Pharmaceutical combinations for use in the treatment of neoplastic diseases

Abstract

The present invention provides pharmaceutical combinations comprising (a) a TTK / PLK1 inhibitor (i.e., a compound of formula (I) or a pharma- ceutically acceptable salt thereof as protected in the claims) and (b) a taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel), as well as methods of using the combinations of the present invention for the treatment of neoplastic diseases, such as cancer.

Description

[Technical field]

[0001] The present invention relates to pharmaceutical combinations comprising two active pharmaceutical compounds as described herein and methods of using the combinations of the invention 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] Paclitaxel belongs to the class of taxane anticancer drugs and is a well-known small molecule approved for the treatment of several cancer indications. It is marketed under the trade name Taxol®.

[0004] There is a continuing need for new effective treatment options for cancer patients. As demonstrated in the following examples, it has now surprisingly been found that the combination of certain compounds of WO2015 / 155042 with paclitaxel provides multiple cures in cancer models. [Prior art documents] [Patent documents]

[0005] [Patent Document 1] International Publication No. 2015 / 155042 Brochure Summary of the Invention [Means for solving the problem]

[0006] In a first aspect, the present invention provides a pharmaceutical combination comprising: (a) A compound of formula (I) [ka] or a pharma- ceutically acceptable salt thereof; and (b) a taxane anticancer drug or a pharma- ceutically acceptable salt thereof (eg, paclitaxel).

[0007] The compound of formula (I) is disclosed in WO 2015 / 155042 as Example 17.

[0008] Surprisingly, in addition to TTK inhibitory activity, the compounds of formula (I) were also found to exhibit Polo-like kinase 1 (PLK1) inhibition (see Examples below). Both kinases cooperate in activating the mitotic spindle assembly checkpoint (SAC) at the centromere to regulate chromosome alignment and separation 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 in Dou et al., Plos ONE 2011,6:4;e18793, which shows that some substrates of both kinases share similar consensus motifs.

[0009] In contrast to TTK-specific inhibitors, the compounds of formula (I) have long-term effects on TTK in combination with a transient effect on PLK1 (see Examples below) that results in more rapid destruction of SAC enhancing aberrant mitotic progression. Thus, the dual TTK / PLK1 inhibitory activity gives the compounds of formula (I) a unique profile, distinguishing them from other molecules that exhibit TTK inhibitory activity without appreciable levels of PLK1 inhibitory activity.

[0010] In a further aspect, the present invention provides a method of treating a neoplastic disease in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a pharmaceutical combination of the present invention.

[0011] In a further aspect, the present invention provides a method for treating a neoplastic disease in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to the subject, wherein said subject is undergoing or will be undergoing treatment with a taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel).

[0012] In a further aspect, the present invention provides a method for treating a neoplastic disease in a subject in need thereof, comprising administering a therapeutically effective amount of a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) to the subject, wherein the subject is undergoing or will be undergoing treatment with a compound of formula (I) or a pharma- ceutically acceptable salt thereof.

[0013] In a further aspect, the present invention provides a pharmaceutical combination of the present invention for use in the treatment of a neoplastic disease in a subject.

[0014] In a further aspect, the present invention provides a compound of formula (I) or a pharma- ceutically acceptable salt thereof for use in combination with a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) for said treatment of a neoplastic disease in a subject.

[0015] In a further aspect, the present invention provides a taxane anticancer agent, or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel), for use in combination with a compound of formula (I) or a pharma- ceutically acceptable salt thereof to treat a neoplastic disease in a subject.

[0016] In a further aspect, the present invention provides the use of a pharmaceutical combination of the present invention in the preparation of a single drug product or as a combination drug product for the treatment of a neoplastic disease in a subject.

[0017] 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 single agent medicament for use in combination with a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) for the treatment of a neoplastic disease in a subject, or in the preparation of a medicament in combination with a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel).

[0018] 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 single agent medicament for use in combination with a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) for the treatment of a neoplastic disease in a subject, or in the preparation of a medicament in combination with a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel).

[0019] Neoplastic diseases for treatment with the combination of the present invention are described below and are particularly contemplated for the treatment of cancer, and particularly for human subjects.

[0020] Further aspects and embodiments of the invention are described in more detail below. [Brief description of the drawings]

[0021] [Figure 1]Figure 1 shows the effect of monotherapy of the compound of formula (I) and paclitaxel (PTX) and their combination in mice bearing subcutaneous patient-derived xenograft (PDX) tumor model BR1282 from the first PDX study. (A) and (B) show the results of BR1282 tumor growth under different treatments (A, mean ± SEM) and comparison of the different growth rates of each tumor for each treatment group (B, mean ± SD), where *** indicates p<0.001 compared to vehicle and both monotherapies (combination groups were not significantly different from each other; p=0.7). Note: On day 21, one mouse died in the compound of formula (I) monotherapy group (believed to be non-drug related) and on day 28, one mouse was culled due to >20% weight loss in the combination 24-hour group. (C) and (D) show the percentage change in body weight under different treatments (C, mean ± SEM) and comparison with the vehicle group on day 16 after disposal, *p<0.05 (D). Statistical analysis used one-way ANOVA with Holm-Sidak post-hoc test. N=8 mice / group. Control mice received both vehicles, i.e., vehicle of the compound of formula (I) and vehicle of paclitaxel, with a gap of 4 hours between administrations. [Diagram 2] Figure 1 shows a comparison of individual tumor growth of five treatment groups in the subcutaneous PDX tumor model BR1282 from the first PDX study. N=8 mice / group. (A) shows a vehicle control group, (B) shows a group administered a compound of formula (I) alone, (C) shows a group administered paclitaxel alone, (D) shows a group administered a combination therapy where a compound of formula (I) was administered 4 hours after paclitaxel when both compounds were administered on the same day, and (E) shows a group administered a combination therapy where a compound of formula (I) was administered 24 hours after paclitaxel when both compounds were administered on consecutive days. [Diagram 3] Hematoxylin and eosin (H&E) staining of mouse skin prepared on day 97 from the first PDX study is shown. (A) Skin of a mouse from the combination 24h group showing residual tumor (indicated by an asterisk). Calcification (indicated by an arrow) is also visible. (B) Skin of a mouse from the combination 24h group showing a complete absence of residual tumor. [Figure 4] Figure 1 shows the effect of monotherapy and their combinations in mice bearing subcutaneous PDX tumor model BR1282 from the second PDX study. (A) and (B) show the results of BR1282 tumor growth under different treatments (A, mean ± SEM) and comparison of the different growth rates of each tumor for each treatment group up to the day of culling or day 51, which is one week after the last treatment (B, mean ± SD), where *** indicates p<0.001, ** indicates p<0.01, and * indicates p<0.05 compared to monotherapy of compound of formula (I). All combination groups show p<0.001 compared to vehicle and paclitaxel monotherapy (combination groups were not significantly different from each other; p=0.957-0.998). NOTE: On day 23, one mouse was culled due to weight loss >20% in the combination group (i.e., treatment group indicated as PTX 15 mg / kg; formula (I) 8 mg / kg 2qw (4 h gap)) with a 4 h gap. (C) and (D) show the weight change in percentage under comparison of day 13 culled with different treatments (C, mean ± SEM) and vehicle group, *p<0.05, **p<0.01 and ***p<0.001 (D). Statistical analysis used one-way ANOVA with Holm-Sidak post-hoc test. N=8 mice / group. Control mice received both vehicles, i.e., vehicle of compound of formula (I) and vehicle of paclitaxel using a 4 h gap between administrations. [Diagram 5]Comparison of individual tumor growth of nine treatment groups in the subcutaneous PDX tumor model BR1282 from the second PDX study shown in Figure 4. N=8 mice / group. (A) represents a vehicle control group, (B) represents a group receiving a compound of formula (I) alone, (C) represents a group receiving paclitaxel alone, (D) represents a group receiving combination therapy where the compound of formula (I) was administered 2 hours after paclitaxel when both compounds were administered on the same day, (E) represents a group receiving combination therapy where the compound of formula (I) was administered 4 hours after paclitaxel when both compounds were administered on the same day, (F) represents a group receiving combination therapy where the compound of formula (I) was administered 24 hours after paclitaxel when both compounds were administered on consecutive days, (G) represents a group receiving combination therapy where the compound of formula (I) was administered as a sole dose 4 hours after paclitaxel, and (H) represents a group receiving combination therapy where the compound of formula (I) was administered 4 hours before paclitaxel when both compounds were administered on the same day. [Figure 6] 1 shows the results of an experiment to determine whether there is a significant drug-drug interaction (DDI) between the compound of formula (I) and paclitaxel. (A) The effect of paclitaxel on the compound of formula (I). Non-tumor-bearing mice (n=3 in each group) were treated once with the compound of formula (I) alone (8 mg / kg, intravenous (iv)), or with the compound of formula (I) (8 mg / kg, iv) 1 hour after administration of the compound of formula (I) (15 mg / kg, iv). Results show the mean ± SD (n=3) concentration-time curves for the different treatment regimens. (B) The effect of the compound of formula (I) on paclitaxel. Non-tumor-bearing mice (n=3 in each group) were treated once with the compound of formula (I) alone (15 mg / kg, iv) or with paclitaxel (15 mg / kg, iv) 1 hour before administration of the compound of formula (I) (8 mg / kg, iv). Results show the mean ± SD (n=3) concentration-time curves for the different treatment regimens. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0022] 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.

[0023] The terms "combination," "therapeutic combination," or "pharmaceutical combination" are interchangeable terms and refer to either a fixed combination or a non-fixed combination.

[0024] The term "combination therapy" refers to the administration of two or more therapeutic agents to treat a therapeutic condition or disorder described in this disclosure. Such administration encompasses the co-administration of these therapeutic agents in a substantially simultaneous manner, as well as the use of each type of therapeutic agent in a sequential and / or separate manner (e.g., according to different administration routes), at about the same time or at different times, e.g., according to different administration regimens, examples of which are described herein. When the therapeutic agents are administered sequentially and / or separately, the administration schedule is such that there is a therapeutic interaction between the therapeutic agents in the patient's body, and / or when the second therapeutic agent is administered, there is a therapeutic effect due to the first therapeutic agent. For example, when the agents are administered according to a cyclical treatment schedule, the cyclical treatment schedules may overlap, or when one therapeutic agent is administered according to a sequential administration schedule and a second therapeutic agent is administered according to a cyclical schedule, at least one dose from the agent administered according to the sequential schedule occurs during the treatment cycle of the other therapeutic agent. Typically, when both therapeutic agents are administered according to a cyclical treatment schedule, there will be an interval of at least 7 days between the dose of one of the therapeutic agents and the dose of the other therapeutic agent.

[0025] The term "pharmaceutical composition" is defined herein to refer to a solid or liquid formulation containing at least one therapeutic agent, optionally one or more pharma- ceutically acceptable excipients, that is administered to a patient to treat a particular disease or condition affecting the patient.

[0026] 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 excessive toxicity or other complications commensurate with a reasonable benefit / risk ratio.

[0027] As used herein, the terms "fixed combination," "fixed dose," "single formulation," and "combination pharmaceutical" refer to a single dosage form formulated to deliver to a patient amounts of both therapeutic agents that are jointly therapeutically effective for the treatment of a neoplastic disease. The single dosage form is designed to deliver a fixed amount of each therapeutic agent, along with any pharma- ceutical acceptable carriers or excipients.

[0028] The terms "non-fixed combination," "kit," "separate formulation," and "monopharmaceutical product" mean that the active ingredients are formulated as separate entities allowing for simultaneous, sequential or separate administration to a patient, such administration providing therapeutically effective levels of the two compounds in the patient's body.

[0029] The term "patient" refers to a human subject to therapeutic treatment.

[0030] The term "subject" refers to a mammal, preferably a patient.

[0031] The term "treatment" used herein in the context of treating 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, improvement 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 "treat" also means to prevent, delay the onset of a disease (i.e., the period before the clinical manifestation of a disease), and / or reduce the risk of onset or aggravation.

[0032] As used herein, the terms "prevent," "preventing" or "prevention" include the prevention of at least one symptom associated with or caused by the disease being prevented.

[0033] The term "pharmacologically effective amount", "therapeutically effective amount" or "clinically effective amount" is an amount sufficient, when administered according to a desired treatment regimen, to provide an observable or clinically significant improvement over baseline clinically observable signs and symptoms of the disease being treated, e.g., commensurate with a reasonable benefit / risk ratio. One skilled in the art will appreciate that the therapeutically effective amount of an agent for use in combination therapy may be lower than the amount required to provide a therapeutic effect when the agent is used as a monotherapy.

[0034] 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.

[0035] 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.

[0036] Compounds of formula (I) In some embodiments, the compound of formula (I) is / is used as a free base. In other embodiments, the compound of formula (I) is used as a pharma- ceutically acceptable salt.

[0037] The pharmaceutically acceptable salt of the compound of formula (I) can be an acid addition salt.Salt is formed, for example, with organic or inorganic acid from the compound of formula (I).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.

[0038] 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.

[0039] Compounds of formula (I) and pharma- ceutically acceptable salts thereof can be synthesised as described in WO 2015 / 155042, in particular pages 17-19, which are incorporated herein by reference, 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.

[0040] Taxane anticancer drugs Taxanes are a well-known class of anti-cancer drugs, including, for example, paclitaxel (sold under the trade name Taxol®), docetaxel (sold under the trade name Taxotere®), and cabazitel (sold under the trade name Jevtana®). Other taxanes, such as larotaxel, mirataxel, ortataxel, and tesetaxel, are in clinical development (see, for example, Ojima et al. Expert Opin. Ther. Pat. 2016, 26(1):1-20). The primary mechanism of action of the taxane class of anti-cancer drugs is the disruption of microtubule function. Taxanes stabilize guanosine diphosphate (GDP)-bound tubulin in microtubules. Stabilization of microtubules thereby inhibits the process of cell division.

[0041] In some embodiments, the taxane anticancer agent or its pharmaceutically acceptable salt is paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel or tesetaxel, including its pharmaceutically acceptable salt. In some embodiments, the taxane anticancer agent or its pharmaceutically acceptable salt is paclitaxel, docetaxel, cabazitaxel, or its pharmaceutically acceptable salt. Preferably, the taxane anticancer agent or its pharmaceutically acceptable salt is paclitaxel or its pharmaceutically acceptable salt, more preferably paclitaxel (e.g., sold under the trade name Taxol®).

[0042] disease The pharmaceutical combination of the present invention can be used to treat neoplastic diseases by administering the combination of the present invention, for example, to inhibit protein kinase TTK (the compound of formula (I) or a pharma- ceutically acceptable salt thereof) and stabilize microtubules (taxane anticancer drugs, e.g., paclitaxel).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 taxane anticancer drugs (e.g., paclitaxel) and TTK inhibitors (e.g., the compound of formula (I)).

[0043] Furthermore, the pharmaceutical combination of the present invention 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 therapeutic setting (e.g., therapeutic, including preventive, adjuvant, neoadjuvant, palliative treatment). The pharmaceutical combination of the present invention 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 progression, or improving or maintaining the quality of life or functional status of a subject (e.g., a patient). The pharmaceutical combination of the present invention can also be used in post-treatment recovery from cancer. The pharmaceutical combination of the present invention can be used to treat metastatic cancer.

[0044] For example, the pharmaceutical combinations of the present invention 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 increase 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.

[0045] As mentioned above, the pharmaceutical combination of the present invention can be used to treat neoplastic diseases.Examples of neoplastic diseases include 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 intramedullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized glandular neoplasms, paraganglioma and breast tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibroma neoplasms, myxomas, lipoma neoplasms, fibroma neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, and the like. These include, but are not limited to, mesothelioma neoplasms, germ cell neoplasms, trophoblastic neoplasms, mesogiomas, vascular tumors, lymphatic tumors, osseous and chondromatous neoplasms, giant cell tumors, various bone tumors, odontogenic tumors, gliomas, neuroepithelioma neoplasms, meningiomas, nerve sheath tumors, granular cell tumors and alveolar soft tissue 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.

[0046] 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 colorectal cancer, 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, kidney, skin, thyroid, head and neck, prostate and testis.

[0047] 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, colorectal 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).

[0048] In some embodiments, the neoplastic disease is breast cancer.

[0049] In some embodiments, the neoplastic disease is triple-negative breast cancer.

[0050] In some embodiments, the neoplastic disease is luminal B breast cancer.

[0051] In some embodiments, the neoplastic disease is gastric cancer.

[0052] In some embodiments, the neoplastic disease is colorectal cancer.

[0053] In some embodiments, the neoplastic disease is hepatocellular carcinoma.

[0054] In some embodiments, the neoplastic disease is endometrial cancer.

[0055] In some embodiments, the neoplastic disease is acute myeloid leukemia (AML) (including complex karyotype AML).

[0056] 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.

[0057] Administration The administration of the pharmaceutical combination of the present invention includes administering the combination as a single preparation, and administering each of the combination drugs as separate preparations.Preferably, the compound of formula (I) or its pharmaceutically acceptable derivative and the taxane anticancer drug or its pharmaceutically acceptable salt are contained in separate preparations.Preferably, the compound of formula (I) or its pharmaceutically acceptable salt and the taxane anticancer drug or its pharmaceutically acceptable salt (e.g. paclitaxel) are intravenously administered to subject (preferably human).

[0058] In some embodiments, the combination of the present invention is used to treat cancer in a subject, comprising administering to the subject a combination therapy comprising a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a therapeutically effective amount of a taxane anticancer drug or a pharmaceutically acceptable salt thereof (e.g., paclitaxel).These compounds are administered at a therapeutically effective dosage, and when combined, provide beneficial effects, such as those described herein.Those skilled in the art will understand that a therapeutically effective dosage for use in combination therapy may be lower than the dosage required to provide a therapeutic effect when either agent is used as a monotherapy.

[0059] The administration of the pharmaceutical combination of the present invention may not only bring about beneficial effects, such as synergistic effects in terms of alleviating symptoms, delaying or inhibiting progression, but also bring about additional beneficial effects, such as reduced side effects, more durable therapeutic effects, improved quality of life and / or reduced morbidity, compared with the monotherapy of applying only one of the pharmaceutical therapeutic agents used in the combination of the present invention.For example, it may be possible to use lower doses of the therapeutic agents of the combination of the present invention, so that not only the dosage may be less frequent, but also it may be applied less frequently, or it may be used to reduce the incidence of side effects observed with only one of the combination partners.

[0060] In some embodiments, the combinations provided herein may exhibit synergistic effects. The term "synergy" as used herein refers to the action of two agents, i.e., a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel), resulting in a therapeutic effect, e.g., slowing the progression of a disease or its symptoms, that is greater than the addition of the same therapeutic effect as each agent administered as such. In general, in determining a synergistic interaction between one or more components, the optimal range for effect and the absolute dose range of each component for effect can be definitively measured by administration to a subject (e.g., a patient) in need of treatment of the components across a range of different w / w ratios and doses. In humans, the complexity and cost of conducting clinical studies on patients may make the use of this form of testing as a primary model for synergy impractical. However, the observation of synergy in a particular experiment may be predictive of the effect in other species, and the synergy can be further quantified using animal models. The results of such studies can also be used to predict effective dose ratio ranges as well as absolute doses and plasma concentrations, for example as illustrated in the Examples below.

[0061] In a further embodiment, the present invention provides a synergistic combination for administration to humans comprising a pharmaceutical combination of the present invention, wherein the dose ranges of each component correspond to the synergistic ranges shown, for example, in appropriate tumor models or clinical trials.

[0062] The combination of the present invention can be used as described above in long-term therapy or as adjuvant therapy in the context of other treatment strategies.Other possible treatments are therapy to maintain the subject's (e.g., patient's) condition after tumor regression, or even prophylactic therapy, for example in subjects (e.g., patients) at risk.

[0063] The method according to the present invention may include (i) administration of a compound of formula (I) in free or pharma- ceutically acceptable salt form, and (ii) administration of a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) in any order, simultaneously, sequentially or separately, in a jointly therapeutically effective amount, e.g., in a synergistically effective amount, e.g., in a continuous or cyclical administration schedule, e.g., corresponding to the amounts described herein. The individual combination partners of the combination of the present invention may be administered separately at different times during the course of treatment, or may be administered simultaneously. Thus, the present invention should be understood to encompass all such treatment regimes, and the term "administration" should be interpreted accordingly. Examples of treatment regimes for use in the present invention are described in detail below.

[0064] The compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) may be administered according to the same treatment schedule, or according to independent treatment schedules. The treatment schedule may be cyclic or continuous.

[0065] A cyclic treatment schedule is defined by a repeated administration schedule in which the repeated 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 more. A continuous treatment schedule is a regular administration schedule that does not incorporate a rest period (i.e., a period longer than the regular interval between doses). For example, doses can be administered once a day, twice a day, once every two days, once every three days, etc. The treatment schedule, whether cyclic or continuous, can be continued as long as necessary ("open-ended treatment"), for example, as long as the subject (e.g., patient) is receiving benefit as determined by the physician supervising the treatment.

[0066] When the compound of formula (I) or its pharmaceutically acceptable salt and the taxane anticancer drug or its pharmaceutically acceptable salt (e.g. paclitaxel) are administered according to independent treatment schedules, both treatment schedules can be cyclic, or one can be cyclic and the other can be continuous.When both treatment schedules are cyclic, the cycles of the two treatment schedules can be the same duration or different duration, and can start on the same day or different days.When the cycles are the same duration, the treatment cycles of both drugs usually start on the same day.

[0067] In some embodiments, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) are administered according to a cyclical treatment schedule, which may be for the same period of time, e.g., 4 weeks / 28 days, with each treatment cycle usually commencing on the same day (i.e., the same treatment cycle).

[0068] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) are administered (e.g., intravenously) according to a four-week treatment cycle, where the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered on the first week of the treatment cycle, e.g., on day 1, followed by a three-week rest period, and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) is administered each week during the first three weeks of the treatment cycle, followed by a week of rest, e.g., on days 1, 8, and 15. Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) are administered to the subject according to the same four-week treatment cycle (i.e., the treatment cycles start on the same day).

[0069] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) are administered (e.g., intravenously) according to a four-week treatment cycle, the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered in the first and third weeks of the treatment cycle, e.g., on days 1 and 15, with weeks 2 and 4 being drug-free weeks, and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) is administered each week during the first three weeks of the treatment cycle, followed by drug-free weeks, e.g., on days 1, 8, and 15. Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) are administered to the subject according to the same four-week treatment cycle (i.e., the treatment cycles start on the same day).

[0070] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) are administered (e.g., intravenously) according to a four-week treatment cycle, where the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered each week during the first three weeks of the treatment cycle, for example, on days 1, 8, and 15, followed by a drug-free week, and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) is administered each week during the first three weeks of the treatment cycle, for example, on days 1, 8, and 15, followed by a drug-free week. Preferably, the compound of formula (I) or a pharmaceutically acceptable salt thereof and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) are administered to the subject according to the same four-week treatment cycle (i.e., the treatment cycles start on the same day).

[0071] The effective dosage of each of the combination partners used in the combination of the present invention may vary depending on the pharmaceutical composition used, the mode of administration, the condition being treated, and the severity of the condition being treated. Thus, the dosage regimen of the combination of the present invention is selected according to various factors, including the route of administration and the renal and hepatic function of the subject (e.g., patient).

[0072] The optimal ratio, individual and combined dosage, and the concentration of the combination partners of the pharmaceutical combination of the present invention that brings about efficacy without toxicity are based on the kinetics of the availability of therapeutic agents to the target site. They can be established using routine clinical trials and procedures well known in the art, and depend on various factors such as the mode of administration, the condition being treated and the severity of the condition being treated, as well as the individual's age, weight, general health, sex and diet, and other drugs that the individual is taking. Similarly, the frequency of administration can vary depending on the compound used and the specific condition being treated. Subjects (e.g., patients) can generally be monitored for therapeutic effectiveness using assays suitable for the condition being treated, which are well known to those skilled in the art.

[0073] In some embodiments, the molar ratio of the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) to the compound of formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose in the combination of the present invention is, for example, from about 0.1:1 to about 18.8:1, such as from about 0.1:1 to about 16.7:1, for example from about 0.2:1 to about 16.7:1, for example from about 0.3:1 to about 2.3:1, for example from about 0.3:1 to about 2.1:1, for example, about 0.3:1 to about 0.7:1, for example, about 0.3:1 to about 0.6:1, for example, about 0.3:1 to about 0.5:1, for example, about 0.4:1 to about 2.1:1, for example, about 0.4:1 to about 1.2:1, for example, about 0.4:1 to about 1.0:1, for example, about 0.4:1 to about 0.5:1, for example, about 0.5:1 to about 1.0:1, for example, about 0.5:1 to about 0.9:1, for example, about 0.6:1 to about 0.9:1. In some embodiments, the molar ratio of the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) to the compound of formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is about 0.4:1 to about 2.1:1.

[0074] In some embodiments, the molar ratio of the taxane anticancer agent or its pharmaceutically acceptable salt (e.g., paclitaxel) to the compound of formula (I) or its pharmaceutically acceptable salt per weekly dose can be, for example, up to about 18.8:1, for example, up to about 16.7:1, for example, up to about 2.3:1, for example, up to about 2.1:1, for example, up to about 1.2:1, for example, up to about 1.0:1, for example, up to about 0.9:1, for example, up to about 0.7:1, for example, up to about 0.6:1, for example, up to about 0.5:1. In some embodiments, the molar ratio of the taxane anticancer agent or its pharmaceutically acceptable salt (e.g., paclitaxel) to the compound of formula (I) or its pharmaceutically acceptable salt per weekly dose is at most about 2.1:1.

[0075] In some embodiments, the molar ratio of the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) to the compound of formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose may be, for example, at least about 0.1:1, for example, at least about 0.2:1, for example, at least about 0.3:1, for example, at least about 0.4:1, for example, at least about 0.5:1, for example, at least about 0.6:1. In some embodiments, the molar ratio of the taxane anticancer agent or a pharma- ceutically acceptable salt thereof to the compound of formula (I) or a pharma- ceutically acceptable salt thereof per weekly dose is at least about 0.4:1.

[0076] 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, B and C, refer to the dosage of the free base. The dosages also apply to the pharma- ceutically acceptable salt 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 weekly dosage (in humans) of the compound of formula (I) is about 5 mg to about 480 mg per week when administered means that the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the 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 when administered.

[0077] The dose of paclitaxel is mg / m 2 The dosages of paclitaxel given are given as mg / m BSA and refer to the free base. Similarly, the dosages of paclitaxel given also apply to pharma- ceutically acceptable salts of paclitaxel, except that when a pharma- ceutical salt of paclitaxel is used, the dosages given are in mg / m 2 Dosage should be adjusted (ie, increased) so that the molar amount of paclitaxel administered is the same as the molar amount of the free base. Paclitaxel is normally used as the free base.

[0078] 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.

[0079] 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.

[0080] Examples of weekly (in humans) doses of the compound of formula (I) when administered include about 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, and about 110 mg to about 120 mg. , about 120mg 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, Approximately 180mg to approximately 190mg, approximately 190mg to approximately 200mg, approximately 200mg to approximately 210mg, approximately 210mg to approximately 220mg, approximately 220mg to approximately 230mg, approximately 230mg to approximately 240mg, approximately 240mg to about 250mg, about 250mg to about 260mg, about 260mg to about 270mg, about 270mg to about 280mg, about 280mg to about 290mg, about 290mg to about 300mg, about 3 00mg~about 310mg, about 310mg~about 320mg, about 320mg~about 330mg, about 330mg~about 340mg, about 340mg~about 350mg, about 350mg~about 360mg, about 36 0 mg to 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.

[0081] Examples of specific weekly dosages of the compounds of formula (I) when administered (in humans) are 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 115mg, about 120mg, about 125mg, about 130mg, about 135mg, about 140mg, about 145mg, about 150mg, about 155mg, about 160mg, about 165mg, about 170mg, about 17 5mg, 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 240mg, about 245mg, about 250mg, about 255mg, about 260mg, about 265mg, about 270mg, about 275mg, about 280mg, about 285mg, about 290mg, about 295mg, about 30 0mg, about 305mg, about 310mg, about 315mg, about 320mg, about 325mg, about 330mg, about 335mg, about 340mg, about 345mg, about 350mg, about 355mg, about 360mg , about 365 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.

[0082] The weekly dose of the compound of formula (I) or a pharma- ceutically acceptable salt thereof may be administered in a single dose, e.g., any time shortly when administered intravenously. Alternatively, the weekly dose may be administered in multiple doses, e.g., when administered intravenously, in two or three doses with a pause between doses, e.g., at least 30 minutes between doses, e.g., at least 1 hour, e.g., at least 2 hours, e.g., at least 4 hours, e.g., 30 minutes to 12 hours, e.g., 30 minutes to 6 hours between doses. Such multiple doses may be administered on the same day or on separate days, e.g., on consecutive days, or, e.g., 3 days after the day of the first dose.

[0083] The compound of formula (I) or its pharma-ceutically acceptable salt is preferably administered intravenously.The duration of infusion is usually at least 30 minutes and can be up to 24 hours.In some embodiments, the duration of 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, such as about 1 hour.

[0084] Exemplary weekly doses (in humans) of paclitaxel when administered include about 60 mg / m 2 to about 90 mg / m 2 , about 60mg / m 2 to about 80 mg / m 2 , and about 70 mg / m 2 to about 80 mg / m 2 Includes:

[0085] An example of a specific weekly (in humans) dose of paclitaxel when administered is about 60 mg / m 2 , about 61mg / m 2 , about 62 mg / m 2 , about 63mg / m 2 , about 64mg / m 2 , about 65mg / m 2 , about 66mg / m 2 , about 67mg / m 2 , about 68mg / m 2 , about 69mg / m 2 , about 70mg / m 2 , about 71mg / m 2, about 72mg / m 2 , about 73mg / m 2 , about 74mg / m 2 , about 75mg / m 2 , about 76mg / m 2 , about 77mg / m 2 , about 78mg / m 2 , about 79mg / m 2 , about 80mg / m 2 , about 81mg / m 2 , about 82mg / m 2 , about 83mg / m 2 , about 84mg / m 2 , about 85mg / m 2 , about 86mg / m 2 , about 87mg / m 2 , about 88mg / m 2 , about 89mg / m 2 , and about 90 mg / m 2 Includes.

[0086] The weekly dose of paclitaxel can be administered in a single dose, e.g., without interruption when administered intravenously. Alternatively, the weekly dose can be administered in multiple doses, e.g., when administered intravenously, in two or three doses with a pause between doses, e.g., at least 30 minutes, e.g., at least 1 hour, e.g., at least 2 hours, e.g., at least 4 hours, e.g., 30 minutes to 12 hours, e.g., 30 minutes to 6 hours, between doses. Such multiple doses can be administered on the same or separate days, e.g., on consecutive days or on the third day after the first dose.

[0087] Paclitaxel is preferably administered intravenously.The duration of infusion is usually at least 30 minutes and can be up to 24 hours.In some embodiments, the duration of 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, such as about 1 hour.

[0088] In some embodiments, the weekly (in humans) dosage of the compound of formula (I) during the week when administered and the weekly (in humans) dosage of paclitaxel during the week when administered are as set forth in any one of embodiments 1A to 21A of Table A. [Table 1]

[0089] As noted above, embodiment 1A is an embodiment in which paclitaxel, when administered, is about 60 mg / m every week of the week. 2 to about 90 mg / m 2 and the compound of formula (I) or a pharma- ceutical 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 of the week when administered. The same applies to embodiments 2A to 21A.

[0090] In some embodiments, the weekly (in humans) dosage of the compound of formula (I) during the week when administered and the weekly (in humans) dosage of paclitaxel during the week when administered are as set forth in any one of embodiments 1B to 194B of Table B. [Table 2-1] [Table 2-2] [Table 2-3]

[0091] As noted above, embodiment 1B is an embodiment in which paclitaxel, when administered, is about 60 mg / m every week of the week. 2 and the compound of formula (I) or a pharma- ceutical 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 10 mg every week of the week when administered. The same applies to embodiments 2B to 194B.

[0092] In some embodiments, the treatment cycle length of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and paclitaxel is 4 weeks, and when administered, the weekly (in humans) dosages of the compound of formula (I) and paclitaxel during the week and the weeks of administration within the cycle are as set forth in any one of embodiments 1C-63C of Table C, and the compound of formula (I) and paclitaxel are administered according to the same treatment cycle (i.e., starting on the same day). [Table 3-1] [Table 3-2]

[0093] As described above, embodiment 1C is an embodiment in which the compound of formula (I) or a pharma- ceutically acceptable salt thereof and paclitaxel are administered to a patient (e.g., intravenously) according to the same four-week treatment cycle, where the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered during week 1 of the treatment cycle, followed by a three-week drug holiday, and paclitaxel is administered each week during the first three weeks of the treatment cycle, followed by a drug holiday, and where paclitaxel, when administered, is administered at about 60 mg / m every week of the week. 2 ~about 90mg / m 2 and the compound of formula (I) or a pharma- ceutical 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 of the week when administered. The same applies to embodiments 2C to 63C.

[0094] In some embodiments, the treatment cycle length of the compound of formula (I) or a pharma- ceutically acceptable salt thereof and paclitaxel is 28 days, and when administered, the weekly (in humans) dosages of the compound of formula (I) and paclitaxel and the days of administration within the cycle are as set forth in any one of embodiments 1D-63D of Table D, and the compound of formula (I) and paclitaxel are administered according to the same treatment cycle (i.e., starting on the same day). [Table 4-1] [Table 4-2]

[0095] As described above, embodiment 1D is an embodiment in which the compound of formula (I) or a pharma- ceutically acceptable salt thereof and paclitaxel are administered to a patient (e.g., intravenously) according to the same 28-day treatment cycle, where the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on day 1 of the treatment cycle, and paclitaxel is administered on days 1, 8, and 15 of the treatment cycle, and where paclitaxel, when administered, is administered at about 60 mg / m every week of the week. 2 ~about 90mg / m 2 and the compound of formula (I) or a pharma- ceutical 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 of the week when administered. The same applies to embodiments 2D to 63D.

[0096] In some embodiments, the weekly dose of paclitaxel (mg / m 2) to the weekly dose (mg) of the compound of formula (I) in the week when administered is, for example, about 0.1:1 to about 18.0:1, such as about 0.1:1 to about 16.0:1, for example, about 0.3:1 to about 2.3:1, for example, about 0.3:1 to about 2.0:1, for example, about 0.4:1 to about 2.0:1, for example, about 0.4:1 to about 1.1:1, for example, about 0.4:1 to about 1.0:1, for example, about 0.5:1 to about 1.0:1, for example, about 0.5:1 to about 0.9:1, for example, about 0.3:1 to about 0.6:1, for example, about 0.3:1 to about 0.5:1, for example, about 0.4:1 to about 0.5:1, for example, about 0.3:1 to about 0.4:1. In some embodiments, the weekly dose (mg / m 2 The weight ratio of the compound of formula (I) (mg) to the weekly dose (mg) of the compound of formula (I) when administered is from about 0.4:1 to about 2.0:1.

[0097] In some embodiments, the weekly dose of paclitaxel (mg / m 2 ) to the weekly dose (mg) of the compound of formula (I) during the week when administered, e.g., at most about 18.0:1, e.g., at most about 16.0:1, e.g., at most about 2.3:1, e.g., at most about 2.0:1, e.g., at most about 1.1:1, e.g., at most about 1.0:1, e.g., at most about 0.9:1, e.g., at most about 0.6:1, e.g., at most about 0.5:1, e.g., at most about 0.4:1. In some embodiments, the weekly dose (mg / m) of paclitaxel is 2 ) to the weekly dose (mg) of the compound of formula (I) when administered is up to about 2.0:1.

[0098] In some embodiments, the weekly dose of paclitaxel (mg / m 2 ) to the weekly dose (mg) of the compound of formula (I) during the week when administered is, for example, at least about 0.1:1, for example, at least about 0.3:1, for example, at least about 0.4:1, for example, at least about 0.5:1. In some embodiments, the mass ratio of the weekly dose (mg / m 2 ) to the weekly dose (mg) of the compound of formula (I) when administered is at least about 0.4:1.

[0099] In some embodiments, when the compound of formula (I) or its pharmaceutically acceptable salt and the taxane anticancer agent (e.g., paclitaxel) are administered on the same day, the compound of formula (I) or its pharmaceutically acceptable salt is administered before the taxane anticancer agent (e.g., paclitaxel). In some embodiments, when the compound of formula (I) or its pharmaceutically acceptable salt and the taxane anticancer agent (e.g., paclitaxel) are administered on the same day, the compound of formula (I) or its pharmaceutically acceptable salt is administered after the taxane anticancer agent (e.g., paclitaxel). Usually, there is a pause between the administration of the compound of formula (I) or its pharmaceutically acceptable salt and the taxane anticancer agent (e.g., paclitaxel), for example, at least 30 minutes, for example at least 1 hour, for example at least 2 hours, for example at least 4 hours, for example up to 24 hours, for example 30 minutes to 24 hours, for example 30 minutes to 12 hours, for example 30 minutes to 6 hours.

[0100] In some embodiments, the taxane anticancer agent (e.g., paclitaxel) is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when the taxane anticancer agent (e.g., paclitaxel) and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within 48 hours, the taxane anticancer agent (e.g., paclitaxel) is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when the taxane anticancer agent (e.g., paclitaxel) and the compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to the subject within 24 hours, then the taxane anticancer agent (e.g., paclitaxel) is administered to the subject before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0101] In some embodiments, the taxane anticancer agent (e.g., paclitaxel) is administered to the subject at least about 30 minutes before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, the taxane anticancer agent (e.g., paclitaxel) is administered to the subject at least about 1 hour before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, the taxane anticancer agent (e.g., paclitaxel) is administered to the subject at least about 4 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, the taxane anticancer agent (e.g., paclitaxel) is administered to the subject at least about 24 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0102] In some embodiments, when a taxane anticancer agent (e.g., paclitaxel) and a compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to a subject within 24 hours, then the taxane anticancer agent (e.g., paclitaxel) is administered to the subject at least about 30 minutes before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when a taxane anticancer agent (e.g., paclitaxel) and a compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to a subject within 24 hours, then the taxane anticancer agent (e.g., paclitaxel) is administered to the subject at least about 1 hour (scheduled dose) before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject. In some embodiments, when a taxane anticancer agent (e.g., paclitaxel) and a compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to a subject within 24 hours, the taxane anticancer agent (e.g., paclitaxel) is administered to a subject at least 4 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject. In some embodiments, when a taxane anticancer agent (e.g., paclitaxel) and a compound of formula (I) or a pharmaceutically acceptable salt thereof are both administered to a subject within 48 hours, the taxane anticancer agent (e.g., paclitaxel) is administered to a subject at least about 24 hours before the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject.

[0103] In some embodiments, when a taxane anticancer agent (e.g., paclitaxel) and a compound of Formula (I) or a pharmaceutically acceptable salt thereof are both administered to a subject within 48 hours, the taxane anticancer agent (e.g., paclitaxel) is administered to a subject about 30 to about 24 hours before the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject. In some embodiments, when a taxane anticancer agent (e.g., paclitaxel) and a compound of Formula (I) or a pharmaceutically acceptable salt thereof are both administered to a subject within 24 hours, the taxane anticancer agent (e.g., paclitaxel) is administered to a subject about 30 to about 12 hours before the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject. In some embodiments, when a taxane anticancer agent (e.g., paclitaxel) and a compound of Formula (I) or a pharmaceutically acceptable salt thereof are both administered to a subject within a 24 hour period, the taxane anticancer agent (e.g., paclitaxel) is administered to a subject about 30 to about 6 hours before the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject. In some embodiments, when a taxane anticancer agent (e.g., paclitaxel) and a compound of Formula (I) or a pharmaceutically acceptable salt thereof are both administered to a subject within a 24 hour period, the taxane anticancer agent (e.g., paclitaxel) is administered to a subject about 2 to about 4 hours before the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to a subject. In some embodiments, when a taxane anticancer agent (e.g., paclitaxel) and a compound of Formula (I) or a pharmaceutically acceptable salt thereof are both administered to a subject within 24 hours, the taxane anticancer agent (e.g., paclitaxel) is administered to the subject about 4 to about 6 hours before the compound of Formula (I) or a pharmaceutically acceptable salt thereof is administered to the subject.

[0104] The possibility of administering a taxane anticancer agent (e.g., paclitaxel) prior to a compound of formula (I) or a pharma- ceutically acceptable salt thereof above applies particularly to the embodiments described in Tables A, B, C and D.

[0105] Generally, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and paclitaxel are administered at doses that do not exceed the maximum tolerated dose (MTD) for the particular mode of administration and indication, as determined in a clinical dose escalation study.

[0106] formulation The compound of formula (I) or its pharmaceutically acceptable salt and the taxane anticancer agent or its pharmaceutically acceptable salt (e.g., paclitaxel) can be provided as a combination drug, but each is usually provided as a single drug. Separate pharmaceutical compositions have some advantages, for example, to allow different administration schedules, different dosages and / or different administration routes for each compound. When provided as a single drug, the combination can be for separate, simultaneous or sequential administration.

[0107] The compounds of the present invention may be formulated in pharmaceutical compositions for non-parenteral administration, such as nasal, buccal, rectal, pulmonary, vaginal, sublingual, topical, transdermal, ophthalmic, aural, or in particular oral administration, such as oral solid dosage forms, such as granules, pellets, powders, tablets, film or sugar-coated tablets, effervescent tablets, hard and soft gelatin or HPMC capsules, orally disintegrating tablets, if applicable coated, oral solutions, lipid emulsions or suspensions, or in pharmaceutical compositions for parenteral administration, such as intravenous, intramuscular or subcutaneous, intrathecal, intradermal or epidural administration, to mammals, in particular humans, in the form of solutions, lipid emulsions or suspensions containing microparticles or nanoparticles. Liposomal formulations provide a convenient way to co-formulate compounds with different solubilities (see, for example, Bulbake et al.Pharmaceutics 2017,9(2):12). The composition may contain the active ingredient alone or, preferably, together with a pharmaceutically acceptable carrier.

[0108] 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.

[0109] Suitable excipients for the preparation of oral solutions, lipid emulsions or suspensions are, for example, water, alcohols, polyols, saccharose, invert sugars, glucose, etc. Suitable excipients for parenteral preparations are, for example, water, alcohols, polyols, glycerol, vegetable oils, lecithins, 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.

[0110] 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, liquid polyethylene glycol, etc.), and suitable mixtures thereof. For intravenous injection of strongly lipophilic molecules, it can be advantageous to include a solubilizing agent, such as a surfactant, a polymeric surfactant, a polymer, a complexing agent, and / or a cosolvent, in the formulation, which can significantly increase the solubility of the compound in water. Examples of solubilizing agents include polyethylene glycol, propylene glycol, ethanol, glycerol, and cyclodextrin (e.g., sulfobutylether-β-cyclodextrin).

[0111] In some embodiments, the compound of formula (I) as a free base is provided in a pharmaceutical composition including β-cyclodextrin, for example for intravenous administration. The β-cyclodextrin can be sulfobutylether-β-cyclodextrin, such as CAS 182410-00-0, such as Captisol™ (Ligand) or Dexolve™ (Cyclolab).

[0112] Sterile injection can be prepared by incorporating the required amount of active compound into suitable solvent with one or combination of the above-listed components as required, followed by filtration sterilization.Generally, dispersion is prepared by incorporating active compound into a sterile vehicle that contains dispersion medium and other components required from above-listed.For the preparation of sterile powder for sterile injection, the preparation method is vacuum drying and freeze-drying, thereby obtaining the powder of active ingredient and any additional desired ingredients from its solution that has been previously sterilized and filtered.

[0113] 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.

[0114] Optionally, the pharmaceutical composition contains a pharma- ceutically acceptable preservative. In some embodiments, the preservative concentration is typically in the range of 0.1 to 2.0% v / v. Suitable preservatives include those known in the pharmaceutical art, such as benzyl alcohol, phenol, m-cresol, methylparaben, and propylparaben.

[0115] In some embodiments, the compound of formula (I) or a pharmaceutically acceptable salt thereof is formulated for intravenous administration with a suitable acceptable carrier. In some embodiments, the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) is formulated for intravenous administration with a suitable acceptable carrier.

[0116] A paclitaxel formulation sold under the trade name Taxol® contains Cremophor® EL (polyethoxylated castor oil) and ethanol that is diluted in a parenteral fluid suitable for intravenous administration. Alternative paclitaxel formulations include: Abraxane®: A nanoparticle formulation of paclitaxel and human serum albumin Taxoplexin®: a prodrug of paclitaxel chemically linked to the fatty acid docosahexaenoic acid Paclitaxel conjugated to poly-(l-glutamic acid) ANG1005: Paclitaxel linked to angiopep-2 (a brain peptide vector) Paccal®: A formulation using an excipient composed of a surfactant-based derivative of retinoic acid (XR-17) that results in a nanoparticle micelle preparation with high water solubility that eliminates the need for Cremophor® (Khanna et al. J Vet Intern Med,2015;29(4):1006-1012).

[0117] kit The present invention also provides pharmaceutical products, such as kits, which may include a container containing a compound of formula (I) or a pharma- ceutically acceptable salt thereof and a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel), which may be provided in an amount sufficient for administration, e.g., a pharma- ceutically acceptable amount. Thus, the kit may include multiple containers, each containing a pharma- ceutical effective amount of the active ingredient. Optionally, the kit may also include tools and / or devices necessary for administering the pharmaceutical composition. In addition, the kit may include additional components, such as instructions or administration schedules, for treating patients with neoplastic disease with the combination of the present invention.

[0118] Thus, in a further aspect, the present invention provides pharmaceutical products, such as kits, in which a compound of formula (I) or a pharma- ceutical acceptable salt thereof and a taxane anticancer agent or a pharma- ceutical acceptable salt thereof (e.g., paclitaxel) are provided as single pharmaceutical agents, e.g., for use in the treatment of a neoplastic disease as described herein. In some embodiments, the kit further comprises instructions for their simultaneous, separate or sequential administration for use in the treatment of a neoplastic disease.

[0119] The following numbered paragraphs describe specific embodiments of the present invention.

[0120] Paragraph 1. A pharmaceutical combination comprising: (a) a compound of formula (I) or a pharma- ceutically acceptable salt thereof; and (b) a taxane anticancer agent or a pharma- ceutically acceptable salt thereof.

[0121] Paragraph 2. The pharmaceutical combination of Paragraph 1, wherein the taxane anticancer drug or a pharma- ceutically acceptable salt thereof is selected from paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel and tesetaxel, including pharma- ceutically acceptable salts thereof.

[0122] Paragraph 3. A pharmaceutical combination according to Paragraph 1, wherein the taxane anticancer drug or a pharma- ceutically acceptable salt thereof is paclitaxel.

[0123] Paragraph 4. A pharmaceutical combination according to any one of Paragraphs 1 to 3, wherein the compound of formula I or a pharma- ceutically acceptable derivative thereof and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof are contained in separate formulations, each formulation preferably for intravenous administration.

[0124] Paragraph 5. The pharmaceutical combination of any one of Paragraphs 1 to 4, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) per weekly dose is from about 0.1:1 to about 18.8:1.

[0125] Paragraph 6. A pharmaceutical combination according to any one of paragraphs 1 to 4, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) per weekly dose is, for example, from about 0.3:1 to about 2.3:1.

[0126] Paragraph 7. A pharmaceutical combination according to any one of paragraphs 1 to 4, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) per weekly dose is, for example, from about 0.4:1 to about 2.1:1.

[0127] Paragraph 8. A pharmaceutical combination according to any one of Paragraphs 1 to 4, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) per weekly dose is, for example, from about 0.6:1 to about 0.9:1.

[0128] Paragraph 9. 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 pharmaceutical combination as defined in any one of paragraphs 1 to 8.

[0129] Paragraph 10. The method of Paragraph 9, wherein the pharmaceutical combination is a compound of formula (I) or a pharma- ceutically acceptable salt thereof and paclitaxel.

[0130] Paragraph 11. The method of Paragraph 9 or Paragraph 10, wherein the compound of formula (I) or a pharma- ceutically acceptable derivative thereof and the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) are administered intravenously to the subject.

[0131] Paragraph 12. The method of any one of paragraphs 9 to 11, wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) are administered to the subject according to a four week treatment cycle (preferably the same four week treatment cycle), wherein the compound of formula (I) or a pharmaceutically acceptable salt thereof is administered during week 1 of the treatment cycle, followed by a three week rest period, and the taxane anticancer agent or a pharmaceutically acceptable salt thereof (e.g., paclitaxel) is administered each week during the first three weeks of the treatment cycle, followed by a rest period.

[0132] Paragraph 13. The method of Paragraph 12, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on day 1 of a treatment cycle, and a taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) is administered on days 1, 8, and 15 of the treatment cycle.

[0133] Paragraph 14. The method of any one of paragraphs 9 to 11, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) are administered to the subject according to a four week treatment cycle (preferably the same four week treatment cycle), wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered during weeks 1 and 3 of the treatment cycle, with weeks 2 and 4 being rest weeks, and wherein the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) is administered each week during the first three weeks of the treatment cycle, followed by a rest week.

[0134] Paragraph 15. The method of Paragraph 14, wherein a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on days 1 and 15 of a treatment cycle, and a taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) is administered on days 1, 8, and 15 of a treatment cycle.

[0135] Paragraph 16. The method of any one of paragraphs 9 to 11, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) are administered to the subject according to a four week treatment cycle (preferably the same 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 drug holiday, and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) is administered each week during the first three weeks of the treatment cycle, followed by a drug holiday.

[0136] Paragraph 17. The method of Paragraph 16, wherein a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on days 1, 8, and 15 of a treatment cycle, and a taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) is administered on days 1, 8, and 15 of a treatment cycle.

[0137] Paragraph 18. The method of any one of Paragraphs 9 to 17, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) per weekly dose is from about 0.1:1 to about 18.8:1.

[0138] Paragraph 19. The method of any one of Paragraphs 9 to 17, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) per weekly dose is, for example, from about 0.3:1 to about 2.3:1.

[0139] Paragraph 20. The method of any one of Paragraphs 9 to 17, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) per weekly dose is, for example, from about 0.4:1 to about 2.1:1.

[0140] Paragraph 21. The method of any one of Paragraphs 9 to 17, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) per weekly dose is, for example, about 0.6:1 to about 0.9:1.

[0141] Paragraph 22. The method of any one of Paragraphs 9 to 17, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof 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 every week of the week, when administered.

[0142] Paragraph 23. The method of any one of Paragraphs 9 to 17, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof, when administered, 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 40 mg to about 200 mg every week of the week.

[0143] Paragraph 24. The method of any one of Paragraphs 9 to 17, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof, when administered, 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 80 mg to about 160 mg every week of the week.

[0144] Paragraph 25. The method of any one of Paragraphs 9 to 21, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof, when administered, 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 90 mg to about 130 mg every week of the week.

[0145] Paragraph 26. The method of any one of Paragraphs 9 to 21, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof, when administered, 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 140 mg to about 240 mg every week of the week.

[0146] Paragraph 27. The method of any one of Paragraphs 9 to 21, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof 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 160 mg to about 220 mg every week of the week, when administered.

[0147] Paragraph 28. The method of any one of Paragraphs 9 to 21, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof, when administered, 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 180 mg to about 200 mg every week of the week.

[0148] Paragraph 29. The taxane anticancer agent or a pharma- ceutically acceptable salt thereof is paclitaxel, and paclitaxel, when administered, is about 60 mg / m per week. 2 to about 90 mg / m 2 29. The method of any one of paragraphs 22 to 28, wherein the patient is administered a dose of

[0149] Paragraph 30. The taxane anticancer agent or a pharma- ceutically acceptable salt thereof is paclitaxel, and paclitaxel, when administered, is about 60 mg / m per week. 2 to about 80 mg / m 2 29. The method of any one of paragraphs 22 to 28, wherein the patient is administered a dose of

[0150] Paragraph 31. The taxane anticancer agent or a pharma- ceutically acceptable salt thereof is paclitaxel, and paclitaxel, when administered, is about 70 mg / m per week. 2 to about 80 mg / m 2 29. The method of any one of paragraphs 22 to 28, wherein the patient is administered a dose of

[0151] Paragraph 32. The method of any one of paragraphs 9 to 31, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) are administered on the same day, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject before the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel).

[0152] Paragraph 33. The method of any one of paragraphs 9 to 31, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) are administered on the same day, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject after the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel).

[0153] Paragraph 34. The method of Paragraph 32 or Paragraph 33, wherein the time interval between administrations is at least about 4 hours.

[0154] Paragraph 35. The method of Paragraph 32 or Paragraph 33, wherein the time interval between administrations is at least about 2 hours.

[0155] Paragraph 36. The method of any one of Paragraphs 9 to 35, wherein the neoplastic disease is a solid tumor.

[0156] Paragraph 37. 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 intramedullary neoplasms, acinar cell neoplasms, composite epithelial neoplasms, specialized glandular neoplasms, paraganglioma and breast tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibroma neoplasms, myxomas, lipoma neoplasms, myoma neoplasms, composite mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, mesothelioma neoplasms. 37. The method of any one of paragraphs 9 to 36, wherein the cancer is selected from the group consisting of: germ cell neoplasms, trophoblastic neoplasms, mesogiomas, vascular tumors, lymphatic tumors, osseous and chondromatous 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, various myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

[0157] Paragraph 38. The method of any one of Paragraphs 9 to 37, wherein the neoplastic disease is treatable by inhibition of PLK1 in addition to treatment with a taxane anticancer drug (e.g. paclitaxel) and a TTK inhibitor (e.g. a compound of formula (I)).

[0158] Paragraph 39. The method of any one of Paragraphs 9 to 38, wherein the neoplastic disease is cancer.

[0159] Paragraph 40. The method of paragraph 39, wherein the cancer relating to the affected organ and body part is selected from brain, breast (including triple negative breast cancer and luminal B breast cancer), cervix, ovary, colon, rectum (including colorectal, 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 lymphoid malignancies), bile duct, bladder, urinary tract, kidney, skin, thyroid, head and neck, prostate and testis.

[0160] Paragraph 41. The method of Paragraph 39, wherein the cancer is selected from breast cancer (including triple negative breast cancer and luminal B breast cancer), gastric cancer, colorectal 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).

[0161] Paragraph 42. The method of Paragraph 39, wherein the cancer is breast cancer.

[0162] Paragraph 43. The method of Paragraph 39, wherein the cancer is triple negative breast cancer.

[0163] Paragraph 44. The method of Paragraph 39, wherein the cancer is luminal B breast cancer.

[0164] Paragraph 45. A method for treating a neoplastic disease in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of formula (I) as defined in paragraph 1, or a pharma- ceutically acceptable salt thereof, wherein the subject is undergoing or will be undergoing treatment with a taxane anticancer agent as defined in any one of paragraphs 1 to 3, or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel).

[0165] Paragraph 46. A method according to Paragraph 45, wherein a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject as defined in any one of Paragraphs 11 to 35.

[0166] Paragraph 47. A method according to paragraph 40 or paragraph 41, wherein the neoplastic disease is as defined in any one of paragraphs 36 to 44.

[0167] Paragraph 48. A method for treating a neoplastic disease in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a taxane anticancer agent, or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel), as defined in any one of paragraphs 1 to 3, wherein the subject is undergoing or will be undergoing treatment with a compound of formula (I) as defined in paragraph 1, or a pharma- ceutically acceptable salt thereof.

[0168] Paragraph 49. A method according to Paragraph 48, wherein a taxane anticancer drug or a pharma- ceutically acceptable salt thereof (eg paclitaxel) is administered to the subject as defined in any one of Paragraphs 11 to 35.

[0169] Paragraph 50. A method according to paragraph 48 or paragraph 49, wherein the neoplastic disease is as defined in any one of paragraphs 36 to 44.

[0170] Paragraph 51. A pharmaceutical combination according to any one of Paragraphs 1 to 8 for use in the treatment of a neoplastic disease in a subject, particularly a human.

[0171] Paragraph 52. A pharmaceutical combination for use according to Paragraph 51, wherein the pharmaceutical combination is a compound of formula (I) or a pharma- ceutically acceptable salt thereof and paclitaxel.

[0172] Paragraph 53. A pharmaceutical combination for use according to Paragraph 51 or Paragraph 52, wherein the compound of formula (I) or a pharma- ceutically acceptable derivative thereof and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof are administered intravenously to the subject.

[0173] Paragraph 54. A pharmaceutical combination for use according to any one of Paragraphs 51 to 53, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) are administered to the subject according to a four week treatment cycle (preferably the same four week treatment cycle), wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered during week 1 of the treatment cycle, followed by a three week rest period, and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) is administered each week during the first three weeks of the treatment cycle, followed by a rest period.

[0174] Paragraph 55. A pharmaceutical combination for use according to Paragraph 54, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on day 1 of a treatment cycle and a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) is administered on days 1, 8 and 15 of the treatment cycle.

[0175] Paragraph 56. A pharmaceutical combination for use according to any one of Paragraphs 51 to 53, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) are administered to the subject according to a four week treatment cycle (preferably the same four week treatment cycle), wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered during weeks 1 and 3 of the treatment cycle, with weeks 2 and 4 being rest weeks, and wherein the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) is administered each week during the first three weeks of the treatment cycle, followed by a rest week.

[0176] Paragraph 57. A pharmaceutical combination for use according to Paragraph 56, wherein a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on days 1 and 15 of a treatment cycle, and a taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) is administered on days 1, 8 and 15 of a treatment cycle.

[0177] Paragraph 58. A pharmaceutical combination for use according to any one of Paragraphs 51 to 53, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) are administered to the subject according to a 4 week treatment cycle (preferably the same 4 week treatment cycle), wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered each week during the first 3 weeks of the treatment cycle, followed by a drug holiday, and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) is administered each week during the first 3 weeks of the treatment cycle, followed by a drug holiday.

[0178] Paragraph 59. A pharmaceutical combination for use according to Paragraph 58, wherein a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered on days 1, 8 and 15 of a treatment cycle, and a taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) is administered on days 1, 8 and 15 of a treatment cycle.

[0179] Paragraph 60. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) per weekly dose is from about 0.1:1 to about 18.8:1.

[0180] Paragraph 61. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) per weekly dose is from about 0.3:1 to about 2.3:1.

[0181] Paragraph 62. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) per weekly dose is from about 0.4:1 to about 2.1:1.

[0182] Paragraph 63. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) per weekly dose is from about 0.6:1 to about 0.9:1.

[0183] Paragraph 64. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a patient in a dose equivalent to the molar equivalent of the free base of the compound of formula (I) of from about 5 mg to about 480 mg every week of the week, when administered.

[0184] Paragraph 65. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, 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 from about 40 mg to about 200 mg every week of the week, when administered.

[0185] Paragraph 66. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, 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 every week of the week, when administered.

[0186] Paragraph 67. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, 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 every week of the week, when administered.

[0187] Paragraph 68. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, 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 every week of the week, when administered.

[0188] Paragraph 69. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, 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 every week of the week, when administered.

[0189] Paragraph 70. A pharmaceutical combination for use according to any one of Paragraphs 51 to 59, 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 every week of the week, when administered.

[0190] Paragraph 71. The taxane anticancer agent or a pharma- ceutically acceptable salt thereof is paclitaxel, and paclitaxel, when administered, is about 60 mg / m every week of the week. 2 ~about 90mg / m 2 71. The pharmaceutical combination for use according to any one of paragraphs 64 to 70, administered to a patient at a dose of

[0191] Paragraph 72. The taxane anticancer agent or a pharma- ceutically acceptable salt thereof is paclitaxel, and the paclitaxel, when administered, is about 60 mg / m every week of the week. 2 ~about 80mg / m 271. The pharmaceutical combination for use according to any one of paragraphs 64 to 70, administered to a patient at a dose of

[0192] Paragraph 73. The taxane anticancer agent or a pharma- ceutically acceptable salt thereof is paclitaxel, and the paclitaxel, when administered, is about 70 mg / m every week of the week. 2 ~about 80mg / m 2 71. The pharmaceutical combination for use according to any one of paragraphs 64 to 70, administered to a patient at a dose of

[0193] Paragraph 74. A pharmaceutical combination for use according to any one of Paragraphs 51 to 73, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) are administered on the same day, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject before the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel).

[0194] Paragraph 75. A pharmaceutical combination for use according to any one of Paragraphs 51 to 73, wherein the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) are administered on the same day, and the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to the subject after the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel).

[0195] Paragraph 76. A pharmaceutical combination for use according to Paragraph 74 or Paragraph 75, wherein the time interval between administrations is at least about 4 hours.

[0196] Paragraph 77. A pharmaceutical combination for use according to Paragraph 74 or Paragraph 75, wherein the time interval between administrations is at least about 2 hours.

[0197] Paragraph 78. A pharmaceutical combination for use according to any one of Paragraphs 51 to 77, wherein the neoplastic disease is a solid tumor.

[0198] Paragraph 79. 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 intramedullary neoplasms, acinar cell neoplasms, composite epithelial neoplasms, specialized glandular neoplasms, paraganglioma and breast tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibroma neoplasms, myxoma, lipoma neoplasms, myoma neoplasms, composite mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, mesothelioma neoplasms, germ cell 79. The pharmaceutical combination for use according to any one of paragraphs 51 to 78, wherein the pharmaceutical combination is selected from the group consisting of neoplasms, trophoblastic neoplasms, mesogiomas, vascular tumors, lymphatic tumors, osseous and chondromatous 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, various myeloproliferative disorders, lymphoproliferative disorders and myelodysplastic syndromes.

[0199] Paragraph 80. A pharmaceutical combination for use according to any one of Paragraphs 51 to 79, wherein the neoplastic disease is treatable by inhibition of PLK1 in addition to treatment with a taxane anticancer drug (e.g. paclitaxel) and a TTK inhibitor (e.g. a compound of formula (I)).

[0200] Paragraph 81. A pharmaceutical combination for use according to any one of Paragraphs 51 to 80, wherein the neoplastic disease is cancer.

[0201] Paragraph 82. A pharmaceutical combination for use according to Paragraph 81, wherein the cancer relating to the affected organ and body part is selected from brain, breast (including triple negative breast cancer and luminal B breast cancer), cervix, ovary, colon, rectum (including colorectal, 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, for example, lymphoma, leukemia, myeloma or lymphoid malignancies), bile duct, bladder, urinary tract, kidney, skin, thyroid, head and neck, prostate and testis.

[0202] Paragraph 83. The pharmaceutical combination for use according to Paragraph 81, wherein the cancer is selected from breast cancer (including triple negative breast cancer and luminal B cancer), gastric cancer, colorectal 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, and bladder cancer and leukemia, such as acute myeloid leukemia (AML) (including mixed karyotype AML).

[0203] Paragraph 84. A pharmaceutical combination for use according to Paragraph 81, wherein the cancer is breast cancer.

[0204] Paragraph 85. A pharmaceutical combination for use according to Paragraph 81, wherein the cancer is triple negative breast cancer.

[0205] Paragraph 86. A pharmaceutical combination for use according to Paragraph 81, wherein the cancer is luminal B breast cancer.

[0206] Paragraph 87. A compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in Paragraph 1 for use in combination with a taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) as defined in any one of Paragraphs 1 to 3 for the treatment of a neoplastic disease in a subject, particularly a human.

[0207] Paragraph 88. A compound of formula (I), or a pharma- ceutically acceptable salt thereof, for use according to Paragraph 87, wherein the compound of formula (I), or a pharma- ceutically acceptable salt thereof, is administered to a subject as defined in any one of Paragraphs 53 to 77.

[0208] Paragraph 89. A compound of formula (I) or a pharma- ceutically acceptable salt thereof for use according to paragraph 78 or 86, wherein the neoplastic disease is as defined in any one of paragraphs 78 or 79.

[0209] Paragraph 90. A taxane anticancer agent, or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel), as defined in any one of paragraphs 1 to 3, for use in combination with a compound of formula (I) as defined in paragraph 1, or a pharma- ceutically acceptable salt thereof, for the treatment of a neoplastic disease in a subject, particularly a human.

[0210] Paragraph 91. A taxane anticancer agent or a pharma- ceutically acceptable salt thereof for use according to Paragraph 90, wherein the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) is administered to a subject as defined in any one of Paragraphs 53 to 77.

[0211] Paragraph 92. A taxane anticancer agent, or a pharma- ceutically acceptable salt thereof, for use in accordance with paragraph 90 or 91, wherein the neoplastic disease is as defined in any one of paragraphs 78 or 86.

[0212] Paragraph 93. Use of a pharmaceutical combination as defined in any one of paragraphs 1 to 8 in the preparation of a single medicinal product or as a combination medicinal product for the treatment of a neoplastic disease in a subject, in particular a human.

[0213] Paragraph 94. The use according to Paragraph 93, wherein the pharmaceutical composition is administered to a subject as defined in any one of Paragraphs 53 to 77.

[0214] Paragraph 95. The use according to paragraph 93 or paragraph 94, wherein the neoplastic disease is as defined in any one of paragraphs 78 to 86.

[0215] Paragraph 96. Use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof as defined in paragraph 1 in the preparation of a monopharmaceutical product for use in combination with a taxane anticancer agent or a pharma- ceutically acceptable salt thereof as defined in any one of paragraphs 1 to 3 (e.g. paclitaxel) for the treatment of a neoplastic disease in a subject, particularly a human.

[0216] Paragraph 97. The use according to Paragraph 96, wherein a compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered to a subject as defined in any one of Paragraphs 53 to 77.

[0217] Paragraph 98. The use according to paragraph 96 or paragraph 94, wherein the neoplastic disease is as defined in any one of paragraphs 78 to 86.

[0218] Paragraph 99. Use of a taxane anticancer agent, or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel), as defined in any one of paragraphs 1 to 3, in the preparation of a monopharmaceutical product for use in combination with a compound of formula (I) or a pharma- ceutically acceptable salt thereof, as defined in paragraph 1, for the treatment of a neoplastic disease in a subject, particularly a human.

[0219] Paragraph 100. The use according to Paragraph 99, wherein a taxane anticancer drug or a pharma- ceutically acceptable salt thereof (eg paclitaxel) is administered to the subject as defined in any one of Paragraphs 53 to 77.

[0220] Paragraph 101. The use according to paragraph 99 or paragraph 100, wherein the neoplastic disease is as defined in any one of paragraphs 78 to 86.

[0221] Paragraph 102. A kit comprising a pharmaceutical combination as defined in any one of paragraphs 1 to 8, wherein component (a) and component (b) are provided as single pharmaceutical agents.

[0222] Paragraph 103. A kit according to Paragraph 102, wherein the kit is for use in the treatment of a neoplastic disease, in particular as defined in any one of Paragraphs 78 to 86.

[0223] Paragraph 104. A kit according to Paragraph 102 or Paragraph 103, further comprising instructions for the simultaneous, separate or sequential administration thereof for use in the treatment of a neoplastic disease, particularly cancer, in a subject, particularly a human.

[0224] 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 herein incorporated by reference in its entirety to the same extent as if each individual reference was specifically and individually indicated to be incorporated by reference.

[0225] Certain embodiments of the present invention are described in the following examples which serve to more fully illustrate the present invention and should not be construed as limiting the invention in any way.

[0226] 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 mL of assay buffer (standard buffer / [γ- 33 The assay contained 10 mL of ATP solution (in water), 5 mL of test compound and 10 mL of enzyme / substrate mixture. Protein kinase assays were performed in 70 mM HEPES-NaOH pH 7.5, 3 mM MgCl2, 3 mM MnCl2, 3 mM Na orthovanadate, 1.2 mM DTT, 50 mg / ml PEG20000, ATP (0.3 mM for TTK and 1 mM for PLK1), [γ- 33 [P]-ATP (approximately 8 × 10 per well 5 cpm), protein kinase (15.8 nM for TTK and 5 nM for PLK1), and substrate (1 mg / 50 mL for TTK and 2 mg / 50 mL for PLK1). All assays were performed using a BeckmanCoulter / SAGIAN™ Core System. The fitting model for IC50 determination was "sigmoidal response (variable slope)" with the parameters "top" fixed at 100% and "bottom" fixed at 0%. The fitting method used was least squares fitting.

[0227] 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 mL / min. Dissociation times were 1200-1800 s, with correction for unstable surfaces using blank runs 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).

[0228] PDX research In the first PDX study, female BALB / c nude mice (CrownBio) weighing at least 20 g were inoculated subcutaneously (sc) into the right flank. Patient-derived xenograft (PDX) triple-negative breast cancer (TNBC) tumors, tumor fragments (3 × 3 × 3 mm) from stock mice bearing BR1282, were used. The mean tumor size was 150–200 mm. 3If so, mice were randomized into five different treatment groups (8 mice per group). Mice were administered intravenously (iv) with compound of formula (I) (8 mg / kg, iv, 5 mL / kg) twice a week (2 qw), or paclitaxel (15 mg / kg, iv, 10 mL / kg) once a week (qw), or a combination of these doses, with compound of formula (I) administered after paclitaxel using a 4-hour or 24-hour gap, with both compounds administered on the same / consecutive days. The fifth group was administered both vehicles using a 4-hour time interval, and all groups were administered twice via the tail vein. In any mice showing a transient weight loss of 10% or more at any time point, dosing was delayed by one day. Treatment continued until day 35 / 36, when dosing had to be stopped due to toxicity (necrosis) at the injection site in the tail vein. At that time, a long-term observation period followed for the remaining two combination groups (no culling due to large tumor volumes was required).

[0229] The second PDX study used the same approach and model as the first study (TNBC BR1282 PDX model), but this time tested additional combinations including the use of the reversed dosing order (i.e., treatment with the compound of formula (I) followed by paclitaxel) as well as a qw schedule regimen of the compound of formula (I) as previously used, as well as a 2qw regimen. Mice (8 mice per group) were administered either the compound of formula (I) (8 mg / kg, iv, 5 mL / kg), paclitaxel (15 mg / kg, iv, 10 mL / kg, qw), a combination of both compounds, or both vehicles as a control group. The single agent group of the compound of formula (I) was first treated with the paclitaxel vehicle (qw, 10 mL / kg) and, 4 hours later, was treated with the compound of formula (I) on the same day, administered 2qw. The paclitaxel single agent group received paclitaxel (15 mg / kg, iv, qw, 10 mL / kg) followed by the vehicle of the compound of formula (I) with a 2 hour interval between doses. Five different combination groups received the following: paclitaxel (15 mg / kg, iv, qw, 10 mL / kg) administered first and compound of formula (I) (8 mg / kg, iv 2qw, 5 mL / kg) administered second using a 2 hour, 4 hour or 24 hour gap between both doses when administered on the same or consecutive days; paclitaxel (15 mg / kg, iv, qw, 10 mL / kg) administered first and compound of formula (I) (8 mg / kg, iv qw, 5 mL / kg) administered second using a 4 hour gap, always treated on the same day; finally, compound of formula (I) (8 mg / kg, iv, 2qw, 5 mL / kg) administered first and paclitaxel (15 mg / kg, iv, qw, 5 mL / kg) administered second using a 4 hour gap. The eighth group received both vehicles using a 4 hour gap with the vehicle of paclitaxel administered first. In any mouse showing a transient weight loss of 10% or more at any time point, dosing was delayed for 1 day. Treatment was continued until day 42 / 43 when dosing had to be stopped due to toxicity (necrosis) at the injection site in the tail vein.At that time, four combination groups of compounds of formula (I) and a four hour gap single agent group (no culls required due to large tumor volume) were observed for potential cures and tumor regrowth (study not completed).

[0230] Paclitaxel was purchased from Beijing Union Pharmaceutical Factory as a solution (6 mg / mL in anhydrous citric acid, polyoxyethylated (35) castor oil, and absolute ethyl alcohol). Compound of formula (I) was supplied as a powder by Basilea Pharmaceutica International Ltd. and freshly prepared as a solution in ethanol:PEG400:citric acid 20 mM in a ratio of 1:1:8 for extemporaneous administration.

[0231] Body weight and tumor volume were determined at least twice a week, the latter measured in two dimensions with a vernier caliper and calculated according to the formula V = (L × W 2 ) / 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% were automatically dosed on one of the following days as soon as the BWL returned to <10%. All animal protocols were reviewed and approved by the relevant local committees in China where the studies were conducted.

[0232] Statistical significance of efficacy was determined at a) 1500 mm 3The tumor growth rate was determined in two different ways: a) using an endpoint of day 16 or day 13 depending on the study, when the vehicle group had to be disposed of due to tumor volumes exceeding 100%, and b) using an endpoint of day 42 or day 51 (one week after the last treatment) depending on the study, when an exponential curve fit was applied to estimate the tumor growth rate in the different groups. Finally, the number of complete cures was compared between groups after confirmation by histopathology within the first study. The extent of effect was quantified by the delta (Δ) treatment / control ratio (ΔT / C), and the statistical significance of the effect was determined by one-way analysis of variance (1W-ANOVA), with Holms-Sidak applied post hoc for multiple determinations, and a p-value <0.05 was considered statistically significant. Furthermore, an assessment of synergy was performed based on the Clark Combination Index (CCI). where CCI=ΔT / CAB-(ΔT / CA*ΔT / CB), where A and B are two different compounds, and CCI<-0.1 indicates synergy (or positive interaction), +0.1 (antagonism, or negative interaction) and between -0.1 and +0.1 indicates additivity (no interaction). See O'Reilly et al. Anti Cancer Drugs 2011;22:58-78.

[0233] 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 work together to recruit SAC components to the SAC protein complex at the centromeres of chromosomes, so 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).

[0234] 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, measured as described in WO2015 / 155042).

[0235] 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 for PLK1 compared to their activity for TTK (data not shown). Importantly, the compound of formula (I) has a very long target retention of over 12 hours for TTK, whereas the target retention of PLK1 is only a few minutes. This long-term inhibition of TTK, coupled with its transient effect on PLK1, leads to rapid disruption of the SAC, leaving cells without sufficient time for correct chromosome segregation.

[0236] 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 treated iv 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 weekly MTD dosing iv showed that tumor-derived TTK was fully drug-occupied for up to 6 days after the last dose.

[0237] 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, compounds of formula (I) had a median GI50 of 35 nM. In mice, compounds of formula (I) showed significant activity against patient-derived tumor xenografts, including TNBC and hepatocellular carcinoma (HCC) models, with effects ranging from minimal to very strong, including substantial regression (data not shown).

[0238] In the first PDX study, the vehicle group required disposal after 16 days due to the rapid growth of the TNBC BR1282 model (Figure 1). At that time, it was clear that all treatments had some level of efficacy (Table 1), and indeed, both monotherapy and combination treatments were highly significantly different to vehicle (all p<0.001). The combinations were also significantly different from the compound of formula (I) alone (p<0.001), but not from paclitaxel alone (p=0.12). The CCI showed a positive interaction with values ​​of -0.08 and -0.09 for the 4-hour and 24-hour combination groups, respectively, but not formal synergy at all (defined as less than -0.1) at that time. Whereas the monotherapy groups continued to grow and had to be culled by day 30, the combination group continued to regress, and by day 42 (1 week after cessation of treatment, i.e., one treatment cycle), all animals had regressed by a mean ± SD of −87 ± 6% and −92 ± 11% for the combination 4 h and combination 24 h groups, respectively (see also Figure 2 ).

[0239] Exponential curve fitting from day 0 to the day of cull or day 42 provided more statistical power and showed a much stronger effect, so both combination groups were now highly significantly different from either monotherapy (Figure 1B), with CCI showing a strong synergistic effect of -0.49 and -0.53 for the 4 h and 24 h combination groups, respectively. After an extended observation period without treatment, pathological evaluation by H&E staining of the skin around the tumor cell injection site in tumor-free animals showed healing in 3 out of 8 treated animals in both combination groups. Examples of H&E staining results are shown in Figure 3.

[0240] Overall, the treatment was well tolerated with no significant differences in weight change in the treatment groups compared to the vehicle group on day 16. Thereafter, the monotherapy groups showed weight gain similar to the combination 4 h group, whereas the combination 24 h group showed a transient weight loss that recovered by day 35. Once treatment was discontinued, there was strong weight recovery by both combination groups. The combination 24 h group also had 1 / 8 mice that had to be culled (day 28) due to a 20% weight loss. Thus, a longer gap between the two treatments in the combination therapy seemed slightly less tolerated in this experiment.

[0241] In conclusion, in the first PDX study, the compound of formula (I) in combination with paclitaxel resulted in a very strong positive interaction inducing 100% tumor regression, including 3 / 8 complete cures in each of the two combination groups differing only in the time interval (4 h or 24 h gap) between administration of paclitaxel (first) and the compound of formula (I) (second). The combination 24 h group appeared to be slightly less tolerable, as indicated by a slightly higher weight loss, albeit transient. [Table 5]

[0242] In the second study, the vehicle control group reached the ethical endpoint on day 13. At that time, it was clear that all treatments had some level of efficacy (Table 2, Figure 4A), and indeed, all of the monotherapy and combination treatments were highly significantly different from vehicle (all p<0.001). The combinations were also significantly different from paclitaxel alone (p<0.01), but not from the compound of formula (I) alone (p>0.78). The CCI showed a positive interaction with values ​​between -0.02 and -0.09 (Table 3). While the monotherapy groups continued to grow and the group treated with paclitaxel alone had to be culled by day 20, the combination group continued to regress and by day 51 (approximately 1 week after treatment was stopped, i.e., one treatment cycle) all animals had regressed by the following mean ± SD: -86 ± 15% in the combination 2 h group, -94 ± 8% in the combination 4 h group, -86 ± 8% in the combination 24 h group, -84 ± 26% in the combination group using the compound of formula (I) qw, and -86 ± 10% in the combination group where the compound of formula (I) was administered before paclitaxel. 3 / 8 animals following monotherapy with the compound of formula (I) also showed regression on that day, but the mean (or median) across the groups showed no regression and tumor growth (Figure 4A).

[0243] The growth curves of the individual tumors also demonstrated that tumors in the compound of formula (I) monotherapy group began to regrow earlier and faster than any of the combination groups (Figure 5). The highly synergistic effect of all combination groups confirmed and extended previous results from the first study. Exponential curve fits from day 0 to the day of disposal or day 51 (approximately one week after treatment was stopped) provided greater statistical power and showed a much stronger effect, so that here all five combination groups were significantly different from either monotherapy (Figure 4B), with CCIs showing synergistic effects between -0.18 and -0.29 (Table 3). Figure 5 shows that there is no tumor regrowth in any of the combination groups by day 51. After 51 days, 1 out of 8 tumors in each combination group showed some regrowth, except for the combination group using compound of formula (I) qw, which showed 3 out of 8.

[0244] Overall, the treatment was well tolerated, with no significant differences in weight change in the treatment groups compared to the vehicle group on day 13 (Figure 4C and Figure 4D, Table 2). Thereafter, the monotherapy groups showed weight gain, as did all combination groups, whereas the combination 24 h group showed a transient weight loss that recovered by day 42. When treatment was stopped, there was a strong weight recovery in all combination groups. Thus, a longer gap between the two treatments in the combination therapy seemed to be slightly less tolerated in this experiment as well as in the first experiment.

[0245] Interestingly, at the end of the observation period (at the latest on day 148), a total of 29 mice from the combination group had either no palpable tumor masses detected or had tumors measuring 25 mm 3 The mice had tumor volumes less than 100 μg / kg / day, indicating the possibility of cure. Therefore, skin samples from these 29 mice, including the tumor cell injection site and surrounding tissue, were harvested and processed into FFPE blocks. Serial sections covering the entire tumor growth area were made, stained by H&E, and subsequently pathologically evaluated for residual tumor cells. The results are shown in Table 4, showing 50-88% cures (4-7 mice out of 8) in the combination group. Interestingly, qw administration of the compound of formula (I), as well as treatment with the compound of formula (I) first and paclitaxel second, resulted in the lowest number of cures (4, 5 mice out of 8). Administration of paclitaxel first, followed by administration of the compound of formula (I) 2 2, 4, or 24 hours later in a 2qw schedule, cured 6-7 mice out of 8. As a result, the latter treatment regimen appeared to be the most effective in terms of the number of cures.

[0246] In conclusion, in a second PDX study, the compound of formula (I) in combination with paclitaxel resulted in a very strong positive interaction inducing 100% tumor regression, regardless of the dosing regimen used. Treatment was stopped on day 42 / 43, and the observation period was then extended until day 148 at the latest. After this, 29 animals in the combination group were pathologically confirmed as cured.

[0247] The combination groups differed in the time interval between administration of paclitaxel (first) and the compound of formula (I) (second) (a gap of 2 h, 4 h or 24 h), the interval between administration of the compound of formula (I) (2qw vs. qw), or the order of administration. Although monotherapy with the compound of formula (I) resulted in this study in tumor regression, the effect of combining it with paclitaxel resulted in stronger regression and tumor-free animals (including cures), which was not the case for the monotherapy groups. All five combination regimens were similarly effective in terms of tumor growth, although the combination using a 24-h gap seemed to be less well tolerated than the other combination groups. These results demonstrate the potential for flexibility in the timing and order of administration of this combination for future clinical studies and support the approach of combining the compound of formula (I) with paclitaxel for the treatment of TNBC patients. [Table 6] [Table 7] [Table 8]

[0248] To determine if there is a significant drug-drug interaction (DDI) between the compound of formula (I) and paclitaxel, a single dose pharmacokinetic (PK) experiment was performed and the results are shown in Figure 6. There was a small, non-significant increase in the plasma AUC of the compound of formula (I) when administered at 8 mg / kg, iv, 1 hour after paclitaxel (15 mg / kg, iv). Under the same circumstances, there was also no effect of the compound of formula (I) on the plasma PK of paclitaxel. These results confirm that the synergistic effects observed above are due to mechanism of action and not due to changes in the exposure of one or both agents.

Claims

1. 1. A pharmaceutical combination comprising: (a) A compound of formula (I) 【Chemistry 1】 or a pharma- ceutically acceptable salt thereof; and (b) a taxane anticancer agent, or a pharma- ceutically acceptable salt thereof.

2. 2. The pharmaceutical combination of claim 1, wherein the taxane anticancer drug or a pharmaceutically acceptable salt thereof is selected from paclitaxel, docetaxel, cabazitaxel, larotaxel, mirataxel, ortataxel and tesetaxel, including pharmaceutically acceptable salts thereof.

3. 2. The pharmaceutical combination of claim 1, wherein the taxane anticancer drug or a pharma- ceutically acceptable salt thereof is paclitaxel.

4. 4. The pharmaceutical combination of any one of claims 1 to 3, wherein the molar ratio of the compound of formula (I) or a pharma- ceutically acceptable salt thereof to the taxane anticancer drug or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) per weekly dose is from about 0.4:1 to about 2.1:

1.

5. 5. A pharmaceutical combination as defined in any one of claims 1 to 4 for use in said treatment of a neoplastic disease in a subject, particularly a human.

6. said compound of formula (I), or a pharma- ceutically acceptable salt thereof, and said taxane anticancer agent, or a pharma- ceutically acceptable salt thereof, are administered to said subject according to a four week treatment cycle; said compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered during the first week of said treatment cycle, followed by a three week drug holiday, and said taxane anticancer agent or a pharma- ceutically acceptable salt thereof is administered each week during the first three weeks of said treatment cycle, followed by a drug holiday; or the compound of formula (I) or a pharma- ceutically acceptable salt thereof is administered during weeks 1 and 3 of the treatment cycle, with weeks 2 and 4 being drug-free weeks, and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g., paclitaxel) is administered each week during the first three weeks of the treatment cycle, followed by a drug-free week; or 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 drug holiday, and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof is administered each week during the first three weeks of the treatment cycle, followed by a drug holiday.

6. The pharmaceutical combination for use according to claim 5, wherein, in each case, the compound of formula (I) or a pharma- ceutically acceptable salt thereof and the taxane anticancer agent or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel) are administered to the subject according to the same 4-week treatment cycle.

7. 7. The pharmaceutical combination for use according to claim 5 or claim 6, 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 from about 40 mg to about 200 mg every week of the week.

8. 7. The pharmaceutical combination for use according to claim 5 or claim 6, 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 every week of the week.

9. The taxane anticancer agent or pharma- ceutically acceptable salt thereof is paclitaxel, and paclitaxel, when administered, is about 70 mg / m every week of the week. ２ ~about 80mg / m ２ The pharmaceutical combination for use according to any one of claims 5 to 8, which is administered to a patient at a dose of

10. Said neoplastic diseases include 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 intramedullary neoplasms, acinar cell neoplasms, complex epithelial neoplasms, specialized glandular neoplasms, paraganglioma and breast tumors, nevi and melanomas, soft tissue tumors and sarcomas, fibroma neoplasms, myxoma, lipoma neoplasms, myoma neoplasms, complex mixed and stromal neoplasms, fibroepithelial neoplasms, synovial neoplasms, mesothelioma neoplasms, germ cell neoplasms, 10. The pharmaceutical combination for use according to any one of claims 5 to 9, wherein the therapeutic agent is selected from the group consisting of: pulmonary sarcoma, ...

11. The pharmaceutical combination for use according to any one of claims 5 to 10, wherein the neoplastic disease is treatable by inhibition of PLK1 in addition to treatment with a taxane anticancer drug (e.g. paclitaxel) and a TTK inhibitor (e.g. the compound of formula (I)).

12. 12. The pharmaceutical combination for use according to any one of claims 5 to 11, wherein the neoplastic disease is cancer, in particular a cancer selected from breast cancer (including triple negative breast cancer and luminal B cancer), gastric cancer, colorectal 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).

13. The pharmaceutical combination for use according to any one of claims 5 to 12, wherein said neoplastic disease is triple negative breast cancer.

14. A compound of formula (I) as defined in claim 1, or a pharma- ceutically acceptable salt thereof, for use in combination with a taxane anticancer agent as defined in any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel), for said treatment of a neoplastic disease in a subject, particularly a human.

15. A taxane anticancer agent, or a pharma- ceutically acceptable salt thereof (e.g. paclitaxel), as defined in any one of claims 1 to 3, for use in combination with a compound of formula (I), or a pharma- ceutically acceptable salt thereof, as defined in claim 1, for use in said treatment of a neoplastic disease in a subject, particularly a human.

Images