimab, or camrelizumab.

[0140] In some embodiments of this application, the combined drug therapy includes a combination of chemotherapy and immune checkpoint inhibitors; or a combination of targeted drugs and immune checkpoint inhibitors; or a combination of chemotherapy and targeted drugs; or a combination of chemotherapy, targeted drugs, and immune checkpoint inhibitors.

[0141] In some embodiments of this application, the multi-drug combination therapy includes combination therapy of gemcitabine, cisplatin and an immune checkpoint inhibitor; or combination therapy of gemcitabine, tegafur and an immune checkpoint inhibitor; combination therapy of gemcitabine, oxaliplatin and an immune checkpoint inhibitor; or combination therapy of lenvatinib, cisplatin and an immune checkpoint inhibitor; or combination therapy of gemcitabine, cisplatin, lenvatinib and an immune checkpoint inhibitor.

[0142] In some of the regimens of this application, the multi-drug combination therapy includes combination therapy with toripalimab, bevacizumab, oxaliplatin, and fluorouracil; or combination therapy with recombinant human endostatin and cisplatin; or combination therapy with gemcitabine, cisplatin, and tislelizumab; or combination therapy with gemcitabine and tegafur; or combination therapy with gemcitabine and cisplatin; or combination therapy with capecitabine and lenvatinib; or combination therapy with lenvatinib, cisplatin, and pembrolizumab; or combination therapy with lenvatinib, gemcitabine, cisplatin, and pembrolizumab; or combination therapy with gemcitabine and oxaliplatin; or combination therapy with gemcitabine and sintilimab; or combination therapy with apatinib and camycin. Combination therapy with linzazumab; or combination therapy with lenvatinib and camrelizumab; or combination therapy with gemcitabine, oxaliplatin, and sintilimab; or combination therapy with gemcitabine and albumin-bound paclitaxel; or combination therapy with gemcitabine and tegafur; or combination therapy with capecitabine and sintilimab; or combination therapy with capecitabine, oxaliplatin, and sintilimab; or combination therapy with gemcitabine, oxaliplatin, and albumin-bound paclitaxel; or combination therapy with camrelizumab, gemcitabine, oxaliplatin, and albumin-bound paclitaxel; or combination therapy with lenvatinib and niraparib; or combination therapy with gemcitabine, cisplatin, anlotinib, and sintilimab.

[0143] In some embodiments of this application, the failure of drug treatment or the failure of first- or second-line treatment refers to the occurrence of disease progression as defined by RECIST 1.1 criteria during a previous treatment course of ≥1 treatment cycle or within 6 months after the end of the treatment cycle; or intolerance to chemotherapy toxicity; or, the failure of drug treatment or the failure of first- or second-line treatment refers to the occurrence of disease progression or relapse as defined by RECIST 1.1 criteria during neoadjuvant or adjuvant therapy or within 6 months after the end of the treatment; or, the failure of drug treatment or the failure of first- or second-line treatment refers to the occurrence of intrahepatic lesions as defined by RECIST 1.1 during hepatic artery infusion chemotherapy or within 6 months after the last treatment.

[0144] In some embodiments of this application, the neoadjuvant or adjuvant therapy refers to adjuvant radiotherapy or chemotherapy after surgical resection of biliary tract cancer, wherein the chemotherapy is as described above.

[0145] In some embodiments of this application, the cholangiocarcinoma is advanced cholangiocarcinoma.

[0146] In some embodiments of this application, the cholangiocarcinoma is advanced cholangiocarcinoma with an IDH1 gene mutation.

[0147] In some embodiments of this application, the cholangiocarcinoma is locally advanced, recurrent, and / or metastatic cholangiocarcinoma.

[0148] In some embodiments of this application, the cholangiocarcinoma is locally advanced, recurrent, and / or metastatic cholangiocarcinoma with IDH1 mutation.

[0149] In some embodiments of this application, the cholangiocarcinoma is locally advanced, recurrent, and / or metastatic cholangiocarcinoma with IDH1 mutation, and the cholangiocarcinoma is intrahepatic cholangiocarcinoma, hilar cholangiocarcinoma, or distal cholangiocarcinoma. Preferably, the cholangiocarcinoma is intrahepatic cholangiocarcinoma.

[0150] In some embodiments of this application, the cholangiocarcinoma is an unresectable advanced cholangiocarcinoma.

[0151] In some embodiments of this application, the cholangiocarcinoma is an unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma.

[0152] In some embodiments of this application, the cholangiocarcinoma is cholangiocarcinoma with at least one measurable lesion according to RECIST 1.1 criteria.

[0153] In some embodiments of this application, the cholangiocarcinoma is an unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma with at least one measurable lesion according to RECIST 1.1 criteria.

[0154] In some embodiments of this application, the cholangiocarcinoma is locally advanced, recurrent, and / or metastatic cholangiocarcinoma that has not previously received systemic therapy for advanced disease.

[0155] In some embodiments of this application, the cholangiocarcinoma is an unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma that has not previously received systemic therapy for advanced disease. In some embodiments of this application, the cholangiocarcinoma is an unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma with at least one measurable lesion according to RECIST 1.1 criteria that has not previously received systemic therapy for advanced disease.

[0156] In some embodiments of this application, the cholangiocarcinoma is cholangiocarcinoma that has failed prior treatment with gemcitabine, and / or fluorouracil, and / or platinum-based drugs. In some embodiments of this application, the cholangiocarcinoma is unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma that has failed prior treatment with gemcitabine, and / or fluorouracil, and / or platinum-based drugs. In some embodiments of this application, the cholangiocarcinoma is unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma that has failed prior treatment with gemcitabine, and / or fluorouracil.

[0157] In some embodiments of this application, the cholangiocarcinoma is locally advanced, recurrent, and / or metastatic cholangiocarcinoma that has failed first- or second-line treatment.

[0158] In some embodiments of this application, the cholangiocarcinoma is unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma that has failed first- or second-line treatment. In some embodiments of this application, the cholangiocarcinoma is unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma that has failed first- or second-line treatment and has at least one measurable lesion according to RECIST 1.1 criteria.

[0159] In some embodiments of this application, the cholangiocarcinoma is an unresectable locally advanced, recurrent, and / or metastatic intrahepatic cholangiocarcinoma that has failed first- or second-line treatment.

[0160] In some embodiments of this application, the cholangiocarcinoma is an unresectable locally advanced, recurrent, and / or metastatic hilar cholangiocarcinoma that has failed first- or second-line treatment.

[0161] In some embodiments of this application, the cholangiocarcinoma is an unresectable locally advanced, recurrent, and / or metastatic distal cholangiocarcinoma that has failed first- or second-line treatment.

[0162] In some embodiments of this application, the cholangiocarcinoma is an unresectable locally advanced, recurrent, and / or metastatic cholangiocarcinoma that has failed first- or second-line treatment.

[0163] In some embodiments of this application, the cholangiocarcinoma is an unresectable locally advanced, recurrent, and / or metastatic intrahepatic cholangiocarcinoma that has failed first- or second-line treatment.

[0164] In some embodiments of this application, the cholangiocarcinoma is an unresectable, locally advanced, recurrent, and / or metastatic poorly differentiated intrahepatic cholangiocarcinoma that has failed first- or second-line treatment.

[0165] In some embodiments of this application, the cholangiocarcinoma is an unresectable, locally advanced, recurrent, and / or metastatic moderately differentiated intrahepatic cholangiocarcinoma that has failed first- or second-line treatment.

[0166] In some embodiments of this application, the biliary tract cancer or bile duct cancer may be combined with liver cancer.

[0167] Application method The following content is not intended to limit the manner of administration of the pharmaceutical compositions of this application.

[0168] The components of the pharmaceutical composition of this application can be administered via a variety of suitable routes, including but not limited to oral or parenteral administration (via intravenous, intramuscular, local, or subcutaneous routes). In some embodiments, the components of the pharmaceutical composition of this application can be administered orally or by injection, such as intravenous or subcutaneous injection.

[0169] Suitable dosage forms for the pharmaceutical compositions of this application include, but are not limited to: tablets, lozenges, pills, capsules (e.g., hard capsules, soft capsules, enteric-coated capsules, microcapsules), elixirs, granules, syrups, injections (intramuscular, intravenous, intraperitoneal), granules, emulsions, suspensions, solutions, dispersants, and sustained-release formulations for oral or non-oral administration.

[0170] Technical effect The compound of Formula I of this application or its pharmaceutically acceptable salt has good safety and antitumor activity, is well tolerated by patients during treatment, and can provide good disease control rate (DCR) and objective response rate (ORR), longer duration of disease response (DOR), and longer survival (e.g., median survival, progression-free survival, or overall survival) in treated patients, thereby demonstrating good clinical benefits.

[0171] Definitions and Explanations Unless otherwise stated, the terms used in this application have the following meanings. A particular term should not be considered uncertain or unclear unless specifically defined, but should be understood in accordance with its ordinary meaning in the art. When a trade name appears in this application, it is intended to refer to the corresponding product or its active ingredient.

[0172] In this document, unless otherwise stated, the terms “comprise,” “comprises,” and “comprising” or their equivalents are open-ended expressions, meaning that they may cover other unspecified elements, components, and steps in addition to those listed.

[0173] For purposes of description and disclosure, all patents, patent applications and other identified publications are expressly incorporated herein by reference. Any reference to these publications herein does not constitute an endorsement that such publication is part of the general knowledge in the art.

[0174] The term "pharmaceutical acceptable" refers to compounds, materials, compositions, and / or dosage forms that, within the bounds of reliable medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic reactions, or other problems or complications, in proportion to a reasonable benefit / risk ratio.

[0175] The term "pharmaceutically acceptable salt" includes salts formed by base ions and free acids or salts formed by acid ions and free bases.

[0176] As used in this application, the content of Formula I compound or its pharmaceutically acceptable salt is calculated in the form of a free base, such as dosage, dose, or content in a pharmaceutical composition.

[0177] As used in this application, compounds in the pharmaceutical composition of this application can form acid addition salts if they have, for example, at least one basic center. If desired, corresponding acid addition salts having additionally present basic centers can also be formed. Compounds having at least one acidic group (e.g., COOH) can also form salts with a base. If the compound contains, for example, both a carboxyl group and an amino group, it can also form corresponding internal salts.

[0178] The terms “patient,” “subject,” or “individual” are used interchangeably and refer to mammals such as humans, dogs, cattle, horses, pigs, sheep, goats, cats, mice, rabbits, rats, and transgenic nonhuman animals. In some protocols, the patient, subject, or individual is a human.

[0179] The term "pharmaceutical composition" refers to a mixture comprising one or more compounds of the present application or salts thereof with pharmaceutically acceptable excipients. The purpose of a pharmaceutical composition is to facilitate the administration of the compounds of the present application or salts thereof to a patient. The pharmaceutical compositions of the present application may be administered to a subject in combination with other drugs / therapeutic agents, etc.

[0180] The term “joint” does not mean that the two or more different objects it refers to must be given at the same time, but should be understood as the different objects being given sequentially, simultaneously, or separately at different frequencies.

[0181] The term “treatment” generally refers to achieving the desired pharmacological and / or physiological effects, including partially or completely stabilizing or curing a disease and / or effects resulting from the disease. As used herein, “treatment” encompasses any treatment of a patient’s disease, including: (a) suppressing the symptoms of the disease, i.e., preventing its progression; or (b) alleviating the symptoms of the disease, i.e., causing the disease or symptoms to regress.

[0182] The term "therapeutic effective amount" means (i) the amount of the compound of this application used to treat a particular disease, condition, or disorder, or (ii) to reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder. The amount of the compound of this application constituting a "therapeutic effective amount" varies depending on the compound, the disease state and its severity, the route of administration, and the age of the mammal to be treated, but may routinely be determined by a person skilled in the art based on their own knowledge and this disclosure.

[0183] The term "single dose" refers to the smallest packaged unit containing a certain amount of medicine. For example, if a box of medicine contains seven capsules, then each capsule is a single dose; or each vial of injection is a single dose.

[0184] Unless the context clearly indicates otherwise, singular terms in this document encompass the plural referents, and vice versa. Similarly, unless the context clearly indicates otherwise, the word "or" in this document is intended to include "and".

[0185] Those skilled in the art will recognize that the scope of this application is not limited to the various specific embodiments described above, but rather that various modifications, substitutions, or recombinations can be made without departing from the spirit of this application, and all such modified solutions fall within the protection scope of this application. Attached Figure Description

[0186] Figure 1 shows the AUC of patient exposure after a single dose (D1) and after 28 days of continuous treatment (D28) in Experimental Case 1. (0-24) Relationship with dosage.

[0187] Figure 2 shows the relationship between the maximum plasma concentration (Cmax) and the mean steady-state plasma concentration (Cavg) and the dose in patients after a single dose (D1) and after 28 days of continuous treatment (D28) in Experiment Example 1. Detailed Implementation

[0188] The invention will be described in more detail through specific embodiments. The following embodiments are provided for illustrative purposes and should not be construed as limiting the invention in any way.

[0189] Example 1: Clinical Trial of Biliary Tract Cancer. This study enrolled patients with locally advanced, recurrent, and / or metastatic biliary tract cancer who had failed ≥1 line of combination chemotherapy regimens containing gemcitabine or fluorouracil. All study drugs were Formula I compound tablets. The purpose of this study was to evaluate the safety and efficacy of Formula I compound therapy.

[0190] 1.1 Investigational Drug and Dosing Regimen 1.1.1 Test drug: Formula I compound tablets, in strengths of 50 mg / tablet and / or 200 mg / tablet, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.

[0191] 1.1.2 Dosage regimen: Formula I compound tablets: The daily dose is 400 mg, 600 mg or 900 mg, taken orally on an empty stomach, once a day, for 28 consecutive days as one treatment cycle.

[0192] 1.2 Inclusion criteria 1) Age 18 ≤ age ≤ 75 (calculated from the date of signing the informed consent form); ECOG score 0~1; expected survival ≥ 12 weeks.

[0193] 2) The IDH1 R132 gene mutation exists (one of R132C, R132G, R132H, R132L, or R132S).

[0194] 3) Major organ functions are good and meet the following criteria: a) Blood biochemistry tests must meet the following criteria: i. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN.

[0195] If liver metastasis is present, ALT and AST ≤ 5 × ULN; ii. Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance estimated by the Cockcroft-Gault glomerular filtration formula ≥ 50 mL / min.

[0196] b) Standards for routine urinalysis: Routine urinalysis shows urine protein <++; if urine protein ≥++, it needs to be confirmed that the 24-hour urine protein quantification is ≤1.0 g.

[0197] c) Echocardiographic assessment: Left ventricular ejection fraction (LVEF) ≥50%.

[0198] d) 12-lead ECG assessment: QTc < 450 ms (male), QTc < 470 ms (female).

[0199] 4) Women of reproductive age should agree to use effective contraception during the study and for 6 months after the study ends, and have a negative serum or urine pregnancy test within 7 days prior to study enrollment; men should agree to use effective contraception during the study and for 6 months after the study ends.

[0200] 5) Participants voluntarily joined the study, signed informed consent forms, and demonstrated good compliance.

[0201] 6) Criteria for advanced biliary tract cancer: a) Biliary tract adenocarcinoma confirmed by histology or cytology, including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC).

[0202] b) Unresectable locally advanced, recurrent, and / or metastatic disease with at least one measurable lesion according to RECIST 1.1 criteria.

[0203] c) Failure of at least one combination chemotherapy regimen based on gemcitabine or fluorouracil, meeting any of the following criteria: i) Previous systemic therapy for advanced disease for ≥1 treatment cycle, with disease progression or intolerance to chemotherapy as defined by RECIST 1.1 occurring during last-line treatment or within 6 months after treatment completion; ii) Previous neoadjuvant or adjuvant therapy, with disease progression or relapse as defined by RECIST 1.1 occurring during treatment or within 6 months after treatment completion.

[0204] d) Complete blood count criteria (no blood transfusion or use of hematopoietic stimulating factor drugs within 7 days prior to screening): Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L, platelets ≥100×10 9 / L, hemoglobin ≥9 g / dL.

[0205] e) In blood biochemistry, total bilirubin (TBIL) ≤ 2 × upper limit of normal (ULN) (≤ 3 × ULN for patients with Gilbert's syndrome), and serum albumin ≥ 28 g / L.

[0206] f) Coagulation function test criteria: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (no history of coagulation therapy).

[0207] g) Weight ≥ 40 kg and BMI ≥ 18.5 kg / m² 2 .

[0208] 1.3 Evaluation Methods and Indicators Safety evaluation criteria: The severity of adverse events is determined using the NCI-CTC AE 5.0 standard.

[0209] Effectiveness evaluation criteria: RECIST 1.1 standard was used for evaluation.

[0210] 1.4 Test Results 1.4.1 Safety: The tablets of compound I are well-tolerated and have controllable safety. The incidence of adverse events (AEs) was low in all dosage groups, with the 600 mg dosage group having the lowest overall AE incidence.

[0211] 1.4.2 Efficacy was evaluable in 34 patients, including 3 with partial remission (PR), 19 with stable disease (SD), and 12 with progressive disease (PD). The objective response rate (ORR) was 9% (3 / 34), and the disease control rate (DCR) was 65% (22 / 34). The results showed that the compound of formula I in this application has clinical benefit in the treatment of biliary tract cancer with IDH1 gene mutation. Table 1 shows the efficacy data of representative patients.

[0212] Table 1. Treatment efficacy data of representative patients

[0213] Note: C represents a 28-day treatment cycle, and Cn represents the number of treatment cycles administered to the patient (i.e., the patient is administered the medication for n × 28 days).

[0214] 1.4.3 In the PK study, the AUC of patient exposure was measured after a single dose (D1) and after 28 days of continuous treatment (D28) in each dose group. (0-24) The maximum plasma concentration (Cmax) and the mean steady-state plasma concentration (Cavg) were determined. The results are shown in Figure 1 and Figure 2, respectively.

[0215] The results showed that the 600 mg dose group had a lower exposure AUC. (0-24) It reached its maximum value in terms of both maximum plasma concentration (Cmax) and average steady-state plasma concentration (Cavg).

[0216] Example 2: Clinical Trial of Biliary Tract Cancer. This study enrolled patients with locally advanced, recurrent, and / or metastatic biliary tract cancer who had not previously received systemic therapy for advanced disease. The study drugs were all Formula I compound tablets combined with chemotherapy drugs. The purpose of this study was to evaluate the safety and efficacy of Formula I compound combined with chemotherapy drugs.

[0217] 2.1 Investigational Drug and Dosing Regimen 2.1.1 Investigational drugs: Formula I compound tablets, with strengths of 50 mg / tablet and / or 200 mg / tablet, provided by Chia Tai Tianqing Pharmaceutical Group Co., Ltd.; Chemotherapy drugs: CapOX regimen (the systemic treatment regimen recommended by the CSCO Guidelines for the Diagnosis and Treatment of Biliary Tract Malignancies 2022).

[0218] 2.1.2 Dosage regimen: Formula I compound tablets: The daily dose is 400 mg or 600 mg, taken orally on an empty stomach, once a day, for 21 or 28 days as one treatment cycle.

[0219] 2.2 Inclusion criteria 1) Age 18 ≤ age ≤ 75 (calculated from the date of signing the informed consent form); ECOG score 0~1; expected survival ≥ 12 weeks.

[0220] 2) The IDH1 R132 gene mutation exists (one of R132C, R132G, R132H, R132L, or R132S).

[0221] 3) Major organ functions are good and meet the following criteria: a) Blood biochemistry tests must meet the following criteria: i. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3×ULN.

[0222] If liver metastasis is present, ALT and AST ≤ 5 × ULN; ii. Serum creatinine (Cr) ≤ 1.5 × ULN or creatinine clearance estimated by the Cockcroft-Gault glomerular filtration formula ≥ 50 mL / min.

[0223] b) Standards for routine urinalysis: Routine urinalysis shows urine protein <++; if urine protein ≥++, it needs to be confirmed that the 24-hour urine protein quantification is ≤1.0 g.

[0224] c) Echocardiographic assessment: Left ventricular ejection fraction (LVEF) ≥50%.

[0225] d) 12-lead ECG assessment: QTc < 450 ms (male), QTc < 470 ms (female).

[0226] 4) Women of reproductive age should agree to use effective contraception during the study and for 6 months after the study ends, and have a negative serum or urine pregnancy test within 7 days prior to study enrollment; men should agree to use effective contraception during the study and for 6 months after the study ends.

[0227] 5) Participants voluntarily joined the study, signed informed consent forms, and demonstrated good compliance.

[0228] 6) Criteria for advanced biliary tract cancer: a) Biliary tract adenocarcinoma confirmed by histology or cytology, including intrahepatic cholangiocarcinoma (ICC), extrahepatic cholangiocarcinoma (ECC), and gallbladder cancer (GBC).

[0229] b) Unresectable locally advanced recurrent and / or metastatic disease with at least one measurable lesion according to RECIST 1.1 criteria.

[0230] c) Patients who have not previously received systemic treatment for advanced disease are eligible in the following two situations: i) Patients who have previously received neoadjuvant or adjuvant therapy and whose disease progresses / relapses more than 12 months after the end of treatment; ii) Patients who have previously received less than one cycle of systemic therapy and who refuse treatment due to their own wishes are eligible, but patients who stop treatment due to intolerance to toxicity must be excluded.

[0231] d) Complete blood count criteria (no blood transfusion or use of hematopoietic stimulating factor drugs within 7 days prior to screening): Absolute neutrophil count (ANC) ≥ 1.5 × 10⁻⁶ 9 / L, platelets ≥100×10 9 / L, hemoglobin ≥9 g / dL.

[0232] e) In blood biochemistry, total bilirubin (TBIL) ≤ 2 × upper limit of normal (ULN) (≤ 3 × ULN for patients with Gilbert's syndrome), and serum albumin ≥ 28 g / L.

[0233] f) Coagulation function test criteria: prothrombin time (PT), activated partial thromboplastin time (APTT), international normalized ratio (INR) ≤ 1.5 × ULN (no history of coagulation therapy).

[0234] g) Weight ≥ 40 kg and BMI ≥ 18.5 kg / m² 2 .

[0235] 2.3 Evaluation Methods and Indicators Safety evaluation criteria: The severity of adverse events is determined using the NCI-CTC AE 5.0 standard.

[0236] Effectiveness evaluation criteria: RECIST 1.1 standard was used for evaluation.

[0237] 2.4 Test Results 2.4.1 Safety: The tablets of compound I, when combined with chemotherapy drugs, are well-tolerated and have a controllable safety profile. The incidence of adverse events (AEs) was low in all dosage groups.

[0238] 2.4.2 Efficacy was evaluable in 5 patients, including 1 with partial remission (PR), 3 with stable disease (SD), and 1 with progressive disease (PD). The objective response rate (ORR) was 20% (1 / 5), and the disease control rate (DCR) was 80% (4 / 5). The results showed that the compound of formula I of this application, in combination with chemotherapy drugs, has clinical benefit in the treatment of biliary tract cancer with IDH1 gene mutation. Table 2 shows the efficacy data of representative patients.

[0239] Table 2. Treatment efficacy data of representative patients

[0240] Note: The CapOX regimen is: oxaliplatin 130 mg / m² for injection. 2 The capecitabine tablets are administered intravenously on day 1 of each treatment cycle, with a total daily dose of 2000 mg / m². 2 Take orally twice a day, half an hour after meals, for two weeks, then stop for one week.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, in the preparation of a medicament for the treatment of biliary tract cancer in patients. 。 2. The use according to claim 1, wherein the pharmaceutical composition contains 100-1200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I; preferably, it contains 100-900 mg, 200-900 mg, 200-800 mg, 200-600 mg, 400-900 mg, 400-600 mg, 400 mg, 600 mg or 900 mg of a compound of formula I or a pharmaceutically acceptable salt thereof, calculated as a compound of formula I.

3. The use according to claim 1 or 2, wherein the pharmaceutical composition contains a single dose of 50 mg and / or 200 mg of a compound of formula I or a pharmaceutically acceptable salt thereof.

4. The use according to any one of claims 1-3, wherein a treatment cycle is 28 days, and the total dose of the pharmaceutical composition containing the compound of formula I or a pharmaceutically acceptable salt thereof is 2.8g~33.6g, 5.6g~25.2g, 11.2g~16.8g or 11.2g~25.2g administered on days 1-28 of each treatment cycle.

5. The use according to any one of claims 1-4, wherein the compound of formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, is used in combination with other chemotherapeutic agents, said other chemotherapeutic agents including pyrimidine antitumor agents, fluorouracil antitumor agents, platinum-based antitumor agents, paclitaxel-based antitumor agents, tyrosine kinase inhibitors, PD-1 / PD-L1 inhibitors, camptothecin-based antitumor agents, BRAF inhibitors, or any combination thereof; preferably, said other chemotherapeutic agents are fluorouracil antitumor agents, platinum-based antitumor agents, or combinations thereof; more preferably, said other chemotherapeutic agents are a combination of capecitabine and oxaliplatin.

6. The use according to any one of claims 1-5, wherein the bile duct cancer is intrahepatic bile duct cancer, extrahepatic bile duct cancer, or gallbladder cancer; or, the bile duct cancer is cholangiocarcinoma.

7. The use according to any one of claims 1-5, wherein the biliary cancer is biliary cancer with an IDH1 gene mutation; preferably, the IDH1 gene mutation includes one or more mutations of R132C, R132G, R132H, R132L or R132S.

8. The use according to any one of claims 1-5, wherein the biliary tract cancer is locally advanced, recurrent and / or metastatic biliary tract cancer; preferably, the biliary tract cancer is locally advanced, recurrent and / or metastatic biliary tract cancer that has not previously received systemic treatment for advanced disease.

9. The use according to any one of claims 1-5, wherein the biliary tract cancer is biliary tract cancer that has failed previous treatment with gemcitabine, and / or fluorouracil, and / or platinum-based drugs; preferably, the biliary tract cancer is locally advanced, recurrent, and / or metastatic biliary tract cancer with IDH1 mutation that has failed previous treatment with gemcitabine, and / or fluorouracil, and / or platinum-based drugs.

10. The use according to any one of claims 1-5, wherein the biliary tract cancer is advanced biliary tract cancer with IDH1 mutation.

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