Methods for treating ribonucleotide reductase-associated disorders using ribonucleotide reductase inhibitors

Abstract

The present invention provides a pharmaceutical composition for preventing and / or treating an RNR-associated disease in a patient in need thereof, wherein the pharmaceutical composition comprises 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof, and is administered to the patient on a 2-week intermittent dosing schedule comprising dosing 1 to 5 days per week. The present invention also provides a method for treating an RNR-associated disease in a patient in need thereof, comprising administering to the patient an effective amount of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof on a two-week intermittent dosing schedule comprising dosing one to five days per week.

Description

[Technical Field]

[0001] The present disclosure relates to methods of treating patients with RNR-associated diseases with ribonucleotide reductase inhibitors according to specific dosing regimens. In particular, the present disclosure relates to methods of treating tumors with ribonucleotide reductase inhibitors according to specific dosing regimens.

[0002] This application claims priority to U.S. Provisional Patent Application No. 63 / 078,844, filed September 15, 2020, the entire contents of which are incorporated herein by reference. [Background technology]

[0003] Ribonucleotide reductase (hereinafter referred to as "RNR") is composed of a hetero-oligomer of a large subunit M1 and a small subunit M2, and expression of both subunits is required for enzymatic activity. RNR recognizes ribonucleoside 5'-diphosphate (hereinafter referred to as "NDP") as a substrate and catalyzes its reduction to 2'-deoxyribonucleoside 5'-diphosphate (hereinafter referred to as "dNDP"). RNR is the rate-limiting enzyme in the de novo dNTP synthesis pathway and plays an essential role in DNA synthesis and repair (Non-Patent Document 1).

[0004] The enzymatic activity of RNR is closely related to cell proliferation, and it has been reported that enzymatic activity is particularly high in cancer (Non-Patent Document 2). Numerous reports have shown a correlation between overexpression of the M2 subunit of RNR and its impact on cancer prognosis in various types of solid tumors and hematological cancers (Non-Patent Documents 3 and 4). Furthermore, inhibition of RNR has been reported to inhibit cell proliferation and have in vivo antitumor effects in cell lines and non-clinical models derived from several carcinomas (Non-Patent Documents 5 and 6). These findings strongly suggest that RNR is an important target molecule for cancer therapy.

[0005] Hydroxyurea (hereinafter also referred to as "HU") and 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (hereinafter also referred to as "3-AP") are known to exhibit RNR inhibitory activity. However, these compounds differ structurally from the sulfonamide compounds disclosed herein. HU has been used clinically for over 30 years, but its RNR inhibitory activity is weak and its effectiveness is limited (Non-Patent Document 7). Furthermore, tolerance to the use of HU is also an issue (Non-Patent Document 8). On the other hand, 3-AP is capable of chelating metal ions, particularly iron (Fe) ions, and is believed to inhibit RNR by chelating with them (Non-Patent Document 9). However, 3-AP has been suggested to have off-target effects on various other Fe-containing proteins, which can cause side effects in clinical settings, such as hypoxia, dyspnea, and methemoglobinemia (Non-Patent Document 10). Therefore, there is a need to develop RNR inhibitors that do not chelate metal ions and can be used to treat RNR-associated diseases, such as cancer.

[0006] On the other hand, the compound 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (referred to herein as Compound A) has been known to have potent RNR inhibitory activity (Patent Document 1). However, no administration schedule or dosage regimen for Compound A has been described in the art. [Prior art documents] [Patent documents]

[0007] [Patent Document 1] International Publication No. 2017 / 209155 Brochure [Non-patent literature]

[0008] [Non-Patent Document 1] Annu. Rev. Biochem. 67, 71-98. (1998) [Non-patent document 2] J. Biol. Chem. 245, 5228-5233. (1970) [Non-patent document 3] Nat. Commun. 5, 3128 doi: 10.1038 / ncomms 4128 (2014) [Non-patent document 4] Clin. Sci. 124, 567-578. (2013) [Non-patent document 5] Expert. Opin. Ther. Targets 17, 1423 - 1437 (2013) [Non-patent document 6] Biochem. Pharmacol. 59, 983-991 (2000) [Non-Patent Document 7] Biochem. Pharmacol. 78, 1178- 11 85 (2009) [Non-patent document 8] Cancer Res. 54, 3686-3691 (1994) [Non-Patent Document 9] Pharmacol. Rev. 57, 547-583 (2005) [Non-Patent Document 10] Future Oncol. 8, 145-150 (2012) Summary of the Invention

[0009] Aspects of the present disclosure include methods of treating tumors in a patient in need thereof by administering an effective amount of Compound A using a specific dosing schedule. The present inventors have discovered that continuous administration of Compound A exhibits antitumor effects. However, such administration may also result in one or more undesirable events or side effects, such as weight loss. The present inventors have conducted extensive research and found that intermittent administration of Compound A, including a relatively high dose on a dosing day and a non-dosing day without administration of Compound A, achieves antitumor effects with fewer undesirable events and side effects than continuous administration using a relatively low dose. The present disclosure is based on this unexpected and surprising discovery.

[0010] In one embodiment, a method of treating a patient having a tumor comprises administering to the patient an effective amount of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof on a two-week intermittent dosing schedule comprising dosing one to five days per week. [Brief explanation of the drawings]

[0011] [Figure 1] Figure 1 shows a graph illustrating relative tumor volume (RTV) for the control group (open circles), continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and QOD dosing group (closed triangles: 200 mg / kg / day; closed diamonds: 300 mg / kg / day). Error bars: standard deviation from the mean. [Figure 2] Figure 1 shows a graph showing body weight (BW) changes in the control group (open circles), continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and QOD dosing group (closed triangles: 200 mg / kg / day; closed diamonds: 300 mg / kg / day). Error bars: standard deviation from the mean. [Figure 3] Figure 1 shows a graph illustrating relative tumor volume (RTV) for the control group (open circles), continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and QW dosing group (closed squares: 700 mg / kg / day; x: 1050 mg / kg / day). Error bars: standard deviation from the mean. [Figure 4] Figure 1 shows a graph showing changes in body weight (BW) for the control group (open circles), continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and QW dosing group (closed squares: 700 mg / kg / day; ×: 1050 mg / kg / day). Error bars: standard deviation from the mean. [Figure 5] Figure 1 shows a graph illustrating relative tumor volume (RTV) for the control group (open circles), continuous dosing groups (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and 3QW dosing group 1 (closed triangles: 233 mg / kg / day; closed diamonds: 350 mg / kg / day). Error bars: standard deviation from the mean. [Figure 6] Figure 1 shows a graph showing changes in body weight (BW) for the control group (open circles), the continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and the 3QW dosing group 1 (closed triangles: 233 mg / kg / day; closed diamonds: 350 mg / kg / day). Error bars: standard deviation from the mean. [Figure 7] Figure 1 shows a graph illustrating relative tumor volume (RTV) for the control group (open circles), continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and 3QW dosing group 2 (closed triangles: 233 mg / kg / day; closed diamonds: 350 mg / kg / day). Error bars: standard deviation from the mean. [Figure 8] Figure 1 shows a graph showing changes in body weight (BW) for the control group (open circles), the continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and the 3QW dosing group 2 (closed triangles: 233 mg / kg / day; closed diamonds: 350 mg / kg / day). Error bars: standard deviation from the mean. [Figure 9] Figure 1 shows a graph illustrating relative tumor volume (RTV) for the control group (open circles), continuous dosing groups (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and 5QW dosing group 1 (closed diamonds: 140 mg / kg / day; open squares: 210 mg / kg / day). Error bars: standard deviation from the mean. [Figure 10]Figure 1 shows a graph showing changes in body weight (BW) for the control group (open circles), the continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and the 5QW dosing group 1 (closed diamonds: 140 mg / kg / day; open squares: 210 mg / kg / day). Error bars: standard deviation from the mean. [Figure 11] Figure 1 shows a graph illustrating relative tumor volume (RTV) for the control group (open circles), continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and 5QW dosing group 2 (closed squares: 140 mg / kg / day; x: 210 mg / kg / day). Error bars: standard deviation from the mean. [Figure 12] Figure 1 shows a graph showing changes in body weight (BW) for the control group (open circles), the continuous dosing group (closed circles: 100 mg / kg / day; open diamonds: 150 mg / kg / day), and the 5QW dosing group 2 (closed squares: 140 mg / kg / day; crosses: 210 mg / kg / day). Error bars: standard deviation from the mean. [Figure 13] FIG. 1 shows a scatter plot showing the correlation between SLFN11 mRNA expression and cell proliferation (%) at 100 μmol / L of Compound A in 11 cell lines. [Figure 14] FIG. 1 shows the effect of Compound A on cell proliferation of A673 cells treated with siRNA against SLFN11 (siSLFN11-1 and siSLFN11-2) or control siRNA (siControl). [Figure 15] FIG. 1 shows caspase-3 / 7 activation by compound A (10 μmol / L) in A673 cells treated with siRNA against SLFN11 (siSLFN11-1 and siSLFN11-2). [Figure 16] Figure 1 shows SLFN11 expression in A673 cells treated with siRNA. A673 cells were treated with siRNA against SLFN11 (siSLFN11-1 and siSLFN11-2) for 24 hours, then harvested and analyzed by immunoblotting. [Figure 17]FIG. 1 shows the effect of Compound A on cell proliferation of NCI-H460 cells treated with siRNA against SLFN11 (siSLFN11-1, siSLFN11-2, and siSLFN11-3) or control siRNA (siControl). [Figure 18] FIG. 1 shows the effect of Compound A on cell proliferation of CFPAC-1 cells treated with siRNA against SLFN11 (siSLFN11-1, siSLFN11-2, and siSLFN11-3) or control siRNA (siControl). [Figure 19] FIG. 1 shows caspase-3 / 7 activation by compound A (10 μmol / L) in NCI-H460 cells and CFPAC-1 cells treated with siRNA against SLFN11 (siSLFN11-1, siSLFN11-2, and siSLFN11-3). DETAILED DESCRIPTION OF THE INVENTION

[0012] Aspects of the present disclosure include methods of treating an RNR-associated disease by administering an RNR inhibitor on a two-week intermittent dosing schedule comprising dosing one to five days per week. In one embodiment, a method of treating an RNR-associated disease comprises administering 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide ("Compound A") or a salt thereof to a patient in need thereof. In some embodiments, the method comprises administering Compound A or a salt thereof on a two-week intermittent dosing schedule comprising dosing one to five days per week. The exemplary intermittent dosing schedule of the present disclosure reduces adverse events or side effects, such as weight loss, compared to conventional continuous dosing schedules, despite the same total dose of Compound A over the two weeks. In some embodiments, the RNR-associated disease is a tumor, such as acute myeloid leukemia (AML).

[0013] 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide is depicted by the following structure: [ka]

[0014] In this application, the above compound is referred to as "Compound A." Compound A is described as the compound of Example 5 in WO 2017 / 209155, the disclosure of which is incorporated herein by reference in its entirety. Compound A can be produced by any method known in the art, including, but not limited to, the methods described in WO 2017 / 209155.

[0015] The novel therapeutic methods described herein demonstrate the effectiveness of reducing one or more undesirable side effects, adverse reactions, or adverse events, such as weight loss, while achieving antitumor efficacy. Furthermore, the novel therapeutic methods using intermittent administration schedules described herein can demonstrate comparable antitumor efficacy (e.g., the same tumor growth inhibition as continuous administration), and in some embodiments, intermittent administration schedules (e.g., QOD, 3QW, and 5QW) can even demonstrate greater antitumor efficacy. In an exemplary embodiment, Compound A is administered on a 2-week intermittent administration schedule comprising 1-5 days of administration per week. This surprising and unexpected discovery allows for longer administration of Compound A with reduced side effects, ultimately contributing to longer survival and / or longer progression-free survival. The exemplary dosing schedules described herein demonstrate benefits with respect to the reduction of one or more adverse events or side effects.

[0016] In the present disclosure, the administration schedule is not particularly limited, as long as it includes intermittent administration for 2 weeks, including administration for 1 to 5 days per week. An administration cycle can be defined as 2 weeks or longer. A cycle can be performed once or repeated two or more times to treat RNR-related diseases.

[0017] An exemplary administration schedule can include a 4-week (28-day) administration schedule, which is defined as one cycle, and administration can be performed for one cycle or more than one cycle, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more cycles. In some embodiments, administration can be performed for a long period of time, including several cycles. For example, administration can be performed for a 6-month period, including about 6 cycles of treatment or administration; for a 1-year period, including about 13 cycles of treatment; for a 3-year period or more, including about 39 cycles of treatment.

[0018] In one embodiment, the dosing schedule can include one day of dosing per week. In this case, Compound A can be administered on days 1 and 8 of a two-week dosing schedule (days 1-14). This schedule is sometimes referred to herein as "QW" dosing.

[0019] In another embodiment, the dosing schedule can include three dosing days and four non-dosing days per week. This schedule may be referred to herein as "3QW" dosing. In this case, the dosing schedule can include three consecutive dosing days per week followed by four non-dosing days. Thus, Compound A can be administered on days 1-3 and days 8-10 of a two-week dosing schedule (days 1-14). Alternatively, the dosing schedule can include three alternate-day dosing days per week followed by two non-dosing days. Thus, Compound A can be administered on days 1, 3, 5, 8, 10, and 12 of a two-week dosing schedule (days 1-14).

[0020] In another embodiment, the dosing schedule can include 5 dosing days and 2 non-dosing days per week. This schedule may be referred to herein as "5QW" dosing. In this case, the dosing schedule can include 5 consecutive dosing days followed by 2 non-dosing days per week. Thus, Compound A can be administered on days 1-5 and 8-12 of a 2-week dosing schedule (days 1-14). Alternatively, the dosing schedule can include (a) 2 consecutive dosing days and 1 non-dosing day per week, followed by (b) 3 consecutive dosing days and 1 non-dosing day, or (b) 3 consecutive dosing days and 1 non-dosing day per week, followed by (a) 2 consecutive dosing days and 1 non-dosing day. Thus, Compound A can be administered on days 1-2, 4-6, 8-9, and 11-13 of a two-week administration schedule (days 1-14), or on days 1-3, 5-6, 8-10, and 12-13 of a two-week administration schedule.

[0021] In another embodiment, the dosing schedule can include dosing every other day and dosing for 7 days within a 2-week period. Thus, Compound A can be administered on days 1, 3, 5, 7, 9, 11, and 13 of a 2-week dosing schedule (days 1-14). This schedule is sometimes referred to herein as "QOD" dosing.

[0022] As long as administration continues for a specified cycle, administration can be stopped after one to several cycles and resumed after a specified period of drug holidays (no administration). Similarly, the administration schedule of the present disclosure can include a schedule having multiple periods of drug holidays.

[0023] In one embodiment, the dosing schedule can include a two-week intermittent dosing schedule, including dosing 1 to 5 days per week and one or more periods of drug holidays. The intermittent dosing schedule can be practiced during the dosing period before the drug holidays and during the dosing period after the drug holidays.

[0024] In another embodiment, the dosing schedule can include a two-week intermittent dosing schedule that includes dosing 1 to 5 days per week and two periods of drug holidays. The intermittent dosing schedule can be practiced during the dosing period before the first period of drug holidays, the dosing period between the two periods of drug holidays, and the dosing period after the second period of drug holidays.

[0025] In another embodiment, the dosing schedule can include a two-week intermittent dosing schedule that includes dosing 1 to 5 days per week and two or more periods of drug holidays. The intermittent dosing schedule can be practiced during the dosing period before the first period of drug holidays, the dosing period between two adjacent periods of drug holidays, and the dosing period after the last period of drug holidays.

[0026] The period of drug holidays is not particularly limited and can be suitably set according to the patient's condition, etc. For example, the period of drug holidays can be within the range of 1 to 35 days. Alternatively, the period of drug holidays can be within the range of 1 to 12 months.

[0027] In some embodiments, Compound A or a salt thereof is administered once or more than once each day on any of the dosing days. In a preferred embodiment, Compound A or a salt thereof is administered once per day. In another embodiment, Compound A or a salt thereof is administered twice per day. In another embodiment, Compound A or a salt thereof is administered three times per day.

[0028] A typical daily dose of Compound A or a salt thereof may be in the range of 100 pg to 100 mg / kg body weight, more typically 10 ng to 25 mg / kg body weight. More typically, a daily dose of Compound A or a salt thereof may be in the range of 100 ng to 20 mg / kg body weight, although higher or lower doses can be administered if necessary. For example, a daily dose may be in the range of 1 μg to 20 mg / kg body weight, more typically 10 μg to 20 mg / kg body weight, and more typically 100 μg to 20 mg / kg body weight.

[0029] Dosage is also defined as the amount of drug administered relative to the patient's body surface area (mg / m 2 A typical daily dose of Compound A or a salt thereof is 3700 pg / m 2 ~3700mg / m 2 The daily dose may be in the range of 370 ng / m 2 ~925mg / m 2 , more typically 3700 ng / m 2 ~740mg / m 2 However, higher or lower doses can be administered if necessary. For example, a daily dose can be 37 μg / m 2 ~740mg / m 2 , and more typically 370 μg / m 2 ~740mg / m 2 , or 3700 μg / m 2 ~740mg / m 2 It could be.

[0030] Compound A or a salt thereof of the present invention can be orally administered in a single dose, for example, in the range of 0.05 to 5000 mg. Typically, the range can be 10 to 1000 mg. Typical examples of dosages include 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 125, 150, 175, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975 and 1000 mg. The dose can be increased or decreased stepwise from any dose within the above range (0.05 to 5000 mg), for example, in increments of 1 mg, 5 mg, 10 mg, 20 mg, 25 mg, or 50 mg. The dose can be varied depending on the patient's symptoms, weight, age, sex, etc.

[0031] In various embodiments, Compound A or a salt thereof is administered in the form of a pharmaceutical composition. Pharmaceutical compositions containing Compound A or a salt thereof used in the present disclosure can be formulated according to known techniques. See, for example, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, USA. The pharmaceutical composition can be in any form suitable for oral, parenteral, topical, intranasal, intrabronchial, sublingual, intraocular, intraaural, rectal, intravaginal, or transdermal administration. Of these, oral administration is preferred. When the composition is intended for parenteral administration, it can be formulated for intravenous, intramuscular, intraperitoneal, subcutaneous administration, or for direct delivery to a target organ or tissue by injection, infusion, or other delivery means. Delivery can be by bolus injection, short-term infusion, or relatively long-term infusion, and can be via passive delivery or via the use of a suitable infusion pump or syringe driver.

[0032] Compound A or its salts used in the present disclosure may be in the form of crystals, including cocrystals.Single crystals and polymorphic crystal mixtures are included within the scope of Compound A or its salts.Such crystals can be produced by crystallization according to crystallization methods known in the art.Compound A or its salts may be solvated (e.g., hydrated) or non-solvated.Any of these forms are included within the scope of the compound or its salts of the present disclosure.Crystal forms, including cocrystals, of Compound A are disclosed in International Publication No. 2019 / 106579, the disclosure of which is incorporated herein by reference in its entirety.

[0033] Compound A may be an isotope (e.g., 3 H, 14 C. 35 S, and 125 I), and such labeled compounds and salts thereof are also included within the scope of Compound A or its salts as used in this disclosure.

[0034] The salt of Compound A used in the present disclosure refers to the salt generally used in the field of organic chemistry.Examples of such salts include base addition salts and acid addition salts.The salt of Compound A is preferably a pharmaceutically acceptable salt.

[0035] In one embodiment, Compound A or a salt thereof is in the free form of Compound A (i.e., not a salt of Compound A). In one embodiment, Compound A is in the form of a co-crystal of Compound A and benzoic acid.

[0036] Due to their excellent RNR inhibitory activity, Compound A or its salt used in the present disclosure is useful as a pharmaceutical preparation for preventing and treating RNR-related diseases. Therefore, the administration schedule of the present disclosure is useful for treating RNR-related diseases. As used herein, "RNR" includes human or non-human RNR, preferably human RNR.

[0037] Examples of "RNR-associated diseases" or "diseases characterized by RNR expression and / or activity," as used interchangeably herein, include diseases whose occurrence can be reduced and whose symptoms can be alleviated, ameliorated, and / or completely cured by removing, suppressing, and / or inhibiting RNR function. Examples of such diseases include, but are not limited to, tumors, including malignant tumors. The type of malignant tumor that can be treated with Compound A or a salt thereof is not particularly limited. Examples of such malignant tumors include ductal tumors, carcinoid tumors, undifferentiated carcinomas, angiosarcomas, adenocarcinomas, gastrointestinal cancers (e.g., colorectal cancer ("CRC"), including colon cancer and rectal cancer), biliary tract cancers, including gallbladder cancer and bile duct cancer, and gallbladder cancers (e.g., bile duct cancer).cancer), anal cancer, esophageal cancer, gastric cancer, gastrointestinal carcinoid tumor, gastrointestinal stromal tumor ("GIST"), liver cancer, duodenal cancer, and small intestine cancer), lung cancer (e.g., non-small cell lung cancer ("NSCLC"), squamous cell lung cancer, large cell lung cancer, small cell lung cancer, mesothelioma, and other lung cancers (such as bronchial tumor and pleuropulmonary blastoma)), urinary tract cancer (e.g., kidney cancer, renal transitional cell carcinoma ("TCC"), renal pelvis and ureter TCC ("PDQ"), bladder cancer, urethral cancer, and prostate cancer), head and neck cancer (e.g., For example, eye cancer, retinoblastoma, intraocular melanoma, hypopharyngeal cancer, pharyngeal cancer, laryngeal cancer, laryngeal papilloma, metastatic squamous cell carcinoma of occult primary, oral cavity cancer, lip cancer, throat cancer, oropharyngeal cancer, nasal neuroblastoma, nasal cavity and paranasal sinus cancer, nasopharyngeal carcinoma, and salivary gland cancer), endocrine cancer (for example, thyroid cancer, parathyroid cancer, multiple endocrine neoplasia syndrome, thymoma and thymic carcinoma, pancreatic cancer including pancreatic ductal adenocarcinoma ("PDAC"), pancreatic neuroendocrine tumors, and islet cell tumors), breast cancer (extrahepatic ductal carcinoma in situ ("DCIS"), intraepithelial cancer, lobular carcinoma of the breast ("LCIS"), triple-negative breast cancer, and inflammatory breast cancer), male and female reproductive tract cancers (e.g., cervical cancer, ovarian cancer, endometrial cancer, uterine sarcoma, uterine cancer, vaginal cancer, vulvar cancer, gestational trophoblastic tumors ("GTD"), extragonadal germ cell tumors, extracranial germ cell tumors, germ cell tumors, testicular cancer, and penile cancer), brain and nervous system cancers (e.g., astrocytoma, brain stem glioma, brain tumor, craniopharyngioma, central nervous system ("CNS") cancer, chordoma, ependymoma, embryonal tumor, neuroblastoma, paraneoplastic anomaly ("PTA"), thyroid cancer ... ganglioneuroma and atypical teratoma), skin cancer (e.g., basal cell carcinoma ("BCC"), squamous cell skin cancer ("SCC"), Merkel cell carcinoma and melanoma), tissue and bone cancer (e.g., soft tissue sarcoma, rhabdomyosarcoma, fibrous histiocytoma of bone, Ewing's sarcoma, malignant fibrous histiocytoma of bone ("MFH"), osteosarcoma and chondrosarcoma), cardiovascular cancer (e.g., cardiac cancer and tumors), appendix cancer, childhood and adolescent cancer (e.g., pediatric adrenocortical carcinoma, midline tract carcinoma, hepatocellular carcinoma ("HCC"), hepatoblastoma and Wilms' tumor), and virus-induced cancer (e.g., HHV-8-associated cancer (Kaposi's sarcoma) and HIV / AIDS-associated cancer). In some embodiments, the cancer is lung cancer, pancreatic cancer, or colorectal cancer. Other preferred examples include solid tumors.

[0038] Examples of such malignancies also include, but are not limited to, hematological and plasma cell malignancies (e.g., cancers affecting the blood, bone marrow, and / or lymph nodes), such as multiple myeloma, leukemia and lymphoma, myelodysplastic syndromes and myeloproliferative disorders (myeloproliferative neoplasms), and myelodysplastic / myeloproliferative neoplasm (MDS / MPN) overlap syndromes. Leukemias include, but are not limited to, acute lymphoblastic leukemia ("ALL"), acute myeloid leukemia ("AML"), chronic lymphocytic leukemia ("CLL"), chronic myelogenous leukemia ("CML"), acute monocytic leukemia ("AMoL"), hairy cell leukemia, and / or other leukemias. Lymphomas include, but are not limited to, Hodgkin's lymphoma and non-Hodgkin's lymphoma ("NHL"). In some embodiments, the NHL is a B-cell lymphoma and / or a T-cell lymphoma. In some embodiments, NHL includes, but is not limited to, diffuse large B-cell lymphoma ("DLBCL"), small lymphocytic lymphoma ("SLL"), chronic lymphocytic leukemia ("CLL"), mantle cell lymphoma ("MCL"), Burkitt's lymphoma, cutaneous T-cell lymphoma including mycosis fungoides and Sézary syndrome, AIDS-related lymphoma, follicular lymphoma, lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia ("WM")), primary central nervous system (CNS) lymphoma and / or other lymphomas.

[0039] Preferred examples include myeloid neoplasms such as acute myeloid leukemia (AML). In one embodiment, the RNR-associated disease targeted by the present disclosure is acute myeloid leukemia (AML), including relapsed or refractory (R / R) acute myeloid leukemia (AML). In another embodiment, the RNR-associated disease targeted by the present disclosure is myelodysplastic syndrome. In another embodiment, the RNR-associated disease targeted by the present disclosure is myeloproliferative disorder (myeloproliferative neoplasm). In another embodiment, the RNR-associated disease targeted by the present disclosure is myelodysplastic / myeloproliferative neoplasm (MDS / MPN) overlap syndrome. Another preferred example includes solid tumors.

[0040] In one embodiment, the RNR-related disease targeted by the present disclosure is an SLFN11 (Schlafen family member 11)-positive tumor. It has been reported that SLFN11 contributes to the sensitivity of Ewing's sarcoma cells to RNR inhibition (Oncotarget, (2016 Sep 27) Vol. 7, No. 39, pp. 63003-63019) and that SLFN11 binds to replication forks in response to replication stress (Mol. Cell (2018) Vol. 69, Issue 3, pp. 371-384.e6). However, the correlation between SLFN11 expression in tumor cells and the effect of Compound A or its salt on tumors remains unclear. This disclosure, for the first time, demonstrates that SLFN11-positive tumors can be targeted by Compound A or its salt, as demonstrated in the following examples.

[0041] In the present disclosure, "SLFN11" refers to human or non-human SLFN11, preferably human SLFN11. Furthermore, "SLFN11" includes isoforms. An example of the nucleotide sequence of the human SLFN11 gene is the sequence represented by NCBI Reference Sequence: NM_001104587.2. An example of the amino acid sequence of the human SLFN11 protein is the sequence represented by NCBI Reference Sequence: NP_001098057.1. The nucleotide and amino acid sequences shown above may contain polymorphic mutations. Polymorphic mutations include, for example, silent mutations that do not result in a change in amino acid residues; or mutations resulting from the deletion, substitution, or insertion of one or more (e.g., about 1 to 5, or 1 to 3) amino acid residues compared to the amino acid sequence of wild-type SLFN11.

[0042] In the present disclosure, " SLFN11 positive " refers to the state that SLFN11 is expressed at a higher level than normal level. SLFN11 positive can be determined by measuring expression level. As long as expression level can be measured quantitatively or semi-quantitatively, there is no specific restriction on what is measured in measuring expression level. Examples include mRNA expression level and protein expression level.

[0043] The expression level can be measured from a sample of a subject. "Sample" includes not only biological samples (e.g., cells, tissues, organs, body fluids (blood, lymph, etc.), digestive fluids, urine), but also nucleic acid extracts (e.g., genomic DNA extracts, mRNA extracts, cDNA or cRNA preparations prepared from mRNA extracts, etc.) or protein extracts obtained from these biological samples. Furthermore, the sample may be subjected to formalin fixation, alcohol fixation, freezing, or paraffin embedding. The sample preferably contains tumor cells. The method for obtaining a biological sample can be appropriately selected depending on the type of biological sample.

[0044] If selected for measurement, the mRNA expression level can be measured by using primers or probes that specifically hybridize with SLFN11 mRNA according to the techniques commonly used for measuring mRNA expression levels, such as Northern blotting, RT-PCR, real-time PCR, DNA microarray, in situ hybridization and RNA sequencing.The detection device can be any known device (GeneChip, microarray, etc.).Primers and probes can be prepared by commonly known methods as polynucleotides that specifically hybridize with the DNA or mRNA of human SLFN11 based on the known DNA or mRNA sequence information of SLFN11 (for example, human SLFN11 mRNA NCBI reference sequence: NM_001104587.2).

[0045] When selected for measurement, the protein expression level can be measured using an antibody that specifically recognizes the SLFN11 protein according to commonly used measurement methods such as ELISA, Western blotting, immunohistochemical staining, and immunofluorescence. The antibody used for measurement is not particularly limited, as long as it specifically recognizes the SLFN11 protein (anti-SLFN11 antibody). Examples include immunoglobulins (IgA, IgD, IgE, IgG, IgM, IgY, etc.), Fab fragments, F(ab')2 fragments, single-chain antibody fragments (scFv), single-domain antibodies, diabodies, etc. Examples of these antibodies include, but are not limited to, polyclonal antibodies and monoclonal antibodies (mouse antibodies, llama antibodies, chicken antibodies, rabbit antibodies, donkey antibodies, chimeric antibodies, humanized antibodies, human antibodies, etc.). These antibodies can be prepared using various known methods. The preparation method is not particularly limited. Examples of known methods include inoculating an animal with the full-length or fragment of the SLFN11 protein to activate the animal's immune system, collecting the animal's serum, and obtaining an anti-SLFN11 polyclonal antibody; or obtaining an anti-SLFN11 monoclonal antibody by hybridoma method, phage display method, or the like. Alternatively, commercially available antibodies can also be used. An example is the anti-SLFN11 antibody (#sc515071) (Santa Cruz Biotechnology).

[0046] The expression level of a protein during staining by immunohistochemistry or immunofluorescence can be calculated from the staining ratio (positive cell occupancy rate) and staining intensity. The expression level of a protein during staining can be, for example, a numerical value obtained by the H score method using the following formula (Am. J. Clin. Pathol., 90 (3): 233-9 (1988)).

[0047]

number

[0048] In addition to the H score method, the Allred method (Allred DC et al., Mod. Pathol., 11: 155-68 (1998)) uses the following formula to calculate the score: Allred score: positive cell occupancy score + staining intensity score (positive cell occupancy score; 0: no staining, 1: less than 1%, 2: 1% or more and less than 10%, 3: 10% or more and less than 1 / 3, 4: 1 / 3 or more and less than 2 / 3, 5: 2 / 3 or more) (staining intensity; 0: no staining, 1: weak staining intensity, 2: intermediate staining intensity, 3: strong staining intensity); and the J score method (Kenbikyo, 44 ​​(1): 30-34) which calculates the score using only the positive cell occupancy (%). (2009)) (J score 0: no staining, J score 1: less than 1% positive cell occupancy, J score 2: 1% or more and less than 10% positive cell occupancy, J score 3: 10% or more positive cell occupancy) can be used.

[0049] If selected for measurement, protein expression levels can be measured by antibody-based methods, e.g., mass spectrometry (MS)-based methods (e.g., LC-MS / MS or MALDI-TOF MS, ESI Q MS, ESI-IT MS), or combinations thereof, optionally in combination with two-dimensional electrophoresis (2-DE).

[0050] The phrase "a condition in which SLFN11 is expressed at a level higher than the normal level" means that the expression level of SLFN11 in a sample from a tumor patient is relatively high; in one embodiment, the expression level of SLFN11 is equal to or higher than a predetermined cutoff point.

[0051] As used herein, cutoff point varies depending on various conditions, such as the type of subject to be measured and the type of measurement method, and cutoff point is not limited to a specific value.Specific cutoff point can be determined by using the SLFN11 expression level of tumor patients measured in advance according to various statistical analysis techniques.For example, the mean and median values ​​of SLFN11 expression level in tumor patients; the cutoff point for separating the SLFN11 high expression group and the SLFN11 low expression group among tumor patients, which is the value that the P value of the log-rank test for the therapeutic effect (tumor shrinkage effect, progression-free survival extension effect, etc.) of chemotherapy using an antitumor agent comprising compound A or its salt is the minimum value and less than the standard value (for example, P value is 0.1 or less or 0.05 or less) in the SLFN11 high expression group and the SLFN11 low expression group; the SLFN11 expression level in patients who have been subjected to chemotherapy using an antitumor agent comprising compound A or its salt, which makes the sum of sensitivity and specificity maximum based on ROC (Receiver Operating Characteristic) analysis, and the SLFN11 expression level of the antitumor agent comprising compound A or its salt, which is the value that the P value of the log-rank test for the therapeutic effect (tumor shrinkage effect, progression-free survival extension effect, etc.) of chemotherapy using an antitumor agent comprising compound A or its salt is the minimum value and less than the standard value (for example, P value is 0.1 or less or 0.05 or less). The cutoff point for separating the SLFN11 high expression group from the SLFN11 low expression group among tumor patients is a value determined from the relationship between the presence or absence of a therapeutic effect (tumor shrinkage effect, progression-free survival extension effect, etc.) of chemotherapy using compound A or its salt to a specific level or more; and the cutoff point for separating the SLFN11 high expression group from the SLFN11 low expression group among tumor patients is a value at which the P value in the chi-square test for the therapeutic effect (tumor shrinkage effect, progression-free survival extension effect, etc.) of chemotherapy using an antitumor agent containing an RNR inhibitor in the SLFN11 high expression group and the SLFN11 low expression group is the minimum value and less than the standard value (for example, a P value of 0.1 or less or 0.05 or less). Among these, the mean and median values ​​of SLFN11 expression levels in tumor patients are preferred, and the mean value of SLFN11 expression levels in tumor patients is more preferred.

[0052] An example of a cutoff point is one in which an H-score equal to or greater than 1 indicates SLFN11 positivity. Other examples of cutoff values ​​are one in which an H-score equal to or greater than 30 indicates SLFN11 positivity, one in which an H-score equal to or greater than 100 indicates SLFN11 positivity, one in which an H-score equal to or greater than 200 indicates SLFN11 positivity, etc. Such cutoff points can be determined based on measurements obtained from samples from patients administered Compound A or a salt thereof and the efficacy of Compound A or a salt thereof in the patient. SLFN11 positivity can also be determined by methods that can show results scientifically similar to those of the methods mentioned above.

[0053] Examples of SLFN11-positive tumors include not only tumors that test positive initially, but also tumors that test positive for SLFN11 at least once during any stage of tumor progression, including metastasis and recurrence.

[0054] When compound A or its salt is used in pharmaceutical preparations, if necessary, pharmaceutical carriers can be added to form suitable dosage forms according to the purpose of prevention and treatment.Acceptable dosage forms include oral preparations, injections, suppositories, ointments, patches, etc.Among them, oral preparations are preferred.Such dosage forms can be formed by methods commonly known to those skilled in the art.

[0055] Regarding pharmaceutical carrier, various common organic or inorganic carrier materials can be used as preparation material.For example, such material can be mixed as excipient, binder, disintegrant, lubricant or coating agent in solid preparation; or as solvent, solubilizer, suspending agent, isotonicity agent, pH adjuster, buffer or soothing agent in liquid preparation.In addition, if necessary, pharmaceutical preparation additives such as preservative, antioxidant, coloring agent, flavoring agent or flavor enhancer and stabilizer can also be used.

[0056] An exemplary oral solid preparation can be prepared as follows: Compound A is added with excipients, optionally together with binders, disintegrants, lubricants, colorants, taste-masking agents or flavoring agents, etc., and the resulting mixture is then formulated into tablets, coated tablets, granules, powders, capsules, etc. by methods known in the art.

[0057] Examples of excipients include lactose, sucrose, D-mannitol, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and anhydrous silicic acid. Examples of binders include water, ethanol, 1-propanol, 2-propanol, simple syrup, liquid glucose, liquid alpha-starch, liquid gelatin, D-mannitol, carboxymethylcellulose, hydroxypropylcellulose, hydroxypropyl starch, methylcellulose, ethylcellulose, shellac, calcium phosphate, polyvinylpyrrolidone, etc. Examples of disintegrants include dry starch, sodium alginate, powdered agar, sodium bicarbonate, calcium carbonate, sodium lauryl sulfate, monoglyceride stearate, lactose, etc. Examples of lubricants include purified talc, sodium stearate, magnesium stearate, borax, polyethylene glycol, etc. Examples of coloring agents include titanium oxide, iron oxide, etc. Examples of flavoring agents include sucrose, bitter orange peel, citric acid, tartaric acid, etc.

[0058] When preparing liquid preparations for oral administration, taste-masking agents, buffers, stabilizers, flavoring agents, etc. can be added to Compound A; and the resulting mixture can be formulated into oral liquid preparations, syrups, elixirs, etc. according to methods known in the art.

[0059] Examples of flavoring agents or flavoring agents may be the same as those mentioned above. Examples of buffering agents include sodium citrate, etc. Examples of stabilizers include tragacanth, gum arabic, gelatin, etc. If necessary, these preparations for oral administration can be coated with enteric coatings or other coatings according to methods known in the art, for example, for the purpose of prolonged effect. Examples of such coatings include hydroxypropylmethylcellulose, ethylcellulose, hydroxymethylcellulose, hydroxypropylcellulose, polyoxyethylene glycol, and TWEEN® 80.

[0060] When preparing injections, pH adjusting agents, buffering agents, stabilizers, isotonicity adjusting agents, local anesthetics, etc. can be added to Compound A; and the resulting mixture can be formulated into subcutaneous, intramuscular, and intravenous injections according to methods known in the art.

[0061] Examples of pH adjusters and buffers include sodium citrate, sodium acetate, sodium phosphate, etc. Examples of stabilizers include sodium pyrosulfite, EDTA, thioglycolic acid, thiolactic acid, etc. Examples of local anesthetics include procaine hydrochloride, lidocaine hydrochloride, etc. Examples of isotonic agents include sodium chloride, glucose, D-mannitol, glycerin, etc.

[0062] The amount of Compound A or a salt thereof formulated in each unit dosage form can generally be about 0.05, 0.1, 1, 5, 10, 20, or 25 to about 100, 500, or 1000 mg per unit dosage form for oral administration, about 0.01 or 0.1 to about 200, 300, or 500 mg for injections, and about 1, 5, or 10 to about 100, 500, or 1000 mg for suppositories, although these amounts can be varied depending on the symptoms of the patient or the dosage form used.

[0063] In one embodiment, Compound A or a salt thereof can be administered in a single dose or in a single cycle of the exemplary administration schedule. In an exemplary embodiment, Compound A or a salt thereof can be administered in combination with other drugs according to the exemplary administration schedule. When Compound A or a salt thereof is administered in combination with other drugs, Compound A or a salt thereof can be administered on the same day and / or at the same time as such other drugs, or Compound A can be administered on a different day and / or at a different time than such other drugs. Such other drugs can be administered continuously, sporadically, or intermittently during the administration schedule of Compound A or a salt thereof.

[0064] The antitumor effect can be enhanced by using Compound A or a salt thereof in combination with one or more other antitumor agents. Therefore, the present disclosure also encompasses administration schedules using Compound A or a salt thereof in such a combined manner. Compound A or a salt thereof and one or more other antitumor agents can be administered in a single preparation (i.e., a combination drug) or in two or more separate preparations to be administered in combination. Anti-tumor effects can be evaluated, for example, as a reduction in tumor volume, tumor growth stasis, or prolonged survival.

[0065] In one embodiment, the administration schedule comprises administering an antitumor formulation comprising a combination of Compound A or a salt thereof with one or more other antitumor agents. In another embodiment, the administration schedule comprises administering an antitumor effect enhancer for the antitumor agent, wherein the enhancer comprises Compound A or a salt thereof as an active ingredient.

[0066] Other antitumor agents are not particularly limited. Examples of additional anticancer agents include chemotherapeutic agents (e.g., cytotoxic agents), immunotherapeutic agents, hormonal and antihormonal agents, targeted therapy agents, and antiangiogenic agents. Many anticancer agents can be classified into one or more of these groups. Although certain anticancer agents are classified into certain groups or subgroups herein, many of these agents can also be listed in one or more other groups or subgroups, as would be currently understood in the art. It should be understood that the classification herein of certain agents into certain groups is not intended to be limiting. Many anticancer agents are currently known in the art and can be used in combination with the compounds of the present disclosure.

[0067] Furthermore, the agent may be an agonist, antagonist, allosteric modulator, toxin, or more generally, may act to inhibit or stimulate its target (e.g., receptor or enzyme activation or inhibition). For example, one or more agents (e.g., antibodies, antigen-binding regions, or soluble receptors) that specifically bind to and inhibit the activity of a growth factor, such as antagonists of hepatocyte growth factor (HGF, also known as scatter factor), and antibodies or antigen-binding regions that specifically bind to its receptor, "c-met," are suitable for use.

[0068] In various embodiments, the additional anti-cancer agent is a chemotherapeutic agent, an immunotherapeutic agent, a hormone, an anti-hormonal agent, a targeted therapy, or an anti-angiogenic agent (or angiogenesis inhibitor). In one embodiment, the additional anti-cancer agent is a chemotherapeutic agent, an antimitotic agent, a plant alkaloid, an alkylating agent, an antimetabolite, a platinum analog, an enzyme, a topoisomerase inhibitor, a retinoid, an aziridine, an antibiotic, a hormone, an anti-hormonal agent, an anti-estrogen, an anti-androgen, an anti-adrenal, an androgen, a targeted therapy, an immunotherapeutic agent, a biological response modifier, a cytokine inhibitor, a tumor vaccine, a monoclonal antibody, an immune checkpoint inhibitor, an anti-PD-1 agent, an anti-PD-L1 agent, a colony-stimulating factor, an immunomodulator, an immunomodulatory imide (IMiD), an anti-CTLA4 agent, an anti-LAG1 agent, an anti-OX40 agent, a GITR agonist, a CAR-T cell, a BiTE, a signal transduction inhibitor, a growth factor inhibitor and a glycolysis inhibitor.

[0069] In various embodiments, the additional anti-cancer agent is a chemotherapeutic agent, non-limiting examples of which include antimitotic agents and plant alkaloids, alkylating agents, antimetabolites, platinum analogs, enzymes, topoisomerase inhibitors, retinoids, aziridines, and antibiotics.

[0070] Non-limiting examples of antimitotic agents and plant alkaloids include taxanes such as cabazitaxel, docetaxel, larotaxel, ortataxel, paclitaxel, and tesetaxel; demecolcine; epothilones; eribulin; etoposide (VP-16); etoposide phosphate; navelbine; noscapine; teniposide; thaliblastine; vinblastine; vincristine; vindesine; vinflunine; and vinorelbine.

[0071] Non-limiting examples of alkylating agents include nitrogen mustards, such as chlorambucil, chlornaphazine, cholophosphamide, cytofosphan, estramustine, ifosfamide, mannomustine, mechlorethamine, mechlorethamine oxide hydrochloride, melphalan, novembichin, phenesterine, prednimustine, tris(2-chloroethyl)amine, trofosfamide, and uracil mustard; alkyl sulfonates, such as busulfan, improsulfan, and piposulfan; nitrosoureas, such as carbapenems; Mustine, chlorozotocin, fotemustine, lomustine, nimustine, ranimustine, streptozocin, and TA-07; ethyleneimines and methylamelamines, such as altretamine, thiotepa, triethylenemelamine, triethylenethiophosphoramide, triethylenephosphoramide, and trimethylolmelamine; ambamustine; bendamustine; dacarbazine; etoglucide; irofulven; mafosfamide; mitobronitol; mitolactol; pipobroman; procarbazine; temozolomide; treosulfan; and triaziquone.

[0072] Non-limiting examples of antimetabolites include folic acid analogs, such as aminopterin, denopterin, edatrexate, methotrexate, pteropterin, raltitrexed, and trimetrexate; purine analogs, such as 6-mercaptopurine, 6-thioguanine, fludarabine, forodesine, thiamiprine, and thioguanine; pyrimidine analogs, such as 5-fluorouracil (5-FU), 6-azauridine, ancitabine, azacitidine, capecitabine, carmofur, and cytarabine. , decitabine, dideoxyuridine, doxifuridine, doxifluridine, enocitabine, floxuridine, galocitabine, gemcitabine, and sapacitabine; 3-aminopyridine-2-carboxaldehyde thiosemicarbazone; broxuridine; cladribine; cyclophosphamide; cytarabine; emitefur; hydroxyurea; mercaptopurine; nelarabine; pemetrexed; pentostatin; tegafur; and troxacitabine.

[0073] Non-limiting examples of platinum analogs include carboplatin, cisplatin, dicycloplatin, heptaplatin, lobaplatin, nedaplatin, oxaliplatin, satraplatin, and triplatin tetranitrate. Non-limiting examples of enzymes include asparaginase and pegaspargase.

[0074] Non-limiting examples of topoisomerase inhibitors include acridine carboxamide, amonafide, amsacrine, belotecan, elliptinium acetate, exatecan, indolocarbazole, irinotecan, lurtotecan, mitoxantrone, razoxane, rubitecan, SN-38, sobuzoxane, and topotecan.

[0075] Non-limiting examples of retinoids include alitretinoin, bexarotene, fenretinide, isotretinoin, liarozole, R1I retinamide, and tretinoin.

[0076] Non-limiting examples of aziridines include benzodopa, carboquone, meturedopa, and uredopa.

[0077] Non-limiting examples of antibiotics include intercalating antibiotics; anthracenediones; anthracycline antibiotics such as aclarubicin, amrubicin, daunomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, menogaril, nogalamycin, pirarubicin, and barbicin; 6-diazo-5-oxo-L-norleucine; aclacinomycin; actinomycin; autramycin; azaserine; bleomycin; cactinomycin; calicheamicin; carabicin; carminomycin; carzino These include filin; chromomycin; dactinomycin; detorubicin; esorubicin; esperamicin; geldanamycin; marcelomycin; mitomycin; mitomycin C; mycophenolic acid; olivomycin; novantrone; peplomycin; porfiromycin; potfiromycin; puromycin; quelamycin; rebeccamycin; rodorubicin; streptonigrin; streptozocin; tanespimycin; tubercidin; ubenimex; zinostatin; zinostatin stimalamer; and zorubicin.

[0078] In various embodiments, the additional anti-cancer agent is a hormonal agent and / or an anti-hormonal agent (i.e., hormone therapy). Non-limiting examples of hormonal agents and anti-hormonal agents include anti-androgens, such as abiraterone, apalutamide, bicalutamide, darolutamide, enzalutamide, flutamide, goserelin, leuprolide, and nilutamide; anti-estrogens, such as 4-hydroxytamoxifen, aromatase-inhibiting 4(5)-imidazole, EM-800, fosfestrol, fulvestrant, keoxifene, LY 117018, onapristone, raloxifene, tamoxifen, toremifene, and trioxifene; antiadrenal agents such as aminoglutethimide, dexaminoglutethimide, mitotane, and trilostane; androgens such as calsterone, dromostanolone propionate, epitiostanol, mepitiostane, and testolactone; abarelix; anastrozole; cetrorelix; deslorelin; exemestane; fadrozole; finasteride; formestane; histrelin (RL 0903); human chorionic gonadotropin; lanreotide; LDI 200 (Milkhaus); letrozole; leuprorelin; mifepristone; nafarelin; nafoxidine; osaterone; prednisone; thyrotropin alfa; and triptorelin.

[0079] In various embodiments, the additional anti-cancer agent is an immunotherapeutic agent (i.e., immunotherapy). Non-limiting examples of immunotherapeutic agents include biological response modifiers, cytokine inhibitors, tumor vaccines, monoclonal antibodies, immune checkpoint inhibitors, colony-stimulating factors, and immunomodulators.

[0080] Non-limiting examples of biological response modifiers, including cytokine inhibitors (cytokines) such as interferons and interleukins, include interferon alfa / interferon alpha, e.g., interferon alfa-2, interferon alfa-2a, interferon alfa-2b, interferon alfa-n1, interferon alfa-n3, interferon alfacon-1, pegylated interferon alfa-2a, pegylated interferon alfa-2b, and leukocyte alpha interferon; interferon beta, e.g., interferon beta-1a, and interferon beta-1b; interferon gamma, e.g., natural interferon gamma-1a, and interferon gamma-1b; aldesleukin; interleukin-1 beta; interleukin-2; oprelvekin; sonermin; tasonermin; and virulizin.

[0081] Non-limiting examples of tumor vaccines include APC 8015, AVICINE, bladder cancer vaccine, cancer vaccine (Biomira), gastrin 17 immunogen, Maruyama vaccine, melanoma lysate vaccine, melanoma oncolysate vaccine (New York Medical College), melanoma vaccine (New York University), melanoma vaccine (Sloan Kettering Institute), TICE® BCG (Bacille Calmette-Guerin), and viral melanoma lysate vaccine (Royal Newcastle Hospital).

[0082] Non-limiting examples of monoclonal antibodies include abagovomab, adecatumumab, aflibercept, alemtuzumab, blinatumomab, brentuximab vedotin, CA 125 MAb (Biomira), cancer MAb (Japan Pharmaceutical Development), daclizumab, daratumumab, denosumab, edrecolomab, gemtuzumab zogamicin, HER-2 and Fc MAb (Medarex), ibritumomab tiuxetan, idiotype 105AD7 MAb (CRC Technology), idiotype CEA MAb (Trilex), ipilimumab, lintuzumab, LYM-1-iodine-131 MAb (Techni These include mitumomab, moxetumomab, ofatumumab, polymorphic epithelial mucin-yttrium 90 MAb (Antisoma), ranibizumab, rituximab, and trastuzumab.

[0083] Non-limiting examples of immune checkpoint inhibitors include anti-PD-1 agents or antibodies, such as cemiplimab, nivolumab, and pembrolizumab; anti-PD-L1 agents or antibodies, such as atezolizumab, avelumab, and durvalumab; anti-CTLA-4 agents or antibodies, such as ipilumumab; anti-LAG1 agents; and anti-OX40 agents.

[0084] Non-limiting examples of colony stimulating factors include darbepoetin alfa, epoetin alfa, epoetin beta, filgrastim, granulocyte macrophage colony stimulating factor, lenograstim, relidistim, millimostim, molgramostim, nartograstim, pegfilgrastim, and sargramostim.

[0085] Non-limiting examples of additional immunotherapeutic agents include BiTEs, CAR-T cells, GITR agonists, imiquimod, immunomodulatory imides (IMiDs), mismatched double-stranded RNA (Ampligen), resiquimod, SRL 172, and thymalfasin.

[0086] In various embodiments, the additional anticancer agent is a targeted therapeutic agent (i.e., targeted therapy). Targeted therapeutic agents include, for example, monoclonal antibodies and small molecule drugs. Non-limiting examples of targeted therapeutic agents include signal transduction inhibitors, growth factor inhibitors, tyrosine kinase inhibitors, EGFR inhibitors, histone deacetylase (HDAC) inhibitors, histone methyltransferase inhibitors, proteasome inhibitors, cell cycle inhibitors, angiogenesis inhibitors, matrix metalloproteinase (MMP) inhibitors, hepatocyte growth factor inhibitors, TOR inhibitors, KDR inhibitors, VEGF inhibitors, fibroblast growth factor (FGF) inhibitors, MEK inhibitors, ERK inhibitors, PI3K inhibitors, AKT inhibitors, MCL-1 inhibitors, BCL-2 inhibitors, SHP2 inhibitors, HER-2 inhibitors, BRAF inhibitors, gene expression regulators, autophagy inhibitors, apoptosis inducers, antiproliferative agents, and glycolysis inhibitors.

[0087] Non-limiting examples of signal transduction inhibitors include tyrosine kinase inhibitors, multiple kinase inhibitors, anlotinib, avapritinib, axitinib, dasatinib, dovitinib, imatinib, lenvatinib, lonidamine, nilotinib, nintedanib, pazopanib, pegvisomant, ponatinib, vandetanib, and EGFR inhibitors.

[0088] Non-limiting examples of EGFR inhibitors include small molecule antagonists of EGFR, such as afatinib, brigatinib, erlotinib, gefitinib, lapatinib, and osimertinib; and antibody-based EGFR inhibitors, including any anti-EGFR antibody or antibody fragment that can partially or completely block EGFR activation by its natural ligand. Antibody-based EGFR inhibitors include, for example, those described in Modjtahedi, H., et al., 1993, Br. J. Cancer 67:247-253; Teramoto, T., et al., 1996, Cancer 77:639-645; Goldstein et al., 1995, Clin. Cancer Res. 1: 1311-1318; Huang, S. M., et al., 1999, Cancer Res. 15:59(8): 1935-40; and Yang, X., et al., 1999, Cancer Res. 59: 1236-1243; the monoclonal antibody Mab E7.6.3 (Yang, 1999, supra); Mab C225 (ATCC Accession No. HB-8508), or an antibody or antibody fragment having its binding specificity; specific antisense nucleotides or siRNA; afatinib, cetuximab; matuzumab; necitumumab; nimotuzumab; panitumumab; and zalutumumab.

[0089] Non-limiting examples of histone deacetylase (HDAC) inhibitors include belinostat, panobinostat, romidepsin, and vorinostat. Non-limiting examples of histone methyltransferase inhibitors include ezh2 inhibitors.

[0090] Non-limiting examples of proteasome inhibitors include bortezomib, carfilzomib, ixazomib, marizomib (salinosporamide a), and oprozomib. Non-limiting examples of cell cycle inhibitors such as CDK inhibitors include abemaciclib, alvocidib, palbociclib, and ribociclib.

[0091] In various embodiments, the additional anti-cancer agent is an anti-angiogenic agent (or angiogenesis inhibitor), including, but not limited to, matrix metalloproteinase (MMP) inhibitors; VEGF inhibitors; EGFR inhibitors; TOR inhibitors, e.g., everolimus and temsirolimus; PDGFR kinase inhibitors, e.g., crenolanib; HIF-1α inhibitors, e.g., PX 478; HIF-2α inhibitors, e.g., velttifan and the HIF-2α inhibitors described in WO 2015 / 035223; fibroblast growth factor (FGF) or FGFR inhibitors, e.g., B-FGF and RG 13577; hepatocyte growth factor inhibitors; KDR inhibitors; anti-Ang1 and anti-Ang2 agents; anti-Tie2 kinase inhibitors; Tek antagonists (U.S. Patent Application Publication No. 2003 / 0162712; U.S. Patent No. 6,413,932); anti-TWEAK agents (U.S. Patent No. 6,727,225); ADAM distintegrin domains that antagonize the binding of integrins to their ligands (U.S. Patent Application Publication No. 2002 / 0042368); anti-eph receptor and / or anti-ephrin antibodies or antigen-binding regions (U.S. Patent Nos. 5,981,245; 5,728,813; 5,969,110; 6,596,852; 6,232,447; and 6,057,124); and anti-PDGF-BB antagonists and antibodies or antigen-binding regions that specifically bind to PDGF-BB ligands.

[0092] Non-limiting examples of matrix metalloproteinase (MMP) inhibitors include MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, prinomastat, RO 32-3555, and RS 13-0830. Examples of useful matrix metalloproteinase inhibitors are described, for example, in International Publication Nos. WO 96 / 33172, WO 96 / 27583, EP 1004578, WO 98 / 07697, WO 98 / 03516, WO 98 / 34918, WO 98 / 34915, WO 98 / 33768, WO 98 / 30566, EP 0606046, and WO 0931788. and EP 0 780 386. Preferred MMP-2 and MMP-9 inhibitors are those that have little or no activity inhibiting MMP-1. More preferred are those that selectively inhibit MMP-2 and / or MMP-9 relative to other matrix metalloproteinases (i.e., MAP-1, MMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13).

[0093] Non-limiting examples of VEGF and VEGFR inhibitors include bevacizumab, cediranib, CEP 7055, CP 547632, KRN 633, orantinib, pazopanib, pegaptanib, pegaptanib octasodium, semaxanib, sorafenib, sunitinib, VEGF antagonist (Borean, Denmark), and VEGF-TRAP™.

[0094] The additional anti-cancer agent may also be another anti-angiogenic agent, including, but not limited to, 2-methoxyestradiol, AE 941, alemtuzumab, α-D148 Mab (Amgen, US), alphastatin, anecortave acetate, angiocidin, an angiogenesis inhibitor (SUGEN, US), angiostatin, anti-Vn Mab (Crucell, Netherlands), atiprimod, axitinib, AZD 9935, BAY RES 2690 (Bayer, Germany), BC 1 (Genoa Institute of Cancer Research, Italy), beloranib, benefin (Lane Labs, US), cabozantinib, CDP 791 (Celltech Group, UK), chondroitinase AC, cilengitide, combretastatin A4 prodrug, CP 564959 (OSI, US), CV247, CYC 381 (Harvard University, US), E 7820, EHT 0101, endostatin, enzastaurin hydrochloride, ER-68203-00 (IVAX, US), fibrinogen-E fragment, Flk-1 (ImClone Systems, US), a form of FLT 1 (VEGFR 1), FR-111142, GCS-100, GW 2286 (GlaxoSmithKline, UK), IL-8, ilomastat, IM-862, irsogladine, KM-2550 (Kyowa Hakko, Japan), lenalidomide, lenvatinib, MAb α5β3 integrin, second generation (Applied Molecular Evolution, USA and MedImmune, US), MAb VEGF (Xenova, UK), marimastat, maspin (Sosei, Japan), metastatin, motuporamine C, M-PGA, ombrulin, OXI4503, PI 88, platelet factor 4, PPI 2458, ramucirumab, rBPI 21 and BPI-derived antiangiogenic agents (XOMA, US), regorafenib, SC-236, SD-7784 (Pfizer, US), SDX 103 (University of California at San Diego, US), SG292 (Telios, US), SU-0879 (Pfizer, US), TAN-1120, TBC-1635, tesevatinib, tetrathiomolybdic acid, thalidomide, thrombospondin 1 inhibitors, Tie-2 ligand (Regeneron, US), tissue factor pathway inhibitor (EntreMed, US), tumor necrosis factor-alpha inhibitors, tumstatin, TZ 93, urokinase plasminogen activator inhibitors, vadimezan, vandetanib, vasostatin, vatalanib, VE-cadherin-2 antagonists, xanthorrhizol, XL 784 (Exelixis, US), ziv-aflibercept, and ZD 6126.

[0095] In various embodiments, the additional anti-cancer agent is an additional active agent that disrupts or inhibits the RAS-RAF-ERK or PI3K-AKT-TOR signaling pathway, or is a PD-1 and / or PD-L1 antagonist. In various embodiments, the additional anti-cancer agent is a RAF inhibitor, an EGFR inhibitor, a MEK inhibitor, an ERK inhibitor, a PI3K inhibitor, an AKT inhibitor, a TOR inhibitor, an MCL-1 inhibitor, a BCL-2 inhibitor, an SHP2 inhibitor, a proteasome inhibitor, or an immunotherapy, such as a monoclonal antibody, an immunomodulatory imide (IMiD), an anti-PD-1, an anti-PDL-1, an anti-CTLA4, an anti-LAG1, and an anti-OX40 agent, a GITR agonist, a CAR-T cell, and a BiTE. Non-limiting examples of RAF inhibitors include dabrafenib, encorafenib, regorafenib, sorafenib, and vemurafenib.

[0096] Non-limiting examples of MEK inhibitors include binimetinib, CI-1040, cobimetinib, PD318088, PD325901, PD334581, PD98059, refametinib, selumetinib, and trametinib.

[0097] Non-limiting examples of ERK inhibitors include LY3214996, LTT462, MK-8353, SCH772984, ravoxertinib, ulixertinib, and ERKi as described in WO 2017 / 068412.

[0098] Non-limiting examples of PI3K inhibitors include 17-hydroxywortmannin analogs (e.g., WO 06 / 044453); AEZS-136; alpelisib; AS-252424; buparlisib; CAL263; copanlisib; CUDC-907; dactolisib (WO 06 / 122806); demethoxyviridine; duvelisib; GNE-477; GSK1059615; IC87114; idelalisib; INK1117; LY294002; Palomid 529; paxalisib; perifosine; PI-103; PI-103 hydrochloride; pictilisib (e.g., WO 09 / 036,082; WO 09 / 055,730); PIK 90; PWT33597; SF1126; sonolisib; TGI 00-115; TGX-221; XL147; XL-765; wortmannin; and ZSTK474.

[0099] Non-limiting examples of AKT inhibitors include Akt-1-1 (inhibits Akt1) (Barnett et al. (2005) Biochem. J., 385 (Pt. 2), 399-408); Akt-1-1,2 (Barnett et al. (2005) Biochem. J. 385 (Pt. 2), 399-408); API-59CJ-Ome (e.g., Jin et al. (2004) Br. J. Cancer 91, 1808-12); 1-H-imidazo[4,5-c]pyridinyl compounds (e.g., WO 05011700); indole-3-carbinol and its derivatives (e.g., U.S. Pat. No. 6,656,963; Sarkar and Li (2004) J Nutr. 134(12 Suppl), 3493S-3498S); perifosine (Dasmahapatra et al. (2004) Clin. Cancer Res. 10(15), 5242-52, 2004); phosphatidylinositol ether lipid analogues (e.g., Gills and Dennis (2004) Expert. Opin. Investig. Drugs 13,787-97); triciribine (Yang et al. (2004) Cancer Res. 64, 4394-9); imidazooxazone compounds including trans-3-amino-1-methyl-3-(4-(3-phenyl-5H-imidazo[1,2-c]pyrido[3,4-e][1,3]oxazin-2-yl)phenyl)-cyclobutanol hydrochloride (WO 2012 / 137870); afuresertib; capivasertib; MK2206; and ipatasertib.

[0100] Non-limiting examples of TOR inhibitors include deforolimus; ATP-competitive TORC1 / TORC2 inhibitors, including PI-103, PP242, PP30, and torin1; TOR inhibitors in the FKBP12 enhancer, including temsirolimus, everolimus, WO 9409010, rapamycin and its derivatives; rapalogs (e.g., as disclosed in WO 98 / 02441 and WO 01 / 14387, e.g., AP23573, AP23464, or AP23841); 40-(2-hydroxyethyl)rapamycin, 40-[3-hydroxy(hydroxymethyl)methylpropanoate]-rapamycin; 40-epi-(tetrazolyl)-rapamycin (also referred to as ABT578); 32-deoxorapamycin; 16-pentaerythropoietin; thionyloxy-32(S)-dihydrorapamycin and other derivatives disclosed in WO 05 / 005434; U.S. Pat. No. 5,258,389; WO 94 / 090101; WO 92 / 05179; U.S. Pat. Nos. 5,118,677; 5,118,678; 5,100,883; 5,151,413; 5,120,842; and derivatives disclosed in WO 93 / 111130, WO 94 / 02136, WO 94 / 02485, WO 95 / 14023, WO 94 / 02136, WO 95 / 16691, WO 96 / 41807, WO 96 / 41807 and U.S. Pat. No. 5,256,790; and phosphorus-containing rapamycin derivatives (e.g., WO 05 / 016252). Non-limiting examples of MCL-1 inhibitors include AMG-176, MIK665, and S63845.

[0101] Additional non-limiting examples of anti-cancer agents suitable for use include 2-ethylhydrazide, 2,2',2"-trichlorotriethylamine, ABVD, aceglatone, acemannan, aldophosphamide glycoside, alpharadin, amifostine, aminolevulinic acid, anagrelide, ANCER, ancestim, anti-CD22 immunotoxin, antitumorigenic herbs, apaziquone, aruglavin, arsenic trioxide, azathioprine, BAM 002 (Novelos), bcl-2 (Genta), bestravcil, biricodar, bisantrene, bromocriptine, brostallicin, bryostatin, buthionine sulfoximine, calyculin, cell cycle non-specific antineoplastic agents, celmoleukin, clodronate, clotrimazole, cytarabine ocfosfate, DA 3030 (Dong-A), defofamine, denileukin diftitox, dexrazoxane, diaziquone, dichloroacetic acid, dilazep, discodermolide, docosanol, doxercalciferol, edelfosine, eflornithine, EL532 (Elan), elfomithine, elsamitrucin, eniluracil, etanidazole, exisulind, ferruginol, folic acid supplements, such as florinic acid acid, gacytosine, gallium nitrate, gimeracil / oteracil / tegafur combination (S-1), glycopine, histamine dihydrochloride, HIT diclofenac, HLA-B7 gene therapy (Vical), human fetal alpha-fetoprotein, ibandronate, ibandronate, ICE chemotherapy regimen, imexon, iobenguane, IT-101 (CRLX101), laniquidar, LC 9018 (Yakult), leflunomide, lentinan, levamisole + fluorouracil, lovastatin, lucantone, masoprocol, melarsoprol, metoclopramide, miltefosine, miproxifen, mitoguazone, mitozolomide, mopidamol, motexafine gadolinium, MX6 (Galderma), naloxone + pentazocine, nitracrine, nolatrexed, NSC631570 Octreotide (Ukrain), olaparib, P-30 protein, PAC-1, palifermin, pamidronate, pamidronic acid, pentosan polysulfate sodium, phenamet, picibanil, pixantrone, platinum, podophyllic acid, porfimer sodium, PSK (polysaccharide-K), rabbit antithymocyte polyclonal antibody, rasburiembodiment, retinoic acid, etidronate rhenium Re 186, romurtide, samarium (Sm 153), lexidronam, sizofiran, sodium phenylacetate, sparfosic acid acid), spirogermanium, strontium-89 chloride, suramin, swainsonine, talaporfin, tariquidar, tazarotene, tegafur-uracil, temoporfin, tenuazonic acid, tetrachlorodecaoxide, thrombopoietin, tin ethyl etiopurpurin, tirapazamine, TLC ELL-12, tositumomab iodine-131, trifluridine and tipiracil combination, troponin I (Harvard University, US), urethane, valspodar, verteporfin, zoledronic acid, and zosuquidar.

[0102] In embodiments, the administration schedule includes administering an antitumor formulation comprising Compound A or a salt thereof in combination with radiation therapy to treat cancer. Techniques for administering radiation therapy are known in the art.

[0103] Radiation therapy can be administered by one of several methods, or a combination of methods, including, but not limited to, external beam radiation therapy, internal beam radiation therapy, implant radiation therapy, stereotactic radiotherapy, total body radiation therapy, radiotherapy, and permanent or temporary interstitial brachytherapy. As used herein, the term "brachytherapy" refers to radiation therapy delivered by a spatially confined radioactive material inserted into the body at or near the site of a tumor or other proliferative tissue disease. This term is intended to include, but is not limited to, exposure to radioactive isotopes (e.g., At-211, I-131, I-125, Y-90, Re-186, Re-188, Sm-153, Bi-212, P-32, and radioactive isotopes of Lu). Suitable radiation sources for use as cell regulators of the present disclosure include both solid and liquid sources. In a non-limiting example, the radiation source can be a radionuclide, such as I-125, I-131, Yb-169, Ir-192, I-125 as a solid source, or other radionuclides that emit photons, beta particles, gamma radiation, or other therapeutic radiation. The radioactive material can also be a fluid made from a solution of any of the radionuclides (e.g., a solution of I-125 or I-131), or a radioactive fluid can be produced using a slurry of a suitable fluid containing small particles of solid radionuclides, e.g., Au-198, Y-90. Additionally, the radionuclide can be embodied in a gel or radioactive microspheres.

[0104] Preparations of one or more other antitumor agents also include drug delivery system (DDS) preparations therefor. For example, "paclitaxel" includes albumin-bound paclitaxel (e.g., Abraxane), paclitaxel micelles (e.g., NK105), etc.; "cisplatin" includes cisplatin micelles (e.g., NC-6004), etc.

[0105] The administration schedules of the present disclosure are applicable to the prevention of diseases or disorders characterized by the expression of RNR. The administration schedules are also applicable for administration in pre- or post-operative treatment, or as adjuvant or post-operative adjuvant therapy. Regardless of the scope of the appended claims, aspects and example embodiments of the present disclosure are described in the following detailed description:

[0106] (1) In one embodiment, the present disclosure provides a method for preventing and / or treating an RNR-associated disease in a patient in need thereof, comprising administering to the patient an effective amount of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof on a two-week intermittent dosing schedule comprising dosing one to five days per week. (2) The method described in (1) above can include a dosing schedule based on a four-week cycle that is administered once or repeated two or more times. (3) In one embodiment, the method described in (1) or (2) above can include a case where the administration schedule includes administration of the medication one day per week.

[0107] (4) In another embodiment, the method described in (1) or (2) above can include a case where the administration schedule includes three dosing days and four non-dosing days per week. (5) In this embodiment, the dosing schedule can include three consecutive days of dosing followed by four days of no dosing in a week. (6) Alternatively, the dosing schedule can include three alternate-day doses followed by two non-drug days during the week.

[0108] (7) In another embodiment, the method described in (1) or (2) above can include a case where the administration schedule includes 5 dosing days and 2 non-dosing days per week. (8) In this embodiment, the dosing schedule can include five consecutive days of dosing followed by two days of no dosing in a week. (9) Alternatively, the administration schedule may be as follows: (a) 2 consecutive days of medication and 1 day off, followed by (b) 3 consecutive days of medication and 1 day off. Contains, or (b) 3 consecutive days of medication and 1 day off, followed by (a) 2 consecutive days of medication and 1 day off. may include:

[0109] (10) In another embodiment, the method described in (1) or (2) above can include a case where the administration schedule includes dosing every other day and dosing for 7 days in a 2-week period. (11) The method according to any one of (1) to (10) above can include oral administration of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof. (12) The method according to any one of (1) to (11) above may include a case where the RNR-associated disease is a tumor, including a malignant tumor.

[0110] (13) The method according to any one of (1) to (11) above can include a case where the RNR-associated disease is acute myeloid leukemia (AML), including relapsed or refractory (R / R) acute myeloid leukemia (AML). In another aspect, the method according to any one of (1) to (11) above can include a case where the RNR-associated disease is an SLFN11-positive tumor.

[0111] (14) The method according to any one of (1) to (13) above may include a case in which 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof is administered at a daily dose within the range of 1 ng to 1000 mg, 2 ng to 40 mg, 2 ng to 20 mg, 1 μg to 20 mg, 10 μg to 20 mg, or 100 μg to 20 mg per kg of patient body weight.

[0112] (15) In another embodiment, the present disclosure provides a method of treating acute myeloid leukemia (AML) in a patient in need thereof, comprising administering to the patient an effective amount of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof on a two-week intermittent dosing schedule comprising dosing one to five days per week.

[0113] (16) The method of claim (15) above may include a case where 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof is administered as a single agent.

[0114] (17) The method of claim (15) above may include a case where 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof is administered together with one or more additional antitumor agents.

[0115] (18) In another embodiment, the present disclosure provides a method for reducing the risk of acute myeloid leukemia (AML) relapse or death in a patient diagnosed with AML, comprising administering to the patient an effective amount of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof on a two-week intermittent dosing schedule comprising dosing one to five days per week.

[0116] (19) The method of (18) above may include a case where 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof is administered as a single agent.

[0117] (20) The method of (18) above may include a case where 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof is administered together with one or more additional antitumor agents.

[0118] (21) In another embodiment, the present disclosure provides use of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof for the manufacture of a medicament for treating an RNR-associated disease, wherein the medicament is formulated for administration on a 2-week intermittent dosing schedule comprising dosing 1 to 5 days per week. (22) The use of (21) above can include cases where the RNR-associated disease is a tumor, including a malignant tumor.

[0119] (23) The use of (21) above can include a case where the RNR-associated disease is acute myeloid leukemia (AML), including relapsed or refractory (R / R) acute myeloid leukemia (AML). In another aspect, the use of (21) above can include a case where the RNR-associated disease is an SLFN11-positive tumor.

[0120] (24) In another embodiment, the present disclosure provides a pharmaceutical composition for preventing and / or treating an RNR-associated disease in a patient in need thereof, wherein the pharmaceutical composition comprises 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof, and is administered to the patient on a 2-week intermittent dosing schedule comprising dosing 1 to 5 days per week. (25) The pharmaceutical composition described in (24) above may contain a pharmaceutical carrier.

[0121] (26) The pharmaceutical composition according to (24) or (25) above can be administered in a dosing schedule based on a 4-week cycle, which can be performed once or repeated two or more times. (27) The pharmaceutical compositions described in (24) to (26) above may be oral compositions. (28) The pharmaceutical compositions described in (24) to (27) above can be used to treat tumors, including malignant tumors.

[0122] (29) The pharmaceutical compositions described in (24) to (27) above can be used to treat acute myeloid leukemia (AML), including relapsed or refractory (R / R) acute myeloid leukemia (AML). In another embodiment, the pharmaceutical compositions described in (24) to (27) above can be used to reduce the risk of AML recurrence or death in patients diagnosed with acute myeloid leukemia (AML). In another embodiment, the pharmaceutical compositions described in (24) to (27) above can be used to prevent and / or treat SLFN11-positive tumors.

[0123] (30) The pharmaceutical compositions described in (24) to (29) above can be administered at a daily dose of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof within the range of 1 ng to 1000 mg, 2 ng to 40 mg, 2 ng to 20 mg, 1 μg to 20 mg, 10 μg to 20 mg, or 100 μg to 20 mg per kg of patient body weight.

[0124] (31) In another embodiment, the present disclosure provides a compound for preventing and / or treating an RNR-associated disease in a patient in need thereof, wherein the compound is 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof, and is administered to the patient on a 2-week intermittent dosing schedule comprising dosing 1 to 5 days per week. (32) The compound described in (31) above may contain a pharmaceutical carrier.

[0125] (33) The compound described in (31) or (32) above can be administered in a dosing schedule based on a 4-week cycle, which can be performed once or repeated two or more times. (34) The compounds described in (31) to (33) above can be provided in an oral composition. (35) The compounds described in (31) to (34) above can be used to treat tumors, including malignant tumors.

[0126] (36) The compounds described in (31) to (35) above can be used to treat acute myeloid leukemia (AML), including relapsed or refractory (R / R) acute myeloid leukemia (AML). In another embodiment, the compounds described in (31) to (35) above or salts thereof can be used to prevent and / or treat SLFN11-positive tumors.

[0127] (37) The compound described in (31) to (36) above can be administered at a daily dose of 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof within the range of 1 ng to 1000 mg, 2 ng to 40 mg, 2 ng to 20 mg, 1 μg to 20 mg, 10 μg to 20 mg, or 100 μg to 20 mg per kg of patient body weight. [Example]

[0128] The present disclosure will be described in more detail below with reference to examples.However, the scope of the present disclosure is not limited to these examples.The present disclosure will be fully described below with examples; however, it is understood that various changes and modifications can be made by those skilled in the art.Therefore, such changes and modifications shall be included in the present disclosure as long as they do not deviate from the scope of the present disclosure.

[0129] Example 1 Antitumor Effect and Body Weight Change with QOD Dosage Regimen Human acute myeloid leukemia (AML) cell line MV-4-11 cells (American Type Culture Collection CRL-9591 TM) was implanted into the right thoracic region of male nude mice (CLEA Japan). After tumor implantation, the long and short axes (mm) of the tumor were measured, and the tumor volume (TV) was calculated for each mouse. Subsequently, mice were assigned to the following groups so that the mean TV of each group was equivalent: control group (open circle), continuous dosing group (closed circle: 100 mg / kg / day; open diamond: 150 mg / kg / day), and QOD dosing group (closed triangle: 200 mg / kg / day; closed diamond: 300 mg / kg / day). The day when group assignment (n=5) was performed was designated as day 0.

[0130] 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (Compound A) was suspended in 5 mg / mL hypromellose solution to provide appropriate test samples for 100 mg / kg, 150 mg / kg, 200 mg / kg, and 300 mg / kg dosing regimens. Control animals received no treatment.

[0131] Mice in the continuous dosing group were orally administered 100 mg / kg / day or 150 mg / kg / day of Compound A once daily from day 1 to day 14. The total dose for mice in the continuous dosing group (group C-1) receiving 100 mg / kg / day was 1400 mg / kg, and the total dose for mice in the continuous dosing group (group C-2) receiving 150 mg / kg / day was 2100 mg / kg.

[0132] Mice in the QOD dosing groups were orally administered 200 mg / kg / day or 300 mg / kg / day of Compound A once every other day (days 1, 3, 5, 7, 9, 11, and 13) for two weeks. The total dose for mice in the QOD dosing group receiving 200 mg / kg / day (group QOD-1) was 1400 mg / kg, and the total dose for mice in the QOD dosing group receiving 300 mg / kg / day (group QOD-2) was 2100 mg / kg.

[0133] On days 4, 8, 11 and 15, the following formula was used: TV (mm 3 )=(long axis x short axis 2 ) / 2, relative tumor volume (RTV) was calculated as an index of antitumor effect during the administration period for each group (FIG. 1).

[0134] As shown in Figure 1, both the continuous administration group and the QOD administration group showed the effect of reducing tumor volume compared with the control group on day 15. When comparing Group C-1 with Group QOD-1, which has a total dose of 1400 mg / kg, the effect of reducing tumor volume in Group QOD-1 is higher than that in Group C-1, and the difference is statistically significant (t-test, p<0.05). When comparing Group C-2 with Group QOD-2, which has a total dose of 2100 mg / kg, the effect of reducing tumor volume in Group QOD-2 and Group C-2 is similar, and the difference is not statistically significant.

[0135] Meanwhile, body weight (BW) was measured on days 4, 8, 11, and 15, and the average body weight change (BW change, %) compared to the body weight on day 0 was calculated as an index of toxicity during the administration period using the following formula: BW change (%) = [(BW on day n) - (BW on day 0)] / (BW on day 0) × 100. The results are shown in Figure 2.

[0136] As shown in Figure 2, weight loss was observed in the continuous and QOD groups. When comparing Group C-1 with Group QOD-1, which had a total dose of 1400 mg / kg, no statistically significant difference was observed. However, when comparing Group C-2 with Group QOD-2, which had a total dose of 2100 mg / kg, the recovery indicated by the % change in BW in Group QOD-2 was statistically significant (t-test, p<0.05) compared to Group C-2 on Day 15. This result indicates improved weight loss as an indicator of side effects of Compound A administration with an intermittent dosing regimen (QOD group) compared to a continuous daily dosing regimen (continuous dosing group).

[0137] The above results revealed that the intermittent regimen (alternate-day dosing) is a very useful method that provides a less toxic dosing schedule and exhibits higher or similar antitumor efficacy while avoiding the toxicity resulting from Compound A administration.

[0138] Example 2: Antitumor Effect and Body Weight Change with QW Dosing Regimen Similar to Example 1, the antitumor effects and body weight changes among five groups were examined in mice bearing MV-4-11 cells: control group (open circle), continuous dosing group (closed circle: 100 mg / kg / day; open diamond: 150 mg / kg / day), and QW dosing group (closed square: 700 mg / kg / day; ×: 1050 mg / kg / day).

[0139] 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (Compound A) was suspended in 5 mg / mL hypromellose solution to provide appropriate test samples for the 100 mg / kg, 150 mg / kg, 700 mg / kg, and 1050 mg / kg dosing regimens. Control animals received no treatment.

[0140] Mice in the continuous dosing group were orally administered 100 mg / kg / day or 150 mg / kg / day of Compound A once daily from day 1 to day 14. The total dose for mice in the continuous dosing group (group C-1) receiving 100 mg / kg / day was 1400 mg / kg, and the total dose for mice in the continuous dosing group (group C-2) receiving 150 mg / kg / day was 2100 mg / kg.

[0141] Mice in the QW dosing groups were orally administered 700 mg / kg / day or 1050 mg / kg / day of Compound A once per week (days 1 and 8) for two weeks. The total dose for mice in the QW dosing group receiving 700 mg / kg / day (group QW-1) was 1400 mg / kg, and the total dose for mice in the QW dosing group receiving 1050 mg / kg / day (group QW-2) was 2100 mg / kg. On days 4, 8, 11, and 15, the relative tumor volume (RTV) was calculated for each group as an index of the antitumor effect during the administration period (FIG. 3).

[0142] As shown in Figure 3, both the continuous administration group and the QW administration group showed the effect of reducing tumor volume compared with the control group on day 15. When comparing Group C-1 and Group QW-1 with a total dose of 1400 mg / kg, the effect of reducing tumor volume in Group QW-1 was similar to that of Group C-1, and the difference was not statistically significant. When comparing Group C-2 and Group QW-2 with a total dose of 2100 mg / kg, the effect of reducing tumor volume in Group QW-2 and Group C-2 was similar, and the difference was not statistically significant.

[0143] On the other hand, as shown in Figure 4, weight loss was observed in the continuous dosing group and the QOD dosing group. When comparing Group C-1 and Group QW-1 with a total dose of 1400 mg / kg, the recovery indicated by the % change in BW in Group QW-1 on day 15 was statistically significant (t-test, p<0.05) compared with Group C-1. Similarly, when comparing Group C-2 and Group QW-2 with a total dose of 2100 mg / kg, the recovery indicated by the % change in BW in Group QW-2 on day 15 was statistically significant (t-test, p<0.05) compared with Group C-2. This result indicates improved weight loss as an indicator of side effects of Compound A administration with an intermittent dosing regimen (QW dosing group) compared with a continuous daily dosing regimen (continuous dosing group).

[0144] The above results revealed that the intermittent regimen (one dose per week) is a less toxic dosing schedule with comparable antitumor efficacy compared to conventional continuous dosing schedules, and is a very useful method for demonstrating antitumor efficacy while avoiding the toxicity resulting from Compound A administration.

[0145] Example 3: Antitumor effects and body weight changes with 3QW dosing regimen 1 Similar to Example 1, the antitumor effects and body weight changes among five groups were examined in mice bearing MV-4-11 cells: control group (open circle), continuous dosing group (closed circle: 100 mg / kg / day; open diamond: 150 mg / kg / day), and 3QW dosing group 1 (closed triangle: 233 mg / kg / day; closed diamond: 350 mg / kg / day).

[0146] 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (Compound A) was suspended in 5 mg / mL hypromellose solution to provide appropriate test samples for the 100 mg / kg, 150 mg / kg, 233 mg / kg, and 350 mg / kg dosing regimens. Control animals received no treatment.

[0147] Mice in the continuous dosing group were orally administered 100 mg / kg / day or 150 mg / kg / day of Compound A once daily from day 1 to day 14. The total dose for mice in the continuous dosing group (group C-1) receiving 100 mg / kg / day was 1400 mg / kg, and the total dose for mice in the continuous dosing group (group C-2) receiving 150 mg / kg / day was 2100 mg / kg.

[0148] Mice in 3QW Dosing Group 1 were orally administered Compound A at 233 mg / kg / day or 350 mg / kg / day for 3 consecutive days per week (Days 1-3 and 8-10) for 2 weeks. The total dose for mice in 3QW Dosing Group 1 (Group 3QW1-1) receiving 233 mg / kg / day was 1400 mg / kg, and the total dose for mice in 3QW Dosing Group 1 (Group 3QW1-2) receiving 350 mg / kg / day was 2100 mg / kg. On days 4, 8, 11, and 15, the relative tumor volume (RTV) was calculated for each group as an index of the antitumor effect during the administration period (FIG. 5).

[0149] As shown in Figure 5, both the continuous administration group and the 3QW administration group 1 showed the effect of reducing tumor volume compared with the control group on day 15. When comparing group C-1 with group 3QW1-1 having a total dose of 1400 mg / kg, the effect of reducing tumor volume in group 3QW1-1 was similar to that of group C-1, and the difference was not statistically significant. When comparing group C-2 with group 3QW1-2 having a total dose of 2100 mg / kg, the effect of reducing tumor volume in group 3QW1-2 and group C-2 was similar, and the difference was not statistically significant.

[0150] On the other hand, as shown in Figure 6, weight loss was observed in the continuous dosing group and the 3QW dosing group 1. When comparing group C-1 with group 3QW1-1, which has a total dose of 1400 mg / kg, the recovery indicated by the % change in BW in group 3QW1-1 on day 15 was statistically significant (t-test, p<0.05) compared with group C-1. Similarly, when comparing group C-2 with group 3QW1-2, which has a total dose of 2100 mg / kg, the recovery indicated by the % change in BW in group 3QW1-2 on day 15 was statistically significant (t-test, p<0.05) compared with group C-2. This result indicates improved weight loss as an indicator of side effects of Compound A administration in the intermittent dosing regimen (3QW dosing group 1) compared with the continuous daily dosing regimen (continuous dosing group).

[0151] The above results revealed that the intermittent regimen (dosing on three consecutive days per week) is a less toxic dosing schedule with comparable antitumor efficacy compared to conventional continuous dosing schedules, and is a very useful method for demonstrating antitumor efficacy while avoiding the toxicity resulting from Compound A administration.

[0152] Example 4: Antitumor effects and body weight changes in 3QW dosing regimen 2 Similar to Example 1, the antitumor effects and body weight changes among five groups were examined in mice bearing MV-4-11 cells: control group (open circle), continuous dosing group (closed circle: 100 mg / kg / day; open diamond: 150 mg / kg / day), and 3QW dosing group 2 (closed triangle: 233 mg / kg / day; closed diamond: 350 mg / kg / day).

[0153] 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (Compound A) was suspended in 5 mg / mL hypromellose solution to provide appropriate test samples for the 100 mg / kg, 150 mg / kg, 233 mg / kg, and 350 mg / kg dosing regimens. Control animals received no treatment.

[0154] Mice in the continuous dosing group were orally administered 100 mg / kg / day or 150 mg / kg / day of Compound A once daily from day 1 to day 14. The total dose for mice in the continuous dosing group (group C-1) receiving 100 mg / kg / day was 1400 mg / kg, and the total dose for mice in the continuous dosing group (group C-2) receiving 150 mg / kg / day was 2100 mg / kg.

[0155] Mice in 3QW dosing group 2 were orally administered 233 mg / kg / day or 350 mg / kg / day of Compound A three times per week (days 1, 3, 5, 8, 10, and 12) every other day for two weeks. The total dose for mice in 3QW dosing group 2 (group 3QW2-1) receiving 233 mg / kg / day was 1400 mg / kg, and the total dose for mice in 3QW dosing group 2 (group 3QW2-2) receiving 350 mg / kg / day was 2100 mg / kg. On days 4, 8, 11 and 15, the relative tumor volume (RTV) was calculated for each group as an index of the antitumor effect during the administration period (FIG. 7).

[0156] As shown in Figure 7, both the continuous administration group and the 3QW administration group 2 showed the effect of reducing tumor volume compared with the control group on day 15. When comparing group C-1 with group 3QW2-1, which has a total dose of 1400 mg / kg, the effect of reducing tumor volume in group 3QW2-1 is higher than that in group C-1, and the difference is statistically significant (t-test, p<0.05). When comparing group C-2 with group 3QW2-2, which has a total dose of 2100 mg / kg, the effect of reducing tumor volume in group QOD-2 and group C-2 is similar, and the difference is not statistically significant.

[0157] On the other hand, as shown in Figure 8, weight loss was observed in the continuous dosing group and the 3QW dosing group 2. When comparing group C-1 with group 3QW2-1, which had a total dose of 1400 mg / kg, the recovery indicated by the % change in BW in group 3QW2-1 on day 15 was statistically significant (t-test, p<0.05) compared to group C-1. Similarly, when comparing group C-2 with group 3QW2-2, which had a total dose of 2100 mg / kg, the recovery indicated by the % change in BW in group 3QW2-2 on day 15 was statistically significant (t-test, p<0.05) compared to group C-2. This result indicates improved weight loss as an indicator of side effects of Compound A administration in the intermittent dosing regimen (3QW dosing group 2) compared to the continuous daily dosing regimen (continuous dosing group).

[0158] The above results revealed that the intermittent regimen (dosing every other day three times per week) is a less toxic dosing schedule with higher or equivalent antitumor efficacy compared to conventional continuous dosing schedules, and is a very useful method that shows higher or equivalent antitumor efficacy while avoiding the toxicity resulting from Compound A administration.

[0159] Example 5: Antitumor effects and body weight changes with 5QW dosing regimen 1 Similar to Example 1, the antitumor effects and body weight changes among five groups were examined in mice bearing MV-4-11 cells: control group (open circle), continuous dosing group (closed circle: 100 mg / kg / day; open diamond: 150 mg / kg / day), and 5QW dosing group 1 (closed diamond: 140 mg / kg / day; open square: 210 mg / kg / day).

[0160] 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (Compound A) was suspended in 5 mg / mL hypromellose solution to provide appropriate test samples for the 100 mg / kg, 150 mg / kg, 140 mg / kg, and 210 mg / kg dosing regimens. Control animals received no treatment.

[0161] Mice in the continuous dosing group were orally administered 100 mg / kg / day or 150 mg / kg / day of Compound A once daily from day 1 to day 14. The total dose for mice in the continuous dosing group (group C-1) receiving 100 mg / kg / day was 1400 mg / kg, and the total dose for mice in the continuous dosing group (group C-2) receiving 150 mg / kg / day was 2100 mg / kg.

[0162] Mice in 5QW Dosing Group 1 were orally administered 140 mg / kg / day or 210 mg / kg / day of Compound A for 5 consecutive days per week (Days 1-5 and Days 8-12) for 2 weeks. The total dose for mice in 5QW Dosing Group 1 (Group 5QW1-1) receiving 140 mg / kg / day was 1400 mg / kg, and the total dose for mice in 5QW Dosing Group 1 (Group 5QW1-2) receiving 210 mg / kg / day was 2100 mg / kg. On days 4, 8, 11 and 15, the relative tumor volume (RTV) was calculated for each group as an index of the antitumor effect during the administration period (FIG. 9).

[0163] As shown in Figure 9, both the continuous administration group and the 5QW administration group 1 showed the effect of reducing tumor volume compared with the control group on day 15. When comparing group C-1 with group 5QW1-1 having a total dose of 1400 mg / kg, the effect of reducing tumor volume in group 5QW1-1 was similar to that of group C-1, and the difference was not statistically significant. When comparing group C-2 with group 5QW1-2 having a total dose of 2100 mg / kg, the effect of reducing tumor volume in group 5QW1-2 and group C-2 was similar, and the difference was not statistically significant.

[0164] On the other hand, as shown in Figure 10, weight loss was observed in the continuous dosing group and the 5QW dosing group 1. When comparing group C-1 with group 5QW1-1, which has a total dose of 1400 mg / kg, the recovery indicated by the % change in BW in group 5QW1-1 on day 15 was statistically significant (t-test, p<0.05) compared with group C-1. Similarly, when comparing group C-2 with group 5QW1-2, which has a total dose of 2100 mg / kg, the recovery indicated by the % change in BW in group 5QW1-2 on day 15 was statistically significant (t-test, p<0.05) compared with group C-2. This result shows that the weight loss is improved as an indicator of the side effects of compound A administration in the intermittent dosing regimen (5QW dosing group 1) compared with the continuous daily dosing regimen (continuous dosing group).

[0165] The above results revealed that the intermittent regimen (dosing for 5 consecutive days per week) is a less toxic dosing schedule with comparable antitumor efficacy compared to conventional continuous dosing schedules, and is a very useful method for demonstrating antitumor efficacy while avoiding the toxicity resulting from Compound A administration.

[0166] Example 6: Antitumor effects and body weight changes in 5QW dosing regimen 2 Similar to Example 1, the antitumor effects and body weight changes among five groups were examined in mice bearing MV-4-11 cells: control group (open circle), continuous dosing group (closed circle: 100 mg / kg / day; open diamond: 150 mg / kg / day), and 5QW dosing group 2 (closed square: 140 mg / kg / day; ×: 210 mg / kg / day).

[0167] 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide (Compound A) was suspended in 5 mg / mL hypromellose solution to provide appropriate test samples for the 100 mg / kg, 150 mg / kg, 140 mg / kg, and 210 mg / kg dosing regimens. Control animals received no treatment.

[0168] Mice in the continuous dosing group were orally administered 100 mg / kg / day or 150 mg / kg / day of Compound A once daily from day 1 to day 14. The total dose for mice in the continuous dosing group (group C-1) receiving 100 mg / kg / day was 1400 mg / kg, and the total dose for mice in the continuous dosing group (group C-2) receiving 150 mg / kg / day was 2100 mg / kg.

[0169] Mice in 5QW dosing group 2 were orally administered 140 mg / kg / day or 210 mg / kg / day of Compound A, 5 days per week (days 1-2, 4-6, 8-9, and 11-13) for 2 weeks. The total dose for mice in 5QW dosing group 2 (group 5QW2-1) receiving 140 mg / kg / day was 1400 mg / kg, and the total dose for mice in 5QW dosing group 2 (group 5QW2-2) receiving 210 mg / kg / day was 2100 mg / kg. On days 4, 8, 11 and 15, the relative tumor volume (RTV) was calculated for each group as an index of the antitumor effect during the administration period (FIG. 11).

[0170] As shown in Figure 11, both the continuous administration group and the 5QW administration group 2 showed the effect of reducing tumor volume compared with the control group on day 15. When comparing group C-1 with group 5QW2-1, which has a total dose of 1400 mg / kg, the effect of reducing tumor volume in group 5QW2-1 was similar to that of group C-1, and the difference was not statistically significant. When comparing group C-2 with group 5QW2-2, which has a total dose of 2100 mg / kg, the effect of reducing tumor volume in group 5QW2-2 was higher than that of group C-2, with a statistically significant difference (t-test, p<0.05).

[0171] On the other hand, as shown in Figure 12, weight loss was observed in the continuous dosing group and the 5QW dosing group 1. When comparing the BW change percentage values ​​of group C-1 and group 5QW2-1 with a total dose of 1400 mg / kg on day 15, no statistically significant difference was observed. However, when comparing group C-2 and group 5QW2-2 with a total dose of 2100 mg / kg, the recovery indicated by the BW change percentage values ​​of group 5QW2-2 on day 15 was better than that of group C-2, with a statistically significant difference (t-test, p<0.05). This result suggests that the improved weight loss as an indicator of the side effects of compound A administration in the intermittent dosing regimen (5QW dosing group 2) is compared with the continuous daily dosing regimen (continuous dosing group).

[0172] Since the antitumor effects between the 5QW dosing group 2 and the continuous dosing group were the same or higher in the former group compared to the latter, the above results revealed that the intermittent regimen (dosing 5 days per week) is a less toxic dosing schedule with higher or equivalent antitumor effects compared to conventional continuous dosing schedules, and is a very useful method for demonstrating antitumor effects while avoiding the toxicity resulting from Compound A administration.

[0173] All animal experimentation protocols in these studies were reviewed by the Institutional Animal Care and Use Committee and approved by the Institutional Director in accordance with the "Guidelines for Animal Experiment of Taiho Pharmaceutical Co., Ltd." Animal handling was carried out appropriately in accordance with these guidelines.

[0174] Example 7: Correlation between SLFN11 expression and cytotoxic effect of Compound A the purpose: We investigated whether SLFN11 expression correlates with the cytotoxic effect of Compound A. method: cell line RD-ES, SK-ES-1, SK-LMS-1, SJSA-1, SW1353, U-2OS, NCI-H460, and CFPAC-1 cell lines were obtained from ATCC. A673 cell line was obtained from DS Pharma Biomedical. ESS-1 cell line was obtained from DSMZ. MG-63, HOS, and G-292 clone A141B1 cell lines were obtained from Dainippon Pharmaceutical.

[0175] Cell proliferation assay Cell proliferation assays were performed according to the conventional method available in Hasako, S., et al. Mol Cancer Ther 17, 1648-1658 (2018). Briefly, cells were seeded and incubated for 1 day, followed by exposure to compounds for 3 days. After exposure to Compound A, viable cells were detected using the CellTiter-Glo Luminescent Cell Viability Assay (Promega). Experiments were performed in triplicate.

[0176] Correlation analysis Correlation analysis between SLFN11 expression and Compound A cytotoxicity was performed using Pearson correlation coefficient (P<0.05) in JMP 13 software. Gene expression data of cell lines were available online at CCLE (http: / / www.broadinstitute.org / ccle / home). Compound A cytotoxicity data from 11 cell lines listed in Table 1 were used for correlation analysis (correlation data not shown).

[0177] [Table 1]

[0178] siRNA treatment A673, NCI-H460, and CFPAC-1 cells were transfected with 1 nM siRNA using Lipofectamine® RNAiMAX Reagent (Thermo Fisher Scientific) for 24 hours, and then seeded onto 96-well plates for cell proliferation and caspase induction assays, and onto dishes for immunoblotting analysis. The following siRNAs were obtained from Thermo Fisher Scientific: Silencer® Select Negative Control #1 siRNA (#4390843, used as siControl), SLFN11 Silencer® Select Predesigned siRNA (#s40703, used as siSLFN11-1, #s40704, used as siSLFN11-2, and #s40702, used as siSLFN11-3).

[0179] Detection of SLFN11 expression was performed by immunoblotting analysis according to the conventional method available in Hasako et al. (supra). Briefly, cells were harvested, and total cellular proteins were extracted on ice using M-PER (Thermo Fisher Scientific). Proteins were separated by SDS-PAGE and analyzed by Western blotting. SLFN11 was detected with anti-SLFN11 polyclonal antibody (#HPA023030, Atlas Antibodies).

[0180] Cell proliferation assay was performed according to the conventional method available in Hasako, et al. (supra). Briefly, cells treated with siRNA for 24 hours were seeded onto a 96-well plate, incubated for 24 hours, and then exposed to Compound A for 3 days. After compound exposure, viable cells were detected by using the CellTiter-Glo luminescent cell viability assay (Promega).

[0181] Caspase induction assay was performed according to the conventional method available in Hasako, et al. (supra). Briefly, cells treated with siRNA for 24 hours were seeded onto a 96-well plate, incubated for 24 hours, and then treated with Compound A for 24 hours. Caspase induction was detected by using the Caspase-Glo 3 / 7 assay (Promega).

[0182] result: The correlation between SLFN11 mRNA expression and the relative proliferation rate (%) of cells treated with 100 μmol / L of Compound A was analyzed in 11 sarcoma cell lines listed in Table 1. In this analysis, a significant correlation was detected between SLFN11 mRNA expression and relative cell proliferation (%) at 100 μmol / L compound A (FIG. 13).

[0183] To determine whether SLFN11 directly affects the cytotoxic properties of Compound A, we investigated the effect of SLFN11 knockdown using siRNA on the cytotoxicity of Compound A in the Ewing sarcoma cell line A673. As a result, SLFN11 knockdown significantly suppressed the cytotoxic effect of Compound A (Figure 14).

[0184] Furthermore, suppression of Compound A (10 μmol / L)-induced caspase-3 / 7 activation was observed in A673 cells transfected with siRNA against SLFN11 (FIG. 15). Furthermore, reduction of SLFN11 expression was confirmed in A673 cells transfected with siRNA against SLFN11 (FIG. 16).

[0185] To further determine whether SLFN11 directly affects the cytotoxic properties of Compound A in other cancer types, we investigated the effect of SLFN11 knockdown using siRNA on the cytotoxicity of Compound A in the non-small cell lung cancer cell line NCI-H460 and the pancreatic cancer cell line CFPAC-1. As a result, SLFN11 knockdown significantly suppressed the cytotoxic effect of Compound A (Figures 17 and 18).

[0186] Furthermore, suppression of Compound A (10 μmol / L)-induced caspase-3 / 7 activation in NCI-H460 and CHPAC-1 cells, both of which had been transfected with siRNA against SLFN11, was observed (FIG. 19). All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Claims

1. A pharmaceutical composition for preventing and / or treating a tumor in a patient in need thereof, comprising 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof, which is administered to the patient on a 2-week intermittent dosing schedule comprising dosing from 1 to 5 days per week; (a) the dosing schedule comprises dosing one day per week; (b) the administration schedule comprises three dosing days and four non-dosing days per week, preferably (b1) the dosing schedule includes three consecutive days of dosing followed by four days of no dosing in a week; or (b2) the dosing schedule includes three alternate-day doses followed by two non-dosing days per week; (c) the administration schedule comprises 5 dosing days and 2 non-dosing days per week, preferably (c1) the dosing schedule includes 5 consecutive days of dosing followed by 2 days of no dosing in a week; or (c2) The administration schedule is, within one week, (a) two consecutive days of medication and one day off, followed by (b) three consecutive days of medication and one day off, or (b) 3 consecutive days of medication and 1 day of non-medication, followed by (a) 2 consecutive days of medication and 1 day of non-medication, or (d) the dosing schedule comprises dosing every other day for a total of 7 days within a 2-week period; A pharmaceutical composition,

2. 10. The composition of claim 1, wherein the administration schedule is based on a four-week cycle, and the cycle is performed once or repeated two or more times.

3. 10. The composition of claim 1, wherein 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof is administered orally.

4. The composition described in claim 1, wherein the tumor is acute myeloid leukemia (AML), including relapsed or refractory (R / R) acute myeloid leukemia (AML).

5. The composition described in claim 1, wherein the tumor is an SLFN11-positive tumor.

6. A pharmaceutical composition for treating acute myeloid leukemia (AML) in a patient in need thereof, comprising 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof, and administered to the patient on a 2-week intermittent dosing schedule comprising dosing for 1 to 5 days per week.

7. The pharmaceutical composition of claim 6, wherein the administration schedule is: (a) involves one day of medication per week; (b) 3 days on medication and 4 days off medication per week, preferably (b1) 3 consecutive days of dosing followed by 4 consecutive days of non-dosing in a week; or (b2) Three alternate-day doses followed by two non-drug days in a week; (c) 5 days on medication and 2 days off medication per week, preferably (c1) 5 consecutive days of dosing followed by 2 non-dosing days in a week; or (c2) During the week, (a) two consecutive days of medication and one day off, followed by (b) three consecutive days of medication and one day off, or (b) 3 consecutive days of medication and 1 day of non-medication, followed by (a) 2 consecutive days of medication and 1 day of non-medication, or (d) includes dosing every other day for a total of 7 days within a 2-week period; A pharmaceutical composition,

8. The composition described in claim 6 or 7, wherein 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or its salt is administered as a single agent.

9. The composition described in claim 6 or 7, wherein 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or its salt is administered together with one or more additional antitumor agents.

10. A pharmaceutical composition for reducing the risk of recurrence or death from acute myeloid leukemia (AML) in a patient diagnosed with AML, comprising 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or a salt thereof, and administered to the patient on a 2-week intermittent dosing schedule comprising dosing for 1 to 5 days per week.

11. The pharmaceutical composition of claim 10, wherein the administration schedule comprises: (a) involves one day of medication per week; (b) 3 days on medication and 4 days off medication per week, preferably (b1) 3 consecutive days of dosing followed by 4 consecutive days of non-dosing in a week; or (b2) Three alternate-day doses followed by two non-drug days in a week; (c) 5 days on medication and 2 days off medication per week, preferably (c1) 5 consecutive days of dosing followed by 2 non-dosing days in a week; or (c2) During the week, (a) two consecutive days of medication and one day off, followed by (b) three consecutive days of medication and one day off, or (b) 3 consecutive days of medication and 1 day of non-medication, followed by (a) 2 consecutive days of medication and 1 day of non-medication, or (d) includes dosing every other day for a total of 7 days within a 2-week period; A pharmaceutical composition,

12. The composition described in claim 10 or 11, wherein 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or its salt is administered as a single agent.

13. The composition described in claim 10 or 11, wherein 5-chloro-2-(N-((1S,2R)-2-(6-fluoro-2,3-dimethylphenyl)-1-(5-oxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)propyl)sulfamoyl)benzamide or its salt is administered together with one or more additional antitumor agents.

14. The composition of claim 6, 7, 10 or 11, wherein the administration schedule is based on a four-week cycle, and the cycle is performed once or repeated two or more times.

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