Combination Therapy for Treating Cancer

Abstract

The present disclosure relates generally to therapeutic combinations and corresponding methods of treatment, pharmaceutical compositions and kits.

Description

[Background technology]

[0001] Although great advances have been made in the treatment of cancer, patients continue to need new, effective therapies.

[0002] AZD5305 (5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide) is a small molecule drug that acts by selectively inhibiting and trapping PARP1 at sites of DNA single strand breaks (SSBs). This prevents DNA repair and leads to the generation of more damaging DNA double strand breaks (DSBs) during DNA replication when the DNA replication machinery collides with the PARP1-DNA noncovalent complex. In situations where accurate DNA repair pathways are active, such as cells proficient in homologous recombination repair (HRR), DSBs are accurately repaired. In contrast, in cells with defective repair pathways, such as those harboring pathogenic mutations in the BRCA genes, treatment with AZD5305 leads to the selective accumulation of genomic instability, ultimately resulting in the selective death of cancer cells while sparing normal cells.

[0003] Platinum chemotherapy agents are drugs used to treat cancer, often in the first-line setting. Examples of platinum chemotherapy agents include cisplatin, oxaliplatin, and carboplatin. Summary of the Invention [Means for solving the problem]

[0004] In some embodiments, a method of treating cancer in a human subject in need thereof is disclosed, comprising administering to the human subject a first amount of AZD5305 or a pharmaceutically acceptable salt thereof, and a second amount of a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount.

[0005] In some embodiments, the cancer is ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer such as stomach cancer and colon cancer, or lung cancer.

[0006] In some embodiments, the cancer is a homologous recombination repair deficient (HRD) cancer. For example, whether a cancer is HRD positive can be determined by Myriad Genetics' myChoice® HRD or myChoice® HRD Plus assay.

[0007] In certain embodiments, the cancer cells comprise an HRD gene mutation selected from BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L gene mutations. In certain embodiments, the cancer cells comprise a BRCA1, BRCA2, and / or ATM gene mutation. In certain embodiments, the cancer cells comprise a BRCA1 and / or BRCA2 gene mutation. For example, in certain embodiments, the cancer cells comprise a tBRCA gene mutation.

[0008] In certain embodiments of the disclosed methods, the cancer comprises a homologous recombination repair deficiency (HRD) positive state defined by a pathogenic or suspected pathogenic BRCA mutation and / or genomic instability.

[0009] In certain embodiments of the methods of the present disclosure, the cancer is ovarian cancer or breast cancer. In certain embodiments of the methods of the present disclosure, the cancer is ovarian cancer. In certain embodiments, the cancer is advanced epithelial ovarian cancer. In certain embodiments, the cancer is high-grade serous ovarian cancer. In certain embodiments, the cancer is high-grade endometrioid ovarian cancer. In certain embodiments, the cancer is epithelial ovarian cancer containing a gBRCA1 or gBRCA2 mutation. In certain embodiments of the methods of the present disclosure, the cancer is fallopian tube cancer. In certain embodiments of the methods of the present disclosure, the cancer is primary peritoneal cancer.

[0010] In certain embodiments, the cancer is ovarian cancer (eg, advanced epithelial ovarian cancer), fallopian tube cancer, or primary peritoneal cancer.

[0011] In certain embodiments, the cancer is ovarian cancer (e.g., advanced epithelial ovarian cancer), fallopian tube cancer, or primary peritoneal cancer, and the cancer has a homologous recombination repair deficiency (HRD) positive status as defined by a pathogenic or suspected pathogenic BRCA mutation and / or genomic instability.

[0012] In certain embodiments, the cancer is breast cancer, hi certain embodiments, the cancer is triple-negative breast cancer.

[0013] In some embodiments, the cancer is platinum-resistant.

[0014] In some embodiments, a kit is disclosed that includes a first pharmaceutical composition comprising AZD5305 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, a second pharmaceutical composition comprising a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof, and instructions for use. [Brief explanation of the drawings]

[0015] [Figure 1] Figure 1 shows the weight change in mice from a PDX model (HBCx-9) treated with AZD5305 monotherapy, carboplatin monotherapy, and combination therapy. [Figure 2] Figure 1 shows the antitumor activity of AZD5305 in combination with carboplatin in a PDX model (HBCx-9). [Figure 3] Figure 1 shows the antitumor activity of AZD5305 in combination with carboplatin in a PDX model (HBCx-9). Individual animal data are shown. [Figure 4] 1 shows the X-ray powder diffraction of AZD5305 Form A. [Figure 5] Figure 1 shows the weight change in mice in a xenograft model (SUM149PT) treated with AZD5305 monotherapy, carboplatin monotherapy, and combination therapy. [Figure 6] Figure 1 shows the antitumor activity of AZD5305 in combination with carboplatin in a xenograft model (SUM149PT). [Figure 7] Figure 1 shows the weight change in mice from a PDX model (HBCx-9) treated with AZD5305 monotherapy, carboplatin monotherapy, and combination therapy. [Figure 8] Figure 1 shows the antitumor activity of AZD5305 in combination with carboplatin in a PDX model (HBCx-9). [Figure 9] Figure 1 shows the antitumor activity of AZD5305 in combination with carboplatin after cessation of treatment in PDX model (HBCx-9) treated with AZD5305 monotherapy, carboplatin monotherapy, and combination therapy. DETAILED DESCRIPTION OF THE INVENTION

[0016] In some embodiments, methods of treating cancer with combination therapy of AZD5305 and a platinum chemotherapeutic agent are disclosed. In some embodiments, the method comprises administering to a subject in need thereof a first amount of AZD5305 or a pharmaceutically acceptable salt thereof and a second amount of the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together comprise a therapeutically effective amount. In some embodiments, the platinum chemotherapeutic agent comprises one of carboplatin, cisplatin, and oxaliplatin. In some embodiments, the platinum chemotherapeutic agent comprises carboplatin. In one embodiment, the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof is administered first, and AZD5305 or a pharmaceutically acceptable salt thereof is administered second. In one embodiment, AZD5305 or a pharmaceutically acceptable salt thereof is administered first, and the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof is administered second.

[0017] The term "AZD5305" refers to the compound having the chemical name 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide and the structure shown below. [ka]

[0018] Preparations of AZD5305 are disclosed herein (see Example 1). In some embodiments, the free base of AZD5305 is administered to a subject. In some embodiments, a pharmaceutically acceptable salt of AZD5305 is administered to a subject. In some embodiments, crystalline AZD5305 is administered to a subject. In some embodiments, crystalline Form A of AZD5305 is administered to a subject.

[0019] The term "platinum-containing chemotherapeutic agent" includes drugs containing the metal platinum, such as cisplatin, carboplatin, and oxaliplatin. In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof and a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered separately, sequentially, or simultaneously. In one embodiment, the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof is administered first, and AZD5305 or a pharmaceutically acceptable salt thereof is administered second. In one embodiment, AZD5305 or a pharmaceutically acceptable salt thereof is administered first, and the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof is administered second.

[0020] In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof and olaparib or a pharmaceutically acceptable salt thereof are administered separately, sequentially or simultaneously in a treatment cycle.

[0021] A "cycle," "treatment cycle," or "dosing schedule," as used herein, refers to a period of combination therapy that is repeated on a regular schedule. For example, treatment may be for 1 week, 2 weeks, or 3 weeks, with AZD5305 and the platinum chemotherapeutic agent being administered in a coordinated manner. In some embodiments, a treatment cycle is from about 1 week to about 3 months. In some embodiments, a treatment cycle is from about 5 days to about 1 month. In some embodiments, a treatment cycle is from about 1 week to about 3 weeks. In some embodiments, a treatment cycle is from about 1 week, about 10 days, about 2 weeks, about 3 weeks, about 4 weeks, about 2 months, or about 3 months.

[0022] In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof and a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered to a human subject in one or more treatment cycles, e.g., a course of treatment. A "course of treatment" includes multiple treatment cycles, which may be repeated on a regular schedule or adjusted as a tapering schedule as the patient's disease progression is monitored. For example, a patient's treatment cycles may have longer treatment periods and / or shorter rest periods at the beginning of the treatment course (e.g., when the patient is first diagnosed), and the length of a single treatment cycle may be increased by lengthening the rest periods as the cancer enters remission. The duration of treatment and rest in a treatment cycle, the number of treatment cycles, and the length of the treatment course can be determined and adjusted throughout the treatment course by one skilled in the art based on the patient's disease progression, treatment tolerance, and prognosis. In some embodiments, the method includes 1 to 10 treatment cycles. In some embodiments, the method includes 2 to 8 treatment cycles.

[0023] In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is administered orally. In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is in capsule dosage form. In some embodiments, AZD5305 or a pharmaceutically acceptable salt thereof is in tablet dosage form.

[0024] The terms "treat," "treating," and "treatment" include reducing or inhibiting PARP or cancer-associated enzyme or protein activity in a subject, ameliorating one or more symptoms of cancer in a subject, or slowing or delaying the progression of cancer in a subject. The terms "treat," "treating," and "treatment" also include reducing or inhibiting tumor growth or cancerous cell proliferation in a subject.

[0025] The terms "inhibit," "inhibition," or "inhibiting" include a decrease in the baseline activity of a biological activity or process.

[0026] The term "cancer" includes, but is not limited to, diseases caused by the uncontrolled division of abnormal cells in parts of the body. In some embodiments, the cancer includes cancers amenable to treatment with PARP inhibitors (e.g., AZD5305). In some embodiments, the cancer is ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer. In some embodiments, the cancer is blood cancer, gastrointestinal cancer such as gastric cancer and colon cancer, or lung cancer. In some embodiments, the cancer is recurrent or refractory cancer. In some embodiments, the cancer is platinum-resistant cancer.

[0027] The term "pharmaceutical composition" includes compositions comprising an active ingredient and a pharmaceutically acceptable excipient, carrier, or diluent, wherein the active ingredient is AZD5305 or a pharmaceutically acceptable salt thereof, or a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof.

[0028] As used herein, unless otherwise indicated, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms that, within the scope of sound medical judgment, are suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable risk-benefit ratio.

[0029] The term "pharmaceutically acceptable excipient, carrier, or diluent" includes compounds, materials, compositions, and / or formulations that are suitable for use in contact with the tissues of humans and animals without undue toxicity, irritation, allergic response, or other problems or complications, as ascertained by one of ordinary skill in the art, within the scope of sound medical judgment. In some embodiments, the pharmaceutical composition is in a solid dosage form, such as a capsule, tablet, granule, powder, sachet, etc. In some embodiments, the pharmaceutical composition is in the form of an injectable sterile solution in one or more aqueous or non-aqueous, non-toxic, parenterally acceptable buffer systems, diluents, solubilizers, cosolvents, or carriers. The sterile injectable preparation may also be a sterile injectable aqueous or oily suspension or a suspension in a non-aqueous diluent, carrier, or cosolvent, which may be formulated according to known procedures using one or more suitable dispersing or wetting agents and suspending agents. The pharmaceutical composition may be a solution for IV bolus / infusion or a lyophilized system (alone or with excipients) for reconstitution with a buffer system, with or without other excipients. The lyophilized freeze-dried material can be prepared from non-aqueous or aqueous solvents. The dosage form can also be a concentrate for further dilution for subsequent infusion.

[0030] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, e.g., a human. In some embodiments, the subject is afflicted with cancer, such as ovarian cancer, breast cancer, pancreatic cancer, and prostate cancer. In some embodiments, the subject is afflicted with cancer, e.g., a hematological cancer, a gastrointestinal cancer, such as gastric cancer and colon cancer, or lung cancer. In some embodiments, the subject is afflicted with ovarian cancer or breast cancer. In some embodiments, the subject is afflicted with recurrent or refractory ovarian cancer. In some embodiments, the subject is afflicted with recurrent or refractory breast cancer. In some embodiments, the subject is afflicted with cancer and is untreated (e.g., has not received any treatment for cancer). In some embodiments, the subject is afflicted with cancer and is platinum-resistant. Platinum-resistant disease is defined by progression within six months of the last platinum-based regimen. Platinum-refractory disease is defined by failure to achieve at least a partial response during a platinum-containing regimen. Platinum-based regimens include drugs containing the metal platinum, such as cisplatin and carboplatin.

[0031] The term "therapeutically effective amount" includes an amount of AZD5305 and an amount of a platinum chemotherapeutic agent that, together, will elicit a biological or medical response in a subject, such as reducing or inhibiting PARP or cancer-associated enzyme or protein activity; ameliorating symptoms of cancer; or slowing or delaying the progression of cancer. In some embodiments, the term "therapeutically effective amount" includes an amount of AZD5305 and an amount of a platinum chemotherapeutic agent that, together, are effective to at least partially reduce, inhibit, and / or ameliorate cancer, or inhibit PARP, and / or reduce or inhibit tumor growth or cancerous cell proliferation in a subject. In some embodiments, the term "therapeutically effective amount" includes an amount of AZD5305 and an amount of a platinum chemotherapeutic agent that, together, are effective to at least partially reduce or inhibit tumor growth or cancerous cell proliferation in a subject.

[0032] In some embodiments, a kit is disclosed that includes a first pharmaceutical composition comprising AZD5305 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising carboplatin or a pharmaceutically acceptable salt thereof; and instructions for using the first and second pharmaceutical compositions in combination. In some embodiments, the first pharmaceutical composition comprises a first amount of AZD5305 or a pharmaceutically acceptable salt thereof, and the second pharmaceutical composition comprises a second amount of a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the first and second amounts together comprise a therapeutically effective amount. [Example]

[0033] The combination therapies disclosed herein will now be further described with reference to the following non-limiting examples.

[0034] Example 1 Preparation of AZD5305 General experimental conditions 1 H NMR spectra were obtained using a Bruker 300 MHz, 400 MHz or 500 MHz spectrometer at 27° C. unless otherwise stated. Chemical shifts are expressed in parts per million (ppm, δ units) and are relative to residual monomolecules of the solvent. 1 The H isotopologues are used as the reference (CHCl3: 7.24 ppm; CHDCl2: 5.32 ppm; CD3S(=O)CD2H: 2.49 ppm). Coupling constants are given in units of hertz (Hz). Splitting patterns indicate apparent multiplicity and are designated as s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), and br s (broad singlet). LC-MS was performed using a Waters UPLC equipped with a Waters SQD mass spectrometer or a Shimadzu LC-20AD LC-20XR LC-30AD equipped with a Shimadzu 2020 mass spectrometer. The reported molecular ion corresponds to [M+H]+ unless otherwise noted. For molecules with multiple isotopic patterns (e.g., Br, Cl), the reported value is that obtained for the lowest isotopic mass unless otherwise noted.

[0035] Flash chromatography was performed using normal phase silica FLASH+™ (40M, 25M, or 12M) or SNAP™ KP-Sil cartridges (340, 100, 50, or 10) on a Biotage™ SP1™ purification system, an ISCO CombiFlash™ Rf, or a Thermo Fisher Gilson system, using straight phase or standard flash chromatography on an Agela Flash Column silica-CS column with a C18 flash column. Generally, all solvents used were commercially available analytical grade. Anhydrous solvents were routinely used for reactions. The phase separator used in the examples was an ISOLUTE™ Phase Separator column. The intermediates and examples named below were named using ACD / Name 12.01 from Advanced Chemistry Development, Inc. (ACD / Labs). Starting materials were obtained from commercial sources or prepared by literature routes.

[0036] XRPD analysis was performed using a Bruker D8 diffractometer commercially available from Bruker AXS Inc™ (Madison, Wisconsin). XRPD spectra were obtained by mounting a sample (approximately 10 mg) of the material to be analyzed on a silicon single crystal wafer mount (e.g., a Bruker silicon zero-background X-ray diffraction sample holder) and spreading the sample into a thin layer using a microscope slide. The sample was spun at 30 revolutions per minute (to improve counting statistics) and irradiated with X-rays generated by a long copper microfocus tube operated at 40 kV and 40 mA at a wavelength of 1.5406 angstroms (i.e., approximately 1.54 angstroms). Samples were exposed in theta-theta mode over a range of 5 degrees to 40 degrees 2-theta, with 1 second exposure per 0.02 degrees 2-theta increment (continuous scan mode). Run time was approximately 15 minutes on the D8.

[0037] XRPD 2θ values ​​can vary within reasonable limits, e.g., ±0.2°, and XRPD intensities can vary for a variety of reasons, including preferred orientation, when measured on essentially the same crystalline form. The principles of XRPD are described in publications such as Giacovazzo, C. et al. (1995), Fundamentals of Crystallography, Oxford University Press; Jenkins, R. and Snyder, RL (1996), Introduction to X-Ray Powder Diffractometry, John Wiley & Sons, New York; and Klug, H.P. & Alexander, L.E. (1974), X-ray Diffraction Procedures, John Wiley and Sons, New York.

[0038] The following abbreviations are used: aq = aqueous; CHCl = dichloromethane; DCM = dichloromethane; DDQ = 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; DIPEA = N,N'-diisopropylethylamine; DMSO = dimethyl sulfoxide; DMSO-d = deuterated dimethyl sulfoxide; ESI = electrospray ionization; MeCN or CHCN = acetonitrile; NMR = nuclear magnetic resonance; Pd / C = palladium on carbon; TFA = trifluoroacetic acid; THF = tetrahydrofuran; TLC = thin layer chromatography; HCl = hydrochloric acid; HBr = hydrobromic acid; CsCO = cesium carbonate; MgSO = magnesium sulfate; NaHCO = sodium bicarbonate; SOCl = thionyl chloride; NHCl = ammonium chloride; NaSO = sodium sulfate; H = hydrogen gas.

[0039] chemical synthesis [ka] Intermediate 2: Ethyl 6-formyl-5-nitro-pyridine-3-carboxylate A mixture of ethyl 6-methyl-5-nitro-pyridine-3-carboxylate (Intermediate 1, 10 g, 47.58 mmol) and selenium dioxide (7.92 g, 71.36 mmol) in 1,4-dioxane (50 mL) was stirred at 110 °C for 20 h. The reaction mixture was cooled to room temperature and filtered through a pad of celite, washing with ethyl acetate. The combined filtrate was concentrated and the residue was purified by flash silica chromatography, eluting with a gradient of 0 to 70% ethyl acetate in hexanes. The product fractions were concentrated under reduced pressure to give ethyl 6-formyl-5-nitro-pyridine-3-carboxylate (Intermediate 2, 9.70 g, 91%) as a brown oil. 1H NMR (500MHz, chloroform-d): 1.48 (3H, t), 4.54 (2H, q), 8.81 (1H, d), 9.51 (1H, d), 10.32 (1H, s); m / z (ES + )[M] + =224.

[0040] Intermediate 3: Ethyl 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitro-pyridine-3-carboxylate (E / Z isomer mixture) To a stirred solution of sodium hydride (9.63 g, 240.89 mmol) (60% in mineral oil) in anhydrous THF (100 mL) was added ethyl 2-(diethoxyphosphoryl)butanoate (60.8 g, 240.89 mmol) dropwise using an addition funnel at 0 °C to give a gray mixture. The resulting mixture was stirred at 0 °C for 10 minutes, warmed to room temperature over 10 minutes, and stirred at 40 °C for 5 minutes. The reaction mixture was cooled to -78 °C, and then a solution of ethyl 6-formyl-5-nitro-pyridine-3-carboxylate (Intermediate 2, 22.5 g, 100.37 mmol) in 100 mL of THF was slowly added to the cooled reaction mixture. The mixture was quenched with saturated NH Cl solution and extracted with ethyl acetate. The combined organic layers were dried over sodium Na SO , filtered, and concentrated to give the crude product. The resulting residue was purified by flash silica chromatography, eluting with a gradient of 0 to 50% ethyl acetate in hexanes. The product fractions were concentrated under reduced pressure to give ethyl 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitro-pyridine-3-carboxylate (Intermediate 3, 24.30 g, 75%) as a yellow oil (1:1 and mixture of E / Z isomers). 1H NMR(500MHz,chloroform-d)1.13(3H,t),1.18(3H,t),1.23(3H,t),1.37(3H,t),1.45(6H,q),2.57(2H,qd),2.66(2H,q),4.1 1-4.24(2H,m),4.32(2H,q),4.45-4.56(4H,m),7.08(1H,s),7.85(1H,s),8.86(2H,dd),9.26(1H,d),9.43(1H,d);m / z(ES + )[M] + =322

[0041] Intermediate 4: Ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate A mixture of ethyl 6-[(E)-2-ethoxycarbonylbut-1-enyl]-5-nitro-pyridine-3-carboxylate (1:1 mixture of E / Z isomers) (Intermediate 3, 3.75 g, 11.63 mmol), Pd / C (1.857 g, 1.75 mmol) (10%) in ethanol (30 mL) was degassed and charged with H (balloon), and the reaction was stirred under an H atmosphere at room temperature overnight. The mixture was filtered through a bed of celite, and the bed was washed with ethanol. After concentration, 4 M HCl in dioxane (15 mL) was added to the resulting residue, and the mixture was stirred at room temperature for 30 min. The mixture was diluted with ether, and the solid was filtered off, washed with diethyl ether, and dried under vacuum to give ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate (Intermediate 4, 2.260 g, 78%) as a white solid. 1H NMR (500 MHz, DMSO-d6) 0.94 (3H, t), 1.33 (3H, t), 1.41-1.51 (1H, m), 1.69-1.81 (1H, m), 2.41-2.48 (1H, m), 2.94 (1H, dd), 3.20 (1H, dd), 4.35 (2H, t), 7.67 (1H, d), 8.61 (1H, d), 10.32 (1H, s); m / z (ES) + ) [M+H] + =249.

[0042] Intermediate 5: Ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate Ethyl 7-ethyl-6-oxo-7,8-dihydro-5H-1,5-naphthyridine-3-carboxylate (Intermediate 4, 2.26 g, 9.10 mmol) was dissolved in 1,4-dioxane (40 mL), DDQ (2.273 g, 10.01 mmol) was added, and the mixture was stirred under reflux for 3 h. The solvent was removed under reduced pressure, saturated NaHCO3 solution was added, and the residue was stirred at room temperature for 1 h. The solid was filtered off and washed with water, followed by 10 mL of diethyl ether. The resulting solid was dried under vacuum to give ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (Intermediate 5, 1.738 g, 78%) as a light brown solid. m / z(ES + ) [M+H] + =247.

[0043] Intermediate 6: 3-Ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one 2 M lithium aluminum hydride in THF (29.2 mL, 58.47 mmol) was added dropwise to ethyl 7-ethyl-6-oxo-5H-1,5-naphthyridine-3-carboxylate (Intermediate 5, 7.2 g, 29.24 mmol) in tetrahydrofuran (150 mL) under nitrogen over 45 minutes at 0° C. The resulting mixture was stirred at 0° C. for 1.5 hours. The reaction mixture was quenched by the dropwise addition of 1 M aqueous HCl (29 mL). The reaction mixture was concentrated, and the solid was diluted with water (approximately 150 mL) and 29 mL of 1 M HCl solution to give a yellow suspension. The solid was collected by filtration, washed with water, diethyl ether, and dried to give the crude product as a yellow solid (contaminated with some inorganic salts). This solid was suspended in a mixture of methanol and DCM (2:1) (400 mL) and heated to reflux. The solid was filtered off. The solid was resuspended in a methanol / DCM mixture, and this procedure was repeated five times to obtain most of the product from the mixture. The combined filtrate was then concentrated to approximately 100 mL, and the solid was collected by filtration, washed with ether, and dried under vacuum to give 3-ethyl-7-(hydroxymethyl)-1H-1,5-naphthyridin-2-one (Intermediate 6, 4.35 g, 72.8%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) 1.18 (3H, t), 2.52-2.56 (2H, m), 4.61 (2H, d), 5.44 (1H, t), 7.61 (1H, s), 7.74 (1H, s), 8.37 (1H, s), 11.87 (1H, br s); m / z (ES+) [M+H]+ = 205.3

[0044] Example 1: 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide [ka] Thionyl chloride (6.41 mL, 88.14 mmol) was added dropwise to a suspension of 3-ethyl-7-(hydroxymethyl)-1,5-naphthyridin-2(1H)-one (Intermediate 6, 3 g, 14.69 mmol) and N,N-dimethylformamide (0.114 mL, 1.47 mmol) in CHCl (60 mL) at 0° C., and the resulting solution was stirred at room temperature for 6 h. The mixture was concentrated to dryness to give crude 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one.

[0045] DIPEA (12.83 mL, 73.45 mmol) was added to a stirred solution of 7-(chloromethyl)-3-ethyl-1H-1,5-naphthyridin-2-one (crude from above), potassium iodide (0.488 g, 2.94 mmol), and N-methyl-5-piperazin-1-yl-pyridine-2-carboxamide, 2HCl (Intermediate 7, 4.31 g, 14.69 mmol) in acetonitrile (50.00 mL) at 20 °C. The resulting solution was stirred at 80 °C for 2 h. The solvent was removed in vacuo. The crude material was diluted with water, basified with aq. NaHCO solution, and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and concentrated to give the crude product. The resulting residue was purified by flash silica chromatography, eluting with a gradient of 0 to 15% MeOH in DCM. The product fractions were concentrated under reduced pressure to give 5-[(4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (Example 1, 3.93 g, 65.8%) as an off-white, partially crystallized solid. NMR(500MHz,DMSO-d6)1.19(3H,t),2.53-2.59(6H,m),2.79(3H,d),3.33-3.39(4H,m),3.66(2H,s),7.39(1H, m / z(ES + )[M] + =406.

[0046] Example 1 - Form A In Example 1, 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide was obtained as a partially crystallized solid by evaporation of a methanol / dichloromethane solution under reduced pressure. The resulting crystalline material was characterized as crystalline Form A.

[0047] In cases where the degree of crystallinity was low, crystalline Form A was obtained by suspending 20 mg of the crude sample in 0.20 ml of water, methanol, ethanol, acetone, acetonitrile, tetrahydrofuran, ethyl acetate or other solvents at ambient temperature or 50° C. for 1 day.

[0048] Form A was analyzed by XRPD and the results are tabulated below (Table 1) and shown in FIG.

[0049] [Table 1]

[0050] Form A is characterized by exhibiting at least one of the following 2θ values ​​as measured using CuKα radiation: 8.3°, 12.4°, and 19.4°.

[0051] Example 2 This in vivo study was conducted to investigate the antitumor effect of AZD5305 in combination with carboplatin (a platinum chemotherapy drug) in an in vivo BRCA wild-type tumor model, HBCx-9. AZD5305 monotherapy arm and carboplatin monotherapy arm were included in the study design as controls.

[0052] Materials and Methods

[0053] [Table 2]

[0054] biota HBCx-9 is a patient-derived tumor xenograft (PDX) model established at XenTech without prior in vitro culture. Tumor fragments were implanted subcutaneously (SC) into donor mice. Tumor volumes ranged from 700 to 1764 mm. 3 When tumor size reached 100 mm, the donor mice were sacrificed and the tumors were aseptically excised and dissected. After removing the necrotic areas, the tumors were enlarged to approximately 20 mm. 3The tumors were cut into 1 / 4" pieces, transferred to culture medium, and then implanted SC into recipient nude female mice. Tumors were measured twice weekly by bilateral caliper measurements (length x width), and tumor volume was calculated using the ellipse formula (π / 6 x width x width x length). Animal weights and tumor status were monitored throughout the study. When tumor volumes reached approximately 100 mm 3 Once the mice reached 100 mg / kg, they were randomly assigned to treatment groups. Animals began treatment the day after randomization. Control animals were treated with vehicle (deionized water acidified with HCl to pH 3.5–4) orally (PO) once daily (QD). AZD5305 was administered at 1 mg / kg PO QD. Carboplatin was administered at 50 mg / kg intraperitoneally (IP) once weekly (QW). In the combination group, mice were first dosed with carboplatin, followed within 10 minutes by AZD5305.

[0055] Tumor growth inhibition from the start of treatment was assessed by comparing the mean change in tumor volume between the control and treatment groups and expressed as percent tumor growth inhibition (TGI, if TV ≥ starting TV) or percent regression (REG, if TV < starting TV). Mean percent body weight change from the start of treatment was also calculated for all groups. Statistical significance was assessed using a one-sample t-test. Statistical significance is indicated as follows: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.

[0056] A tolerability study using AZD5305 at 10 mg / kg PO QD in combination with carboplatin at 50 mg / kg IP QW was performed in SCID female mice prior to the initiation of efficacy studies and showed no adverse effects on the condition of the animals or significant changes in body weight.

[0057] Test material formulation AZD5305 was formulated for oral dosing in a water / HCl (pH 3.5-4) vehicle to be administered at a dose volume of 0.1 ml / 10 g. The solid was diluted by adding the appropriate volume of 1N HCl to a drug / HCl molar ratio of approximately 1:1.25 and adding 80% of the final volume of sterile deionized water while stirring / vortexing / sonicating until a solution was obtained. The volume of 1N HCl required was calculated according to the following formula: Volume of 1N HCl added (ml) = 1.25 x [concentration (mg / ml) ÷ 406.48 (g / mol) ÷ 1M] x final volume (ml).

[0058] The pH of the solution was adjusted to 3.5-4 with 1N HCl or 1N NaOH. The final volume was made up with sterile water for injection or deionized water, and the final pH was measured and recorded. Dosage formulations were dispensed weekly and protected from light.

[0059] Carboplatin (Teva®) was formulated freshly on each dosing day by diluting the stock solution to 5 mg / ml in 0.9% NaCl to give a 50 mg / kg dose (0.1 ml / 10 g dose volume).

[0060] result HBCx-9 is a TNBC PDX model available from XenTech in France. It has been reported as a BRCA1 wt model with BRCA1 methylation [1]. HBCx-9 has also been shown to be moderately sensitive to olaparib monotherapy [2].

[0061] In efficacy studies, AZD5305 at 1 mg / kg, 0.1 mg / kg, and 0.01 mg / kg QD and carboplatin at 50 mg / kg QW were tested as monotherapy and in combination. The treatment period was 28 days. Both treatments were well tolerated during the study period, with no significant weight loss observed (Figures 1 and 7). AZD5305 monotherapy demonstrated dose-dependent antitumor efficacy, resulting in a 72% TGI, while 88% TGI was observed in the carboplatin monotherapy group. Administering AZD5305 and carboplatin together demonstrated a clear combination effect by resulting in 88% tumor regression (Figure 2 and Table 2). Furthermore, all animals (8 / 8) in the combination group achieved complete remission (CR; TV < 14 mm). 3 (defined as "the number of days between the start of a newborn baby" or "the first day of pregnancy") was reached (Figure 3

[0062] In conclusion, AZD5305 in combination with carboplatin demonstrated improved antitumor efficacy compared with either monotherapy in the HBCx-9 PDX model in vivo. The combination of AZD5305 and carboplatin resulted in complete remission in 100% of animals and was well tolerated in mice.

[0063] [Table 3]

[0064] [1]Coussy F, de Koning L, Lavigne M, et al.A large collection of integrated genomically characterized patient-derived xenografts highlighting the heterogeneity of triple-negative breast cancer.Int J Cancer.2019;145(7):1902‐1912.doi:10.1002 / ijc.32266 [2]LC Riches(2020)Mol Cancer Ther 2020;19:13-25

[0065] Example 3 This study was conducted to investigate the antitumor effect of AZD5305 in combination with carboplatin in an in vivo BRCA1 mutant tumor model, SUM149PT. AZD5305 monotherapy arm and carboplatin monotherapy arm were included in the study design as controls.

[0066] Materials and Methods SUM149PT cells (2 × 10 6 ) were implanted into the mammary fat pad (MFP) of female SCID mice (weighing >18 g) with 50% Matrigel. Tumors were measured twice weekly by bilateral caliper measurements (length x width), and tumor volume was calculated using the ellipse formula (π / 6 x width x width x length). Animal weight and tumor status were monitored throughout the study. When tumor volumes reached approximately 0.3 cm 3 Once the mice reached 100 mg / kg, they were randomly assigned to treatment groups. Animals began receiving treatment the day after randomization. Control animals received vehicle (deionized water acidified with HCl to pH 3.5-4) orally (PO) once daily (QD) and PBS intraperitoneally (IP) once weekly (QW). AZD5305 was administered PO QD at 0.1 mg / kg, 0.03 mg / kg, or 0.01 mg / kg. Carboplatin was administered IP at 37.5 mg / kg once weekly (QW). In the combination group, mice were first dosed with carboplatin, followed within 10 minutes by AZD5305.

[0067] Tumor growth inhibition from the start of treatment was assessed by comparing the mean change in tumor volume between the control and treatment groups and expressed as percent tumor growth inhibition (TGI, if TV ≥ starting TV) or percent regression (REG, if TV < starting TV). Mean percent body weight change from the start of treatment was also calculated for all groups. Statistical significance was assessed using a one-sample t-test. Statistical significance is indicated as follows: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.

[0068] A tolerability study using AZD5305 at 10 mg / kg PO QD in combination with carboplatin at 50 mg / kg IP QW was performed in SCID female mice prior to the initiation of efficacy studies and showed no adverse effects on the condition of the animals or significant changes in body weight.

[0069] Test material formulation AZD5305 was formulated for oral dosing in a water / HCl (pH 3.5-4) vehicle to be administered at a dose volume of 0.1 ml / 10 g. The solid was diluted by adding the appropriate volume of 1N HCl to a drug / HCl molar ratio of approximately 1:1.25 and adding 80% of the final volume of sterile deionized water while stirring / vortexing / sonicating until a solution was obtained. The volume of 1N HCl required was calculated according to the following formula: Volume of 1N HCl added (ml) = 1.25 x [concentration (mg / ml) ÷ 406.48 (g / mol) ÷ 1M] x final volume (ml).

[0070] The pH of the solution was adjusted to 3.5-4 with 1N HCl or 1N NaOH. The final volume was made up with sterile water for injection or deionized water, and the final pH was measured and recorded. Dosage formulations were dispensed weekly and protected from light. Carboplatin (Sigma Aldrich) was formulated freshly each dosing day by diluting the stock solution to 3.75 mg / ml in 0.9% NaCl to achieve a 37.5 mg / kg dose (0.1 ml / 10 g dose volume).

[0071] result In an efficacy study of the SUM149PT TNBC BRCA1m xenograft model, AZD5305 at 0.1 mg / kg, 0.03 mg / kg, and 0.01 mg / kg QD and carboplatin at 37.5 mg / kg QW were tested as monotherapy and in combination. All treatments were well tolerated throughout the study period (28 days), with no significant weight loss observed (Figure 5). AZD5305 monotherapy demonstrated dose-dependent antitumor efficacy, resulting in a 24% TGI at 0.1 mg / kg QD and a 9% TGI at 0.03 mg / kg QD. AZD5305 administered at 0.01 mg / kg QD did not inhibit tumor growth. Carboplatin monotherapy resulted in a 61% TGI. The combination of 0.1 mg / kg AZD5305 with carboplatin demonstrated a combined effect, resulting in an 86% TGI. This antitumor effect was maintained when the dose level of AZD5305 in combination with carboplatin was reduced to 0.03 mg / kg or 0.01 mg / kg (75% and 79% TGI, respectively) (Figure 6 and Table 3).

[0072] In conclusion, AZD5305 in combination with carboplatin demonstrated improved antitumor efficacy compared with monotherapy in the SUM149PT xenograft model in vivo. Reducing the dose level of AZD5305 in combination with carboplatin by 10-fold (from 0.1 mg / kg to 0.01 mg / kg) did not affect tumor growth inhibition.

[0073] [Table 4]

[0074] Example 4 This study was conducted to investigate the antitumor effects of a range of doses of AZD5305 in combination with carboplatin in an in vivo BRCA1 / 2 wild-type tumor model, HBCx-9. An AZD5305 monotherapy arm and a carboplatin monotherapy arm were included in the study design as controls.

[0075] Materials and Methods HBCx-9 is a patient-derived tumor xenograft (PDX) model established at XenTech without prior in vitro culture. Tumor fragments were implanted subcutaneously (SC) into donor mice. When tumor volumes reached 1008–1764 mm3, the donor mice were sacrificed, and tumors were aseptically excised and dissected. After removing necrotic areas, tumors were cut into approximately 20 mm3 fragments, transferred to culture medium, and then SC implanted into recipient nude female mice. Tumors were measured bilaterally with calipers (length × width) twice weekly, and tumor volume was calculated using the ellipse formula (π / 6 × width × width × length). Animal weight and tumor status were monitored throughout the study. When tumor volumes reached approximately 110 mm3, mice were randomly assigned to treatment groups. Animals began receiving treatment the day after randomization. Control animals received vehicle (deionized water acidified with HCl to pH 3.5-4) orally (PO) once daily (QD). AZD5305 was administered at 1 mg / kg, 0.1 mg / kg, or 0.01 mg / kg PO QD. Carboplatin was administered at 50 mg / kg IP once weekly (QW). In the combination group, mice were first dosed with carboplatin, followed within 10 minutes by AZD5305.

[0076] Tumor growth inhibition from the start of treatment was assessed by comparing the mean change in tumor volume between the control and treatment groups and expressed as percent tumor growth inhibition (TGI, if TV ≥ starting TV) or percent regression (REG, if TV < starting TV). Mean percent body weight change from the start of treatment was also calculated for all groups. Statistical significance was assessed using a one-sample t-test. Statistical significance is indicated as follows: *p ≤ 0.05, **p ≤ 0.01, ***p ≤ 0.001.

[0077] A tolerability study using AZD5305 at 10 mg / kg PO QD in combination with carboplatin at 50 mg / kg IP QW was performed in SCID female mice prior to the initiation of efficacy studies and showed no adverse effects on the condition of the animals or significant changes in body weight.

[0078] Plasma PK samples were obtained by collecting 400–600 μL of whole blood via intracardiac puncture under xylazine-ketamine anesthesia. Blood was transferred to a BD Microtainer Hep-Li with separator gel tubes and centrifuged at 5,000 RPM for 5–10 minutes at 4°C. The separated plasma was collected and stored at -80°C. To measure compound levels in plasma samples, each plasma sample (25 μl) was compared with an 11-point standard calibration curve (1–10,000 nM) prepared in DMSO and spiked into blank plasma using the appropriate dilution factor. Acetonitrile (100 μl) was added along with the internal standard, followed by centrifugation at 3,000 RPM for 10 minutes. The supernatant (50 μl) was then diluted with 300 μl of water and analyzed by UPLC-MS / MS.

[0079] Test material formulation AZD5305 was formulated for oral dosing in a water / HCl (pH 3.5-4) vehicle to be administered at a dose volume of 0.1 ml / 10 g. The solid was diluted by adding the appropriate volume of 1N HCl to a drug / HCl molar ratio of approximately 1:1.25 and adding 80% of the final volume of sterile deionized water while stirring / vortexing / sonicating until a solution was obtained. The volume of 1N HCl required was calculated according to the following formula: Volume of 1N HCl added (ml) = 1.25 x [concentration (mg / ml) ÷ 406.48 (g / mol) ÷ 1M] x final volume (ml).

[0080] The pH of the solution was adjusted to 3.5-4 with 1N HCl or 1N NaOH. The final volume was made up with sterile water for injection or deionized water, and the final pH was measured and recorded. Dosage formulations were compounded weekly and protected from light. Carboplatin (Sandoz) was compounded freshly each dosing day by diluting the stock solution to 5 mg / ml in 0.9% NaCl to give a 50 mg / kg dose (0.1 ml / 10 g dose volume).

[0081] result HBCx-9 is a TNBC PDX model available from XenTech in France. It has been described as a BRCA1 / 2 wt model with BRCA1 methylation and "BRCAness features" [1]. HBCx-9 has also been shown to have moderate sensitivity to olaparib monotherapy [2].

[0082] In efficacy studies, AZD5305 at 1 mg / kg, 0.1 mg / kg, and 0.01 mg / kg QD and carboplatin at 50 mg / kg QW were tested as monotherapy and in combination. All treatments were well tolerated over the course of the study (28 days), with no significant weight loss observed. (Error! Reference not found.) AZD5305 monotherapy demonstrated dose-dependent antitumor efficacy, resulting in a 66% TGI at 1 mg / kg QD, a 44% TGI at 0.1 mg / kg QD, and a 7% TGI at 0.01 mg / kg QD. Carboplatin monotherapy resulted in a 68% TGI. Treatment with 1 mg / kg AZD5305 and carboplatin demonstrated a combined effect, resulting in a 90% regression. This antitumor effect was maintained even when the dose level of AZD5305 in combination with carboplatin was reduced to 0.1 mg / kg (86% regression). When carboplatin was combined with AZD5305 at 0.01 mg / kg, the effect was slightly reduced (49% TGI). However, this group still achieved a combination effect compared with either monotherapy arm (Error! Reference source not found, and Table).

[0083] In this study, treatment continued for 28 days, after which treatment was discontinued and the duration of remission monitored. The graph in Error! Reference source not found shows that in the most effective group (carboplatin combined with 1 mg / kg or 0.1 mg / kg AZD5305), tumors began to regrow around day 49 (3 weeks after treatment was discontinued), and the regrowth rate was similar between the two groups. Furthermore, in the carboplatin + 0.01 mg / kg AZD5305 group, tumors began to regrow approximately 2 weeks after treatment was discontinued. Error! Reference source not found.

[0084] In conclusion, AZD5305 in combination with carboplatin demonstrated improved antitumor efficacy compared to monotherapy in the in vivo HBCx-9 PDX model. Reducing the dosage level of AZD5305 in combination with carboplatin by 10-fold (from 1 mg / kg to 0.1 mg / kg) did not affect tumor regression efficacy.

[0085] [Table 5]

[0086] This specification uses examples to disclose the invention and to enable any person skilled in the art to practice the invention (e.g., make and use any of the disclosed salts, materials, or compositions and perform any of the disclosed methods or processes). The patentable scope of the invention is defined by the claims, and may include other examples that those skilled in the art recognize. Such other examples are intended to be within the scope of the claims if they contain elements that do not differ from the literal wording of the claims or if they contain equivalent elements that have insubstantial differences from the literal wording of the claims. While preferred embodiments of the invention have been shown and described herein, such embodiments are provided by way of example only and are not intended to otherwise limit the scope of the invention. Various alternatives to the described embodiments of the invention may be employed in practicing the invention. The section headings used in this section and throughout this disclosure are not intended to be limiting.

[0087] All references (patent and non-patent) cited above are incorporated by reference into this patent application. The discussion of these references is intended merely to summarize the assertions made by their authors. No admission is made that any reference (or any portion of any reference) is relevant prior art (or any prior art). Applicant reserves the right to challenge the accuracy and pertinence of the cited references. The present application also includes the following aspects. [Aspect 1] A method of treating cancer in a human subject in need thereof, comprising administering to the human subject a first amount of AZD5305 or a pharmaceutically acceptable salt thereof and a second amount of a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof, wherein the first amount and the second amount together constitute a therapeutically effective amount. [Aspect 2] 2. The method of embodiment 1, wherein the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer such as gastric cancer and colon cancer, and lung cancer. [Aspect 3] The method of any one of aspects 1 to 2, wherein the chemotherapeutic platinum agent is selected from any one of cisplatin, oxaliplatin, and carboplatin. [Aspect 4] The method according to any one of aspects 1 to 3, wherein the cancer is a homologous recombination repair deficient (HRD) cancer. [Aspect 5] 5. The method of embodiment 4, wherein the cancer comprises one or more cells with a mutation in an HRR gene selected from BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L. [Aspect 6] The method of embodiment 5, wherein the mutated HRR gene is selected from BRCA1, BRCA2, and ATM. [Aspect 7] A kit comprising: a first pharmaceutical composition comprising AZD5305 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; Instructions for use and Kit including: [Aspect 8] AZD5305 or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject, said treatment comprising the separate, sequential or simultaneous administration to said subject of i) said AZD5305 or a pharmaceutically acceptable salt thereof, and ii) a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof. [Aspect 9] The compound according to aspect 8, wherein the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, blood cancer, gastrointestinal cancer such as gastric cancer and colon cancer, and lung cancer. [Aspect 10] The compound of aspect 8 or 9, wherein the platinum chemotherapeutic agent is selected from any one of cisplatin, oxaliplatin, and carboplatin. [Aspect 11] The compound according to any one of aspects 8 to 10, wherein the cancer is a homologous recombination repair deficient (HRD) cancer. [Aspect 12] 12. The compound of embodiment 11, wherein the cancer comprises cells with a mutation in an HRR gene selected from BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L. [Aspect 13] 13. The compound of aspect 12, wherein the mutated HRR gene is selected from BRCA1, BRCA2, and ATM. [Aspect 14] A pharmaceutical product comprising i) AZD5305 or a pharmaceutically acceptable salt thereof, and ii) a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof. [Aspect 15] 15. The pharmaceutical product of aspect 14, wherein AZD5305 or a pharmaceutically acceptable salt thereof and said platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are present in a single dosage form. [Aspect 16] 15. The pharmaceutical product of aspect 14, wherein AZD5305 or a pharmaceutically acceptable salt thereof and said platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are present in separate dosage forms. [Aspect 17] Aspect 17. The method, compound or pharmaceutical composition of any one of Aspects 1 to 16, wherein said platinum chemotherapeutic agent comprises carboplatin. [Aspect 18] Aspect 18. The method, compound or pharmaceutical composition according to any one of Aspects 1 to 17, wherein said platinum chemotherapeutic agent is carboplatin. [Aspect 19] Aspect 19. A method, compound or pharmaceutical composition according to any one of aspects 1 to 18, wherein said AZD5305 is a free base.

Claims

1. 1. A pharmaceutical combination for the treatment of cancer in a human subject in need thereof, comprising a first amount of 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (AZD5305) or a pharmaceutically acceptable salt thereof and a second amount of a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof, said first amount and said second amount together comprise a therapeutically effective amount; AZD5305 or a pharmaceutically acceptable salt thereof and a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are administered separately, sequentially or simultaneously; The platinum chemotherapeutic agent is selected from any one of cisplatin, oxaliplatin, and carboplatin. The combination drug.

2. A pharmaceutical for treating cancer, comprising 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (AZD5305) or a pharmaceutically acceptable salt thereof, administered separately, sequentially or simultaneously with a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof; The platinum chemotherapeutic agent is selected from any one of cisplatin, oxaliplatin, and carboplatin. The medicine.

3. A kit for treating cancer, comprising: a first pharmaceutical composition comprising 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (AZD5305) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; a second pharmaceutical composition comprising a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier; Instructions for use and Including, wherein the platinum chemotherapeutic agent is selected from any one of cisplatin, oxaliplatin, and carboplatin. The kit.

4. A pharmaceutical for treating cancer, comprising: i) 5-[4-[(7-ethyl-6-oxo-5H-1,5-naphthyridin-3-yl)methyl]piperazin-1-yl]-N-methyl-pyridine-2-carboxamide (AZD5305) or a pharmaceutically acceptable salt thereof; and ii) a platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof; wherein the platinum chemotherapeutic agent is selected from any one of cisplatin, oxaliplatin, and carboplatin. The medicine.

5. 5. A pharmaceutical combination or medicament according to any one of claims 1, 2 and 4, wherein AZD5305 or a pharmaceutically acceptable salt thereof and the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are present in a single dosage form.

6. 5. A pharmaceutical combination or medicament according to any one of claims 1, 2 and 4, wherein AZD5305 or a pharmaceutically acceptable salt thereof and the platinum chemotherapeutic agent or a pharmaceutically acceptable salt thereof are present in separate dosage forms.

7. The combination pharmaceutical, kit, or medicament according to any one of claims 1 to 6, wherein the cancer is selected from ovarian cancer, breast cancer, pancreatic cancer, prostate cancer, blood cancer, digestive cancer such as gastric cancer and colon cancer, and lung cancer.

8. The combination pharmaceutical, kit, or medicament according to any one of claims 1 to 7, wherein the cancer is homologous recombination repair deficient (HRD) cancer.

9. 9. The combination pharmaceutical, kit or medicament of claim 8, wherein the cancer comprises one or more cells having a mutation in a homology directed repair (HRR) gene selected from BRCA1, BRCA2, ATM, BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D and RAD54L.

10. The pharmaceutical combination, kit or medicament according to claim 9, wherein the HRR gene is selected from BRCA1, BRCA2 and ATM.

11. The combination pharmaceutical, kit or medicament according to any one of claims 1 to 10, wherein the platinum chemotherapeutic agent is carboplatin.

12. A pharmaceutical combination, kit or medicament according to any one of claims 1 to 11, wherein the AZD5305 is the free base.

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