BE1026615B1 - COMBINATION OF AN A2A RECEPTOR INHIBITOR AND AN ANTI-CANCER AGENT - Google Patents

Abstract

The present invention relates to a combination comprising an inhibitor of the A2A receptor of formula (I) or the pharmaceutically acceptable salts thereof, and an anti-cancer agent. The anticancer agent is, for example, an immunotherapeutic agent, such as a checkpoint inhibitor. The invention further relates to a pharmaceutical composition and a kit comprising such a combination. In addition, the combination of the invention is particularly useful for the treatment and / or prevention of cancers.

Description

COMBINATION OF AN A2A RECEPTOR INHIBITOR AND ANTI-CANCER AGENT

FIELD OF THE INVENTION

The present invention relates to a combination comprising an inhibitor of the adenosine A2A receptor (A2AR) and an anti-cancer agent. The A2AR inhibitor is a thiocarbamate derivative of formula (I) as defined below. The anticancer agent is, for example, an immunotherapeutic agent, such as a checkpoint inhibitor. The invention further relates to a pharmaceutical composition and a kit comprising this combination. The combination of the invention is particularly useful for the treatment and / or prevention of cancers.

BACKGROUND OF THE INVENTION

There are a large number of anti-cancer agents, such as, for example, immunotherapeutic agents, chemotherapeutic agents or antiangiogenic agents or combinations thereof. However, their anticancer effect may remain insufficient. This may be due, at least in part, to immune escape mechanisms.

Many of the immunosuppressive mechanisms in tumors are common to physiological immunoregulation in normal tissues. In addition to immunosuppressive signal transducers located on the cell surface, for example, CTLA-4 and PD-1, immunosuppression in the tumor microenvironment also involves anti-inflammatory cytokines (IL-10, TGF-β), enzymes (indoleamine-2,3-dioxygenase), and professional immunoregulatory cells (regulatory T lymphocytes, myeloid suppressor cells (MDSC)). These immunosuppressive mechanisms play an important role in regulating the immune response in normal tissues. Since tumors take advantage of these physiological immunoregulatory mechanisms to protect their tissue from immune attack, these mechanisms are now found to be major obstacles preventing spontaneous cancer regression and immunological treatment of cancer.

Identification of immunosuppressive mechanisms in tumors has shown molecular targets to restore immune response

BE2018 / 0114 antitumor. For example, so-called immune checkpoint mechanisms have become a center of attention in drug research. Checkpoint inhibitors, including antibodies against PDI, PDL1, or CTLA4 have received approval as anticancer therapies for a large number of indications, such as metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, urothelial carcinoma, hepatocellular carcinoma, as well as as a treatment for patients with solid tumors that exhibit one of two characteristics specific genetics known as mismatch repair deficiency and high microsatellite instability (independent of cancer type).

Extracellular adenosine is known to be 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 G protein-coupled adenosine receptors 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 take advantage of 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).

Of the four types of known adenosine receptors, the A2A adenosine receptor (A2AR) is the subtype primarily expressed in most immune cells. A2AR stimulation generally provides an immunosuppressive signal which inhibits the activities of T lymphocytes (proliferation, cytokine production, cytotoxicity), NK cells (cytotoxicity), NKT cells (cytokine production, upregulation of CD40L), macrophages / dendritic cells (presentation of antigens, production of cytokines), and neutrophils (oxidative explosion).

The presence of elevated levels of extracellular adenosine in tumors has been shown to play a significant role in evading the anti-tumor immune response. It has been demonstrated in particular in mice deficient in

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A2AR that the inoculated tumor could spontaneously regress, whereas no wild type mice showed similar tumor regression. A2AR antagonists have also been shown to be beneficial in wild-type tumor-bearing animals. It is important to note that T lymphocyte and NK cell depletion altered the retardation of 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 the stimulation of A2AR. In addition, when activated in the presence of an A2AR agonist, T cell effector function remains impaired even after withdrawal of the A2AR agonist. This result suggests that the environment rich in adenosine in tumors can induce T lymphocytes that are anergic to tumor cells.

Therefore, given that the A2A receptor is expressed in most immune cells and especially in effector immune cells such as T lymphocytes and NK cells and given that the A2A receptor is engaged in tissues where adenosine is produced, it is believed that 2A2R inhibitors may be useful in all indications of cancer.

The applicant has provided a series of non-brain penetrating A2A inhibitors in international patent application PCT / EP2018 / 058301, which are thiocarbamate derivatives, which are useful in restoring immune functions in the environment of the tumor. However, the specific combination of A2AR inhibitors with other anticancer agents has not been reported.

In the present document, the applicant proposes a combination comprising an inhibitor of the adenosine A2A receptor as described in the international patent application PCT / EP2018 / 058301 and another anticancer agent, for example an immunosuppressive agent such as an inhibitor of control points.

ABSTRACT

The invention thus relates to a combination comprising:

(a) a compound of formula (I):

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o (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ and R ² are as defined below; and (b) an anti-cancer agent.

In one embodiment, the compound of formula (I) is of formula (la), (Ia-1) or (la-b) as defined below.

In one embodiment, the anti-cancer agent is selected from immunotherapeutic agents, chemotherapeutic agents, antiangiogenic agents, inhibitors of multidrug resistance associated proteins, radiotherapeutic agents, and any combination thereof.

In one embodiment, the immunotherapeutic agent is selected from checkpoint inhibitors, checkpoint agonists, IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, inhibitors of enzymes producing adenosine, immune cells, therapeutic vaccines, or any combination thereof.

In one embodiment, the checkpoint inhibitor is an inhibitor of a checkpoint protein selected from PD-1, PD-L1, and CTLA-4.

In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody; the PD-L1 inhibitor is an anti-PD-L1 antibody; and the CTLA-4 inhibitor is an anti-CTLA-4 antibody.

In one embodiment, the chemotherapeutic agent is selected from anti-cancer alkylating agents, anti-cancer antimetabolites, anti-cancer antibiotics, anti-cancer agents derived from plants, anti-cancer platinum coordinating compounds, and any combination thereof.

The invention also relates to a pharmaceutical composition comprising:

(a) a compound of formula (I) as defined in this document; and

BE2018 / 0114 (b) an anticancer agent as defined in this document.

The invention also relates to a kit comprising:

(a) a first part comprising compound of formula (I) as defined in the present document; and (b) a second part comprising an anticancer agent as defined in this document.

In one embodiment, the combination, pharmaceutical composition or kit according to the invention are intended for medical use.

In one embodiment, the combination, pharmaceutical composition or kit according to the invention is for use in the treatment and / or prevention of cancer.

In one embodiment, the cancer is selected from cancers of the breast, carcinoids, cervix, colorectal, endometrium, glioma, cancers of the head and neck, of the liver, of the lung, melanoma, ovarian, pancreatic, prostate, kidney, gastric, thyroid and urothelial cancers.

In one embodiment, the combination, or the kit according to the invention is intended to be administered to a patient in need thereof sequentially and / or at the same time.

In one embodiment, the combination, or the kit according to the invention is intended to be administered to a patient in need thereof by different routes of administration.

DEFINITIONS

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

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

The term "alkenyl" refers to an unsaturated hydrocarbyl group, which may be linear or branched, comprising one or more carbon-carbon double bonds. Suitable alkenyl groups have 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.

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The term “alkenylcarbonyl” refers to a - (C = O) -alkenyl group in which alkenyl is as defined herein.

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

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

The term "alkyl" refers to a hydrocarbyl radical of 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, moreover. Preferably, the alkyl groups of this invention have from 1 to 6 carbon atoms. 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 herein.

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

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

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

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

The term "alkylheteroaryl" refers to a heteroaryl group substituted with an alkyl group in which alkyl is as defined herein.

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

The term "alkylsulfonyl" refers to a -SCL-alkyl group in which alkyl is as defined herein.

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The term "alkylsulfonealkyl" refers to an -alkyl-SCh-alkyl group in which alkyl is as defined herein.

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

The term "alkylsulfoxide" refers to a - (S = O) -alkyl group in which the alkyl group is as defined herein.

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

The term "alkyne" refers to a class of monovalent unsaturated hydrocarbyl groups, in which the unsaturation arises 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 "alkynealkyl" refers to an -alkyl-alkyne group in which alkyl and alkyne are as defined herein.

The term "amino" refers to an -NH2 group.

The term "aminoalkyl" refers to an -alkyl-NH 2 group in which the alkyl group is as defined herein.

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

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

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 an -alkyl- (C = O) -NH2 group, in which alkyl is as defined in this document.

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

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

The term "aryl" refers to a polyunsaturated aromatic hydrocarbyl group having a single ring (in other words, phenyl) or multiple

BE2018 / 0114 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 phenyl, naphthalenyl.

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

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

The term "cycloalkyl" refers to a cyclic alkyl group, in other words, a monovalent, saturated, or unsaturated hydrocarbyl group having 1 or 2 ring structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups have 3 or more carbon atoms in the ring and generally in accordance with the present invention have 3 to 10, more preferably 3 to 8 carbon atoms; still 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 herein.

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 herein.

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

The term "dialkylaminoalkylaminocarbonyl" refers to a group - (CO) -NH-alkyl-NR ¹ R ² in which R ¹ and R ² are both an alkyl group, as defined herein.

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 herein.

The term "dihydroxyalkyl" refers to an alkyl group as defined herein and is substituted with two hydroxyl groups (-OH).

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

The term "heteroaryl" refers to an aryl group as defined herein in which at least one carbon atom is replaced by a heteroatom. In other words, it refers to single aromatic rings of 5 to 12 carbon atoms or ring systems containing 2 rings which are fused to each other, typically containing 5 to 6 atoms; wherein one or more carbon atoms are replaced by oxygen, nitrogen and / or sulfur atoms, wherein the nitrogen and sulfur heteroatoms can be optionally oxidized and the nitrogen heteroatoms can optionally be quaternized . Non-limiting examples of such heteroaryl groups include the groups: oxazolyl, thiazolyl, imidazolyl, furanyl and pyrrolyl. Preferably the heteroaryl group is a 5 or 6 membered heteroaryl group, more 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 (eg, 3- to 7-membered monocyclic, 7 to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) which have 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 may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulfur atoms, where the nitrogen and sulfur heteroatoms may optionally be oxidized and the nitrogen heteroatoms may optionally be quaternized. The heterocyclic group can be bonded to any heteroatom or carbon atom of the ring or ring system, when the valence permits. The rings of multi-ring heterocycles can be fused, bridged and / or joined through one or more spiroatoms. 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,

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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, tetrahydroquinolinyl, tetrahydroisoquinolin-1 -yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetraholin-4-thoolin-coolinid-3-yl, tetrahole-4-thoolinidolinid-3-yl yl, 1-dioxido-1-thiomorpholin-4-yl, 1,3-dioxolanyl, 1,4oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolizinyl, tetrahydro-1,1dioxothiophenyl, N- formylpiperazinyl, and morpholin-4-yl.

The term "heterocyclylalkylaminocarbonyl" refers to an (OO) -NH-alkyl-heterocyclyl group, in which alkyl and heterocyclyl are as defined herein.

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

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

The term "heterocyclylalkyl" refers to an -alkylheterocyclyl group in which alkyl and heterocyclyl are as defined herein.

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

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

The term "hydroxyalkyl" refers to an -alkyl-OH group in which alkyl is as defined herein.

The term "hydroxyalkylaminoalkyl" refers to an -alkyl-NHalkyl-OH group in which alkyl is as defined herein.

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

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

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

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The term "approximately", before a figure, covers plus or minus 10%, or less, of the value of the said figure. It should be understood that the value to which the term "about" refers is itself also specifically, and preferably, described.

The term "administering", or a variation thereof (eg, "administering"), means providing the active agent or the active ingredient (eg, an A2AR inhibitor or an anti-cancer agent), alone or as an agent. a part of a pharmaceutically acceptable composition, to the patient in whom the condition, symptom, or disease is to be treated or prevented.

The term "autologous" refers to any material derived from the same individual as that in which it will subsequently be reintroduced.

The term "allogeneic" refers to any material derived from a different individual of the same species as the individual into whom the material is introduced. Two or more individuals are said to be allogeneic to each other when the genes at one or more loci are not identical. In some aspects, the allogenic material from individuals of the same species may be genetically non-similar enough to interact antigenically.

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 significantly reduce or down-regulate the expression of a gene and / or protein or which has a biological effect of inhibition or significant reduction in the biological activity of a protein. Therefore, an "A2AR inhibitor" refers to a compound which has a biological effect of significantly inhibiting or reducing or downregulating 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, infant, child, adolescent, adult).

The term "patient" refers to a mammal, more preferably a human, who is awaiting, or is being administered, medical care or who is / will be the subject of a medical procedure.

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The term "pharmaceutically acceptable" refers to 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 an adverse, allergic or other adverse reaction when administered to an animal, preferably a human. It includes any inactive substance such as for example solvents, cosolvents, antioxidants, surfactants, stabilizers, 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, coating agents, fillers, release agents, absorption retarders, sweetening agents, flavoring agents and the like. For human administration, preparations must meet standards for sterility, pyrogenicity, general safety and purity as required by regulatory offices such as, for example, the FDA or EMA.

The term "premedication", as used herein, means any compound which will be modified to form a species of drug, wherein the modification can take place inside or outside the body, and either before the drug reaches, or after it has reached, the area of the body where administration of the drug is indicated.

The terms “prevent”, “prevent” and “prevention” as used in this document refer to a process of delaying or preventing the onset of a disease 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 herein means pharmacologically acceptable derivatives of compounds of formula (I), such as for example esters or amides, the biotransformation product of which in vivo generates the biologically active drug. . Prodrugs are

BE2018 / 0114 generally characterized by increased bioavailability and are readily metabolized to biologically active compounds in vivo.

The terms “therapeutically effective amount” or “therapeutically effective dose” refer to the amount or dose of the active ingredient intended to, without causing negative or undesirable side effects for the subject, (1) delay or prevent the onset of. cancer in the subject; (2) reduce the severity or incidence of cancer; (3) reduce or stop the progression, worsening, or worsening of one or more symptoms of cancer affecting the subject; (4) allow improvements in symptoms of cancer affecting the subject; or (5) cure cancer affecting the subject. A therapeutically effective amount can be administered before the onset of cancer for prophylactic or preventive action. Alternatively, or in addition, a therapeutically effective amount can be administered after initiation of cancer for therapeutic action.

The terms "treat" or "treatment" refer to therapeutic treatment; wherein the object is to prevent or slow down the pathological condition or disease targeted. 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 or absence of. at least one of the following: reduction in the number of cancer cells; 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 the success of treatment and improvement of the disease can be easily measured by routine procedures familiar to a physician.

The term "subject" refers to a mammal, preferably a human. In one embodiment, cancer is diagnosed in a subject. In one embodiment, the subject is a patient, preferably a human patient, who is awaiting, or is being administered, medical care, or who has been / has been / will be the subject of a procedure. medical, or in whom the development or progression of a disease, such as cancer, is monitored. In one embodiment, the subject is a human patient who is receiving treatment and / or being monitored for the development or progression of cancer. In

BE2018 / 0114 one embodiment, the subject is a man. In another embodiment, the subject is a woman. In one embodiment, the subject is an adult. In another embodiment, the subject is a child.

The terms "tumor specific antigen" or "tumor associated antigen" refer to an antigen specifically and / or abundantly expressed by cancer cells or tumor cells. It is possible to refer to T lymphocytes expressing T lymphocyte receptors recognizing said antigens and binding thereto as with T lymphocytes recognizing a tumor specific or associated with a tumor, T lymphocytes specific for a specific antigen of a tumor. a tumor or associated with a tumor, with T lymphocytes specific for a tumor specific or associated with a tumor antigen, or with T lymphocytes directed against a specific antigen of a tumor or associated with a tumor.

The term "vaccine" refers to a preparation comprising a substance or a group of substances (in other words, a vaccine) intended to induce and / or enhance in a subject a targeted immune response to an infectious agent (such as viruses, bacteria, fungi or parasites) or to cancer cells. Prophylactic vaccination is used to prevent a subject from contracting a particular disease or to limit the disease to a moderate form of the disease. Therapeutic vaccination is intended to treat a particular disease in a subject. For example, therapeutic cancer vaccines may comprise tumor associated antigen or tumor associated antigens, aimed at inducing and / or enhancing a cell-mediated immune response, in particular an immune response of T cells, directed against cells. cancer cells expressing said antigen (s) associated with a tumor.

DETAILED DESCRIPTION

Combination

The invention relates to a combination comprising:

(a) at least one inhibitor of the adenosine A2A receptor (A2AR), and (b) at least one anticancer agent.

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In a preferred embodiment, the invention relates to a combination comprising:

(a) at least one A2AR inhibitor which is a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I)

or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ and R ² are as defined below; and (b) at least one anticancer agent.

As detailed below, the anticancer agent can be selected from immunotherapeutic agents, chemotherapeutics, antiangiogenic agents, inhibitors of multidrug resistance associated proteins, radiotherapeutic agents, and any combination. of these.

In the context of the present invention, the term "combination" preferably means a combined occurrence of an A2AR inhibitor and an anti-cancer agent. Therefore, the combination of the invention either can occur in the form of a composition, comprising all of the components in one and the same mixture (eg, a pharmaceutical composition), or can occur in the form of a kit, in which the different constituents form different parts of such a kit. The administration of the A2AR inhibitor and the anticancer agent can take place simultaneously or be staggered over time, with a similar or different timing of administration (in other words, similar or different numbers of administration of each component), either at the same administration site or at different administration sites, in similar or different dosage forms.

The invention is based on the surprising finding that the combination of an A2AR inhibitor and an anti-cancer agent (as per

BE2018 / 0114 (example an immunotherapeutic agent, especially a checkpoint inhibitor), exhibits extremely beneficial inhibition of tumor growth and / or reduction in the number of cancer cells, resulting in improved survival which could not be achieved. 'wait in the prior art. Thus, combined treatment with an A2AR inhibitor and an anticancer agent could greatly reduce the adverse impact of a disease to be treated, for example, the rate of tumor growth. These effects are illustrated in the examples below.

A2AR inhibitor

As the first component, the combination of the invention comprises an A2AR inhibitor. Preferably, the A2AR inhibitor is a thiocarbamate derivative, in particular a thiocarbamate derivative such as those described in document PCTZEP2018 / 058301. Preferably, the A2AR inhibitor is a thiocarbamate derivative of formula (I) as described below.

In a preferred embodiment, the combination of the invention thus comprises, as an A2AR inhibitor, 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, in which the heteroaryl or aryl groups are optionally substituted with 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 ¹ represents a furyl group;

R ² represents a 6-membered aryl group or a 6-membered heteroaryl group,

BE2018 / 0114 wherein 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, hydroxycarbonyl, heterocyclylcarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfonsulfonycylcarbonyl, heterocyclylcarbonyl, alkylsulfonyclyl, alkylsulfonylcarbonyls 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) (heterocyclylalkyl) 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 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 with one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl, aminoalkyl, heteroalkaryl) (alkyl) (alkyl )aryl , alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl ,

BE2018 / 0114 alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyl.

In one embodiment, the preferred compounds of formula (I) are of formula (Ia):

(Ia) 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 methyl) and a halo group (preferably 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, alkylsulfonylsulfonylsulfonylsulfonylsulfonyl, alkylsulfonylsulfonylsulfonylsulfonylsulphonylsulfonylsulfonylsulfonyl, alkylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl, alkylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl, alkylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl

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) (heterocyclylalkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl

BE2018 / 0114 alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonylcarbonyl, alkylsulfonealcarbonyl, alkylsulfonalkylcarbonyl, alkylsulfonealcarbonyl, alkylsulfonealcarbonyl

R ² is H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyle, carbonylamino, sulfonylamino, or alkylsulfonealkyle;

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) (heterocyclylalkyl) 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 6 links; optionally substituted with one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl, aminoalkyl, heteroalkaryl) (alkyl) (alkyl )aryl , alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,

BE2018 / 0114 alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkylsulfonylcarbonyl, alkylsulfonealcarbonyl, alkylsulfonalkylcarbonyl, alkylsulfonealcarbonyl, alkylsulfonealcarbonyl

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 * 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 with one or more substituents selected from a group of substituents. C1-C6 alkyl group (preferably methyl) 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.

In a specific embodiment of the invention, X ¹ and X ² each independently represent C or N. In another specific embodiment, X * 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, alkylsulfoxyl, alkylsulfonyl, aminosulfonycycyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino or alkylsulfonealkyle; 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) (heterocyclylalkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl,

BE2018 / 0114 alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyle alkylsulfonyl and alkylsulfonealkyle.

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

In a specific embodiment of the invention, R ² represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonlsulfonimidycinoyl, alkylcarbonyl, heterocycylinoyl, aminosulfonlsulfonimidycinoyl, alkylcarbonyl, heterocyclyl, alkylcarbonyl sulfonylamino, or alkylsulfonealkyle; 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) (heterocyclylalkyl) 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 / 0114 alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyl.

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

In another specific embodiment of the invention, 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. 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, (heterocyclyl, aminoalkyl, heteroalkaryl) (alkyl) (alkyl )aryl , 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 alkylsulfonealkyl.

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.

BE2018 / 0114

In one embodiment, the preferred compounds of formula (Ia) are those 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 formula (la).

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

(la-la) or a pharmaceutically acceptable salt or solvate thereof, wherein:

R ¹ and R ³ 'are as defined in formula (Ia); and

R ¹ represents an alkyl or heterocyclyl group substituted with one or more groups selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, (aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, dialkylaminoalkyl, aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl,

BE2018 / 0114 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, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylcarbonyl, aminocarbonylcarinoalkylcarbonyl, aminocarbonylcarinoalkylcarbonyl, aminocarbonylaminocarbonylcarbonylcarbonyl) (alkylcarbonylcarbonyl) (aminocarbonylcarbonyl) (aminocarbonylcarbonyl) (aminocarbonylcarbonyl) , dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulphoxeal, alkylsulphoxide, alkylsulphoxide, alkylsulphoxide, alkylsulphoxeal, alkylsulphoxide, alkylsulphoxeal

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

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

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

O (la-lb)

BE2018 / 0114 or a pharmaceutically acceptable salt or solvate thereof, in which:

R ¹ and R ³ 'are as defined in formula (Ia);

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, dialkylaminoalkyl, 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, alkylsulfoxydealkyle, 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 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, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylcarbonylalkylamino, (aminocarbonylaminocarbonyl) aminocarbonyl, aminocarbonyl, aminocarbonyl, aminocarbonyl, aminocarbonyl) alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl,

BE2018 / 0114 alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyl, alkylsulfonyl and alkylsulfonealkyl.

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, dialkylaminoalkylcarbonylsulfoxide, alkylsulfoxide, alkylheteroaryl, alkylsulfoxide, alkylaminoalkylcarbonylsulfoxide, alkylsulfoxide, alkylcarbonyl

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

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, alkykaryl, alkyalkaryl, heterocykaryl, alkykaryl aryalkyl alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl,

BE2018 / 0114 alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylkylkylcarbonyl, alkylkylkylcarbonyl, alkylkynalkylcarbonyl; 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, alkylheterocealhoaryl, heterocyclyl, alkyalkoaryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxydealkyle or alkylsulfonealkyle.

In a specific embodiment of the invention, R * 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 R ¹¹¹ 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, alkylsulfoxydealkyle or alkylsulfonealkyle.

In a preferred embodiment, R ¹¹ or R ¹¹¹ each independently represent a hydrogen, alkyl, heterocyclylalkyl, hydroxyalkyl,

BE2018 / 0114 hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl orheterocyclylalkylaminocarbonyl.

In a specific embodiment of the invention, 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, 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, alkylsulfoxydealkyle or alkylsulfonealkyle. In a preferred embodiment, R ²¹ or R ²¹¹ each independently represent a hydrogen, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl or heterocyclylalkylaminocarbonyl atom. In a preferred embodiment, R ²¹ or R ²¹¹ each independently represent a hydrogen, alkyl or dialkylaminoalkyl atom.

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

BE2018 / 0114 or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ² , R ³ , R ⁴ and R ⁵ are as defined in formula (Ia).

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

TABLE 1

Cp n ° Structure Chemical name MW 1 0 sA _ WArNyN A ° N = N nh ₂ 3- (2- (4- (4 - ((1H-1,2,3triazolo-4-yl) methoxy-2fluorophenyl) piperazin-1 yl) ethyl) -5-amino- (8- (furan2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 577.60 2 sA ° Z * ^{7 u} n-nh nh ₂ 5 - ((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) methyl) - 1,3,4-oxadiazol-2 (3H) -one 594.58 3 sA ° ^Ζ ~~ Λ ^F V nh ₂ 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 h ₂ n _r o AxAÛf υ ' _Ν -ΝγΝ / nh ₂ 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) acetamide 571.56 5 + / T Z 0 V ω-Α \> _ g t (S) -5-amino-3- (2- (4- (2fluoro-4- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [ 5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 586.66

BE2018 / 0114

6 AT Z <N V \) 4 i _ Ό ~ 0-θ ^ ”F (R) -5-amino-3- (2- (4- (2fluoro-4- (2 (methylsulfinyl) ethoxy) phe nyl) -piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 586.66 7 Ä V '° V? 'O ^ _F F (R, S) -5-amino-3- (2- (4- (2,4difluoro-5- (2 (methylsulfinyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2- yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 604.65 8a ^W -Y \) - z Z., zo Ό-s *? / - Λ P 'O ^ _F F (+) - 5-amino-3- (2- (4- (2,4difluoro-5- (2 (methylsulfinyl) ethoxy) phe nyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 604.65 8b o s- \ / - irUA ^ ^ ο-Ν- ^Ν γ ^Ν nh ₂ W? Ό-V) V ^F F (-) - 5-amino-3- (2- (4- (2,4difluoro-5- (2 (methylsulfmyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 604.65 9 ? f ° = <X ï “Y 'nAA oh 5-amino-8- (furan-2-yl) -3 (2- (4- (4- (2-hydroxyethoxy) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4e] [1,2,4 ] triazolo [1,5c] pyrimidin-2 (3H) -one 522.58 10 h ₂ n An (N “N TO N ζΑν-Λ X-An '\\ / N \ i ^V ° sA 0 2- (4- (4- (2- (5-amino8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- acid 3 (2H) yl) ethyl) piperazin-1 yl) phenoxy) acetic 536.56 11 0, o _x nJV ~ <IZXrN ^ N nh ₂ - ⁷ 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) phenoxy) acetamide 535.58

BE2018 / 0114

12 Q- 0 SX \ 'ΝγΝ nh ₂ HO A1 / -4 A / ⁰ OH 5-amino-3 - (2- (4- (4- (2,3 dihydroxypropoxy) phenyl) p iperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1, 2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 552.61 13 o- sX °. Ν ' ^Ν γ ^Ν nh ₂ ^ N ^/ A V / ^N A A z ~~ v ^NH2 = ^ / - c> 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 [l, 5- c] pyrimidin-2 (3H) -one 521.60 14 a, Q A ^ν ύ ^ ^ν 'N' ^N Y ^N nh ₂ ^ O ' nh ₂ o 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-1 yl) benzamide 505.55 15 Λ Q ^Η γ ' ^ζ Z's ^H A 4 N- 0 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 O- 0 nh ₂ ^{Ν =} γΑ Γ I ^S A 0 -N ^/ 'naC 0 lA J ^ ° 5-amino-8- (furan-2-yl) -3 (2- (4- (4- (2morpholinoethoxy) phenyl) p iperazin-1yl) ethyl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 591.68 17 at 0 A'z ί Λ '? κ> Z— F ° O ~ o 5-amino-3 - (2- (4- (4- (2 (dimethylamino) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1 , 2,4] triazolo [1,5- c] pyrimidin-2 (3H) -one 549.65 18 o 0 0 SX Vn ^ n nh ₂ '^ ⁿ CZ ^ ⁿ fk? ^ = /, S ~ NH ₂ 0 4- (4- (2- (5-amino-8- (fiiran2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 yl) benzenesulfonamide 541.61 19 Ô 0 A NyÇ ^N '> ^Ν γ ^Ν nh ₂ o // 0 H 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 / 0114

20 <-o, 0 s- \ Χ'ΝγΝ ^V nh ₂ G, 9 === // 9 ^ ó ' 5-amino-8- (furan-2-yl) -3 (2- (4- (4- (methylsulfonyl) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 540.62 21 rO _x Q ZG: H-T? N> Z-Y Γ 0 / x = / 9 b 5-amino-8- (furan-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 Q 0 0 S \ \ \ ' ^Ν γΝ nh ₂ O _o Gnh ₂ 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 cv 0 K ° 'z Ν _ί ψΛγ ^Ν ' ~ ^ '0 ^ N n' ⁿ y ⁿ nh ₂ Λ Ο-ΛΌΗ 5-amino-8- (furan-2-yl) -3 (2- (4- (3 - (2-hydroxyethoxy) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4e] [1,2,4 ] triazolo [1,5c] pyrimidin-2 (3H) -one 522.58 24 NOT; - ⁷ N ' to Z —- Ç V 0 G ^ NH 5-amino-3- (2- (4- (2-fluoro4- (2-oxo-2- (piperazin-1 yl) ethoxy) phenyl) piperazin1 -yl) ethyl) -8- (furan-2yl) thiazolo [ 5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 622.67 25 NOT- NOT o S'A z ~ _ '- \ π Ύ T ^F nh ₂ - ^ o 5-amino-3- (2- (4- (2-fluoro4- (piperidin-4-ylmethoxy) phenyl) piperazin-1 yl) ethyl) -8- (ftiran-2yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 593.68 26 r-O. G ^ Y / ^Z HG μ z —- Ç L_ V 0 Y ZNH Vz ⁿ G 0 5-amino-3- (2- (4- (2-fluoro4- (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 rX z ^N - Γ> - <\ ON 0 jyn ^ ~ gg Ί Ί V / -N ^> N / nh ₂ ^ NH 5-amino-3- (2- (4- (2-fluoro4- (2- (piperazin-1 yl) ethoxy) phenyl) piperazin1 -yl) ethyl) -8- (füran-2- 608.69

BE2018 / 0114

yl) thiazolo [5,4e] [1,2,4] triazolo [1,5clpyrimidin-2 (3H) -one 28 X o! Λ ° oo 'V 1 L— z «A z ⁷ z X 5-amino-3- (2- (4- (2-fluoro4- (piperazin-lylsulfonyl) phenyl) piperazin -1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2 , 4] triazolo [1,5c] pyrimidin-2 (3H) -one 628.70 29 sZ ° ^F \ aA Au ^ 0 Ν ' ^Ν γ ^Ν 0 nh ₂ 5-amino-3- (2- (4- (2-fluoro4- (methylsulfonyl) phenyl) piperazin-1 -yl) ethyl) - 8 (furan-2-yl) thiazolo [5,4e] [1,2, 4] triazolo [1,5c] pyrimidin-2 (3H) -one 558.61 30 i s ^x v ° 0 0 "--A s 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 0 s - \ _ z ^. λ JV'V \ .Nyx n ^^ - n 0 /> - <X Ί Ί LK <H <7 n'N. X = Z ^N γ 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 (methylamino) ethyl) benzamide 580.64 32 X zii s' o P ° s 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 _r o Μ> ΝγΝ f ^^ C) 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 / 0114

34 # Αχ s ° 0 Ca ¹ / O X f O X 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) -3fluorobenzamide 597.62 35 S— \ 7 ~~ \ \ nvL ⁿ⁷ 'VY1 A Γ / - 4 Μ N ⁰ 0 ^ 0 Ν' ^Ν η # · ^Ν nh ₂ 2- (4- (4- (2- (5-amino8- (furan-2-yl) -2oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) acid) yl) ethyl) piperazin-1 -yl) -3fluorophenoxy) acetic 554.55 36 J \ _ nA ^ VAA L / -NN / = / ^- ° 0 ^ o N ' ^N Y ^N f ^z nh ₂ 2- (4- (4- (2- (5-amino8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- acid 3 (2H) -yl) ethyl) piperazin-1 -yl) -3,5 difluorophenoxy) acetic 572.54 37 2 Ax has " V 0 P x ^ o o o o X 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 -yl) -3 fluorophenoxy) propanoic 568.58 38 O sa / ^ a pa ί ί a ° \ ^ 0 Ν ' ^Ν · γ ^Ν F,. · CÖOH NH ₂ (S) -2- (4- (4- (2- (5 amino-8- (furan-2-yl) -2oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin- acid) 3 (2H) yl) ethyl) piperazin-1 -y 1) - 3 fluorophenoxy) propanoic acid 568.58 39 X i ~ t °? N> Z— .. 0 όO 7 ° A ¹ 2- (4- (4- (2- (5-amino8- (furan-2-yl) -2oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) acid) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) -2methylpropanoic acid 582.61 40 S ίΐΥχ V 0 7 o o o X 3- (4- (4- (2- (5-amino8- (furan-2-yl) -2oxothiazolo [5,4-) acid e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenyl) propanoic 552.58

BE2018 / 0114

41 0 _r o _x n0 / 0 0 ⁿ 0> ⁷ - ί> 0 il 00 ° ⁰ U- ^ Vn ^ n nh ₂ 4- (4- (4- (2- (5-amino8- (fùran-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- acid 3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluorophenoxy) butanoic acid 582.61 42 0 0 z 0 'Z / Z Λ 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 43 î i! H0 <? μ z —- Ç V 0 ’0 V ° O X 2- (5- (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) -2,4difluorophenoxy) acetic 572.54 44 s> ° Z-, 0, / Gv ''' ¹ ' ⁷ G ^N 00 / Oh 000 >> 0 ^N γ Fo nh ₂ 4- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) acid ethyl) piperazin-1 -yl) -3 fluorobenzoic acid 524.53 45 Ä Gcn FJ Z — 0 V. 0 'ç5 ° i ç _o z ___________________________________- FJ 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) ethyl) amino) acetamide 596.64 46 °? z ^x z 0G °? FJ z ^ ~ Ç 0. V 03 ^ 5 ° 1 z ^ ç _o z X ________________ ΛΛ _______ 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) ethyl) (methy l) amino) acetamide 610.66 47 1 zx qG ^ G 0 ‘ Z 'b — Z ™ m-0 0z î 5-amino-3- (2- (4- (2-fluoro4- (piperidin-4-yloxy) phenyl) piperazin-1 -yl) ethyl) -8- (fiiran-2-yl) thiazolo [5,4- e] [1,2,4] triazolo [1,5-c] pyrimidin2 (3H) -one 579.65

BE2018 / 0114

48 s- / z-Λ ^NH * Vnh 5-amino-3- (2- (4- (2-fluoro4- (pyrrolidin-3yloxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2, 4] triazolo [1,5c] pyrimidin-2 (3H) -one 565.62 49 sA ° nAx ^{/ N} / ^N \ Μ-AR, N, rfA_ / ί ί \\ A „/ A ^NH II / V Μ Jl jA / O '- /% Ν' ^Ν · γ · ^Ν nh ₂ 3- (2- (4- (4 - ((lH-1,2,4triazol-3-yl) methoxy) -2fluorophenyl) piperazin-1 yl) ethyl) -5-amino-8- (furan2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 577.59 50 0 XX3- <y A “ ¹ Ç ^ A ' ⁿ y ⁿ ~ A / ⁰ 0 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) -3 fluorophenoxy) -N- (2 (methylamino) ethyl) acetamide 610.66 51 A / ^x o ^ ⁷ 0 O. ^ Z — Z w À 'S 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) -N- (2 (dimethylamino) ethyl) acetamide 624.69 52 [A ^ _nH ₂ Aa ^{n NH} 2 Lo 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 SA / -f / T z-_ n _î A / ⁿ ' ^z V / ^N Xk ΓΑΑ Ai A / R 0 Ν'Ύ ^Ν F yAcOOH nh ₂ (R) -2- (4- (4- (2- (5 amino-8- (furan-2-yl) -2oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin- acid) 3 (2H) yl) ethyl) piperazin-1 -y 1) - 3 fluorophenoxy) propanoic acid 568.58 54 0 S'A X ~ X ry% n ύ A Ν ' ^Ν γ ^Ν F AonH ₂ 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) -3 - 553.57

BE2018 / 0114

fluorophenoxy) acetamide 55 0 S-Λ \ / γ y% λ 1 γζ ~ χ% Ν- ^Ν γ ^Ν Ρ ^Λ 0 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) -3 fluoro-N-methyl-N- (2 (methylamino) ethyl) benzamide 594.66 56 Ä s ° Ο X ^Ζ Χ 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) -3fluoro-N-methylbenzamide 608.69 57 (V ^ Of-V Ν ' ^Ν γ ^Ν F ^Z 0 νη ₂ (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-2yl) -3 -fluorobenzamide 608.69 58 / χζ ? 0 Lz * ° κ X X 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 S κ> Ζ —- Ç S 0 X χχ ^ ο ο X 2- (5- (4- (2- (5-amino8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- acid 3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluorophenoxy) -2 methylpropanoic 600.60 60 / P COOH ΓΥλ Λ ί lY'F Y Ν- ^Ν γ ^Ν f ^Z νη ₂ (S) -2- (5- (4- (2- (5 amino- 8 - (furan-2-yl) -2oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin- acid) 3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluorophenoxy) propanoic 586.57

BE2018 / 0114

61 s + ° O ₍ ^COOH iy - <\ 1 ί l / -f Xn'Y L nh ₂ (R) -2- (5- (4- (2- (5 amino-8- (furan-2-yl) -2oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin- acid 3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluorophenoxy) propanoic 586.57 62 z ^x / ^z Η X κ> Z — K 1 V. 0 O / o 'Ço IZ z ZI _______ / 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) -N- (2 (methylamino) ethyl) acetamide 628.65 63 \ 0 N O VL z- / K n ^ Ä / ⁿ ^ VTl ß-4 J i VZ ~ F X N ' ^N Y ^N F nh ₂ 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) -2,4difluorophenoxy) -N- (2 (dimethylamino) ethyl) acetamide 642.68 64 z ° u. 0 L 'b-z \ ^ Z Î 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 (2- (dimethylamino) ethyl) 2,4-difluoro-N-methylbenzamide 626.69 65 Q ___COOH s- ^ _ Z ~~> O- ^ ry <j ί k / ~~ ^f ^ / Λ- ^ν υ ^ν f ^ nh ₂ 4- (5- (4- (2- (5-amino8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] pyrimidin- acid 3 (2H) yl) ethyl) piperazin-1 -yl) -2,4difluorophenoxy) butanoic 600.60 66 ο ^ γΝχ / θγ ⁰ ) = N N - ^ \ ^H * ^N N „HN-N JVM, N ρΛα ⁿ F 3- (2- (4- (5 - ((1H-tetrazol-5yl) methoxy) -2,4difluorophenyl) piperazin-1 yl) ethyl) -5-amino-8- (furan2-yl) thiazolo [5,4e ] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 596.58

BE2018 / 0114

67 0 / =, _N ifA / ii ^vz VJ ~ c>'L / \ ^χ N zN N ^- N 0 N N'-JF \ nh ₂ 5-amino-3- (2- (4- (2-fluoro4 - ((1 -methyl-1 H-1,2,4triazol-3 -yl) methoxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 591.62 68 <M - ^z ~ X ° _x J Yj 0 Ÿ • -G ¹ Z γΖ i 5-amino-3- (2- (4- (2,4difluoro-5 - ((1 -methyl-1Hl, 2,4-triazol-3-yl) methoxy) phenyl) piperazin1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 609.62 69 U. Z s ï J 1 —z <n \) - i z ^, z ί 4- (4- (2- (5 -amino- 8 - (fiiran2-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 S -Λ -T \ A γμ ^ν Χ ^ν 'Oy ⁸ ' ⁷ '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) -3fluoro-N- (2 - ((2hydroxyethyl) amino) ethyl) b enzamide 610.67 71 sj ° _r 0 xX ^ V T7 UX'NyN R ⁰ 0 nh ₂ 2-amino-N- (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) ethyl) acetamide 596.64 72 î z ^x z HY? FJ Z — J V 0 ZI _Â - <k ^M O ^ \. Z (S) -2-amino-N- (2- (4- (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) -3fluorophenoxy) ethyl) -3methylbutanamide 638.72

BE2018 / 0114

73 / 9 COOEt fyA ί ί ^ ⁷ X Ν ' ^Ν Υ ^Ν f ⁷ ^ νη ₂ 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) ethyl acetate 600.60 74 A Ο ^ γΝ SyO ΝίμΧ ^Ν \ ^ \) = Ν ^Η * ^Ν Αν 'Αχχ__ fAA F 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) acetonitrile 553.54 75 0 sA _ / —1 1 ku _ / ”~ N 'ζ ~ _,, ^ Ο. ΝχΑν ^Ν \ Ν- ~ .ζΖ \\ Η / Α <\ '1 Α ^Ν νη ₂ 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 A _r o N ^ _r A ₁ / ^N '~ ^ ^, Vz ^N ^ X ^ Α ^> / jN ^ N NSA nh ₂ 5-amino-8- (fiiran-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 77 ο Ί ° sA / A z ° _r o νΑυ ^ν ~ ⁷ ^ Χ ^ν ΧΧ Γ z> —X 7 IK / ^F ΑΑΐ'ΝγΝ nh ₂ 5-amino-3- (2- (4- (2,4difluoro-5- (2 (methylsulfonyl) ethoxy) phe nyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5, 4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 620.65 78 X χΑ Αω ΙΌ Z —- <\ “0 'XA ζ ^ω o ^zx 5-amino-3- (2- (4- (2-fluoro4- (2 (methylsulfonyl) ethoxy) phe nyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 602.66 79 sA ° ^ -o ⁿ ~~ <A/ ⁿ ~~^' ⁿ \ z ⁿ aA^^a ⁰ Π /> - <\ 1 1 V zA ^nh ΑΛ-ΝγΝ 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 ] triazolof 1,5c] pyrimidin-2 (3H) -one 535.55

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80 zP F 's-Λ L N' 9 Xn ' ^N γ ^{Ν Z} NH nh ₂ 5-amino-3- (2- (4- (2-fluoro4- (Smethylsulfonimidoyl) phenyl) piperazin-1 -yl) ethyl) -8 (fiiran-2-yl) thiazolo [5,4e] [1,2, 4] triazolo [1,5clpyrimidin-2 (3H) -one 557.62 81 \ o // HN S- \ X- _r O ⁰ 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 (2- (dimethylamino) ethyl) 2,4-difluorobenzamide 612.65 82 nh ₂ W ^F n ^ nN /% n V ά kxHJ Y ^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 r \ Xy-X ^ -NS ^ O 1 YY ' ⁿ ~ n Vn X = N ^^^ N ^ X H ₂ N / / XN YA hq f-XX / - \ O ^ ° 5-amino-3- (2- (4- (2-fluoro4 - (((3R, 4R) -4hydroxytetrahydrofuran-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 582.61 84 ^δ γΟ N- _N ^ yN ^ _) = N NA H ₂ N (/ XN 4T ° b 5 -amino-3 - (2- (4- (2-fluoro4 - (((3S, 4S) -4hydroxytetrahydrofuran-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) - 8 - (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5clpyrimidin-2 (3H) -one 582.61 85 Γ ° \ \ AN S ^ O T> - / / n- _n yN T ⁼ N H ₂ N / / F O ΟΆ ^ Χ- HO 5-amino-3- (2- (4- (2-fluoro4- (2-hydroxy-2methylpropoxy) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [ 1,2,4] triazolof 1,5c] pyrimidin-2 (3H) -one 568.62 86 0 γ, ΝγΧγ ^Ν ^ Χν ^Ν ^ ΧΎ / ^0Η Y / V ^N Y ^N _F ^ / \ NH ₂ 5-amino-3- (2- (4- (2-fluoro4- (2-hydroxypropan-2yl) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4- 538.60

BE2018 / 0114

e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 87 0 NS ”> 0 / n ~ _n y_N) = N ^X ” ^ N \ H ₂ N / / F Y- ^N xJ O F 000 HO ^F 5-amino-3- (2- (4- (2-fluoro4- (3,3,3-trifluoro-2hydroxypropoxy) phenyl) pip erazin-1 -yl) ethyl) -8- (furan2-yl) thiazolo [5 , 4th] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 608.57 88 HO * 7 jo 00-00 G N ' ^N x ^ ^N nh ₂ 5-amino-3- (2- (4- (2-fluoro5- (2hydroxyethoxy) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2, 4] triazolo [1,5c] pyrimidin-2 (3H) -one 540.57 89 OA / Gv, z 0 '0 —Z ⁰⁴ V μ Ζ0Ζ λ 5-amino-3- (2- (4- (2,4difluoro-5- (morpholin-2ylmethoxy) phenyl) piperazin -1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [l , 2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 613.64 90 ^H O Ο S ~ \ Ζ-Ι0Λ z ° ç- c> _/ N ^ 0 _ÿ z ^NN \ N -00 ^ N ' ^N x ^ N [.G ^{7 f} h ₂ n 5-amino-3- (2- (4- (2,4difluoro-5- (morpholin-3ylmethoxy) phenyl) piperazin -1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1 , 2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 613.64 91 HN \ _c NH ₂ O ^F QG'nGn <0 O 0 nGx r \ _ / ⁿ Gv \ N ^{7 k} - V./0F ^S 0 F O 5-amino-3- (2- (4- (2,4difluoro-5 - (((3S, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (füran-2yl ) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 601.60 92 O G-γ. -> 0 _{N =} / 0 ^ 3 / ⁿ A__G 00 .N0 ^N O / N '\, ·' ° NH ₂ / \ HN0 ^ -F 5-amino-3- (2- (4- (2,4difluoro-5 - (((3S, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl ) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 601.60

BE2018 / 0114

93 H 0 ^s AL) P / n- ⁿ v ⁿ 1 V \ / λ ~~ F nh ₂ ⁷ 5-amino-3- (2- (4- (2,4difluoro-5 - (((3R, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl ) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 601.60 94 H 0 ^s AL? n ^ ^N À \ -z ^F 'b n' ⁿ v ⁿ t U // - V nh ₂ Λ- / 5-amino-3- (2- (4- (2,4difluoro-5 - (((3S, 4R) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (fùran-2yl ) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 601.60 95 X H λ <? Μ Z-J. s ” ÜvO (S) -5-amino-3- (2- (4- (2,4difluoro-5 - ((2oxopyrrolidin-3yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (füran-2yl) thiazolo [ 5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 597.60 96 HN Λ s A z ^ _N ^ \ _z o Ν _{; =} ζΛγ · ^Ν '~ ^ ^Ζ ^ U ^ ^N AAl ί ^ Ά-ΝγΝ _F KÀF nh ₂ (R) -5-amino-3- (2- (4- (2,4difluoro-5 - ((2oxopyrrolidin-3yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (fluoran-2yl) thiazolo [ 5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 597.60 97 ö 0 zLz X _ 2- (5- (4- (2- (5-amino-8 (faran-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 ƒ F β-4; ί Ύ ΙΑ An ' ⁿ v ⁿ U 1 A ~ nh nh ₂ 0 \ ° Vz ^NH 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) -2,4difluoro-N- (morpholin-3 ylmethyl) benzamide 640.66

BE2018 / 0114

99 0 sA F ï N— \ \ N '' X - <) NH ₂ '“• O 5-amino-3- (2- (4- (2-fluoro4- (morpholin-3ylmethoxy) phenyl) piperazin -1 -yl) ethyl) -8- (ftiran-2yl) thiazolo [5,4e] [1,2 , 4] triazolo [1,5c] pyrimidin-2 (3H) -one 595.65 100 Ύ z ^x z iW? N> Z— j ö o Zc> IZ ^ ____ 5-amino-3- (2- (4- (2-fluoro4- (morpholin-2ylmethoxy) phenyl) piperazin -1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2 , 4] triazolo [1,5c] pyrimidin-2 (3H) -one 595.65 101 0 ^S A _/ ^N * rÄ ^{/ N} A / - ^ ^F \ ^F '- ^ 0? - <\ ï 1 A' \ A \ ^NH Yn ' ⁿ VV / ⁿ A \ A ⁷ IA Zo nh ₂ 5-amino-3- (2- (4- (2-fluoro4 - (((3R, 4R) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5clpyrimidin-2 (3H) -one 583.61 102 o sA N ^ z / ^N ~~ \ E f- ^ ΓΗ.7 1 Α _Ν Ά A. \, ^NH X N'Y Α ^ γΥθΑ- ⁷ nh ₂ - 5-amino-3- (2- (4- (2-fluoro4 - (((3 S, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (füran-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 583.61 103 sZ Οα ^Ν; Λ ^ν ^ F ⁰ AA ⁷ nA \ / XT NH H ₂ N XX ₀ V 5-amino-3- (2- (4- (2-fluoro4 - (((3R, 4S) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (füran-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 583.61 104 0 sA _/ n < _t Äz ⁿ A / ^. ^F \ ^F '- <^ F? - <\ 1 1 A \ ^NH A / n'Vn V z ⁿ aY A- / NH ₂ 5-amino-3- (2- (4- (2-fluoro4 - (((3S, 4R) -4fluoropyrrolidin-3 yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (foran-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 583.61

BE2018 / 0114

105 47 N-Ny-N ^,) = N Ny ^HzN χ JX ^F θΥτ'Χχ 0 N ^ \) Y o 2- (4- (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) -3 fluorophenoxy) -N- (2morpholinoethyl) acetamide 666.73 106 0 s X G 1 '' i --- Z <N W μ X 4- (4- (2- (5-amino-8- (füran2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3fluoro-N- (2morpholinoethyl) benzamide 636.70 107 sj ° A vy _F + -y nh ₂ 4- (4- (2- (5-amino-8- (fiiran2-yl) -2-oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H) yl) ethyl) piperazin-1 -yl) -3 fluoro-N- (morpholin-3ylmethyl) benzamide 622.67 108 0 S- \ r- \ r — NH _r o NXP y /> - <Ύ 1 \ = Λο </ \ - N ^ N nh ₂ 5-amino-3- (2- (4- (4 (azetidin-3yloxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 533.61 109 P Ό S— \ z ~ = c + _r o ί / Λ- ^Ν γΝ _f \ 7 ^f nh ₂ (S) -5-amino-3- (2- (4- (2,4difluoro-5 (methylsulfinyl) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 560.60 110 + / üο ' ^ω νΛ' Q 0 'X' Z. > z (R) -5-amino-3- (2- (4- (2,4difluoro-5 (methylsulfinyl) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5clpyrimidin-2 (3H) -one 560.60

BE2018 / 0114

111 Ό ./ Q Xn ' ⁿ y ⁿ nh ₂ 5-amino-3- (2- (4- (2,4difluoro-5 - (((1 s, 4s) -1 oxidotetrahydro-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 0 1 ^Z ™ ^w - / \) - z Î 5-amino-3 - (2- (4- (2,4difluoro-5 - (((1 r, 4r) -1 oxidotetrahydro-2Hthiopyran-4yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- ( fûran-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 630.69 113 \ Γ 0 HN tHV A ^ ^F nh ₂ (S) -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) -2,4difluoro-N- (2 (methylsulfinyl) ethyl) benza mide 631.68 114 Ό ₀ Γ 0 HN S-Λ ζ ~ Λ X ^ NyL ^ UXÎ O ^ Ο ^ Ν- ^Ν γΝ _f KX ^F nh ₂ (R) -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) -2,4difluoro-N- (2 (methylsulfinyl) ethyl) benza mide 631.68 115 Ό X P -N ^Z s— \ λ — V V- __ / ^N X ^{=: =?} V ⁰ ίΛΛ-ΝγΝ _f xZ ~ f νη ₂ (S) -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) -2,4difluoro-N-methyl-N- (2 (methylsulfinyl) ethyl) benza mide 645.70

BE2018 / 0114

116 ƒ s-Λ Y nJv ⁿ ^ Y ⁿ TI Γνγ Ύ ί 1 / -F Y n- ⁿ v ⁿ y 1 7 = 0 NH ₂ ~ N / So- (R) -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) -2,4difluoro-N-methyl-N- (2 (methylsulfmyl) ethyl) benza mide 645.70 117 0 w / ^s ~ ^ p Y ' ^S GZ ~ - <Y_ 0 * —Gif xY ^f Y Ν' ^Ν γ ^Ν nh ₂ 5-amino-3- (2- (4- (2,4difluoro-5- (loxidothiomorpholine-4carbonyl) phenyl) piperazin1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2 , 4] triazolo [1,5c] pyrimidin-2 (3H) -one 643.69 118 0 'o / 0 S — X /, κι __ / -χΑΛΛ-Λ Ύ-γ _F LA ^F nh ₂ 5-amino-3 - (2- (4- (2,4difluoro-5- (loxidothiomorpholino) phenyl) piperazin-1 -yl) ethyl) - 8 (furan-2-yl) thiazolo [5,4e] [1 , 2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 615.68 119 0 s-λ / -, ^Ν χΥγ ' ^Ν ~~ ^ ~ Ύ ^ ^Ν YY / U Kl NL / S ^{+ N} YF 0- nh ₂ (R) -5-amino-3- (2- (4- (2fluoro-4 (methylsulfinyl) phenyl) pipé razin-1 -yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1 , 2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 542.61 120 0 SG / -γ ^F \ r-0 ^Ν Υ / ^Ν ~ Ύ n / Y il X — Il X zz — s ⁺ ^ Y'N ^ n X nh ₂ (S) -5-amino-3- (2- (4- (2fluoro-4 (methylsulfinyl) phenyl) pipé razin-1 -yl) ethyl) -8- (fiiran-2yl) thiazolo [5,4e] [1 , 2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 542.61 121 îW'Y ^v O-oY Y N ' ^N y ^N F ⁷ ^ nh ₂ 5-amino-3- (2- (4- (2-fluoro4 - (((ls, 4s) -loxidotetrahydro-2Hthiopyran-4yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 612.70

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122 ƒ .O 'P νη ₂ 5-amino-3- (2- (4- (2-fluoro4 - (((lr, 4r) -loxidotetrahydro-2Hthiopyran-4yl) oxy) phenyl) piperazin-1 yl) ethyl) -8- (füran-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 612.70 123 2 ί Αχ 0 ° ζ- \ ° (S) -4- (4- (2- (5-amino-8 (furan-2-yl) -2oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H ) yl) ethyl) piperazin-1 -y 1) - 3 fluoro-N- (2 (methylsulfmyl) ethyl) benza mide 613.69 124 ^S ^ ° k γ ^ο \ α ^ν * ΓΎ \ Κ / ^ΝΗ U ^ V ⁿ y ⁿ νη ₂ (R) -4- (4- (2- (5-amino-8 (fiiran-2-yl) -2oxothiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-3 (2H ) yl) ethyl) piperazin-1 -yl) -3fluoro-N- (2 (methylsulfmyl) ethyl) benza mide 613.69 125 S- / F \ z- _s ^z ° r ° \ / ^N kv ^N '^ k ^N zk \ 0 CMV a nh ₂ 5 -amino-3 - (2- (4- (2 -fluoro4- (1 -oxidothiomorpholine4- carbonyl) phenyl) piperazin1 -yl) ethyl) -8- (fiiran-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 625.70 126 0 '__ ^F \? A_Z ~ ^N ' ₀ "Ä W-VA GX; ' nh ₂ 5-amino-3- (2- (4- (2-fluoro4- (1oxidothiomorpholino) phenyl) piperazin-1 -yl) ethyl) -8 (furan-2-yl) thiazolo [5,4e] [1,2 , 4] triazolo [1,5c] pyrimidin-2 (3H) -one 597.69 127 ? Z Z Η λ <? "Ό Z - Ç s ° . 0 θ IC / '' .____ “Π O I z (S) -5-amino-3- (2- (4- (5- (2,3dihydroxypropoxy) -2,4difluorophenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 588.59

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128 T T O Μ ü- ά 0 □ Y — Z LAi s (R) -5-amino-3 - (2- (4- (5 (2,3-dihydroxypropoxy) 2,4difluorophenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 588.59 129 ^Η0 \ γΗ P HN ST _ / 'Λ A nh ₂ (S) -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) -N (2,3-dihydroxypropyl) -2,4difluorobenzamide 615.61 130 ^ho \ ^ oh P HN / nA ⁿ A, z ^ Z ⁰ Π / 7 — κι κι <7 _Ν -ΝγΝ _f / ^ 7 nh ₂ (R) -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) -N (2,3-dihydroxypropyl) -2,4difluorobenzamide 615.61 131 î Z ^x / Z Η_Γΐ to za V 0 ¥ 'n ______I 5-amino-3 - (2- (4- (4 (azetidin-3-yloxy) -2fluorophenyl) piperazin-1 yl) ethyl) -8- (ftiran-2yl) thiazolo [5,4e] [1,2, 4] triazolo [1,5c] pyrimidin-2 (3H) -one 551.60 132 HN sZ ° A zm ^ AP r- ° N ^^ Âz ^N ~~ ^/ ^ t κι κι LÀ a _N -N ^ N _f A / nh ₂ 5-amino-3- (2- (4- (5 (azetidin-3-yloxy) -2,4difluorophenyl) piperazin-1 yl) ethyl) -8- (furan-2yl) thiazolo [5,4e] [1, 2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 569.59 133 Ό., ⁰ A z ^ nA _z o _f A ' ^f nh ₂ (S) -5-amino-3- (2- (4- (2,4difluoro-5- (3 (methylsulfmyl) propoxy) ph enyl) piperazin-1 -yl) ethyl) 8- (furan-2-yl) thiazolo [5,4e] [1,2,4] triazolo [1,5c] pyrimidin-2 (3H) -one 618.68

and their pharmaceutically acceptable salts and solvates.

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

BE2018 / 0114

Compounds in Table 1 were named using ChemBioDraw® Ultra version 12.0 (PerkinElmer).

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

(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] pyrimidin2 (3H) -one (compound 7);

(+) - 5-amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfmyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2 -yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin2 (3H) -one (compound 8a) and (-) - 5-amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfmyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1 , 2,4] triazolo [1,5-c] pyrimidin2 (3H) -one (compound 8b).

In a specific embodiment, the combination comprises a compound of formula (I) selected from the following:

(R, S) -5-amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfmyl) ethoxy) phenyl) piperazin-1 -yl) ethyl) -8- (furan -2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidin2 (3H) -one (compound 7); and (+) - 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] pyrimidin2 (3H) -one (compound 8a).

In a preferred embodiment, the combination comprises (+) - 5 amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazin-lyl) ethyl) -8- (furan-2-yl) thiazolo [5,4-5e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one (compound 8a).

In one embodiment, the present invention also relates to the enantiomers, salts, solvates, polymorphs, multi-component complexes and liquid crystals of the compounds of formula (I) and sub-formulas thereof.

In one embodiment, the present invention also relates to polymorphs and crystalline forms of compounds of formula (I) and subformulas thereof, their prodrugs and isomers (including optical, geometric and tautomeric isomers) and them. isotopically labeled compounds of formula (I) and sub-formulas thereof.

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Compounds of formula (I) and sub-formulas thereof may contain an asymmetric center and thus may exist as different stereoisomeric forms. Accordingly, the present invention encompasses 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 as a single enantiomer, it can be obtained by stereospecific synthesis, by resolution of the final product or any suitable intermediate, or by chiral chromatographic methods as are each known in the art. . Resolution of the final product, intermediate, or starting material can be accomplished by any method known in the art.

The compounds of the invention may be in the form of the pharmaceutically acceptable salts. Pharmaceutically acceptable salts of 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, hydrochloride / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogen phosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate and xinofoate. Appropriate 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. Acid and base hemi-salts can also be formed, for example, the hemisulfate and hemicalcium salts. Preferred pharmaceutically acceptable salts include

BE2018 / 0114 hydrochloride / chloride, hydrobromide / bromide, bisulfate / sulfate, nitrate, citrate, and acetate.

When the compounds of the invention contain an acidic 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 this invention. When the compounds of the invention contain a hydrogen donor heteroatom (eg, NH), the invention also includes salts and / or isomers formed by transferring said hydrogen atom to a basic group or an atom to inside the molecule.

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

(i) by reacting the compound of formula (I) with the desired acid;

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

(iii) by removing a labile protecting group in an acidic or basic medium from a suitable 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 a salt of the compound of formula (I) to another by reaction with a suitable acid or by means of a suitable ion exchange column.

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

BE2018 / 0114 palmitate, esylate, pantothenate, fumarate, phosphate / diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycollylarsanilate, sulfate, hexylresorcinate, subacetate , hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, teoclate, iodide, tosylate, isothionate, triethiodide, lactate, panoate, valerate, and the like which can be used in dosage form to modify solubility or hydrolysis characteristics or can be used in sustained release formulations or prodrugs. Depending on the particular functionality of the compound of the present invention, pharmaceutically acceptable salts of the compounds of this invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc. , and bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, omithine, choline, Ν, Ν'-dibenzylethylene-diamine, chloroprocaine, diethanolamine , procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris (hydroxymethyl) aminomethane, and tetramethylammonium hydroxide.

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

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

The compounds of the invention can be in the form of pharmaceutically acceptable solvates. Pharmaceutically acceptable solvates of formula (I) and sub-formulas thereof contain stoichiometric or substoichiometric amounts of one or more solvent molecules

BE2018 / 0114 pharmaceutically acceptable, for example ethanol or water. The term "hydrate" refers to the case where said solvent is water.

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

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

Anticancer agent

As a second component, the combination of the invention comprises at least one anticancer agent.

In one embodiment, the anti-cancer agent is selected from immunotherapeutic agents, chemotherapeutic agents, antiangiogenic agents, inhibitors of multidrug resistance associated proteins, radiotherapeutic agents, and any combination thereof.

Immunotherapeutic agent

In one embodiment, the combination of the invention comprises an immunotherapeutic agent as an anti-cancer agent.

In such a case, the invention relates to a combination comprising:

(a) at least one adenosine A2A receptor (A2AR) inhibitor, and (b) at least one immunotherapeutic agent.

In a preferred embodiment, the invention relates to a combination comprising:

(a) at least one A2AR inhibitor which is a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I)

BE2018 / 0114

or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ and R ² are as defined below; and (b) at least one immunotherapeutic agent.

In the present invention, immunotherapy refers to therapy aimed at inducing and / or improving an immune response towards a specific target, for example targeting cancer cells. In the latter case, it is referred to as anti-cancer immunotherapy.

The immunotherapeutic agent is, for example, selected from checkpoint inhibitors, checkpoint agonists (also called T lymphocyte agonists), IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors , inhibitors of adenosine-producing enzymes, immune cells (to effect adoptive transfer), therapeutic vaccines, and combinations thereof. In a specific embodiment, the immunotherapeutic agent is a checkpoint inhibitor.

In one embodiment, the immunotherapeutic agent to be combined with the A2AR inhibitor of formula (I) as described above comprises or consists of checkpoint inhibitors, checkpoint agonists, IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, inhibitors of adenosine-producing enzymes, immune cells (to achieve adoptive transfer), therapeutic vaccines, or any mixture of these.

In the context of the present invention, the term "combination" preferably means a combined occurrence of an A2AR inhibitor and an immunotherapeutic agent.

BE2018 / 0114

Therefore, the combination of the invention either can occur in the form of a composition, comprising all of the compounds in one and the same mixture (eg, a pharmaceutical composition), or can occur in the form of a kit, in which the different constituents form different parts of such a kit. The administration of the A2AR inhibitor and the immunotherapeutic agent can take place simultaneously or be staggered over time, with a similar or different timing of administration (in other words, similar or different numbers of administration of each component), either at the same administration site or at different administration sites, in similar or different dosage forms. Such a combination can induce an active immune response and thus prevent, for example, tumor growth or induce tumor regression.

Checkpoint inhibitors

In one embodiment, the combination of the invention comprises at least one checkpoint inhibitor as an immunotherapeutic agent.

Checkpoint inhibitors (CPIs), which can also be referred to as immune checkpoint inhibitors (ICIs), block interactions between inhibitory receptors expressed on T cells and their ligands. As a treatment for cancer, the use of a checkpoint inhibitor is aimed at preventing activation of inhibitory receptors expressed on T cells by ligands expressed by tumor cells. The use of checkpoint inhibitors is thus aimed at preventing the inhibition of the T lymphocytes present in the tumor, in other words, of the T lymphocytes infiltrating the tumor, and thus at improving the immune response of the subject towards the cells. tumor.

Thus, the combination of the invention can restore immune functions in tumor environments using an A2A inhibitor as the first component, and antagonize checkpoint pathway signaling preferably by inhibiting or suppressing transduction of signal using as a second component a checkpoint inhibitor as an immunotherapeutic agent.

Examples of checkpoint inhibitors include, but are not limited to:

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- inhibitors of the cell surface receptor PD-1 (programmed cell death protein 1 (programmed cell death protein 1)), also known as CD279 (differentiation cluster 279);

- PD-L1 ligand inhibitors (programmed death-ligand 1), also known as CD274 (differentiation cluster 274) or B7-H1 (homolog 1 of B7);

- inhibitors of the cell surface receptor CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4 (protein 4 associated with cytotoxic T lymphocytes)), also known as CD 152 (differentiation cluster 152);

- LAG-3 inhibitors (lymphocyte-activation gene 3 (lymphocyte activation gene 3)), also known as CD223 (differentiation cluster 223);

- TIM-3 inhibitors (T-cell immunoglobulin and mucin-domain containing-3 (protein 3 containing the mucin domain and the immunoglobulin of T lymphocytes), also known as HAVCR2 (cell receptor 2 of the virus of the hepatitis A) or CD366 (differentiation cluster 366);

- TIGIT inhibitors (T cell immunoreceptor with Ig and ITIM domains (immunoreceptors of T lymphocytes with Ig and ITIM domains), also known as VSIG9 (V-Set And Immunoglobulin Domain-Containing Protein 9 (protein 9 containing immunoglobulin and V-Set domains)) or VSTM3 (V-Set And Transmembrane Domain-Containing Protein 3 (protein 3 containing the transmembrane and V-Set domains));

- BTLA inhibitors (attenuator of B and T lymphocytes), also known as CD272 (differentiation cluster 272);

- CEACAM-1 inhibitors (carcinoembryonic antigen-related cell adhesion molecule 1 (cell adhesion molecule 1 associated with carcinoembryonic antigen)) also known as CD66a (differentiation cluster 66a); and

- GITR (glucocorticoid-induced TNFR-related protein) inhibitors, also known as TNFRSF18 (tumor necrosis factor receptor superfamily member 18 (member 18 of the tumor necrosis factor receptor family) ) or AITR (activation

BE2018 / 0114 inducible TNFR family receptor (receptor of the TNFR family by activation).

In one embodiment, the checkpoint inhibitor is selected from the group consisting of or consisting of PD-1 inhibitors, inhibitors of

PD-L1, CTLA4 inhibitors, LAG-3 inhibitors, inhibitors of

TIM-3, TIGIT inhibitors, BTLA inhibitors,

CEACAM-1, GITR inhibitors, and any mixture thereof.

In one embodiment, the checkpoint inhibitor is selected from the group consisting of or consisting of PD-1 inhibitors, PD-L1 inhibitors, CTLA-4 inhibitors, and any mixture thereof.

In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor, also referred to as an anti-PD-1. PD-1 inhibitors can include antibodies targeting PD-1, particularly monoclonal antibodies, and inhibitors other than antibodies such as small molecule inhibitors.

Examples of PD-1 inhibitors include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, tislelizumab, spartalizumab, ABBV-181, JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034. Pembrolizumab is also known as MK-3475, MK03475, lambrolizumab, or SCH-900475. The trade name for pembrolizumab is Keytruda®. Nivolumab is also known as ONO-4538, BMS-936558, MDX1106, OR GTPL7335. The trade name for nivolumab is Opdivo®. Cemiplimab is also known as REGN2810 or REGN-2810. Tislelizumab is also known as BGB-A317. Spartalizumab is also known as PDR001 orPDR-001.

In one embodiment, the checkpoint inhibitor is selected from the group consisting of or consisting of pembrolizumab, nivolumab, cemiplimab, tislelizumab, spartalizumab, ABBV-181, JNJ-63723283, BI 754091 , MAG012, TSR-042, AGEN2034, and any mixture of these.

In one embodiment, the checkpoint inhibitor is a PD-L1 inhibitor, also referred to as an anti-PD-L1. PD-L1 inhibitors may include antibodies targeting PD-L1, in particular

BE2018 / 0114 monoclonal antibodies, and inhibitors other than antibodies such as small molecule inhibitors.

Examples of PD-L1 inhibitors include, but are not limited to avelumab, aezolizumab, durvalumab, and LY3300054. Avelumab is also known as MSB0010718C, MSB-0010718C, MSB0010682, or MSB-0010682. Avelumab's trade name is Bavencio®. Atezolizumab is also known as MPDL3280A (clone YW243.55.S70), MPDL-3280A, RG7446 or RG7446. The trade name for aezolizumab is Tecentriq®. Durvalumab is also known as MEDI4736 or MEDI-4736. The trade name for durvalumab is Imfinzi®.

In one embodiment, the checkpoint inhibitor is selected from the group consisting of or consisting of avelumab, aezolizumab, durvalumab, LY3300054, and any mixture thereof.

In one embodiment, the checkpoint inhibitor is a CTLA-4 inhibitor, which is also referred to as an anti-CTLA-4.

CTLA-4 inhibitors can include antibodies targeting CTLA-4, particularly monoclonal antibodies, and inhibitors other than antibodies such as small molecule inhibitors.

Examples of CTLA-4 inhibitors include, but are not limited to, ipilimumab and tremelimumab. Ipilimumab is also known as BMS-734016, MDX-010, or MDX-101. The trade name for ipilimumab is Yervoy®. Tremelimumab is also known as ticilimumab, CP-675, or CP-675,206.

In one embodiment, the at least one checkpoint inhibitor is selected from the group consisting of or consisting of ipilimumab, tremelimumab, and any mixture thereof.

In one embodiment, the checkpoint inhibitor is a TIGIT inhibitor, which is also referred to as an anti-TIGIT.

Checkpoint agonists (T cell agonists)

In one embodiment, the combination of the invention comprises at least one checkpoint agonist (also referred to as a T cell agonist) as an immunotherapeutic agent.

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T cell agonists act by activating stimulatory receptors expressed on immune cells, such as T cells. As used herein, the term "stimulatory receptors" refers to receptors which induce a signal from stimulation upon activation, and thus lead to an improvement in the immune response. As a treatment for cancer, therapy with T cell agonists aims to activate stimulatory receptors expressed on immune cells present in a tumor. In particular, therapy with T lymphocyte agonists aims to improve the activation of T lymphocytes present in a tumor, in other words, the T lymphocytes infiltrating the tumor, and thus to improve the immune response of the subject towards the cells. tumor.

Examples of T cell agonists include, but are not limited to:

- CD 137 agonists (137 differentiation cluster) also known as 4-IBB or TNFRS9 (tumor necrosis factor receptor superfamily, member 9 (member 9 of the tumor necrosis factor receptor superfamily));

- OX40 receptor agonists also known as CD 134 (cluster of differentiation 134) or TNFRSF4 (tumor necrosis factor receptor superfamily, member 4 (member 4 of the tumor necrosis factor receptor superfamily)).

In one embodiment, the checkpoint inhibitor is selected from the group consisting of or consisting of CD137 agonists, OX40 agonists, and any mixture thereof.

Examples of CD 137 agonists include, but are not limited to, Futomilumab and urelumab.

IDO inhibitors

In one embodiment, the combination of the invention comprises at least one indoleamine-2,3-dioxygenase (IDO) inhibitor as an immunotherapeutic agent.

The enzyme indoleamine 2,3-dioxygenase catalyzes the first, kinetically limiting step in the catabolism of L-tryptophan (Trp). IDO is involved in immune modulation through its ability to limit lymphocyte function

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T and initiate immune tolerance mechanisms. IDO activity in tumor cells serves to compromise anti-tumor responses. Inhibiting IDO thus restores immune surveillance of tumors.

Examples of IDO inhibitors include beta-carboline (also known as norharmane), rosmarinic acid, 1-methyl-L-tryptophan (also known as Ll-MT), epacadostat, navoximod or those described in WO2015 / 173764, and more preferably those of formula II, II 'or Π ”.

In a preferred embodiment, the IDO inhibitor is selected from those described in WO2015 / 173764, and more preferably those of formula II, II ’or Π”.

PI3Kgamma inhibitors

In one embodiment, the combination of the invention comprises at least one PI3K inhibitor as an immunotherapeutic agent.

A phosphoinositide 3-kinase inhibitor (PI3K inhibitor) is a class of pharmaceutical drug that works by inhibiting one or more of the phosphoinositide 3-kinase enzymes, which are part of the PI3K / AKT / mTOR pathway, an important signaling pathway for a large number of cellular functions such as the control of growth, metabolism and the initiation of translation. In many types of cancer the PI3K pathway is activated, which prevents apoptosis of tumor cells.

There are a large number of different classes and isoforms of PI3K. Class 1 PI3Ks have a catalytic subunit known as p1 10, with four types (isoforms) - p1 10 alpha, p1 10 beta, p1 10 gamma and p1 10 delta.

In a preferred embodiment, the PI3K inhibitor is a PI3K-gamma inhibitor.

Examples of PI3K inhibitors include wortmannin, LY294002, demethoxyviridon, hibiscone C, idelalisib, copanlisib, duvelisib, taselisib, buparlisib, alpelisib, umbralisib, dactolisib, voxtalisib , IPI-549, RP6530, IC87114 and TG100-115.

Examples of PI3K-gamma inhibitors include copanlisib, duvelisib, IPI-549, RP6530, IC87114 and TG100-115.

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Adenosine receptor inhibitors

In one embodiment, the combination of the invention comprises at least one other adenosine receptor inhibitor as an immunotherapeutic agent.

As mentioned in the introduction, adenosine receptors are a class of purinergic receptors coupled to G protein with adenosine as an endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B, and A3.

The combination of the invention comprises, as the first constituent, an inhibitor of the A2A receptor, of formula (I) as defined above. The second component of the combination can be another adenosine receptor inhibitor, including an inhibitor of the A1, A2A, A2B or A3 receptors. Preferably, the second constituent of the combination of the invention is an inhibitor of the A2B receptor or an inhibitor of the A3 receptor.

Examples of the A2B receptor inhibitor include ATL-801, CVT6883, MRS-1706, MRS-1754, OSIP-339,391, PSB-603, PSB-0788 and PSB-1115.

Examples of the A3 receptor inhibitor include KF-26777, MRS545, MRS-1191, MRS-1220, MRS-1334, MRS-1523, MRS-3777, MRE-3005-F20, MRE-3008-F20, PSB-11 , OT-7999, VUF-5574 and SSR161421.

Adenosine-producing enzyme inhibitors

In one embodiment, the combination of the invention comprises at least one other inhibitor of the enzymes producing adenosine as an immunotherapeutic agent.

Ectonucleotidases are families of nucleotide-metabolizing enzymes that metabolize nucleotides to nucleosides. The ectonucleotidase subfamilies include: CD39 / NTPDases (ectonucleotide triphosphate diphosphohydrolases), nucleotide pyrophosphatase / phosphodiesterase (NPP) ecto-phosphodiesterases, alkaline phosphatases, and ecto-5'nucleotidases / CD7 3.

Among other functions, ectonucleotidases generate extracellular adenosine, the first step involving the conversion of ATP / ADT to AMP,

BE2018 / 0114 performed by ENTPD1, also known as CD39. The second step involves the conversion of AMP to adenosine. It is performed by NT5E, also known as CD73. Thus, ectonucleotidases are enzymes that produce adenosine.

As mentioned in the introduction, elevated extracellular adenosine levels play a significant role in evading the anti-tumor immune response. Thus, the use of inhibitors of adenosine-producing enzymes, by reducing extracellular adenosine levels, is beneficial in cancer therapy.

Examples of inhibitors of adenosine-producing enzymes include:

- CD39 inhibitors, also known as ENTPD1 or ectonucleoside triphosphate diphosphohydrolases (EC 3.6.1.5, apyrase),

- CD73 inhibitors, also known as 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase or NT5E,

- ectonucleotide pyrophosphatase / PDE inhibitors (EC 3.6.1.9 and EC 3.1.4.1) and

- alkaline phosphatase inhibitors (AP; EC 3.1.3.1),

- CD38 inhibitors, also known as cyclic ADP ribose hydrolase or cyclic ADP-ribosyl cyclase / ADP-ribose hydrolase (cADPR).

Examples of inhibitors of adenosine producing enzymes include IPH5201, A001485, SRF617, IPH5301, A000830, A001190, A001421, SRF373 / NZV930, darutumumab. Specifically, examples of CD39 inhibitors include IPH5201, A001485 and SRF617; examples of CD73 inhibitors include IPH5301, A000830, A001190, A001421 and SRF373 / NZV930; and examples of CD38 inhibitors include daratumumab.

Immune cells - adoptive transfer

According to one embodiment, the immunotherapeutic agent is immune cells for use in adoptive cell transfer, which is also referred to as adoptive cell therapy (also referred to as ACT), particularly a. adoptive transfer of T lymphocytes,

BE2018 / 0114 which is also referred to as adoptive T cell therapy.

As used herein, adoptive cell transfer or adoptive cell therapy is defined as the transfer, e.g., in the form of an infusion, of immune cells to a subject. As a treatment for cancer, the adoptive transfer of immune cells to a subject is aimed at enhancing the subject's immune response to the cancer cells.

In one embodiment, the immune cells are T lymphocytes, especially effector T lymphocytes. Examples of effector T lymphocytes include CD4 ⁺ T lymphocytes and CD8 ⁺ T lymphocytes.

In one embodiment, the transferred T lymphocytes are cytotoxic cells. Examples of cytotoxic T lymphocytes include CD8 ⁺ T lymphocytes and NK (natural killer) cells, particularly NK T lymphocytes (natural killer).

In one embodiment, the transferred immune cells as described above are cells specific for an antigen. In one embodiment, the transferred immune cells as described above are immune cells specific for an antigen, in which said antigen is specifically and / or abundantly expressed by cancer cells. In one embodiment, the transferred immune cells as described above are cancer-specific immune cells, in other words the transferred immune cells as described above specifically recognize cancer cells through an antigen specifically and / or abundantly expressed by said cancer cells. In one embodiment, the transferred immune cells as described above are cancer-specific effector T lymphocytes. In one embodiment, the transferred immune cells as described above are cancer-specific CD8 ⁺ effector T lymphocytes, particularly cancer-specific cytotoxic CD8 ⁺ T lymphocytes. In one embodiment, the transferred immune cells as described above are cancer-specific cytotoxic cells. In one embodiment, the transferred immune cells as described above are cancer specific NK cells. In one embodiment, the transferred immune cells as described

BE2018 / 0114 above are tumor-specific immune cells, in other words transferred immune cells as described above specifically recognize tumor cells through a specifically and / or abundantly expressed antigen by said tumor cells. In one embodiment, the transferred immune cells as described above are tumor-specific effector T lymphocytes. In one embodiment, the transferred immune cells as described above are tumor-specific CD8 ⁺ effector T lymphocytes, particularly tumor-specific cytotoxic CD8 ⁺ T lymphocytes. In one embodiment, the transferred immune cells as described above are tumor-specific cytotoxic cells. In one embodiment, the transferred immune cells as described above are tumor specific NK cells.

In one embodiment, the transferred immune cells as described above are autologous immune cells, particularly autologous T lymphocytes. In another embodiment, the transferred immune cells as described above are allogeneic (or allogeneic) immune cells, in particular allogeneic NK cells.

Methods of isolating T cells from a subject, particularly T cells specific for an antigen, e.g., tumor specific T cells, are well known in the art (see e.g. Rosenberg & Restifo, 2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs & Rosenberg, 2014, hnmunol Rev 257, 5671). Methods of expanding T cells ex vivo are well known in the art (see, e.g., Rosenberg & Restifo, 2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs & Rosenberg, 2014, Immunol Rev 257, 56-71). Protocols for infusing T cells into a subject, including pre-infusion conditioning regimens, are well known in the art (see, e.g., Rosenberg & Restifo, 2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs & Rosenberg, 2014, Immunol Rev 257, 56-71).

In one embodiment, the immune cells are CAR immune cells, particularly CAR T lymphocytes, in the context of

BE2018 / 0114 respectively CAR immune therapy and CAR T cell therapy.

As used herein, the term CAR immune cell therapy is an adoptive therapy in which the transferred cells are immune cells as described above, for example T lymphocytes or NK cells, genetically modified. to express a chimeric antigen receptor (CAR). As a treatment against cancer, the adoptive transfer of CAR immune cells to a subject is aimed at enhancing the subject's immune response directed against the cancer cells.

CARs are synthetic receptors made up of a targeting moiety that is associated with one or more signaling domains in a single fusion molecule or in multiple molecules. In general, the binding moiety of a CAR consists of an antigen binding domain of a single chain antibody (scFv), comprising the light and variable fragments of a monoclonal antibody joined by a flexible linker. . Binding moieties based on receptor or ligand domains have also been used successfully. Signaling domains for the first generation of CAR are generally derived from the cytoplasmic region of CD3zeta or the gamma chains of the Fc receptor. First generation CARs have been shown to successfully redirect T cell cytotoxicity, however, they did not allow prolonged expansion or anti-tumor activity in vivo. Thus, the signaling domains of co-stimulatory molecules including CD28, OX40 (CD134), and 4-1BB (CD137) were added alone (second generation) or in combination (third generation) to improve survival and increase proliferation of T cells modified by CAR.

Thus, in one embodiment, the transferred T lymphocytes as described above are CAR T lymphocytes. Expression of a CAR allows T cells to be redirected against a selected antigen, such as an antigen expressed on the surface of cancer cells. In one embodiment, the transferred CAR T cells recognize a tumor-specific antigen.

In another embodiment, the transferred NK cells as described above are NK CAR cells. Expression of a CAR allows NK cells to be redirected against a selected antigen, for example a

BE2018 / 0114 antigen expressed on the surface of cancer cells. In one embodiment, the transferred NK CAR cells recognize a tumor specific antigen.

In one embodiment, the CAR immune cells as described above are autologous CAR immune cells, particularly autologous CAR T lymphocytes. In another embodiment, the CAR immune cells as described above are allogeneic (or allogeneic) CAR immune cells, in particular allogeneic NK CAR cells.

Therapeutic vaccines

According to one embodiment, the immunotherapeutic agent is a therapeutic vaccine (sometimes referred to as a treatment vaccine).

As used herein, a therapeutic vaccine is defined by the administration of at least one tumor specific antigen (eg, long synthetic peptides or SLP), or nucleic acid encoding said tumor specific antigen; the administration of recombinant viral vectors entering and / or replicating selectively in tumor cells; administration of tumor cells; and / or administration of immune cells (eg, dendritic cells) genetically engineered to present tumor-specific antigens and elicit an immune response against those antigens.

As a treatment against cancer, therapeutic vaccines aim to improve the subject's immune response against tumor cells.

Examples of therapeutic vaccines aimed at enhancing the subject's immune response against tumor cells include, but are not limited to, viral vector based therapeutic vaccines such as adenoviruses (eg, oncolytic adenoviruses), vaccinia viruses (eg, modified Ankara vaccinia virus (MVA)), alpha viruses (eg, Semliki forest virus (SFV)), measles virus, herpes simplex virus (HSV) ), and a coxsackievirus; synthetic long peptide (SLP) vaccines; and dendritic cell vaccines.

Chemotherapeutic agent

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In one embodiment, the combination of the invention comprises at least one chemotherapeutic agent as an anti-cancer agent.

The chemotherapeutic agent is, for example, selected from anti-cancer alkylating agents, anti-cancer antimetabolites, anti-cancer antibiotics, anti-cancer agents derived from plants, anti-cancer platinum coordinating compounds and any combination thereof.

In one embodiment, the chemotherapeutic agent to be combined with the A2AR inhibitor of formula (I) as described above comprises or consists of anti-cancer alkylating agents, anti-cancer antimetabolites, antibiotics anti-cancer drugs, anti-cancer agents derived from plants, anti-cancer platinum coordinating compounds, and any combination thereof.

Anticancer alkylating agent

In one embodiment, the combination of the invention comprises at least one anti-cancer alkylating agent as a chemotherapeutic agent.

An anti-cancer alkylating agent refers to an alkylating agent having anti-cancer activity, and the term "alkylating agent" herein refers to an agent providing an alkyl group in the alkylation reaction in which a hydrogen atom of an organic compound is substituted with an alkyl group.

Examples of anticancer alkylating agents include nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, mitobronitol, carboquone, thiotepa, rammustine, nimustine, temozolomide and la carmustine.

Antimetabolite anticancer

In one embodiment, the combination of the invention comprises at least one anti-cancer antimetabolite as a chemotherapeutic agent.

Anti-cancer antimetabolite refers to an antimetabolite having anti-cancer activity, and the term "antimetabolite" in this document includes, in a broad aspect, substances which disrupt normal metabolism and substances which inhibit the electron transfer system for cancer. prevent the production of energy-rich intermediates, due to their

BE2018 / 0114 Structural or functional similarities with metabolites which are important for living organisms (such as vitamins, coenzymes, amino acids and saccharides).

Examples of anticancer antimetabolites include methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (also referred to as 5-FU), tegafur, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate , enocitabine, Sl, gemcitabine, fludarabine and pemetrexed disodium. Preferably, the anticancer antimetabolite is selected from 5FU, gemcitabine and pemetrexed.

Anticancer antibiotic

In one embodiment, the combination of the invention comprises at least one anti-cancer antibiotic as a chemotherapeutic agent.

An "anti-cancer antibiotic" refers to an antibiotic having anti-cancer activity, and "antibiotic" in this document includes substances which are produced by microorganisms or by partial or total synthesis, and derivatives thereof; and inhibit cell growth and other functions of microorganisms and other living organisms.

Examples of anticancer antibiotics include actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, peplomycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, stimalameric zinostatin, idarubicin, sirolimus and valrabicin. Preferably the anti-cancer antibiotic and doxorubidin.

Anticancer agent derived from plants

In one embodiment, the combination of the invention comprises at least one anti-cancer agent derived from plants as a chemotherapeutic agent.

A "plant-derived anticancer agent", as used in the specification, includes compounds having anticancer activities which are derived from plants, or compounds prepared by applying a chemical modification to the foregoing compounds.

Examples of an anticancer agent derived from plants include vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel,

BE2018 / 0114 paclitaxel and vinorelbine. Preferably, the anti-cancer agent derived from plants is docetaxel.

Anti-cancer platinum coordination compound

In one embodiment, the combination of the invention comprises at least one anti-cancer platinum coordinating compound as a chemotherapeutic agent.

An "anti-cancer platinum coordinating compound" refers to a platinum coordinating compound having anticancer activity, and the term "platinum coordinating compound" herein refers to a platinum coordinating compound which provides platinum. in ionic form.

Preferred platinum compounds include cisplatin; a cisdiamminediaquoplatin (O) -ion; chloro (diethylenetriamine) -platinum (II) chloride; dichloro (ethylenediamine) -platinum (II); diamine (1,1cyclobutanedicarboxylato) platinum (II) (carboplatin); spiroplatin; iproplatin; platinum (II) diamine (2-ethylmalonato); ethylenediaminemalonatoplatin (H); aqua (1,2-diaminodicyclohexane) sulfatoplatin (II); aqua (1,2diaminodicyclohexane) malonatoplatin (II); (1,2diaminocyclohexane) malonatoplatin (II); (4-carboxyphthalato) (1,2diaminocyclohexane) platinum (II); (1,2-diaminocyclohexane) - (isocitrato) platinum (II); (1,2-diaminocyclohexane) oxalatoplatin (II); ormaplatin; tetraplatin; carboplatin, nedaplatin and oxaliplatin. Preferably, the anticancer platinum coordinating compound is selected from carboplatin and oxaliplatin.

Combinations of chemotherapeutic agents

Combinations of chemotherapeutic agents can be used as the second component of the combination of the invention.

For example, the combination known as folfox can be used. Folfox includes the combined use of fluorouracil (an antimetabolite), oxaliplatin (a compound of platinum) and folinic acid (a chemoprotector).

Anti-angiogenic agent

BE2018 / 0114

In one embodiment, the combination of the invention comprises at least one anti-angiogenic agent as an anti-cancer agent.

Angiogenesis, in other words the growth of new vessels, plays an important role in the development of tumors and the progression of malignancies. Inhibition of angiogenesis has been shown to suppress tumor growth and metastasis. The most obvious target of antiangiogenic agents is vascular endothelial growth factor (VEGF) and its receptors.

Several other factors are also of interest, including integrins, matrix metalloproteinases, and endogenous antiangiogenic factors.

Anti-angiogenic agents thus include VEGF inhibitors, integrin inhibitors and matrix metalloproteinase inhibitors.

Examples of antiangiogenic agents include ramucirumab, IMC-18F1, bevacizumab, ziv-aflibercept, sorafenib, sunitinib, axitinib, nintedanib, regorafenib, pazobanib, cabozantinib, vandetanib, and thalidomide. In a specific embodiment, the anti-angiogenic agent is a VEGF inhibitor, for example ramucirumab.

Protein inhibitors associated with multidrug resistance

In one embodiment, the combination of the invention comprises at least one inhibitor of proteins associated with multidrug resistance as an anticancer agent.

Proteins associated with multidrug resistance (MRP / ABCC) are a subfamily of ΓΑΤΡ binding cassette transporters, which are able to actively pump a wide variety of organic anionic compounds across the plasma membrane against their gradient. of concentration. Proteins are involved in multidrug resistance by transporting a wide variety of drugs outside of cells, including cancer drugs. Inhibition of proteins associated with multidrug resistance may thus improve the effectiveness of anticancer drugs.

Examples of protein inhibitors associated with multidrug resistance include inhibitors of MRP4 / ABCC4, inhibitors of MRP5 / ABCC5 and inhibitors of MRP8 / ABCC11.

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Radiotherapeutic agents - Radiotherapy

In one embodiment, the combination of the invention comprises at least one radiotherapeutic agent as an anti-cancer agent.

"Radiation therapy" refers to a method of treating cancer using different types of radiation such as x-rays, γ-rays, neutron radiation, an electron beam, a proton beam and radiation sources. It is used as part of cancer treatment to control or kill malignant cells. Radiation therapy can be curative in a number of types of cancer if it is localized to an area of the body. It can also be used as part of adjunct therapy, to prevent tumor recurrence after surgery to remove a primary malignant tumor.

The three main divisions of radiation therapy are: external beam radiation therapy (EBRT or XTR); sealed-source brachytherapy or radiotherapy; and systemic radioisotope therapy (RIT) or unsealed source radiotherapy. The differences relate to the position of the radiation source; the external is outside the body, brachytherapy uses sealed radioactive sources placed precisely in the area being treated, and systemic radioisotopes are given by infusion or oral ingestion. Particle therapy is a special case of external beam radiation therapy where the particles are protons or heavier ions. Radiation can be delivered by a linear accelerator.

Systemic radioisotopic therapy (RIT) is a form of targeted therapy. The targeting may be due to the chemical properties of an isotope such as radioactive iodine which is specifically absorbed by the thyroid gland a thousand times better than other organs in the body. Targeting can also be achieved by attaching the radioisotope to another molecule or antibody to guide it to the target tissue, forming a radiopharmaceutical.

In order to improve the radiosensitivity of the cancer, radiosensitizers can be administered during radiation therapy. Examples of radiosensitizers include: cisplatin, nimorazole, and cetuximab.

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Thus, in one embodiment, the radiotherapeutic agent is selected from sealed sources of radiation, radioisotopes, radiopharmaceuticals, radiosensitizers, and the like useful during radiotherapy.

In another embodiment, the invention also relates to the use of A2A inhibitors as described above, in combination with radiotherapy, including radiotherapy carried out by external beam radiation or X-ray radiation. ; brachytherapy; and systemic radioisotopic therapy.

Pharmaceutical composition

The invention further relates to a pharmaceutical composition comprising the combination of the invention.

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

(a) at least one A2AR inhibitor, (b) at least one anticancer agent, and (c) at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

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

(a) at least one A2AR inhibitor which is a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I)

or a pharmaceutically acceptable salt or solvate thereof, as defined above;

BE2018 / 0114 (b) at least one anticancer agent as defined above, such as for example immunotherapeutic agents, chemotherapeutic agents, antiangiogenic agents, inhibitors of proteins associated with multidrug resistance, radiotherapeutic agents, or any combination thereof, and (c) at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

The at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant for use in the preparation of the dosage 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, lipid carriers, antioxidants, surfactants, emulsifying agents, buffering agents, agents. pH modifiers, preservatives (or preservatives), isotonifying agents, stabilizers, granulating agents or binders, lubricants, disintegrating agents, slip agents, diluents or fillers, adsorbents, dispersing agents, suspending agents, fillers, releasing agents, sweetening agents, flavoring agents, and the like.

In a preferred embodiment, the pharmaceutical composition of the invention comprises one or more pharmaceutically acceptable cosolvents. 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 comprises PEG as a cosolvent, the PEG is of low molecular weight, preferably the PEG is PEG400.

In a specific embodiment, the pharmaceutical composition of the invention comprises one or more pharmaceutically acceptable lipid vectors. In a preferred embodiment, the lipid vector is lauroyl

BE2018 / 0114 polyoxyl-32 glycerides. This excipient corresponds to Gélucire® 44/14 prepared by Gattefossé (Saint-Priest - France). This excipient is also known under the following references: lauroyl polyoxyl-32 glycerides NF / USP (NF: national formulary; USP: US Pharmacopoeia); lauroyl macrogol-32 glycerides EP (European Pharmacopoeia); hydrogenated coconut PEG-32 ester (INCI); CAS number 57107-95-6. Gélucire® 44/14 is a well-defined multi-component substance consisting of mono-, di- and triglycerides and mono- and diesters PEG-32 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 balance (HLB) value of 14.

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 some embodiments, surfactants are added, such as, for example, polyethylene glycols, fatty acid esters of polyoxyethylene sorbitan, sorbitan esters, docusate sodium, 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 RH4O (polyoxyl 40 hydrogenated castor oil), cremophor EL (polyoxyl 35 hydrogenated castor oil), polyethylene glycol 660 12-monostearate, HS 15 solutol (polyoxyethylated 12-hydroxystearic acid), labrasol (caprylocaproyl poly glycerides), labrafil Ml944 (oleoyl polyoxyl-6 glycerides).

In some embodiments, emulsifying agents 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 emulsifying agents are, for example, poloxamer, propylene glycol monolaurate, propylene glycol dilaurate, and propylene glycol monocaprylate.

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In some embodiments, buffering agents are used to help maintain the pH in the range which approximates physiological conditions. Suitable buffering agents include organic and inorganic acids and salts thereof, eg citrate buffers (eg, monosodium citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture. , etc.), succinate buffers (for example, succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffers (for example, mixture tartaric acid-sodium tartrate, a mixture of tartaric acid-sodium tartrate, a mixture of tartaric acid and sodium tartrate, etc.), fumarate buffers (for example, a mixture of fumaric acid-monosodium fumarate, a mixture of fumaric acid-disodium fumarate, a mixture of monosodium fumarate-disodium fumarate, etc.), gluconate buffers (for example, a mixture of gluconic acid-sodium gluconate, a mixture of gluconic acid-sodium hydroxide, a gluconic acid-potassium gluconate mixture, etc.), an oxalate buffer (for example, an oxalic acid-sodium oxalate mixture, an oxalic acid-sodium hydroxide mixture, an oxalic acid-potassium oxalate mixture, etc.), lactate buffers (for example, lactic acid-sodium lactate mixture, lactic acid-sodium hydroxide mixture, lactic acid-potassium lactate mixture, etc.) and acetate buffers (for example, acetic acid-mixture sodium acetate, a mixture of acetic acid and sodium hydroxide, etc.). Additionally, phosphate buffers, histidine buffers, and trimethylamine salts such as Tris can be used.

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

In some embodiments, preservatives are added to retard microbial growth. Preservatives suitable for use with the present disclosure include phenol, benzyl alcohol, metacresol, methyl paraben, propyl paraben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides (eg, chloride, bromide , and iodide), hexamethonium chloride, and

BE2018 / 0114 alkyl parabens such as methyl or propyl paraben, catechol, resorcinol, cyclohexanol, and 3-pentanol.

In some embodiments, isotonifying agents sometimes known as "stabilizers" are added and include polyhydric polyols, for example trihydric or higher polyols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol. Stabilizers refer to a broad class of excipients whose functions can range from a filler to an additive which solubilizes the therapeutic agent or helps prevent denaturation or adhesion to the container wall. or helps to inhibit the precipitation, growth or agglomeration of 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; polymers of amino acids; sulfur-containing reducing agents, such as urea, glutathione, thiocic acid, sodium thioglycolate, thioglycerol, Γα-monothioglycerol, and sodium thio sulfate; low molecular weight polypeptides (eg, peptides of 10 residues or less); proteins such as human serum albumin, 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; polyethylene glycol-blockpoly methyl ether block copolymer (D-L lactide); 1/2/1 poly (butyl methacrylate-co-methacrylate (2dimethylaminoethyl) -co-methacrylate). Preferred stabilizers are, for example, glycerol; polyethylene glycol; polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, phthalate

BE2018 / 0114 of hydroxypropylmethylcellulose or hydroxypropylmethylcellulose acetate succinate; carboxymethylcellulose (Na / Ca); a polyethylene glycol-block-poly (D-L lactide) methyl ether block copolymer; and poly (butyl methacrylate-co-methyl (2dimethylaminoethyl) -co-methyl methacrylate) 1/2/1.

In some embodiments, granulating agent / binder (s) are added, such as for example starch, gums (including natural, semi-synthetic and synthetic gums), microcrystalline cellulose, ethyl cellulose , methylcellulose, hydroxypropylcellulose, polymers of liquid glucose 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 Nf glycerides (Compritol HD5 ATO), sodium stearyl fumarate and the like.

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

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

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

In some 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, etc.

BE2018 / 0114 disintegrating agents, slip agents, diluents, adsorbents and the like.

By way of non-limiting examples, the pharmaceutical composition may be in a form suitable for oral administration, for parenteral administration (for example by intravenous, intramuscular or subcutaneous injection or by intravenous infusion), topical administration (including ocular), rectal administration, administration by inhalation, by skin patch, by implant, by suppository, etc. These suitable forms of administration, which may be solid, semi-solid or liquid, depending on the route of administration, as well as the methods and vehicles, diluents and excipients to be used in their preparation, will be obvious to those skilled in the art. job ; reference is made to the latest edition of Remington’s Pharmaceutical Sciences.

The compositions can be formulated to provide rapid, sustained or delayed release of the active compound (s) contained therein.

According to one embodiment, the pharmaceutical composition is in a form suitable for oral administration. Forms suitable for oral administration can be solid, semi-solid or liquid. Some preferred but not restrictive examples of these forms include liquid, pasty or solid compositions, and more particularly tablets, tablets formulated for sustained or sustained release, capsules (including soft and hard gelatin capsules), pills. , dragees, tablets, sachets, cachets, powder, liquids, gels, syrups, porridge, elixirs, emulsions, solutions, and suspensions.

According to another embodiment, the pharmaceutical composition is in a form suitable for injection, in particular suitable for being injected into the subject by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous or transdermal injection or infusion.

Sterile injectable forms of the pharmaceutical composition of the invention include sterile injectable solutions and sterile packaged powders (which are generally reconstituted before use) for administration as a bolus and / or for continuous administration.

□ The sterile injectable forms of the pharmaceutical composition of the invention can be an aqueous or oleaginous solution. These suspensions

BE2018 / 0114 can be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic pharmaceutically acceptable diluent or solvent. Among the vehicles and solvents which can be used are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils are conventionally used as a solvent or suspending medium. For this purpose, any bland fixed oil can be used including synthetic mono- and diglycerides. Fatty acids, such as oleic acid and its glyceridic derivatives are useful in the preparation of injectables, as are pharmaceutically acceptable natural oils, such as olive oil or castor oil, in particular in their polyoxyethylated versions. These oily solutions or suspensions may also contain a long chain alcohol dispersant or diluent, such as carboxymethyl cellulose or similar dispersing agents which are commonly used in the formulation of pharmaceutically acceptable dosage forms including emulsions and suspensions. Other commonly used surfactants, such as Tweens, Spans, and other emulsifiers or bioavailability enhancers which are commonly used in the preparation of solid, liquid or other pharmaceutically acceptable dosage forms can also be used for formulation purposes.

According to another embodiment, the pharmaceutical composition of the invention is in a form suitable for topical administration. Examples of forms suitable for topical administration include, without limitation, liquid, pasty or solid compositions, and more particularly aqueous compositions, drops, dispersions, sprays, ointments, creams, lotions, etc. microcapsules, microor nanoparticles, polymer patches, or controlled release patches, and the like.

According to another embodiment, the pharmaceutical composition of the invention is in a form suitable for rectal administration. Examples of forms suitable for rectal administration include, but not

BE2018 / 0114 restrictive, a suppository, micro-enemas, enemas, gel, rectal foam, cream, ointment, and the like.

According to another embodiment, the pharmaceutical composition of the invention is in a form suitable for administration by inhalation. Examples of forms suitable for administration by inhalation include, but are not limited to, aerosols.

The pharmaceutical preparations of the invention are preferably in unit dosage form, and may suitably be packaged, for example, in a box, blister pack, vial, bottle, sachet, ampoule or other carrier. or suitable container for a single dose or multiple doses (which can be correctly labeled); optionally with one or more leaflets containing product information and / or instructions for use.

Kit

The invention further relates to a kit comprising the combination of the invention.

In one embodiment, the kit of the invention comprises:

(a) a first part comprising at least one inhibitor of A2AR, and (b) a second part comprising at least one anticancer agent.

In a preferred embodiment, the invention relates to a kit comprising:

(a) a first part comprising at least one A2AR inhibitor which is a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I)

BE2018 / 0114 or a pharmaceutically acceptable salt or solvate thereof, as defined above, and (b) a second part comprising at least one anticancer agent as defined above, such as for example agents immunotherapeutics, chemotherapeutic agents, antiangiogenic agents, inhibitors of proteins associated with multidrug resistance, radiotherapeutic agents, or any combination thereof.

In one embodiment, the first part comprises a pharmaceutical composition comprising an A2AR inhibitor, preferably a thiocarbamate derivative of formula (I) as defined above, and at least one carrier, a diluent, an excipient and / or a pharmaceutically acceptable adjuvant.

Pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant of the pharmaceutical composition of the first part of the kit may be those listed above in relation to the pharmaceutical composition of the invention.

Similarly, the dosage form and the route of administration of the pharmaceutical composition of the first part of the kit may be those listed above in relation to the pharmaceutical composition of the invention.

In one embodiment, the second part comprises an anti-cancer agent as defined above. Depending on the type of anticancer agent, the second part of the kit may be in the form of a pharmaceutical composition. The excipients, dosage form and route of administration of such a pharmaceutical composition will be obvious to those skilled in the art (reference is made to the latest edition of Remington's Pharmaceutical Sciences), and especially those listed above in connection with the composition. pharmaceutical of the invention.

As discussed below, the administration of the different parts of the kit can be carried out simultaneously or be staggered over time, with a similar or different timing of administration (in other words, similar or different numbers of times). administration of each component), either at the same administration site or at different administration sites, in similar or different dosage forms.

BE2018 / 0114

Diet and doses

In the context of the present invention, the administration of the A2AR inhibitor and the anticancer agent can take place simultaneously or be staggered over time, with a similar or different timing of administration (in other words , similar or different numbers of administration of each component), either at the same administration site or at different administration sites, in similar or different dosage forms, as will be further discussed below.

To ensure that the distinct mechanisms elicited by the A2AR inhibitor and the anticancer agent are not negatively influenced by each other, the anticancer agent and the A2AR inhibitor are preferably administered separately in the drug. time (over time), in other words sequentially, and / or are administered at different administration sites. This means that the A2AR inhibitor can be administered, for example, before, at the same time as or after the anticancer agent, or vice versa. Alternatively or additionally, the A2AR inhibitor and anti-cancer agent can be administered to different sites of administration, or to the same site of administration, preferably, when administered spread across the body. time.

In one embodiment, the A2AR inhibitor must be administered before and / or concurrently with an immunotherapeutic agent as described above. In one embodiment, the immunotherapeutic agent is a checkpoint inhibitor and the A2AR inhibitor should be administered before the day of administration of the checkpoint inhibitor, or on the same day, as described. above.

In one embodiment, the A2AR inhibitor is to be administered before and / or concurrently with an immunotherapeutic agent as described above and continuously thereafter.

In one embodiment, the A2AR inhibitor should be administered before and / or simultaneously with an immunotherapeutic agent as described above and then thereafter for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days after that. In another embodiment, the A2AR inhibitor should be administered before and / or simultaneously with an immunotherapeutic agent as described above and then thereafter for at least 1, 2, 3, 4, 5, 6 , 7, 8, 9, or 10 weeks after that. In another way of

BE2018 / 0114 realization, the A2AR inhibitor should be administered before and / or simultaneously with an immunotherapeutic agent as described above and then thereafter for at least 1, 2, 3, 4, 5, 6, 7 , 8, 9, or 10 months after that.

In one embodiment, the immunotherapeutic agent is a checkpoint inhibitor and the A2AR inhibitor must be administered before or at the same time as said checkpoint inhibitor.

In one embodiment, the immunotherapeutic agent is a checkpoint inhibitor and the A2AR inhibitor must be administered before or at the same time as said checkpoint inhibitor and continuously thereafter. In one embodiment, the immunotherapeutic agent is a checkpoint inhibitor and the A2AR inhibitor should be administered before or at the same time as said checkpoint inhibitor and thereafter for at least 1,2,3, 4, 5,6, 7, 8,9, or 10 weeks after that.

Depending on the condition to be prevented or treated and the form of administration, the combination of the invention may be administered as a single daily dose, divided into one or more daily doses.

According to one embodiment, a therapeutically effective dose of the A2AR inhibitor as described above is to be administered for use in the treatment of cancer in a subject in need thereof, wherein said A2AR inhibitor is. used in combination with an anticancer agent, such as for example an immunotherapeutic agent. Thus, in one embodiment, the pharmaceutical combination or kit of the invention comprises a therapeutically effective dose of an A2AR inhibitor as described above and a therapeutically effective dose of an anti-cancer agent as described above. -above.

It will be understood that the total daily use of the A2AR inhibitor and anti-cancer agent will be decided by the attending physician as part of sound medical judgment. The specific dose for any particular subject will depend on a variety of factors such as the cancer to be treated; the patient's age, body weight, general health, gender and diet; and similar factors well known in the medical field.

In one embodiment, the subject is a mammal, preferably a human, and the dose of the A2AR inhibitor, preferably a therapeutically effective dose, is a dose ranging from about 0.01 mg per kilogram of weight

BE2018 / 0114 body (mg / kg) to about 5 mg / kg, preferably from about 0.08 mg / kg to about 3.3 mg / kg, more preferably from about 0.15 mg / kg to about 1.7 mg / kg.

In one embodiment, the subject is a mammal, preferably a human, and the dose of the A2AR inhibitor, preferably a therapeutically effective dose, is a dose ranging from about 0.01 mg per kilogram of body weight per day (mg / kg / day) to about 5 mg / kg / day, preferably from about 0.08 mg / kg / day to about 3.3 mg / kg / day, more preferably about 0.15 mg / kg / day to about 1.7 mg / kg / day.

In one embodiment, the subject is a mammal, preferably a human, and the dose of the A2AR inhibitor, preferably a therapeutically effective dose, is a dose ranging from about 1 mg to about 500 mg, preferably from about 5 mg to about 200 mg, more preferably from about 10 mg to about 100 mg.

In one embodiment, the subject is a mammal, preferably a human, and the dose of the A2AR inhibitor, preferably a therapeutically effective dose, is a dose ranging from about 1 mg to about 500 mg per. administration, preferably from about 5 mg to about 200 mg per administration, more preferably from about 10 mg to about 100 mg per administration.

In one embodiment, the subject is a mammal, preferably a human, and the dose of the A2AR inhibitor, preferably a therapeutically effective dose, is a daily dose ranging from about 1 mg to about 500 mg. , preferably from about 5 mg to about 200 mg, more preferably from about 10 mg to about 100 mg.

In one embodiment, the subject is a mammal, preferably a human, and the dose of the A2AR inhibitor, preferably a therapeutically effective dose, is a daily dose to be administered in one, two, three or more doses. more. In one embodiment, the subject is a mammal, preferably a human, and the dose of the A2AR inhibitor, preferably a therapeutically effective dose, is a once or twice daily dose.

Uses

BE2018 / 0114

Another object of this invention is the use of the combination of the invention in the form of a medicament. Thus, in one embodiment, the invention relates to the use of the combination of the invention for the preparation of a medicament. In particular, the invention relates to the use of the pharmaceutical composition of the invention or of the kit of the invention for the preparation of a medicament.

In particular, the invention relates to the combination, pharmaceutical composition or kit of the invention, for their use in the treatment and / or prevention of cancer.

In one embodiment, the invention relates to the treatment and / or prevention of cancer, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the combination, pharmaceutical composition or kit of the drug. 'invention.

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

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

Various cancers are known in the art. Cancers which can be treated using the methods of the invention include solid and non-solid cancers, including solid benign and malignant tumors and non-solid benign and malignant tumors. Cancer can be metastatic or non-metastatic. Cancer can be familial or sporadic.

In one embodiment, the cancer to be treated according to the present invention is a solid cancer. As used herein, the term "solid cancer" includes any cancer (also referred to as malignancy) which forms a discrete tumor mass, as opposed to cancers (or malignancies) which diffusely infiltrate tissue without forming tissue. mass.

Examples of solid tumors include, but are not limited to: bile duct cancer, brain cancer (including glioblastoma and medullobastoma), breast cancer, a carcinoid, cervical cancer, a

BE2018 / 0114 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, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including those incipient 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; liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell cancer and squamous cell cancer), testicular cancer including germinal tumors es (seminomas, and non-seminomas such as teratomas and choriocarcinomas), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma) and urothelial cancer.

In another embodiment, the cancer to be treated according to the present invention is a non-solid cancer. Examples of non-solid tumors include, but are not limited to, hematologic neoplasms. As used herein, hematologic neoplasm is a term of the art which 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, lymphoma, myeloma, and chronic lymphoid leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin lymphomas, and lymphocytic lymphomas). Chronic lymphoid leukemias include, for example, chronic T-cell lymphoid leukemias and chronic B-cell lymphoid leukemias.

In a specific embodiment, the cancer is selected from cancers of the breast, carcinoids, cervix, colorectal, endometrium, glioma, cancers of the head and neck, of the liver, of the lung. , melanoma, ovarian, pancreatic, prostate, kidney, gastric, thyroid and urothelial cancers.

BE2018 / 0114

In a specific embodiment, the 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 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 cancer of the liver. In a specific embodiment, the cancer is lung cancer. In a specific embodiment, the cancer is 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.

In another specific embodiment, the cancer is selected from the group consisting of: leukemia and multiple myeloma.

In one embodiment, the invention relates to the combination, pharmaceutical composition or kit as defined above for use in immunotherapy, preferably as immunotherapy against cancer.

In one embodiment, the invention relates to a method of immunotherapy, preferably anticancer immunotherapy, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the combination, pharmaceutical composition or drug. kit of the invention.

The invention further relates to the use of the combination, pharmaceutical composition or kit of the invention for the preparation of a medicament for carrying out immunotherapy, preferably anticancer immunotherapy.

In one embodiment, the invention relates to the use of the combination, pharmaceutical composition or kit of the invention, to increase the immune recognition and destruction of cancer cells.

BE2018 / 0114

In one embodiment, the invention relates to a method of increasing the immune recognition and destruction of cancer cells, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of the combination, pharmaceutical composition or kit of the invention.

The invention further relates to the use of the combination, pharmaceutical composition or kit of the invention for the preparation of a medicament for increasing the immune recognition and destruction of cancer cells.

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

In one embodiment, the patient receiving the A2A inhibitor as described herein also receives immunotherapy, chemotherapy, radiation therapy, or a combination thereof.

In one embodiment, the subject is resistant to immunotherapy. In one embodiment, the subject is resistant to cancer immunotherapy.

In one embodiment, the subject is resistant to chemotherapy. In one embodiment, the subject is resistant to cancer chemotherapy.

In one embodiment, the subject is resistant to radiation therapy. In one embodiment, the subject is resistant to cancer radiation therapy.

The invention also relates to a compound of formula (I) as defined above for its use in therapy in combination with an anticancer agent as defined above, in particular immunotherapeutic agents, chemotherapeutic agents, anti-angiogenic agents, inhibitors of proteins associated with multidrug resistance, radiotherapeutic agents, or any combination of these.

The invention also relates to a compound of formula (I) as defined above for its use in a patient treated by immunotherapy, chemotherapy, radiotherapy or a combination thereof.

The invention further relates to a method of treating cancer in a subject resistant to an anti-cancer agent, comprising administering to the patient a compound of formula (I) as defined above and said anti-cancer agent. In one

BE2018 / 0114 embodiment, said anticancer agent is immunotherapy, chemotherapy, radiotherapy or a combination thereof.

The invention further relates to a method of increasing the therapeutic response of a subject to an anti-cancer agent, further comprising administering to the patient a compound of formula (I) as defined above. In one embodiment, said anticancer agent is immunotherapy, chemotherapy, radiotherapy or a combination thereof.

The invention also relates to an anticancer agent as defined above for its use in therapy in combination with a compound of formula (I) as defined above.

BRIEF DESCRIPTION OF THE FIGURES

Figure 1 shows the antitumor efficacy of Ä2AR inhibitor Compound 7 administered as a single agent in a syngeneic Hepa 1-6 hepatic tumor model. Figure 1A is a graph showing tumor volume over time after inoculation. Figure IB shows the distribution of tumor volume on day 22.

Figure 2 shows tumor growth of A20 under treatment with compound 7 as the sole agent or in combination with anti-PD-L1. Figure 2A is a graph showing tumor volume over time after inoculation. Figure 2B shows the distribution of tumor volume on day 23.

Figure 3 shows tumor growth of EMT6 under treatment with compound 8a in combination with antagonist anti-CTLA4 MAb. The number of complete responders (CR) in 10 mice per group is indicated. Tumor growth over time: median (Figure 3A), vehicle (Figure 3B) and aCTLA-4, 3 mg / kg Q3Dx2 (day 9, 12) alone (Figure 3C) or in combination with D) compound 8, 0 , 1 mg / kg QDx25 (Figure 3D) or compound 8, 0.6 mg / kg QDx25 (Figure 3E).

FIG. 4 demonstrates that the A2AR inhibitor compound 8a in combination with an anti-PD-L1 mAb modulates the infiltrate of T lymphocytes in the microenvironment of the tumor A20. The absolute quantification of the number of CD3 ⁺ T lymphocytes (Figure 4A) and CD8 ⁺ T lymphocytes (Figure 4B) was measured by calculation from the average of 10 high voltage fields / sections (10 HPF) of independent tumors (the symbols represent individual mice;

BE2018 / 0114 η = 5 to 7 mice per group). Median range and interquartile range are shown, p values were calculated using Mann Whitney's nonparametric t test.

EXAMPLES

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

The following abbreviations are used:

BID: bis in die (in other words twice a day)

RC: full answering machine

DMSO: dimethyl sulfoxide

MAb: monoclonal antibody

QD: quaque die (in other words once a day)

Q3D: almost 3 die (in other words every 3 days),

ICT: inhibition of tumor growth

LIT: lymphocytes infiltrating tumors

I. COMPOUNDS

The compounds of formula (I) are prepared as described in document PCT / EP2018 / 05 8301

II. IN VIVO STUDIES

Summary of Findings:

Compound 7 at 3 mg / kg BID significantly retarded the growth of HEPA-1-6 tumors compared to the control vehicle in a syngeneic host.

In combination with an anti-PD-L1, compound 7 exhibited antitumor activity at 0.3 mg / kg BID and, at 3 mg / kg BID, significantly retarded tumor growth versus the anti-PD-L1 control in a model of A20 lymphoma in syngeneic mice.

In combination with an anti-CTLA-4, compound 8a exhibited anti-tumor activity at 0.1 mg / kg and from 0.6 mg / kg considerably slowed down

BE2018 / 0114 Tumor growth in a dose dependent manner in the EMT6 breast cancer model in syngeneic mice. In addition, in a recovered mouse, it inhibited growth after re-inoculation suggesting induction of a memory response.

Further illustrating the mechanism of action, in combination with an anti-PDL1, compound 8a at 3 mg / kg BID dramatically increased infiltration of CD3 ⁺ and CD8 ⁺ cells with no effect from cells expressing FOXP3.

IL 1. HEPATIC TUMOR MODEL HEPA1-6 SYNGENIC MURINE

The purpose of this study was to evaluate the antitumor activity of compound 7 in a model of murine hepatoma (NCR-A2A-032).

C57BL / 6 female mice (8 weeks old) were inoculated subcutaneously in the right flank region with Hepa 1-6 tumor cells (day 0). When the tumor size reached about 50 mm ³ (day 4), mice randomly were divided into experimental groups and insider treatment the ^4th to ^25th day. Mice were administered po vehicle (10% DMSO, 10% Solutol HS 15 in dHiO bp) or compound 7 at 0.3 and 3 mg / kg, po BIDx 21.

At 3 mg / kg, compound 7 exhibited significant antitumor efficacy with 44% tumor growth inhibition (TIA) calculated on day 22 (p = 0.024). (Figures 1A and IB)

II.2. SYNGENIC A20 EXPERIMENTAL LYMPHOMA MODEL IN COMBINATION WITH ANTI-PD-L1

In this study, the antitumor efficacy of compound 7 was evaluated either as a single agent (monotherapy) or in combination with an antagonist anti-apoptosis 1 ligand (anti-PD-L1) monoclonal antibody (10F.9G2, BioXcell) in a model of B-cell lymphoma (NCR-A2A-031).

Female BALB / c mice (8 weeks old) were inoculated with murine A20 B-cell tumor cells, subcutaneously in the lower right flank region (day 0). When the tumors reached a size of about 50 mm3 (day 7), the mice were randomly assigned to groups and treatment was initiated. Mice were administered po vehicle (10% DMSO, 10% Solutol HS 15 in dH ₂ O pH?) As a control or compound 7 at 0.3 and

BE2018 / 0114 mg / kg, p.o., BIDx 21 (days 7-28) or anti-PD-L1 mAb at 5mg / kg i.p., Q3Dx3 (days 9,12,15) as a single agent or in combination.

Compound 7 administered po at 0.3 mg / kg, BID, in combination with anti-PD-L1 mAb, exhibited antitumor activity (ICT = 76%, determined on day 23) without, however, reaching statistical significance (p = 0.106) compared to anti-PD-L1 monotherapy (ICT = 49%).

Compound 7, administered at 3 mg / kg BID in combination with antiPD-L1 mAb, showed significant improvement in anti-tumor activity (p = 0.039 for PICT and p = 0.0008 for overall suppression of tumor growth) compared to the single agent MAb anti-PD-L1 (ICT = 82 and 49%, observed on day 23, respectively). (Figures 2A and 2B).

Statistical analysis also showed that compound 7 synergizes with anti-PD-L1 mAb to significantly inhibit the growth of the established A20 syngeneic tumor (p = 0.017).

II.3. SYNGENIC EMT6 BREAST CANCER MODEL IN COMBINATION WITH ANTI-CTLA-4

Compound 8a was evaluated for antitumor efficacy in combination with cytotoxic T lymphocyte associated antigen 4 antagonist MAb (CTLA-4) (9H10, BioXcell) in a triple negative breast cancer model.

EMT6 mammary tumor cells were orthotopically inoculated into the lower right mammary fat pad of 8 week old female BALB / c mice (day 0). When the tumors reached a size of about 60 mm ³ (day 9), the mice were randomly assigned to groups. Mice were administered po control vehicle (10% DMSO, 10% Solutol HS15 in dlLO pFh) or 3 mg / kg anti-CTLA-4 mAb ip, Q3Dx2 (days 9, 12) alone or in combination. with compound 8a at 0.1 mg / kg po QDx25 or 0.6 mg / kg po QDx25.

Compound 8a combined with anti-CTLA-4 dramatically reduced tumor growth when administered at 0.6 mg / kg (p = 0.0153, mean ICT = 99% determined on day 31 - full responder ( CR) = 7/10) vs. antiCTLA4 alone (OR = 3, mean ICT = 72%, determined on day 31) (Figures 3A, 3B, 3C and 3E). Although compound 8A at 0.1 mg / kg in combination with antiCTLA-4 mAb (as above) did not reach statistical significance (p = 0.8665)

BE2018 / 0114 vs. Anti-CTLA4 mAb as the sole agent, resulted in CR = 5 (n = 10 mice per group) and TIA = 85% (Figures 3A and 3D). In addition, there was no statistically significant difference between the doses. This suggests that compound 8a already exhibits in vivo activity at 0.1 mg / kg in combination with an anti-CTLA4 MAb (FIG. 1).

When the complete responders (cured mice) were again exposed to EMT6 tumor cells (specific antigen) or unrelated colon CT26 cells (nonspecific antigen), the mice previously treated with compound 8a at 0.1 and 0 , 6 mg / kg in combination with an anti-CTLA-4 mAb, were not protected against exposure to unrelated CT26 cells (100% tumor incidence) but totally rejected EMT6 cells (no formation tumor) in 66% (0.1 mg / kg) and 100% (0.6 mg / kg) of mice, respectively.

Therefore, compound 8a significantly inhibited the growth of established EMT6 syngeneic tumors in combination with an antiCTLA-4 antagonist mAb and induced a long-term memory response which results in a specific long-lasting anti-tumor response.

II.4. MECHANISM OF ACTION OF COMPOUND 8A TO REDUCE TUMOR GROWTH IN A MODEL OF LYMPHOMA A20

Having established that compound 8a (or its racemate mixture, compound 7) demonstrates antitumor activity in several experimental tumor models at well tolerated doses, this study evaluated the mechanism of action responsible for this effect.

Compound 8a was evaluated in a B-cell lymphoma tumor model, as a single agent and in combination with an anti-PD-L1 antagonist MAb. Mice bearing A20 tumors (tumor size approximately 70 mm ³ , day 12 post-inoculation) were treated with the po control vehicle (10% DMSO, 10% Solutol HS15 in dHiO pHs) or a Anti-PD-L1 mAb at 1 mg / kg ip, Q3Dx3 (days 14, 17 and 20) and compound 8a at 3 mg / kg po, BIDx10 as sole agent or in combination with an anti-PD- MAb Ll. By IHC staining, tumor infiltrating lymphocytes (LITs), including CD3 ⁺ T lymphocytes, CD8 ⁺ T lymphocytes and total FOXP3 ⁺ Treg lymphocytes, were characterized and compared using a semi-quantitative technique.

BE2018 / 0114

Compound 8a at 3 mg / kg as a single agent regimen had a moderate effect on CD3 ⁺ and CD8 ⁺ LITs in the tumor environment but the increase in infiltrate was not significant. . The combination of compound 8a at 3 mg / kg with anti-PD-L1 mAb demonstrated a significant increase in infiltration of CD3 ⁺ T cells (p = 0.0068) and CD8 ⁺ T cells ( p = 0.0035) in the tumor compared to the anti-PD-L1 mAb used as the sole agent (Figures 4A and 4B). No tistically significant change in Treg infiltration was demonstrated with any treatment with the single agent or the combination.

These results strongly suggest that compound 8a in combination with a

Anti-PDL-1 mAb significantly modulated the immunosuppressive nature of the tumor microenvironment by increasing the infiltration of LITs.

Claims (18)

BE2018 / 0114 1. Combination including: (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, in which the heteroaryl or aryl groups are optionally substituted with 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 ¹ represents a furyl group; R ² represents a 6-membered aryl group or a 6-membered heteroaryl group, wherein 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 alkylsulfonealkyle; 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) (heterocyclylalkyl) heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, BE2018 / 0114 (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyle, alkylaminoalkylaminocarbonyle, dialkylaminoalkylaminocarbonyle, hétérocyclylalkylaminocarbonyle (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxydealkyle alkylsulfonyl and alkylsulfonealkyl; 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 with one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl, aminoalkyl, heteroalkaryl) (alkyl) (alkyl )aryl , 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 alkylsulfonealkyl; and (b) an anti-cancer agent. 2. Combination according to claim 1, wherein the compound is of formula (Ia) BE2018 / 0114

(Ia) or a pharmaceutically acceptable salt or solvate thereof, wherein: R ¹ is as defined in claim 1; 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, alkylsulfonylsulfonylsulfonylsulfonylsulfonyl, alkylsulfonylsulfonylsulfonylsulfonylsulphonylsulfonylsulfonylsulfonyl, alkylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl, alkylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl, alkylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonylsulfonyl 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) (heterocyclylalkyl) 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 is H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, alkoxycarbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyle, carbonylamino, sulfonylamino, or alkylsulfonealkyle; BE2018 / 0114 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, dialkylaminoalkly, aminoalkyl (amino) alkyl , 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; 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 with one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl, alkylaryl) (alkyl) (alkyl )aryl , 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 alkylsulfonealkyl; 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. 100 BE2018 / 0114 3. A combination 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. Combination according to any one of claims 1 to 3, wherein the compound is of formula (la-lb)

O (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, dialkylaminoalkyl, aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonylaminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonylamino, alkyloxycarbonylaminocarbonylaminocarbonylaminocarbonylaminocarbonylamino 101 BE2018 / 0114 heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulphoxide, alkylsulphoxydealkyl, alkylsulphoxydealkyl, alkylsulphoxidealkyl, alkylsulphoxidealkyl 5. Combination according to any one of claims 1 to 4, wherein the compound of formula (I) is selected from the group consisting of: 3- (2- (4- (4 - ((1H1,2,3- triazolo-4yl) methoxy-2fluorophenyl) piperazine-1 -yl) ethyl) -5-amino- (8- (furan2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5- c] pyrimidin-2 (3H) -one; 5 - ((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) 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-difluorophenoxy) acetamide; (S) -5-amino-3- (2- (4- (2-fluoro-4- (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; (R) -5-amino-3 - (2- (4- (2-fluoro-4- (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; (R, S) -5-amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazin1 -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- (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-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; 5-amino-8- (furan-2-yl) -3- (2- (4- (4- (2-hydroxyethoxy) phenyl) piperazin-lyl) ethyl) 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] [1,2,4] triazolo [1,5c) acid pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) phenoxy) acetic; 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; 102 BE2018 / 0114 5-amino-3- (2- (4- (4- (2,3-dihydroxypropoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan-2yl) thiazolo [5,4-e] [l , 2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 5-amino-3- (2- (4- (4- (2-aminoethoxy) phenyl) piperazin-1-yl) ethyl) -8- (furan-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-morpholinoethoxy) phenyl) piperazin-1 yl) ethyl) thiazolo [5,4-e] [1, 2,4] triazolo [1,5-c] pyrimidin-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- (methylsulfonyl) 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 -y 1) -3 - (2- (4- (4- (methylsulfinyl) phenyl) piperazin-1 yl) 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-lyl) ethyl) thiazolo [5,4-e] [1,2 , 4] triazolo [1,5-c] pyrimidin-2 (3H) -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 (fiiran-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; 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; 103 BE2018 / 0114 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; 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c) acid pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) acetic; 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c) acid pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3,5-difluorophenoxy) acetic; 2- (4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c) acid 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 [5,4e] [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- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c) acid pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -2-methylpropanoic acid; 3- (4- (4- (2- (5-amino-8- (furan-2-yl) -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) acid 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) acid pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,6-difluorophenoxy) acetic; 2- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c) acid pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluorophenoxy) acetic; 104 BE2018 / 0114 4- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c] acid pyrimidin-3 (2H) -yl) ethyl) piperazm-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 , 5c] 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 - ((1 H-1,2,4-triazol-3-yl) methoxy) -2-fluorophenyl) piperazin-1 -yl) ethyl) -5amino-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] [1,2,4] triazolo [1,5c] pyrimidin) -3 (2H) -yl) ethyl) piperazin-1-yl) -3-fluorophenoxy) -N- (2 (methylamino) ethyl) acetamide; 2- (4- (4- (2- (5-ammo-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; (R) -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) propanoic 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) 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; 105 BE2018 / 0114 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; 2- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c) acid 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 [5,4e] [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 [5,4e] [1,2,4] triazolo [1, 5-c] pyrimidin-3 (2H) -yl) ethyl) piperazin-1-yl) -2,4-difluorophenoxy) propanoic acid; 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 [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1 - y 1) -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-N-methylbenzamide; 4- (5- (4- (2- (5-amino-8- (furan-2-yl) -2-oxothiazolo [5,4-e] [1,2,4] triazolo [1,5c) acid pyrimidin-3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluorophenoxy) butanoic acid; 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; 106 BE2018 / 0114 5-amino-3 - (2- (4- (2-fluoro-4 - ((1 -methyl-1 H-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- (fiiran-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- (furan-2-yl) -3- (2- (4- (pyridin-4-yl) piperazin-1-yl) ethyl) thiazolo [5,4e] [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- (furan-2yl) thiazolo [5,4-e] [ 1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; 107 BE2018 / 0114 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-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- (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) piperazm-lyl) 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- (2,4-difluoro-5- (morpholin-3-ylmethoxy) phenyl) piperazm-lyl) 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- (2,4-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 [1.5 c] pyrimidin-2 (3H) -one; 5-ammo-3- (2- (4- (2,4-difluoro-5 - (((3 S, 4S) -4-fluoropyrrolidin-3 yl) 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 - (((3R, 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; 108 BE2018 / 0114 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-amino-3- (2- (4- (2,4-difluoro-5 - ((2-oxopyrrolidin-3-yl) oxy) 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- (2,4-difluoro-5 - ((2-oxopyrrolidm-3-yl) oxy) phenyl) piperazin-lyl) ethyl) -8- (furan -2-yl) 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 [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1 -yl) -2,4-difluorophenoxy) -N- (2morpholinoethyl) 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) -2,4-difluoro-N- (morpholin-3-ylmethyl) benzamide; 5-amino-3- (2- (4- (2-fluoro-4- (morpholin-3-ylmethoxy) phenyl) piperazm-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] pyrimidm-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) piperazinl-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-fluoropyrrolidm-3-yl) oxy) phenyl) piperazml-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 - (((3S, 4R) -4-fluoropyrrolidin-3-yl) oxy) phenyl) piperazin1 -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] [1,2,4] triazolo [1,5c] pyrimidin -3 (2H) -yl) ethyl) piperazin-1 -yl) -3-fluorophenoxy) -N- (2morpholinoethyl) acetamide; 4- (4- (2- (5-ammo-8- (fiiran-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-ammo-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- (morpholin-3-ylmethyl) benzamide; 109 BE2018 / 0114 5-amino-3- (2- (4- (4- (azetidin-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] pyrimidin-2 (3H) -one; (R) -5-amino-3- (2- (4- (2,4-difluoro-5- (methylsulfmyl) 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 - (((ls, 4s) -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; 5-amino-3 - (2- (4- (2,4-difluoro-5 - (((Ir, 4r) -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; (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; (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-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- (l-oxydothiomorpholine-4carbonyl) phenyl) piperazin-1 - yl) ethy 1) - 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- (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; (R) -5-ammo-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; 110 BE2018 / 0114 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 - (((1 r, 4r) -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; (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 (methylsulfmyl) ethyl) benzamide; 5-amino-3- (2- (4- (2-fluoro-4- (l-oxydothiomorpholine-4-carbonyl) phenyl) piperazinl-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- (l-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] pyrimidm-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 pharmaceutically acceptable salts or solvates thereof. 111 BE2018 / 0114 6. Combination according to any one of claims 1 to 5, 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) piperazin1 -yl) ethyl) -8- (furan-2 -yl) thiazolo [5.4-5 e] [1,2,4] triazolo [1,5-c] pyrimidin-2 (3H) -one; (+) - 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; and pharmaceutically acceptable salts or solvates thereof. 7. Combination according to any one of claims 1 to 6, in which the anticancer agent is selected from immunotherapeutic agents, chemotherapeutic agents, anti-angiogenic agents, inhibitors of proteins associated with multidrug resistance, agents. radiotherapeutics, and any combination thereof. The combination of claim 7, wherein the immunotherapeutic agent is selected from checkpoint inhibitors, checkpoint agonists, IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors. , inhibitors of adenosine producing enzymes, immune cells, therapeutic vaccines, or any combination thereof. 9. The combination of claim 8, wherein the checkpoint inhibitor is an inhibitor of a checkpoint protein selected from PD1, PD-L1 and CTLA-4. 10. The combination of claim 9, wherein the PD-1 inhibitor is an anti-PD-1 antibody; the PD-L1 inhibitor is an anti-PD-L1 antibody; and the CTLA-4 inhibitor is an anti-CTLA-4 antibody. 11. The combination of claim 7, wherein the chemotherapeutic agent is selected from anti-cancer alkylating agents, anti-cancer antimetabolites, anti-cancer antibiotics, anti-cancer agents. 112 Plant-derived anticancer BE2018 / 0114, anticancer platinum coordination compounds and any combination thereof. 12. Pharmaceutical composition comprising: (a) a compound of formula (I) as defined in any one of the preceding claims; and (b) an anti-cancer agent as defined in any one of the preceding claims. 13. Kit including: (a) a first part comprising a compound of formula (I) as defined in any one of the preceding claims; and (b) a second part comprising an anti-cancer agent as defined in any one of the preceding claims. 14. Combination according to any one of claims 1 to 11, the pharmaceutical composition according to claim 12, the kit according to claim 13 for their medical use. 15. A combination according to any one of claims 1 to 11, the pharmaceutical composition according to claim 12, the kit according to claim 13, for their use in the treatment and / or prevention of cancer. 16. Combination for its use, pharmaceutical composition for its use or kit for its use according to claim 15, in which the cancer is selected from breast, carcinoid, cervical, colorectal and endometrial cancers, glioma, head and neck cancers, liver, lung, melanoma, ovarian, pancreatic, prostate, kidney, gastric, thyroid and urothelial cancers. 17. Combination for its use or kit for its use according to any one of claims 14 to 16, in which the anticancer agent and the 113 BE2018 / 0114 compound of formula (I) are intended to be administered to a patient in need thereof sequentially and / or at the same time. 18. Combination for its use or kit for its use according to one Any of claims 14 to 16, wherein the anticancer agent and the compound of formula (I) are for administration to a patient in need thereof by different routes of administration.