Methods for Treating Neoplastic Disease

Abstract

The present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in the claims for use in the treatment of a neoplastic disease in a subject, said treatment comprising administering to the subject the compound of formula (I) or a pharma- ceutically acceptable salt thereof according to an intermittent dosing schedule.

Description

[Technical field]

[0001] The present invention relates to methods of using the compounds of formula (I) and pharma- ceutically acceptable salts thereof as described herein in the treatment of neoplastic diseases, particularly cancer. [Background technology]

[0002] WO 2015 / 155042 describes a recently discovered class of inhibitors of threonine tyrosine kinase (TTK) for use in the treatment of cancer.

[0003] There is a continuing need for new and effective treatment options for cancer patients.As demonstrated in the following examples, it has now surprisingly been found that intermittent administration of the compound of formula (I) described herein in cancer models provides superior efficacy compared to continuous administration, including cure.Furthermore, it has also been found that changing from daily oral administration to intermittent weekly intravenous administration in preclinical species provides consistent drug exposure over time with improved tolerability and gastrointestinal toxicity profile. [Prior art documents] [Patent documents]

[0004] [Patent Document 1] International Publication No. 2015 / 155042 Summary of the Invention [Means for solving the problem]

[0005] In a first aspect, the present invention provides a compound of formula (I) for use in the treatment of a neoplastic disease in a subject [ka] or a pharma- ceutically acceptable salt thereof, wherein treatment comprises administering to the subject a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to an intermittent dosing schedule.

[0006] The compound of formula (I) is disclosed in WO 2015 / 155042 as Example 17.

[0007] Surprisingly, in addition to TTK inhibitory activity, the compound of formula (I) was also found to exhibit Polo-like kinase 1 (PLK1) inhibition (see examples below). Both kinases cooperate to activate the mitotic spindle assembly checkpoint (SAC) at centromeres, regulating the alignment and separation of chromosomes before cells can exit mitosis. Von Schubert et al., Cell Reports, 2015, 12; 66-78, disclose that PLK1 and TTK (also known as MPS1) cooperate to regulate the spindle assembly checkpoint (SAC) in human cells. This possibility of enhanced effects from the inhibition of both TTK and PLK1 is also suggested by Dou et al., Plos ONE 2011, 6: 4; e18793, which shows that some substrates of both kinases share similar consensus motifs.

[0008] In contrast to TTK-specific inhibitors, the compounds of formula (I) combine a sustained effect on TTK with a transient effect on PLK1 (see Examples below), resulting in more rapid disruption of SACs that reinforce aberrant mitotic progression. Thus, the dual TTK / PLK1 inhibitory activity gives the compounds of formula (I) a unique profile that distinguishes them from other molecules that exhibit TTK inhibitory activity without any appreciable level of PLK1 inhibitory activity.

[0009] In a further aspect, the present invention provides a method of treating a neoplastic disease in a subject in need thereof, said treatment comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to an intermittent dosing schedule.

[0010] In a further aspect, the present invention provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for treating a neoplastic disease in a subject, said treatment comprising administering to the subject a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to an intermittent dosing schedule.

[0011] Neoplastic diseases for treatment with a compound of formula (I) or a pharma- ceutically acceptable salt thereof are described below, and in particular the treatment of cancer is contemplated, particularly for human subjects.

[0012] Further aspects and embodiments of the invention are described in more detail below. [Brief description of the drawings]

[0013] [Figure 1] Figure 1 shows the antitumor activity of weekly and twice weekly intermittent intravenous (iv) dosing of the compound of formula (I) in the triple-negative breast cancer (TNBC) MDA-MB-231 model. The compound of formula (I) was administered iv, QW or 2QW at the MTD or a fraction thereof as indicated in the legend. (A) shows the mean tumor volume and (B) shows the mean percent body weight change through day 65. The dashed vertical line indicates the washout period for the QW and 2QW MTD dose groups. N=8 animals were used for the treatment and vehicle control groups. Doxorubicin was administered for the first 5 days using a standard dosing regimen of 3 mg / kg. One non-drug-related animal death occurred in the vehicle group and each of the following dose groups (3 mg / kg 2QW, 9.4 mg / kg 2QW, 12.5 mg / kg 2QW). Three non-drug-related animal deaths occurred in the 25 mg / kg QW dose group. [Diagram 2]Figure 1 shows the evaluation of cure by weekly MTD iv administration in the TNBC MDA-MB-231 model. H&E sections of skin and surrounding tissue from tumor implantation sites were prepared from apparently tumor-free animals (n=3) treated weekly with MTD iv administration of the compound of formula (I) (animals 2, 3 and 8). No neoplastic epithelial cells (residual tumor cells) were observed in samples from mouse 2 or mouse 3, while mouse 8 still exhibited some neoplastic tissue. [Diagram 3] FIG. 1 shows the antitumor activity of daily oral MTD vs. iv weekly intermittent dosing of the compound of formula (I) in the TNBC MDA-MB-231 model. The compound of formula (I) was orally administered daily at the MTD (7.5 mg / kg) or ivQW at the MTD or a fraction thereof, as indicated in the legend. (A) shows the mean tumor volume and (B) shows the mean body weight change in %. N=8 animals were used for the treatment and vehicle control groups. No animal deaths were recorded. [Figure 4] Figure 1 shows the antitumor activity of daily oral MTD vs. iv twice weekly intermittent dosing of the compound of formula (I) in the TNBC MDA-MB-231 model. The compound of formula (I) was orally administered daily at the MTD (7.5 mg / kg) or iv 2QW at the MTD or a fraction thereof, as indicated in the legend. (A) shows the mean tumor volume and (B) shows the mean body weight change in %. N=8 animals were used for the treatment and vehicle control groups. No animal deaths were recorded. [Diagram 5] 1 shows the mean (±SD) plasma concentration-time profiles of compound of formula (I) administered orally to female mice (n=3 per time point). (A) shows plasma concentrations on day 1 after a single oral dose using formulation 2. (B) shows plasma concentrations on day 1 after a single oral dose using formulation 1. [Figure 6] 1 shows the mean (±SD) plasma concentration-time profiles of compound of formula (I) administered orally to female mice (n=3 per time point). (A) shows plasma concentrations after 5 days of daily oral dosing using formulation 1. (B) shows plasma concentrations after 5 days of daily oral dosing using formulation 2. [Figure 7] Figure 1 shows the mean (±SD) plasma concentration-time profiles of the compound of formula (I) administered intravenously to female mice (n=3 per time point). (A) Plasma concentrations on day 1 after a single intravenous dose. (B) Plasma concentrations on day 6 after 5 days of oral dosing followed by a single intravenous dose on day 6. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0014] definition Certain terms used herein are described below: Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs.

[0015] As used herein, the term "pharmacologically acceptable" refers to items such as compounds, materials, compositions and / or dosage forms that are suitable, within the scope of sound medical judgment, for contact with human tissue without undue toxicity or other complications commensurate with a reasonable benefit / risk ratio.

[0016] The term "patient" refers to a human presenting himself / herself for therapeutic treatment.

[0017] The term "subject" refers to a mammal, preferably a patient.

[0018] The term "treatment," as used herein in the context of treating a disease in a subject, generally refers to treatments and therapies that achieve one or more of the following desired therapeutic effects: inhibition of disease progression, slowing progression rate, stopping progression rate, prevention of disease progression, alleviation of disease symptoms, amelioration of disease, and cure of disease. For example, treatment can be the attenuation of one or several symptoms of a disorder or the complete eradication of a disorder. Within the meaning of this disclosure, the term "treatment" also means preventing, delaying the onset of a disease (i.e., the period before the clinical manifestation of a disease), and / or reducing the risk of onset or worsening.

[0019] As used herein, the terms "prevent", "prevention" or "prevention" include the prevention of at least one symptom associated with or caused by the disease being prevented.

[0020] The terms "pharmacologically effective amount," "therapeutically effective amount," or "clinically effective amount" are those amounts sufficient, when administered in accordance with a desired treatment regimen, to provide an observable or clinically significant improvement over baseline clinically observable signs and symptoms of the disease being treated with the compound of formula (I) or a pharma- ceutically acceptable salt thereof, e.g., commensurate with a reasonable benefit / risk ratio.

[0021] The term "about" refers to a variation of up to 10% of the associated figure. In some embodiments, the term "about" refers to a variation of up to 5% of the associated figure.

[0022] For the avoidance of doubt, where a range is provided (eg, 5 mg to 480 mg), that range includes the stated upper limit (480 mg) and lower limit (5 mg) of that range.

[0023] Compounds of formula (I) In some embodiments, the compound of formula (I) is used as a free base. In other embodiments, the compound of formula (I) is used as a pharma- ceutically acceptable salt.

[0024] The pharmaceutically acceptable salt of the compound of formula (I) can be an acid addition salt.Salt is formed from the compound of formula (I) using, for example, organic acid or inorganic acid.Pharmaceutically acceptable salt is within the scope of the common knowledge of those skilled in the art.Pharmaceutically acceptable salt can contain two or more molecules or ions of the corresponding acid.

[0025] The compounds of formula (I) and their pharma- ceutically acceptable salts may be solvated, in particular hydrated. During the preparation process, solvation and / or hydration may occur.

[0026] The compounds of formula (I) and pharma- ceutically acceptable salts thereof may be synthesized as described in WO 2015 / 155042, which is incorporated herein by reference, in particular pages 17-19, and as described in Example 17 on page 49 of WO 2015 / 155042, which is also incorporated herein by reference (including references to Examples 17-9, Intermediate H and Example 1).

[0027] disease The compound of formula (I) or a pharmaceutically acceptable salt thereof can be used to treat neoplastic diseases, for example, to inhibit protein kinases, by administering the compound of formula (I) or a pharmaceutically acceptable salt thereof.Furthermore, in view of the observation that the compound of formula (I) further has PLK1 inhibitory activity, the neoplastic disease may be treatable by inhibition of PLK1 in addition to treatment with a TTK inhibitor (e.g., the compound of formula (I)).

[0028] Furthermore, the compound of formula (I) or its pharmaceutically acceptable salt can be used to treat cancer at any clinical stage or pathological grade (e.g., tumor stage I, tumor stage II, tumor stage III, tumor stage IV) or treatment setting (e.g., preventive, adjuvant, neoadjuvant, therapeutic, including palliative treatment). The compound of formula (I) or its pharmaceutically acceptable salt can be for use in delaying, delaying or stopping cancer progression or cancer growth, or increasing overall survival time or cancer progression-free survival time or time to cancer progression, or improving or maintaining the quality of life or functional status of a subject (e.g., patient). The compound of formula (I) or its pharmaceutically acceptable salt can also be used in post-treatment recovery from cancer. The compound of formula (I) or its pharmaceutically acceptable salt can be used to treat metastatic cancer.

[0029] For example, the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be used to (i) reduce the number of cancer cells; (ii) reduce tumor volume; (iii) increase tumor regression rate; (iv) reduce or delay cancer cell invasion into peripheral organs; (v) reduce or delay tumor metastasis; (vi) reduce or inhibit tumor growth; (vii) prevent or delay the onset and / or recurrence of cancer and / or prolong disease-free or tumor-free survival; (viii) increase overall survival; (ix) reduce the frequency of treatment; and / or (x) alleviate one or more symptoms associated with cancer.

[0030] As mentioned above, the compound of formula (I) or its pharmacologic acceptable salt can be used to treat neoplastic disease.Examples of neoplastic disease include epithelial neoplasm, squamous cell neoplasm, basal cell neoplasm, transitional cell papilloma and carcinoma, adenoma and adenocarcinoma, adnexal and skin adnexal neoplasm, mucoepidermoid neoplasm, cystic neoplasm, mucinous and serous neoplasm, ductal, lobular and medullary neoplasm, acinar cell neoplasm, complex epithelial neoplasm, specialized glandular neoplasm, paraganglioma and glomus tumor, nevi and melanoma, soft tissue tumor and sarcoma, fibroma neoplasm, myxoma neoplasm, lipoma neoplasm, fibroma neoplasm, complex mixed and stromal neoplasm, fibroepithelial neoplasm These include, but are not limited to, pulmonary neoplasms, synovial neoplasms, mesothelioma neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesogiomas, vascular tumors, lymphatic tumors, bone and chondrogenic neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepithelioma neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, other lymphoreticular neoplasms, plasma cell neoplasms, mast cell tumors, immunoproliferative disorders, leukemias, various myeloproliferative disorders, lymphoproliferative disorders, and myelodysplastic syndromes.

[0031] In some embodiments, neoplastic disease is cancer.Examples of cancers of affected organs and body parts include, but are not limited to, brain, breast (including triple negative breast cancer and luminal B breast cancer), cervix, ovary, colon, rectum (including colon and rectum, i.e., colorectal cancer), lung (including small cell lung cancer, non-small cell lung cancer, large cell lung cancer and mesothelioma), endocrine system, bone, adrenal gland, thymus, liver, stomach, intestine (including gastric cancer), pancreas, bone marrow, hematological malignancies (such as lymphoma, leukemia, myeloma or lymphatic malignancies), bile duct, bladder, urinary tract, skin, thyroid, head, neck, prostate and testis.

[0032] In some embodiments, the neoplastic disease is a cancer selected from breast cancer (including triple negative breast cancer and luminal B breast cancer), gastric cancer, colon cancer, liver cancer (including hepatocellular carcinoma), endometrial cancer, ovarian cancer, esophageal cancer, lung cancer (including small cell lung cancer, non-small cell lung cancer), Kaposi's sarcoma, cervical cancer, pancreatic cancer, melanoma, prostate cancer, testicular cancer, cervical cancer, bladder cancer, head and neck cancer, brain tumors (e.g., glioma, medulloblastoma), neuroblastoma, retinoblastoma, Wilms' tumor, leukemia, e.g., acute myeloid leukemia (AML) (including complex karyotype AML), and malignant mesothelioma.

[0033] In some embodiments, the neoplastic disease is breast cancer.

[0034] In some embodiments, the neoplastic disease is triple-negative breast cancer.

[0035] In some embodiments, the neoplastic disease is luminal B breast cancer.

[0036] In some embodiments, the neoplastic disease is gastric cancer.

[0037] In some embodiments, the neoplastic disease is colon cancer.

[0038] In some embodiments, the neoplastic disease is hepatocellular carcinoma.

[0039] In some embodiments, the neoplastic disease is endometrial cancer.

[0040] In some embodiments, the neoplastic disease is acute myeloid leukemia (AML), including complex karyotype AML.

[0041] In some embodiments, the neoplastic disease is lung cancer (eg, small cell lung cancer, non-small cell lung cancer).

[0042] In some embodiments, the neoplastic disease is cervical cancer (eg, metastatic or recurrent cervical cancer).

[0043] In some embodiments, the neoplastic disease is head and neck cancer (eg, recurrent or metastatic squamous cell carcinoma of the head and neck).

[0044] In some embodiments, the neoplastic disease is Wilms' tumor.

[0045] In some embodiments, the neoplastic disease is a brain tumor (eg, a glioma, such as a progressive or recurrent glioma, a medulloblastoma, such as a recurrent medulloblastoma).

[0046] In some embodiments, the neoplastic disease is neuroblastoma.

[0047] In some embodiments, the neoplastic disease is testicular cancer (eg, metastatic non-seminomatous germ cell tumors).

[0048] In some embodiments, the neoplastic disease is bladder cancer (eg, advanced bladder cancer, including those with abnormal renal function).

[0049] In some embodiments, the neoplastic disease is retinoblastoma (eg, recurrent or progressive retinoblastoma).

[0050] The cancer may be a primary tumor and / or a metastasis. The cancer may originate from a solid or liquid (e.g., hematological or intraperitoneal) tumor. In some embodiments, the neoplastic disease (e.g., cancer) to be treated is a tumor, e.g., a solid tumor.

[0051] Administration The compound of formula (I) or its pharmaceutically acceptable salt is administered according to an intermittent administration schedule. An intermittent administration schedule is one that includes an interval of more than one day between scheduled administrations. An intermittent administration schedule is different from a continuous administration schedule in which the subject is administered every day. Preferably, the compound of formula (I) or its pharmaceutically acceptable salt is administered intravenously to the subject (preferably human).

[0052] In some embodiments, the intermittent dosing schedule comprises an interval of at least 2 days, such as at least 3 days, such as at least 4 days, such as at least 5 days, such as at least 6 days, such as at least 7 days, during which a compound of formula (I) or a pharma- ceutically acceptable salt thereof is not administered to the subject.

[0053] The subject may receive the scheduled dose in one dose or more than one dose, for example on the same day. For example, half of the scheduled dose may be administered in the morning and the other half in the afternoon. After the complete scheduled dose is administered, there is an interval of more than one day before the next scheduled dose is administered. Thus, in some embodiments, there is an interval of at least 2 days, for example at least 3 days, for example at least 4 days, for example at least 5 days, for example at least 6 days, for example at least 7 days between successive scheduled doses. In some embodiments, there is an interval of at least 2 days, for example at least 3 days, for example at least 4 days, for example at least 5 days, for example at least 6 days, for example at least 7 days between each successive scheduled dose.

[0054] Intervals between scheduled doses can be regular (eg, equal number of days apart) or irregular (eg, different number of days apart), depending, for example, on the subject's response to the drug.

[0055] It is also contemplated that the subject can receive the scheduled dose in one administration, i.e., in a single administration without any break.Thus, in some embodiments, there is an interval of at least 2 days, such as at least 3 days, such as at least 4 days, such as at least 5 days, such as at least 6 days, such as at least 7 days between successive administrations.In some embodiments, there is an interval of at least 2 days, such as at least 3 days, such as at least 4 days, such as at least 5 days, such as at least 6 days, such as at least 7 days between each successive administration.

[0056] Intermittent dosing schedules are usually cyclic treatment schedules. Cyclic treatment schedules are defined by a repetitive dosing schedule in which the repetitive element (cycle) has a specific duration and the dose is administered on a specific day within the cycle. The cycle can incorporate a period of no administration ("rest period"), usually at the end of the cycle, for example, to allow a period for recovery. The treatment cycle can be, for example, 7 days, 14 days, 21 days, 28 days or longer. The treatment schedule can continue as long as necessary ("open-ended treatment"), for example, as long as the subject (e.g., patient) is receiving benefit as judged by the physician supervising the treatment.

[0057] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a three week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on week 1, e.g., day 1, of the treatment cycle, followed by a two week drug holiday.

[0058] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a three week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on weeks 1 and 2, e.g., days 1 and 8, of the treatment cycle, followed by a one week drug holiday.

[0059] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a four week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on week 1, e.g., day 1, of the treatment cycle, followed by a three week drug holiday.

[0060] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a four week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on weeks 1 and 3, e.g., days 1 and 15, of the treatment cycle, with weeks 2 and 4 being drug-free weeks.

[0061] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a four week treatment cycle, where the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered each week during the first three weeks of the treatment cycle, e.g., on days 1, 8, and 15, followed by a one week rest week.

[0062] The following dosage examples are for humans. The dosages of the compound of formula (I) are given in mg per person, regardless of body weight or body surface area (BSA). The dosages of the compound of formula (I) shown below, including Tables A and B, refer to the dosage of the free base. The dosages also apply to pharma- ceutically acceptable salts of the compound of formula (I), except that when a pharma- ceutically acceptable salt of the compound of formula (I) is used, the mg dosages listed should be adjusted (i.e., increased) so that the molar amount of the pharma- ceutically acceptable salt of the compound of formula (I) administered is the same as the molar amount of the free base listed below. For example, a statement that the (human) weekly dosage of the compound of formula (I) is about 5 mg to about 480 mg per week, if administered, means that the compound of formula (I) or a pharma- ceutically acceptable salt thereof, if administered, is administered to a patient at a dosage equivalent to the molar equivalent of the free base of the compound of formula (I) of about 5 mg to about 480 mg per week for several weeks.

[0063] In some embodiments, the weekly human dose of the compound of formula (I), when administered, is about 5 mg to about 480 mg per week. In some embodiments, the weekly human dose of the compound of formula (I), when administered, is about 40 mg to about 200 mg per week. In some embodiments, the weekly human dose of the compound of formula (I), when administered, is about 80 mg to about 160 mg per week. In some embodiments, the weekly human dose of the compound of formula (I), when administered, is about 90 mg to about 130 mg per week.

[0064] In some embodiments, the weekly human dose of a compound of formula (I), when administered, is about 140 mg to about 240 mg per week. In some embodiments, the weekly human dose of a compound of formula (I), when administered, is about 160 mg to about 220 mg per week. In some embodiments, the weekly human dose of a compound of formula (I), when administered, is about 180 mg to about 200 mg per week.

[0065] Examples of weekly doses of the compound of formula (I) when administered to humans include 10 mg to about 20 mg, about 20 mg to about 30 mg, about 30 mg to about 40 mg, about 40 mg to about 50 mg, about 50 mg to about 60 mg, about 60 mg to about 70 mg, about 70 mg to about 80 mg, about 80 mg to about 90 mg, about 90 mg to about 100 mg, about 100 mg to about 110 mg, about 110 mg to about 120 mg, about 130 mg to about 140 mg, about 140 mg to about 150 mg, about 150 mg to about 160 mg, about 160 mg to about 170 mg, about 170 mg to about 180 mg, about 180 mg to about 200 mg, about 190 mg to about 210 mg, about 220 mg to about 230 mg, about 230 mg to about 250 mg, about 240 mg to about 260 mg, about 250 mg to about 270 mg, about 260 mg to about 280 mg, about 270 mg to about 300 mg, about 280 mg to about 310 mg, about 290 mg to about 320 mg, about 290 mg to about 330 mg, about 290 mg to about 340 mg, about 290 mg to about 350 mg, about 290 mg to about 360 mg, about 290 mg to about 370 mg, about 290 mg to about 380 mg, about 380 mg to about 390 mg, about 390 mg to about 400 mg, about 390 mg to about 400 mg, about 390 mg to about 410 mg, about 390 mg to 20mg to about 130mg, about 130mg to about 140mg, about 140mg to about 150mg, about 150mg to about 160mg, about 160mg to about 170mg, about 170mg to about 180mg, about 18 0mg to about 190mg, about 190mg to about 200mg, about 200mg to about 210mg, about 210mg to about 220mg, about 220mg to about 230mg, about 230mg to about 240mg, about 240 mg ~ about 250mg, about 250mg - about 260mg, about 260mg - about 270mg, about 270mg - about 280mg, about 280mg - about 290mg, about 290mg - about 300mg, about 300m g ~ about 310mg, about 310mg - about 320mg, about 320mg - about 330mg, about 330mg - about 340mg, about 340mg - about 350mg, about 350mg - about 360mg, about 360mg about 370 mg, about 370 mg to about 380 mg, about 380 mg to about 390 mg, about 390 mg to about 400 mg, about 400 mg to about 410 mg, about 410 mg to about 420 mg, about 420 mg to about 430 mg, about 430 mg to about 440 mg, about 440 mg to about 450 mg, about 450 mg to about 460 mg, about 460 mg to about 470 mg, and about 470 mg to about 480 mg.

[0066] Specific examples of weekly (human) doses of the compounds of formula (I) when administered include about 5 mg, about 10 mg, about 15 mg, about 20 mg, about 25 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 75 mg, about 80 mg, about 85 mg, about 90 mg, about 95 mg, about 100 mg, about 105 mg, about 110 mg, about 115 mg, about 120 mg, about 125 mg, about 130 mg, about 135 mg, about 140 mg, about 145 mg, about 150 mg, about 155 mg, about 160 mg, about 165 mg, about 170 mg, about 175 mg, about 180 mg, about 185 mg, about 190 mg, about 195 mg, about 200 mg, about 205 mg, about 210 mg, about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260 mg, about 270 mg, about 280 mg, about 290 mg, about 300 mg, about 310 mg, about 320 mg, about 330 mg, about 340 mg, about 350 mg, about 360 mg, about 370 mg, about 380 mg, about 390 mg, about 400 mg, about 410 mg, about 420 mg, about 430 mg, about 440 mg, about 450 mg, about 450 mg, about 460 mg, about 470 mg, about 480 mg, about 490 mg, about 500 mg, about 500 mg mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 175mg, About 180mg, about 185mg, about 190mg, about 195mg, about 200mg, about 205mg, about 210mg, about 215mg, about 220mg, about 225mg, about 230mg, about 235mg, about 24 0mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 300mg , about 305 mg, about 310 mg, about 315 mg, about 320 mg, about 325 mg, about 330 mg, about 335 mg, about 340 mg, about 345 mg, about 350 mg, about 355 mg, about 360 mg, about 3 Examples of effective dosages include about 65 mg, about 370 mg, about 375 mg, about 380 mg, about 385 mg, about 390 mg, about 395 mg, about 400 mg, about 405 mg, about 410 mg, about 415 mg, about 420 mg, about 425 mg, about 430 mg, about 435 mg, about 440 mg, about 445 mg, about 450 mg, about 455 mg, about 460 mg, about 465 mg, about 470 mg, about 475 mg, and about 480 mg.

[0067] The weekly dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered in a single dose, for example, in the case of intravenous administration, without any break. Alternatively, the weekly dose may be administered in multiple doses, for example, in the case of intravenous administration, in two or three doses with a break between doses, for example, at least 30 minutes apart, for example at least 1 hour apart, for example at least 2 hours apart, for example at least 4 hours apart, for example, at least 30 minutes to 12 hours apart, for example, at least 30 minutes to 6 hours apart. Such multiple doses may be administered on the same or different days, for example on consecutive days or, for example, 3 days after the day of the first administration, provided that the administration schedule is an intermittent administration schedule as described above.

[0068] The compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered to a subject according to a conventional route of administration known to those skilled in the art, but is preferably administered intravenously to a subject. The duration of the infusion is usually at least 30 minutes and may be up to 24 hours. In some embodiments, the duration of the infusion is 30 minutes to 12 hours, such as 30 minutes to 6 hours, such as 30 minutes to 3 hours, such as 1 to 2 hours, for example about 1 hour.

[0069] In some embodiments, the treatment cycle duration, weeks of administration and (human) weekly dosage of the compound of formula (I) are as set forth in any one of embodiments 1A-35A of Table A, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably administered to the patient intravenously. [Table 1]

[0070] As described above, embodiment 1A refers to the situation where the compound of formula (I) or its pharmaceutically acceptable salt is administered to the patient according to a 3-week treatment cycle, the compound of formula (I) or its pharmaceutically acceptable salt is administered in the first week of the treatment cycle, followed by a 2-week drug holiday, and the compound of formula (I) or its pharmaceutically acceptable salt is administered to the patient at a dose equivalent to about 5mg to about 480mg of the molar equivalent of the free base of the compound of formula (I) per week for several weeks, if administered.The same applies to embodiments 2A to 32A.

[0071] In some embodiments, the treatment cycle duration, the number of administration days within the cycle, and the (human) weekly dosage of the compound of formula (I) are as set forth in any one of embodiments 1B to 35B of Table B, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably administered to the patient intravenously. [Table 2]

[0072] As described above, embodiment 1B refers to the situation where the compound of formula (I) or its pharmaceutically acceptable salt is administered to the patient according to a 21-day treatment cycle, the compound of formula (I) or its pharmaceutically acceptable salt is administered on day 1 of the treatment cycle, and the compound of formula (I) or its pharmaceutically acceptable salt is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 5 mg to about 480 mg per week for several weeks, if administered. The same applies to embodiments 2B to 32B.

[0073] In some embodiments, the treatment cycle duration, administration weeks, (human) weekly dosage, and neoplastic disease are as set forth in any one of embodiments 1C to 210C of Table C, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably administered intravenously to the patient. [Table 3-1] [Table 3-2] [Table 3-3] [Table 3-4] [Table 3-5] [Table 3-6]

[0074] As described above, embodiment 1C refers to the situation where the neoplastic disease to be treated is breast cancer, and the compound of formula (I) or its pharmaceutically acceptable salt is administered to the patient according to a 3-week treatment cycle, the compound of formula (I) or its pharmaceutically acceptable salt is administered in the first week of the treatment cycle, followed by a 2-week drug holiday, and the compound of formula (I) or its pharmaceutically acceptable salt is administered to the patient at a dose equivalent to about 5mg to about 480mg of the molar equivalent of the free base of the compound of formula (I) per week for several weeks, if administered.The same applies to embodiments 2C to 210C.

[0075] In some embodiments, the treatment cycle duration, number of days of administration within the cycle, the (human) weekly dosage, and the neoplastic disease are as set forth in any one of embodiments 1D to 210D of Table D, and the compound of formula (I) or a pharmaceutically acceptable salt thereof is preferably administered intravenously to the patient. [Table 4-1] [Table 4-2] [Table 4-3] [Table 4-4] [Table 4-5] [Table 4-6]

[0076] As described above, embodiment 1D refers to the situation where the neoplastic disease to be treated is a breast cancer compound of formula (I) or its pharmaceutically acceptable salt, and is administered to the patient according to a 21-day treatment cycle, and the compound of formula (I) or its pharmaceutically acceptable salt is administered on day 1 of the treatment cycle, and the compound of formula (I) or its pharmaceutically acceptable salt is administered to the patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 5 mg to about 480 mg per week for several weeks, if administered.The same applies to embodiments 2D to 210D.

[0077] Generally, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered at a dose that does not exceed the maximum tolerated dose (MTD) for the particular mode of administration and indication, as determined in a clinical dose escalation study.

[0078] formulation The compound of formula (I) or a pharma- ceutically acceptable salt thereof may be formulated as a pharmaceutical composition for parenteral administration, for example nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, aural, or in particular for oral administration, for example in the form of oral solid dosage forms, for example granules, pellets, powders, tablets, films or dragees, effervescent tablets, hard and soft gelatin or HPMC capsules, coated where applicable, orally disintegrating tablets, oral solutions, lipid emulsions or suspensions, or in a pharmaceutical composition for parenteral administration, for example in the form of solutions containing microparticles or nanoparticles, lipid emulsions or suspensions, to mammals, in particular humans. The composition may comprise the active ingredient alone or, preferably, together with a pharma- ceutically acceptable carrier.

[0079] Pharmaceutical compositions can be processed with pharma- ceutical inert inorganic or organic excipients for the preparation of oral solid dosage forms, such as granules, pellets, powders, tablets, films or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules, or orally disintegrating tablets.Fillers, such as lactose, cellulose, mannitol, sorbitol, calcium phosphate, starch or its derivatives, binders, such as cellulose, starch, polyvinylpyrrolidone or its derivatives, flow agents, such as talcum, stearic acid or its salts, flow agents, such as fumed silica, can be used as such excipients for the formulation and preparation of oral solid dosage forms, such as granules, pellets, powders, tablets, films or sugar-coated tablets, effervescent tablets, hard gelatin or HPMC capsules, or orally disintegrating tablets.Suitable excipients for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid and liquid polyols, etc.

[0080] Suitable excipients for the preparation of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, saccharose, invert sugar, glucose, etc. Suitable excipients for parenteral preparations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithin, surfactants, etc. In addition, pharmaceutical preparations can contain preservatives, solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners, colorants, flavorings, salts for changing osmotic pressure, buffers, masking agents or antioxidants. They can also contain other therapeutically valuable substances.

[0081] Pharmaceutical compositions suitable for injection use include sterile aqueous solutions (if water soluble) or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. For intravenous administration, suitable carriers include physiological saline, bacteriostatic water, Cremophor® EL, or phosphate buffered saline (PBS). The carrier can be, for example, a solvent or dispersion medium containing water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, etc.), and suitable mixtures thereof. For intravenous injection of strongly lipophilic molecules, it can be advantageous to include a solubilizer, such as a surfactant, polymeric surfactant, polymer, complexing agent, and / or cosolvent, in the formulation, which can significantly increase the solubility of the compound in water. Examples of solubilizers include polyethylene glycol, propylene glycol, ethanol, glycerol, and cyclodextrin (e.g., sulfobutylether-β-cyclodextrin).

[0082] In some embodiments, the compound of formula (I) as a free base is provided in a pharmaceutical composition comprising β-cyclodextrin, e.g., for intravenous administration. The β-cyclodextrin can be sulfobutylether-β-cyclodextrin, e.g., CAS 182410-00-0, e.g., Captisol™ (Ligand) or Dexolve™ (Cyclolab).

[0083] Sterile injection can be prepared by incorporating the required amount of active compound into suitable solvent together with the compound of formula (I) or its pharmaceutically acceptable salt as required, and then sterilizing by filtration.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains dispersion medium and other necessary ingredients from above-listed.For the preparation of sterile powder for sterile injection, the preparation method is vacuum drying and freeze-drying, whereby the powder of active ingredient and any additional desired ingredient is obtained from its solution that has been previously sterilized and filtered.

[0084] In addition, the pharmaceutical compositions used in the present invention optionally include buffers such as phosphate, citrate, or other organic acids; antioxidants including butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), ascorbic acid; low molecular weight (less than about 10 residues) polypeptides; proteins such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone, amino acids such as glycine, glutamine, asparagine, arginine, or lysine; monosaccharides, disaccharides, or other carbohydrates including glucose, mannose, or dextrins; chelating agents such as EDTA; sugar alcohols such as mannitol or sorbitol; salt-forming counterions such as sodium; and / or non-ionic surfactants, e.g., TWEEN®, PLURONICS®, or PEG.

[0085] Optionally, the pharmaceutical composition contains a pharma- ceutically acceptable preservative. In some embodiments, the preservative concentration is in the range of 0.1-2.0%, typically v / v. Suitable preservatives include those known in the pharmaceutical art, such as benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben.

[0086] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof is formulated for intravenous administration with a suitable acceptable carrier.

[0087] The following numbered paragraphs describe specific embodiments of the present invention.

[0088] Item 1. A method for treating a neoplastic disease in a subject, particularly a human, in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to an intermittent dosing schedule.

[0089] Item 2. The method according to item 1, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered intravenously to the subject.

[0090] Item 3. The method according to item 1 or 2, wherein the administration schedule includes an interval of at least 2 days during which the compound of formula (I) or a pharma- ceutically acceptable salt thereof is not administered to the subject.

[0091] Item 4. The method of item 1 or 2, wherein there is an interval of at least 7 days between each successive scheduled dose.

[0092] Item 5. The method according to any one of items 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 3-week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on week 1, e.g., day 1, of the treatment cycle, followed by a 2-week drug holiday.

[0093] Item 6. The method according to any one of items 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 3-week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on weeks 1 and 2, e.g., days 1 and 8, of the treatment cycle, followed by a one-week drug holiday.

[0094] Item 7. The method according to any one of items 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 4-week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on week 1, e.g., day 1, of the treatment cycle, followed by a 3-week drug holiday.

[0095] Item 8. The method according to any one of items 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 4-week treatment cycle, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on weeks 1 and 3, e.g., days 1 and 15, of the treatment cycle, with weeks 2 and 4 being drug-free weeks.

[0096] Item 9. The method according to any one of items 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 4-week treatment cycle, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered each week, for example, on days 1, 8 and 15, during the first 3 weeks of the treatment cycle, followed by a 1-week drug holiday.

[0097] Item 10. The method according to any one of items 1 to 9, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 5 mg to about 480 mg per week for several weeks.

[0098] Item 11. The method according to any one of items 1 to 9, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 40 mg to about 200 mg per week for several weeks.

[0099] Item 12. The method according to any one of items 1 to 9, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 80 mg to about 160 mg per week for several weeks.

[0100] Item 13. The method according to any one of items 1 to 9, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 90 mg to about 130 mg per week for several weeks.

[0101] Item 14. The method according to any one of items 1 to 9, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 140 mg to about 240 mg per week for several weeks.

[0102] Item 15. The method according to any one of items 1 to 9, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 160 mg to about 220 mg per week for several weeks.

[0103] Item 16. The method according to any one of items 1 to 9, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 180 mg to about 200 mg per week for several weeks.

[0104] Item 17. Neoplastic diseases are epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin adnexal neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal, lobular and medullary neoplasms, acinar cell neoplasms, composite epithelial neoplasms, specialized glandular neoplasms, paraganglionic and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, composite mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, 17. The method according to any one of items 1 to 16, wherein the tumor is selected from the group consisting of: tumors, mesothelioma neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesogiomas, vascular tumors, lymphatic tumors, osteo- and chondrogenic neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepithelioma neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, other lymphoreticular neoplasms, plasma cell neoplasms, mast cell tumors, immunoproliferative diseases, leukemias, myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

[0105] Clause 18. The method according to any one of clauses 1 to 17, wherein the neoplastic disease is treatable by inhibition of PLK1 in addition to treatment with a TTK inhibitor (eg, a compound of formula (I)).

[0106] Item 19. The method according to any one of items 1 to 19, wherein the neoplastic disease is cancer, in particular a cancer selected from breast cancer (including triple-negative breast cancer and luminal B breast cancer), gastric cancer, colon cancer, liver cancer (including hepatocellular carcinoma), endometrial cancer, ovarian cancer, esophageal cancer, lung cancer (including non-small cell lung cancer), Kaposi's sarcoma, cervical cancer, pancreatic cancer, melanoma, prostate cancer, bladder cancer and leukemia, such as acute myeloid leukemia (AML) (including complex karyotype AML).

[0107] Item 20. The method according to any one of items 1 to 19, wherein the neoplastic disease is breast cancer.

[0108] Item 21. The method according to any one of items 1 to 19, wherein the neoplastic disease is triple-negative breast cancer.

[0109] Item 22. The method according to any one of items 1 to 19, wherein the neoplastic disease is luminal B-type breast cancer.

[0110] Item 23. The method according to any one of items 1 to 19, wherein the neoplastic disease is gastric cancer.

[0111] Item 24. The method according to any one of Items 1 to 19, wherein the neoplastic disease is colon cancer.

[0112] Item 25. The method according to any one of Items 1 to 19, wherein the neoplastic disease is hepatocellular carcinoma.

[0113] Item 26. The method according to any one of items 1 to 19, wherein the neoplastic disease is endometrial cancer.

[0114] Item 27. The method according to any one of items 1 to 19, wherein the neoplastic disease is acute myeloid leukemia (AML).

[0115] Item 28. The method according to any one of items 1 to 19, wherein the neoplastic disease is complex karyotype AML.

[0116] Item 1A. A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in the treatment of a neoplastic disease in a subject, particularly a human, wherein the treatment comprises administering to the subject a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to an intermittent dosing schedule.

[0117] Item 2A. The compound for use according to Item 1A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered intravenously to the subject.

[0118] Item 3A. The compound for use according to item 1A or 2A, wherein the administration schedule includes an interval of at least two days during which the compound of formula (I) or a pharma- ceutically acceptable salt thereof is not administered to the subject.

[0119] Item 4A. The compound for use according to paragraphs 1A or 2A, wherein there is an interval of at least 7 days between each successive scheduled dose.

[0120] Item 5A. The compound for use according to any one of items 1A to 4A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 3-week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on week 1, e.g., day 1, of the treatment cycle, followed by a 2-week drug holiday.

[0121] Item 6A. The compound for use according to any one of items 1A to 4A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 3-week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on weeks 1 and 2, e.g., days 1 and 8, of the treatment cycle, followed by a one-week drug holiday.

[0122] Item 7A. The compound for use according to any one of items 1A to 4A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 4-week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on week 1, e.g., day 1, of the treatment cycle, followed by a 3-week drug holiday.

[0123] Item 8A. The compound for use according to any one of items 1A to 4A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 4-week treatment cycle, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on weeks 1 and 3, for example days 1 and 15, of the treatment cycle, and weeks 2 and 4 are drug-free weeks.

[0124] Item 9A. The compound for use according to any one of items 1A to 4A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a four week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered each week, for example, on days 1, 8 and 15, during the first three weeks of the treatment cycle, followed by a one week rest week.

[0125] Item 10A. The compound for use according to any one of items 1A to 9A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 5 mg to about 480 mg per week for several weeks.

[0126] Item 11A. The compound for use according to any one of items 1A to 9A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of 40 mg to about 200 mg per week for several weeks.

[0127] Item 12A. The compound for use according to any one of items 1A to 9A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 80 mg to about 160 mg per week for several weeks.

[0128] Item 13A. The compound for use according to any one of items 1A to 9A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of 90 mg to about 130 mg per week for several weeks.

[0129] Item 14A. The compound for use according to any one of items 1A to 9A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 140 mg to about 240 mg per week for several weeks.

[0130] Item 15A. The compound for use according to any one of items 1A to 9A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 160 mg to about 220 mg per week for several weeks.

[0131] Item 16A. The compound for use according to any one of items 1A to 9A, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 180 mg to about 200 mg per week for several weeks.

[0132] Item 17A. The compound for use according to any one of items 1A to 16A, wherein the neoplastic disease is a solid tumor.

[0133] Section 18A. Neoplastic diseases are epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and skin adnexal neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal, lobular and medullary neoplasms, acinar cell neoplasms, composite epithelial neoplasms, specialized glandular neoplasms, paraganglionic and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, composite mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, mesothelial neoplasms, myxomatous ... The compound for use according to any one of items 1A to 17A, which is selected from the group consisting of epithelial neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesogiomas, vascular tumors, lymphatic tumors, bone and chondrogenic neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepithelioma neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcomas, Hodgkin's lymphomas and non-Hodgkin's lymphomas, other lymphoreticular neoplasms, plasma cell neoplasms, mast cell tumors, immunoproliferative diseases, leukemias, myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

[0134] Paragraph 19A. The compound for use according to any one of paragraphs 1A to 18A, wherein the neoplastic disease is treatable by inhibition of PLK1 in addition to treatment with a TTK inhibitor (e.g., a compound of formula (I)).

[0135] Clause 20A. The compound for use according to any one of clauses 1A to 19A, wherein the neoplastic disease is cancer, in particular a cancer selected from breast cancer (including triple negative breast cancer and luminal B breast cancer), gastric cancer, colon cancer, liver cancer (including hepatocellular carcinoma), endometrial cancer, ovarian cancer, esophageal cancer, lung cancer (including non-small cell lung cancer), Kaposi's sarcoma, cervical cancer, pancreatic cancer, melanoma, prostate cancer, bladder cancer and leukemia, such as acute myeloid leukemia (AML) (including complex karyotype AML).

[0136] Item 21A. The compound for use according to any one of items 1A to 19A, wherein the neoplastic disease is breast cancer.

[0137] Item 22A. The compound for use according to any one of items 1A to 19A, wherein the neoplastic disease is triple-negative breast cancer.

[0138] Item 23A. The compound for use according to any one of items 1A to 19A, wherein the neoplastic disease is luminal B breast cancer.

[0139] Item 24A. The compound for use according to any one of items 1A to 19A, wherein the neoplastic disease is gastric cancer.

[0140] Paragraph 25A. The compound for use according to any one of paragraphs 1A to 19A, wherein the neoplastic disease is colorectal cancer.

[0141] Item 26A. The compound for use according to any one of items 1A to 19A, wherein the neoplastic disease is hepatocellular carcinoma.

[0142] Item 27A. The compound for use according to any one of items 1A to 19A, wherein the neoplastic disease is endometrial cancer.

[0143] Item 28A. The compound for use according to any one of items 1A to 19A, wherein the neoplastic disease is acute myeloid leukemia (AML).

[0144] Item 29A. The compound for use according to any one of items 1A to 19A, wherein the neoplastic disease is complex karyotype AML.

[0145] Item 1B. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof in the preparation of a medicament for treating a neoplastic disease in a subject, wherein said treatment comprises administering to the subject a compound of formula (I) or a pharma- ceutically acceptable salt thereof according to an intermittent dosing schedule.

[0146] Item 2B. The use according to item 1B, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject as defined in any one of items 2A to 16A.

[0147] Item 3B. The use according to item 1B or 2B, wherein the neoplastic disease is as defined in any one of items 17A to 29A.

[0148] In order to more fully describe and disclose the present invention and the state of the art to which it pertains, several publications are cited herein. Each of these references is incorporated herein by reference in its entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0149] Specific embodiments of the present invention are described in the following examples, which are intended to more fully illustrate the present invention and should not be construed as limiting the present invention in any manner.

[0150] Working Example method Kinase assay A radiometric protein kinase assay (33PanQinase® Activity Assay) was used to measure the kinase activity of TTK and PLK1. TTK and PLK1 protein kinases were expressed as recombinant full-length GST fusion proteins. The reaction cocktail consisted of 25 μL of assay buffer (standard buffer / [γ- 33 The assay contained 10 μL of ATP solution (in water), 5 μL of test compound and 10 μL of enzyme / substrate mixture. Protein kinase assays were performed in 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 μM Na orthovanadate, 1.2 mM DTT, 50 μg / ml PEG20000, ATP (0.3 μM for TTK and 1 μM for PLK1), [γ- 33 [P]-ATP (approximately 8 × 10 per well 5cpm), protein kinase (15.8 nM for TTK and 5 nM for PLK1), and substrate (1 μg / 50 μL for TTK and 2 μg / 50 μL for PLK1). All assays were performed using a BeckmanCoulter / SAGIAN™ Core System. The fitting model for IC50 determination was "sigmoidal response (variable slope)" with parameters "top" fixed at 100% and "bottom" fixed at 0%. The fitting method used was least squares fitting.

[0151] Target residence time assay The affinity of the compounds of formula (I) for TTK and PLK1, i.e., the equilibrium dissociation constant (KD) (referred to as residence time), was determined using a Biacore T200™ surface plasmon resonance instrument using recombinantly expressed TTK kinase domain (amino acids 519-808) or biotinylated PLK1. Immobilization of TTK was performed as described in Maia et al., Annals of Oncology, 2015; 26: 2180-2192. Immobilization of biotinylated PLK1 was performed as described in Willemsen-Seegers et al., Journal of Molecular Biology, 2017; 429: 574-586. Subsequent single cycle kinetic assays were performed at 22 °C using compound concentration gradients of 1, 3.6, 10, 31.6 and 100 nM for TTK and 10, 31.6, 100, 316 and 1000 nM for PLK1, a contact time of 100 s and a flow rate of 30 μL / min. The dissociation period was 1200-1800 s and a correction for unstable surfaces was performed using a blank run with buffer. Binding kinetics were calculated based on the binding curves and demonstrated good signal-to-noise ratios for all compounds tested (data not shown).

[0152] xenograft research Female NCr nu / nu nude mice (Charles River Laboratories) aged 8–12 weeks were inoculated subcutaneously (sc) in the flank with 5 × 106 MDA-MB-231 tumor cells. The average tumor size was 100–150 mm. 3 If yes, they were randomized into treatment groups (8 mice per group). Mice were treated with different compounds and schedules as indicated in the figure.

[0153] Body weight and tumor volume were measured in two dimensions with a caliper and calculated using the formula: V = (L × W 2 The tumor volume was determined at least twice a week by applying the formula: (V) / 2 (where V is the tumor volume, L and W are the length and width of the tumor, respectively). 3 Individual mice were culled when they reached or were found to have a body weight loss (BWL) of more than 20%. Mice were also culled if the BWL was determined to be >15% for three consecutive days. Any mice with a BWL of >10% underwent drug rest days until the BWL returned to <10%. All animal protocols were reviewed and approved by the relevant local committee in the United States (IACUC) where the study was conducted.

[0154] Pharmacokinetic (PK) studies In the first study groups, 1, 2, and 3 (9 mice each) received a single oral dose of 5, 7.5, or 10 mg / kg of formulation 1, respectively. Groups 4, 5, and 6 (9 mice each) received a single oral dose of 5, 7.5, or 10 mg / kg of formulation 2, respectively. Plasma samples were collected on day 1 for groups 1-6. Formulation 1 consisted of DMSO, Cremophor EL, and 5% mannitol in water (10 / 10 / 80; v / v / v). Formulation 2 consisted of ethanol, PEG400, and citric acid 20 mM (10 / 10 / 80; v / v / v). Blood samples were collected at 1, 2, 4, 8, 12, and 24 hours (3 mice / time point) after dosing.

[0155] In the second study, female Swiss Albino mice were orally administered 5, 7.5, or 10 mg / kg of a compound of formula (I) daily for 5 days. Groups 1, 2, and 3 (9 mice each) were administered a daily oral dose of 5, 7.5, or 10 mg / kg, respectively, in Formulation 1 for 5 days. Groups 4, 5, and 6 (9 mice each) were administered a daily oral dose of 5, 7.5, or 10 mg / kg, respectively, in Formulation 2 for 5 days. PK samples were collected on day 5 for groups 1-6. Formulation 1 consisted of DMSO, Cremophor EL, and 5% mannitol in water (10 / 10 / 80; v / v / v). Formulation 2 consisted of ethanol, PEG400, and citric acid 20 mM (10 / 10 / 80; v / v / v). Blood samples were collected at 1, 2, 4, 8, 12, and 24 hours post-dose (3 mice / time point).

[0156] In the third study, female Swiss Albino mice were administered an intravenous (bolus, 5 mL / kg) dose of 5 mg / kg of the compound of formula (I). Group 1 (9 mice) received a single iv dose on day 1. Group 2 (9 mice) received daily oral doses of 10 mg / kg of the compound of formula (I) on days 1 through 5, followed by a single iv dose of 5 mg / kg of the compound of formula (I) on day 6. PK samples were collected on day 1 for group 1 and on day 6 for group 2. The formulation vehicle consisted of ethanol, PEG400 and citric acid 20 mM (10 / 10 / 80; v / v / v) in water for injection (WFI). Blood samples were collected pre-dose and 0.083, 0.25, 0.5, 1, 2, 6, 12 and 24 hours post-dose (3 mice / time point).

[0157] In each of the three studies, blood was collected via the sephanous vein into K2-EDTA tubes kept on ice until centrifugation at 4°C. Plasma was stored at approximately -80°C. Sample workup for analysis consisted of 15 μL of plasma mixed with 45 μL of acetonitrile containing the compound of formula (I)-d3 as an internal standard, followed by centrifugation and injection of 2 μL of the supernatant into the LC-MS / MS system. PK parameters were calculated using Phoenix® WinNonLin 6.4. PK analysis was based on sparse sampling.

[0158] result TTK and PLK1 are kinases that play an essential role in controlling the spindle assembly checkpoint (SAC), a cell cycle surveillance mechanism that ensures optimal cell division through proper chromosome alignment. TTK and PLK1 cooperate to recruit SAC components to the SAC protein complex at the centromeres of chromosomes, and thus inhibition of both enzymes should maximize mitotic progression through more rapid cleavage of the SAC (Von Schubert et al., Cell Reports 2015,12;66-78). This has been proven to be the case in tumor cell lines when comparing compounds of formula (I) with TKK inhibitors that do not have any significant PLK1 inhibitory activity (data not shown).

[0159] In general, the compounds of formula (I) show strong specificity for TTK, with other kinase IC50s at least 10-fold higher than that of TTK. The above TTK kinase assay confirmed that the compounds of formula (I) are highly potent for TTK, giving an IC50 of 7 nM (0.4 nM when measured as described in WO2015 / 155042).

[0160] The PLK1 kinase assay described above also showed that the compound of formula (I) targets PLK1. The compound of formula (I) was found to inhibit PLK1 with an IC50 of 72 nM. When measured as described in WO 2015 / 155042, the compound of formula (I) inhibited PLK1 with an IC50 of 46 nM. Other TTK inhibitors reported in the literature have similar or slightly better overall specificity for TTK, but conversely, have little or no activity against PLK1 compared to their activity against TTK (data not shown). Importantly, the compound of formula (I) has a very long target residence time for TTK, exceeding 12 hours, whereas the target residence time for PLK1 is only a few minutes. This long-term inhibition of TTK, combined with its transient effect on PLK1, results in rapid disruption of the SAC, leaving chromosome segregation with insufficient time to segregate correctly.

[0161] Long-term TTK target occupancy was also measured in tumors derived from mice bearing MDA-MB-231 xenografts treated with an intermittent iv dosing regimen of the compound of formula (I). To determine the tumor TTK target occupancy time of the compound of formula (I), mice bearing the TNBC xenograft model MDA-MB-231 were IV treated twice weekly with the MTD and sub-MTD doses of the compound of formula (I). Analysis of vehicle-treated and compound of formula (I)-treated tumors for TTK target occupancy showed that the compound of formula (I) occupied tumor-derived TTK in a concentration-dependent manner. TTK was fully occupied by the compound of formula (I) for at least 72 hours after administration of the last MTD dose. Repeated experiments using IV, MTD weekly dosing showed that tumor-derived TTK was fully drug-occupied for up to 6 days after the last dose.

[0162] In cell lines, compounds of formula (I) have high potency against sensitive cells. In a 5-day anti-proliferative screen of 18 different triple-negative breast cancer cell lines (TNBC), compounds of formula (I) had a median GI50 of 35 nM. In mice, compounds of formula (I) showed significant activity against tumor patient-derived xenografts (PDX), including TNBC and hepatocellular carcinoma (HCC) models, with effects ranging from minimal to very strong, including substantial regression (data not shown).

[0163] The efficacy of the compound of formula (I) was extensively tested in the TNBC xenograft model MDA-MB-231, where once-weekly (QW) and twice-weekly (2QW) intermittent iv dosing schedules were evaluated (Figure 1). For both schedules, the compound of formula (I) was administered at the MTD and fractions thereof (QW at the MTD: 25 mg / kg and 0.75 x MTD: 18.75 mg / kg; 2QW at the MTD: 12.5 mg / kg, 0.75 x MTD: 9.4 mg / kg, 0.5 x MTD: 6.25 mg / kg, and 0.25 x MTD: 3 mg / kg).

[0164] No drug-related animal deaths were recorded, and all treatments were generally well tolerated as judged by changes in body weight. Administration of the compound of formula (I) at the MTD had some effect on body weight loss, but body weight loss remained within the acceptable 10% threshold. Tumor stasis and tumor regression were observed with MTD administration. Weekly IV administration was associated with the most potent antitumor activity. Different fractions of the MTD administration for both QW and 2QW showed dose-dependent antitumor activity, but in general, QW administration showed higher activity, even though the total weekly dose administered was identical between both schedules.

[0165] Mice in the weekly MTD dose group were observed for tumor regrowth for an additional 20 days after cessation of treatment with D100. Surprisingly, three of the eight tumors continued to shrink to a volume of ≦6 mm3, and were therefore investigated for the presence of residual tumor cells by histopathological analysis of the tumor implantation site and surrounding tissue / skin. Two mice showed no detectable residual tumor cells, whereas one mouse had two small aggregates of neoplastic cells at the inoculation site (Figure 2). Thus, 25% of the mice treated weekly with the compound of formula (I) at the MTD dose could be considered cured based on pathological analysis (Table 1). [Table 5]

[0166] Since the compound of formula (I) can also be administered orally, it is interesting to compare the efficacy after daily oral administration with that obtained with intermittent iv administration in the same tumor model. Intermittent iv administration was performed in both QW and 2QW regimens at doses of MTD, 0.5×MTD and 0.25×MTD (see graph legend for exact doses), while daily oral administration was performed only at MTD. Dose-dependent efficacy was observed for both iv administration schedules, with MTD iv administration being significantly superior to MTD oral daily treatment, regardless of schedule. 0.5×MTD iv administration induced equipotent efficacy with MTD daily oral administration (see Figures 3 and 4).

[0167] All treatments were relatively well tolerated, with no animal deaths. For the MTD dosing of 2QW, treatment was stopped on day 30 due to tail vein irritation (eschar) induced by repeated IV injections. In contrast, QW MTD dosing was continued until day 98, with strong maintenance of antitumor activity. Animals were then observed for tumor regrowth until day 125. Consistent with the data above, 2 out of 8 animals (25%) did not show measurable / palpable tumor masses from day 80 to day 125. Therefore, the tumor implantation sites of these two animals, including the surrounding tissue and skin, were excised and processed for FFPE, followed by H&E staining and examination of residual tumor cells. As a result, both animals were defined as tumor-free.

[0168] Taken together, data obtained from the MDA-MB-231 TNBC tumor model suggest that intermittent i.v. dosing can achieve greater anticancer efficacy than daily oral dosing, with tumor regressions and pathologically confirmed cures observed.

[0169] The first PK study compared the exposure of the compound of formula (I) in female Swiss Albino mice after a single oral dose at three different dose levels and using two different formulations. The derived PK parameters are shown in Table 2 and the mean concentration-time profiles are shown in Figure 5. After oral administration, the compound of formula (I) was absorbed slowly with a median Tmax of 4 hours. The maximum plasma concentration (Cmax) and systemic exposure (AUClast) of the compound of formula (I) increased approximately dose-proportionally from 5 to 10 mg / kg, independent of the formulation used. The exposure observed using formulation 2 (citric acid) showed slightly higher exposure than formulation 1. Oral bioavailability after a single dose was high, ranging from 76% to 96% based on the exposure observed after iv administration. [Table 6]

[0170] The second PK study compared the exposure of the compound of formula (I) in female Swiss Albino mice on day 5 after daily oral dosing using the two different formulations. The derived PK parameters are shown in Table 3 and the mean concentration-time profiles are shown in Figure 6. After oral dosing, the compound of formula (I) was absorbed slowly with a median Tmax of 2 to 4 hours. The maximum concentration (Cmax) and systemic exposure (AUClast) of the compound of formula (I) after multiple daily oral doses increased in a less than dose-proportional manner from 5 to 10 mg / kg, independent of the formulation used. Exposure was higher for formulation 2 (citric acid). Oral bioavailability after multiple daily doses was low to moderate, ranging from 18% to 41% based on the exposure observed after iv dosing (Table 3). [Table 7]

[0171] The third PK study compared the exposure of the compound of formula (I) in female Swiss Albino mice after a 5 mg / kg intravenous dose on days 1 and 6 (day 6 after daily oral administration of 10 mg / kg of the compound of formula (I)). The derived PK parameters are shown in Table 4, and the mean concentration-time profiles are shown in Figure 7. After intravenous administration, the PK parameters showed no obvious differences between groups 1 and 2 (Table 4), but reduced exposure was observed after daily oral administration of the compound of formula (I). A large amount of distribution (more than total body water; 15.4-19.0 L / kg) and moderate plasma clearance (55.4-57.9 mL / min / kg) were observed, resulting in a half-life of 4.00-4.70 hours for both groups. Concentrations at 24 hours were >100-fold lower than C0, suggesting that AUC0-24 hours adequately reflected total exposure. AUCinf was calculated with a maximum extrapolation confidence of 2.54%. The AUC0-24h exposures after intravenous administration on days 1 and 6 (day 6 after daily oral dosing) were similar between days 1 and 6. The data suggest that daily administration of an oral dose of 10 mg / kg of the compound of formula (I) does not induce systemic induction. [Table 8]

Claims

1. A compound of formula (I) for use in the treatment of a neoplastic disease in a subject, particularly a human. 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof, wherein said treatment comprises administering to said subject said compound of formula (I) or a pharma- ceutically acceptable salt thereof according to an intermittent dosing schedule.

2. 2. The method of claim 1, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered intravenously to the subject.

3. 3. The compound for use according to claim 1 or 2, wherein said administration schedule comprises an interval of at least 2 days during which said subject is not administered a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

4. 3. The compound for use according to claim 1 or 2, wherein there is an interval of at least 7 days between each successive scheduled dose.

5. 5. The compound for use according to any one of claims 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 3 week treatment cycle, the compound of formula (I) or a pharma- ceutically acceptable salt thereof being administered in week 1 of the treatment cycle, followed by a 2 week drug holiday.

6. 5. The compound for use according to any one of claims 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a three week treatment cycle, the compound of formula (I) or a pharma- ceutically acceptable salt thereof being administered in weeks 1 and 2 of the treatment cycle, followed by a one week drug holiday.

7. 5. The compound for use according to any one of claims 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a 4 week treatment cycle, the compound of formula (I) or a pharma- ceutically acceptable salt thereof being administered in week 1 of the treatment cycle followed by a 3 week drug holiday.

8. 5. The compound for use according to any one of claims 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a four week treatment cycle, the compound of formula (I) or a pharma- ceutically acceptable salt thereof being administered in weeks 1 and 3 of the treatment cycle, with weeks 2 and 4 being drug-free weeks.

9. 5. The compound for use according to any one of claims 1 to 4, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered according to a four week treatment cycle, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered each week during the first three weeks of the treatment cycle, followed by a one week drug holiday.

10. The compound for use according to any one of claims 1 to 9, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof, when administered, is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 40 mg to about 200 mg per week for several weeks.

11. The compound for use according to any one of claims 1 to 9, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof, when administered, is administered to a patient at a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of about 80 mg to about 160 mg per week for several weeks.

12. The neoplastic disease may be epithelial neoplasms, squamous cell neoplasms, basal cell neoplasms, transitional cell papillomas and carcinomas, adenomas and adenocarcinomas, adnexal and cutaneous adnexal neoplasms, mucoepidermoid neoplasms, cystic neoplasms, mucinous and serous neoplasms, ductal, lobular and medullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized glandular neoplasms, paraganglionic and glomus tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibromatous neoplasms, myxomatous neoplasms, lipomatous neoplasms, myomatous neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, mesothelial neoplasms, 12. The compound for use according to any one of claims 1 to 11, selected from the group consisting of tumor neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesogiomas, vascular tumors, lymphatic tumors, osteo- and chondroplastic neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepithelioma neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft part sarcomas, Hodgkin's and non-Hodgkin's lymphomas, other lymphoreticular neoplasms, plasma cell neoplasms, mast cell tumors, immunoproliferative diseases, leukemias, myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

13. The compound for use according to any one of claims 1 to 12, wherein the neoplastic disease is treatable by inhibition of PLK1 in addition to treatment with a TTK inhibitor (e.g. the compound of formula (I)).

14. 14. The compound for use according to any one of claims 1 to 13, wherein the neoplastic disease is cancer, in particular a cancer selected from breast cancer (including triple negative breast cancer and luminal B breast cancer), gastric cancer, colon cancer, liver cancer (including hepatocellular carcinoma), endometrial cancer, ovarian cancer, esophageal cancer, lung cancer (including non-small cell lung cancer), Kaposi's sarcoma, cervical cancer, pancreatic cancer, melanoma, prostate cancer, bladder cancer and leukemia, such as acute myeloid leukemia (AML) (including mixed karyotype AML).

15. The compound for use according to any one of claims 1 to 13, wherein said neoplastic disease is triple negative breast cancer.

Images