Masitinib for the treatment of castration-resistant prostate cancer

Abstract

The present invention relates to masitinib, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of metastatic castration-resistant prostate cancer (mCRPC) in a subject in need thereof. In particular, the present invention relates to masitinib, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of mCRPC in a subject suffering from early stage mCRPC, which is associated with (i) a baseline alkaline phosphatase (ALP) level of 250 IU / L or less, or (ii) a baseline Halaby Prognostic Score (H) of 33 or less, or (iii) a baseline ALP level of 250 IU / L or less and a baseline Halaby Prognostic Score (H) of 33 or less.

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the treatment of prostate cancer, in particular castration-resistant prostate cancer (CRPC). [Background technology]

[0002] 2. Background of the Invention Prostate cancer is one of the most common cancers in men. An estimated 1,414,259 new cases of prostate cancer were diagnosed worldwide in 2020, representing 7.3% of all estimated new cancer cases (Sung H. et al. CA Cancer J Clin. 2021 May;71(3):209-249. doi:10.3322 / caac.21660). In the United States, the incidence rate based on data from 2013-2017 was 104.6 new cases per 100,000 men per year (American Cancer Society, 2018 - Data source: North American Association of Central Cancer Registries (NAACCR), 2020). In Europe, the average incidence rate was estimated to be 151.2 new cases per 100,000 men in 2018, and the average mortality rate was estimated to be 32.8 per 100,000 men in the same year (Hofmarcher, T. et al. (2019) Comparative Report on Cancer in Europe 2019 - Disease Burden, Costs and Access to Medicines. IHE Report 2019:7. IHE: Lund, Sweden).

[0003] Prostate cancer is driven by male hormones called androgens, including testosterone and dihydrotestosterone (DHT). Hormonal therapy aimed at either lowering androgen levels or blocking androgen action can suppress the growth of prostate cancer. Usually, the first type of hormone therapy administered to treat prostate cancer is so-called androgen deprivation therapy (ADT), which consists of treatment to reduce androgen production by the testes. ADT therefore includes surgical castration (i.e., orchiectomy) and chemical (or medical) castration. Chemical castration can be achieved by administration of luteinizing hormone releasing hormone (LHRH) agonists, sometimes called LHRH analogs, or by administration of LHRH antagonists. Of note, LHRH is sometimes referred to as gonadotropin-releasing hormone (GnRH), and thus, LHRH agonists (or analogs) are also known as GnRH agonists (or analogs), and LHRH antagonists are also known as GnRH antagonists.

[0004] Most prostate cancers eventually stop responding to androgen deprivation therapy, and thus become castrate (or castration) resistant. Castration-resistant prostate cancer (CRPC) is defined by disease progression despite androgen deprivation therapy, and may manifest as either a continued rise in serum prostate-specific antigen (PSA) levels, progression of existing disease, and / or the appearance of new metastases (Saad et al. Can Urol Assoc J. 2010 Dec;4(6):380-4). Treatment options then include additional hormonal therapy, such as antiandrogen therapy, including androgen receptor blockers and androgen synthesis inhibitors (e.g., abiraterone), immunotherapy, and chemotherapy, particularly docetaxel or cabazitaxel.

[0005] Of note, androgen deprivation therapy is also now part of the standard treatment for metastatic prostate cancer. Although the majority of patients with metastatic prostate cancer initially respond to either surgical or chemical castration, almost all patients with metastatic prostate cancer also eventually develop castration resistance. These patients then suffer from metastatic castrate (or castration)-resistant prostate cancer (mCRPC). Treatment options for mCRPC primarily aim to prolong life and improve quality of life. However, the median survival of mCRPC patients ranges from approximately 15 to 36 months in recent studies, and the 5-year survival rate is only 28% (Crawford et al. Urol Oncol. 2017 May;35S:S1-S13). The reported impact of currently approved therapeutic agents for mCRPC remains modest. Summary of the Invention [Problem to be solved by the invention]

[0006] Thus, there remains a need for effective treatments for metastatic castrate (or castration)-resistant prostate cancer (mCRPC). In particular, it would be helpful to identify mCRPC patients who are most likely to benefit from treatment. [Means for solving the problem]

[0007] The present invention therefore relates to masitinib, or a pharma- ceutical acceptable salt or solvate thereof, for use in the treatment of metastatic castration-resistant prostate cancer (mCRPC) in subjects in need thereof, particularly subjects most likely to benefit from the administration of masitinib, or a pharma- ceutical acceptable salt or solvate thereof, such as subjects with baseline alkaline phosphatase levels of 250 IU / L or less, or a baseline Halabi prognostic score (H) of 33 or less.

[0008] The present invention relates to masitinib, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of metastatic castration-resistant prostate cancer (mCRPC) in a subject in need thereof, wherein the subject has early stage mCRPC associated with (i) a baseline alkaline phosphatase (ALP) level of 250 IU / L or less, or (ii) a baseline Halaby Prognostic Score (H) of 33 or less, or (iii) a baseline ALP level of 250 IU / L or less and a baseline Halaby Prognostic Score (H) of 33 or less. Effect of the Invention

[0009] In one embodiment, the subject has a baseline ALP level of 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less. In one embodiment, the subject has a baseline ALP level of 200 IU / L or less. In one embodiment, the subject has a baseline ALP level of 150 IU / L or less. In one embodiment, the subject has a baseline ALP level of 100 IU / L or less.

[0010] In one embodiment, the subject has a baseline Halaby Prognostic Score (H) of less than or equal to 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15. In one embodiment, the subject has a baseline Halaby Prognostic Score (H) of less than or equal to 22.

[0011] In one embodiment, the subject has received a hormone therapy selected from the group consisting of a luteinizing hormone releasing hormone (LHRH) agonist (also known as a gonadotropin releasing hormone (GnRH) agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0012] In one embodiment, the pharma- ceutically acceptable salt of masitinib is masitinib mesylate.

[0013] In one embodiment, masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration at a dose in the range of about 1 to about 12 mg / kg / day (mg per kilogram of body weight per day), preferably at a dose in the range of about 3 to about 6 mg / kg / day. In one embodiment, masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration at a dose of about 6 mg / kg / day.

[0014] In one embodiment, masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for oral administration. In one embodiment, masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration taken twice daily.

[0015] In one embodiment, masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration with at least one additional pharma- ceutically active agent, in one embodiment, said at least one additional pharma- ceutically active agent is selected from a chemotherapeutic agent and a corticoid.

[0016] definition In the present invention, the following terms have the following meanings:

[0017] The term "about" preceding a number includes plus or minus 10% of the value of said number, or less. It is to be understood that the value to which the term "about" refers is itself also specifically, and preferably, disclosed.

[0018] "ALP" refers to alkaline phosphatase. ALP is a membrane-bound glycoprotein that catalyzes the hydrolysis of organophosphates present in the extracellular space. ALP is ubiquitous and can be found in many different tissues, such as placenta, intestine, kidney, bone, and liver, from which it is released into the blood. As used herein, "ALP level" refers to the ALP level in blood, particularly in serum.

[0019] "Baseline" as used herein refers to the time preceding the start of treatment with 2-aminoarylthiazole derivatives described herein, particularly masitinib, or its pharmaceutically acceptable salt or solvate.For example, for a given subject, the ALP level at baseline is the ALP level before administering to the subject 2-aminoarylthiazole derivatives described herein, particularly masitinib, or its pharmaceutically acceptable salt or solvate.Therefore, for a given subject, the Halaby prognostic score (H) at baseline is the Halaby prognostic score (H) before administering to the subject 2-aminoarylthiazole derivatives described herein, particularly masitinib, or its pharmaceutically acceptable salt or solvate.

[0020] "Pharmaceutically acceptable excipient" or "pharmaceutically acceptable carrier" refers to an excipient or carrier that does not cause harmful, allergic or other undesirable reactions when administered to a subject. It includes any and all solvents, such as dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, etc. Pharmaceutically acceptable excipients or carriers refer to non-toxic solid, semi-solid or liquid fillers, diluents, encapsulating materials or any type of formulation auxiliary. For human administration, preparations must meet the standards of sterility, pyrogenicity, general safety and purity required by regulatory authorities such as the FDA (US Food and Drug Administration) or EMA (European Medicines Agency).

[0021] "Subject" refers to a mammal, preferably a human. In one embodiment, the mammal is selected from cats, dogs, cows, pigs, horses, monkeys, apes, and humans. In one embodiment, the mammal is selected from cats, dogs, and humans. In one embodiment, the subject is a primate. In one embodiment, the subject is a human. In one embodiment, the subject may be a "patient", i.e., a mammal, preferably a human, who is waiting to receive or is receiving medical care, or who has / is / will be the subject of medical treatment, or who is being monitored for the development of prostate cancer. In one embodiment, the "subject in need of treatment" is a subject who is waiting to receive or is receiving medical care, or who has / is / will be the subject of medical treatment, or who is being monitored for the development of prostate cancer, particularly metastatic castration-resistant prostate cancer (mCRPC).

[0022] A "therapeutically effective amount" or "therapeutically effective dose" refers to an amount or concentration of a 2-aminoarylthiazole derivative, particularly masitinib, as described herein, or a pharma- ceutically acceptable salt or solvate thereof, that results in at least one of the following: (1) delaying or halting the progression, worsening, or progression of one or more symptom(s) of castration-resistant prostate cancer (CRPC), particularly mCRPC, and in particular extending the survival, particularly progression-free survival, of the subject, without causing significant negative or deleterious side effects in the subject in need of treatment; (2) resulting in an improvement in the symptoms of CRPC, particularly mCRPC; (3) reducing the severity or incidence of CRPC, particularly mCRPC; (4) reducing prostate-specific antigen (PSA) levels (e.g., at least 30% from baseline PSA levels), (5) curing CRPC, particularly mCRPC, (6) improving quality of life, or (7) reducing pain intensity.

[0023] "Treating" or "treatment" refers to therapeutic treatment, prophylactic (or preventative) treatment, or both therapeutic and prophylactic (or preventative) treatment, the objective being to prevent, reduce, or delay (alleviate) one or more of the symptom(s) or sign(s) of castration-resistant prostate cancer (CRPC), particularly mCRPC. In one embodiment, a subject is successfully "treated" for CRPC, particularly mCRPC, if, after receiving a therapeutic amount of a 2-aminoarylthiazole derivative, particularly masitinib, or a pharma- ceutically acceptable salt or solvate thereof, the subject shows an observable and / or measurable reduction in the number or percentage of cancer cells or metastatic cells; and / or if the subject shows some degree of alleviation of one or more of the symptoms associated with CRPC, particularly mCRPC; reduced PSA levels; reduced pain; reduced morbidity and mortality; and / or improved quality of life issues. In one embodiment, a subject is successfully "treated" for CRPC, particularly mCRPC, if the subject benefits from extended survival, particularly extended progression-free survival, after receiving a therapeutic amount of a 2-aminoarylthiazole derivative as described herein, particularly masitinib, or a pharma- ceutically acceptable salt or solvate thereof. The above parameters for assessing successful treatment and improvement in the disease are easily measurable by routine procedures familiar to physicians. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] Detailed Description The present invention relates to a 2-aminoarylthiazole derivative, in particular masitinib, as defined herein, or a pharma- ceutically acceptable salt or solvate thereof, for use in the treatment of prostate cancer in a subject in need thereof as defined below.

[0025] According to one embodiment, the prostate cancer is castration-resistant prostate cancer, also known as castration-resistant prostate cancer (CRPC).

[0026] According to one embodiment, the prostate cancer is metastatic prostate cancer, in particular metastatic castration-resistant prostate cancer (mCRPC).

[0027] According to one embodiment, the subject in need of treatment has a baseline alkaline phosphatase (ALP) level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less. Thus, according to one embodiment, prior to treatment with a 2-aminoarylthiazole derivative as described herein, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, the subject has an ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less.

[0028] Methods for measuring ALP levels are well known to those skilled in the art and include, for example, alkaline phosphatase isoenzyme blood tests. ALP levels are expressed in IU / L (International Units per Liter) or microkatals per Liter (μkat / L). The normal range of ALP levels in healthy human adults is generally considered to be about 44 to about 147 IU / L. ALP levels are often elevated in subjects suffering from prostate cancer (including CRPC), particularly in subjects suffering from metastatic prostate cancer (including mCRPC). ALP levels can therefore reach up to about 1000 to 3000 IU / L in human subjects suffering from metastatic prostate cancer (including mCRPC).

[0029] In one embodiment, the subject in need of treatment has a baseline ALP level of 250 IU / L or less. In one embodiment, the subject in need of treatment has a baseline ALP level of 200 IU / L or less. In one embodiment, the subject in need of treatment has a baseline ALP level of 150 IU / L or less. In one embodiment, the subject in need of treatment has a baseline ALP level of 100 IU / L or less.

[0030] According to one embodiment, a subject in need of treatment has a baseline Halaby Prognostic Score (H) of less than or equal to 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15. Thus, according to one embodiment, prior to treatment with a 2-aminoarylthiazole derivative described herein, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, the subject has a Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less.

[0031] As used herein, the so-called Halabi Prognostic Score (H) is based on the method described by Halabi et al. (J Clin Oncol. 2003 Apr 1;21(7):1232-7), which is incorporated herein by reference.

[0032] More specifically, the Harabi Prognostic Score (H), as defined herein, is derived using a mathematical formula used to model and predict patient survival, which is based on a measurement of visceral disease (yes or no, the value of this parameter is equal to 1 if the subject is affected by visceral disease and equal to 0 otherwise), initial Gleason score (equal to 1 if the Gleason score measured for the subject is in the range of 8-10 and equal to 0 if the Gleason score is less than 8), ECOG (Eastern Cooperative Oncology Group) performance status (range 0-2), prostate specific antigen (PSA) level (PSA, measured in ng / mL), lactate dehydrogenase (LDH) level (LDH, measured in IU / L), alkaline phosphatase (ALP) level (ALP or AP, measured in IU / L), and hemoglobin (HB, measured in g / dL).

[0033] In one embodiment, the Harabi Prognostic Score (H) (i.e., survival estimate) is calculated using the following formula: H = [0.392 × (2 if ECOG = 2, 1 if ECOG = 1, 0 if ECOG = 0)] + [0.335 × (1 if Gleason score is [8-10], or 0 if Gleason score < 8) + [exp(0.312 × log(LDH) + 0.211 × log(AP) + 0.093 × log(PSA))] + [0.161 × (1 if there is visceral disease, 0 otherwise)] - [0.082 × HB].

[0034] In the above formula, ECOG refers to the Eastern Cooperative Oncology Group status, which corresponds to a scale published in 1982 and describes the patient's functional level in terms of their ability to take care of themselves, their daily activities, and their physical abilities (walking, working, etc.) (Oken et al., Am J Clin Oncol. 1982;5:649-655). The ECOG performance status includes six grades ranging from 0 (fully active and able to perform all pre-disease performance without limitation) to 5 (death). Grade 1 corresponds to patients who are limited in physically strenuous activities but can walk and perform tasks of a light or sedentary nature, e.g., light housework, clerical work. Grade 2 corresponds to patients who are ambulatory and able to perform all self-care, but are unable to perform work activities with the ability to get up and move around for more than about 50% of their waking hours. Grade 3 corresponds to patients who are bed- or chair-bound for more than 50% of their waking hours and are able to perform only limited self-care. And Grade 4 corresponds to patients who are completely disabled, completely bed- or chair-bound and unable to perform self-care. In the present invention, the subject's ECOG performance status ranges from 0 to 2.

[0035] In one embodiment, a subject has an ECOG performance status of 0 or 1, and the Halaby Prognostic Score (H) (i.e., survival estimate) may be calculated using the following formula: H = [0.392 × (1 if ECOG = 1, 0 if ECOG = 0)] + [0.335 × (1 if Gleason score is [8-10], or 0 if Gleason score < 8) + [exp(0.312 × log(LDH) + 0.211 × log(AP) + 0.093 × log(PSA))] + [0.161 × (1 if visceral disease is present, 0 otherwise)] - [0.082 × HB]

[0036] The Gleason score is a prognostic score for prostate cancer patients and is derived from a prostate biopsy sample based on its appearance under a microscope. Scores range from 2 to 10, with higher numbers indicating greater risk and higher mortality. To determine the score, two patterns are measured, the first based on the predominant or most common cellular morphology (scored 1 to 5) and the second based on the less predominant cellular pattern (also scored 1 to 5). The two patterns are therefore combined to obtain a score ranging from 2 to 10. The Gleason patterns are: 1- small, uniform glands, 2- more stroma between the glands, 3- clearly invasive peripheral areas, 4- irregular clumps of neoplastic glands, and 5- only occasional gland formation.

[0037] Visceral disease is the clinical manifestation of metastatic CRPC, corresponding to the presence of metastases, primarily in the lungs and liver.

[0038] Methods for measuring lactate dehydrogenase (LDH), alkaline phosphatase (ALP or AP), prostate specific antigen (PSA) and hemoglobin (HB) levels are well known to those of skill in the art and are commonly performed in clinical laboratories.

[0039] In one embodiment, the subject in need of treatment has a baseline Halaby Prognostic Score (H) of 33 or less. In one embodiment, the subject in need of treatment has a baseline Halaby Prognostic Score (H) of 27 or less. In one embodiment, the subject in need of treatment has a baseline Halaby Prognostic Score (H) of 22 or less. In one embodiment, the subject in need of treatment has a baseline Halaby Prognostic Score (H) of 21 or less. In one embodiment, the subject in need of treatment has a baseline Halaby Prognostic Score (H) of 19 or less. In one embodiment, the subject in need of treatment has a baseline Halaby Prognostic Score (H) of 18 or less. In one embodiment, the subject in need of treatment has a baseline Halaby Prognostic Score (H) of 17 or less. In one embodiment, the subject in need of treatment has a baseline Halaby Prognostic Score (H) of 16 or less. In one embodiment, the subject in need of treatment has a baseline Halaby Prognostic Score (H) of 15 or less.

[0040] According to one embodiment, the subject in need of treatment has previously been treated with castration therapy, which corresponds to a reduction in available androgens, testosterone or dihydrotestosterone (DHT), by chemical or surgical means.

[0041] According to one embodiment, the subject in need of treatment has received a hormone therapy selected from the group consisting of a luteinizing hormone releasing hormone (LHRH) agonist (also known as a gonadotropin releasing hormone (GnRH) agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone. Thus, according to one embodiment, prior to treatment with the 2-aminoarylthiazole derivatives described herein, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, the subject has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone. In one embodiment, the subject in need of treatment has previously received an LHRH agonist (also known as a GnRH agonist). Examples of LHRH agonists include, but are not limited to, leuprolide, goserelin, triptorelin, and histrelin. In one embodiment, the subject in need of treatment has previously received an LHRH antagonist (also known as a GnRH antagonist). Examples of LHRH antagonists include, but are not limited to, degarelix and relugolix. In one embodiment, the subject in need of treatment has previously received abiraterone. In one embodiment, the subject has previously been treated with surgical castration.

[0042] According to one embodiment, a subject in need of treatment has a baseline ALP level of less than or equal to 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L and a baseline Hallabi Prognostic Score (H) of less than or equal to 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15.

[0043] According to one embodiment, a subject in need of treatment has a baseline ALP level of 250 IU / L or less and a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less. According to one embodiment, a subject in need of treatment has a baseline ALP level of 200 IU / L or less and a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less. According to one embodiment, a subject in need of treatment has a baseline ALP level of 150 IU / L or less and a baseline Hallabi Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less. According to one embodiment, a subject in need of treatment has a baseline ALP level of less than or equal to 100 IU / L and a baseline Halaby Prognostic Score (H) of less than or equal to 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15.

[0044] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 33 or less. According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 27 or less. According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 22 or less. According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 21 or less. According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 20 or less. According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 19 or less. According to one embodiment, a subject in need of treatment has a baseline ALP level of less than 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L and a baseline Hallabi Prognostic Score (H) of 18 or less.According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 17 or less. According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 16 or less. According to one embodiment, a subject in need of treatment has a baseline ALP level of less than 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L and a baseline Hallabi Prognostic Score (H) of 15 or less.

[0045] According to one embodiment, the subject in need of treatment has a baseline ALP level of less than or equal to 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L and has received a hormone therapy selected from the group consisting of a luteinizing hormone releasing hormone (LHRH) agonist (also known as a gonadotropin releasing hormone (GnRH) agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0046] In one embodiment, the subject in need of treatment has a baseline ALP level of less than or equal to 250, 200, 150, or 100 IU / L and is receiving a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0047] According to one embodiment, the subject in need of treatment has a baseline Hallabi Prognostic Score (H) of less than or equal to 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0048] In one embodiment, the subject in need of treatment has a baseline Hallabi Prognostic Score (H) of less than or equal to 33, 27, 22, 21, 20, 19, 18, 17, 16, or 15 and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0049] According to one embodiment, the subject in need of treatment has a baseline ALP level of less than or equal to 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L; had a baseline Hallabi Prognostic Score (H) of less than or equal to 8, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15; and received hormone therapy selected from the group consisting of LHRH agonists (also known as GnRH agonists), LHRH antagonists (also known as GnRH antagonists), and abiraterone.

[0050] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250 IU / L or less and a baseline Hallabi Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone. According to one embodiment, the subject in need of treatment has a baseline ALP level of 200 IU / L or less and a baseline Hallabi Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone. According to one embodiment, the subject in need of treatment has a baseline ALP level of 150 IU / L or less and a baseline Hallabi Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.According to one embodiment, the subject in need of treatment has a baseline ALP level of 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0051] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 33 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0052] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 27 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0053] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 22 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0054] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 21 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0055] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 20 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0056] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 19 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0057] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 18 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0058] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 17 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0059] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 16 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0060] According to one embodiment, the subject in need of treatment has a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Hallabi Prognostic Score (H) of 15 or less; and has received a hormone therapy selected from the group consisting of an LHRH agonist (also known as a GnRH agonist), an LHRH antagonist (also known as a GnRH antagonist), and abiraterone.

[0061] According to one embodiment, the subject in need of treatment has early stage metastatic castration-resistant prostate cancer (mCRPC) associated with a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less, and / or a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less. Thus, according to one embodiment, a subject in need of treatment is characterized by: (i) a baseline ALP level of less than or equal to 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L; or (ii) a baseline Hallabi Prognostic Score of less than or equal to 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15. (H), or (iii) have early stage mCRPC associated with a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less.

[0062] According to one embodiment, the subject in need of treatment has mCRPC associated with a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less.

[0063] According to one embodiment, the subject in need of treatment has early stage mCRPC which is associated with a baseline ALP level of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less.

[0064] According to one embodiment, the subject in need of treatment has early stage mCRPC which is associated with a baseline ALP level of 250 or less, and / or a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC which is associated with a baseline ALP level of 200 or less, and / or a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC which is associated with a baseline ALP level of 150 or less, and / or a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC which is associated with a baseline ALP level of 100 or less, and / or a baseline Halaby Prognostic Score (H) of 45, 44, 43, 42, 41, 40, 39, 38, 37, 36, 35, 34, 33, 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15 or less.

[0065] According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 33 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 27 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 22 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 21 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 20 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 19 or less.According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 18 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 17 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 16 or less. According to one embodiment, the subject in need of treatment has early stage mCRPC associated with baseline ALP levels of 250, 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L or less and a baseline Halaby Prognostic Score (H) of 15 or less.

[0066] According to one embodiment, the subject in need of treatment is suffering from early stage mCRPC as defined above and has received (preferably prior to initiation of treatment with the 2-aminoarylthiazole derivatives described herein) a hormone therapy selected from the group consisting of luteinizing hormone releasing hormone (LHRH) agonists (also known as gonadotropin releasing hormone (GnRH) agonists), LHRH antagonists (also known as GnRH antagonists), and abiraterone.

[0067] In one embodiment, the subject in need of treatment is an adult. According to the present invention, an adult is a subject over 18, 19, 20, or 21 years of age. In one embodiment, the subject in need of treatment is older than 20, 25, or 30 years of age. According to one embodiment, the subject in need of treatment is a child. According to the present invention, a child is a subject under 21, 20, 19, or 18 years of age.

[0068] In one embodiment, the subject in need of treatment has an ECOG performance status of 0 or 1. In another embodiment, the subject in need of treatment has an ECOG performance status of 2.

[0069] In one embodiment, the subject is receiving androgen deprivation therapy selected from the group consisting of luteinizing hormone releasing hormone (LHRH) agonists (also known as gonadotropin releasing hormone (GnRH) agonists) and LHRH antagonists (also known as GnRH antagonists).

[0070] As used herein, 2-aminoarylthiazole derivatives refer to compounds characterized by the presence of a thiazolyl group substituted at the 2-position (i.e., between the nitrogen and sulfur atoms of the heterocycle) with a secondary or tertiary amine, and the nitrogen atom of the amine is substituted with at least one aryl group.

[0071] According to one embodiment, the aryl group is substituted with an arylamide group (ie, NHCOaryl).

[0072] In one embodiment, the 2-aminoarylthiazole derivative of the present invention has the following formula (I): [ka] (In the formula, R1 and R2 are hydrogen, halogen, (C1-C 10 ) Alkyl, (C3-C 10) cycloalkyl groups, trifluoromethyl, alkoxy, cyano, dialkylamino, solubilizing groups, and solubilizing groups substituted (C1-C 10 ) alkyl; m is 0 to 5; n is 0 to 4; R3 is the following: (i) An aryl group (e.g., phenyl) that is halogen, (C1-C 10 ) aryl groups, optionally substituted with one or more substituents such as alkyl groups, trifluoromethyl, cyano, and alkoxy; (ii) a heteroaryl group (e.g., a 2-, 3-, or 4-pyridyl group), which is a halogen atom, (C1-C 10 ) heteroaryl groups, optionally substituted with one or more substituents such as alkyl groups, trifluoromethyl, and alkoxy; (iii) a five-membered aromatic heterocyclic group (e.g., 2-thienyl, 3-thienyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, etc.), which is selected from halogen, (C1-C 10 ) Aromatic heterocyclic groups, optionally substituted with one or more substituents such as alkyl groups, trifluoromethyl, and alkoxy groups. (One of the has.

[0073] Thus, in one embodiment, the 2-aminoarylthiazole derivative or a pharma- ceutically acceptable salt or solvate thereof of the present invention is a 2-aminoarylthiazole derivative of formula (I) or a pharma- ceutically acceptable salt or solvate thereof:

[0074] In one embodiment, the 2-aminoarylthiazole derivative of the present invention has the following formula (II): [ka] (In the formula, R1 is hydrogen, halogen, (C1-C 10 ) Alkyl, (C3-C 10) cycloalkyl groups, trifluoromethyl, alkoxy, amino, alkylamino, dialkylamino, solubilizing groups, and solubilizing group-substituted (C1-C 10 ) alkyl; and m is 0 to 5. has.

[0075] In one embodiment, R1 in formula (II) is a solubilizing group. In one embodiment, R1 in formula (II) is substituted with a solubilizing group (C1-C 10 ) alkyl.

[0076] In one embodiment, R1 in formula (II) is (C1-C 10 )Alkyl-(C2-C 11 )Heterocycloalkyl-(C1-C 10 In one embodiment, R1 in formula (II) is (C1-C4)alkyl-(C2-C 11 )Heterocycloalkyl-(C1-C 10 ) alkyl-, preferably (C1-C2) alkyl-(C2-C 11 )Heterocycloalkyl-(C1-C 10 In one embodiment, R1 in formula (II) is (C1-C 10 )Alkyl-(C2-C 11 )heterocycloalkyl-(C1-C4)alkyl-, preferably (C1-C 10 )Alkyl-(C2-C 11 In one embodiment, R1 in formula (II) is (C1-C 10 )Alkyl-(C2-C6)Heterocycloalkyl-(C1-C 10 ) alkyl-, preferably (C1-C 10 )Alkyl-(C4)Heterocycloalkyl-(C1-C 10) alkyl. In one embodiment, R1 in formula (II) is (C1-C4) alkyl-(C2-C6) heterocycloalkyl-(C1-C4) alkyl-, preferably (C1-C2) alkyl-(C4) heterocycloalkyl-(C1-C2) alkyl-. In one embodiment, R1 in formula (II) is (C1-C4) alkyl piperazinyl (C1-C4) alkyl-, preferably (C1-C2) alkyl piperazinyl-(C1-C2) alkyl-. In one embodiment, R1 in formula (II) is methyl piperazinyl-(C1-C2) alkyl-, preferably methyl piperazinyl-methyl-, more preferably 4-methyl piperazinyl-methyl-.

[0077] Therefore, in one embodiment, the 2-aminoarylthiazole derivative or a pharma- ceutically acceptable salt or solvate thereof of the present invention is a 2-aminoarylthiazole derivative of the above formula (II) or a pharma- ceutically acceptable salt or solvate thereof.

[0078] As used herein, the term "aryl group" refers to a polyunsaturated aromatic hydrocarbyl group having a single aromatic ring (i.e., phenyl) or multiple aromatic rings, usually having 5 to 12 atoms, preferably 6 to 10, fused together (e.g., naphthyl) or linked by covalent bonds, in which at least one ring is aromatic. The aromatic ring optionally contains 1 to 2 additional rings (either cycloalkyl, heterocyclyl, or heteroaryl) fused thereto. Aryl is also intended to include the partially hydrogenated derivatives of the carbocyclic ring systems enumerated herein. Examples of suitable aryl groups include, but are not limited to, phenyl, tolyl, anthracenyl, fluorenyl, indenyl, azulenyl, and naphthyl, as well as benzo-fused carbocyclic moieties such as 5,6,7,8-tetrahydronaphthyl. An aryl group can be unsubstituted or substituted with one or more substituents. In one embodiment, an aryl group is a monocyclic ring, and the ring contains 6 carbon atoms, referred to herein as "(C6)aryl."

[0079] As used herein, the term "alkyl group" refers to a saturated straight-chain or branched, non-cyclic hydrocarbon having 1 to 10 carbon atoms, preferably 1 to 6 carbon atoms. Representative saturated straight-chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n-pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl. Saturated branched alkyls include, but are not limited to, isopropyl, sec-butyl, isobutyl, tert-butyl, isopentyl, 2-methylbutyl, 3-methylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 2,3-dimethylbutyl, 2,3-dimethylpentyl, 2,4-dimethylpentyl, 2,3-dimethylhexyl, 2,4-dimethylhexyl, 2,5-dimethylhexyl, 2,2-dimethylpentyl, 2,2-dimethylhexyl, 3,3 -dimethylpentyl, 3,3-dimethylhexyl, 4,4-dimethylhexyl, 2-ethylpentyl, 3-ethylpentyl, 2-ethylhexyl, 3-ethylhexyl, 4-ethylhexyl, 2-methyl-2-ethylpentyl, 2-methyl-3-ethylpentyl, 2-methyl-4-ethylpentyl, 2-methyl-2-ethylhexyl, 2-methyl-3-ethylhexyl, 2-methyl-4-ethylhexyl, 2,2-diethylpentyl, 3,3-diethylhexyl, 2,2-diethylhexyl, 3,3-diethylhexyl. The alkyl groups contained in the compounds of the present invention may be optionally substituted with one or more substituents.

[0080] As used herein, the term "alkoxy" refers to an alkyl group attached to another moiety by an oxygen atom. Examples of alkoxy groups include, but are not limited to, methoxy, isopropoxy, ethoxy, and tert-butoxy. Alkoxy groups may be optionally substituted with one or more substituents.

[0081] As used herein, the term "cycloalkyl" refers to a saturated cyclic alkyl group having 3 to 10 carbon atoms. Representative cycloalkyl groups include cyclopropyl, 1-methylcyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, and cyclodecyl. Cycloalkyl groups can be optionally substituted with one or more substituents.

[0082] As used herein, the term "halogen" refers to -F, -Cl, -Br or -I.

[0083] As used herein, the term "heteroaryl" refers to a monocyclic or polycyclic heteroaromatic ring containing carbon atom ring members and one or more heteroatom ring members, such as oxygen, sulfur, or nitrogen. Typically, heteroaryl groups have from 1 to about 5 heteroatom ring members and from 1 to about 14 carbon atom ring members. Representative heteroaryl groups include, but are not limited to, pyridyl, 1-oxo-pyridyl, furanyl, benzo[1,3]dioxolyl, benzo[1,4]dioxinyl, thienyl, pyrrolyl, oxazolyl, imidazolyl, thiazolyl, isoxazolyl, quinolinyl, pyrazolyl, isothiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, triazolyl, thiadiazolyl, isoquinolinyl, indazolyl, Examples of heteroaryl groups include benzoxazolyl, benzofuryl, indolizinyl, imidazopyridyl, tetrazolyl, benzimidazolyl, benzothiazolyl, benzothiadiazolyl, benzoxadiazolyl, indolyl, tetrahydroindolyl, azaindolyl, imidazopyridyl, quinazolinyl, purinyl, pyrrolo[2,3]pyrimidinyl, pyrazolo[3,4]pyrimidinyl, imidazo[1,2-a]pyridyl, and benzo(b)thienyl. Heteroatoms may be substituted with protecting groups known to those skilled in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Heteroaryl groups may be optionally substituted with one or more substituents. Additionally, the nitrogen or sulfur heteroatom ring members may be oxidized. In one embodiment, the heteroaromatic ring is selected from 5-8 membered monocyclic heteroaryl rings. The point of attachment of a heteroaromatic or heteroaryl ring to another group can be at either a carbon atom or a heteroatom of the heteroaromatic or heteroaryl ring.

[0084] As used herein, the term "heterocycle" is generic to heterocycloalkyl and heteroaryl groups.

[0085] As used herein, the term "heterocycloalkyl" refers to a monocyclic or polycyclic group having at least one heteroatom selected from O, N or S, and having 2 to 11 carbon atoms that may be saturated or unsaturated, but not aromatic. Examples of heterocycloalkyl groups include, but are not limited to, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl, pyrrolidinyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydropyrindinyl, tetrahydropyrimidinyl, tetrahydrothiopyranyl sulfone, tetrahydrothiopyranyl sulfoxide, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxide, thiomorpholinyl sulfone, 1,3-dioxolane, tetrahydrofuranyl, dihydrofuranyl-2-one, tetrahydrothienyl, and tetrahydro-1,1-dioxothienyl. Typically, monocyclic heterocycloalkyl groups have 3 to 7 members. Preferred 3 to 7 member monocyclic heterocycloalkyl groups are those having 5 or 6 ring atoms. Heteroatoms may be substituted with protecting groups known to those skilled in the art, for example, the hydrogen on a nitrogen may be substituted with a tert-butoxycarbonyl group. Furthermore, heterocycloalkyl groups may be optionally substituted with one or more substituents. In addition, the position of attachment of a heterocycle to another group may be either at a carbon atom or at a heteroatom of the heterocycle. Only stable isomers of such substituted heterocyclic groups are contemplated in this definition.

[0086] As used herein, the term "substituent" or "substituted" means that a hydrogen radical on a compound or group is replaced with any desired group that is substantially stable to the reaction conditions, either in unprotected form or when protected using a protecting group. Examples of preferred substituents include, but are not limited to, halogen (chloro, iodo, bromo, or fluoro); alkyl; alkenyl; alkynyl; hydroxy; alkoxy; nitro; thiol; thioether; imine; cyano; amide; phosphonato; phosphine; carboxyl; thiocarbonyl; sulfonyl; sulfonamide; ketone; aldehyde; ester; oxygen (-O); haloalkyl (e.g., trifluoromethyl); cycloalkyl (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which may be monocyclic or fused or non-fused polycyclic, or heterocycloalkyl (e.g., pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, or thiazinyl), monocyclic or fused or non-fused polycyclic aryl or heteroaryl (e.g., phenyl, naphthyl, pyrrolyl, indolyl, furanyl, thiophenyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyridyl, quinolinyl, isoquinolinyl, acridinyl, pyrazinyl, pyridazinyl, pyrimidinyl, benzimidazolyl, benzothiophenyl, or benzofuranyl); amino (primary, secondary, or tertiary); CO2CH3; CONH2; OCH2CONH2; NH2; SO2NH2; OCHF2; CF3; OCF3. 、 Such moieties may also be optionally substituted with fused ring structures or bridges, e.g., -OCHO-. These substituents may be optionally further substituted with substituents selected from such groups. In certain embodiments, the term "substituent" or the adjective "substituted" refers to any of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, heterocycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, haloalkyl, -C(O)NR 11 R 12 , -NR 13 C(O)R14 , Halo, -OR 13 , cyano, nitro, haloalkoxy, -C(O)R 13 , -NRR 11 R 12 , -SR 13 , -C(O)OR 13 , O.C.(O)R 13 , -NR 13 C(O)NR 11 R 12 , -OC(O)NR 11 R 12 , -NR 13 C(O)OR 14 , -S(O)rR 13 , -NR 13 S(O)rR 14 , -OS(O)rR 14 , S(O)rNR 11 R 12 , -O, -S, and -NR 13 where r is 1 or 2; R 11 and R 12 is, independently for each occurrence, H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl; or R 11 and R 12 together with the nitrogen to which they are attached, are optionally substituted heterocycloalkyl or optionally substituted heteroaryl; and R 13 and R 14is independently at each occurrence H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted cycloalkyl, optionally substituted cycloalkenyl, optionally substituted heterocycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted arylalkyl, or optionally substituted heteroarylalkyl. In certain embodiments, the term "substituent" or the adjective "substituted" refers to a solubilizing group.

[0087] As used herein, the term "solubilizing group" refers to any group ("water-soluble group") that can be substantially ionized and allows the compound to be soluble in a desired solvent, such as water or a water-containing solvent. In addition, the solubilizing group may increase the lipophilicity of the compound or complex. In one embodiment, the solubilizing group is selected from an alkyl group substituted with one or more heteroatoms, such as N, O, S, each of which is optionally substituted with an alkyl group independently substituted with alkoxy, amino, alkylamino, dialkylamino, carboxyl, cyano, or substituted with cycloheteroalkyl or heteroaryl, or a phosphate, or a sulfate, or a carboxylic acid. In one embodiment, the solubilizing group is selected from the following: - alkyl, cycloalkyl, aryl, heteroaryl groups containing at least one either nitrogen or oxygen heteroatom, and / or alkyl, cycloalkyl, aryl, heteroaryl groups substituted with at least one amino group or oxo group (including but not limited to 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 4-piperidonyl, hydantoinyl, valerolactamyl, oxiranyl, oxetanyl, tetrahydropyranyl, morpholinyl, 1,3-dioxolane, tetrahydrofuranyl and dihydrofuranyl-2-one); - an amino group which may be a saturated cyclic amino group (including but not limited to piperidinyl, piperazinyl and pyrrolidinyl) optionally substituted by the group consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl (including but not limited to methylpiperidinyl, methylpiperazinyl and methylpyrrolidinyl); one of the structures a) to i) shown below (wherein the wavy lines and the arrows correspond to the points of attachment to the core structure of the 2-aminoarylthiazole derivative of the invention, e.g. of formula (I) or (II)) It is one of the following. [ka]

[0088] In one embodiment, the solubilizing group is: - an alkyl, cycloalkyl, aryl, heteroaryl group containing at least one heteroatom, either nitrogen or oxygen, or an alkyl, cycloalkyl, aryl, heteroaryl group substituted by at least one amino or oxo group; an amino group which may be a saturated cyclic amino group optionally substituted by groups consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl; - one of the structures a) to i) shown above (wherein the wavy lines and the arrowed lines correspond to the points of attachment to the core structure of the 2-aminoarylthiazole derivative of the invention, e.g. of formula (I) or (II)) It is one of the following.

[0089] In one embodiment, the solubilizing group is a saturated cyclic amino group (including but not limited to piperidinyl, piperazinyl and pyrrolidinyl) which may be substituted by the group consisting of alkyl, alkoxycarbonyl, halogen, haloalkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, carbamoyl, monoalkylcarbamoyl and dialkylcarbamoyl (including but not limited to methylpiperidinyl, methylpiperazinyl and methylpyrrolidinyl).

[0090] In one embodiment, the solubilizing group is structure c) shown above, where the wavy line corresponds to the point of attachment to the core structure of a 2-aminoarylthiazole derivative of the invention, such as formula (I) or (ii).

[0091] As used herein, "pharmaceutical acceptable salts" refers to salts of biologically desirable free acids or free bases, and are generally prepared by reacting a free base with a suitable organic or inorganic acid, or by reacting a free acid with a suitable organic or inorganic base. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, hydrogen sulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate. , lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, hydrogen phosphate, dihydrogen phosphate, phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts.

[0092] In one embodiment, the pharma- ceutically acceptable salt is, for example, a pharma- ceutically acceptable acid addition salt with an inorganic acid, such as hydrochloric acid, sulfuric acid or phosphoric acid, or a pharma- ceutically acceptable acid addition salt with a suitable organic carboxylic or sulfonic acid, for example an aliphatic mono- or dicarboxylic acid, such as trifluoroacetic acid, acetic acid, propionic acid, glycolic acid, succinic acid, maleic acid, fumaric acid, hydroxymaleic acid, malic acid, tartaric acid, citric acid or oxalic acid, or an amino acid, such as arginine or lysine, an aromatic carboxylic acid, such as benzoic acid, 2-phenoxybenzoic acid, 2-acetoxybenzoic acid, salicylic acid, 4-aminosalicylic acid, an aromatic aliphatic carboxylic acid, such as mandelic acid or cinnamic acid, a heteroaromatic carboxylic acid, such as nicotinic acid or isonicotinic acid, an aliphatic sulfonic acid, such as methane-, ethane- or 2-hydroxyethane-sulfonic acid, in particular methanesulfonic acid, or an aromatic sulfonic acid, such as benzene-, p-toluene- or naphthalene-2-sulfonic acid.

[0093] In one embodiment, a pharma- ceutically acceptable salt of a 2-aminoarylthiazole derivative of the invention is a mesylate salt.

[0094] Unless otherwise indicated, the term "mesylate" is used herein to refer to a salt of a named pharmaceutical agent (such as a 2-aminoarylthiazole derivative of formula (I) or (II)) with methanesulfonic acid. Use of mesylates other than mesylate is in accordance with the INNM (International nonproprietary names modified) issued by the WHO (e.g., World Health Organization (February 2006) International Nonproprietary Names Modified INN Working Paper 05.167 / 3.WHO).

[0095] As used herein, "a pharma- ceutically acceptable solvate" refers to a molecular complex comprising a 2-aminoarylthiazole derivative of the present invention and a stoichiometric or substoichiometric amount of one or more pharma- ceutically acceptable solvent molecules, such as ethanol. The term "hydrate" refers to when the solvent is water.

[0096] In one particular embodiment, the 2-aminoarylthiazole derivative of the invention, or a pharma- ceutically acceptable salt or solvate thereof, is masitinib, or a pharma- ceutically acceptable salt or solvate thereof.

[0097] The chemical name of masitinib is 4-(4-methylpiperazin-1-ylmethyl)-N-[4-methyl-3-(4-pyridin-3ylthiazol-2-ylamino)phenyl]benzamide - CAS number 790299-79-5: [ka] It is. Masitinib was first described in U.S. Patent No. 7,423,055 and EP 1 525 200 B1.

[0098] In one embodiment, the 2-aminoarylthiazole derivative of the present invention or its pharma- ceutically acceptable salt or solvate is masitinib mesylate.Therefore, in one embodiment, the pharma-ceutically acceptable salt of masitinib is masitinib mesylate.As stated above, in other words, the pharma-ceutically acceptable salt of masitinib is the methanesulfonate salt of masitinib.

[0099] Detailed procedures for the synthesis of masitinib mesylate are described in WO 2008 / 098949.

[0100] In one embodiment, "masitinib mesylate" refers to the orally bioavailable mesylate salt of masitinib - CAS 1048007-93-7 (MsOH); C28H30N6OS.CH3SO3H; MW 594.76: [ka] Refers to...

[0101] According to one embodiment, the 2-aminoarylthiazole derivative as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration in a therapeutically effective dose.

[0102] In one embodiment, the 2-aminoarylthiazole derivatives, particularly masitinib, or a pharma- ceutically acceptable salt or solvate thereof, as described above, are for administration at a dose in the range of about 1 to about 12 mg / kg / day (mg per kilo body weight per day). In one embodiment, the 2-aminoarylthiazole derivatives, particularly masitinib, or a pharma-ceutically acceptable salt or solvate thereof, as described above, are for administration at a dose in the range of about 1.5 to about 7.5 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivatives, particularly masitinib, or a pharma-ceutically acceptable salt or solvate thereof, as described above, are for administration at a dose in the range of about 3 to about 12 mg / kg / day, preferably about 3 to about 6 mg / kg / day.

[0103] In one embodiment, the 2-aminoarylthiazole derivatives as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, are for administration at a dose of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivatives as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, are for administration at a dose of about 1.5, 3, 4.5, 6, 7.5, 9, 10.5, or 12 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivatives as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, are for administration at a dose of about 3, 4.5, or 6 mg / kg / day, preferably at a dose of about 6 mg / kg / day.

[0104] In one embodiment, the 2-aminoarylthiazole derivative as described above, particularly masitinib, or a pharma- ceutically acceptable salt or solvate thereof, may be dose escalated in increments of about 1.5 mg / kg / day to reach a maximum of about 7.5 mg / kg / day, more preferably about 4.5 or about 6 mg / kg / day, with each dose escalation being subject to toxicity management to allow for dose escalation to occur without toxic events.

[0105] In one embodiment, the dose escalation of the 2-aminoarylthiazole derivative, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, occurs at any time point at least 4 weeks after administration of the initial dose and before 26 weeks after administration of the initial dose; for example, at 4 weeks, 8 weeks, 12 weeks, 16 weeks, 20 weeks, or 24 weeks after administration of the initial dose, preferably at 12 weeks after administration of the initial dose. Each dose escalation may, for example: include a prior 4-week treatment period at a stable dose of study treatment, undergo toxicity control, and have no reported serious suspected adverse events, and have not led to treatment discontinuation, and have not progressed at the time of the dose escalation, regardless of their severity.

[0106] In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharma- ceutically acceptable salt or solvate thereof, as described above, is for administration at an initial dose of about 3 mg / kg / day for 6 weeks, followed by a dose of about 4.5 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharma-ceutically acceptable salt or solvate thereof, as described above, is for administration at an initial dose of about 4.5 mg / kg / day for 6 weeks, followed by a dose of about 6 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharma-ceutically acceptable salt or solvate thereof, as described above, is for administration at an initial dose of about 3 mg / kg / day for 12 weeks, followed by a dose of about 4.5 mg / kg / day. In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharma- ceutically acceptable salt or solvate thereof, as described above, is for administration at an initial dose of about 4.5 mg / kg / day for 12 weeks, followed by a dose of about 6 mg / kg / day thereafter.In one embodiment, the 2-aminoarylthiazole derivative, particularly masitinib, or a pharma- ceutically acceptable salt or solvate thereof, as described above, is for administration at an initial dose of about 3 mg / kg / day for 4 weeks, followed by a dose of about 4.5 mg / kg / day for at least 4 weeks, followed by a dose of about 6 mg / kg / day thereafter, with each dose escalation being subject to toxicity management.

[0107] According to one embodiment, any dose indicated herein refers to the amount of active ingredient itself, not its pharma- ceutically acceptable salt or solvate form.Therefore, compositional variations of the 2-aminoarylthiazole derivatives of the present invention, particularly the pharma-ceutically acceptable salt or solvate of masitinib, will not affect the dose to be administered.

[0108] According to one embodiment, the 2-aminoarylthiazole derivatives of the invention, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, are adapted for administration in dosages as described above.

[0109] According to one embodiment, the 2-aminoarylthiazole derivative, preferably masitinib, or a pharma- ceutically acceptable salt or solvate thereof as described above may be administered orally, intravenously, parenterally, topically, by inhalation, in particular by inhalation spray, enterally, nasally, or bucally.In one embodiment, the 2-aminoarylthiazole derivative, preferably masitinib, or a pharma- ceutically acceptable salt or solvate thereof as described above is for oral administration.

[0110] In one embodiment, the 2-aminoarylthiazole derivative, preferably masitinib, or a pharma- ceutically acceptable salt or solvate thereof as described above, is for administration at least once a day, preferably twice a day.In one embodiment, the 2-aminoarylthiazole derivative, preferably masitinib, or a pharma- ceutically acceptable salt or solvate thereof as described above, is for chronic administration, for example for at least 1, 2, 3, 6, 9, or 12 months.

[0111] In one embodiment, the 2-aminoarylthiazole derivative as described above, preferably masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is adapted or in a form adapted for oral administration. Examples of forms adapted for oral administration include, but are not limited to, liquids, pastes or solid compositions, more particularly tablets, pills, capsules, liquids, gels, syrups, slurries and suspensions.

[0112] In one embodiment, the 2-aminoarylthiazole derivative, preferably masitinib, or a pharma- ceutically acceptable salt or solvate thereof as described above, is for administration as a tablet, preferably a 100 mg or 200 mg tablet.

[0113] According to one embodiment, the 2-aminoarylthiazole derivative as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration with at least one further pharma- ceutical active agent.

[0114] According to the present invention, the 2-aminoarylthiazole derivative, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof as described above may be administered simultaneously, separately or sequentially with the at least one further pharma- ceutical active agent as described above.

[0115] In one embodiment, the 2-aminoarylthiazole derivative as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is to be administered in combination with at least one further pharma- ceutical active agent as described above, e.g. in a combined preparation, pharmaceutical composition or medicament.

[0116] In one embodiment, the 2-aminoarylthiazole derivative as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, and the at least one further pharma- ceutical active agent are to be administered separately.

[0117] In one embodiment, the at least one further pharma- ceutical active agent is selected from a chemotherapeutic agent and a corticoid.

[0118] In one embodiment, the 2-aminoarylthiazole derivative as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration with a chemotherapeutic agent, in one embodiment, the chemotherapeutic agent is docetaxel or cabazitaxel.

[0119] In one embodiment, the 2-aminoarylthiazole derivative as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration with docetaxel.

[0120] In one embodiment, the 2-aminoarylthiazole derivative as described above, particularly masitinib, or its pharmaceutically acceptable salt or solvate, is for administration with at least one corticosteroid. Examples of corticosteroids include but are not limited to prednisone. In one embodiment, the 2-aminoarylthiazole derivative as described above, particularly masitinib, or its pharmaceutically acceptable salt or solvate, is for administration with prednisone.

[0121] In one embodiment, the 2-aminoarylthiazole derivatives as described above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, are for administration with a chemotherapeutic agent, such as docetaxel, and at least one corticosteroid, such as, for example, prednisone. In one embodiment, the 2-aminoarylthiazole derivatives as described above, in particular masitinib, or a pharma-ceutically acceptable salt or solvate thereof, are for administration with docetaxel and prednisone.

[0122] Another object of the present invention is a method for treating prostate cancer (preferably CRPC, more preferably mCRPC, and especially early stage mCRPC associated with a baseline alkaline phosphatase (ALP) level of less than or equal to 250 IU / L, and / or a baseline Halaby Prognostic Score (H) of less than or equal to 45) in a subject in need thereof, as defined above, comprising administering to the subject a 2-aminoarylthiazole derivative as defined above, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof.

[0123] In one embodiment, the method is for treating early stage mCRPC as defined herein.

[0124] In one embodiment, the method comprises administering a therapeutically effective dose of a 2-aminoarylthiazole derivative as described above, particularly masitinib, or a pharma- ceutically acceptable salt or solvate thereof.

[0125] In one embodiment, the method comprises administering at least one additional pharma- ceutical active agent as described herein, hi one embodiment, the at least one additional pharma- ceutical active agent is selected from a chemotherapeutic agent and a corticoid.

[0126] Another object of the present invention is a pharmaceutical composition for or for use in the treatment of prostate cancer (preferably CRPC, more preferably mCRPC, and in particular early stage mCRPC associated with a baseline alkaline phosphatase (ALP) level of less than or equal to 250 IU / L, and / or a baseline Halaby Prognostic Score (H) of less than or equal to 45) in a subject in need thereof as defined above, said pharmaceutical composition comprising a 2-aminoarylthiazole derivative, in particular masitinib, or a pharma- ceutical acceptable salt or solvate thereof, as described above, and optionally at least one pharma- ceutical acceptable excipient.

[0127] In one embodiment, the pharmaceutical composition is for or use in the treatment of early stage mCRPC as defined herein.

[0128] In one embodiment, the pharmaceutical composition is for administration with at least one additional pharmacologic active agent as described herein. According to the present invention, the pharmaceutical composition may be administered simultaneously, separately or sequentially with said at least one additional pharmacologic active agent. In one embodiment, said at least one additional pharmacologic active agent is selected from chemotherapeutic agents and corticoids.

[0129] Another object of the present invention is the use of a 2-aminoarylthiazole derivative, in particular masitinib, or a pharma- ceutically acceptable salt or solvate thereof, for the manufacture of a medicament for the treatment of prostate cancer (preferably CRPC, more preferably mCRPC, and in particular early stage mCRPC associated with a baseline alkaline phosphatase (ALP) level of less than or equal to 250 IU / L, and / or a baseline Halaby Prognostic Score (H) of less than or equal to 45) in a subject in need thereof, as defined above.

[0130] In one embodiment, the invention relates to the use of a 2-aminoarylthiazole derivative, in particular masitinib, or a pharma- ceutical acceptable salt thereof, for the manufacture of a medicament for the treatment of early stage mCRPC as defined herein.

[0131] In one embodiment, the medicament is for administration with at least one additional pharmacologic active agent as described herein. According to the present invention, the medicament may be administered simultaneously, separately or sequentially with said at least one additional pharmacologic active agent. In one embodiment, said at least one additional pharmacologic active agent is selected from chemotherapeutic agents and corticoids.

[0132] Working Example The present invention is further illustrated by the following examples.

[0133] Example 1: Materials and Methods A prospective, multicenter, randomized, double-blind, placebo-controlled, two-parallel group, phase 3 study was conducted to evaluate the efficacy and safety of masitinib in combination with docetaxel compared with placebo in combination with docetaxel in first-line metastatic castration-resistant prostate cancer (mCRPC).

[0134] The objective of this study was to evaluate the efficacy and safety of masitinib in combination with docetaxel compared with docetaxel in combination with placebo in first-line metastatic castration-resistant prostate cancer (mCRPC). Efficacy was assessed based on progression-free survival (PFS), measured in months.

[0135] Patients recruited in this study consisted of adult men with prostate cancer who had progressed to castration-resistant prostate cancer (CRPC) after castration treatment (reduction of androgens (e.g., testosterone, dihydrotestosterone (DHT)) by chemical or surgical means). These patients were considered to be first-line metastatic castration-resistant prostate cancer (mCRPC) patients.

[0136] Patients recruited in this study were randomized in a 1:1 ratio into two groups: Group 1: masitinib (6 mg / kg / day) + docetaxel (75 mg / m 2 6 cycles - preferably 8 or 10 cycles) + prednisone; - Group 2: placebo + docetaxel (75 mg / m 2 6 cycles - preferably 8 or 10 cycles) + prednisone. Docetaxel was routinely combined with prednisone. Patients were centrally randomized to one of two treatment groups by IWRS (Interactive Web Response System) according to a minimization procedure.

[0137] Selection criteria: - Patients aged 18 years or older with histologically or cytologically confirmed metastatic castration-resistant prostate cancer (medically or surgically castrated: patients with androgen deprivation with GnRH agonists or antagonists or surgical castration; biologically confirmed hormonal castration (testosterone <0.5 ng / mL) using one of the following criteria: * If surgical castration is performed, there is no need to perform testosterone testing. Previously treated with abiraterone and documented disease progression, or - Have an indication for initiating docetaxel (e.g., extensive visceral disease or rapidly progressing disease). - Patients with evidence of progressive metastatic disease. Disease progression at the time of study entry is based on progression of at least one change as described in the Prostate Cancer Clinical Trials Working Group (PCWG2) definitions of response and disease symptom progression in prostate cancer (Scher et al. J Clin Oncol. 2008;26:1148-1159): [Table 1] JPEG2024518110000007.jpg91159 - Patients with ECOG ≤ 1 - Patients with adequate organ function: Absolute neutrophil count (ANC) ≥ 1.5 × 10 9 / L Hemoglobin ≧ 10g / dL 〇Platelets (PTL)≧75×10 9 / L AST (aspartate aminotransferase) / ALT (alanine aminotransferase) ≦3×upper limit of normal, i.e. ULN (≦5×ULN in the case of liver metastasis) Gamma glutamyltransferase (GGT) ≦2.5×ULN (≦5×ULN in the case of liver metastasis) Bilirubin ≦1.5×ULN (≦3×ULN in case of liver metastasis) For normal or abnormal creatinine, creatinine clearance ≥ 50 mL / min (Cockcroft-Gault equation) 〇Urea≦2×ULN Albumin > 1 × LLN (lower limit of normal) Dipstick proteinuria < 30 mg / dL (1+); if dipstick proteinuria ≥ 1+, 24-hour proteinuria must be ≤ 1.5 g / 24 hours - Patients with a life expectancy of more than 3 months - BMI > 18 kg / m 2 and patients weighing >40 kg - Male patients with a female partner of childbearing potential who agree to use a highly effective method of contraception and an acceptable method of contraception by their female partner during the study and for 3 months after the last dose of treatment, or who agree to use an acceptable method of contraception and a highly effective method of contraception by their female partner during the study and for 3 months after the last dose of treatment.

[0138] Exclusion criteria: - Patients previously treated with chemotherapy - Patients with bone marrow irradiation >40% within 12 months prior to baseline - Patients who have been treated for cancer other than prostate cancer within 3 years prior to enrollment, excluding basal cell carcinoma (and pTa or pT1 tumors) - Patients with active central nervous system (CNS) metastases or a history of CNS metastases - Patients with cardiac impairment defined by at least one of the following conditions: Patients with the following recent cardiac history (within 6 months): acute coronary syndrome Acute heart failure (New York Heart Association (NYHA) Class III or IV) Major ventricular arrhythmias (sustained ventricular tachycardia, ventricular fibrillation, sudden death after resuscitation) - Patients with NYHA class III or IV heart failure Patients with severe conduction disorders not prevented by permanent pacing (atrioventricular block type 2 and 3, sinoatrial block) Syncope of unknown etiology within the past 3 months - Severe, uncontrolled hypertension or symptomatic hypertension according to the investigator's judgment - Patients with a history of poor compliance or drug / alcohol abuse that would interfere with their ability to comply with the study protocol or who have consumed excessive alcoholic beverages, or current or past psychiatric illness that may interfere with their ability to comply with the study protocol or give informed consent. - Patients undergoing treatment with anti-tumor therapy (radiotherapy, chemotherapy, biological or anti-androgen therapy excluding GnRH / LHRH analogues)

[0139] For each patient included in the study, the Harabi Prognostic Score (i.e., survival time estimate), also referred to as (H), was calculated using the following formula: H = [0.392 × (2 if ECOG = 2, 1 if ECOG = 1, 0 if ECOG = 0)] + [0.335 × (1 if Gleason score is [8-10], or 0 if Gleason score < 8) + [exp(0.312 × log(LDH) + 0.211 × log(AP) + 0.093 × log(PSA))] + [0.161 × (1 if there is visceral disease, 0 otherwise)] - [0.082 × HB].

[0140] As used herein, the Halabi Prognostic Score (H) is based on the method described by Halabi et al. (J Clin Oncol. 2003 Apr 1;21(7):1232-7) and is used as an estimate of patient survival. As mentioned above, the formula is based on the measurement of visceral disease (yes or no, the value of this parameter is equal to 1 if the subject is affected by visceral disease and equal to 0 otherwise), initial Gleason score (equal to 1 if the Gleason score measured for the subject is in the range of 8-10 and equal to 0 if the Gleason score is less than 8), ECOG (Eastern Cooperative Oncology Group) performance status (range 0-2), prostate specific antigen (PSA) level (PSA, measured in ng / mL), lactate dehydrogenase (LDH) level (LDH, measured in IU / L), alkaline phosphatase (ALP) level (ALP or AP, measured in IU / L) and hemoglobin (HB, measured in g / dL).

[0141] In particular, the Halaby Prognostic Score (H) was calculated for subjects with an ECOG performance status of 0 or 1 using the following procedure: -VISCERAL1: Enter if the patient has been diagnosed with a visceral disease (yes / no) (VISCERAL_n) - ECOG1: Enter the patient's ECOG value (0 vs. 1 vs. 2) (ecog_SCR) - GLEASON11: Enter the patient's Gleason score - Range: Must be an integer from [2-10] (QSSCORE) - LDH1: Enter the patient's LDH value - must be a decimal number from the range [6-4000 IU / L] (ldh_SCR) - AP1: Enter the patient's alkaline phosphatase value (AP1) - must be a decimal number in the range [10-2500 IU / L] (SCREEN_LOCALV) - HB1: Enter the patient's hemoglobin value - must be a decimal number from the range [10-20 g / dl] (HEMO_SCR) - PSA1: Enter the patient's PSA value - must be a decimal number from the range [0.0001-5000ng / ml] (PSA_SCR). Based on these values, the interactive web response system used for randomization calculated the Harabi Prognostic Score (H) using the following Statistical Analysis System (SAS) program code: HALABI Score Derive; if QSSCORE <8 then GLEASON1=0; else if 8 <= QSSCORE <=10 then GLEASON1=1; else GLEASON1=.; ECOG1 = 0.392*ecog_SCR; GLEASON11 = 0.335*GLEASON1; LDH1 = 0.312*(log(ldh_SCR)); AP1 = 0.211*(log (SCREEN_LOCALV)); PSA1 = 0.093*(log(PSA_SCR)); VISCERAL1 = 0.161*VISCERAL_n; HB1 = 0.082*HEMO_SCR; d1=exp(LDH1+AP1+PSA1); H = (ECOG1+GLEASON11+d1+VISCERAL1-HB1). Below is an example working with patient data (001-003) with the following values: ECOG1 = 0 (i.e., ECOG 0) GLEASON11 = 1 (i.e., Gleason score 8–10) LDH1 = 184 AP1 = 88 PSA1 = 3.9 VISCERAL1 = 1 (i.e., visceral disease) HB1 = 13.0 So, for this patient: H = [0.392*0] + [0.335*1] + [exp (0.312*(log (184)) + 0.211*(log (88)) + 0.093*(log (3.90)))] + [0.161*1] - [0.082*13.0] = 14.29

[0142] result The efficacy of masitinib for treating mCRPC was evaluated based on progression-free survival (expressed as median progression-free survival measured in months ("median"), with its associated 95% confidence interval ("95%CI") and p-value), and on two parameters measured in the study population. First, the hazard ratio (HR) is measured, which corresponds to the probability of death when treated with masitinib (+docetaxel+prednisone) relative to the probability of death when treated with placebo (+docetaxel+prednisone). Thus, an HR<1 indicates that the probability of death when treated with masitinib is lower than the probability of death when treated with placebo (and thus indicates a treatment benefit). Second, the "risk-benefit" is measured, which allows to evaluate the effect of masitinib in a specific subgroup compared to a mirror subgroup.

[0143] The results obtained first demonstrate that the therapeutic benefit of masitinib depends on the alkaline phosphatase (ALP) levels measured at baseline in the subjects, as shown in Tables 1-4 below. Table 1: Masitinib treatment effect in terms of median PFS (in months) according to baseline ALP level ≤ 250 IU / L [Table 2] Table 2: Masitinib treatment effect in terms of median PFS (in months) according to baseline ALP level ≤ 200 IU / L [Table 3] Table 3: Masitinib treatment effect in terms of median PFS (in months) according to baseline ALP level ≤ 150 IU / L [Table 4] Table 4: Masitinib treatment effect in terms of median PFS (in months) according to baseline ALP level below 100 IU / L [Table 5]

[0144] As shown in Table 1, patients with baseline ALP levels of 250 IU / L or less show an increased response to masitinib. In addition, as shown in Tables 1-4, lower baseline ALP levels are associated with improved hazard ratios (reaching 0.53 for baseline ALP levels of 100 IU / L or less) corresponding to increased risk benefit (reaching 47% for baseline ALP levels of 100 IU / L or less).

[0145] Secondly, the results obtained demonstrate that the therapeutic benefit of masitinib depends on the subjects' Hallabi score (H) measured at baseline, as shown in Table 5 below. Table 5: Masitinib treatment effect in terms of median PFS (in months) according to the Harabi Prognostic Score (H) at baseline [Table 6] JPEG2024518110000013.jpg218159

[0146] As shown in Table 5, patients with a baseline Halaby Prognostic Score (H) of 33 or less show increased response to masitinib. In addition, the therapeutic benefit of masitinib increases as the baseline Halaby Score (H) decreases.

[0147] Furthermore, as shown in Tables 6-10, the therapeutic benefit of masitinib is increased in patients who present with both a low ALP level measured at baseline (i.e., a baseline ALP level of 250 IU / L or less) and a low Halaby score (H) measured at baseline (i.e., a baseline Halaby prognostic score (H) of 33 or less). Table 6: Masitinib treatment effect in terms of median PFS (in months) according to baseline ALP level ≤ 250 IU / L and baseline Harabi Prognostic Score (H) ≤ 18 [Table 7] Table 7: Masitinib treatment effect in terms of median PFS (in months) according to baseline ALP level ≤ 250 IU / L and baseline Harabi Prognostic Score (H) ≤ 19 [Table 8] Table 8: Masitinib treatment effect in terms of median PFS (in months) according to baseline ALP level ≤ 250 IU / L and baseline Harabi Prognostic Score (H) ≤ 20 [Table 9] Table 9: Masitinib treatment effect in terms of median PFS (in months) according to baseline ALP level ≤ 250 IU / L and baseline Harabi Prognostic Score (H) ≤ 21 [Table 10] Table 10: Masitinib treatment effect in terms of median PFS (in months) according to baseline ALP level ≤ 250 IU / L and baseline Harabi Prognostic Score (H) ≤ 22 [Table 11]

[0148] Similar results were obtained in patients with baseline ALP levels below 250 IU / L. For example, in a patient group with baseline ALP levels below 200 IU / L and a baseline Halaby Prognostic Score (H) below 18, the measured hazard ratio is about 0.5 and the risk benefit is about 50%. In a patient group with baseline ALP levels below 150 IU / L and a baseline Halaby Prognostic Score (H) below 18, these values ​​are 0.46 and 55%, respectively, and in a patient group with baseline ALP levels below 100 IU / L and a baseline Halaby Prognostic Score (H) below 18, they are 0.46 and 56%.

[0149] Overall, these data demonstrate a strong beneficial effect of masitinib for treating mCRPC in patients with low baseline ALP levels (e.g., ≤250 IU / L) and / or low baseline Halaby score (H) (e.g., ≤33).

Claims

1. A pharmaceutical composition comprising masitinib, or a pharma- tically acceptable salt or solvate thereof, for use in the treatment of metastatic castration-resistant prostate cancer (mCRPC) in a subject in need thereof, wherein the subject has early stage mCRPC associated with (i) an alkaline phosphatase (ALP) level at baseline equal to or lower than 250 IU / L, or (ii) a Harabi Prognostic Score (H) at baseline equal to or lower than 33, or (iii) an ALP level at baseline equal to or lower than 250 IU / L and a Harabi Prognostic Score (H) at baseline equal to or lower than 33.

2. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has a baseline ALP level equal to or lower than 240, 230, 220, 210, 200, 190, 180, 170, 160, 150, 140, 130, 120, 110, or 100 IU / L.

3. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has a baseline ALP level equal to or lower than 200 IU / L.

4. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has a baseline ALP level equal to or lower than 150 IU / L.

5. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has a baseline ALP level equal to or lower than 100 IU / L.

6. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has a baseline Halaby Prognostic Score (H) equal to or lower than 32, 31, 30, 29, 28, 27, 26, 25, 24, 23, 22, 21, 20, 19, 18, 17, 16, or 15.

7. 2. The method of claim 1, wherein the subject has a baseline Halaby Prognostic Score (H) of less than or equal to 22.

8. 2. The pharmaceutical composition for use according to claim 1, wherein the subject has received a hormone therapy selected from the group consisting of luteinizing hormone releasing hormone (LHRH) agonists (also known as gonadotropin releasing hormone (GnRH) agonists), LHRH antagonists (also known as GnRH antagonists), and abiraterone.

9. 9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the pharma- ceutically acceptable salt of masitinib is masitinib mesylate.

10. 9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration at a dose in the range of about 1 to about 12 mg / kg / day (mg per kilogram of body weight per day).

11. The pharmaceutical composition for use according to claim 10, wherein the masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration at a dose ranging from about 3 to about 6 mg / kg / day.

12. 9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration at a dose of about 6 mg / kg / day.

13. 9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for oral administration.

14. 9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein said masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration taken twice daily.

15. 9. The pharmaceutical composition for use according to any one of claims 1 to 8, wherein the masitinib, or a pharma- ceutically acceptable salt or solvate thereof, is for administration with at least one further pharma- ceutical active agent.

16. 16. The pharmaceutical composition for use according to claim 15, wherein said at least one further pharma- ceutical active agent is selected from chemotherapeutic agents and corticoids.