Methods of treating disorders with phthalazinone derivatives

Abstract

This invention relates to a method for treating diseases (e.g., breast cancer, ovarian cancer, or pancreatic cancer) with a derivative of a poly(ADP-ribose) polymerase inhibitor or a pharmaceutical composition thereof.

Description

[Technical Field]

[0001] This invention relates to compounds and compositions comprising phthalazinone derivatives capable of inhibiting poly(ADP-ribose) polymerase activity, and methods of using thereof. [Previous Technology]

[0002] The poly(ADP-ribose) polymerase (PARP) family plays many fundamental roles in cellular processes, including regulating transcription, apoptosis, and DNA damage responses. PARP inhibitors target the enzyme poly(ADP-ribose) polymerase (PARP) and are being investigated in several types of malignancies. PARP is a protein involved in repairing single-strand breaks in DNA, and inhibitors of this enzyme prevent DNA repair and allow the accumulation of single-strand breaks. During DNA replication, these single-strand breaks lead to double-strand breaks as the DNA helix unwinds.

[0003] Patients with tumors containing mutations in certain homologous recombination repair enzymes (e.g., mutations in BRCA1, BRCA2, and PALB2) are unable to repair these doublet breaks, thereby causing the affected cells to undergo apoptosis. PARP inhibitors are among the most promising treatments for many types of cancer that exhibit relatively high rates of these types of mutations in homologous recombination repair enzymes in these malignancies. Specifically, given the limited treatment options available for the disease, including endocrine therapy and chemotherapy, PARP inhibitors are a beneficial treatment for patients with BRCA-mutated breast and ovarian cancer, and have become a mainstay of treatment for patients with BRCA-mutated breast cancer. Therefore, safe and effective PARP inhibitors represent a promising solution for addressing unmet medical needs in cancer treatment. [Summary of the Invention]

[0004] The present invention provides phthalazinone derivatives and compositions comprising such compounds, and methods of treating conditions, such as cancers (e.g., ovarian cancer, breast cancer, and pancreatic cancer), using such compounds and compositions. Each of these different embodiments may be more specifically described by way of the various examples described herein, which are equally applicable to the different embodiments.

[0005] In one embodiment, this article provides a method for treating an individual in need of cancer with a BRCA1 mutation, BRCA2 mutation, ATM mutation or homologous recombination repair mutation, comprising administering to the individual about 2 mg to about 300 mg of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0006] In one embodiment, this article provides a method for treating an individual in need of cancer with a BRCA1 mutation, BRCA2 mutation, ATM mutation, or homologous recombination repair mutation, comprising administering to the individual a pharmaceutical composition comprising: (i) a compound of formula I, or a pharmaceutically acceptable salt thereof, of about 2 mg to about 300 mg; and (ii) at least one pharmaceutically acceptable excipient.

[0007] In another embodiment, this article provides a method for obtaining clinical benefit in an individual with ovarian cancer, comprising administering to the individual about 2 mg to about 300 mg of a compound of formula I: formula I or a pharmaceutically acceptable salt thereof.

[0008] In one embodiment, this document provides a method for obtaining clinical benefit in an individual suffering from breast cancer, comprising administering to the individual about 2 mg to about 300 mg of a compound of formula I: formula I or a pharmaceutically acceptable salt thereof.

[0009] In one embodiment, this document provides a method for obtaining clinical benefit in an individual suffering from pancreatic cancer, comprising administering to the individual about 2 mg to about 300 mg of a compound of formula I: formula I or a pharmaceutically acceptable salt thereof.

Implementation Method

[0020] Related Applications

[0021] This application claims the benefit and priority of USSN 63 / 196,036 filed on June 2, 2021 and USSN 63 / 331,371 filed on April 15, 2022, the contents of which are incorporated herein by reference in their entirety.

[0022] This invention provides a method for treating a condition in an individual in need (e.g., cancer with BRCA1 mutation, BRCA2 mutation, ATM mutation, or homologous recombination repair mutation). Examples of cancers with such mutations include (but are not limited to) breast cancer, ovarian cancer, small cell lung cancer, biliary tract cancer, urothelial carcinoma, and pancreatic cancer. Other examples of homologous recombination repair mutations include (but are not limited to) the following mutations: PALB2, XRCC1, CTPS, RPA, RPA1, RPA2, RPA3, XPD, ERCC1, XPF, MMS19, RAD51, RAD51B, RAD51C, RAD51D, DMC1, XRCC2, XRCC3, RAD52, RAD54, RAD50, MRE11, NBS1, WRN, BLM, Ku70, Ku80, ATR, chk1, chk2, FANCA, FANCB, FANCC, FANCD1, FANCD2, FANCE, FANCF, FANCG, RAD1, RAD9, FEN-1, Mus81, Eme1, DDS1, and BARD. Preferably, the method comprises administering the active ingredient of Formula 1 in an amount of about 2 mg to about 300 mg. The present invention also provides a method of administering a pharmaceutical composition comprising a compound of formula 1 or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient. According to the present invention, when measured in a 1% (w / v) aqueous suspension, the pharmaceutical composition preferably has a pH of about 2.6 to about 6.74.

[0023] As provided in more detail in the examples, experimental results show that compounds of Formula I (i.e., compound 1) described herein demonstrate anticancer activity in individuals with cancer, which may have certain mutations such as BRCA1, BRCA2, ATM, or homologous recombination repair mutations. Specifically, compounds of Formula 1 described herein demonstrate anticancer activity in individuals with breast cancer, ovarian cancer, or pancreatic cancer. I. Methods of Use and Treatment

[0024] The method of the present invention includes the use of a compound of Formula I or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I described herein, for providing clinical benefits including, but not limited to, prevention, treatment, or improvement of a disease, symptom, or condition. In some embodiments, the disease is ovarian cancer with a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation. In some embodiments, the disease is breast cancer with a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation. In some embodiments, the cancer is platinum-resistant ovarian cancer. In some embodiments, the disease is cancer with a homologous recombination repair mutation. In some embodiments, the disease is pancreatic cancer with a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation. In some embodiments, the disease is cancer with a BRCA1 mutation. In some embodiments, the disease is cancer with a BRCA2 mutation. In some embodiments, the disease is cancer with an ATM mutation. In some embodiments, the disease is cancer with a homologous recombination repair mutation.

[0025] In one embodiment, this document provides a method for treating an individual in need of cancer with a BRCA1 mutation, BRCA2 mutation, ATM mutation or homologous recombination repair mutation, comprising administering to the individual about 2 mg to about 300 mg of a compound of Formula 1 or a pharmaceutically acceptable salt thereof.

[0026] In another embodiment, this document provides a method for treating an individual in need of cancer having a BRCA1 mutation, BRCA2 mutation, ATM mutation, or homologous recombination repair mutation, comprising administering to the individual a pharmaceutical composition comprising: (i) a compound of formula I, of formula I or a pharmaceutically acceptable salt thereof, of about 2 mg to about 300 mg; and (ii) at least one pharmaceutically acceptable excipient.

[0027] In various embodiments, the pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof is administered once, twice, three times, four times, or five times daily. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered twice daily.

[0028] In another embodiment, this document provides a method for treating an individual with cancer having BRCA1 mutations or BRCA2 mutations with homologous recombination repair mutations, comprising administering to the individual a pharmaceutical composition comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient; and at least one pharmaceutically acceptable excipient, wherein the pH of the composition, as measured in a 1% w / v aqueous suspension, is from about 2.6 to about 6.74: Formula I.

[0029] In another embodiment, this document provides a method for treating an individual in need of cancer with a BRCA1 mutation, BRCA2 mutation, ATM mutation, or homologous recombination repair mutation, comprising administering to the individual a solid oral dosage form comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient; and at least one excipient selected from the group consisting of: diluents, binders, disintegrants, lubricants, and any combination thereof. Formula I.

[0030] In another embodiment, this article provides a method for treating cancer in an individual in need that has a BRCA1 mutation, BRCA2 mutation, ATM mutation, or homologous recombination repair mutation, comprising administering to the individual a stable solid oral dosage form comprising a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient; wherein the oral dosage form maintains at least 99 wt% of the compound of Formula 1 after being stored at 20°C and 75% relative humidity for at least one month: Formula 1.

[0031] In any of the methods described herein, the cancer is ovarian cancer, breast cancer, or pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is platinum-resistant ovarian cancer.

[0032] In any of the methods described herein, the method comprises administering to an individual about 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, or 240 mg of a compound or a pharmaceutically acceptable salt thereof, preferably about 40 mg, 80 mg, 120 mg, 160 mg, or 240 mg of a compound or a pharmaceutically acceptable salt thereof, and most preferably about 80 mg of a compound or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to an individual about 160 mg or about 240 mg of a compound or a pharmaceutically acceptable salt thereof.

[0033] In some embodiments, the method described herein comprises administering to an individual about 40 mg of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the method described herein comprises administering to an individual about 80 mg of the compound or a pharmaceutically acceptable salt thereof. In some embodiments, the method described herein comprises administering to an individual about 120 mg of the compound or a pharmaceutically acceptable salt thereof.

[0034] In some embodiments, the active ingredient is the hydrochloride salt of a compound of formula 1. In some embodiments, pharmaceutically acceptable excipients are diluents, binders, disintegrants, lubricants, or any combination thereof.

[0035] In some embodiments, the composition comprises about 40 to about 90 wt% of a diluent based on the total weight of the composition; about 0.1 to about 30 wt% of an adhesive based on the total weight of the composition; about 1 to about 40 wt% of a disintegrant based on the total weight of the composition; and about 0.5 to about 40 wt% of a lubricant based on the total weight of the composition.

[0036] In some embodiments, the diluent is selected from the group consisting of: hydrated lactose, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, hydrated dicalcium phosphate, or any combination thereof; the adhesive is selected from the group consisting of: hydroxypropyl cellulose (HPC) and povidone, or any combination thereof; the disintegrant is selected from the group consisting of: carboxymethyl cellulose, crospovidone, crospovidone sodium carboxymethyl cellulose, sodium glycolate starch, carboxymethyl cellulose (CMC), CMC-Ca, low-substituted hydroxypropyl cellulose, corn starch, and polacrilin potassium, or any combination thereof; and the lubricant is selected from the group consisting of: colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof. In some embodiments, the diluent is selected from the group consisting of: hydrated lactose, anhydrous lactose, and microcrystalline cellulose. In some embodiments, the diluent is hydrated lactose. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the adhesive is hydroxypropyl cellulose. In some embodiments, the adhesive is provitamin.

[0037] In some embodiments, the disintegrant is selected from the group consisting of: low-substituted hydroxypropyl cellulose, corn starch, potassium polacrine, and carboxymethyl cellulose. In some embodiments, the disintegrant is carboxymethyl cellulose. In some embodiments, the lubricant is selected from the group consisting of colloidal silicon dioxide and magnesium stearate.

[0038] In some embodiments, the pharmaceutical composition further comprises a pH control agent. In some embodiments, the pH control agent has a pH of about 1 to about 5. In some embodiments, the pH control agent is selected from the group consisting of citric acid, fumaric acid, maleic acid, or any combination thereof. In some embodiments, the pH control agent is fumaric acid. In some embodiments, the pharmaceutical composition further comprises a hyperdisintegrant. In some embodiments, the composition comprises about 0.01 to about 20 wt% of a hyperdisintegrant based on the total weight of the composition. In embodiments, the hyperdisintegrant is selected from the group consisting of crosupialone, crosupialized sodium carboxymethyl cellulose, sodium glycolate starch, or any combination thereof.

[0039] In some embodiments, the composition comprises about 10 mg to about 240 mg of active ingredient per unit dose. In some embodiments, the composition comprises about 80 mg of active ingredient per unit dose.

[0040] In some embodiments, the composition is in solid form. In embodiments, the solid form is selected from the group consisting of: tablets, wet granules, dry granules, microparticles, or capsules. In embodiments, the solid form is a tablet. In embodiments, the solid form is a film-coated tablet. In embodiments, the solid form is a casing tablet. In embodiments, after storage at 20°C and 75% relative humidity for 1 month, the composition contains 0.50 wt% or less of impurities of the active ingredient.

[0041] In some embodiments, the solid dosage form is an tablet. In some embodiments, the compound is present in the solid oral dosage form for about 3 months after formulation. In some embodiments, the solid oral dosage form includes a diluent, a binder, a disintegrant, and a lubricant. In some embodiments, the solid oral dosage form includes about 40 to about 90 wt% of the total weight of the solid oral dosage form; about 0.1 to about 30 wt% of the total weight of the solid oral dosage form; about 1 to about 40 wt% of the total weight of the solid oral dosage form; and about 0.5 to about 40 wt% of the total weight of the solid oral dosage form.

[0042] In another embodiment, this article provides a method for obtaining clinical benefit in an individual with ovarian cancer, comprising administering to the individual about 2 mg to about 300 mg of a compound of formula I: formula I or a pharmaceutically acceptable salt thereof.

[0043] In some embodiments, the ovarian cancer is platinum-resistant ovarian cancer.

[0044] In one embodiment, this document provides a method for obtaining clinical benefit in an individual suffering from breast cancer, comprising administering to the individual about 2 mg to about 300 mg of a compound of formula I: formula I or a pharmaceutically acceptable salt thereof.

[0045] In one embodiment, this document provides a method for obtaining clinical benefit in an individual suffering from pancreatic cancer, comprising administering to the individual about 2 mg to about 300 mg of a compound of formula I: formula I or a pharmaceutically acceptable salt thereof.

[0046] In one embodiment, this document provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of an individual with cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation, wherein the use comprises administering the compound to the individual once daily at a dose of about 2 mg to about 300 mg.

[0047] In one embodiment, this document provides a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment of an individual with cancer having a BRCA1 mutation, a BRCA2 mutation, an ATM mutation, or a homologous recombination repair mutation, wherein the use comprises administering the compound to the individual twice daily at a dose of about 2 mg to about 300 mg.

[0048] In any of the above methods, the cancer is ovarian cancer, breast cancer, or pancreatic cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is ovarian cancer. In some embodiments, the cancer is breast cancer. In some embodiments, the cancer is pancreatic cancer. In some embodiments, the cancer is platinum-resistant ovarian cancer.

[0049] In any of the above methods, the method comprises administering to an individual about 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, or 240 mg of a compound or a pharmaceutically acceptable salt thereof, preferably about 40 mg, 80 mg, 120 mg, 160 mg, or 240 mg of a compound or a pharmaceutically acceptable salt thereof, and most preferably about 80 mg of a compound or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises administering to an individual about 160 mg or about 240 mg of a compound or a pharmaceutically acceptable salt thereof.

[0050] In various embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once, twice, three times, four times, or five times daily. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered once daily. In some embodiments, the compound of formula I or a pharmaceutically acceptable salt thereof is administered twice daily. II. Compound

[0051] The method of the present invention includes providing clinical benefit to an individual in need, preventing and / or treating a disease, condition or symptom (e.g., a disease, condition or symptom associated with ovarian cancer, breast cancer or pancreatic cancer, for example having a BRCA1 mutation, BRCA2 mutation, ATM mutation or homologous recombination repair mutation), comprising administering a compound (e.g., a compound of Formula 1) to the individual.

[0052] In some embodiments, the compound is a compound of Formula 1: <Formula 1>, or a pharmaceutically acceptable salt thereof.

[0053] Compounds of Formula 1 have IUPAC (International Union of Pure and Applied Chemistry) nomenclature, such as 4-[3-(3-[(cyclopropylamino)methyl]acetate-1-carbonyl)-4-fluorobenzyl]phthalazine-1(2H)-one. Formula 1 or its pharmaceutically acceptable salts can be obtained by any method known to a person generally skilled in the art. Suitable methods of preparation are disclosed, for example, in U.S. Patent No. 9,682,973, which is incorporated herein by reference in its entirety.

[0054] The crystalline form of the phthalazinone compound is also disclosed in U.S. Patent Application No. 16 / 858,158, filed April 24, 2020, which is incorporated herein by reference in its entirety.

[0055] In some embodiments, the hydrochloride of Formula 1 is in a crystalline form, the X-ray powder diffraction (XRPD) pattern of which includes peaks at diffraction angles of 2θ ± 0.2° at 13.7°, 15.9°, and 24.1° (hereinafter referred to as "crystalline form A"). In some embodiments, the XRPD pattern of crystalline form A may include peaks at 2θ ± 0.2° values ​​selected from the group consisting of: 9.1°, 11.9°, 13.2°, 13.7°, 15.9°, 16.8°, 18.1°, 23.2°, 24.1°, 25.5°, and 26.6°. Specifically, the XRPD pattern of crystalline form A contains peaks at 2θ ± 0.2° values ​​of 9.1°, 13.2°, 13.7°, 15.9°, 16.8°, 24.1°, and 26.6°. More specifically, the XRPD pattern of crystalline form A contains peaks at 2θ ± 0.2° values ​​of 9.1°, 11.9°, 13.2°, 13.7°, 15.9°, 16.8°, 18.1°, 23.2°, 24.1°, 25.5°, and 26.6°. XRPD patterns can be obtained using any method known to those skilled in the art, including illumination with a Cu-Kα light source (e.g., a D8 Advance (Bruker ASX, Germany) analyzer). The Cu-Kα light source may have a wavelength of 1.54056 Å. III. Dosage Forms and Compositions

[0056] In one embodiment, the present invention provides a dosage form or composition suitable for providing clinical benefit in an individual in need, the clinical benefit including but not limited to prevention and / or treatment of the diseases, conditions or symptoms described herein (e.g., ovarian cancer, breast cancer or pancreatic cancer with BRCA1 mutation, BRCA2 mutation, ATM mutation or homologous recombination repair mutation), the use comprising administering a compound (e.g., a compound of formula 1) to the individual.

[0057] The present invention provides a pharmaceutical composition comprising a compound described herein (e.g., compound 1) or a pharmaceutically acceptable salt thereof as an active ingredient and one or more pharmaceutically acceptable excipients, including but not limited to any one or more of the following: carriers, diluents, binders, disintegrants, and lubricants. The pharmaceutical composition may be administered alone or in combination with other therapeutic agents.

[0058] Based on the total weight of the composition, the pharmaceutical composition of the present invention may contain about 0.1 to about 70 wt%, preferably about 1 to 40 wt%, of compound 1 or a pharmaceutically acceptable salt thereof. In total, the pharmaceutical composition of the present invention contains about 1 to about 400 mg per unit dose, preferably about 2 to about 240 mg of compound 1 or a pharmaceutically acceptable salt thereof. Other examples of the pharmaceutical composition include 2 mg, 5 mg, 10 mg, 20 mg, 40 mg, 80 mg, 120 mg, 160 mg, or 240 mg of compound 1 or a pharmaceutically acceptable salt thereof. The above amounts are in the form of the free base of compound 1.

[0059] In one embodiment, the composition of the present invention has a preferred critical limit value for total impurities in the pharmaceutical composition after stability testing. After the pharmaceutical composition of the present invention is stored at a temperature of 25°C to 70°C (e.g., 25°C, 40°C, 50°C, 60°C, or 70°C) and a relative humidity (RH) of 60% to 75% (e.g., 60% or 75%) for approximately 1 week to 12 months (e.g., 1 week, 2 weeks, 4 weeks, 1 month, 3 months, 6 months, or 12 months), the total impurity content of the pharmaceutical composition, measured by HPLC, based on the total weight of the pharmaceutical composition, is 1.50% or less, preferably 1.0% or less, more preferably 0.80% or less, and more preferably 0.40% or less. For example, after the composition of the present invention is stored at 50°C and 75% relative humidity for 1 month, the total impurity content of the active ingredient may be 1.0% or less.

[0060] In another embodiment, the composition of the present invention has a preferred critical limit value for M1 impurities in the pharmaceutical composition after stability testing. After the pharmaceutical composition of the present invention is stored at a temperature of 25°C to 70°C (e.g., 25°C, 40°C, 50°C, 60°C, or 70°C) and a relative humidity (RH) of 60% to 75% (e.g., 60% or 75%) for approximately 1 week to 12 months (e.g., 1 week, 2 weeks, 4 weeks, 1 month, 3 months, 6 months, or 12 months), the content of M1 impurities in the active ingredient, measured by HPLC, is 0.50% or less, preferably 0.4% or less, and more preferably 0.20% or less, based on the total weight of the pharmaceutical composition. For example, after the composition of the present invention is stored at 50°C and 75% relative humidity for 1 month, the content of M1 impurities in the active ingredient may be 0.50% or less.

[0061] The pharmaceutical compositions of the present invention contain at least one pharmaceutically acceptable excipient. The type and amount of excipient can be suitably selected to ensure that the pharmaceutical compositions of the present invention satisfy a pH of about 2.6 to about 6.74 as measured in a 1% w / v aqueous suspension prepared according to Example 3 of the present invention. Furthermore, excipients can improve the processing characteristics of the formulation, such as flowability and / or aggregation, to allow for better compression of the pharmaceutical composition. Excipients are also preferably selected considering the dissolution rate of the pharmaceutical composition.

[0062] In one embodiment, the pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable excipients, including but not limited to any one or more of the following: carriers, diluents, binders, disintegrants and lubricants.

[0063] The diluent may include (but is not limited to) the following: lactose, such as anhydrous lactose or hydrated lactose (e.g., Flowlac 100); microcrystalline cellulose (e.g., Avicel pH-101 or Pharmacel 101); hydrated dicalcium phosphate (e.g., carboxymethyl cellulose, EMCOMPRESS); mannitol, such as D-mannitol (e.g., Mannogem EZ); sorbitol, such as D-sorbitol (e.g., XTAB 200S); refined sugar, such as compressible sugar, glucose binder, dextrin, or dextrose; powdered cellulose; or any combination thereof. Preferably, the diluent of the present invention may be hydrated lactose, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, hydrated dicalcium phosphate, or any combination thereof, more preferably hydrated lactose, mannitol, sorbitol, microcrystalline cellulose, or any combination thereof, and most preferably hydrated lactose, microcrystalline cellulose, or any combination thereof.

[0064] In some embodiments, the diluent is hydrated lactose. In some embodiments, the diluent is anhydrous lactose. In some embodiments, the diluent is microcrystalline cellulose. In some embodiments, the diluent is hydrated dicalcium phosphate. In some embodiments, the diluent is mannitol. In some embodiments, the diluent is sorbitol. In some embodiments, the diluent is refined sugar. In some embodiments, the diluent is powdered cellulose.

[0065] The diluent may be contained in an amount of about 40 to about 90 wt%, preferably about 70 to about 90 wt%, based on the total weight of the composition.

[0066] In some embodiments, the pharmaceutical composition of the present invention comprises about 40 to about 90 wt% of a diluent based on the total weight of the composition; about 0.1 to about 30 wt% of a binder based on the total weight of the composition; about 1 to about 40 wt% of a disintegrant based on the total weight of the composition; and about 0.5 to about 40 wt% of a lubricant based on the total weight of the composition.

[0067] In some embodiments, the diluent is selected from the group consisting of: hydrated lactose, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, hydrated dicalcium phosphate, or any combination thereof; the adhesive is selected from the group consisting of: hydroxypropyl cellulose (HPC) and provitamin, or any combination thereof; the disintegrant is selected from the group consisting of: carboxymethyl cellulose, crosupialone, crosupialone sodium carboxymethyl cellulose, sodium glycolate starch, carboxymethyl cellulose (CMC), CMC-Ca, low-substituted hydroxypropyl cellulose, corn starch, and potassium polacolin, or any combination thereof; and the lubricant is selected from the group consisting of: colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof.

[0068] The adhesive may include (but is not limited to) the following: hydroxypropyl cellulose (e.g., HPC-L or HPC-EXF), provitamin (e.g., K-30); hydroxyethyl cellulose; hydroxypropyl methylcellulose (e.g., METHOCEL); sucrose; dextrose; corn syrup; polysaccharides; or any combination thereof. Preferably, the adhesive of the present invention may be hydroxypropyl cellulose, provitamin, or any combination thereof, and more preferably hydroxypropyl cellulose.

[0069] In some embodiments, the adhesive is hydroxypropyl cellulose. In some embodiments, the adhesive is provitamin. In some embodiments, the adhesive is hydroxyethyl cellulose. In some embodiments, the adhesive is sucrose. In some embodiments, the adhesive is dextrose. In some embodiments, the adhesive is corn syrup. In some embodiments, the adhesive is a polysaccharide.

[0070] The adhesive may be included in an amount of about 0.1 to about 30 wt%, preferably about 0.5 to about 20 wt%, based on the total weight of the composition.

[0071] The disintegrant may include (but is not limited to) the following: carboxymethyl cellulose (CMC; also known as carboxymethyl cellulose, e.g., NS-300); calcium carboxymethyl cellulose (CMC-Ca); sodium carboxymethyl cellulose (CMC-Na); low-substituted hydroxypropyl cellulose (e.g., LH-11, LH-21, LH-31 grades, etc., having an 11% hydroxypropoxy content); corn starch; polacling potassium; pregelatinized starch; clay; alginate; rubber; or any combination thereof. Preferably, the disintegrant of the present invention may be CMC, CMC-Ca, CMC-Na, low-substituted hydroxypropyl cellulose, corn starch, polacling potassium, or any combination thereof, and more preferably CMC.

[0072] In some embodiments, the disintegrant is carboxymethyl cellulose. In some embodiments, the disintegrant is calcium carboxymethyl cellulose. In some embodiments, the disintegrant is sodium carboxymethyl cellulose. In some embodiments, the disintegrant is low-substituted hydroxypropyl cellulose. In some embodiments, the disintegrant is corn starch. In some embodiments, the disintegrant is potassium pluckleine. In some embodiments, the disintegrant is pregelatinized starch. In some embodiments, the disintegrant is clay. In some embodiments, the disintegrant is alginate. In some embodiments, the disintegrant is rubber.

[0073] The disintegrant may be contained in an amount of about 1 to about 40 wt%, preferably about 3 to about 20 wt%, based on the total weight of the composition.

[0074] The lubricant may include (but is not limited to) the following: colloidal silica; talc; stearic acid, magnesium stearate, calcium stearate; sodium stearyl fumarate (e.g., Pruv); or any combination thereof. Preferably, the lubricant of the present invention may be colloidal silica, magnesium stearate, sodium stearyl fumarate, talc, stearic acid or any combination thereof, and more preferably colloidal silica, magnesium stearate or any combination thereof.

[0075] In some embodiments, the lubricant is colloidal silicon dioxide. In some embodiments, the lubricant is talc. In some embodiments, the lubricant is stearic acid, magnesium stearate, or calcium stearate. In some embodiments, the lubricant is sodium stearate fumarate.

[0076] The lubricant may be contained in an amount of about 0.5 to about 40 wt%, preferably about 1 to about 20 wt%, based on the total weight of the composition.

[0077] In another embodiment, the pharmaceutical composition of the present invention may further comprise a pH control agent. When the pH of the pharmaceutical composition, measured in a 1% w / v aqueous suspension prepared according to Example 3 of the present invention, is in the range of about 2.6 to 6.74 without any pH control agent, no additional pH control agent is required. When the pH of the pharmaceutical composition exceeds this range without any pH control agent, a pH control agent may be appropriately added to adjust the pH of the pharmaceutical composition to within this pH range. In an exemplary embodiment, when the pharmaceutical composition contains CMC as a disintegrant (test sample 2), the pH in the 1% w / v aqueous suspension prepared according to Example 3 of the present invention is about 4.3, meaning that no additional pH control agent is required. On the other hand, when the pharmaceutical composition contains polacolin potassium as a disintegrant, the pH is about 7.97 and the content of impurities increases, thereby becoming unstable (test sample 9). In this case, an additional pH control agent will be required to bring it within the desired pH range. It was also found that the impurity content increased when CMC-Na (test sample 11) was used, and that the stability of the pharmaceutical composition could be increased by using an additional pH control agent.

[0078] Any pH control agent or combination of pH agents known in this technology may be used, as long as the desired pH range is achieved.

[0079] In a preferred embodiment, the pH control agent used in this invention may be a pH control agent having a pH of about 1 to about 5, more preferably about 1.5 to about 3, and even more preferably about 2 to about 2.5. Hereinafter, the pH of a pH control agent is defined as the pH of the solution or suspension obtained when the pH control agent is dissolved or suspended in water at a concentration of 1% w / v at room temperature.

[0080] The pH control agent may include (but is not limited to) the following: acidic substances, such as tartaric acid, citric acid, lactic acid, fumaric acid, maleic acid, ascorbic acid, acetic acid, or acidic amino acids (e.g., glutamic acid or aspartic acid); inorganic salts of acidic substances (e.g., alkali metal salts, alkaline earth metal salts, ammonium, etc.); salts of acidic substances having organic bases (e.g., basic amino acids, such as lysine, arginine, meglumine, etc.); and their hydrates, solvates, or any combination thereof. Preferably, the pH control agent may be citric acid, fumaric acid, maleic acid, or any combination thereof.

[0081] The pH control agent may be contained in an amount of about 0.01 to about 20 wt%, and more preferably about 0.05 to about 10 wt%, based on the total weight of the composition.

[0082] In another embodiment, the pharmaceutical composition of the present invention may further comprise a hyperdisintegrant. The hyperdisintegrant may include (but is not limited to) the following: crosuppliconone; crosupplicon sodium; sodium glycolate starch; natural, modified, or pregelatinized starch; a foaming disintegration system; or any combination thereof. Preferably, the hyperdisintegrant may be crosuppliconone, crosupplicon sodium, sodium glycolate starch, or any combination thereof.

[0083] In some embodiments, the superdisintegrant is crosupplione. In some embodiments, the superdisintegrant is crosupplied carboxymethyl cellulose sodium. In some embodiments, the superdisintegrant is sodium glycolate starch. In some embodiments, the superdisintegrant is natural, modified, or pregelatinized starch. In some embodiments, the superdisintegrant is a foaming disintegration system.

[0084] The superdisintegrant may be contained in an amount of about 0.01 to about 20 wt%, more preferably about 1 to about 10 wt%, and even more preferably about 1 to about 5 wt% based on the total weight of the composition.

[0085] The functions or effects of excipients described above are not absolute, and in some cases, an excipient may have at least two functions. For example, some disintegrants may also act as adhesives and fillers. The various functions or effects of excipients can be determined as known in the art.

[0086] Oral administration is a route of administration of the compounds according to the invention. Administration may be via capsules, tablets, or similar. In the manufacture of pharmaceutical compositions comprising at least one compound described herein, the active ingredient is typically diluted and / or sealed in a carrier, which may be in the form of capsules, pouches, paper, or other containers, by means of excipients. When the excipients are used as diluents, they may be in the form of solid, semi-solid, or liquid materials (as described above), which act as a mordant, carrier, or medium for the active ingredient. Thus, the compositions may be in the following forms: tablets, pills, powders, lozenges, pouches, capsules, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0087] The pharmaceutical compositions of the present invention may be in the form of solid oral dosage forms or solid preparations, such as tablets, granules, microparticles, capsules, pills, and the like. Solid preparations are preferably tablets, such as tablets coated with a film-coating agent. In some embodiments, the pharmaceutical composition may be formulated as a tablet. In some embodiments, tablets comprising the pharmaceutical composition described herein may be coated with a film. In some embodiments, tablets comprising the pharmaceutical composition described herein may be coated with an enteric coating.

[0088] Tablets containing the pharmaceutical compositions of the present invention may also be coated with a film. For example, the film is used for enteric coating. In some embodiments, the film comprises a cellulose polymer (e.g., hydroxypropyl cellulose, hydroxypropyl methylcellulose, methylcellulose, or any combination thereof). An exemplary coating agent may be Opadry® containing hydroxypropyl methylcellulose, such as Opadry® White 03B28796.

[0089] In one embodiment, this document provides a pharmaceutical composition comprising an active ingredient of Formula 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient, wherein the composition has a pH of about 2.6 to about 6.74 when measured in a 1% w / v aqueous suspension. <Formula 1>.

[0090] In some embodiments, the active pharmaceutical ingredient may be the hydrochloride salt of Formula 1.

[0091] In another embodiment, a pharmaceutically acceptable excipient may be a diluent, binder, disintegrant, lubricant, or any combination thereof.

[0092] In some embodiments, the composition comprises about 40 to about 90 wt% of a diluent based on the total weight of the composition; about 0.1 to about 30 wt% of an adhesive based on the total weight of the composition; about 1 to about 40 wt% of a disintegrant based on the total weight of the composition; and about 0.5 to about 40 wt% of a lubricant based on the total weight of the composition.

[0093] In some embodiments, the diluent is selected from the group consisting of: hydrated lactose, anhydrous lactose, mannitol, sorbitol, microcrystalline cellulose, hydrated dicalcium phosphate, or any combination thereof; the adhesive is selected from the group consisting of: hydroxypropyl cellulose (HPC) and provitamin, or any combination thereof; the disintegrant is selected from the group consisting of: carboxymethyl cellulose, crosupialone, crosupialone sodium carboxymethyl cellulose, sodium glycolate starch, carboxymethyl cellulose (CMC), CMC-Ca, low-substituted hydroxypropyl cellulose, corn starch, and polaclin potassium, or any combination thereof; and the lubricant is selected from the group consisting of: colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, talc, stearic acid, or any combination thereof.

[0094] In one embodiment, this document provides a solid oral dosage form comprising a compound of formula I: , or a pharmaceutically acceptable salt thereof; and at least one excipient selected from the group consisting of: diluents, binders, disintegrants, lubricants, and any combination thereof.

[0095] In one embodiment, this document provides a stable solid oral dosage form comprising a pharmaceutically acceptable excipient and a compound of formula I, or a pharmaceutically acceptable salt thereof, wherein the oral dosage form retains at least 99 wt% of the compound of formula I after being stored at 20°C and 75% relative humidity for at least one month.

[0096] In one embodiment, the solid oral dosage form is a tablet.

[0097] In one embodiment, the solid oral dosage form comprises about 40 to about 90 wt% of a diluent based on the total weight of the composition; about 0.1 to about 30 wt% of a binder based on the total weight of the composition; about 1 to about 40 wt% of a disintegrant based on the total weight of the composition; and about 0.5 to about 40 wt% of a lubricant based on the total weight of the composition.

[0098] In one embodiment, this document provides a method for preparing a pharmaceutical composition having a pH of about 2.6 to about 6.74 as measured in a 1% w / v aqueous suspension, comprising: (a) mixing a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient with at least one pharmaceutically acceptable excipient to obtain a blend <Formula 1>; and (b) directly compressing the blend.

[0099] In one embodiment, this document provides a product obtained by the method described herein.

[0100] As provided in more detail in the examples, experimental results show that when the pH of a composition comprising the active pharmaceutical ingredient of Formula 1 or a pharmaceutically acceptable salt thereof is adjusted to a predetermined range, the degradation of the active ingredient of Formula 1 is significantly lower during long-term storage. The resulting pharmaceutical composition exhibits improved stability over the expected normal storage period of the composition.

[0101] The pH of the pharmaceutical composition was measured by preparing an aqueous suspension of the composition in a 1% w / v (weight / volume) aqueous suspension prepared at room temperature according to Example 3. Methods for measuring pH are well known to those skilled in pharmaceutical composition techniques. For example, the pH of the substance is measured by dissolving the subject substance in water at a concentration of 1% w / v to obtain an aqueous suspension prepared according to Example 3, and then measuring the pH of the suspension. The pH value can be determined using any standard technique.

[0102] The pH of the pharmaceutical composition of the present invention may be from about 2.6 to about 6.74, preferably from about 2.9 to about 6.5, and more preferably from about 2.95 to about 4.95. In some embodiments, when measured by preparing an aqueous suspension of the composition in a 1% w / v (weight / volume) aqueous suspension, the pH of the pharmaceutical composition is between about 2 and about 8 (e.g., between about 2 and about 7.5, between about 2 and about 7, between about 2 and about 6.5, between about 2 and 6, between about 2 and about 5.5, between about 2 and about 5, between about 2 and about 4.5, between about 2.5 and about 7.5, between about 2.5 and about 7, between about 2.5 and about 6.5, between about 2.5 and about 6, between about 2.5 and about 5.5, between about 2.5 and about 5, between about 2.5 and about 4.5), or any specific value within that range. In some embodiments, when measured by preparing an aqueous suspension of the composition in a 1% w / v (weight / volume) aqueous suspension, the pH of the pharmaceutical composition is preferably between about 3 and about 8 (e.g., between about 3 and about 7.5, between about 3 and about 7, between about 3 and about 6.5, between about 3 and about 6, between about 3 and about 5.5, between about 3 and about 5). The pH of the pharmaceutical composition of the present invention may be in any of the above-mentioned specific ranges, i.e., the word "about" is not preceding the pH value. IV. Manufacturing Method

[0103] The pharmaceutical composition of the present invention can be prepared by any known method or process, such as grinding, mixing or blending, granulation, drying, molding (ingot making), coating, crystallization and the like.

[0104] Therefore, the present invention also provides a method for preparing a pharmaceutical composition with a pH of 2.6 to 6.74 as measured in a 1% w / v aqueous suspension, comprising: (a) mixing a compound of Formula 1 or a pharmaceutically acceptable salt thereof as an active ingredient with at least one pharmaceutically acceptable excipient to obtain a blend; <Formula 1> (b) directly compressing the blend.

[0105] In one embodiment, the present invention provides a direct compression method for preparing a pharmaceutical composition, comprising the following steps: (a) pre-blending an active ingredient with some or most of an excipient in a mixer to obtain a pre-blended compound; (b) dry sieving the pre-blended compound via a sieve, if applicable, to separate viscous particles and improve the uniformity of the contents; (c) mixing the pre-blended compound from step (a) or (b) with the remaining excipient in a mixer to obtain a final blend; (d) compressing and tableting the final blend from step (c) in a tablet press to prepare a tablet core; and (e) coating the tablet core from step (d), if applicable, with a film.

[0106] According to a particular embodiment, the active ingredient, diluent, binder, disintegrant, and lubricant are pre-blended in a diffusion mixer, sieved in a hand screen or sieve mill, and pre-blended again in a diffusion mixer to prepare a blended intermediate composition. An additional lubricant is sieved separately in a hand screen or sieve mill and then blended with the blended intermediate in a diffusion mixer to prepare a blend. The blend is subjected to direct compression in a rotary ingot maker to obtain ingots (plain tablets), and a coating agent is subsequently added to prepare a coated ingot.

[0107] The particles of the pharmaceutical composition according to the present invention can be prepared by any method known to those skilled in the art. Preferred methods for granulating the active ingredient together with the excipient include wet granulation (such as high-shear wet granulation or fluidized bed wet granulation) and dry granulation, also known as roll forming.

[0108] In a wet granulation process, the granulation liquid is a formulation consisting of a solvent alone or one or more binders in a solvent or a mixture of solvents. Suitable binders are described above. Examples include hydroxypropyl methylcellulose, hydroxypropyl cellulose, provitamin, and coprovitamin. Suitable solvents include, for example, purified water, ethanol, methanol, isopropanol, acetone, preferably purified water, including mixtures thereof. The solvent is a volatile component that is not retained in the final product. One or more active ingredients and other excipients, specifically one or more diluents and one or more disintegrants (usually other than lubricants), are premixed with the granulation liquid and granulated, for example using a high-shear granulator. The wet granulation step is typically followed by one or more drying and sieving steps. For example, a drying oven or fluidized bed dryer may then be used for drying.

[0109] The dried particles are sieved through a suitable screen. After adding other excipients, specifically disintegrants, binders, fillers and / or lubricants as appropriate, the mixture is blended in a suitable mixer, such as a free-fall mixer, followed by the addition of one or more lubricants (e.g., magnesium stearate), and finally blended in the mixer.

[0110] In one particular embodiment, the present invention provides a wet granulation method for preparing a pharmaceutical composition, comprising the following steps: (a) pre-blending an active ingredient and some or most of an excipient including a binder in a mixer to obtain a pre-blended compound; (b) granulating the pre-blended compound of step (a) by adding a granulation liquid, preferably purified water; (c) drying the granules of step (b) in a fluidized bed dryer or drying oven; (d) dry sieving the dried granules of step (c) as appropriate; (e) mixing the dried granules of step (d) with a lubricant, slip agent and the like in a mixer to obtain a final mixture; (f) forming the final mixture of step (e) into tablets by compressing it on a suitable tablet forming machine to produce tablet cores; and (g) coating the tablet cores of step (f) as appropriate.

[0111] In another embodiment, the present invention provides a dry granulation method for preparing a pharmaceutical composition, comprising the following steps: (a) mixing an active ingredient with all or part of an excipient in a mixer; (b) compacting the mixture of step (a) on a suitable roller press; (c) converting the strip obtained during step (b) into granules, preferably small granules, by a suitable grinding or sieving step; (d) mixing the granules of step (c) with the remaining excipient in a mixer, as appropriate, to obtain a final mixture; (e) forming the granules of step (c) or the final mixture of step (d) into tablets to produce tablet cores by compressing the granules of step (c) or the final mixture of step (d) on a suitable tablet maker; and (f) coating the tablet cores of step (e) with a film, as appropriate.

[0112] The present invention also provides pharmaceutical compositions such as tablets, which can be obtained by the following methods.

[0113] Granules and microgranules can be prepared by granulation using methods similar to those used for tablets (e.g., wet granulation or dry granulation). Alternatively, they can be prepared by spraying a coating liquid containing active ingredients and excipients (especially binders such as sucrose, hydroxypropyl cellulose, and hydroxypropyl methyl cellulose) onto glycospheres. Therefore, granules can be wet or dry granules.

[0114] Capsules are manufactured by filling gelatin (e.g., hydroxypropyl methylcellulose) with granules or microparticles, or by filling gelatin (e.g., hydroxypropyl methylcellulose) with active ingredients and excipients (e.g., lactose, sucrose, glucose, starch, saccharose, microcrystalline cellulose, powdered licorice, mannitol, sodium bicarbonate, calcium phosphate, calcium sulfate, etc.). V. Definition

[0115] The terms "active pharmaceutical ingredient of Formula 1" or "compound of Formula 1" may also be referred to as "compound 1" or "compound of the present invention". Similarly, "salt of active pharmaceutical ingredient of Formula 1" may also be referred to as "salt of compound 1" or "salt of compound of the present invention". For example, an active pharmaceutical ingredient of Formula 1 in the form of a hydrochloride salt may be referred to as "hydrochloride salt of compound 1" or "hydrochloride salt of compound of the present invention".

[0116] The "medically acceptable salt" described herein can be prepared by any suitable method available in this technology, such as by treating the active pharmaceutical ingredient of Formula 1 in its free base form with an inorganic acid. Examples of suitable inorganic acids include (but are not limited to) hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, methanesulfonic acid, phosphoric acid and the like, or organic acids such as acetic acid, trifluoroacetic acid, maleic acid, succinic acid, mandelic acid, fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid, salicylic acid, piperanonic acid (such as glucuronic acid or galacturonic acid), α-hydroxy acid (such as citric acid or tartaric acid), amino acid (such as aspartic acid or glutamic acid), aromatic acid (such as benzoic acid or cinnamic acid), sulfonic acid (such as p-toluenesulfonic acid or ethanesulfonic acid) or the like. The hydrochloride salt of the active pharmaceutical ingredient of Formula 1 is preferred.

[0117] As used herein, "pharmaceutically acceptable carrier" means a non-toxic carrier, adjuvant, or mediator that does not impair the pharmacological activity of the compound formulated with it. Pharmaceutically acceptable carriers, adjuvants, or mediators that may be used in the compositions described herein include (but are not limited to) ion exchangers; alumina; aluminum stearate; buffering substances such as phosphates; glycine; sorbic acid; potassium sorbate; mixtures of saturated vegetable fatty acids in the form of glycerides; water; salts or electrolytes such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts; colloidal silica; magnesium trisilicate; polyvinylpyrrolidone; cellulose-based substances; polyethylene glycol; sodium carboxymethyl cellulose; polyacrylates; waxes; polyethylene-polyoxypropylene-block polymers; polyethylene glycol; and lanolin.

[0118] The terms "stable" and "reliable" as used herein mean that a pharmaceutical composition is stable, for example, in terms of heating, light, temperature, and / or humidity. For example, a pharmaceutical composition of the present invention is stable when the total impurity mass of the active ingredient ("M1 impurity") contained in the pharmaceutical composition, or the M1 impurity mass, is a certain percentage or lower after storing the pharmaceutical composition under certain conditions. M1 impurity is any inactive form of the active ingredient, such as synthetic intermediates, metabolic intermediates, byproducts, or degradation products of the active ingredient.

[0119] Total impurities measured by HPLC can be defined as having a relative retention time ("RRT") relative to the peak of compound 1 of about 0.11 to 2.10, and more specifically about 0.90, about 1.12, about 1.35, or about 1.38. Impurity M1 can be defined as having an RRT of about 0.90 relative to the peak of compound 1. As is well known in the art, RRT values ​​in HPLC can have an experimental error of ±10% of the specified value. Therefore, the values ​​described above should be interpreted in light of experimental error.

[0120] As used herein, the term "individual" intended to be addressed includes (but is not limited to) humans (i.e., males or females of any age group, such as pediatric individuals (e.g., infants, children, adolescents) or adult individuals (e.g., young adults, middle-aged adults, or older adults)). In some embodiments, the individual is a human. In some embodiments, the individual is a non-human animal. The terms "human," "patient," and "individual" are used interchangeably herein.

[0121] As used herein and unless otherwise stated, the term “treat / treating / treatment” includes actions that reduce the severity of a disease, condition or symptom or delay or slow the progression of a disease, condition or symptom while an individual has developed a particular disease, condition or symptom (“therapeutic treatment”), and also includes actions that occur before an individual develops a particular disease, condition or symptom (“preventive treatment”).

[0122] As used herein and unless otherwise specified, a "therapeuticly effective amount" of a compound is an amount sufficient to provide therapeutic benefit in the treatment of a disease, condition, or symptom, or to delay or minimize one or more symptoms associated with the disease, condition, or symptom. A therapeutically effective amount of a compound means an amount of a therapeutic agent, alone or in combination with other therapies, that provides therapeutic benefit in the treatment of a disease, condition, or symptom. The term "therapeuticly effective amount" may encompass amounts that improve overall therapy, reduce or prevent symptoms or causes of a disease or symptom, or enhance the therapeutic efficacy of another therapeutic agent.

[0123] As used herein, “about” should be understood by one generally skilled in the art and will vary to some extent depending on the context in which it is used. If a term is used that is not familiar to one generally skilled in the art, then, given the context in which it is used, “about” will mean that the particular term is added to or subtracted by at most 10%. For pH values, the term “about” will mean that the pH value is added to or subtracted by at most 0.5%.

[0124] As used herein, "analysis" refers to a procedure for determining the specific indicated stability of a drug substance content. For example, analysis may involve chromatographic methods (e.g., HPLC) using reference standards.

[0125] As used herein, "crystal" refers to a solid with a highly regular chemical structure, that is, a solid with a long-range structural order in the crystal lattice. Molecules are arranged in a regular periodic manner in the three-dimensional space of the crystal lattice. Specifically, crystallization can occur in one or more single crystal forms.

[0126] As used herein, "excipient" refers to a pharmaceutically acceptable inactive ingredient commonly used in the preparation of pharmaceutical formulations. Examples of suitable excipients can be found in Sheskey et al., Handbook of Pharmaceutical Excipients, 8th Edition, written (Pharmaceutical Press 2017), which is incorporated herein by reference in its entirety. Excipients can be classified according to their functional characteristics, such as diluents, binders, disintegrants, hyperdisintegrants, lubricants, pH controllers, slip agents, fillers, stabilizers, antioxidants, and coating agents. However, as is well known in the art, depending on when and how the excipient is used, a particular excipient may be classified into more than one of the previously listed functional groups; for example, an excipient may be classified as a disintegrant in one formulation and as a binder in another. In some cases, a particular excipient may be multifunctional, i.e., classified into more than one functional group within the same formulation. General considerations in the formulation and / or manufacture of pharmaceutical composition reagents can be found in, for example, Remington's Pharmaceutical Sciences, 16th edition, EW Martin (Mack Publishing Co., Easton, Pa., 1980) and Remington: The Science and Practice of Pharmacy, 21st edition (Lippincott Williams & Wilkins, 2005), all of which are incorporated herein by reference in their entirety.

[0127] As used herein, "binder" is an excipient that imparts enhanced cohesiveness or tensile strength (e.g., hardness) to a pharmaceutical composition. Examples of binders include dicalcium phosphate, sucrose, corn starch, microcrystalline cellulose, and modified cellulose (e.g., hydroxymethyl cellulose).

[0128] As used herein, "diluent" is an excipient that increases the volume of a pharmaceutical composition. Examples of diluents include lactose, sorbitol, cellulose, calcium phosphate, starch, sugars (e.g., mannitol, sucrose, or the like) or any combination thereof.

[0129] As used herein, a "disintegrant" is an excipient that hydrates a pharmaceutical composition and helps disperse tablets. Examples of disintegrants include sodium croscarmellose and / or sodium glycolate starch.

[0130] As used herein, "lubricant" is an excipient added to a pharmaceutical composition that is compressed into tablets. Lubricants facilitate the compression of granules into tablets and the extrusion of the pharmaceutical composition into tablets by a die press. Examples of lubricants include magnesium stearate, stearic acid (stear), hydrogenated oil, sodium stearyl fumarate, or any combination thereof.

[0131] As used herein, "Compound 1" refers to a compound of Formula I as described herein. Example

[0132] To provide a more comprehensive understanding of the invention described herein, the following examples are set forth. The examples described in this application are provided to illustrate the nature of the invention and its embodiments provided herein, and should not be construed as limiting its scope in any way. Abbreviations BRT Below the reporting threshold BOR CBR CMC Best overall response Clinical efficacy Carboxymethyl cellulose CMC-Ca Carboxymethyl cellulose calcium HDPE High-density polyethylene HPLC High performance liquid chromatography HPC Hydroxypropyl cellulose ND Not detected ORR QD RH Objective response rate Once a day relative humidity UV UV Example 1. Clinical study of compound 1 in patients with advanced solid tumors (Phase 1a).

[0133] A Phase I clinical trial was conducted to determine the recommended dose of Compound 1 as monotherapy and to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and anticancer efficacy of Compound 1 in patients with advanced solid tumors who had progressed after trying standard care and for whom no effective therapy was available. This study consisted of a conventional 3+3 dose-escalation design, as shown in Figure 1. The Phase I study was conducted in a conventional 3+3 design, starting at the lowest dose level (2 mg) and continuing until the maximum tolerated dose (“MTD”) was determined. Dose-limiting toxicities (“DLT”) and pharmacokinetics were assessed during the first cycle.

[0134] During the first period of DLT evaluation following product administration, no individuals experienced DLT among those in grades 1 (2 mg QD), 2 (5 mg QD), 3 (10 mg QD), 4 (20 mg QD), 5 (20 mg QD), 6 (40 mg QD), 7 (80 mg QD), 8 (120 mg QD), 9 (160 mg QD), and 10 (240 mg QD), and no MTD was measured. Therefore, for a continuous daily administration regimen lasting 3 weeks, the MTD of oral administration of compound 1 is expected to exceed 240 mg / day.

[0135] The pharmacokinetics of Formula 1 compounds were examined using a standardized enzyme-linked immunosorbent assay (ELISA) method with PAR levels in peripheral blood mononuclear cells (“PBMCs”) and tumors. PAR measurements in PBMCs and tumors are presented at dose levels and time points of presentation, along with results of tumor responses exhibiting PAR inhibition. Results are provided in Table 1 and illustrated in Figure 2. Formula 1 compounds demonstrated >90% PAR inhibition in pharmacokinetic analysis of tumor biopsy samples using doses starting at 10 mg. Table 1. Pharmacokinetic data for Formula 1 compounds. patient RA009 RA010 RA012 RA016 RA017 Dosage level 10 mg 20 mg 20 mg 20 mg 40 mg Tumor Par level (pg / mg tumor) forward 32676.5 8403.3 11721.6 12489.2 13535.9 > 3 days later BLQ BLQ 1022.1 BLQ 666.4 inhibition% > 98.8 >95.4 91.2 >96.9 95.1 *BLQ: Below the limit of quantitation (LLOQ: 390.6 pg / mg tumor) Tumor response assessment

[0136] The anticancer activity of compound 1 in the relevant patient population was assessed based on objective response rate (ORR = complete response [CR] + partial response [PR]) and clinical benefit rate (CBR = complete response [CR] + partial response [PR] + stable disease [SD]) according to RECIST, version 1.1 (RECIST, v1.1). Therefore, the term "clinical benefit" should mean providing any of the following responses after disease treatment: complete response; partial response; or stable disease. Table 2 presents data on compound 1 administration in selected patients, where the objective response rate (ORR) and clinical benefit rate (CBR) were determined by best overall response (BOR) in the overall response assessed during the Phase 1 period. Figures 3 (ORR) and 4 (CBR) illustrate this data graphically. Table 2. Objective response rate and clinical benefit rate according to RECIST version 1.1 Level 1 2mg QD (N=2) Level 2 5mg QD (N=3) Level 3 10mg QD (N=3) Level 4 20mg QD (N=3) Level 5 20mg QD (N=4) Level 6 40mg QD (N=3) Level 7 80mg QD (N=2) Level 8 120mg QD (N=2) Level 9 160mg QD (N=4) Level 10 240mg QD (N=3) total (N=29) ORR, n(%) 0 0 0 0 0 1(33.33) 1 (50.00) 1 (50.00) 0 2(66.67) 5 (17.24) CBR, n(%) 1 (50.00) 1(33.33) 1(33.33) 3 (100.00) 1 (25.00) 2(66.67) 1 (50.00) 2 (100.00) 0 3 (100.00) 15 (51.72)

[0137] Compound of Formula 1 was found to be effective against BRCA-mutated breast and ovarian cancer, as well as against BRCA wild-type breast, ovarian, and other cancers (i.e., those without BRCA mutations but potentially containing other mutations). Table 3 provides data on patients with BRCA-mutated breast or ovarian cancer as illustrated in Figure 5. Table 4 provides data on patients with BRCA wild-type breast, ovarian, and other cancers as illustrated in Figure 6. Table 3. Patients with BRCA-mutated breast or ovarian cancer Cancer types Number of patients ORR (%) CBR (%) total PR SD Ovarian cancer 3 1 1 33.3 66.7 Breast cancer 6 1 1 16.6 33.3 total 9 2 2 22.2 44.4 Table 4. Patients with BRCA wild-type breast cancer, ovarian cancer, or other cancers Cancer types Number of patients ORR (%) CBR (%) total PR SD Ovarian cancer 6 2 3 33.3 83.3 Breast cancer 6 1 3 17 66.7 Other cancers 3 0 0 0 0 total 15 3 6 20.0 60.0 Example 2. Clinical study of compound 1 in patients with advanced solid tumors (Phase 1b / 2a).

[0138] This is an open-label, multicenter, phase 1b / 2a basket trial investigating the safety and anticancer activity of compound 1 as monotherapy in patients with solid tumors harboring homologous recombination repair mutations. The primary objective was to assess the safety and tolerability of compound 1 to determine the recommended phase 2a dose in patients with solid tumors harboring homologous recombination repair mutations.

[0139] This study consists of two parts: a phase 1b trial for dose selection of compound 1 to determine the recommended phase 2a dose, and an open-label, non-randomized phase 2a trial to confirm and evaluate the safety and efficacy of the recommended phase 2 dose. Figure 7 illustrates the protocol used in this phase 1b / 2a clinical study.

[0140] The starting doses in the Phase 1b trials ranged from 80 mg to 240 mg (i.e., 80 mg, 120 mg, 160 mg, and 240 mg), with safety and tolerability assessed in Phase 1, and the doses were increased after the safety and tolerability assessments. The following are illustrative results from the four study cohorts: 12 patients with breast cancer (Group 1), 4 patients with ovarian cancer (Group 2), 3 patients with pancreatic cancer (Group 6), and 2 patients with platinum-resistant ovarian cancer (Group 7). Patients in these cohorts had received at least one dose of the compound prior to assessment. Tumor Response Assessment

[0141] The anticancer activity of compound 1 in the relevant patient population was assessed based on objective response rate (ORR = complete response [CR] + partial response [PR]) and clinical benefit rate (CBR = complete response [CR] + partial response [PR] + stable disease [SD]) according to RECIST, version 1.1 (RECIST, v1.1). Furthermore, this study assessed duration of response (DOR), time to response (TTR), time to progression (TTP), progression-free survival (PFS), and overall survival (OS) in patients.

[0142] The ORR and CBR, measured by the best overall response (BOR) assessed during the phase 1b period, are presented in Table 5. Table 5. Results of Group 1 (breast), Group 2 (ovary), Group 6 (pancreas), and Group 7 (platinum-resistant ovary). assessment Group 1 (N=11) Group 2 (N=4) Group 6 (N=3) Group 7 (N=2) Objective response rate*, n (%) 9(81.82) 2 (50.00) 1(33.33) 1 (50.00) Clinical benefit rate*, n (%) 11 (100.00) 3 (75.00) 1(33.33) 1 (50.00) Optimal overall response*, n (%) CR (Complete Reaction) 1 (9.09) 0 0 0 PR (Partial Response) 8(72.73) 2 (50.00) 1(33.33) 1 (50.00) SD (Stable Disorder) 2(18.18) 1 (25.00) 0 0 PD (progressive disease) 0 1 (25.00) 2(66.67) 1 (50.00) NE (Unassessed) 0 0 0 0 *For tumor response, the assessment of tumor response after administration of compound 1 was performed according to RECIST v 1.1.

[0143] As used in Table 5 above, a complete response is defined as the disappearance of all signs of disease; a partial response is defined by the World Health Organization (WHO) as a reduction of more than 50% in the sum of the products of the vertical diameters of all measurable lesions or by RECIST as a reduction of 30% in the sum of the longest diameters of lesions; progressive disease refers to the appearance of any new lesion, i.e., an increase of more than 25% in the sum of the products of the vertical diameters of all measurable lesions according to WHO, or an increase of 20% in the sum of the longest diameters according to RECIST; and stable disease refers to tumor shrinkage or growth that does not meet any of the aforementioned criteria.

[0144] Additionally, waterfall plots showing the change in tumor size relative to baseline after administration of compound 1 to selected patients in groups 1, 2, 6, and 7 are shown in Figures 8 (Group 2 - Ovary), 9 (Group 6 - Pancreas), and 10 (Group 7 - Platinum-resistant Ovary). These plots indicate changes in tumors with mutations in germline BRCA1 (gBRCA1), germline BRCA2 (gBRCA2), germline ATM (gATM), somatic BRCA1 (sBRCA1), somatic BRCA1 (sBRCA1), or somatic ATM (sATM). Example 3. Testing the stability of tablets of samples 1 to 9 relative to different pH values.

[0145] The hydrochloride salt of the compound of the present invention and the excipient were mixed according to the composition listed in Table 6 below and prepared into tablets to prepare uncoated tablets. Each tablet was placed in three times its volume of distilled water to make the tablet concentration 1% w / v (weight / volume) and stirred at 1,200 rpm for five (5) minutes at room temperature using a magnetic stir bar to form an aqueous suspension (referred to as "1% w / v aqueous suspension"). After the suspension was allowed to stand for five (5) minutes, the pH of the suspension was measured at room temperature using an S20 SevenEasy pH meter manufactured by Mettler Toledo. The pH of each tablet prepared in test samples 1 to 9 was measured, and the results are presented in Table 6 below.

[0146] In addition, the stability of each tablet prepared in Examples 1 to 9 was evaluated. Each tablet was stored at 50°C and 75% RH (relative humidity) together with a desiccant (silicone) sealed in an HDPE bottle for 2 weeks and 4 weeks, and then the content (%) of M1 impurity and the content (%) of total impurities in each tablet were determined by HPLC.

[0147] HPLC analysis was performed using a C18 column (4.6 mm × 15 cm; 5 μm) on a detector with UVmax set to or close to 280 nm, using a mixture of purified water and formic acid or a mixture of methanol and formic acid as the mobile phase. The content (%) of M1 impurities and the total impurities (%) were analyzed on the initial date (day 0), week 2, and week 4. The impurity content (%) was calculated as follows: M1 impurity content (%) Total impurity content (%)

[0148] The results are presented in Table 6 below. Table 6. Function Element Test sample 1 2 3 4 5 6 7 8 9 Active ingredients Compound 1 hydrochloride 21.8 21.8 21.8 21.8 21.8 21.8 21.8 21.8 21.8 diluent hydrated lactose 254.2 254.2 254.2 268.9 268.3 266.2 254.2 254.2 254.2 Adhesive Hydroxypropyl cellulose 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 Disintegrant Carboxymethyl cellulose -- 15.0 - - - - - - - Disintegrant Pollacklin Potassium - - - - - - - - 15.0 lubricant colloidal silicon dioxide 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 lubricant magnesium stearate 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 3.0 pH control agent Citric acid - - 15.0 - - - - - - pH control agent fumaric acid - - - 0.3 0.9 3.0 15.0 - - pH control agent maleic acid - - - - - - - 15.0 - Total amount (mg) of a tablet 285.0 300.0 300.0 300.0 300.0 300.0 300.0 300.0 300.0 pH measured in 1% w / v aqueous suspension 6.48 4.31 3.05 4.95 3.95 3.4 2.97 2.6 7.97 M1 impurities (%) Sealed, 50℃ / 75% RH initial 0.01 0.02 0.01 0 ND ND 0.01 0.01 0.02 2 weeks 0.15 0.13 0.04 0.17 0.16 0.11 0.03 0.01 0.58 4 weeks 0.27 0.24 0.07 0.29 0.28 0.17 0.05 0.01 0.86 Total impurities (%) Sealed, 50℃ / 75% RH initial 0.05 0.07 0.06 0.05 0.04 0.04 0.07 0.07 0.09 2 weeks 0.25 0.27 0.15 0.27 0.26 0.21 0.14 0.68 0.74 4 weeks 0.36 0.36 0.2 0.38 0.38 0.36 0.19 1.09 1.08 ※ ND: Not detected

[0149] Pharmaceutical compositions containing hydrochloride salts of the compounds of the present invention with a pH range of about pH 2.6 to pH 6.48 (test samples 1 to 8) exhibit significant stability, as demonstrated by low impurity content after long-term storage. Specifically, optimal stability was found around pH 3.0 (test samples 3 and 7). On the other hand, when the pH is above 7.0, the amount of impurities increases rapidly and stability decreases (test sample 9).

[0150] This confirms that the compounds of the present invention are stable in the range of approximately pH 2.6 to pH 6.48. Example 4. Stability of test samples 2 and tablets 10 to 21 based on different excipients.

[0151] Based on the preparation method described in test samples 1 to 9, the hydrochloride salt of the compound of the present invention and each additive are mixed according to the composition shown in Tables 7 and 8 below and ingots are prepared to prepare uncoated bare ingots.

[0152] The pH of each tablet prepared in test samples 2 and 10 to 21 was measured as described in Example 3, and the results are presented in Tables 7 and 8 below.

[0153] The stability of the tablets prepared from test samples 2 and 10 to 21 containing different excipients was evaluated. After storage in an open state at 50°C and 75% RH for one week, the content (%) of impurities (M1) in each tablet was measured according to the HPLC method described in Example 3. Tables 7 and 8 show the results. Table 7. Test samples 2 and 10 to 17 Function Element Test sample 2 10 11 12 13 14 15 16 17 Active ingredients Compound 1 hydrochloride 21.8 21.8 21.8 21.8 21.8 21.8 21.8 21.8 21.8 diluent hydrated lactose (Flowlac 100) 254.2 254.2 254.2 224.2 251.2 251.2 245.2 245.2 245.2 diluent microcrystalline cellulose (101) - - 30 - - - - - Adhesive HPC EXF 3 3 3 3 - 6 3 3 3 Adhesive Provitamin (K-30) - - - 6 - - - - Disintegrant Cross-linked provitamin - - - - - 9 - - Disintegrant Sodium croscarmellose - - - - - - 9 - Disintegrant Sodium glycolate starch - - - - - - - 9 Disintegrant Carboxymethyl cellulose (CMC; NS-300) 15 - - 15 15 15 15 15 15 Disintegrant CMC-Ca 15 - - - - - - - Disintegrant CMC-Na - 15 - - - - - - lubricant colloidal silicon dioxide 3 3 3 3 3 3 3 3 3 lubricant magnesium stearate 3 3 3 3 3 3 3 3 3 Total amount (mg) of a tablet 300 300 300 300 300 300 300 300 300 pH measured in 1% w / v aqueous suspension 4.31 5.96 7.04 4.56 4.44 4.58 4.8 5.74 5.27 M1 impurities (%) Open, 50℃ / 75% RH initial BRT BRT BRT BRT BRT BRT BRT BRT BRT 1 week BRT 0.18 0.68 0.07 BRT BRT 0.08 BRT BRT ※ BRT (below the reporting limit)

[0154] The above results confirm that tablets of test samples 2, 10, and 12 to 17 exhibited excellent stability, while tablet of test sample 11 showed lower stability. In test sample 11, CMC-Na was used as a disintegrant, and it was determined that this component increased the pH of the entire tablet, thereby reducing the stability of the active ingredient. Table 8. Test samples 18 to 21 Function Element Test sample 18 19 20 twenty one Active ingredients Compound 1 hydrochloride 21.8 21.8 21.8 21.8 diluent Flowlac 100 (Hydrated Lactose) 275.2 275.2 275.2 275.2 Adhesive Hydroxypropyl cellulose (HPC EXF) 3 3 3 3 Disintegrant Low-substituted hydroxypropyl cellulose (11) 15.15 Disintegrant corn starch 15.15 Disintegrant Pollacklin Potassium 15.15 Disintegrant Carboxymethyl cellulose (CMC, NS-300) 15.15 lubricant magnesium stearate 3 3 3 3 Total amount (mg) of a tablet 318.15 318.15 318.15 318.15 pH measured in 1% w / v aqueous suspension 6.70 6.74 7.23 4.86 M1 impurities (%) Open, 50℃ / 75% RH initial ND BRT BRT BRT 1 week 0.34 0.40 0.50 BRT ※ ND: Not detected

[0155] Test sample 21 provides the best stability results. Although test samples 18 to 20 are less stable than test sample 21 with increased M1 impurities, test samples 18 and 19 (and 21) still exhibit M1 impurities below the required amount (less than 0.50%). Test sample 20 is an exception. Example 5. Stability of tablets based on test samples 22 to 33 with different excipients

[0156] Based on the preparation methods described in test samples 1 to 9, the hydrochloride salt of the compound of the present invention and each additive are mixed and ingots are prepared according to the composition shown in Table 9 below to prepare uncoated bare ingots.

[0157] The pH of each tablet prepared in test samples 22 to 33 was measured as described in Example 3, and the results are presented in Table 9 below.

[0158] The stability of the tablets prepared from test samples 22 to 33 containing different excipients was evaluated. After storing each tablet in a closed state at 50°C for 2 weeks and 4 weeks without controlling RH, the content (%) of M1 impurity and the total impurity content (%) in each tablet were measured according to the HPLC method described in Example 3. Table 9 shows the results. Table 9. Test samples 22 to 33. Function Element Test sample twenty two twenty three twenty four 25 26 27 28 29 30 31 32 33 Active ingredients Compound 1 hydrochloride 21.8 21.8 21.8 21.8 21.8 21.8 21.8 21.8 21.8 21.8 21.8 21.8 diluent hydrated lactose (Flowlac 100) 269.2 254.2 254.2 239.2 254.2 239.2 254.2 239.2 254.2 239.2 254.2 239.2 Adhesive HPC EXF 3 3 3 3 3 3 3 3 3 3 3 3 Disintegrant Low-substituted hydroxypropyl cellulose - - 15 15 - - - - - - - - Disintegrant corn starch - - - - 15 15 - - - - - - Disintegrant Pollacklin Potassium - - - - - - 15 15 - - - - - CMC-Ca - - - - - - - - 15 15 - - - CMC-Na - - - - - - - - - - 15 15 lubricant colloidal silicon dioxide 3 3 3 3 3 3 3 3 3 3 3 3 lubricant magnesium stearate 3 3 3 3 3 3 3 3 3 3 3 3 pH control agent fumaric acid - 15 - 15 - 15 - 15 - 15 - 15 - Total amount (mg) of a tablet 300 300 300 300 300 300 300 300 300 300 300 300 pH measured in 1% w / v aqueous suspension 6.55 2.85 6.75 2.81 6.76 2.81 7.79 3.23 5.57 2.99 7.0 3.06 M1 impurities (%) Sealed, 50℃ initial ND ND ND ND ND ND ND ND ND ND ND ND 2 weeks 0.29 0.02 0.46 0.05 0.60 0.04 0.83 0.24 0.28 0.05 0.68 0.04 4 weeks 0.35 0.04 0.64 0.06 0.86 0.07 1.09 0.35 0.48 0.09 1.01 0.10 Total impurities (%) Sealed, 50℃ initial 0.05 0.06 0.08 0.06 0.05 0.05 0.04 0.04 0.06 0.06 0.05 0.05 2 weeks 0.42 0.12 0.57 0.24 0.69 0.23 0.98 0.44 0.36 0.34 0.81 0.27 4 weeks 0.53 0.16 0.8 0.35 1.04 0.41 1.49 0.77 0.62 0.56 1.28 0.47 ※ ND: Not detected

[0159] The above results demonstrate the improved stability of the compositions of the present invention at pH values ​​from 2.8 to 6.55. In fact, all test samples except test sample 28 were stable. Specifically, the test samples that used pH control agents to bring the pH to approximately 3 (i.e., test samples 23, 25, 27, 29, 31, and 33) exhibited significantly improved stability. Example 6. Stability of film-coated tablets of test samples 34 to 36 based on different excipients.

[0160] Based on the preparation method described in test samples 1 to 9, the hydrochloride salt of the compound of the present invention and each additive are mixed according to the composition shown in Table 10 below, and ingots are prepared to prepare ingots (bare ingots), and coated with Opadry® to prepare coated ingots of test samples 34 to 36.

[0161] The stability of each tablet prepared in test samples 34 to 36 was evaluated. Each tablet was stored in an Alu-Alu package at 40°C and 75% RH in a sealed state for 3 months and 6 months, and subsequently, the M1 impurity content (%) and total impurity content (%) in each tablet were determined by HPLC according to Example 3. Table 10 shows the results. Table 10. Test samples 34 to 36. Test sample 34 35 36 Amount of Compound 1 10 mg 20 mg 40 mg Element mg / tablet % w / w mg / tablet % w / w mg / tablet % w / w core Compound 1 hydrochloride 10.9 7.27 21.8 7.27 43.6 7.27 hydrated lactose 127.1 84.73 254.2 84.73 508.4 84.73 Hydroxypropyl cellulose 1.5 1 3 1 6 1 Carboxymethyl cellulose 7.5 5 15 5 30 5 colloidal silicon dioxide 1.5 1 3 1 6 1 magnesium stearate 1.5 1 3 1 6 1 Total amount of core 150 100 300 100 600 100 Tablet Coating Opadry ® white, 03B28796 5 3.33 10 3.33 20 3.33 Purified water 45 - 90 - 180 - Total amount of coated tablets 155 310 620 pH measured in 1% w / v aqueous suspension 4.77 4.74 4.78 M1 impurities (%) Alu-Alu packaging, 40℃ / 75% RH initial 0 0 0 3 months 0.2 0.2 0.1 6 months 0.2 0.2 0.3

[0162] When the composition has a pH in the range of about 2.6 to about 6.74 when measured in a 1% w / v aqueous suspension prepared according to Example 3, the stability of the film-coated pharmaceutical composition comprising the active pharmaceutical ingredient of Formula 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient is confirmed. Equivalents and Scope

[0163] In the claims, unless indicated to the contrary or otherwise obvious from the context, articles such as "a / an" and "the" may mean one or more. Unless indicated to the contrary or otherwise obvious from the context, the claims or descriptions including "or" among one or more members of the group are deemed satisfied if one, more than one, or all of the group members are present in, used in, or otherwise related to the given product or method. The invention includes embodiments in which exactly one member of the group is present in, used in, or otherwise related to the given product or method. The invention includes embodiments in which more than one or all of the group members are present in, used in, or otherwise related to the given product or method.

[0164] Furthermore, this invention covers all variations, combinations, and arrangements of limitations, elements, clauses, and descriptive terms derived from one or more of the listed technical solutions when introduced into another technical solution. For example, any technical solution dependent on another technical solution may be modified to include one or more limitations visible in any other technical solution dependent on the same basic technical solution. Where elements are presented in list form, such as in Markush group format, subgroups of elements are also disclosed, and any element may be removed from that group. It should be understood that, generally, when the invention or a purported embodiment is referred to as comprising a particular element and / or feature, certain embodiments of the invention or a purported embodiment consist of or are substantially composed of such elements and / or features. For simplicity, such embodiments have not been specifically described in words herein. It should also be noted that the terms "comprising" and "containing" are intended to be open-ended and allow for the inclusion of additional elements or steps. When a scope is given, endpoints are included. Furthermore, unless otherwise indicated or otherwise apparent from the context and understanding of someone generally skilled in the art, values ​​expressed as ranges may take any particular value or subrange within the stated range in different embodiments of the invention, up to one-tenth of the unit of the lower limit of the range unless otherwise expressly specified by the context.

[0165] References to various granted patents, published patent applications, journal articles, and other publications are incorporated herein by reference. In the event of any conflict between any incorporated reference and this specification, this specification shall prevail. Furthermore, specific embodiments of the invention that fall under the prior art may be explicitly excluded from any one or more of the claims. Since such embodiments are considered to be known to those skilled in the art, they may be excluded, even if such exclusion is not explicitly stated herein. Any specific embodiment of the invention may be excluded from any technical solution for any reason, whether or not related to the existence of prior art.

[0166] Those skilled in the art will recognize or be able to determine many equivalents of the particular embodiments described herein using only conventional experiments. The scope of the embodiments of the invention described herein is not intended to be limited to the foregoing description, but is actually set forth in the appended claims. Those skilled in the art will understand that various changes and modifications can be made to this specification without departing from the spirit or scope of the invention as defined in the following claims. [Simplified Explanation of the Diagram]

[0010] Figure 1 illustrates the design of an exemplary phase 1 clinical trial for the treatment of individuals with advanced cancerous solid tumors.

[0011] Figure 2 illustrates the pharmacokinetics of compound 1.

[0012] Figure 3 illustrates the objective response rates of a series of concentrations of the compound of formula 1 used in a phase 1 clinical trial.

[0013] Figure 4 illustrates the clinical efficacy of a series of concentrations of the compound of formula 1 used in a phase 1 clinical trial.

[0014] Figure 5 illustrates the results of different concentrations of compound 1 in patients with BRCA-mutated breast or ovarian cancer in a phase 1 clinical trial.

[0015] Figure 6 illustrates the results of different concentrations of compound 1 in patients with BRCA wild-type breast cancer, ovarian cancer or other cancers in a phase 1 clinical trial.

[0016] Figure 7 illustrates an exemplary phase 1b / 2a clinical trial study design for treating individuals with cancer, such as breast cancer, ovarian cancer, or pancreatic cancer, using compound 1.

[0017] Figure 8 illustrates a waterfall plot of tumor size changes in ovarian cancer patients who received a specific dose of compound of formula 1, wherein the tumors studied had specific BRCA1 or BRCA2 mutations.

[0018] Figure 9 illustrates a waterfall plot of changes in tumor size in pancreatic cancer patients who received a specific dose of compound of formula 1, wherein the tumors studied had specific BRCA2 or ATM mutations.

[0019] Figure 10 illustrates a waterfall plot of tumor size changes in patients with platinum-resistant ovarian cancer who received a specific dose of compound of formula 1, wherein the tumors studied had a specific BRCA2 mutation.

Claims

1. Use of a compound of formula I or a pharmaceutically acceptable salt thereof: Formula I, which is used to prepare a pharmaceutical product for treating cancers in an individual with BRCA1 mutations, BRCA2 mutations, ATM mutations or homologous recombination repair mutations, wherein the pharmaceutical product is formulated for administration of 40 mg to 240 mg of the compound to the individual once daily.

2. As requested in claim 1, wherein the cancer is ovarian cancer, breast cancer, or pancreatic cancer.

3. As requested in claim 2, wherein the cancer is platinum-resistant ovarian cancer.

4. Use of a pharmaceutical composition comprising: (i) 40 mg to 240 mg of a compound of formula I: Formula I or a pharmaceutically acceptable salt thereof; and (ii) at least one pharmaceutically acceptable excipient, the use being for the preparation of a pharmaceutical product for treating cancer in an individual having a BRCA1 mutation, BRCA2 mutation, ATM mutation or homologous recombination repair mutation, wherein the pharmaceutical product is formulated for administration to the individual once daily.

5. As claimed in claim 4, wherein the pH of the composition, as measured in a 1% w / v aqueous suspension, is 2.6 to 6.

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6. As requested in claim 4, wherein the cancer is ovarian cancer, breast cancer, or pancreatic cancer.

7. As requested in claim 6, wherein the cancer is platinum-resistant ovarian cancer.

8. The use as claimed in any of claims 1 to 7, wherein the pharmaceutical product is formulated for administering to the individual once daily in doses of 40 mg, 80 mg, 120 mg, 160 mg or 240 mg of the compound or a pharmaceutically acceptable salt thereof.

9. For any of the uses of claims 1 to 7, wherein the cancer has a BRCA1 mutation.

10. For any of the uses of claims 1 to 7, wherein the cancer has a BRCA2 mutation.

11. For the purposes of any of claims 1 to 7, wherein the cancer has an ATM mutation.

12. As used in any of claims 1 to 7, wherein the cancer has a homologous recombination repair mutation.

13. Use of a compound of formula I or a pharmaceutically acceptable salt thereof: Formula I, which is used to prepare a pharmaceutical product for clinical benefit to an individual suffering from ovarian cancer, wherein the pharmaceutical product is formulated for administration of 40 mg to 240 mg of the compound to the individual once daily.

14. As claimed in claim 13, wherein the ovarian cancer is platinum-resistant ovarian cancer.

15. Use of a compound of formula I or a pharmaceutically acceptable salt thereof: Formula I, which is used to prepare a pharmaceutical product for clinical benefit to an individual suffering from breast cancer, wherein the pharmaceutical product is formulated for administration of 40 mg to 240 mg of the compound to the individual once daily.

16. Use of a compound of formula I or a pharmaceutically acceptable salt thereof: Formula I, which is used to prepare a pharmaceutical product for clinical benefit to an individual suffering from pancreatic cancer, wherein the pharmaceutical product is formulated for administration of 40 mg to 240 mg of the compound to the individual once daily.

17. The use as claimed in any of claims 13 to 16, wherein the pharmaceutical product is formulated for administering to the individual once daily in the form of 40 mg, 80 mg, 120 mg, 160 mg or 240 mg of the compound or a pharmaceutically acceptable salt thereof.

18. As claimed in any of claims 13 to 16, wherein the cancer has a BRCA1 mutation.

19. As claimed in any of claims 13 to 16, wherein the cancer has a BRCA2 mutation.

20. As claimed in any of claims 13 to 16, wherein the cancer has an ATM mutation.

21. As claimed in any of claims 13 to 16, wherein the cancer has a homologous recombination repair mutation.

22. The use of any one of claims 13 to 16, wherein the pharmaceutical product further comprises a pharmaceutically acceptable excipient, and wherein the pH of the pharmaceutical product, as measured in a 1% w / v aqueous suspension, is 2.6 to 6.

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23. Use of a compound of formula I or a pharmaceutically acceptable salt thereof: Formula I, which is used to prepare a pharmaceutical product for treating cancers in an individual with BRCA1 mutations, BRCA2 mutations, ATM mutations or homologous recombination repair mutations, wherein the pharmaceutical product is formulated for administration to the individual once daily at a dose of 40 mg to 240 mg of the compound, wherein the cancer is ovarian cancer, breast cancer, pancreatic cancer or platinum-resistant ovarian cancer.

24. As claimed in claim 23, wherein the cancer is ovarian cancer, breast cancer, pancreatic cancer, or platinum-resistant ovarian cancer.

25. As claimed in claim 23, wherein the pharmaceutical product is formulated for administering to the individual once daily in doses of 40 mg, 80 mg, 120 mg, 160 mg or 240 mg of the compound or a pharmaceutically acceptable salt thereof.

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