BE1026758B1 - PHARMACEUTICAL COMPOSITION COMPRISING THIOCARBAMATE DERIVATIVES A2A INHIBITORS - Google Patents

Abstract

The present invention relates to a pharmaceutical composition comprising an A2A inhibitor of formula (I) or the pharmaceutically acceptable salts or solvates thereof, and a lipid vector such as lauryol macrogol-32 glycerides. The pharmaceutical composition of the invention is particularly useful for oral administration in the treatment of cancers.

Description

PHARMACEUTICAL COMPOSITION COMPRISING THIOCARBAMATE DERIVATIVES ΡΆ2Α

FIELD OF THE INVENTION

The present invention relates to a pharmaceutical composition comprising a thiocarbamate derivative as an adenosine A2A receptor inhibitor. The pharmaceutical composition of the invention is particularly useful for oral administration in the treatment of cancers.

BACKGROUND OF THE INVENTION

Many of the immunosuppressive mechanisms in tumors are common to physiological immunoregulation in normal tissues. This immunoregulation is very important to keep the immune system under control so as to block an auto-reactive immune response and prevent an ongoing immune response from causing critical tissue damage. The lack of physiological immunoregulation often results in overwhelming immune activation that accompanies autoimmunity. For example, CTLA-4 is a physiological mechanism that negatively regulates T cell activity by blocking a co-stimulation signal through the CD28B7 interaction. The absence of CTLA4 leads to activation of non-specific T lymphocytes, and mice deficient in CTLA-4 die within several weeks after massive lymphocyte infiltration of the tissues. PD-1 also provides a T-cell inhibitory signal after interaction with its ligands, PD-L1 and PD-L2. It is known that PD-1 deficiency in mice causes different types of autoimmune disorders depending on the genetic strains.

In addition to immunosuppressive signal transducers located on the cell surface, for example, CTLA-4 and PD-1, immunosuppression in the tumor microenvironment involves anti-inflammatory cytokines (IL-10, TGF-ß), enzymes (indoleamine-2,3-dioxygenase), and professional immunoregulatory cells (regulatory T lymphocytes, myeloid suppressive cells (MDSC)). These immunosuppressive mechanisms play an important role in regulating the immune response in normal tissue. Since tumors take advantage of these immunoregulatory mechanisms

BE2018 / 0103 physiological to protect their tissue from a massive immune attack, these mechanisms intended to prevent an inflammatory complication, are now proven to be major obstacles preventing spontaneous regression of cancer and immunological treatment of cancer. The identification of immunosuppressive mechanisms in tumors has revealed molecular targets to restore the anti-tumor immune response. Thus, these negative immunoregulatory mechanisms, called immune checkpoints, have become a center of attention in drug research. Antibodies to PDI, PDL1 or CTLA4 have been approved as cancer therapies for a large number of indications, such as metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, lymphoma. Hodgkin, head and neck cancer, urothelial carcinoma, hepatocellular carcinoma, as well as treatment for patients with solid tumors who have one of two specific genetic characteristics known as deficiency in mismatch repair and great microsatellite instability (regardless of the type of cancer).

Extracellular adenosine is known as an inhibitor of immune functions. While intracellular adenosine is involved in energy metabolism, nucleic acid metabolism, and the methionine cycle, extracellular adenosine plays an important role in intracellular signaling. Its signal is transmitted by adenosine receptors coupled to the G protein on the cell surface, and it affects various physiological functions including the neurological, cardiovascular, and immunological systems.

Tumors contain high levels of extracellular adenosine, suggesting that tumor cells may benefit from its immunosuppressive effect and production of catabolic energy (Allard et al., Curr. Opin. Pharmacol., 2016, 29, 7-16; Otta A., Frontiers in Immunology, 2016, 7: 109). This high level of extracellular adenosine is likely due to the overexpression of the CD73 enzyme, which is responsible for the production of extracellular adenosine. CD73 is overexpressed by a large number of tumors, all of the following tumors expressing moderate or high levels of CD73 in> 50% of the tumor surface by immunohistochemistry (www.proteinatlas.org): breast,

BE2018 / 0103 carcinoids, cervix, colorectal, endometrium, glioma, head and neck, liver, lung, melanoma, ovary, pancreas, prostate, kidney, gastric, thyroid, urothelial.

Among the four known types of adenosine receptors, the adenosine A2A receptor (A2AR) is the subtype mainly expressed in most immune cells. The stimulation of A2AR generally provides an immunosuppressive signal which inhibits the activities of T lymphocytes (proliferation, production of cytokines, cytotoxicity), NK cells (cytotoxicity), NKT cells (production of cytokines, upregulation of CD40L), macrophages / dendritic cells (presentation of antigens, production of cytokines), and neutrophils (oxidative explosion). The presence of high levels of extracellular adenosine in tumors has been shown to play a significant role in the escape of the anti-tumor immune response. In particular, it has been demonstrated in mice deficient in A2AR that the inoculated tumor could spontaneously regress, while no wild-type mouse exhibited similar tumor regression. A2AR antagonists have also been beneficial in wild-type animals with tumors. It is important to note that depletion of T lymphocytes and NK cells altered the delay in tumor growth by A2AR antagonists, suggesting an improvement in the cellular anti-tumor immune response. The effector functions of T lymphocytes and NK cells are susceptible to stimulation of A2AR. In addition, when activated in the presence of an A2AR agonist, the effector function of T cells remains impaired even after removal of the A2AR agonist. This result suggests that the environment rich in adenosine in tumors can induce T cells anergic to tumor cells.

Consequently, since the A2A receptor is expressed in most immune cells and in particular in effector immune cells such as T lymphocytes and NK cells and since the A2A receptor is engaged in tissues where adenosine is produced, it is assumed that 2A2 inhibitors may be useful in all indications of cancer.

Therefore, there is a need for A2A inhibitors capable of restoring immune functions in a tumor environment.

Adenosine is known to be an endogenous modulator of a number of other physiological functions. For example, in the nervous system

BE2018 / 0103 central (CNS), adenosine is known to induce sedative, anxiolytic and antiepileptic effects.

Thus, A2A inhibitors have previously been developed for the treatment of depression and neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease (Pinna A. CNS Drugs, 2014, 28,455). One of the most advanced A2A inhibitors developed for the treatment of CNS diseases is Preladenant (Hodgson RA et al., J. Pharmacol. Exp. Ther., 2009, 330 (1), 294-303 ; Hauser RA et al., JAMA Neurol., 2015,72 (12), 1491-500).

However, these previously developed A2A inhibitors have been designed to cross the blood-brain barrier to target the A2A receptor in the CNS.

Given the higher level of adenosine in tumors compared to the brain, much higher amounts of compounds will be required to achieve the desired effect on restoring immune functions for the treatment of cancer. Thus, in order to avoid unwanted side effects, provision should be made of A2A inhibitors which have limited CNS penetration, if any, unlike all of the A2A inhibitors developed to date.

The applicant has provided a series of non-brain A2A inhibitors in international patent application PCT / EP2018 / 058301, which are derivatives of thiocarbamate.

However, these compounds have very low solubility in aqueous buffers, low intestinal solubility and thus low oral bioavailability. Therefore, there is a need for a pharmaceutical formulation of these compounds which would be suitable for oral administration.

As highlighted in the experimental part below, the applicant provides by the present invention a pharmaceutical composition which makes possible the appropriate oral bioavailability of the A2A inhibitor thiocarbamates.

ABSTRACT

The invention therefore relates to a pharmaceutical composition comprising:

(a) a compound of formula (I) as defined below;

BE2018 / 0103 (b) lauroyl polyoxyl-32 glycerides; and (c) optionally one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants.

In one embodiment, the compound of formula (I) corresponds to the subformulas defined below, in particular to the formulas (la), (Ia-1), (la-la), (la-lb), (la-le ) or (la-ld). In one embodiment, the compound of formula (I) is one of those proposed in the list in Table 1 below. In a specific embodiment, the compound of formula (I) is selected from:

(R, S) -5-amino-3- (2- (4- (2,4-difluoro-5- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan -2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; and (+) - 5-amino-3- (2- (4- (2,4-difluoro-5- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan- 2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one.

In one embodiment, the pharmaceutical composition of the invention further comprises PEG400.

In one embodiment, the pharmaceutical composition of the invention further comprises caprylic acid.

In one embodiment, the pharmaceutical composition of the invention further comprises an antioxidant, which may for example be butylated hydroxytoluene (BHT).

In one embodiment, in the pharmaceutical composition of the invention, the compound of formula (I) is present in an amount ranging from 1% to 20% w / w, preferably from 5% to 15% w / w.

In one embodiment, in the pharmaceutical composition of the invention, the lauroyl polyoxyl-32 glycerides are present in an amount ranging from 55% to 99% w / w.

In one embodiment, the pharmaceutical composition of the invention comprises:

a) from 5% to 15% w / w of the compound of formula (I);

b) from 70% to 85% w / w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w / w of PEG400; and

d) optionally from 0.01% to 0.5% w / w of BHT.

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In one embodiment, the pharmaceutical composition of the invention comprises:

a) from 5% to 15% w / w of the compound of formula (I);

b) from 70% to 85% w / w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w / w of caprylic acid; and

d) optionally from 0.01% to 0.5% w / w of BHT.

In one embodiment, the pharmaceutical composition of the invention can be formulated in the form of capsules, tablets or granules.

The present invention further relates to a method of treating cancer, comprising administering to a patient in need thereof a therapeutically acceptable effective amount of a pharmaceutical composition according to the invention. In one embodiment, the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung, melanoma, ovarian, pancreatic, prostate, kidney, gastric, thyroid and urothelial cancers.

DEFINITIONS

In the present invention, the following terms have the following meanings:

The term "aldehyde" refers to a group -CHO.

The term "alkenyl" refers to an unsaturated hydrocarbyl group, which can be linear or branched, comprising one or more carbon carbon double bonds. Suitable alkenyl groups include between 2 and 6 carbon atoms, preferably between 2 and 4 carbon atoms, more preferably between 2 and 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2hexenyl and its isomers, 2,4-pentadienyl and the like.

The term "alkenylcarbonyl" refers to a - (C = O) -alkenyl group in which alkenyl is as defined in this document.

The term "alkenylcarbonylamino" refers to an -NH- (C = O) alkenyl group in which alkenyl is as defined in this document.

The term "alkoxy" refers to an -O-alkyl group in which alkyl is as defined in this document.

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The term "alkyl" refers to a hydrocarbyl radical of the formula C _n H2n + i in which n is a number greater than or equal to 1. Generally, the alkyl groups of this invention comprise from 1 to 8 carbon atoms, more preferred, the alkyl groups of this invention comprise from 1 to 6 carbon atoms. The alkyl groups can be linear or branched. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl groups.

The term "alkylaminoalkyl" refers to an -alkyl-NH-alkyl group in which alkyl is as defined in this document.

The term "alkylaminoalkylaminocarbonyl" refers to a group - (C = O) -NH-alkyl-NH-alkyl in which alkyl is as defined in this document.

The term "(alkylaminoalkyl) (alkyl) aminocarbonyl" refers to a group - (CO) -NR ¹ R ² in which R ¹ is an alkyl group and R ² is a group -alkylNH-alkyl, in which alkyl is such that defined in this document.

The term "alkylaminoalkylcarbonyl" refers to a group - (C = O) alkyl-NH-alkyl in which alkyl is as defined in this document.

The term "alkylcarbonyl" refers to a - (C = O) -alkyl group in which alkyl is as defined in this document.

The term "alkyl heteroaryl" refers to a heteroaryl group substituted by an alkyl group in which alkyl is as defined in this document.

The term "alkyloxycarbonyl" refers to a group - (C = O) -O-alkyl in which alkyl is as defined in this document.

The term "alkylsulfonyl" refers to a group -SOz-alkyl in which alkyl is as defined in this document.

The term "alkylsulfonealkyle" refers to an -alkyl-SCh-alkyl group in which alkyl is as defined in this document.

The term "alkylsulfonimidoyl" refers to a group -S (= O) (= NH) alkyl in which alkyl is as defined in this document.

The term "alkyl sulfoxide" refers to a - (S = O) -alkyl group in which alkyl is as defined in this document.

The term "alkylsulfoxydealkyl" refers to an -alkyl-SO-alkyl group in which alkyl is as defined in this document.

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The term "alkyne" refers to a class of monovalent unsaturated hydrocarbyl groups in which saturation results from the presence of one or more carbon-to-carbon triple bonds. Alkynyl groups typically, and preferably, have the same number of carbon atoms as described above with respect to alkyl groups. Non-limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers and the like.

The term "alkynealkyle" refers to an -alkyl-alkyne group in which alkyl and alkyne are as defined in this document.

The term "amino" refers to a group -NEL.

The term "aminoalkyl" refers to an -alkyl-NH group? in which alkyl is as defined in this document.

The term "aminoalkylaminocarbonyl" refers to a group - (C = O) NH-alkyl-NH2 in which alkyl is as defined in this document.

The term "aminoalkylcarbonylamino" refers to a group -NH (C = O) -alkyl-NH2 in which alkyl is as defined in this document.

The term "aminocarbonyl" refers to a group - (C = O) -NH2.

The term "(aminocarbonylalkyl) (alkyl) amino" refers to a group -NR'R ² in which R ¹ is an alkyl group and R ² is a group -alkyl- (C = O) -NH2 in which alkyl is as defined in this document.

The term "aminocarbonylalkylamino" refers to a group -NH-alkyl (C = O) -NH2 in which alkyl is as defined in this document.

The term "aminosulfonyl" refers to a group -SO2-NH2.

The term "antioxidant" refers to an agent that decreases or prevents the oxidation of other substances.

The term "aryl" refers to a polyunsaturated aromatic hydrocarbyl group having a single ring (in other words, phenyl) or multiple aromatic rings fused together (eg naphthyl), typically containing 5 to 12 atoms; preferably from 5 to 10; more preferably the aryl group is a 5- or 6-membered aryl group. Non-limiting examples of the aryl group include a phenyl, naphthalenyl group.

The term "carbonyl" refers to a group - (C = O) -.

The term "carbonylamino" refers to a group -NH- (C = O) -.

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The term "cycloalkyl" refers to a cyclic alkyl group, in other words, a monovalent, saturated, or unsaturated, hydrocarbyl group having 1 or 2 cyclic structures. Cycloalkyl includes monocyclic or bicyclic hydrocaibyl groups. The cycloalkyl groups comprise 3 or more carbon atoms in the ring and generally, according to the present invention, comprise from 3 to 10, more preferably from 3 to 8 carbon atoms; and even more preferably the cycloalkyl group is a 5- or 6-membered cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

The term "cycloalkyloxy" refers to an -O-cycloalkyl group in which the cycloalkyl group is as defined in this document.

The term "dialkylamino" refers to a group -NR'R ² in which R ¹ and R ² are both independently an alkyl group as defined in this document.

The term "dialkylaminoalkyl" refers to an -alkyl-NR * R ^{2 group} in which R ¹ and R ² are both independently an alkyl group, as defined in this document.

The term "dialkylaminoalkylaminocarbonyl" refers to a group (C = O) -NH-alkyl-NR'R ² in which R * and R ² are both an alkyl group, as defined in this document.

The term "dialkylaminoalkylcarbonyl" refers to a group - (C = O) alkyl-NR'R ² in which R ¹ and R ² are both an alkyl group, as defined in this document.

The term "dihydroxyalkyl" refers to an alkyl group as defined in this document substituted by two hydroxyl groups (-OH).

The term "halo" or "halogen" refers to a fluoro, chloro, bromo, or iodo group.

The term "heteroaryl" refers to an aryl group as defined in this document in which at least one carbon atom is replaced by a heteroatom. In other words, it refers to single aromatic rings with 5 to 12 carbon atoms or ring systems containing 2 rings which are fused to each other, typically containing 5 to 6 atoms; in which one or

BE2018 / 0103 several carbon atoms are replaced by oxygen, nitrogen and / or sulfur atoms, in which the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatoms can optionally be quaternized. Non-limiting examples of these heteroaryl groups include the groups: oxazolyl, thiazolyl, imidazolyl, furanyl and pyrrolyl. Preferably, the heteroaryl group is a 5- or 6-membered heteroaryl group, preferably the 5 or 6-membered heteroaryl group is a furyl group.

The term "heterocyclyl" refers to non-aromatic, fully saturated or partially unsaturated cyclic groups (for example, 3- to 7-membered monocyclic, 7 to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) at least one heteroatom in at least one ring containing carbon atoms. Preferably, the heterocyclyl group is a 5- or 6-membered heterocyclyl group. Each ring of the heterocyclic group containing a heteroatom can have 1,2,3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms can optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group can be linked to any heteroatom or carbon atom of the ring or cyclic system, when the valence allows it. The cycles of multi-cycle heterocycles can be fused, bridged and / or joined via one or more spiro-atoms. Non-limiting examples of such heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl, imidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl , 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl,

3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2Hpyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5dioximidazolidinyl, 2-oxopiperidinyl, 2- oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinoline, tetrahydroisoquinoline-1 -yl, tetrahydroisoquinoline-2-yle, tetrahydroisoquinoline-3-ylnol, tetrahydro-1-yloquinoline-1-yloquine yle, 1 -dioxydo-1 -thiomorpholin-4-yle, 1,3-dioxolanyl,

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1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolizinyl, tetrahydro-1,1dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl.

The term "heterocyclylalkylaminocarbonyl" refers to a group - (C = O) -NH-alkyl-heterocyclyl, in which alkyl and heterocyclyl are as defined in this document.

The term "(heterocyclyl) (alkyl) aminoalkyl" refers to a group -alkyl-NR'R ² in which R ¹ is an alkyl group and R ² is a heterocyclyl group in which alkyl and heterocyclyl are as defined in this document.

The term "heterocyclylcarbonyl" refers to a group - (C = O) heterocyclyl in which heterocyclyl is as defined in this document.

The term "heterocyclylalkyl" refers to a group -alkylheterocyclyl in which alkyl and heterocyclyl are as defined in this document.

The term "heterocyclyloxy" refers to an -O-heterocyclyl group in which heterocyclyl is as defined in this document.

The term "heterocyclylsulfonyl" refers to a group -SO2heterocyclyl in which heterocyclyl is as defined in this document.

The term "hydroxyalkyl" refers to a group -alkyl-OH in which alkyl is as defined in this document.

The term "hydroxyalkylaminoalkyl" refers to a group -alkyl-NHalkyl-OH in which alkyl is as defined in this document.

The term "hydroxycarbonyl" refers to a group -C (= O) -OH in which carbonyl is as defined in this document. In other words, "hydroxycarbonyl" corresponds to a carboxylic acid group.

The term "oxo" refers to a substituent = 0.

The term "sulfonylamino" refers to a group -NH-SO2.

The term "approximately" before a number means roughly 1% of the value of that number.

The term "administration", or a variant thereof (for example, "to administer"), means to provide the active agent or the active ingredient (for example, an A2A inhibitor), alone or as part of a pharmaceutically acceptable composition to the patient in whom the condition, symptom, or disease is to be treated or prevented.

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The term "IC50" or "50 inhibitory concentration" represents the concentration of an inhibitor that is required for 50% inhibition in vitro.

The term "inhibitor" refers to a natural or synthetic compound which has a biological effect to inhibit or considerably reduce or downregulate the expression of a gene and / or a protein or which has a biological effect of significant inhibition or reduction of the biological activity of a protein. Therefore, an "A2A inhibitor" refers to a compound that has a biological effect of significantly inhibiting or reducing or down-regulating the biological activity of the A2A receptor.

The term "human" refers to a subject of both genders at any stage of development (in other words, a newborn, an infant, a child, an adolescent, an adult).

The term "patient" refers to a warm-blooded animal, more preferably a human, who is waiting to be administered, or who is being administered, medical care or who is / will be the subject of a procedure. medical.

The term "pharmaceutically acceptable" refers to the ingredients of a pharmaceutical composition which are compatible with each other and not harmful to the subject to which it is administered.

The term "pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant" refers to a substance which does not cause other adverse, allergic or adverse reactions when administered to an animal, preferably a human. It includes any inactive substance such as, for example, solvents, cosolvents, antioxidants, surfactants, stabilizing agents, emulsifying agents, buffering agents, pH modifiers, preservatives (or preservatives), antibacterial and antifungal agents, isotonifying agents, granulating agents or binders, lubricants, disintegrating agents, slip agents, diluents or fillers, adsorbents, dispersing agents, suspending agents, coating agents, fillers, release agents, absorption delaying agents, sweetening agents, flavoring agents and the like. For human administration, preparations must meet standards of sterility, pyrogenicity, general safety and purity as required by regulatory offices such as, for example, the FDA or EMA.

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The term "premedication", as used in this document, means any compound which will be modified to form a kind of drug, the modification being able to take place inside or outside the body, and either before that the drug does not reach, either once it has reached, the area of the body where the administration of the drug is indicated.

The terms “prevent”, “preventive” and “prevention”, as used in this document, refer to a process intended to delay or prevent the declaration of a condition or disease and / or related symptoms, blocking the acquisition of a condition or disease in a patient, or reducing the risk of acquiring a condition or disease for a patient.

The term “prodrug” as used in this document means the pharmacologically acceptable derivatives of the compounds of formula (I), such as for example esters or amides, the biotransformation product of which generates the biologically active drug in vivo . Prodrugs are generally characterized by increased bioavailability and are readily metabolized to biologically active compounds in vivo.

The terms "treat" or "treatment" refer to therapeutic treatment; in which the object is to prevent or slow down the targeted disease or disease. A subject or mammal is successfully "treated" for a disease or condition or condition if, after receiving treatment according to the present invention, the subject or mammal exhibits an observable and / or measurable reduction in or an absence of '' at least one of the following: reduction of tumors; and / or relief to some degree, for at least one of the symptoms associated with the specific disease or condition; reduced morbidity and mortality, and improved quality of life. The above parameters for evaluating treatment success and disease improvement can be easily measured by routine procedures familiar to a doctor.

The term "volunteer" or "subject" refers to an animal, including a human. Within the meaning of the present invention, a subject may be a patient, in other words, an individual receiving medical attention, undergoing or having undergone medical treatment, or being subject to developmental monitoring.

BE2018 / 0103 of a disease. In one embodiment, the subject is a man. In another embodiment, the subject is a woman.

DETAILED DESCRIPTION

Pharmaceutical composition

The invention thus relates to a pharmaceutical composition comprising as a pharmaceutically active principle an A2A inhibitor, preferably being a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I) as described below, and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

In one embodiment, the pharmaceutical composition of the invention comprises an A2A inhibitor, such as a thiocarbamate derivative of formula (I) as described below, and at least one lipid vector. In one embodiment, the lipid vector is lauroyl polyoxyl-32 glycerides.

In one embodiment, the invention thus relates to a pharmaceutical composition comprising:

(a) a compound of formula (I);

or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ and R ² are as defined below;

(b) lauroyl polyoxyl 32 glycerides; and (c) optionally one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants.

Active ingredient

The pharmaceutical composition of the invention thus comprises, as a pharmaceutically active principle, a compound of formula (I):

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or a pharmaceutically acceptable salt or solvate thereof, wherein:

R ¹ represents a 5- or 6-membered heteroaryl group or a 5 or 6-membered aryl group, in which the heteroaryl or aryl groups are optionally substituted with one or more substituents selected from a C1-C6 alkyl group (preferably a group methyl) and a halo group (preferably a fluoro or chloro group); preferably R ¹ represents a 5-membered heteroaryl group; more preferably R ¹ represents a furyl group;

R ² represents a 6-membered aryl group or a 6-membered heteroaryl group, in which the heteroaryl or aryl groups are optionally substituted with one or more substituents selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino and alkylsulfonealkyl;

said substituents being optionally substituted with one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,

BE2018 / 0103 alkenylcarbonyl, alkynylcarbonyl, alkylsulfonyl and alkylsulfonealkyl;

alkylsulfoxide, alkylsulfoxydealkyl, or heteroaryl or aryl groups are optionally substituted with one or two substituents which together with the atoms to which they are attached form a 5 or 6-membered aryl ring, a 5 or 6-membered heteroaryl ring, a 5-membered cycloalkyl ring or 6-membered or a 5 or 6-membered heterocyclyl ring; optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl), heterocyclyl) (alkyl) aminoalkyl) , alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl , alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle.

In an embodiment, the preferred compounds of formula (I) are of formula (la):

or a pharmaceutically acceptable salt or solvate thereof, in which:

R ¹ represents a 5- or 6-membered heteroaryl group or a 5 or 6-membered aryl group, in which the heteroaryl or aryl groups are optionally substituted with one or more substituents selected from a C1-C6 alkyl group (preferably a group methyl) and a halo group (preferably a group

BE2018 / 0103 fluoro or chloro); preferably R ¹ represents a 5-membered heteroaryl group; more preferably R ¹ represents a furyl group;

X ¹ and X ² each independently represent C or N;

R ¹ 'is absent when X ¹ is N; or when X ¹ is C, R ¹ 'represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocycyllyl sulfonyl ;

said substituents being optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle;

R ² represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonylonylsulfonyl,

said substituents being optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl,

BE2018 / 0103 alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyle alkylsulfonyl and alkylsulfonealkyle;

or R ¹ and R ² together with the atoms to which they are attached form a 5 or 6-membered aryl ring, a 5 or 6-membered heteroaryl ring, a 5 or 6-membered cycloalkyl ring or a 5 or 6-membered heterocyclyl ring ; optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl), heterocyclyl) (alkyl) aminoalkyl) , alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl , alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle;

R ³ is absent when X ² is N; or when X ² is C, R ³ represents H or halo, preferably H or F;

R ⁴ represents H or halo, preferably H or F; and

R ⁵ represents H or halo, preferably H or F.

In a specific embodiment of the invention, R ¹ represents a 5 or 6-membered heteroaryl group or a 5 or 6-membered aryl group, in which the heteroaryl or aryl groups are optionally substituted by one or more substituents selected from among C1 to C6 alkyl group (preferably a methyl group) and a halo group (preferably fluoro or chloro). In a preferred embodiment, R ¹ represents a 5-membered heteroaryl group; more preferably, R ¹ represents a furyl group.

BE2018 / 0103

In a specific embodiment of the invention, X ¹ and X ² each independently represent C or N. In another specific embodiment, X ¹ and X ² both represent C.

In a specific embodiment of the invention, R ¹ is absent when X ¹ is N.

In another specific embodiment, when X ¹ is C, R ¹ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, aminosulfonyl , carbonylamino, sulfonylamino or alkylsulfonealkyle; said substituents being optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle.

In a preferred embodiment, the substituents R ¹ are optionally substituted with one or more substituents selected from halo, hydroxy, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl , alkylheteroaryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, heterocyclylalkylaminocarbonyl, (aminocarbonylalkyl) (alkyl) amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkaminaminocarbonyl

BE2018 / 0103 (alkylaminoalkyl) (alkyl) aminocarbonyl, heterocyclylcarbonyl, alkylsulfoxide and alkylsulfonealkyle.

In a specific embodiment of the invention, R ² ′ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterosycyllyl, alkylsulphonylsulfonyl , sulfonylamino, or alkylsulfonealkyle; said substituents being optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle.

In a preferred embodiment, the substituents R ² are optionally substituted with one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl, heteroaryl, alkyl heteroaryl, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminocarbonyl, alkylaminocarbonyl , dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyle.

In another specific embodiment of the invention, R ¹ and R ² form, together with the atoms to which they are linked, a 5 or 6-membered aryl ring, a 5 or 6-membered heteroaryl ring, a 5 or 6-membered cycloalkyl ring 6-membered or a 5 or 6-membered heterocyclyl ring; optionally substituted with one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl,

BE2018 / 0103 (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, aminocarbonylalkyl, aminoalkylcarbonyl, aminoalkylcarbonyl, alkyl , heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonyl.

In a specific embodiment of the invention, R ³ is absent when X ² is N. In another specific embodiment of the invention, when X ² is C, R ³ represents H or halo. In a preferred embodiment, when X ² is C, R ³ represents H or F.

In a specific embodiment of the invention, R ⁴ represents H or halo. In a preferred embodiment, R ⁴ represents H or F.

In a specific embodiment of the invention, R ⁵ represents H or halo. In a preferred embodiment, R ⁵ represents H or F.

In one embodiment, the preferred compounds of formula (la) are those of formula (Ia-1):

(Ia-1) or a pharmaceutically acceptable salt or solvate thereof, in which R ¹ , R ¹ ', R ² , R ³ , R ⁴ and R ⁵ are as defined in formula (la).

In one embodiment, the preferred compounds of formula (Ia-1) are those of formula (la-la):

BE2018 / 0103

O (Ia-la) or a pharmaceutically acceptable salt or solvate thereof, in which:

R ¹ and R ³ are as defined in formula (la): and

R ¹ ”represents an alkyl or heterocyclyl group substituted by one or more groups selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclic) ) aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl ) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle.

In a specific embodiment of the invention, R ¹ represents an alkyl or heterocyclyl group substituted by one or more groups selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl , alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylalkylamino, carbonylamino, carbonyl, aminocarbonyl, alkylcarbonyl, amino , dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,

BE2018 / 0103 alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle.

In a preferred embodiment, R ¹ represents an alkyl or heterocyclyl group substituted by one or more groups selected from hydroxy, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, (aminocarbonylalkyl) (alkyl) amino, aminoalkylaminocarbon , dialkylaminoalkylaminocarbonyl, heterocyclylcarbonyl, alkylsulfoxide,

In one embodiment, those of formula (la-lb):

aminocarbonylalkylamino, hydroxycarbonyl, aminocarbonyl, alkylaminoalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylsulfonealkyle.

the preferred compounds of formula (Ia-1) are

or a pharmaceutically acceptable salt or solvate thereof, in which:

R ¹ and R ³ are as defined in formula (la):

R ¹ represents H or halo, preferably H or F; and

R ² ”represents alkyl or heterocyclyl substituted by one or more groups selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocycyl) amino , heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl ,

BE2018 / 0103 alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle.

In a specific embodiment of the invention, R ¹ represents H or halo. In a preferred embodiment, R ¹ represents H or F.

In a specific embodiment of the invention, R ² ”represents alkyl or heterocyclyl substituted by one or more groups selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylalkylcarbonaminoalkylcarbonyl, carbonylamino, carbonylamino, alkylcarbonyl, alkyl dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkylsulfoxidealkylsulfoxideealkylsulfoxide

In a preferred embodiment, R ² ”represents an alkyl or heterocyclyl group substituted by one or more groups selected from hydroxy, cyano, heteroaryl, alkylheteroaryl, alkyne, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfoxide, alkylsulfoxide.

In one embodiment, the preferred compounds of formula (Ia-1) are those of formula (la-le) or (la-ld):

BE2018 / 0103

or a pharmaceutically acceptable salt or solvate thereof, in which:

R ¹ and R ³ are as defined in formula (la):

R ¹ represents H or halo, preferably H or F;

R ² represents H or halo, preferably H or F;

R ¹¹ or R ¹¹¹ each independently represent a hydrogen atom, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl alkyl, heteroaryl alkyl alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxydealkyl or alkylsulfonealkyle; and

R ²¹ or R ²¹¹ each independently represent a hydrogen atom, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl alkyl, heteroaryl alkyl alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,

BE2018 / 0103 alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyle, heterocyclylalkylaminocarbonyle, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonylalkylcarbonyl, dialkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkenylcarbonyl

In a specific embodiment of the invention, R ¹ represents H or halo. In a preferred embodiment, R ¹ represents H or F.

In a specific embodiment of the invention, R ² represents H or halo. In a preferred embodiment, R ² represents H or F.

In a specific embodiment of the invention, R ¹¹ or ^Rlu each independently represent a hydrogen atom, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alcynealkyle, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxydealkyl or alkylsulfonealkyle.

In a preferred embodiment, R ¹¹ or ^Rln each independently represent a hydrogen atom, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl or heterocyclylalkylaminocarbonyl.

In a specific embodiment of the invention, R ²¹ or ^R211 each independently represent a hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) atom. aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, aminocarbonyl, aminocarbonyl, alkyloxycarbonyl

BE2018 / 0103 heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxydealkyl or alkylsulfonealkyl.

In a preferred embodiment, R ²¹ or ^R211 each independently represent a hydrogen, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl or heterocyclylalkylaminocarbonyl atom. In a preferred embodiment, R ²¹ or ^ ¹¹ each independently represents a hydrogen, alkyl or dialkylaminoalkyl atom.

In one embodiment, the preferred compounds of formula (la) are those of formula (la-2) or (Ia-3):

(Ia-3) or a pharmaceutically acceptable salt or solvate thereof, in which R ¹ , R ² , R ³ , R ⁴ 'and R ⁵ are as defined in formula (la).

Particularly preferred compounds of formula (I) of the invention are those whose list is provided in Table 1 below.

TABLE 1

PC n ° Structure Chemical name MW 1 sY ° r-0 Ν ₅ Χγ ^Ν Ύ ^Ν \ _ ' ^N ' / \. _n / Y'NH X ⁷ N = N nh ₂ 3- (2- (4- (4 - ((1 H-1,2,3triazolo-4-yl) 2-methoxyfluorophenyl) piperazine-1 yl) ethyl) -5-amino- (8- (furan- 577.60

BE2018 / 0103

2-yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5- c] pyrimidine-2 (3H) -one 2 0, 0 Ν, Χ, νη ₂ N-xTZ ^ .. χθ-χ ^ Ο ^ζ νΛ ~ ο \\ '/ = Ζ Ν-ΝΗ F 5 - ((4- (4- (2- (5-amino-8 (fiiran-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) methyl) - 1,3,4-oxadiazol-2 (3H) -one 594.58 3 κ ° _Ν γΛγ νη ₂ F ^V - 'V ^ N 5-amino-3 - (2- (4- (3fluoropyridin-4yl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1 , 5c] pyrimidin-2 (3H) -one 481.51 4 0 S-Λ / □ Y / νη ₂ Η ₂ Ν Ζ ~~~ Ά ° ^? 0 \ == / ^F 2- (5- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4-e] [1,2,4]] triazolo [1,5- c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluorophenoxy) acetamide 571.56 5 s- / / ΝγΧ / Ν- ^ Λ ν- ^ν υ ^ν νη ₂ 1 'μ / = Λ / ^{S +} - - ^ Ό ~ ο “V (S) -5-amino-3- (2- (4- (2fluoro-4- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [ 5.4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 586.66

BE2018 / 0103

6 _S A zz '9 AZWA-pA Y Ν' ^Ν η ^ ^Ν F nh ₂ (R) -5-amino-3- (2- (4- (2fluoro-4- (2 (methylsulfmyl) ethoxy) phenyl) -piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5.4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 586.66 7 O-S + β-ά ζ Ί k / ' ^F A) Ν' ^ν υ ^ν f ^ νη ₂ (R, S) -5-amino-3- (2- (4- (2,4difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8 (fiiran-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 604.65 8a o ~ _s * ^z Z ΓΥα ί ί - KA ^{f 1} ΟΝ ' ^Ν γ ^Ν F ^ νη ₂ (+) - 5-amino-3- (2- (4- (2,4difluoro-5- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-1 -yl) ethy 1) - 8 (furan-2-yl ) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 604.65 8b 'W ρ ZV / ⁿ zA ^zN ^ ^N O ⁿ Y ^ ΓΥυ ί ί KA ^f Υ ^ Λ'ΝγΝ νη ₂ (-) - 5-amino-3- (2- (4- (2,4difluoro-5- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2-yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 604.65 9 0 Γ1Α Λ _ ΓΎΑυ οη V ^ - ^N A. X < ^Ν ~ (ΥΥ Ν ΝΗ ₂ 1-0 5-amino-8- (furan-2-yl) -3 (2- (4- (4- (4- (2-hydroxyethoxy) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4- 522.58

BE2018 / 0103

e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 10 0 h ₂ n £ Y ° ^ oh NN \ _Λ Ji J A / ^V o sM ₀ acid 2- (4- (4- (2- (5-amino8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- 3 (2H) yl) ethyl) piperazin-1 yl) phenoxy) acetic 536.56 11 0 M nARU / I ^ nh ₂ ΙΛΛ-ΝγΝ ^{: = /} ^ ° ° nh ₂ 2- (4- (4- (2- (5-amino-8 (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- 3 (2H) yl) ethyl) piperazin-1 yl) phenoxy) acetamide 535.58 12 o S-Λ / -, HO / N —— / N; z2 ~ M \ <7 ^Ν Ά zY Μ \ -ΝγΝ \ _qh nh ₂ 5-amino-3- (2- (4- (4- (2,3dihydroxypropoxy) phenyl) p ipérazin-1 -yl) ethyl) -8- (furan-2-yl) thiazolo [5,4e] [l, 2,4] triazolo [l, 5c] pyrimidin-2 (3H) -one 552.61 13 s / ° _r O /./ ^H2 ΥΥΰγΝ // ° nh ₂ 5-amino-3- (2- (4- (4- (2 aminoethoxy) phenyl) pipera zin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4-e] [1,2, 4] triazolo [1,5c] pyrimidin-2 (3H) -one 521.60 14 s / ° M, Ο Ν _β γΛγ ^{Ν /} V_z ^N Z '1, ^N H2 Μ \ -ΝγΝ ^{X === /} O nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-lyl) benzamide 505.55

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15 s- / Z r'WS'Ÿ 0-0 ”- nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -Nmethylbenzamide 519.58 16 Γ-Λ Z // ^N 0N N — G // O Γ nZ v_7 0 5-amino-8- (fiiran-2-yl) -3 (2- (4- (4- (4- (2morpholinoethoxy) phenyl) p ipérazin-1- yl) ethyl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 591.68 17 0 S- \ Z ~ z 0 / N ^ 4 ^ ^N ^ ^N 0 ^N -fY y / —VZ μ L / o 0 N ' ^N y ^N \ ^NH 2 5-amino-3- (2- (4- (4- (2 (dimethylamino) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8 (fiiran-2-yl) thiazolo [5,4e] [1 , 2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 549.65 18 0 0/0 0Ν0Λ 0 00γ ^Ν 00S'NH ₂ nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 yl) benzenesulfonamide 541.61 19 s ^ ° 0 _Π Ν0 ^ 00 0 kH-V ^ 0'h nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5-c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -Nmethylbenzenesulfonamide 555.63

BE2018 / 0103

20 o s ~ \ ^ 0, \, N ~ / 0 CM V "'nh ₂ 5-amino- 8 - (furan-2-yl) -3 (2- (4- (4- (4- methyl-sulfonyl) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 540.62 21 0 9 ~ Λ Τ '/''' Z-, n ^ / Ln- ⁷ Μ / ^ν '/ Λ / L ^ V ^N y ^N ®6 nh ₂ 5 -amino- 8 - (fiiran-2-yl) -3 (2- (4- (4- (methylsulfinyl) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 524.62 22 s- / / M M n ' ⁿ m ⁿ k 1 Mnh ₂ nh ₂ 0 3- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 yl) benzamide 505.55 23 H ° ΐτΑ / νΎ% ν ' ^ν ψ ^ν μ 7h ₂ ° ^ ^oh 5-amino-8- (furan-2-yl) -3 (2- (4- (3- (2-hydroxyethoxy) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 522.58 24 / 0 / '' NH S— \ / Ά \) _r o _x nX- ^ U / Vx CM'Nyi ° nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4- (2-oxo-2- (piperazin-1 yl) ethoxy) phenyl) piperazin- 1 -yl) ethyl) -8- (fiiran-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 622.67

BE2018 / 0103

25 s0 ° H / - »NN jL0 ~ O 0 Ν ' ^Ν γ ^Ν 0/0 nh ₂ V ^ nh 5-amino-3- (2- (4- (2-fluoro- 4- (piperidin-4-ylmethoxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 593.68 26 0 S ~ \ y—> ZNH ^N γ Fo nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4- (piperazine-1 -carbonyl) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H ) -one 592.65 27 0 ⁷ - \ rM-rV ^ - ^ Ao O ^H O N ' ^N ^ ^N F' - 'nh ₂ 5-amino-3 - (2- (4- (2-fluoro- 4- (2- (piperazin-1 yl) ethoxy) phenyl) piperazin- 1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [l, 2,4] triazolo [l, 5- c] pyrimidin-2 (3H) -one 608.69 28 s / ° ^ ΝγγΑ? · Α \ 0 Ay fAO ^h nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4- (piperazin-lylsulfonyl) phenyl) piperazin -1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 628.70 29 s / ° / 0 ^F \ C / A Ύ i 0/0 0 Ν ' ^Ν γ ^Ν 0 nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4- (methylsulfonyl) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4- 558.61

BE2018 / 0103

e] [1,2,4] triazolo [1,5- c] pyrimidin-2 (3H) -one 30 / PF _x S — X / Λ V Μβ'ΝγΝ ^^ 0 nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -N (2-aminoethyl) -3fluorobenzamide 566.61 31 o s— \ / -. '- \ (rYAT'S ⁷ nX ~~ n ^Z M ^ _n -n _t n nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluoro-N- (2 (methylamino) ethyl) benzamide 580.64 32 sZ ° / ~ Λ ß, W OfL “-zf ^ Ν'ΝγΝ> ^ ₀ nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -N (2- (dimethylamino) ethyl) -3fluorobenzamide 594.66 33 0 ₀ Ν _Ύ Λγ ^Ν ' ^ν ' ^Ν Ο? ^Ν - '/ Λ, Ν-Ζ'ΟΗ Μβ ^ ΝγΝ nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -y 1) -3 fluoro-N- (2hydroxyethyl) benzamide 567.60

BE2018 / 0103

34 sZ ° L nh ₂ Xoh OH 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -N (2,3 -dihydroxypropyl) -3 fluorobenzamide 597.62 35 s- / ^F \ _ uXOΛ ^ ^0H C / NN Λ / ⁰ Q ^ 0 Ν ' ^Ν γ ^Ν nh ₂ acid 2- (4- (4- (2- (5-amino- 8- (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) acetic 554.55 36 s- / V vM ^ UΛ w ^0H r / —4 iyy = / ° o% Ν ' ^Ν ψ ^Ν F NH ₂ acid 2- (4- (4- (2- (5-amino8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- 3 (2H) -yl) ethyl) piperazin-1-yl) -3.5 difluorophenoxy) acetic 572.54 37 0 ν ^ Α / ^ν ^ ^ν Ο ^ν λΓΧ Γ y - <\ Λ ~ ζ? N ' ^N Y ^N F / ^ COOH nh ₂ acid 2- (4- (4- (2- (5-amino- 8- (furan-2-yl) -2oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) propanoic 568.58 38 o S'A Z--, Γ \ -Λ Z ί 7-Z ~ 9 ^ 0 N ' ^N \ ^ ^N F _c ' COOH nh ₂ acid (S) -2- (4- (4- (2- (5 amino-8- (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) - 568.58

BE2018 / 0103

yl) ethyl) piperazin-1 -y 1) -3 fluorophenoxy) propanoic 39 Z / ° F, o nUj ^ O-A'Aî ⁰ U% -M ⁰ nh ₂ acid 2- (4- (4- (2- (5-amino8- (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -y 1) -3 fluorophenoxy) -2methylpropanoic 582.61 40 0 s ~ {/ \ cwX ^v iX ^ 0 N ' ^N Y ^N F ^ -COOH nh ₂ acid 3- (4- (4- (2- (5-amino- 8- (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5- c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -y 1) -3 fluorophenyl) propanoic 552.58 41 0 S— \, 0H _<Οχ ν _<ύ Λ / ^ν ^ VxYX / '- K, Μ'Λ-ΝγΝ nh ₂ acid 4- (4- (4- (2- (5-amino8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- 3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) butanoic 582.61 42 0 n _{= ï <} X _î / ⁿ ~ ^^ ^ 'Y /% ^NH ' Kh 0 acid 2- (3- (4- (2- (5-amino8- (furan-2-yl) -2oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2,6difluorophenoxy) acetic 572.54

BE2018 / 0103

43 0 s- / <- 'Λ _z oJ ^ ^OH ί Μ Ί Ί K / ^ F Ζ / \ - ΝγΝ (Ζ νη ₂ acid 2- (5- (4- (2- (5-amino- 8- (fiiran-2-yl) -2oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2, 4difluorophenoxy) acetic 572.54 44 ο r ^o v, ^N ZY ^N ~ ^x 'V / ^N ' / ~ Vz ^0H Λα νη ₂ acid 4- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorobenzoic acid 524.53 45 ο ν ”~ ΛνΗ! ολ V Λ ^ ⁰ νη ₂ 2 - ((2- (4- (4- (2- (5-amino-8 (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1, 5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -y 1) - 3 fluorophenoxy) ethyl) amino) acetamide 596.64 46 Η ° \ ° "N ^ V ^ V / N-Tl Ν ^ ΝΗ ₂ ϋ / -Μ Μ Χ / ^ 0 ^Ζ <0 Ν ' ^Ν γ ^Ν / νη ₂ 2 - ((2- (4- (4- (2- (5-amino-8 (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1, 5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) ethyl) (methyl 1) amino) acetamide 610.66 47 0 n ^ JL ⁿ ^ Ox ^ v Ç ^ A ' ⁿ y ⁿ νη ₂ V / Ν Η 5-amino-3- (2- (4- (2-fluoro- 4- (piperidin-4-yloxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2-yl) 579.65

BE2018 / 0103

thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin2 (3H) -one 48 0 ^s ' z- ~ '- \ Γ / -NN Xz ⁰ A Ν' ^Ν γ ^Ν \ ^NH * Vnh 5-amino-3- (2- (4- (2-fluoro- 4- (pyrrolidin-3yloxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 565.62 49 0 ^s Z--, _[Γ ζΝ _Ύ γ ^Ν VX / - YSh n ' ⁿ y ⁿ _f X ° y nh ₂ 3- (2- (4- (4 - ((1H-l, 2,4- triazol-3-yl) methoxy) -2fluorophenyl) piperazin-1 yl) ethyl) -5-amino-8- (furan- 2-yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5- c] pyrimidin-2 (3H) -one 577.59 50 0 nX ^ G ƒ! Γ> -NNA / ⁰ 0 A Ν ' ^Ν γ ^Ν F nh ₂ 2- (4- (4- (2- (5-amino-8 (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- 3 (2H) yl) ethyl) piperazin-1 -yl) -3fluorophenoxy) -N- (2 (methylamino) ethyl) acetamide 610.66 51 sY ° ΝγΥ ^Ν η F Vl'Y L ^N X ^NH 2 HN- ~. \ 2- (4- (4- (2- (5-amino-8 (furan-2-yl) -2-oxothiazolo [5,4-e] [l, 2,4] triazolo [l, 5c] pyrimidin- 3 (2H) -yl) ethyl) piperazin-1 -y 1) -3 fluorophenoxy) -N- (2 (dimethylamino) ethyl) 624.69

BE2018 / 0103

acetamide 52 o Ko ƒ ïï γ 'Λ. / Γ -Λ nV-nh ₂ Y - ⁿ F / χχ ^N nh ₂ Vq 2- (4- (4- (2- (5-amino-8 (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- 3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) -N- (2 aminoethyl) acetamide 596.64 53 0 nK ⁿ ^ OYY ΓΥλ ί ί) l / o ~ Ο Ν ' ^Ν γ ^Ν FY ~ COOH νη ₂ acid (R) -2- (4- (4- (2- (5 amino-8- (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5- c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -y 1) -3 fluorophenoxy) propanoic 568.58 54 0 SK Fy - <\ ί Ύ Λ-ζ 9 Ν ' ^Ν γ ^Ν F ^V CONH ₂ νη ₂ 2- (4- (4- (2- (5-amino-8 (fiiran-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- 3 (2H) -yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) acetamide 553.57 55 0 rV / N Υγ ^Ν ^ Κ ^Ν ^ 0 Ν ' ^Ν γ ^Ν f ^ o νη ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -y 1) -3 fluoro-N-methyl-N- (2 (methylamino) ethyl) benzamide 594.66 56 Λ ζ Y Ν ' ^Ν γ ^Ν F 0 νη ₂ 4- (4- (2- (5-amino-8- (furan- 2-yl) -2-oxothiazolo [5,4- e] [1,2,4] triazolo [1,5- 608.69

BE2018 / 0103

c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -N (2- (dimethylamino) ethyl) -3fluoro-N-methylbenzamide 57 _s 0 ° 0 / 00'00 /% Ν ' ^Ν γ ^Ν 0 nh ₂ (R) -4- (4- (2- (5-amino-8 (fiiran-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1 -yl) -N- (1 (dimethylamino) propan-2yl) -3 -fluorobenzamide 608.69 58 θ Vvo S ^A N-0 _N ^/ 3 ^N ^ ^r - X - ^N— (/ 0 ^N NH ₂ vo 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) -N-methylN- (2- (methylamino) ethyl) acetamide 624.69 59 O 0 S- ^ z ^ _N 0 0 \ __ _/ N0 ⁼ 0 l 'P / * - μ μ L / F 0 n'N ^ n _f 0 / nh ₂ acid 2- (5- (4- (2- (5-amino8- (fiiran-2-yl) -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [1,5c] pyrimidin- 3 (2H) yl) ethyl) piperazin-1 -yl) -2,4 difluorophenoxy) -2 methylpropanoic 600.60 60 / 9 COOH S-Λ / - λ z ° -, ^Ν · ζ / ζ ^{Νν Ν} </ ^Ν 0Κ ¹ 000 I ^ ⁷ 0 ^F ' ^L o n- ⁿ zN 0 nh ₂ acid (S) -2- (5- (4- (2- (5- amino-8- (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2,4- 586.57

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difluorophenoxy) propanoic 61 / 9 „COOH S '\' \ ΓΥλ y 1 YY ~ ^F 0 N ' ^N Y ^N f nh ₂ acid (R) -2- (5- (4- (2- (5 amino-8- (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluorophenoxy) propanoic 586.57 62 „H 0 z --- / ^N '~ ^S_J \ Z ~~ A 0- / N / N - / ^ ^N 1. ^ = / H, nYy V / ^N Y \ i | 2— <x 1 1 /} - f Y n ' ⁿ y ⁿ nh ₂ 2- (5- (4- (2- (5-amino-8 (fiiran-2-yl) -2oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) - yl) ethyl) piperazin-1 -yl) -2,4 difluorophenoxy) -N- (2 (methylamino) ethyl) acetamide 628.65 63 \ 0 N ~, o ÏL / —z K z ~ n ^/ Y ΓVYx Ί Ί Kz ~ ^F % N ' ^N Y ^N F ^Z nh ₂ 2- (5- (4- (2- (5-amino-8 (fiiran-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- 3 (2H) yl) ethyl) piperazin-1 -yl) -2,4 difluorophenoxy) -N- (2 (dimethylamino) ethyl) acetamide 642.68 64 \ N— O ~~ N A / = A ⁰ ΓΥλ yy Y N ' ^N Y ^N f ⁷ ^ nh ₂ 5- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -N- 626.69

BE2018 / 0103

(2- (dimethylamino) ethyl) - 2,4-difluoro-Nmethylbenzamide 65 O COOH s-Λ Μ ζ ° ~ ^ Γυμ j V / -F “'ο'Ν'ΝγΝ F νη ₂ acid 4- (5- (4- (2- (5-amino8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- 3 (2H) yl) ethyl) piperazin-1 -yl) -2,4 difluorophenoxy) butanoic 600.60 66 Λτ Υ ^Ν _Η γ) = Ν NM Η ₂ Ν Λ / π ΗΝ ~ Ν Γγ ° ^ Λ, Ν fAa ^ν F 3- (2- (4- (5 - ((1H-tetrazol-5yl) methoxy) -2,4difluorophenyl) piperazin-1 yl) ethyl) -5 -amino-8 - (furan2-yl) thiazolo [5,4 - e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 596.58 67 s / ° Μ L. / \ ^χ NA Ν ^_ Ν 0 Ν ' ^Ν γ ^Ν F \ νη ₂ 5-amino-3- (2- (4- (2-fluoro4 - ((1-methyl-1H-1,2,4-triazol-3-yl) methoxy) phenyl) piperazin-1 yl) ethyl) -8- ( furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 591.62 68 ν ^ ν- Ρ < ^Ν 'Γυα' 1 1Y ^{F L} '0 ^/ ' Ν ' ^Ν γ ^Ν F ^Z νη ₂ 5-amino-3- (2- (4- (2,4difluoro-5 - ((1-methyl-1Hl, 2,4-triazol-3-yl) methoxy) phenyl) piperazin- 1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [l, 2,4] triazolo [l, 5- 609.62

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c] pyrimidin-2 (3H) -one 69 sF ° D ^o N ' ^N Y ^N f ^ o nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl ) ethyl) piperazin-1 -yl) -3 fluoro-N- (2- (methyl (oxetan-3 -yl) amino) ethyl) benzamide 636.70 70 0 θΛ / -ZX z ^ / ^0H ννγ ZT nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluoro-N- (2 - ((2hydroxyethyl) amino) ethyl) b enzamide 610.67 71 sF ° / λ ₀ / - JzC ^NH2 ϋΚ'ΝγΝ K '~ ° ° nh ₂ 2-amino-N- (2- (4- (4- (2- (5 amino-8- (fiiran-2-yl) -2oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) ethyl) acetamide 596.64 72 0 _F h ₂ n _r o _x vH V \ 'ί Η Ί Ϊ ΥΛ0 0 nh ₂ (S) -2-amino-N- (2- (4- (4- (2 (5-amino-8- (fiiran-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) ethyl) -3 - 638.72

BE2018 / 0103

methylbutanamide 73 0 ƒ nA'Î yy ΛτΥ ^ν U Ν ' ^Ν γ ^Ν νη ₂ θ ^ ΟΟΟΕί XA ^f F 2- (5- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin- 3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4 difluorophenoxy) ethyl acetate 600.60 74 A ο ^ γΥΖγ ^{0 n} 'N7- ⁿ _v __} = Ν Ν' Η ₂ Ν 1 F ^ Y, F 2- (5- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluorophenoxy) acetonitrile 553.54 75 0 ^s Ο _χ _ _/ NyY ' ^N ^ ^z νη ₂ Ά \ V / ^Ν ~ τ w Z / ^N 5-amino-8- (furan-2-yl) -3- (2- (4- (pyridin-4-yl) piperazin-1yl) ethyl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 463.52 76 0 ^s - \ _ ^ Ν _ΐ γΑγ ^Ν ~~ ^/ νη ₂ AY \ _z ^N ~ v "U 5-amino-8- (furan-2-yl) -3 (2- (4- (pyrimidin-4yl) piperazin-lyl) ethyl) thiazolo [5,4e] [1,2,4] triazolo [1,5c ] pyrimidin-2 (3H) -one 464.50

BE2018 / 0103

77 00 tA _N 'NyN nh ₂ 5-amino-3- (2- (4- (2,4difluoro-5- (2 (methylsulfonyl) ethoxy) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5, 4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 620.65 78 , O s-ΐ / 0 V nJv ^ GAv A Α_ά ί ί VA ° N ' ^N xj0 F nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4- (2- (methylsulfonyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 602.66 79 0 S0 0 Ν07 ^Ν Ά N-00/0 ° V00 ' ^N Y ^N nh ₂ 5-amino-3- (2- (4- (6-fluoro2-oxoindolin-5yl) piperazin-1 -yl) ethyl) -8 (furan-2 -yl) thiazolo [5,4e] [1,2,4 ] triazolo [1,5c] pyrimidin-2 (3H) -one 535.55 80 ƒ f S0 V nA ⁿ ^ 0 ⁿ Al <ph \ s ___ / 1 1 \ __ z ^ S 0 Ν ' ^Ν η ^ ^Ν NH nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4- (Smethylsulfonimidoyl) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 557.62 81 \ V / 0 HN sA z ^ 0 ν / κι N »θ <θ ⁿ Av U à-» Μ M A0 ^ F 0 / _Ν -ΝγΝ nh ₂ 5- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -N- 612.65

BE2018 / 0103

(2- (dimethylamino) ethyl) - 2,4-difluorobenzamide 82 nh ₂ > Λν n ^ nV ⁿ / ^s O 5-amino-3 - (2- (4- (5-fluoro2-methylpyridin-4yl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1,2,4 ] triazolo [1,5c] pyrimidin-2 (3H) -one 495.53 83 <n ζθ ^ ⁰ »// / n ~ n yN ^ -) = NN \ h ₂ n / / VN Vy ^H Q οΎ3 ° 5-amino-3- (2- (4- (2-fluoro- 4 - (((3R, 4R) -4hydroxytétrahydrofuran-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 582.61 84 / n nm. h ₂ n / / VN Xfv ^ O '<O 5-amino-3- (2- (4- (2-fluoro- 4 - (((3S, 4S) -4- hydroxytetrahydrofuran-3yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (ftiran-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 582.61 85 r? W \ _N S ^ o N -N ____) = NN ^ X H ₂ N / / F Q ovy HO 5-amino-3- (2- (4- (2-fluoro- 4- (2-hydroxy-2methylpropoxy) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 568.62

BE2018 / 0103

86 0? λ / —iX'T / = ¾ / ^ν Ύ \ / ^οη ιΓΥ-ζα ύ κλ / Λ / ν ^Ν γ ^Ν / \ νη ₂ 5-amino-3- (2- (4- (2-fluoro4- (2-hydroxypropan-2yl) phenyl) piperazin-1 y l) ethy 1) - 8 - (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 538.60 87 Γ ° \ Ν_S ^ O Ν - _Ν 'y- Ν) = Ν ΝΧ Η ₂ Ν / / F Ϊ7 \ = Χ ε qoY-f HO ^F 5-amino-3- (2- (4- (2-fluoro- 4- (3,3,3-trifluoro-2hydroxypropoxy) phenyl) pip erazin-1 -yl) ethyl) -8- (furan2-yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5- c] pyrimidin-2 (3H) -one 608.57 88 HO sf / 0 Ν γΧγ ^Ν ~ Χ) Λ / Α-ΝγΝ _f AX νη ₂ 5-amino-3- (2- (4- (2-fluoro- 5- (2hydroxyethoxy) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5- c] pyrimidin-2 (3H) -one 540.57 89 ƒ F '? -Λ /-./T V. C ^ X'NyN ^F X γ _ο ηνΧ 5-amino-3- (2- (4- (2,4difluoro-5- (morpholin-2ylmethoxy) phenyl) piperazin -1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 613.64 90 ^Η Ο 0 ( ⁷ \ ⁰ [-0. ^Ν -γ ^ Χγ ^Ν '~ ^' ^Ν \ __ '' -Μ-γ-ι X ^f Η ₂ Ν 5-amino-3- (2- (4- (2,4difluoro-5 - (3-morpholinylmethoxy) phenyl) piperazine-1 -yl) ethyl) -8- (furan-2- 613.64

BE2018 / 0103

yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5- c] pyrimidin-2 (3H) -one 91 HN ^ \ r nh ₂ L>' ^{f k} o ν ^ \ Λ A //! \ N- ^ V / -F MF 0 5-amino-3- (2- (4- (2,4difluoro-5 - (((3S, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl ) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 601.60 92 0 _S X ^F y-, n = A <Hj-vt .nT o \\ / NT ___ ƒ ^ -0 NH ₂ / \ ΗΝ ^ / Λ-F 5-amino-3- (2- (4- (2,4difluoro-5 - (((3S, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl ) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 601.60 93 H 0 ^ -N sA I) / - Λ ^F />'' -o n- ⁿ ^ ⁿ Vz-zZ nh _{2 f} / - ' 5-amino-3- (2- (4- (2,4difluoro-5 - (((3R, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl ) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 601.60 94 H A, .ö (Τν ^ ^Ν Ύ \ ^Ν Ύ ^ ^F > ^ óN ' ^N a * ^N 1 V // - V nh _{2 f} / ^ / 5-amino-3- (2- (4- (2,4difluoro-5 - (((3S, 4R) -4fluoropynolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2 - 601.60

BE2018 / 0103

yl) thiazolo [5.4e] [1.2.4] triazolo [1.5c] pyrimidin-2 (3H) -one 95 H r- ^N > = 0 ο Y / S'A \ 0 γ Ν _{; ϊ} γΧ ^Ν '~ ^ ίΧ'ΝγΝ _f XXf νη ₂ (S) -5-amino-3- (2- (4- (2,4difluoro-5 - ((2oxopyrrolidin-3yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [ 5.4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 597.60 96 ΗΝγ f- \ / ~ 'Ν ^Ζ ' Υ ζ ° ν ^ ζΥζ ^ν '~ ^/ νη ₂ (R) -5-amino-3- (2- (4- (2,4difluoro-5 - ((2oxopyrrolidin-3yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [ 5.4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 597.60 97 ^ο Ο ^ν Λ Υνη sY ° ° î} ° _ nXJn ^ O Χί ΡΥγΎΥ 1X ^F YVy f ⁷ ^ νη ₂ 2- (5- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4e] [1,2,4]] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluorophenoxy) -N- (2morpholinoethyl) acetamide 684.72 98 J? ^F \ SY ζ ^ κ / Υ V νΧ / ^ν ^ Χ ^ν Χ \ β-ο ί 1X ^f ν-Υ ^ν γ 1 Υνη νη ₂ 0 \ Ο ^Η 5- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2.4- 640.66

BE2018 / 0103

difluoro-N- (3-morpholinylmethyl) benzamide 99 0 S- ^ F Ï / ^N ^ / - \ \ V0 Ν '0 - () nh ₂ ' —o 5-amino-3- (2- (4- (2-fluoro- 4- (morpholin-3ylmethoxy) phenyl) piperazine -1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 595.65 100 p 0 ^F \ N ' ^N 0 ^{N 7} 0 ⁷ Ïh ₂ ^h 5-amino-3- (2- (4- (2-fluoro- 4- (morpholin-2ylmethoxy) phenyl) piperazine -1 -yl) ethyl) -8- (fiiran-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 595.65 101 0 S— \ r-Λ / ^N 0 '^ ï ^zN 0 Z —- X ^F \ ^F - 0 0 n- ⁿ v ⁿ \ 0 T ^ - ⁷ L0 nh ₂ 5-amino-3- (2- (4- (2-fluoro4 - (((3R, 4R) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethy 1) - 8 - (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 583.61 102 s ^ ° Ν ^ / ^Ν Λ _ ^F \ F ^ 0 Au 1 Ί 00 0 V NH 0 _Ο ^Κ Ν'ΝγΝ nh ₂ - 5-amino-3- (2- (4- (2-fluoro- 4 - (((3 S, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 583.61

BE2018 / 0103

103 o ^s \ (ΑΜΑ f ⁰ nn ^ n \ ^F x ^ / VT NH H ₂ N Uo ^ 5-amino-3- (2- (4- (2-fluoro4 - (((3R, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5.4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 583.61 104 0 sY ^F \ R. ^ f VY y 1 w \ Y, \ ^NH An ' ⁿ v ⁿ ύΆ Y ⁷ T - VY ~ o nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4 - (((3 S, 4R) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 583.61 105 Vy ⁿ _w ^s y ° Ν'Ν'ΥΝ ^) = N NX ^H2N Yn JA F AA U 0Ύ ^ Ν _χ ___ 0 ^ 0 2- (4- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5- c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) -N- (2morpholinoethyl) acetamide 666.73 106 0 ^Ν Υ _ν ^Ν ^ ^Ν '3 ^Ν -γ \ nV'A β-Ο ί YA Y / V ^N Y ^N o nh ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluoro-N- (2morpholinoethyl) benzamide 636.70

BE2018 / 0103

107 s-Ï ° <° λ ΓΥ- <ττ ί 1. ^Η νΥΝγΝ νη ₂ 4- (4- (2- (5-amino-8- (furan2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3fluoro-N- (morpholin-3ylmethyl) benzamide 622.67 108 0 SX S ~~ \ ι-ΝΗ _<0 K ⁿ Kl ρ CY ^ N-ΝγΝ Y / ⁰ νη ₂ 5-amino-3- (2- (4- (4 (azetidin-3yloxy) phenyl) piperazin-1 yl) ethyl) - 8 - (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 533.61 109 Ρ Ό S-Λ χ ^ μ ^Ζ ^ Λ X, _r O ΝίΥγ Υ / ^Ν ΛΙ ΚΑ- ^Ν γ ^Ν _f KKf νη ₂ (S) -5-amino-3- (2- (4- (2,4difluoro-5- (methylsulfinyl) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 560.60 110 Ρ '9 ΥΚγγΝ _f \ Kf νη ₂ (R) -5-amino-3- (2- (4- (2,4difluoro-5- (methylsulfinyl) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 560.60

BE2018 / 0103

111 Ό VV ^N Y ^N F nh ₂ 5-amino-3- (2- (4- (2,4difluoro-5 - (((1 s, 4s) -1 oxydotetrahydro-2Hthiopyran-4yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- ( furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 630.69 112 Ό 7 S-χ .0 rV / ^N vV ^N ~ ^ K ⁿ KX _f % N ' ^N Y ^N nh ₂ 5-amino-3- (2- (4- (2,4difluoro-5 - (((lr, 4r) -1 oxydotetrahydro-2Hthiopyran-4yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan -2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 630.69 113 Γ 0 HN ΟΛίγ F ^{> F} nh ₂ (S) -5- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4e] [l, 2,4] triazolo [l, 5c] pyrimidin-3 (2H ) yl) ethyl) piperazin-1 -yl) -2,4difluoro-N- (2 (methylsulfinyl) ethyl) benza mide 631.68 114 ό Γ .0 HN S-Λ Z irWrV ^ ^ν ίΓΧ VAy _f K nh ₂ (R) -5- (4- (2- (5-amino-8- (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2,4- 631.68

BE2018 / 0103

difluoro-N- (2- (methylsulfinyl) ethyl) benza mide 115 Ό / P -N S— \ / -> V 1 N — yny zsm 'θ Μ · γ _f V ~ ^f nh ₂ (S) -5- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluoro-N-methyl-N- (2 (methylsulfinyl) ethyl) benza mide 645.70 116 s-Λ _ _μ / ~~ λ V ^ ⁷ IAf Vn ' ⁿ v ⁿ V T Ao nh ₂ ~~~ n?. / S'Cr (R) -5- (4- (2- (5 -amino-8 (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluoro-N-methyl-N- (2 (methylsulfinyl) ethyl) benza mide 645.70 117 0. Ö S— \ / N AN 'x - / * ⁰ __, NMv ^N ' ^y \ ^N - / x Vn ' ⁿ y ⁿ nh ₂ 5-amino-3- (2- (4- (2,4difluoro-5- (loxydothiomorpholine-4carbonyl) phenyl) piperazin- 1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 643.69 118 Oo z ^ s ⁺ S-Λ z - m ^/ M NM yD / ^ ^N '- / ⁼ Y LHy nh ₂ 5-amino-3- (2- (4- (2,4difluoro-5- (loxydothiomorpholino) phen 615.68

BE2018 / 0103

yl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 119 0 SA _ ZA NyA / ^N \ _z f | // - <x Il z) - _s + Az nN. ^ NA 1 ^N YF 0 'nh ₂ (R) -5-amino-3- (2- (4- (2- fluoro-4 (methylsulfinyl) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 542.61 120 p _S -Y zy \ A n ^ aUz ⁿ ^ ^// ~ ^ ^N \ ζ ^ν Αλ z il 11 i \ X — c + ^ 0- nh ₂ (S) -5-amino-3- (2- (4- (2fluoro-4 (methylsulfinyl) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 542.61 121 ^s ^ ° ζγθ nvV ^N ^ ^N 1 ΝΫΛ L / ŒY — Yn A ~ Z ~ ° A N ' ^N y ^N A nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4 - (((ls, 4s) -loxydotetrahydro-2Hthiopyran-4yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 612.70 122 P .0- A N ' ^N y ^N F nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4 - (((lr, 4r) -loxydotetrahydro-2Hthiopyran-4yl) oxy) phenyl) piperazin-1 - 612.70

BE2018 / 0103

yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 123 _ 0 * -e + o \ sA _ / -Λ ^F \) ΊΖΛ'ΝγΝ ^ 1 nh ₂ (S) -4- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluoro-N- (2- (methylsulfinyl) ethyl) benza mide 613.69 124 V Ί nh ₂ (R) -4- (4- (2- (5-amino-8- (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3fluoro-N- (2- (methylsulfinyl) ethyl) benza mide 613.69 125 o r> sA z ^ \ ^ s ° rV / ^N vV A Al na U \ -n ^ n nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4- (1 -oxydothiomorpholine- 4carbonyl) phenyl) piperazin- 1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 625.70

BE2018 / 0103

126 0 ^F \ .. zLz ^N v / xz ^S 'O O / ^N; Y '' - ^/ C / Sr ^N Y ^N nh ₂ 5-amino-3- (2- (4- (2-fluoro- 4- (1oxydothiomorpholino) phen yl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 597.69 127 0 o Moh s- \ M o irw / r VmC Ι / Λγ _F M ~ ^F nh ₂ (S) -5-amino-3- (2- (4- (5- (2,3- dihydroxypropoxy) -2,4 difluorophenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 588.59 128 / o / oh S- ^ λ 0 ₀ ^Ν γΥγ ^Ν '~ ^^ Υ / ^Ν ' ~ γν Μ ^ Λΐ'ΝγΝ _ρ ΧΥ ^Ρ νη ₂ (R) -5-amino-3- (2- (4- (5 (2,3-dihydroxypropoxy) 2,4difluorophenyl) piperazin-1 yl) ethyl) - 8 - (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 588.59 129 ^ηο ^ οη P ΗΝ S— \ / ^ ~ \ V ρ-ο UYj-n ^ n _f / Y ^f νη ₂ (S) -5- (4- (2- (5 -amino-8 (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -N (2,3 -dihydroxypropyl) -2,4difluorobenzamide 615.61

BE2018 / 0103

130 HO \ JDH P HN S — X / Ί V nh ₂ (R) -5- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -N (2,3-dihydroxypropyl) -2,4difluorobenzamide 615.61 131 0, ο va û ^NH 0A V 0 ⁰ nh ₂ 5-amino-3- (2- (4- (4 (azetidin-3-yloxy) -2fluorophenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 551.60 132 H S- / / 0 Α / γ _f A ^F nh ₂ 5-amino-3- (2- (4- (5 (azetidin-3-yloxy) -2,4difluorophenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [l, 2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 569.59 133 Ό A ^{/ S} >UA'NyN _f Wf nh ₂ (S) -5-amino-3- (2- (4- (2,4difluoro-5- (3 (methylsulfinyl) propoxy) phenyl) piperazin-1 -yl) ethyl) 8- (furan-2-yl) thiazolo [5,4e] [l, 2,4] triazolo [l, 5c] pyrimidin-2 (3H) -one 618.68

and their pharmaceutically acceptable salts and solvates.

In Table 1, the term "Cp" means compound.

BE2018 / 0103

The compounds of Table 1 were named using ChemBioDraw® Ultra version 12.0 (PerkinElmer).

In one embodiment, the pharmaceutical composition comprises a compound of formula (I) selected from:

(R, S) -5-amino-3- (2- (4- (2,4-difluoro-5- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan- 2-yl) thiazolo [5,4-

e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one (compound 7);

(+) - 5-amino-3- (2- (4- (2,4-difluoro-5- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-10 1 -yl) ethyl) -8- (furan-2 -yl) thiazolo [5,4-

e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one (compound 8a) and (-) - 5-amino-3- (2- (4- (2,4 -difluoro-5- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5 -c] pyrimidin-2 (3H) -one (compound 8b).

All references to compounds of formula (I) and sub-formulas thereof include references to enantiomers, salts, solvates, polymorphs, multi-component complexes and liquid crystals thereof.

The compounds of the invention include compounds of formula (I) and sub-formulas thereof as defined above, including all polymorphs and their crystalline forms, their prodrugs and their isomers (including optical, geometric and tautomeric isomers) and isotopically labeled compounds of formula (I) and sub-formulas thereof.

The compounds of formula (I) and sub-formulas thereof may contain an asymmetric center and may therefore exist as different stereoisomeric forms. Consequently, the present invention includes all possible stereoisomers and includes not only racemic compounds but also individual enantiomers as well as their non-racemic mixtures. When a compound is desired in the form of a single enantiomer, it can be obtained by stereospecific synthesis, by resolution of the final product or of any suitable intermediate, or by chiral chromatographic methods as they are each known in the art . The resolution of the final product, of an intermediate, or of a raw material can be carried out by any process known in the art.

BE2018 / 0103

The compounds of the invention can be in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the compounds of formula (I) and sub-formulas thereof include acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the salts of acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, d 'esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, iodide hydrate / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenophosphate / dihydrogen 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 the salts of 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. Hemisalts of acids and bases can also be formed, for example, the hemisulfate and hemicicalcium salts. Preferred pharmaceutically acceptable salts include the hydrochloride / chloride, hydrobromide / bromide, bisulphate / sulphate, nitrate, citrate, and acetate.

When the compounds of the invention contain an acid group as well as a basic group, the compounds of the invention can also form internal salts, and these compounds are within the scope of the invention. When the compounds of the invention contain a hydrogen donor heteroatom (for example, NH), the invention also comprises the salts and / or isomers formed by transfer of said hydrogen atom to a basic group or to an atom inside the molecule.

The pharmaceutically acceptable salts of the compounds of formula (I) and of sub-formulas thereof can be prepared by one or more of these methods:

BE2018 / 0103 (i) by reaction of the compound of formula (I) with the desired acid;

(ii) by reacting the compound of formula (I) with the desired base;

(iii) by removal of a labile protecting group in an acidic or basic medium of an appropriate precursor of the compound of formula (I) or by ring opening of a suitable cyclic precursor, for example, a lactone or a lactam, using the desired acid; or (iv) by converting one salt of the compound of formula (I) into another by reaction with an appropriate acid or by means of an appropriate ion exchange column.

All of these reactions are typically carried out in solution. The salt can precipitate in a solution and be collected by filtration or can be recovered by evaporation of the solvent. The degree of ionization in the salt can vary from fully ionized to practically non-ionized.

The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate , mesylate, borate, methylbromide, bromide, methylnitrate, calcium edetate, methylsulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine , citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estolate, palmitate, esylate, pantothenate, fumarate, phosphate / diphosphate, glucideptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamine, succinate, hydrobromide, tannate , hydrochloride, tartrate, hydroxynaphtoate, teoclate, iodide, tosy late, isothionate, triethiodide, lactate, panoate, valerate, and the like which may be used in a dosage form to modify the characteristics of solubility or hydrolysis or may be used in sustained release formulations or prodrugs. According to the particular functionality of the compound of the present invention, the pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium,

BE2018 / 0103 lithium, magnesium, zinc, and bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, omithine, choline, Ν, Ν '-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, and tetramethylammonium hydroxide.

These salts can be prepared by standard procedures, for example, by reacting a free acid with a suitable organic or inorganic base. When a basic group is present, such as an amino group, an acid salt, for example hydrochloride, hydrobromide, acetate, palmoate, and the like, can be used as a dosage form.

Furthermore, although the pharmaceutically acceptable salts are generally preferred relative to the salts of the compounds of the invention, it should be noted that the invention in its broadest sense also includes non-pharmaceutically acceptable salts, which can for example be used in isolation and / or purification of the compounds of the invention. For example, the salts formed with optically active acids or bases can be used to form diastereomeric salts which can facilitate the separation of optically active isomers of the compounds of formula (I) above.

The compounds of the invention can be in the form of pharmaceutically acceptable solvates. The pharmaceutically acceptable solvates of formula (I) and sub-formulas thereof contain stoichiometric or sub-stoichiometric amounts of one or more molecules of pharmaceutically acceptable solvent, for example ethanol or water. The term "hydrate" refers to the case where said solvent is water.

The invention also generally relates to all pharmaceutically acceptable pre-drugs and prodrugs of the compounds of formula (I) and sub-formulas thereof.

In addition, when an alcohol group is present, pharmaceutically acceptable esters can be used, for example, acetate, maleate, pivaloyloxymethyl, and the like, and esters known in the art for modifying solubility characteristics or hydrolysis for use in sustained release formulations or prodrugs.

BE2018 / 0103

Lauroyl polyoxyl-32 glycerides

The pharmaceutical composition of the invention comprises a lipid vector, preferably lauroyl polyoxyl-32 glycerides.

This excipient corresponds to Gélucire® 44/14 prepared by Gattefossé (SaintPriest - France). This excipient is also known by the following references:

- lauroyl polyoxyl-32 glycerides NF / USP (NF: National Formulary; USP: US Pharmacoeia);

- lauroyl macrogol-32 glycerides EP (European Pharmacopeia);

- PEG-32 ester of hydrogenated coconut (INCI);

- CAS number 57107-95-6.

Gélucire® 44/14 corresponds to a well-defined multi-component substance consisting of mono-, di- and triglycerides and PEG-32 mono- and diesters of lauric acid (C12). Gélucire® 44/14 has a melting point ranging from 42.5 ° C to 47.5 ° C (with an average of 44 ° C) and a hydrophilic / lipophilic equilibrium value (HLB) of

14.

Gélucire® 44/14 is used to improve the solubility and bioavailability of the active ingredient.

Other ingredients

The pharmaceutical composition of the invention may optionally include one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants. These vectors, diluents, excipients and / or adjuvants suitable for use in the preparation of administration forms will be obvious to those skilled in the art; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

In particular, the pharmaceutical composition of the invention may optionally contain inactive substances which are commonly used in pharmaceutical formulations, such as, for example, cosolvents, antioxidants, surfactants, emulsifying agents, buffering agents, pH-modifying agents , preservatives (or preservatives), isotonifying agents, stabilizing agents, granulating agents or binders, lubricants, disintegrating agents, slip agents, diluents or fillers, adsorbents , dispersing agents, setting agents

BE2018 / 0103 in suspension, filling agents, release agents, sweetening agents, flavoring agents, and the like.

According to one embodiment, the pharmaceutical composition of the invention comprises one or more pharmaceutically acceptable inactive ingredients selected from: caprylic acid, polyethylene glycol, propylene glycol, ethanol, glycerol, dimethylsulfoxide, dimethylacetamide, dimethylisosorbide, cellulose derivatives (including hydroxypropylmethylcellulose, methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate acetate), cremophor RH40 (hydrogenated castor oil), polyox 40 crémophor EL (polyoxyl 35 hydrogenated castor oil), polysorbate 20 (polyoxyethylenesorbitan monolaurate), polysorbate 80 (polyoxyethylenesorbitane monooleate), poloxamer 188 (poly (ethylene glycol) -6 / oc-poly (propylene glycol) - /? / oopoly (ethylene glycol)), poloxamer 407 (poly (ethylene glycol) -Z? / oc-poly (propylene glycol) -6 / oc-poly (ethylene glycol)), TPG S of vitamin E (polyethylene glycol succinate of vitamin E), solutol HS 15 (polyoxyethylated 12-hydroxystearic acid), labrasol (caprylocaproyl polyoxyl-8 glycerides), labrafil Μ1944 (oleoyl polyoxyl-6 glycerides), polyvinylpyrrolidone (also known as p , preferably polyvinylpyrrolidone K17, K19, K29-K32, K90), a polyvinyl pyrrolidone-vinyl acetate copolymer, carboxymethylcellulose (Na / Ca), a methyl ether copolymer of polyethylene glycol-b / oc-poly ( DL lactide), sodium lauryl sulfate, docusate sodium, propylene glycol monolaurate, propylene glycol dilaurate, propylene glycol monocaprylate, polyethylene glycol 660 12-monostearate, poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate - methyl methacrylate) 1/2/1.

In a preferred embodiment, the pharmaceutical composition of the invention comprises one or more pharmaceutically acceptable co-solvents. Preferably, the cosolvents are selected from caprylic acid, polyethylene glycol (PEG), propylene glycol, ethanol, dimethylsulfoxide, dimethylacetamide, dimethylisosorbide and mixtures thereof. In a specific embodiment, the pharmaceutical composition of the invention comprises caprylic acid and / or PEG. Advantageously, when the composition

BE2018 / 0103 comprises PEG as a cosolvent, the PEG is of low molecular weight, preferably the PEG is PEG400.

In one embodiment, the pharmaceutical composition of the invention further comprises one or more antioxidants; preferably the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid, sodium metabisulfite, ascorbic acid, methionine and vitamin E; more preferably the antioxidant is BHT.

In certain embodiments, surfactants are added, such as for example polyethylene glycols, fatty acid esters of polyoxyethylene sorbitan, sorbitan esters, sodium docusate, sodium lauryl sulfate, polysorbates (20, 80, etc.), poloxamers (188, 407 etc.), Pluronic polyols, polyoxethylene sorbitan monoethers (TWEEN®-20, TWEEN®-80 etc.), vitamin E TPGS (vitamin E polyethylene glycol succinate ), cremophor RH40 (hydrogenated castor oil of polyoxyl 40), cremophor EL (hydrogenated castor oil of polyoxyl 35), polyethylene glycol 660 12-monostearate, solutol HS15 (polyoxyethylated 12-hydroxystearic acid), labrasol (caprylocaproyl polyox ), labrafil Μ1944 (oleoyl polyoxyl-6 glycerides).

In certain embodiments, emulsifiers are added, such as for example a carbomer, carrageenan, lanolin, lecithin, mineral oil, oleic acid, oleyl alcohol, pectin, a poloxamer, esters of polyoxyethylene sorbitan fatty acid, sorbitan esters, triethanolamine, propylene glycol monolaurate, propylene glycol dilaurate, propylene glycol monocaprylate. Preferred emulsifiers are, for example, poloxamer, propylene glycol monolaurate, propylene glycol dilaurate, and propylene glycol monocaprylate.

In some embodiments, buffering agents are used to help maintain the pH within the range that approximates physiological conditions. Suitable buffering agents include organic and inorganic acids and the salts thereof, for example citrate buffers (for example, a sodium citrate-disodium citrate mixture, a citric acid-trisodium citrate mixture, a citric acid-monosodium citrate mixture , etc.), succinate buffers (for example, a succinic acid-monosodium succinate mixture, a succinic acid-sodium hydroxide mixture, a succinic acid-disodium succinate mixture,

BE2018 / 0103 etc.), tartrate pads (for example, a tartaric acid-sodium tartrate mixture, a tartaric acid-sodium tartrate mixture, a tartriquetartrate sodium acid mixture, etc.), fumarate pads (for example, a fumaric acid-monosodium fumarate mixture, a fumaric acid-disodium fumarate mixture, a monosodium fumarate-disodium fumarate mixture, etc.), gluconate buffers (for example, a gluconic acid-sodium gluconate mixture, a gluconic acid-hydroxide mixture sodium, a gluconic acid-potassium gluconate mixture, etc.), an oxalate buffer (for example, an oxalic acid-sodium oxalate mixture, a oxalic acid-sodium hydroxide mixture, an oxalic acid-potassium oxalate mixture, etc.), lactate buffers (for example, a lactic acid-sodium lactate mixture, a lactic acid-sodium hydroxide mixture, a lactic acid-potassium lactate mixture, etc.) and acetate buffers (for example, a acetic acid mixture tick-sodium acetate, acetic acid-sodium hydroxide mixture, etc.). In addition, phosphate buffers, histidine buffers and trimethylamine salts such as Tris can be used.

In certain embodiments, pH modifiers are used, such as for example sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, meglumine, sodium carbonate, acid citric, tartaric acid, ascorbic acid and malic acid.

In some embodiments, preservatives are added to retard microbial growth. Preservatives suitable for use with the present description include phenol, benzyl alcohol, metacresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalconium halides (e.g. chloride, bromide , and iodide), hexamethonium chloride, and alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol.

In certain embodiments, isotonification agents sometimes known as “stabilizers” are added and include polyhydric polyols, for example trihydric polyols or more, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol. Stabilizers refer to a broad category of excipients, the functions of which can range from a filler to an additive that solubilizes the agent

BE2018 / 0103 therapeutic or helps to prevent denaturation or adhesion to the wall of the container or helps to inhibit the precipitation, the growth or the agglomeration of the particles of the active ingredient. Typical stabilizers can be polyhydric polyols (listed above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, omithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc. ; organic sugars or polyols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol and the like, including cyclitols such as inositol ; polyethylene glycol; amino acid polymers; reducing agents containing sulfur, such as urea, glutathione, thiocic acid, sodium thioglycolate, thioglycerol, α-monothioglycerol and sodium thio sulfate; low molecular weight polypeptides (e.g., peptides of 10 residues or less); proteins such as human albumin serum, bovine serum albumin, gelatin or immunoglobulins; hydrophilic polymers, such as polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate or hydroxypropylmethylcellulose acetate succinate acetate succinate; carboxymethylcellulose (Na / Ca); monosaccharides, such as xylose, mannose fructose, glucose; disaccharides such as lactose, maltose, sucrose and trisaccharides such as raffinose; polysaccharides such as dextran; a polyether glycol-6 / oc-poly (D-L lactide) methyl ether copolymer; poly (butyl methacrylate-(2-dimethylaminoethyl) co-methacrylate-methyl co-methacrylate) 1/2/1. Preferred stabilizers are, for example, glycerol; polyethylene glycol; polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate or hydroxypropylmethylcellulose acetate succinate; carboxymethylcellulose (Na / Ca); a polyethylene glycol-ol / oc-poly (D-L lactide) methyl ether copolymer; and poly (butyl methacrylate-(2-dimethylaminoethyl) co-methacrylate-methyl methacrylate) 1/2/1.

In certain embodiments, a granulating agent (s) / binder (s) are added, such as for example starch, gums (including natural, semi-synthetic and synthetic gums), microcrystalline cellulose,

BE2018 / 0103 ethylcellulose, methylcellulose, hydroxypropylcellulose, liquid glucose polymers such as povidone, copolymers of polyvinyl pyrrolidone and vinyl acetate and the like. Preferred granulating agents are, for example, methylcellulose, hydroxypropylcellulose, povidone and a polyvinyl pyrrolidone-vinyl acetate copolymer.

In certain embodiments, lubricants are added, such as for example magnesium stearate, glyceryl esters, behenoyl polyoxyl-8 glycerides Nf (Compritol HD5 ATO), sodium stearyl fumarate and the like.

In certain embodiments, disintegrants are added, such as for example synthetics such as sodium starch glycolate, crosslinked povidone, crosslinked sodium carmellose, kollidon CL, and of natural origin such as locust bean gum. and the like.

In certain embodiments, slip agents are added, such as, for example, talc, magnesium stearate, colloidal silicon dioxide, starch and the like.

In certain embodiments, diluents (or fillers) are added, such as for example dextrose, lactose, mannitol, microcrystalline cellulose, sorbitol, sucrose, dibasic calcium phosphate, calcium sulphate dihydrate, starch and the like.

In certain embodiments, adsorbents are added, such as for example silicon dioxide, purified aluminum silicate and the like.

In certain embodiments, the pharmaceutical composition of the invention is in the form of tablets and compression excipients are added, such as for example granulating agents, binders, lubricants, disintegrating agents, slip, thinners, adsorbents and the like.

Quantities

In one embodiment, the pharmaceutical composition of the invention comprises an amount of the compound of formula (I) ranging from 1% to 20% by weight relative to the total weight of the composition (w / w). Preferably, the pharmaceutical composition of the invention comprises an amount of compound of formula (I) ranging from 5% to 15% w / w, preferably from 8% to 12% w / w, more

BE2018 / 0103 preferred from 9% to 11% w / w, even more preferably about 10% w / w.

In one embodiment, the pharmaceutical composition of the invention comprises an amount of lauroyl polyoxyl-32 glycerides ranging from 55% to 99% by weight relative to the total weight of the composition (w / w). Preferably, the pharmaceutical composition of the invention comprises an amount of lauroyl polyoxyl-32 glycerides ranging from 60% to 95% w / w, preferably from 65% to 90% w / w, more preferably from 70% to 85% w / w, even more preferably about 70% w / w, about 71% w / w, about 72% w / w, about% w / w, about 74 % w / w, approximately 75% w / w, approximately 76% w / w, approximately% w / w, approximately 78% w / w, approximately 79% w / w, d '' approximately 80% w / w, approximately% w / w, approximately 82% w / w, approximately 83% w / w, approximately 84% w / w, approximately% w / w .

In one embodiment, the pharmaceutical composition of the invention can comprise PEG400, in an amount ranging from 0% to 30% by weight relative to the total weight of the composition (w / w). Preferably, the pharmaceutical composition of the invention comprises an amount of PEG400 ranging from 5% to 30% w / w, preferably from 10% to 25% w / w, more preferably from 15% to 20% w / p, even more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / p, of about 20% w / w, even more preferably of about 18% w / w.

In one embodiment, the pharmaceutical composition of the invention can comprise caprylic acid, in an amount ranging from 0% to 20% by weight relative to the total weight of the composition (w / w). Preferably, the pharmaceutical composition of the invention comprises an amount of caprylic acid ranging from 1% to 20% w / w, preferably from 3% to 15% w / w, more preferably from% to 10% w / p, even more preferably about 5% w / w, about% w / w, about 7% w / w, about 8% w / w, about 9% w / w p, more preferably about 9% w / w.

In one embodiment, the pharmaceutical composition of the invention can comprise an antioxidant agent, preferably BHT, in an amount ranging from 0% to 5% by weight relative to the total weight of the composition (w / w). Preferably, the pharmaceutical composition of the invention comprises an amount of

BE2018 / 0103

BHT ranging from 0.001% to 5% w / w, preferably from 0.005% to 1% w / w, more preferably from 0.01% to 0.5% w / w, even more preferably from about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, even more so preferred about 0.10% w / w.

In one embodiment, the pharmaceutical composition of the invention comprises:

a) from 1% to 20% by weight relative to the total weight of the composition (w / w) of the compound of formula (I); preferably from 5% to 15% w / w, more preferably from 8% to 12% w / w, still more preferably from 9% to 11% w / w, even more preferably about 10% w / p; and

b) from 55% to 99% w / w of lauroyl polyoxyl-32 glycerides, preferably from 60% to 95% w / w, preferably from 65% to 90% w / w, more preferably from 70% to 85% w / w, even more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / p, approximately 76% w / w, approximately 77% w / w, approximately 78% w / w, approximately 79% w / w, approximately 80% w / w, approximately 81% w / w, approximately 82% w / p, about 83% w / w, about 84% w / w, about 85% w / w.

In one embodiment, the pharmaceutical composition of the invention comprises:

a) from 1% to 20% by weight relative to the total weight of the composition (w / w) of the compound of formula (I); preferably from 5% to 15% w / w, more preferably from 8% to 12% w / w, still more preferably from 9% to 11% w / w, even more preferably about 10% w / p;

b) from 55% to 99% w / w of lauroyl polyoxyl-32 glycerides, preferably from 60% to 95% w / w, preferably from 65% to 90% w / w, more preferably from 70% to 85% w / w, even more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / p, approximately 76% w / w, approximately 77% w / w, approximately 78% w / w, approximately 79% w / w, approximately 80% w / w, approximately 81% w / w, approximately 82% w / p, about 83% w / w, about 84% w / w, about 85% w / w;

BE2018 / 0103

c) from 0% to 30% w / w of PEG400, preferably from 5% to 30% w / w, preferably from 10% to 25% w / w, more preferably from 15% to 20% w / p, even more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, even more preferably about 18% w / w; and

d) from 0% to 5% w / w of BHT, preferably from 0.001% to 5% w / w, preferably from 0.005% to 1% w / w, more preferably from 0.01% to 0, 5% w / w, even more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0, 20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, even more preferably about 0, 10% w / w by weight relative to the total weight of the composition (w / w).

In one embodiment, the pharmaceutical composition of the invention comprises:

a) from 1% to 20% by weight relative to the total weight of the composition (w / w) of the compound of formula (I); preferably from 5% to 15% w / w, more preferably from 8% to 12% w / w, still more preferably from 9% to 11% w / w, even more preferably about 10% w / p;

b) from 55% to 99% w / w of lauroyl polyoxyl-32 glycerides, preferably from 60% to 95% w / w, preferably from 65% to 90% w / w, even more preferably from 70% at 85% w / w, even more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, approximately 76% w / w, approximately 77% w / w, approximately 78% w / w, approximately 79% w / w, approximately 80% w / w, approximately 81% w / w, approximately 82% w / p, about 83% w / w, about 84% w / w, about 85% w / w;

c) from 0% to 20% w / w caprylic acid, preferably from 1% to 20% w / w, preferably from 3% to 15% w / w, more preferably from 5% to 10% w / w, more preferably about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, even more preferably about 9% w / w; and

d) from 0% to 5% w / w of BHT, preferably from 0.001% to 5% w / w, preferably from 0.005% to 1% w / w, more preferably from 0.01% to 0, 5% w / w, even more preferably about 0.01% w / w, about 0.05% w / w,

BE2018 / 0103 approximately 0.10% w / w, approximately 0.15% w / w, approximately 0.20% w / w, approximately 0.25% w / w, approximately 0.30% w / w, approximately 0 , 40% w / w, about 0.50% w / w, even more preferably about 0.10% w / w by weight relative to the total weight of the composition (w / w).

In one embodiment, the pharmaceutical composition of the invention comprises:

a) from 5% to 15% w / w of the compound of formula (I);

b) from 70% to 85% w / w of lauroyl polyoxyl-32 glycerides;

c) from 10% to 25% w / w of PEG400; and

d) optionally from 0.01% to 0.5% w / w of BHT.

In one embodiment, the pharmaceutical composition of the invention comprises:

a) from 5% to 15% w / w of the compound of formula (I);

b) from 70% to 85% w / w of lauroyl polyoxyl-32 glycerides;

c) from 5% to 10% w / w of caprylic acid; and

d) optionally from 0.01% to 0.5% w / w of BHT.

Pharmaceutical form

In one embodiment, the pharmaceutical composition of the invention is in a form suitable for oral administration. This suitable form of administration can be solid, semi-solid or liquid. This suitable form of administration will be obvious to those skilled in the art; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

Some preferred, but not limiting, examples of these forms include capsules (including soft and hard gelatin capsules), tablets, pills, powders, tablets, sachets, cachets, elixirs, suspensions, emulsions, solutions and syrups.

The pharmaceutical composition of the invention is preferably in a unit dosage form, and may suitably be packaged, for example, in a box, a blister pack, a vial, a bottle, a sachet, an ampoule or any other support. or suitable container for a single dose or multiple doses (which can be properly labeled); optionally with one or more sheets containing product information and / or instructions for use. Such a

BE2018 / 0103 unit dosage form may contain for example from about 5 mg to about 200 mg of the pharmaceutically active principle, preferably from about 10 mg to about 100 mg.

The pharmaceutical composition of the invention can also be formulated to provide rapid, prolonged or delayed release of the active compound (s) contained therein.

Manufacturing of the pharmaceutical composition

The pharmaceutical composition of the invention can be manufactured by methods well known to those skilled in the art.

In one embodiment, the pharmaceutical composition of the invention is in a solid or semi-solid form. A solid dispersion can be conventionally prepared using methods such as for example melting (melting), solvent evaporation, spray drying, freeze drying (freeze drying), hot melt extrusion, a method electrostatic spinning, coating on sugar beads using a fluidized bed coating system or supercritical fluid technology.

In one embodiment, the pharmaceutical composition of the invention is in the form of capsules, preferably hard gelatin capsules. In such a case, the capsules can be made from a common blend using conventional capsule mixing and filling processes in accordance with Good Manufacturing Practice.

In one embodiment, the process for preparing the capsules comprises the following steps:

i) the lauroyl polyoxyl-32 glycerides are melted at a temperature not less than 50 ° C but not more than 80 ° C;

ii) optionally, other excipients, for example caprylic acid, PEG and / or BHT, are then added to the lauroyl polyoxyl-32 glycerides and mixed together using an appropriate mixer;

iii) the compound of formula (I) is then gradually added under continuous mixing using a mixer suitable for producing a visually uniform distribution of the medicinal substance without lumps or observable agglomerates;

BE2018 / 0103 iv) mixing is then continued for at least 30 minutes to ensure that the drug substance is distributed homogeneously as determined visually;

v) the mixture is then kept in the molten state with continuous stirring and it is filled in gelatin capsule envelopes of an appropriate size up to the target capsule filling weight.

Capsule filling is undertaken using conventional capsule filling methods and equipment suitable for use with melted semi-solid formulations.

Dose

Depending on the condition to be prevented or treated and the form of administration, the pharmaceutical composition of the invention can be administered in the form of a single daily dose, or divided into one or more daily doses.

In one embodiment, the pharmaceutical composition of the invention is administered in a dose such that it corresponds to the administration of approximately 5 mg to approximately 200 mg of the pharmaceutically active principle to the subject per administration, preferably of approximately 10 mg to about 100 mg.

In one embodiment, an effective dose of the pharmaceutically active principle can range from about 0.08 to about 3.3 mg / kg, preferably from about 0.15 to about 1.7 mg / kg.

Uses

Another object of this invention is a medicament comprising the pharmaceutical composition of the invention.

The invention further relates to the use of the pharmaceutical composition of the invention for inhibiting the A2A receptor.

According to another characteristic of the present invention, a method of modulating the activity of A2A is provided in a patient, preferably a warm-blooded animal, and even more preferably a human being, in need of such treatment, which comprises administering to said patient an effective amount of the pharmaceutical composition of the invention.

BE2018 / 0103

According to another characteristic, the present invention relates to the use of the pharmaceutical composition of the invention for the preparation of a medicament for modulating the activity of A2A in a patient, requiring such treatment, which comprises administration to said patient of an effective amount of the pharmaceutical composition of the invention.

In one embodiment, the invention relates to the use of the pharmaceutical composition of the invention, for increasing the immune recognition and destruction of cancer cells.

The pharmaceutical composition of the invention is therefore useful for the prevention and / or treatment of cancer, in particular useful for the treatment of cancer.

The invention further relates to a method of treating cancer, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the pharmaceutical composition of the invention.

The invention further relates to the use of the pharmaceutical composition of the invention for the preparation of a medicament for the treatment and / or prevention of cancer.

The invention also relates to a method for delaying the onset of cancer in a patient comprising administering a pharmaceutically effective amount of the pharmaceutical composition of the invention to a patient in need thereof.

Preferably, the patient is a warm-blooded animal, more preferably a human.

Different cancers are known in the art. Cancer can be metastatic or non-metastatic. Cancer can be familial or sporadic. In certain embodiments, the cancer is selected from the group consisting of: leukemia and multiple myeloma. Other cancers that can be treated using the methods of the invention include, for example, benign and malignant solid tumors and benign and malignant non-solid tumors. In a specific embodiment, the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver and lung cancers , melanoma, ovarian, pancreatic, prostate, kidney, gastric, thyroid and urothelial cancers. In a fashion

BE2018 / 0103 of specific achievement, cancer is breast cancer. In a specific embodiment, the cancer is carcinoid cancer. In a specific embodiment, the cancer is cancer of the cervix. In a specific embodiment, the cancer is colorectal cancer. In a specific embodiment, the cancer is an endometrial cancer. In a specific embodiment, the cancer is a glioma. In a specific embodiment, the cancer is cancer of the head and neck. In a specific embodiment, the cancer is liver cancer. In a specific embodiment, the cancer is lung cancer. In a specific embodiment, the cancer is a melanoma. In a specific embodiment, the cancer is ovarian cancer. In a specific embodiment, the cancer is pancreatic cancer. In a specific embodiment, the cancer is prostate cancer. In a specific embodiment, the cancer is kidney cancer. In a specific embodiment, the cancer is gastric cancer. In a specific embodiment, the cancer is thyroid cancer. In a specific embodiment, the cancer is urothelial cancer.

Examples of solid tumors include, but are not limited to: bile duct cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, carcinoid, cervical cancer, chorio-carcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells , stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, kidney cancer (including adenocarcinoma and Wilms tumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma; li posarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell cancer and squamous cell cancer), testicular cancer including germ cell tumors (seminomas, not seminomas such as teratomas and choriocarcinomas), tumors

BE2018 / 0103 stromal, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma) and urothelial cancer.

Examples of solid tumors include, but are not limited to: bile duct cancer, brain cancer (including glioblastomas and medulloblastomas), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastomas, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, cancer prostate, rectal cancer, kidney cancer (including adenocarcinoma and Wilms' tumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma; liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including l melanoma, Kaposi's sarcoma, basal cell cancer and squamous cell cancer), testicular cancer including germinal tumors (seminomas, and non-seminomas such as teratomas and choriocarcinomas), stromal tumors, tumors of the germ cells, and thyroid cancer (including an adenocarcinoma of the thyroid and a bone marrow carcinoma).

Examples of non-solid tumors include, but are not limited to, hematological neoplasms. As used herein, a hematologic neoplasm is a term in the art that includes lymphoid disorders, myeloid disorders, and leukemias associated with AIDS.

Lymphoid disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphoproliferative disorders (eg, lymphomas, myelomas, and chronic lymphoid leukemias). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphomas, and lymphocytic lymphomas. Chronic lymphoid leukemias include, for example, chronic lymphoid leukemias with T cells and chronic lymphoid leukemias with B cells.

The invention further relates to the use of the pharmaceutical composition of the invention for the prevention and / or treatment of fibrosis induced by

BE2018 / 0103 radiation, diseases of the connective tissue (for example Sjogren syndrome, in other words scleroderma), chronic bacterial infection (for example Helicobacter pylori), abnormal scarring (keloids) and polymicrobial sepsis.

The invention further relates to a method of treating or preventing radiation-induced fibrosis, connective tissue diseases (e.g. Sjogren syndrome, in other words scleroderma), chronic bacterial infection ( for example Helicobacter pylori), abnormal scarring (keloids) and polymicrobial sepsis, which comprises administering to a mammalian species in need a therapeutically effective amount of the pharmaceutical composition of the invention.

The invention further relates to the use of the pharmaceutical composition of the invention for the preparation of a medicament for the treatment and / or prevention of radiation-induced fibrosis, of connective tissue diseases (e.g. syndrome de Sjogrën, in other words scleroderma), chronic bacterial infection (for example Helicobacter pylori), abnormal scarring (keloids) and polymicrobial sepsis.

The invention further relates to a method of delaying the onset in a patient of radiation-induced fibrosis, connective tissue disease (e.g. Sjogren syndrome, in other words scleroderma), d chronic bacterial infection (e.g. Helicobacter pylori), abnormal scarring (keloids) and polymicrobial sepsis, comprising administering a pharmaceutically effective amount of the composition of the invention to a patient in need thereof .

EXAMPLES

The present invention will be better understood by reference to the following examples. These examples are intended to represent specific embodiments of the invention, and are not intended to limit the scope of the invention.

The following abbreviations are used:

BHT: butylated hydroxytoluene ca. : about

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EDTA: ethylenediaminetetraacetic acid

FeSSIF: nourished simulated intestinal fluid

HPLC: high performance liquid chromatography,

CL-SM: liquid chromatography-mass spectrometry mg: milligram

SM: mass spectrometry

PB S: phosphate buffered saline

PEG: polyethylene glycol rpm: revolutions per minute

UV: ultraviolet μΐ: microliter% v / v: percentage by volume relative to the total volume of the composition% w / w: percentage by weight relative to the total weight of the composition

I. COMPOUNDS

The compounds of formula (I) are prepared as described in the document

PCT / EP2018 / 058301

PHARMACEUTICAL COMPOSITIONS

Two compositions according to the invention were prepared in the form of capsules, comprising the following ingredients (Table 2):

Table 2. Capsule compositions

Constituents Capsules 1 (% w / w) 2A capsules (% w / w) Compound 8a 10 10 Gélucire® 44/14 71.9 80.9 PEG400 18 \ Caprylic acid \ 9 Butylated hydroxytoluene (BHT) 0.1 0.1

The 2A capsules were prepared from a common blend using conventional capsule blending and filling procedures in accordance with Good Manufacturing Practice. The lauroyl polyoxyl-32 glycerides were melted to

BE2018 / 0103 a product temperature not lower than 50 ° C but not higher than 80 ° C. Caprylic acid and then butylated hydroxytoluene (BHT) were then added to the lauroyl polyoxyl-32 glycerides and mixed together using a suitable mixer. Compound 8a was then added gradually to the lauroyl polyoxyl32 glycerides / caprylic acid / ΒΗΤ mixture which was under continuous mixing using a suitable mixer to produce a visually uniform distribution of the drug substance without lumps or agglomerates observable. Mixing was continued for at least 30 minutes to ensure that the drug substance was distributed homogeneously as determined visually. The mixture was then kept in the molten state under continuous mixing and then it was filled in gelatin capsule envelopes of suitable size up to the target filling weight of the capsule. Filling of the capsules is undertaken using conventional capsule filling methods and equipment suitable for use with melted semi-solid formulations.

A similar process was carried out for the preparation of capsules 1.

III. PHARMACOLOGICAL EXAMPLES

III. 1. THERMODYNAMIC SOLUBILITY BY HPLC STirring BOTTLE

This example aims to demonstrate that the compounds of formula (I) are poorly soluble in water or in aqueous buffers and that it is necessary to provide a formulation of said compounds.

Compound 8a (2.0 mg, crystalline solid) was weighed into the lower chambers of Whatman MiniUniprep vials. 450 μΐ of medium tested were added to each chamber. After this addition, the filter pistons of the MiniUniprep vials were placed and compressed to the liquid level position to allow contact of the medium and the compound with the filter during incubation. The samples were vortexed for 2 minutes, then allowed to incubate at room temperature (about 22 ~ 25 ° C) for 24 hours with shaking at 880 rpm. The MiniUniprep vials were compressed to prepare the filtrates for injection into an HPLC system. The supernatants were diluted with the medium by a magnitude factor of 50 to prepare diluents. We injected three standard UV solutions into the HPLC system from low to high concentration,

BE2018 / 0103 then the diluents and the supernatants were tested. The test samples were injected in duplicate.

The results are presented in Table 3:

Table 3. Solubility of compound 8a in the aqueous medium tested.

Test environment Thermodynamic solubility of compound 8a (pg / ml) Water <0.6 pH 7.4 2 FeSSIF 10

In all the aqueous media tested, the solubility is very low and the test in the FeSSIF (simulated intestinal fluid fed) is representative of low intestinal solubility.

III.2. EXHIBITIONS IN DOGS AFTER ORAL ADMINISTRATION

The objective of this test is to determine the exposure in dogs after oral administration of the pharmaceutical composition of the invention. Pentagastrin was administered to dogs just prior to the administration of capsule formulations to stimulate the secretion of stomach acid.

Five male Beagle dogs (age> 6 months, weight 7-9 kg) were fed in the afternoon (3:30 to 4:00 p.m.) the day before oral administration and the remaining food was removed at approximately 7:00 p.m. Feeding was suspended until after the blood sample 4 hours after administration.

Pentagastrin (Sigma, 1 mg) was dissolved in 200 μΐ (0.200 ml) of 10% (v / v) ammonium hydroxide (NH4OH) solution / phosphate buffered saline (PBS) ). 0.12 ml of this stock solution was then diluted by adding 4.88 ml of PBS solution, then the flask was vortexed. The solution was filtered (under a laminar flow hood) through a 0.22 μm syringe filter in an amber glass serum bottle. Pentagastrin 6 pg / kg was administered to animals by intramuscular injection approximately 30 minutes (± 2 minutes) before administration of the capsules.

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The dose capsule formulations (80 mg / dog, in other words about 10 mg / kg of animals) were administered by placing the capsules at the back of the dogs throats and then pushed beyond their pharynx using the thumb or forefinger. The capsules were wetted with water to facilitate dosing. After administration of the dose, swallowing was induced, if necessary, by gently stroking the dog's throat or tapping the dog under the chin. Immediately after administration of the capsule, water (4 ml / kg) or an aqueous HCl solution of pH 2.5 (4 ml / kg) was put into the mouth of the animal to help it to swallow the capsule. After administration, the mouths of the animals were inspected to ensure that the dose had been swallowed.

Blood was taken at the time points shown in Table 4 in a tube (Jiangsu Kangjian medical supplies co., LTD) containing potassium (K2) EDTA * 2H2O (0.85 to 1.15 mg) on ice and it was treated to obtain plasma by centrifugation (3,000 xg for 10 minutes at 2 to 8 ° C) within one hour of collection. The plasma samples (0.2 ml) were transferred to microcentrifuge tubes and stored frozen at -60 ° C or below until biological analysis.

The concentrations of compound 8a in the plasma were quantified by CLSM / SM. The measured concentrations (average of five dogs) are shown in Table 4, while the pharmacokinetic parameters are shown in Table 5.

Table 4. Concentration of compound 8a in plasma.

Time point (h) Formulation 1 Concentration (ng / ml) Formulation 2 A Concentration (ng / ml) 0.25 94.7 94.4 0.50 431 292 1.0 242 384 2.0 161 108 4.0 9.91 10.5 8.0 3.42 3.45 12 4.68 <1

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Table 5. Pharmacokinetic parameters

Formulation 1 Formulation 2 A Dose (mg / dog) (Active ingredient) 80 80 Additional liquid Water Aqueous HCl pH 2.5 Cmax (ng / ml) 481 674 Tmax (h) 0.9 1 ASCiast (h * ng / ml) 554 1818 ASCinf (h * ng / ml) 561 1823

Cmax: maximum concentration in plasma of the active ingredient obtained after administration; T _m ax: time to reach Cmax; AUC: area under the curve, 5 corresponding to the integral of the concentration-time curve (ASCiast: AUC until the last sample taken; ASCinf: AUC until infinity)

The above results clearly demonstrate that the use of the pharmaceutical composition of the invention allows suitable oral bioavailability of the A2A inhibitor thiocarbamates.

Claims (15)

1. Pharmaceutical composition comprising: (a) a compound of formula (I):

or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ represents a 5- or 6-membered heteroaryl group or a 5 or 6-membered aryl group, wherein the heteroaryl or aryl groups are optionally substituted by one or more substituents selected from a C1-C6 alkyl group (preferably methyl) and a halo group (preferably fluoro or chloro); preferably R ¹ represents a 5-membered heteroaryl group; more preferably R * represents a furyl group; R ² represents a 6-membered aryl group or a 6-membered heteroaryl group, in which the heteroaryl or aryl groups are optionally substituted with one or more substituents selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino and alkylsulfonealkyl; said substituents being optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) heteroaryl, BE2018 / 0103 alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl , dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle; or the heteroaryl or aryl groups are optionally substituted with one or two substituents which together with the atoms to which they are attached form a 5 or 6 membered aryl ring, a 5 or 6 membered heteroaryl ring, a 5 or 6 membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring; optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl), heterocyclyl) (alkyl) aminoalkyl) , alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl , alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle; (b) lauroyl polyoxyl 32 glycerides; and (c) optionally one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants. BE2018 / 0103 2. Pharmaceutical composition according to claim 1, in which the compound is of formula (la) NHo

or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ is as defined in claim 1; X * and X ² each independently represent C or N; R ¹ is absent when X ¹ is N; or when X ¹ is C, R ¹ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocycyllyl sulfonyl said substituents being optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle; R ² 'represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, BE2018 / 0103 heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyle; said substituents being optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle; or R ¹ and R ² 'together with the atoms to which they are attached form a 5 or 6-membered aryl ring, a 5 or 6-membered heteroaryl ring, a 5 or 6-membered cycloalkyl ring or a 5 or 6-membered heterocyclyl ring links; optionally substituted by one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl), heterocyclyl) (alkyl) aminoalkyl) , alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl , alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle; R ³ is absent when X ² is N; or when X ² is C, R ³ 'represents H or halo, preferably H or F; BE2018 / 0103 R ⁴ represents H or halo, preferably H or F; and R ⁵ represents H or halo, preferably H or F. 3. Pharmaceutical composition according to claim 1 or claim 2, wherein the compound is of formula (Ia-1)

(Ia-1) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ¹ ', R ² , R ³ , R ⁴ and R ⁵ are as defined in claim 2. 4. Pharmaceutical composition according to any one of claims 1 to 3, in which the compound is of formula (la-la)

or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ and R ³ are as defined in claim 2; and R ¹ represents an alkyl or heterocyclyl group substituted by one or more groups selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyc) aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminooxycarbonyl BE2018 / 0103 alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkenylcarbonyl, alkenylcarbonyl 5. Pharmaceutical composition according to any one of claims 1 to 3, in which the compound has the formula (la-lb)

(la-lb) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ and R ³ are as defined in claim 2; R ¹ represents H or halo, preferably H or F; and R ² represents an alkyl or heterocyclyl group substituted by one or more groups selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyc) aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyle. BE2018 / 0103 6. Pharmaceutical composition according to any one of claims 1 to 3, in which the compound is of formula (la-le) or (la-ld)

or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ and R ³ are as defined in claim 2; R ¹ represents H or halo, preferably H or F; R ² represents H or halo, preferably H or F; R ¹¹ or R ¹ “each independently represent a hydrogen atom, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl alkyl , alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl , alkynylcarbonyl, alkylsulfoxydealkyl or alkylsulfonealkyle; and R ²¹ or R ²¹¹ each independently represent a hydrogen atom, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroarylalkyl, heteroaryl alkyl , alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, BE2018 / 0103 aminocarbonylalkylamino, (ammocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxydealkyle or alkylsulfonealkyle . 7. Pharmaceutical composition according to any one of claims 1 to 6, in which the compound of formula (I) is selected from the group consisting of: 3- (2- (4- (4 - ((1 H-1,2,3 -triazolo-4yl) 2-methoxyfluorophenyl) piperazine-1 -yl) ethyl) -5amino- (8- (furan-2-yl ) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidine-2 (3H) -one; 5 - ((4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [l, 2,4]] triazolo [l, 5- c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) methyl) -1,3,4oxadiazol-2 (3H) -one; 5-amino-3- (2- (4- (3-fluoropyridin-4-yl) piperazin-1-yl) ethyl) -8- (furan-2yl) thiazolo [5,4-e] [1,2, 4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 2- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [1,5-c ] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difhiorophenoxy) acetamide; (S) -5-amino-3- (2- (4- (2-fluoro-4- (2- (methylsulfinyl) ethoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (R) -5-amino-3- (2- (4- (2-fluoro-4- (2- (methylsulfinyl) ethoxy) phenyl) -piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (R, S) -5-amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazinl-yl) ethyl) -8- (furan-2 -yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (R) -5-amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl ) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (S) -5-amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfmyl) ethoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl ) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-8- (furan-2-yl) -3- (2- (4- (4- (4- (2-hydroxyethoxy) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4-e] [1, 2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; acid 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) phenoxy) acetic; BE2018 / 0103 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5- c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) phenoxy) acetamide; 5-amino-3- (2- (4- (4- (2,3-dihydroxypropoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan-2yl) thiazolo [5,4-e] [1 , 2,4] triazolo [1,5-c] pyrimidm-2 (3H) -one; 5-amino-3- (2- (4- (4- (2-aminoethoxy) phenyl) piperazin-1-yl) ethyl) -8- (fiiran-2yl) thiazolo [5,4-e] [1,2 , 4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1-yl) benzamide; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) -N-methylbenzamide; 5 -amino-8- (furan-2-yl) -3 - (2- (4- (4- (2- (2-morpholinoethoxy) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4-e] [1, 2,4] triazolo [1,5-c] pyrimidm-2 (3H) -one; 5- amino-3- (2- (4- (4- (2- (dimethylamino) ethoxy) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) benzenesulfonamide; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1-yl) -N-methylbenzenesulfonamide; 5- amino-8- (furan-2-yl) -3 - (2- (4- (4- (4- methyl-sulfonyl) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4-e] [1,2, 4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-8- (furan-2-yl) -3- (2- (4- (4- (methylsulfinyl) phenyl) piperazin-lyl) ethyl) thiazolo [5,4-e] [1,2,4 ] triazolo [1,5-c] pyrimidin-2 (3H) -one; 3- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) benzamide; 5-amino-8- (furan-2-yl) -3- (2- (4- (3- (2-hydroxyethoxy) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4-e] [1, 2,4] triazolo [1,5 -c] pyrimidin-2 (3 H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (2-oxo-2- (piperazin-1 -yl) ethoxy) phenyl) piperazin-1 yl) ethyl) -8- (furan- 2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (piperidin-4-ylmethoxy) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4 -e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (piperazine-1 -carbonyl) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4 -e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; BE2018 / 0103 5-amino-3- (2- (4- (2-fluoro-4- (2- (piperazin-1 -yl) ethoxy) phenyl) piperazin-1 -yl) ethyl) 8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (piperazin-1-ylsulfonyl) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5.4 -e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (methylsulfonyl) phenyl) piperazin-1-yl) ethyl) -8- (furan2-yl) thiazolo [5,4-e] [1 , 2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1-yl) -N- (2-aminoethyl) -3-fluorobenzamide; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) -3-fluoro-N- (2- (methylamino) ethyl) benzamide; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) -N- (2- (dimethylamino) ethyl) -3-fluorobenzamide; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) -3-fluoro-N- (2-hydroxyethyl) benzamide; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1-yl) -N- (2,3-dihydroxypropyl) -3-fluorobenzamide; acid 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3 -fluorophenoxy) acetic; acid 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3,5-difluorophenoxy) acetic; acid 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3-fluorophenoxy) propanoic; acid (S) -2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4- e] [1,2,4] triazolo [1,5-c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3fluorophenoxy) propanoic; acid 2- (4- (4- (2- (5-amino-8- (fiiran-2-yl) -2-oxothiazolo [5,4-e] [l, 2,4]] triazolo [l, 5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3-fluorophenoxy) -2-methylpropanoic; 3- (4- (4- (2- (5-amino-8- (furan-2-yl) -2 -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [1,5c] acid pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3 -fluorophenyl) propanoic; acid 4- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3-fluorophenoxy) butanoic; acid 2- (3- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,6-difluorophenoxy) acetic; BE2018 / 0103 acid 2- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [l , 5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluorophenoxy) acetic; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 acid (2H) -yl) ethyl) piperazin-1 -yl) -3-fluorobenzoic acid; 2 - ((2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [l , 5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) ethyl) amino) acetamide; 2- ((2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [l , 5- c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) ethyl) (methyl) amino) acetamide; 5-amino-3- (2- (4- (2-fluoro-4- (piperidin-4-yloxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2-yl) thiazolo [5, 4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (pyrrolidin-3-yloxy) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5,4 -e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 3- (2- (4- (4 - ((1H-1,2,4-triazol-3-yl) methoxy) -2-fluorophenyl) piperazin-1-yl) ethyl) -5- amino-8- ( furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [l, 2,4] triazolo [l, 5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N- (2 (methylamino) ethyl) acetamide; 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N- (2 (dimethylamino) ethyl) acetamide; 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N- (2 aminoethyl) acetamide; acid (R) -2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4- e] [1,2,4] triazolo [1,5-c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3fluorophenoxy) propanoic; 2- (4- (4- (2- (5-amino-8- (fiiran-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1 -yl) -3-fluorophenoxy) acetamide; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1-yl) -3-fluoro-N-methyl-N- (2- (methylamino) ethyl) benzamide; BE2018 / 0103 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1-yl) -N- (2- (dimethylamino) ethyl) -3-fluoro-N-methylbenzamide; (R) -4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -N- (1 - (dimethylamino) propan-2-yl) -3fluorobenzamide; 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N-methyl-N- (2 (methylamino) ethyl) acetamide; acid 2- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [l, 2,4]] triazolo [l, 5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluorophenoxy) -2methylpropanoic; acid (S) -2- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4- e] [1,2,4] triazolo [1,5-c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluorophenoxy) propanoic; acid (R) -2- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4- e] [1,2,4] triazolo [1,5-c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluorophenoxy) propanoic; 2- (5- (4- (2- (5 -amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) -N- (2 (methylamino) ethyl) acetamide; 2- (5- (4- (2- (5 -amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5- c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) -N- (2 (dimethylamino) ethyl) acetamide; 5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1-yl) -N- (2- (dimethylamino) ethyl) -2,4-difluoro-Nmethylbenzamide; acid 4- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) butanoic; 3- (2- (4- (5 - ((1H-tetrazol-5-yl) methoxy) -2,4-difluorophenyl) piperazin-1-yl) ethyl) -5amino-8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; BE2018 / 0103 5 -amino-3- (2- (4- (2-fluoro-4 - ((1 -methyl- 1H-1,2,4-triazol-3-yl) methoxy) phenyl) piperazin-1 -yl) ethyl ) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5 - ((1-methyl-1H-1,2,4-triazol-3-yl) methoxy) phenyl) piperazin-1-yl ) ethyl) -8- (furan-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1-yl) -3-fluoro-N- (2- (methyl (oxetan-3-yl) amino) ethyl) benzamide; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1-yl) -3-fluoro-N- (2 - ((2-hydroxyethyl) amino) ethyl) benzamide; 2-amino-N- (2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [1,5-c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3fluorophenoxy) ethyl) acetamide; (S) -2-amino-N- (2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4e]] [1,2, 4] triazolo [1,5-c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -3fluorophenoxy) ethyl) -3-methylbutanamide; 2- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4]] triazolo [1,5-c ] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) ethyl acetate; 2- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluorophenoxy) acetonitrile; 5- amino-8- (fiiran-2-yl) -3- (2- (4- (pyridin-4-yl) piperazin-1-yl) ethyl) thiazolo [5,4- e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-8- (furan-2-yl) -3- (2- (4- (pyrimidin-4-yl) piperazin-1-yl) ethyl) thiazolo [5,4e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfonyl) ethoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5 , 4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (2- (methylsulfonyl) ethoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5,4 -e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (6-fluoro-2-oxoindolin-5-yl) piperazin-1-yl) ethyl) -8- (fiiran-2yl) thiazolo [5,4-e] [ 1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; BE2018 / 0103 5-amino-3- (2- (4- (2-fluoro-4- (S-methylsulfonimidoyl) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5,4-e ] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) -N- (2- (dimethylamino) ethyl) -2,4-difluorobenzamide; 5-amino-3- (2- (4- (5-fluoro-2-methylpyridin-4-yl) piperazin-1-yl) ethyl) -8- (furan-2yl) thiazolo [5,4-e] [ 1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4 - (((3R, 4R) -4-hydroxytetrahydrofuran-3yl) oxy) phenyl) piperazin-1-yl) ethyl) -8- (furan -2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4 - (((3S, 4S) -4-hydroxytétrahydroftiran-3yl) oxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan -2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (2-hydroxy-2-methylpropoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5, 4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5 -amino-3 - (2- (4- (2-fluoro-4- (2-hydroxypropan-2-yl) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5 , 4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (3,3,3-trifluoro-2-hydroxypropoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-5- (2-hydroxyethoxy) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5,4-e ] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5- (morpholin-2-ylmethoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5, 4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5- (morpholin-3-ylmethoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5, 4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5 - (((3S, 4S) -4-fluoropyrrolidin-3yl) oxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5 - (((3S, 4S) -4-fluoropyrrolidin-3yl) oxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5 - (((3 R, 4S) -4-fluoropyrrolidin-3yl) oxy) phenyl) piperazin-1 -yl) ethyl) -8 - (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; BE2018 / 0103 5-amino-3- (2- (4- (2,4-difluoro-5 - (((3S, 4R) -4-fluoropyrrolidin-3yl) oxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; (S) -5-ammo-3- (2- (4- (2,4-difluoro-5 - ((2-oxopyrrolidin-3-yl) oxy) phenyl) piperazm-lyl) ethyl) -8- (furan -2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (R) -5-amino-3- (2- (4- (2,4-difluoro-5 - ((2-oxopyrrolidin-3-yl) oxy) phenyl) piperazm-lyl) ethyl) -8- (furan -2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidm-2 (3H) -one; 2- (5- (4- (2- (5-amino-8- (fiiran-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazm-1-yl) -2,4-difluorophenoxy) -N- (2morpholinoethyl) acetamide; 5- (4- (2- (5-ammo-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluoro-N- (morpholin-3-ylmethyl) benzamide; 5-amino-3- (2- (4- (2-fluoro-4- (morpholin-3-ylmethoxy) phenyl) piperazin-1-yl) ethyl) 8- (furan-2-yl) thiazolo [5,4 -e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4- (morpholin-2-ylmethoxy) phenyl) piperazin-1-yl) ethyl) 8- (furan-2-yl) thiazolo [5,4 -e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4 - (((3R, 4R) -4-fluoropyrrolidin-3yl) oxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan -2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4 - (((3S, 4S) -4-fluoropyrrolidin-3-yl) oxy) phenyl) piperazin- 1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4 - (((3R, 4S) -4-fluoropyrrolidin-3-yl) oxy) phenyl) piperazin- 1- yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4 - (((3S, 4R) -4-fluoropyrrolidin-3-yl) oxy) phenyl) piperazin- 1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [l, 2,4] triazolo [l, 5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1 -yl) -3-fluorophenoxy) -N- (2morpholinoethyl) acetamide; 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) -3-fluoro-N- (2-morpholinoethyl) benzamide; 4- (4- (2- (5-amino-8- (ftiran-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin3 ( 2H) -yl) ethyl) piperazin-1 -yl) -3-fluoro-N- (morpholin-3-ylmethyl) benzamide; BE2018 / 0103 5-amino-3- (2- (4- (4- (azetidm-3-yloxy) phenyl) piperazin-1-yl) ethyl) -8- (furan-2yl) thiazolo [5,4-e] [1 , 2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (S) -5-amino-3- (2- (4- (2,4-difluoro-5- (methylsulfinyl) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5 , 4-e] [1,2,4] triazolo [1,5-c] pyrimidm-2 (3H) -one; (R) -5-amino-3- (2- (4- (2,4-difluoro-5- (methylsulfinyl) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5 , 4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5 - (((1 s, 4s) -1 -oxydotetrahydro-2H-thiopyran-4yl) oxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5 - (((lr, 4r) -l-oxydotetrahydro-2H-thiopyran-4yl) oxy) phenyl) piperazin-1 -yl) ethyl ) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; (S) -5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluoro-N- (2 (methylsulfinyl) ethyl) benzamide; (R) -5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -2,4-difluoro-N- (2 (methylsulfinyl) ethyl) benzamide; AAA 4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluoro-N-methyl-N- (2 (methylsulfinyl) ethyl) benzamide; (R) -5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -2,4-difluoro-N-methyl-N- (2 (methylsulfinyl) ethyl) benzamide; 5-amino-3- (2- (4- (2,4-difluoro-5- (1 -oxydothiomorpholine-4carbonyl) phenyl) piperazin-1 -yl) ethyl) -8 - (furan-2-yl) thiazolo [ 5.4e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2,4-difluoro-5- (l-oxydothiomorpholino) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (R) -5-amino-3- (2- (4- (2-fluoro-4- (methylsulfinyl) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5,4 -e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (S) -5-amino-3- (2- (4- (2-fluoro-4- (methylsulfinyl) phenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5,4 -e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 100 BE2018 / 0103 5-amino-3- (2- (4- (2-fluoro-4 - (((1 s, 4s) -1 -oxydotetrahydro-2H-thiopyran-4yl) oxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (2-fluoro-4 - (((lr, 4r) -l-oxydotetrahydro-2H-thiopyran-4yl) oxy) phenyl) piperazin-1 -yl) ethyl) - 8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one; (S) -4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluoro-N- (2 (methylsulfinyl) ethyl) benzamide; (R) -4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluoro-N- (2 (methylsulfinyl) ethyl) benzamide; 5-amino-3- (2- (4- (2-fluoro-4- (l-oxydothiomorpholine-4-carbonyl) phenyl) piperazin- 1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidm-2 (3H) -one; 5 -amino-3 - (2- (4- (2-fluoro-4- (1 -oxydothiomorpholino) phenyl) piperazin-1 -yl) ethyl) 8- (furan-2-yl) thiazolo [5,4-e ] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (S) -5-amino-3- (2- (4- (5- (2,3-dihydroxypropoxy) -2,4-difluorophenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (R) -5-amino-3- (2- (4- (5- (2,3-dihydroxypropoxy) -2,4-difluorophenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (S) -5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -N- (2,3-dihydroxypropyl) -2,4difluorobenzamide; (R) -5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -N- (2,3-dihydroxypropyl) -2,4difluorobenzamide; 5-amino-3- (2- (4- (4- (azetidin-3-yloxy) -2-fluorophenyl) piperazin-1-yl) ethyl) -8- (furan2-yl) thiazolo [5,4-e ] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (5- (azetidin-3-yloxy) -2,4-difluorophenyl) piperazin-1-yl) ethyl) -8 (furan-2-yl) thiazolo [5, 4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (S) -5-amino-3- (2- (4- (2,4-difluoro-5- (3- (methylsulfinyl) propoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl ) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; and the pharmaceutically acceptable salts or solvates thereof. 101 BE2018 / 0103 8. Pharmaceutical composition according to any one of claims 1 to 7, in which the compound of formula (I) is selected from: (R, S) -5-amino-3- (2- (4- (2, 4-difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazin- 1-yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-5 e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; and (+) - 5-amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2- yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one. 9. Pharmaceutical composition according to any one of claims 1 to 8, further comprising PEG400 and / or caprylic acid. 10. A pharmaceutical composition according to any of claims 1 to 9, further comprising an antioxidant; preferably the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid, sodium metabisulfite, ascorbic acid, methionine and vitamin E; more preferably the antioxidant is BHT. 11. Pharmaceutical composition according to any one of claims 1 to 10, wherein the compound of formula (I) is present in an amount ranging from 1% to 20% w / w, preferably from 5% to 15% w / w, more preferably from about 10% w / p. 12. Pharmaceutical composition according to any one of claims 1 to 11, the lauroyl polyoxyl-32 glycerides are present in an amount ranging from 55% to 99% w / w, preferably from 60% to 95% w / w, more preferably from 70% to 85% w / w. 13. Pharmaceutical composition according to any one of claims 1 to 12, wherein the composition can be formulated in the form of different dosage forms such as capsules, tablets or granules. 102 BE2018 / 0103 14. Pharmaceutical composition according to any one of claims 1 to 13, for use in the treatment and / or prevention of cancer. 15. Pharmaceutical composition for its use according to claim 14, 5 in which the cancer is selected from breast, carcinoid, cervical, colorectal, endometrial, glioma, head and neck, liver, lung and melanoma cancers, ovarian, pancreatic, prostate, kidney, gastric, thyroid and urothelial cancers.