Use of ENT family transporter inhibitors and their combination with adenosine receptor antagonists in cancer treatment

Abstract

The present invention relates to the use of an ENT family transporter inhibitor for the treatment of cancer. The present invention further relates to the combination of said ENT family transporter inhibitor with an adenosine receptor antagonist for the treatment of cancer. The present invention further relates to pharmaceutical compositions and kits of parts comprising said combination.

Description

[Technical field]

[0001] The present invention relates to the use of an ENT family transporter inhibitor for the treatment of cancer. The present invention further relates to the combination of said ENT family transporter inhibitor with an adenosine receptor antagonist for the treatment of cancer. The present invention further relates to pharmaceutical compositions and kits of parts comprising said combination. [Background technology]

[0002] The equilibrative nucleoside transporter (ENT) family, also known as SLC29, is a group of plasma membrane transport proteins that transport nucleoside substrates into cells. There are four known ENTs, named ENT1, ENT2, ENT3, and ENT4.

[0003] One of the endogenous substrates of ENT is adenosine, which is a potent physiological and pharmacological regulator of many functions. Cell signaling by adenosine occurs through four known G protein-coupled adenosine receptors, A1, A2A, A2B, and A3. By affecting the concentration of adenosine provided to these receptors, ENT plays an important regulatory role in various physiological processes, such as regulating coronary blood flow, inflammation, and neurotransmission (Griffith DA and Jarvis SM, Biochim Biophys Acta, 1996, 1286, 153-181; Shryock JC and Belardinelli L, Am J Cardiol, 1997, 79(12A), 2-10; Anderson CM et al., J Neurochem, 1999, 73, 867-873).

[0004] A variety of drugs that interact with ENT and alter adenosine levels, such as dilazep, dipyridamole, and draflazine, have been developed for cardioprotective or vasodilatory effects.

[0005] Adenosine is also a potent immunosuppressive metabolite and is often found elevated in the extracellular tumor microenvironment (TME) (Blay J et al., Cancer Res, 1997, 57, 2602-2605). Extracellular adenosine is primarily generated by the conversion of ATP by the ectonucleotidases CD39 and CD73 (Stagg J and Smyth MJ, Oncogene, 2010, 2, 5346-5358). Adenosine activates four G protein-coupled receptor subtypes (A1, A2A, A2B, and A3). In particular, activation of the A2A receptor is thought to be a major promoter of innate and adaptive immune cell suppression leading to suppression of antitumor immune responses (Ohta and Sitkovsky, Nature, 2001, 414, 916-920) (Stagg and Smyth, Oncogene, 2010, 2, 5346-5358) (Antonioli L et al., Nature Reviews Cancer, 2013, 13, 842-857) (Cekic C and Linden J, Nature Reviews, Immunology, 2016, 16, 177-192) (Allard B et al., Curr Op Pharmacol, 2016, 29, 7-16) (Vijayan D et al., Nature Reviews Cancer, 2017, 17, 709-724).

[0006] To assess whether adenosine could reduce T cell activity via ENT uptake, we identified the mRNA expression levels of plasma membrane-localized ENT transporters (ENT1, ENT2, and ENT4) in human primary lymphocytes using public RNA-seq databases (Bonnal RJP et al., Nature, 2015, 2:150051). + T cells and CD8 + T cells expressed ENT1 (SLC29A1), ENT2 (SLC29A2), and ENT4 (SLC29A4) (Figures 1A, 1B, and 1C).

[0007] Applicants herein have demonstrated that adenosine as well as ATP significantly inhibits T cell proliferation and cytokine secretion (IL-2) and significantly reduces T cell viability. Adenosine- and ATP-mediated inhibition of T cell viability and proliferation was restored to normal using ENT inhibitors.

[0008] Furthermore, combining an ENT inhibitor with an adenosine receptor antagonist was able to restore not only adenosine- and ATP-mediated suppression of T cell viability and proliferation, but also T cell cytokine secretion. Thus, the present invention provides the use of an ENT family transporter inhibitor for the treatment of cancer, and also provides the combination of said ENT family transporter inhibitor with an adenosine receptor antagonist for the treatment of cancer. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Griffith DA and Jarvis SM, Biochim Biophys Acta, 1996, 1286, 153-181 [Non-Patent Document 2] Shryock JC and Belardinelli L,Am J Cardiol,1997,79(12A),2-10 [Non-Patent Document 3] Anderson CM et al., J Neurochem, 1999, 73, 867-873 [Non-Patent Document 4] Blay J et al.,Cancer Res,1997,57,2602-2605 [Non-Patent Document 5] Stagg J and Smyth MJ,Oncogene,2010,2,5346-5358 [Non-Patent Document 6] Ohta and Sitkovsky,Nature,2001,414,916-920 [Non-Patent Document 7] Antonioli L et al.,Nature Reviews Cancer,2013,13,842-857 [Non-Patent Document 8] Cekic C and Linden J,Nature Reviews,Immunology,2016,16,177-192 [Non-Patent Document 9] Allard B et al.,Curr Op Pharmacol,2016,29,7-16 [Non-Patent Document 10] Vijayan D et al.,Nature Reviews Cancer,2017,17,709-724 [Non-Patent Document 11] Bonnal RJP et al.,Nature,2015,2:150051 Summary of the Invention [Means for solving the problem]

[0010] Thus, the present invention relates to a method of treating cancer comprising administering an effective amount of an ENT family transporter inhibitor to a human subject in need thereof.

[0011] In one embodiment, the ENT family transporter is ENT1 and the inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a peptide, and an antibody.

[0012] In one embodiment, the subject is treated with an additional therapeutic agent in combination with an ENT family transporter inhibitor or has received the additional therapeutic agent within about 14 days of administration of an ENT family transporter inhibitor. In one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist.

[0013] In one embodiment, the subject has previously undergone at least one prior therapeutic treatment and has progressed since administration of the at least one prior therapeutic treatment prior to administration of the ENT family transporter inhibitor, in one embodiment, the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, hormone therapy, and surgery.

[0014] The present invention also provides a combination comprising an ENT family transporter inhibitor in an amount effective for treating cancer in a human subject.

[0015] In one embodiment, the ENT family transporter inhibitor is administered prior to, concurrently with, or following administration of an additional therapeutic agent comprising an adenosine receptor antagonist.

[0016] The present invention also relates to a method of treating cancer comprising administering to a patient in need thereof a combination of an adenosine receptor antagonist and an ENT family transporter inhibitor.

[0017] In one embodiment, the adenosine receptor antagonist is an A2A or A2B receptor antagonist.

[0018] In one embodiment, the adenosine receptor antagonist is selected from: 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide.

[0019] In one embodiment, the adenosine receptor antagonist is a compound of formula (I) as defined hereinafter.

[0020] In one embodiment, the ENT family member is ENT1.

[0021] In one embodiment, the A2A or A2B receptor antagonist and the ENT1 inhibitor are provided in the same formulation.

[0022] The present invention further provides a formulation comprising an effective amount of an adenosine receptor antagonist in combination with an effective amount of an ENT family member inhibitor, in addition to a pharma- ceutically acceptable excipient.

[0023] In one embodiment, the adenosine receptor antagonist in the formulation is an A2A or A2B receptor antagonist.

[0024] In one embodiment, the adenosine receptor antagonist in the formulation is selected from: 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide.

[0025] In one embodiment, the adenosine receptor antagonist in the formulation is a compound of formula (I) as defined hereinafter.

[0026] In one embodiment, the ENT family member inhibitor in the formulation is an ENT1 inhibitor.

[0027] In one embodiment, the formulation further comprises an additional therapeutic agent.

[0028] definition In the present invention, the following terms have the following meanings.

[0029] The term "aldehyde" refers to the group --CHO.

[0030] The term "alkenyl" refers to an unsaturated hydrocarbyl group that contains one or more carbon-carbon double bonds and may be linear or branched. Suitable alkenyl groups contain 2 to 6 carbon atoms, preferably 2 to 4 carbon atoms, and even more preferably 2 to 3 carbon atoms. Examples of alkenyl groups are ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl, and the like.

[0031] The term "alkenylcarbonyl" refers to the group -(C=O)-alkenyl, where alkenyl is as defined herein.

[0032] The term "alkenylcarbonylamino" refers to the group -NH-(C=O)-alkenyl, where alkenyl is as defined herein.

[0033] The term "alkoxy" refers to the group --O-alkyl, where alkyl is as defined herein.

[0034] The term “alkyl” refers to a group of the formula C n H 2n+1 (wherein n is a number equal to or greater than 1). Generally, the alkyl groups of the present invention contain 1 to 8 carbon atoms, and more preferably, the alkyl groups of the present invention contain 1 to 6 carbon atoms. The alkyl groups may be linear or branched. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

[0035] The term "alkylaminoalkyl" refers to the group -alkyl-NH-alkyl, where alkyl is as defined herein.

[0036] The term "alkylaminoalkylaminocarbonyl" refers to the group -(C=O)-NH-alkyl-NH-alkyl, where alkyl is as defined herein.

[0037] The term “(alkylaminoalkyl)(alkyl)aminocarbonyl” refers to the group —(C═O)—NR 1 R 2 In the formula, R 1 is an alkyl group, and R 2 is an -alkyl-NH-alkyl group, where alkyl is as defined herein.

[0038] The term "alkylaminoalkylcarbonyl" refers to the group -(C=O)-alkyl-NH-alkyl, where alkyl is as defined herein.

[0039] The term "alkylcarbonyl" refers to the group -(C=O)-alkyl, where alkyl is as defined herein.

[0040] The term "alkylheteroaryl" refers to any heteroaryl substituted with an alkyl group, where alkyl is as defined herein.

[0041] The term "alkyloxycarbonyl" refers to the group -(C=O)-O-alkyl, where alkyl is as defined herein.

[0042] The term "alkylsulfonyl" refers to the group -SO2-alkyl, where alkyl is as defined herein.

[0043] The term "alkylsulfonealkyl" refers to the group -alkyl-SO2-alkyl, where alkyl is as defined herein.

[0044] The term "alkylsulfonimidoyl" refers to the group -S(=O)(=NH)-alkyl, where alkyl is as defined herein.

[0045] The term "alkylsulfoxide" refers to the group -(S=O)-alkyl, where alkyl is as defined herein.

[0046] The term "alkylsulfoxidealkyl" refers to the group -alkyl-SO-alkyl, where alkyl is as defined herein.

[0047] The term "alkyne" refers to a class of monovalent unsaturated hydrocarbyl groups in which the unsaturation occurs due to the presence of one or more carbon-carbon triple bonds. Alkynyl groups typically and preferably have the same number of carbon atoms as described above for 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, etc.

[0048] The term "alkynealkyl" refers to the group -alkyl-alkyne, where alkyl and alkyne are defined herein.

[0049] The term "amino" refers to the group -NH2.

[0050] The term "aminoalkyl" refers to the group -alkyl-NH2, where alkyl is as defined herein.

[0051] The term "aminoalkylaminocarbonyl" refers to the group -(C=O)-NH-alkyl-NH2, where alkyl is as defined herein.

[0052] The term "aminoalkylcarbonylamino" refers to the group -NH-(C=O)-alkyl-NH2, where alkyl is as defined herein.

[0053] The term "aminocarbonyl" refers to the group -(C=O)-NH2.

[0054] The term “(aminocarbonylalkyl)(alkyl)amino” refers to the group —NR 1 R 2 In the formula, R 1 is an alkyl group, and R 2is an -alkyl-(C=O)-NH group, where alkyl is as defined herein.

[0055] The term "aminocarbonylalkylamino" refers to the group -NH-alkyl-(C=O)-NH2, where alkyl is as defined herein.

[0056] The term "aminosulfonyl" refers to the group -SO2-NH2.

[0057] The term "aryl" refers to a polyunsaturated aromatic hydrocarbyl group having a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl), typically containing 5 to 12, preferably 5 to 10, atoms, more preferably 5 or 6 membered aryl. Non-limiting examples of aryl include phenyl, naphthalenyl.

[0058] The term "carbonyl" refers to the group -(C=O)-.

[0059] The term "carbonylamino" refers to the group -NH-(C=O)-.

[0060] The term "cycloalkyl" refers to a cyclic alkyl group, i.e., a monovalent, saturated, or unsaturated hydrocarbyl group having one or two ring structures. Cycloalkyl includes monocyclic or bicyclic hydrocarbyl groups. Cycloalkyl groups may contain three or more carbon atoms in the ring, and according to the present invention generally contain 3 to 10, more preferably 3 to 8 carbon atoms, and even more preferably, the cycloalkyl is a 5- or 6-membered cycloalkyl. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0061] The term "cycloalkyloxy" refers to the group --O-cycloalkyl, where cycloalkyl is as defined herein.

[0062] The term "dialkylamino" refers to the group -NR 1 R 2 R 1 and R 2 are each independently an alkyl group as defined herein.

[0063] The term "dialkylaminoalkyl" refers to the group -alkyl-NR 1 R 2 R 1 and R 2 are each independently an alkyl group as defined herein.

[0064] The term "dialkylaminoalkylaminocarbonyl" refers to the group -(C=O)-NH-alkyl-NR 1 R 2 R 1 and R 2 are all alkyl groups as defined herein.

[0065] The term "dialkylaminoalkylcarbonyl" refers to the group -(C=O)-alkyl-NR 1 R 2 R 1 and R 2 are all alkyl groups as defined herein.

[0066] The term "dihydroxyalkyl" refers to an alkyl group, as defined herein, substituted with two hydroxyl (-OH) groups.

[0067] The term "halo" or "halogen" refers to fluoro, chloro, bromo, or iodo.

[0068] 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 a ring system containing an aromatic monocyclic ring of 5-12 carbon atoms, or two rings fused together, usually containing 5-6 atoms, in which one or more carbon atoms in the ring are replaced by oxygen, nitrogen, and / or sulfur atoms, in which the nitrogen and sulfur heteroatoms may be optionally oxidized, and the nitrogen heteroatom may be optionally quaternized. Non-limiting examples of such heteroaryls include oxazolyl, thiazolyl, imidazolyl, furanyl, and pyrrolyl. Preferably, the heteroaryl is a 5- or 6-membered heteroaryl, and more preferably, the 5- or 6-membered heteroaryl is furyl.

[0069] The term "heterocyclyl" refers to a non-aromatic, fully saturated, or partially unsaturated cyclic group having at least one heteroatom in a ring containing at least one carbon atom (e.g., a 3- to 7-membered monocyclic, a 7- to 11-membered bicyclic, or one containing a total of 3 to 10 ring atoms). Preferably, the heterocyclyl is a 5- or 6-membered heterocyclyl. Each ring of a heteroatom-containing heterocyclic group may have 1, 2, 3, or 4 heteroatoms selected from nitrogen, oxygen, and / or sulfur atoms, where the heteroatom nitrogen and sulfur may be optionally oxidized and the heteroatom nitrogen may be optionally quaternized. The heterocyclic group may be attached to any heteroatom or carbon atom of the ring or ring system, as valence permits. The rings of a polycyclic heterocycle may be fused, bridged, and / or joined through one or more spiro atoms.Non-limiting examples of heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinylimidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolinyl, 2H-pyrrolidinyl, 3 ... aryl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolidinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4-dioxaniyl aryl, 2,5-dioximidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolodinyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, 1-oxide-1-thiomorpholin-4-yl, 1-dioxide-1-thiomorpholin-4-yl, 1,3-dioxolanyl, 1,4-oxathianyi, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholin-4-yl.

[0070] The term "heterocyclylalkylaminocarbonyl" refers to the group -(C=O)-NH-alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined herein.

[0071] The term "(heterocyclyl)(alkyl)aminoalkyl" refers to the group -alkyl-NR 1 R 2 In the formula, R 1 is an alkyl group, and R 2 is a heterocyclyl group, where alkyl and heterocyclyl are as defined herein.

[0072] The term "heterocyclylcarbonyl" refers to the group -(C=O)-heterocyclyl, where heterocyclyl is as defined herein.

[0073] The term "heterocyclylalkyl" refers to the group -alkyl-heterocyclyl, where alkyl and heterocyclyl are as defined herein.

[0074] The term "heterocyclyloxy" refers to the group --O-heterocyclyl, where heterocyclyl is as defined herein.

[0075] The term "heterocyclylsulfonyl" refers to the group -SO2-heterocyclyl, where heterocyclyl is as defined herein.

[0076] The term "hydroxyalkyl" refers to the group -alkyl-OH, where alkyl is as defined herein.

[0077] The term "hydroxyalkylaminoalkyl" refers to the group -alkyl-NH-alkyl-OH, where alkyl is as defined herein.

[0078] The term "hydroxycarbonyl" refers to the group -C(=O)-OH, where carbonyl is as defined herein. In other words, "hydroxycarbonyl" corresponds to a carboxylic acid group.

[0079] The term "oxo" refers to the substituent ═O.

[0080] The term "sulfonylamino" refers to the group -NH-SO2.

[0081] The term "about" preceding a number encompasses values ​​above and below that number by 10%. It should be understood that the value that the term "about" refers to is itself preferably explicitly disclosed.

[0082] The term "administration" or variations thereof (e.g., "administering") means providing an active agent or ingredient, either alone or as part of a pharma- ceutically acceptable composition, to a patient whose condition, symptom, or disease is to be treated or prevented.

[0083] The term "antagonist" refers to a natural or synthetic compound that binds to a protein and blocks the biological activation of the protein and the action of said protein. The protein may be a receptor, i.e., a protein molecule that receives a chemical signal from outside the cell. Thus, an "adenosine receptor antagonist" encompasses any chemical substance that, when administered to a patient, results in the inhibition or downregulation of the biological activity associated with the activation of the adenosine receptor in the patient. The biological activity includes any downstream biological effect that would otherwise result from the binding of a natural ligand to the adenosine receptor. Such adenosine receptor antagonists include any agent that can block the activation of the adenosine receptor or any downstream biological effect of the adenosine receptor activation.

[0084] The term "inhibitor" refers to a natural or synthetic compound that has the biological effect of inhibiting or significantly reducing or downregulating the expression of a gene and / or protein, or inhibiting or significantly reducing the biological activity of a protein. Thus, an "ENT inhibitor" or an "ENT family transporter inhibitor" refers to a compound that has the biological effect of inhibiting or significantly reducing or downregulating the biological activity of an ENT family transporter.

[0085] The term "antibody" as used herein includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), and antibody fragments, so long as they exhibit the desired biological activity.

[0086] The term "chemotherapy" refers to a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents) as part of a standard chemotherapy regimen. Chemotherapy may be performed with curative intent or with the intent of prolonging life or alleviating symptoms. Chemotherapeutic agents may be selected from, for example, anti-cancer alkylating agents, anti-cancer antimetabolites, anti-cancer antibiotics, plant-derived anti-cancer agents, anti-cancer platinum coordination compounds, and any combination thereof.

[0087] The term "hormonal therapy" refers to the use of hormones in medical treatment. In one embodiment, the hormone therapy is oncological hormone therapy.

[0088] The term "human" refers to subjects of both sexes at any stage of development (i.e., neonate, infant, juvenile, adolescent, adult).

[0089] The term "patient" refers to a mammal, more preferably a human, awaiting or receiving medical care, or being the subject or intended recipient of medical treatment.

[0090] The term "immunotherapy" refers to therapy aimed at inducing and / or enhancing an immune response against a specific target, e.g., cancer cells. Immunotherapy may involve the use of checkpoint inhibitors, checkpoint agonists (also known as T cell agonists), IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, adenosine-producing enzyme inhibitors, adoptive transfer, therapeutic vaccines, and combinations thereof.

[0091] The term "nucleic acid" refers to a polymer of nucleotides covalently linked by phosphodiester bonds, such as deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), in either single- or double-stranded form. Unless specifically limited, the term encompasses nucleic acids containing known analogs of natural nucleotides that have similar binding properties as the reference nucleic acid and are metabolized in a manner similar to naturally occurring nucleotides.

[0092] The term "peptide" refers to a linear polymer of fewer than 50 amino acids joined together by peptide bonds.

[0093] The term "pharmaceutical acceptable" means that the components of a pharmaceutical composition are compatible with each other and not harmful to the subject to which it is administered.

[0094] The expression "pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant" refers to a substance that does not produce side effects, allergic reactions, or other harmful reactions when administered to an animal, preferably a human. It includes any inactive substance, such as, for example, solvents, cosolvents, antioxidants, surfactants, stabilizers, emulsifiers, buffers, pH adjusters, preservatives (or preservatives), antibacterial and antifungal agents, isotonicity agents, granulating or binding agents, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersing agents, suspending agents, coating agents, bulking agents, stripping agents, absorption retardants, sweeteners, flavoring agents, etc. For human administration, preparations should meet the standards of sterility, pyrogenicity, general safety, and purity required by regulatory authorities, such as, for example, the FDA or EMA.

[0095] As used herein, the terms "prevent", "preventing" and "prevention" refer to a method of delaying or eliminating the onset of a condition or disease and / or its attendant symptoms, barring a patient from contracting a condition or disease, or reducing a patient's risk of contracting a condition or disease.

[0096] The term "prodrug" as used herein refers to a pharmacologically acceptable derivative of a compound of formula (I), such as an ester or amide, whose in vivo biotransformation product produces a biologically active drug. Prodrugs are generally characterized by increased bioavailability and are readily metabolized in vivo to the biologically active compound.

[0097] The term "radiotherapy" refers to cancer treatment using various types of radiation, such as X-rays, gamma rays, neutrons, electrons, protons, and radioactive sources. It is used as part of cancer treatment to control or kill malignant cells. Many types of cancer can be cured with radiation therapy if they are localized to one area of ​​the body. It can also be used as part of adjuvant therapy to prevent tumor recurrence after surgery to remove the primary malignant tumor. Radiation therapy is primarily divided into three types: external beam radiation therapy (EBRT or XRT); brachytherapy or sealed source radiation therapy; and total body radioisotope therapy (RIT) or unsealed source radiation therapy.

[0098] The term "therapeutically effective amount" or "effective amount" or "therapeutically effective dose" refers to an amount or dosage of an active ingredient intended to (1) delay or prevent the onset of cancer in a subject; (2) reduce the severity or incidence of cancer; (3) slow or stop the progression, severity, or worsening of one or more symptoms of cancer affecting the subject; (4) effect an improvement in the symptoms of cancer affecting the subject; or (5) cure the cancer affecting the subject, without causing significant negative or harmful side effects to the subject. A therapeutically effective amount may be administered prior to the onset of cancer as a prophylactic or preventative treatment. Alternatively, or in addition, a therapeutically effective amount may be administered after the onset of cancer as a therapeutic treatment.

[0099] The term "treating" or "treatment" refers to curative treatment, where the aim is to prevent or slow down the targeted pathological condition or disease. A subject or mammal is successful in "treating" a disease or disorder or condition if, after undergoing treatment according to the present invention, the subject or mammal shows an observable and / or measurable reduction or elimination of one or more of the following: reduction in the number of cancer cells; and / or some alleviation of one or more symptoms associated with a particular disease or condition; reduced morbidity and mortality, and improved quality of life issues. The above parameters for assessing the success and improvement of disease treatment can be easily measured by routine procedures familiar to physicians.

[0100] The term "stem cell transplant" refers to a procedure in which healthy hematopoietic cells (stem cells) are given to a patient to replace autologous cells destroyed by disease or by radiation or high doses of anti-cancer drugs given as part of the procedure. The healthy stem cells can come from the patient's blood or bone marrow, a donor, or from the umbilical cord blood of a newborn. Stem cell transplants can be autologous (using the patient's own stem cells that were harvested and stored before the procedure), allogeneic (using stem cells donated by someone other than an identical twin), or allogeneic (using stem cells donated by an identical twin).

[0101] The term "subject" refers to a mammal, preferably a human. In one embodiment, the subject has been diagnosed with cancer. In one embodiment, the subject is a patient, preferably a human patient, awaiting or undergoing medical treatment, or being the subject of a medical procedure, or being monitored for the development or progression of a disease, such as cancer. In one embodiment, the subject is a human patient being treated and / or monitored for the development or progression of cancer. In one embodiment, the subject is male. In another embodiment, the subject is female. In one embodiment, the subject is an adult. In another embodiment, the subject is a child. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0102] ENT inhibitors for use in the treatment of cancer The present invention relates to the use of ENT family transporter inhibitors for the treatment of cancer.

[0103] Hereinafter, ENT family transporter inhibitors are also referred to as ENT inhibitors.

[0104] The equilibrative nucleoside transporter (ENT) family, also known as SLC29, is a group of plasma membrane transport proteins that transport nucleoside substrates, such as adenosine, into cells. There are four known ENTs, named ENT1, ENT2, ENT3, and ENT4.

[0105] In one embodiment, the ENT inhibitor is an inhibitor of ENT1.

[0106] In one embodiment, the ENT inhibitor is a selective inhibitor of ENT1. In one embodiment, the ENT inhibitor is a selective inhibitor of ENT1 relative to other ENT inhibitors, particularly relative to ENT2 and ENT4.

[0107] In one embodiment, the ENT inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a peptide, and an antibody.

[0108] Examples of ENT inhibitors include dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, soluflazine, miofurazine, decinium-22, lopinavir, quinidine, 8MDP, TC-T 6000, 5-iodotubercidin, cilostazol, salts thereof, and any mixtures thereof. In a specific embodiment, the ENT inhibitor is selected from NBMPR, dipyridamole, dilazep, ticagrelor, and salts thereof (including dilazep hydrochloride). In a specific embodiment, the ENT inhibitor is selected from dipyridamole, dilazep, ticagrelor, and salts thereof (including dilazep hydrochloride). In one embodiment, the ENT inhibitor is NBMP or a salt thereof. In one embodiment, the ENT inhibitor is dipyridamole or a salt thereof. In one embodiment, the ENT inhibitor is dilazep or a salt thereof (including dilazep hydrochloride). In one embodiment, the ENT inhibitor is ticagrelor or a salt thereof.

[0109] Examples of ENT1 inhibitors include dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), draflazine, STI-571 (Gleevec), ticagrelor, 8MDP, 5-iodotubercidin, cilostazol, salts thereof, and any mixtures thereof. Examples of selective ENT1 inhibitors include NBMPR, STI-571 (Gleevec), ticagrelor, salts thereof, and any mixtures thereof.

[0110] Thus, the present invention relates to ENT family transporter inhibitors for use in the treatment of cancer in human subjects.

[0111] In one embodiment, the subject is treated with an additional therapeutic agent in combination with an ENT family transporter inhibitor, or is given an additional therapeutic agent within about 14 days of administering an ENT family transporter inhibitor. In one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist. In one embodiment, the ENT family transporter inhibitor is administered before, simultaneously with, or after administration of the additional therapeutic agent comprising an adenosine receptor antagonist.

[0112] In one embodiment, the subject has previously undergone at least one prior therapeutic treatment and has progressed since administration of the at least one prior therapeutic treatment prior to administration of the ENT family transporter inhibitor, in one embodiment, the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, hormone therapy, and surgery.

[0113] Thus, the present invention relates to a method of treating cancer comprising administering an effective amount of an ENT family transporter inhibitor to a human subject in need thereof.

[0114] In one embodiment, in the method of the present invention, the subject is treated with an additional therapeutic agent in combination with the ENT family transporter inhibitor, or is given the additional therapeutic agent within about 14 days of administering the ENT family transporter inhibitor.In one embodiment, in the method of the present invention, the additional therapeutic agent comprises an adenosine receptor antagonist.Further details regarding adenosine receptor antagonists are described below.

[0115] In one embodiment, in the method of the present invention, the subject has previously undergone at least one prior therapeutic treatment and has progressed since administration of the at least one prior therapeutic treatment prior to administration of the ENT family transporter inhibitor. In one embodiment, in the method of the present invention, the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, hormone therapy, and surgery.

[0116] The present invention also relates to a combination comprising an ENT family transporter inhibitor in an amount effective for treating cancer in a human subject.

[0117] In one embodiment, in the formulations of the invention, an ENT family transporter inhibitor is administered prior to, concurrently with, or following administration of an additional therapeutic agent, including an adenosine receptor antagonist.

[0118] Combination: ENT inhibitors and adenosine receptor antagonists The present invention further relates to the combination of an ENT inhibitor with an adenosine receptor antagonist.

[0119] Thus, the present invention provides (a) an effective amount of an ENT inhibitor; (b) an effective amount of an adenosine receptor antagonist.

[0120] In the context of the present invention, the term "combination" preferably means that the ENT inhibitor and the A2AR antagonist are present in combination.Therefore, the combination of the present invention may be present as one composition (e.g., pharmaceutical composition) that contains all components in one and the same mixture, or as a kit of parts, with different components forming different parts of the kit of parts.The administration of the ENT inhibitor and the administration of the A2AR antagonist can be performed simultaneously or staggered, at approximately the same or different administration times (i.e., the number of administrations of each component is approximately the same or different), at the same administration site or different administration sites, and in approximately the same or different dosage forms.

[0121] The present invention further relates to a method of treating cancer comprising administering a combination of an adenosine receptor antagonist and an ENT inhibitor to a patient in need thereof.

[0122] The above embodiments relating to the ENT inhibitor also apply to the combination of the present invention. In particular, in one embodiment, in the combination of the present invention, the ENT inhibitor is an inhibitor of ENT1.

[0123] The combinations of the present invention comprise as a second component at least one adenosine receptor antagonist.

[0124] As defined above, "adenosine receptor antagonist" refers to a compound that, when administered to a patient, causes the patient to inhibit or downregulate the biological activity associated with the activation of adenosine receptor. Biological activity includes any downstream biological effect that would otherwise result from the binding of a natural ligand to adenosine receptor. Such adenosine receptor antagonists include any agent that can block the activation of adenosine receptor or any downstream biological effect of adenosine receptor activation.

[0125] Adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors for which adenosine is the endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B, and A3, each encoded by a different gene (ADOARA1, ADORA2A, ADORA2B, and ADORA3, respectively).

[0126] In one embodiment, the adenosine receptor antagonist is an antagonist of the A1 receptor, the A2A receptor, the A2B receptor, the A3 receptor, or a combination thereof.

[0127] In one embodiment, the adenosine receptor antagonist is an antagonist of the A2A receptor, the A2B receptor, or a combination thereof. In one embodiment, the adenosine receptor antagonist is an A2A or A2B receptor antagonist.

[0128] In one embodiment, the adenosine receptor antagonist is an antagonist of the A2A receptor (A2AR antagonist). In one embodiment, the adenosine receptor antagonist is an antagonist of the A2B receptor (A2BR antagonist).

[0129] In one embodiment, the adenosine receptor antagonist is a selective antagonist for the A2A receptor compared to other adenosine receptors. In one embodiment, the adenosine receptor antagonist is a selective antagonist for the A2A receptor compared to the A2B receptor.

[0130] In one embodiment, the adenosine receptor antagonist is a selective antagonist for the A2B receptor compared to other adenosine receptors. In one embodiment, the adenosine receptor antagonist is a selective antagonist for the A2B receptor compared to the A2A receptor.

[0131] In a specific embodiment, the combination of the present invention comprises at least one A2A receptor antagonist as defined herein and at least one ENT inhibitor as defined above, such as, for example, at least one ENT1 inhibitor.

[0132] A2A receptor antagonists In one embodiment, the combination of the present invention comprises at least one A2AR antagonist.

[0133] "A2AR antagonist" refers to a compound that, when administered to a patient, causes the patient to inhibit or downregulate the biological activity associated with the activation of the A2A receptor. Biological activity includes any downstream biological effect that would otherwise result from the binding of a natural ligand to the A2A receptor. Such A2AR antagonists include any agent that can block the activation of the A2A receptor or any downstream biological effect of the A2A receptor activation.

[0134] Examples of A2AR antagonists include preladenant (SCH-420,814), bipadenant (BIIB-014), tozadenant (SYK-115), ATL-444, istradefylline (KW-6002), MSX-3, SCH-58261, SCH-412,348, SCH-442,416, ST-1535, caffeine, VER-6623, VER-6947, VER-7835, ZM-241,385, and theophylline. Also included are A2AR antagonists disclosed in WO2018 / 178338, WO2011 / 121418, WO2009 / 156737, WO2011 / 095626, or WO2018 / 136700.

[0135] In one embodiment, the A2AR antagonist is a thiocarbamate derivative, in particular a thiocarbamate derivative such as those disclosed in WO2018 / 178338. More preferably, the A2AR antagonist is a thiocarbamate derivative of formula (I) as described below.

[0136] Thus, in a specific embodiment, the present invention provides (a) an ENT inhibitor; (b) Formula (I) [ka] (In the formula, R 1 and R 2 is as defined below), or a pharma- ceutically acceptable salt or solvate thereof; The present invention provides a combination comprising:

[0137] In a preferred embodiment, the A2AR antagonist has formula (I): [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1 represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, the heteroaryl or aryl group being optionally substituted with one or more substituents selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro), preferably R 1 represents a 5-membered heteroaryl, more preferably R 1 stands for frill; R 2 represents a 6-membered aryl or a 6-membered heteroaryl; The heteroaryl or aryl group is optionally substituted with one or more substituents selected from halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, and alkylsulfonealkyl; The above substituents are optionally selected from the group consisting of 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, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydrocarbyl, hydroxyalkyl, hydroxyalkylamino ... or substituted with one or more substituents selected from oxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl; Alternatively, a heteroaryl or aryl group is optionally substituted with two substituents which, together with the atom 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, and is optionally selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonyl, and substituted with one or more substituents selected from: arylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl.

[0138] In one embodiment, preferred compounds of formula (I) have the formula (Ia): [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, the heteroaryl or aryl group being optionally substituted with one or more substituents selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro), preferably R 1 represents a 5-membered heteroaryl, more preferably R 1 stands for frill; X 1 and X 2 each independently represents C or N; R 1’ X 1 does not exist if N, or X 1 If C, then R 1’ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl; The above substituents are optionally selected from the group consisting of 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, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydride, substituted with one or more substituents selected from alkyloxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl; R 2’ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl; The above substituents are optionally selected from the group consisting of 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, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydrocarbyl, hydroxyalkyl, hydroxyalkylamino ... or substituted with one or more substituents selected from oxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl; 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, and are optionally selected from the group consisting of 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, aminocarbonylalkyla substituted with one or more substituents selected from amino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl; R 3’ X 2 does not exist if N, or X 2 If C, then R 3’ represents H or halo, preferably H or F; R 4’ represents H or halo, preferably H or F; R 5’ represents H or halo, preferably H or F.

[0139] In one specific embodiment of the present invention, R 1represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, the heteroaryl or aryl group being optionally substituted with one or more substituents selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or chloro). 1 represents a 5-membered heteroaryl, more preferably R 1 represents a frill.

[0140] In a specific embodiment of the present invention, X 1 and X 2 each independently represents C or N. In another specific embodiment, X 1 and X 2 Both represent C.

[0141] In one specific embodiment of the present invention, R 1’ X 1 does not exist when N.

[0142] In another specific embodiment, X 1 If C, then R 1’represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl, wherein the above substituents are optionally selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, a and substituted with one or more substituents selected from alkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl.

[0143] In a preferred embodiment, R 1’The substituents are optionally substituted with one or more substituents selected from halo, hydroxy, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, heterocyclylalkylaminocarbonyl, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, heterocyclylcarbonyl, alkylsulfoxide, and alkylsulfonealkyl.

[0144] In one specific embodiment of the present invention, R 2’represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimidoyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl, wherein the above substituents are optionally selected from oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, a and substituted with one or more substituents selected from alkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl.

[0145] In a preferred embodiment, R 2’The substituents are optionally substituted with one or more substituents selected from oxo, halo, hydroxy, cyano, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.

[0146] 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, or a 5- or 6-membered heterocyclyl ring, and are optionally selected from the group consisting of 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, and substituted with one or more substituents selected from: (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl.

[0147] In one specific embodiment of the present invention, R 3’ X 2 is absent when R is N. 3’ X 2 When is C, it represents H or halo. In a preferred embodiment, R 3’ X 2 When is C, it represents H or F.

[0148] In one specific embodiment of the present invention, R 4’ represents H or halo. In a preferred embodiment, R 4’ represents H or F.

[0149] In one specific embodiment of the present invention, R 5’ represents H or halo. In a preferred embodiment, R 5’ represents H or F.

[0150] In one embodiment, a preferred compound of formula (Ia) has the formula (Ia-1): [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1 , R 1’ , R 2’ , R 3’ , R 4’ , and R 5’ is as defined in formula (Ia).

[0151] In one embodiment, a preferred compound of formula (Ia-1) is of formula (Ia-1a): [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1 and R 3’ is as defined in formula (Ia); R 1’’is an 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, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxy, and represents an alkyl or heterocyclyl group substituted with one or more groups selected from the group consisting of alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl.

[0152] In one specific embodiment of the present invention, R 1’’is an 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, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxy, and represents an alkyl or heterocyclyl group substituted with one or more groups selected from the group consisting of alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl.

[0153] 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, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, heterocyclylcarbonyl, alkylsulfoxide, and alkylsulfonealkyl.

[0154] In one embodiment, preferred compounds of formula (Ia-1) have the formula (Ia-1b): [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1 and R 3’ is as defined in formula (Ia); R 1’ represents H or halo, preferably H or F; R 2’’ is an 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, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxy, and represents an alkyl or heterocyclyl group substituted with one or more groups selected from the group consisting of alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl.

[0155] In one specific embodiment of the present invention, R 1’ represents H or halo. In a preferred embodiment, R 1’ represents H or F.

[0156] In one specific embodiment of the present invention, R 2’’is an 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, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxy, and represents an alkyl or heterocyclyl group substituted with one or more groups selected from the group consisting of alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl.

[0157] In a preferred embodiment, R 2’’ represents an alkyl or heterocyclyl group substituted with one or more groups selected from hydroxy, cyano, heteroaryl, alkylheteroaryl, alkyne, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, and alkylsulfonealkyl.

[0158] In one embodiment, preferred compounds of formula (Ia-1) have the formula (Ia-1c) or (Ia-1d): [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R1 and R 3’ is 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 1i and R 1ii each independently represents hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl, or alkylsulfonealkyl; R 2i and R 2iieach independently represents hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl, or alkylsulfonealkyl.

[0159] In one specific embodiment of the present invention, R 1’ represents H or halo. In a preferred embodiment, R 1’ represents H or F.

[0160] In one specific embodiment of the present invention, R 2’ represents H or halo. In a preferred embodiment, R 2’ represents H or F.

[0161] In one specific embodiment of the present invention, R 1i and R 1iieach independently represents hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl, or alkylsulfonealkyl.

[0162] In a preferred embodiment, R 1i and R 1ii each independently represents hydrogen, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, or heterocyclylalkylaminocarbonyl.

[0163] In one specific embodiment of the present invention, R 2i and R 2iieach independently represents hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynealkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl, or alkylsulfonealkyl.

[0164] In a preferred embodiment, R 2i and R 2ii each independently represents hydrogen, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl, or heterocyclylalkylaminocarbonyl. 2i and R 2ii each independently represents hydrogen, alkyl, or dialkylaminoalkyl.

[0165] In one embodiment, preferred compounds of formula (Ia) have the formula (Ia-2) or (Ia-3): [ka] [ka] or a pharma- ceutically acceptable salt or solvate thereof, wherein R 1 , R2’ , R 3’ , R 4’ , and R 5’ is as defined in formula (Ia).

[0166] Particularly preferred compounds of formula (I) of the present invention are those listed in Table 1 below. and pharma-ceutically acceptable salts and solvates thereof. Table 1 [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Table 1-9] [Table 1-10] [Table 1-11] [Table 1-12] [Table 1-13] [Table 1-14]

Table 1-15

Table 1-16

Table 1-17

Table 1-18

Table 1-19

Table 1-20

Table 1-21

Table 1-22

Table 1-23

Table 1-24

Table 1-25

Table 1-26

Table 1-27

Table 1-28

Table 1-29

Table 1-30

Table 1-31

[0167] In Table 1, the term "Cpd" refers to compound.

[0168] The compounds in Table 1 were named using ChemBioDraw® Ultra version 12.0 (PerkinElmer).

[0169] In one embodiment, the A2AR antagonist is selected from: (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 7); (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 8a) and (−)-5-Amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 8b).

[0170] In specific embodiments, the A2AR antagonist is 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]pyrimidin-2(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]pyrimidin-2(3H)-one (compound 8a).

[0171] In a preferred embodiment, the A2AR antagonist is (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 8a).

[0172] In another preferred embodiment, the A2AR antagonist is (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one (compound 8b). In one embodiment, the present invention also relates to the enantiomers, salts, solvates, polymorphs, multicomponent complexes, and liquid crystals of the compounds of formula (I) and its subformulas.

[0173] In one embodiment, the present invention also relates to polymorphs and crystal phases of compounds of formula (I) and sub-formulas thereof, prodrugs and isomers thereof (including optical isomers, geometric isomers and tautomeric isomers), and isotopically labeled compounds of formula (I) and sub-formulas thereof.

[0174] The compounds of formula (I) and its subformulas may contain asymmetric centers and therefore may exist in different stereoisomeric forms. The present invention therefore encompasses all possible stereoisomers, including not only racemates but also individual enantiomers and non-racemic mixtures thereof. When a compound is desired as a single enantiomer, it can be obtained by stereospecific synthesis, by resolution of the final product or any convenient intermediate, or by chiral chromatographic methods, each of which are known in the art. Resolution of the final product, intermediate, or starting material can be carried out by any suitable method known in the art.

[0175] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the compounds of formula (I) and its subformulas include the acid addition and base salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hybenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isothioate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, tosylate, trifluoroacetate, and xinafoate. Suitable base salts are formed from bases that form non-toxic salts. Examples include aluminum salt, arginine salt, benzathine salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumine salt, olamine salt, potassium salt, sodium salt, tromethamine salt, 2-(diethylamino)ethanol salt, ethanolamine salt, morpholine salt, 4-(2-hydroxyethyl)morpholine salt, and zinc salt. Hemisalts of acids and bases can also be formed, such as hemisulfate and hemicalcium salts. Preferred pharmaceutically acceptable salts include hydrochloride / chloride salt, hydrobromide / bromide salt, bisulfate / sulfate salt, nitrate salt, citrate salt, tosylate salt, esylate salt, and acetate salt. In a particularly preferred embodiment, the compound of formula (I) is in the form of HCl salt or esylate salt.

[0176] When the compounds of the present invention contain a basic group in addition to an acidic group, the compounds of the present invention can also form internal salts, and such compounds are within the scope of the present invention. When the compounds of the present invention contain a hydrogen-donating heteroatom (e.g., NH), the present invention also includes salts and / or isomers formed by the transfer of said hydrogen atom to a basic group or atom within the molecule.

[0177] Pharmaceutically acceptable salts of the compounds of formula (I) and sub-formulas thereof include (i) reacting a compound of formula (I) with a desired acid; (ii) reacting a compound of formula (I) with a desired base; (iii) removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula I, or ring-opening a suitable cyclic precursor, such as a lactone or lactam, with a desired acid; or (iv) can be prepared by one or more of the following methods: converting one salt of a compound of formula (I) to another salt by reaction with an appropriate acid or by using a suitable ion exchange column.

[0178] All of these reactions are usually carried out in solution. The salts can precipitate from solution and be collected by filtration or recovered by evaporation of the solvent. The degree of ionization in the salts can vary from completely ionized to nearly non-ionized.

[0179] The compounds of the present invention can be administered in the form of a pharma- ceutically acceptable salt. The term "pharma-ceutically acceptable salt" includes acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, mesylate, borate, methyl bromide, bromide, methyl nitrate, calcium edetate, methyl sulfate, camsylate, mucate, carbonate, napsylate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (embonate), estholate, palmitate, esylate, pantothenate, fumarate, lysine ... The term "acid salt" is intended to include all acceptable salts which can be used as dosage forms to modify solubility or hydrolysis characteristics or can be used in sustained release or prodrug formulations, such as phosphate / diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolylarsanilate, sulfate, hexylresorcinate, subacetate, hydrabamate, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, theoclate, iodide, tosylate, isothioate, triethiodide, lactate, pamoate, valerate, and the like. Depending on the specific function of the compound of the present invention, pharma- ceutically acceptable salts of the compounds of the present invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and the like, and those formed from bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylene-diamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethyl-amine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane, and tetramethylammonium hydroxide.

[0180] These salts can be prepared by standard procedures, for example by reacting the free acid with a suitable organic or inorganic base. When a basic group, such as amino, is present, acid salts, i.e., hydrochloride, hydrobromide, acetate, pamoate, esylate, tosylate, etc., can be used as dosage forms.

[0181] In addition, with regard to salts of the compounds of the present invention, generally, pharma- ceutically acceptable salts are preferred, but in the broadest sense, it should be noted that non-pharma-ceutically acceptable salts that can be used, for example, for isolating and / or purifying the compounds of the present invention are also included in the present invention. For example, salts formed with optically active acids or bases can be used to form diastereoisomeric salts that can facilitate the separation of optically active isomers of the compounds of formula (I) above.

[0182] The compounds of the present invention may be in the form of pharmaceutically acceptable solvates.The pharmaceutically acceptable solvates of the compounds of formula (I) and its sub-formulas contain stoichiometric or substoichiometric amounts of one or more pharmaceutically acceptable solvent molecules, such as ethanol or water.The term "hydrate" refers to when the solvent is water.

[0183] Also, where an alcohol group is present, pharma- ceutically acceptable esters, such as acetates, maleates, pivaloyloxymethyl, and the like, can be used and are known in the art to have altered solubility or hydrolysis characteristics and are used as sustained-release or prodrug formulations.

[0184] In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2011 / 121418. In particular, the A2AR antagonist is the compound of Example 1 of WO2011 / 121418, namely 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine, also known as NIR178: [ka]

[0185] In another embodiment, the A2AR antagonist is the A2AR antagonist disclosed in WO2009 / 156737.In particular, the A2AR antagonist is the compound of Example 1S of WO2009 / 156737, namely (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy))methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine, also known as CPI-444: [ka]

[0186] In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2011 / 095626. In particular, the A2AR antagonist is compound (cxiv) of WO2011 / 095626, namely 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine, also known as AZD4635: [ka]

[0187] In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2018 / 136700. In particular, the A2AR antagonist is the compound of Example 1 of WO2018 / 136700, namely 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile, also known as AB928: [ka]

[0188] In another embodiment, the A2AR antagonist is preladenant (SCH-420,814), i.e., 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine: [ka]

[0189] In another embodiment, the A2AR antagonist is bipadenant (BIIB-014), i.e., 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine: [ka]

[0190] In another embodiment, the A2AR antagonist is tozadenant (SYK-115), i.e., 4-hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide: [ka]

[0191] Thus, in one embodiment, the adenosine receptor antagonist is selected from: 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide.

[0192] In one embodiment, the adenosine receptor antagonist is 5-bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine. In one embodiment, the adenosine receptor antagonist is (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine. In one embodiment, the adenosine receptor antagonist is 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine. In one embodiment, the adenosine receptor antagonist is 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile.

[0193] A2B receptor antagonists In one embodiment, the combination of the present invention comprises at least one A2BR antagonist.

[0194] "A2BR antagonist" refers to a compound that, when administered to a patient, inhibits or downregulates the biological activity associated with the activation of the A2B receptor in the patient. Biological activity includes any downstream biological effect that would otherwise result from the binding of a natural ligand to the A2B receptor. Such A2BR antagonists include any agent that can block the activation of the A2B receptor or any downstream biological effect of A2B receptor activation.

[0195] Examples of A2BR antagonists include bipadenant (BIIB-014), CVT-6883, MRS-1706, MRS-1754, PSB-603, PSB-0788, PSB-1115, OSIP-339,391, ATL-801, theophylline, and caffeine.

[0196] Specific combinations In one embodiment, the combination of the present invention comprises: (a) an effective amount of an ENT inhibitor, preferably an ENT1 inhibitor, preferably selected from NBMPR, dipyridamole, dilazep, ticagrelor, and salts thereof (including dilazep hydrochloride); (b) preferably, (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; and an effective amount of an adenosine receptor antagonist, preferably an A2AR antagonist, selected from the group consisting of:

[0197] In one embodiment, the combination of the present invention comprises: (a) an ENT inhibitor effective amount of dipyridamole; (b) preferably, (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; and an effective amount of an adenosine receptor antagonist, preferably an A2AR antagonist, selected from the group consisting of:

[0198] In one embodiment, the combination of the present invention comprises: (a) an effective amount of an ENT inhibitor, preferably an ENT1 inhibitor, preferably selected from NBMPR, dipyridamole, dilazep, ticagrelor, and salts thereof (including dilazep hydrochloride); (b) an effective amount of (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one as an A2AR antagonist.

[0199] In one embodiment, the combination of the present invention comprises: (a) an effective amount of an ENT inhibitor, preferably an ENT1 inhibitor, preferably selected from NBMPR, dipyridamole, dilazep, ticagrelor, and salts thereof (including dilazep hydrochloride); (b) an effective amount of (-)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one as an A2AR antagonist.

[0200] Formulations and pharmaceutical compositions The present invention further relates to formulations comprising the combination of the present invention. In particular, the present invention provides formulations comprising an effective amount of an adenosine receptor antagonist in combination with an effective amount of an ENT family member inhibitor, in addition to pharma- ceutically acceptable excipients.

[0201] The specific embodiments relating to adenosine receptor antagonists and ENT family transporter inhibitors listed above also apply in the context of the formulations of the present invention.

[0202] The present invention further relates to a pharmaceutical composition comprising a combination according to the invention.

[0203] In one embodiment, the pharmaceutical composition comprises: (a) an effective amount of an ENT inhibitor; (b) an effective amount of an adenosine receptor antagonist; and (c) at least one pharma- ceutically acceptable carrier, diluent, excipient, and / or adjuvant.

[0204] The embodiments described above regarding the ENT inhibitors and adenosine receptor antagonists also apply to the pharmaceutical compositions of the present invention.

[0205] In a preferred embodiment, the present invention comprises: (a) an effective amount of an ENT inhibitor, such as an ENT1 inhibitor; (b) thiocarbamate derivatives, more preferably those of formula (I) as defined above [ka] or a pharma- ceutically acceptable salt or solvate thereof; and (c) at least one pharma- ceutically acceptable carrier, diluent, excipient, and / or adjuvant.

[0206] In one embodiment, a formulation or pharmaceutical composition of the invention further comprises an additional therapeutic agent.

[0207] The at least one pharma- ceutically acceptable carrier, diluent, excipient, and / or adjuvant used in preparing the dosage form will be apparent to those skilled in the art, see the most recent edition of Remington's Pharmaceutical Sciences.

[0208] In particular, the pharmaceutical compositions of the present invention may optionally contain such inactive substances commonly used in pharmaceutical formulations, such as cosolvents, lipid carriers, antioxidants, surfactants, wetting agents, emulsifiers, buffers, pH adjusters, preservatives (or preservatives), isotonicity agents, stabilizers, granulating or binding agents, precipitation inhibitors, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersing agents, suspending agents, bulking agents, release agents, sweeteners, flavoring agents, and the like.

[0209] In a preferred embodiment, the pharmaceutical composition of the present invention comprises one or more pharma- ceutically acceptable co-solvents. Preferably, the co-solvents are selected from caprylic acid, polyethylene glycol (PEG), propylene glycol, ethanol, dimethyl sulfoxide, dimethylacetamide, dimethylisosorbide, and mixtures thereof. In a specific embodiment, the pharmaceutical composition of the present invention comprises caprylic acid and / or PEG. Advantageously, when the composition comprises PEG as a co-solvent, the PEG is of low molecular weight, preferably, the PEG is PEG400. In an alternative embodiment, when the composition comprises PEG, the PEG is of medium molecular weight, preferably, the PEG is PEG3350.

[0210] In a specific embodiment, the pharmaceutical composition of the invention comprises one or more pharma- ceutically acceptable lipid carriers. In a preferred embodiment, the lipid carrier is lauroyl polyoxyl-32 glyceride. This excipient corresponds to Gelucire® 44 / 14, manufactured by Gattefosse (Saint-Priest-France). This excipient is also known under the following references: lauroyl polyoxyl-32 glyceride NF / USP (NF: National Formulary; USP: United States Pharmacopoeia); lauroyl macrogol-32 glyceride EP (European Pharmacopoeia); hydrogenated coconut PEG-32 ester (INCI); CAS number 57107-95-6. Gelucire® 44 / 14 is a glyceride derived from lauric acid (C 12 Gelucire® 44 / 14 corresponds to a well-defined multicomponent substance composed of mono-, di- and triglycerides of 1,2-dihydroxybutyric acid, 1,3-dimethylbenzylglyceride, 1,4-dimethylbenzylglyceride, 1,5-dimethylbenzylglyceride, 1,6-dimethylbenzylglyceride, 1,7-dimethylbenzylglyceride, 1,8-dimethylbenzylglyceride, 1,9 ...

[0211] In another embodiment, the lipid carrier is Vitamin E TPGS. This excipient is also known by the reference names D-α-tocopherol polyethylene glycol-1000 succinate; Tocophersolan; Tocofersolan; VEGS; α-[4-[[(2R)-3,4-dihydro-2,5,7,8-tetramethyl-2-[(4R,8R)-4,8,12-trimethyltridecyl]-2H-1-benzopyran-6-yl]oxy]-1,4-dioxobutyl]-ω-hydroxy-poly(oxy-1,2-ethanediyl); Vitamin E PEG succinate, which is formed from Vitamin E complexed to polyethylene glycol 1000 via a succinic acid linker. Vitamin E TPGS has a melting point in the range of 37-41° C. and a hydrophilic / lipophilic balance (HLB) value of 13.

[0212] In one embodiment, the pharmaceutical composition of the present 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.

[0213] In some embodiments, surfactants such as polyethylene glycol, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, sodium docusate, sodium lauryl sulfate, polysorbates (20, 80, etc.), poloxamers (188, 407, etc.), Pluronic® polyols, polyoxyethylene sorbitan monoethers (TWEEN®-20, TWEEN®-80, etc.), vitamin E TPGS (vitamin E polyethylene glycol succinate), cremophor RH40 (polyoxyl 40 hydrogenated castor oil), cremophor EL (polyoxyl 35 hydrogenated castor oil), polyethylene glycol 660 12-monostearate, solutol HS15 (polyoxyethylated 12-hydroxystearic acid), labrasol (caprylocaproyl polyoxyl-8 glyceride), labrafil M1944 (oleoyl polyoxyl-6 glyceride), polylactide-polyethylene glycol copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®), etc. are added.

[0214] In some embodiments, wetting agents are added, such as sodium lauryl sulfate, vitamin E TPGS, sodium docusate, polysorbate 80, poloxamer 407, etc. A preferred wetting agent is poloxamer 407.

[0215] In some embodiments, emulsifiers are added, such as carbomer, carrageenan, lanolin, lecithin, mineral oil, oleic acid, oleyl alcohol, pectin, poloxamer, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, triethanolamine, propylene glycol monolaurate, propylene glycol dilaurate, propylene glycol monocaprylate, etc. Preferred emulsifiers are, for example, poloxamer, propylene glycol monolaurate, propylene glycol dilaurate, and propylene glycol monocaprylate.

[0216] In some embodiments, a buffer is used to help maintain the pH in a range that approximates physiological conditions. Suitable buffers include organic and inorganic acids and their salts, such as citrate buffers (e.g., monosodium citrate-disodium citrate mixture, citric acid-trisodium citrate mixture, citric acid-monosodium citrate mixture, etc.), succinate buffers (e.g., succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffers (e.g., tartaric acid-sodium tartrate mixture, tartaric acid-potassium tartrate mixture, tartaric acid-sodium hydroxide mixture, etc.), fumarate buffers (e.g., fumaric acid-monosodium fumarate mixture, fumaric acid-fumarate mixture, etc.), and the like. Examples of suitable buffers include: disodium fumarate mixture, monosodium fumarate-disodium fumarate mixture, etc.), gluconate buffers (e.g., gluconic acid-sodium gluconate mixture, gluconic acid-sodium hydroxide mixture, gluconic acid-potassium gluconate mixture, etc.), oxalate buffers (e.g., oxalic acid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture, oxalic acid-potassium oxalate mixture, etc.), lactate buffers (e.g., lactic acid-sodium lactate mixture, lactic acid-sodium hydroxide mixture, lactic acid-potassium lactate mixture, etc.), and acetate buffers (e.g., acetic acid-sodium acetate mixture, acetic acid-sodium hydroxide mixture, etc.). Additionally, phosphate buffers, histidine buffers, and trimethylamine salts such as Tris can be used.

[0217] In some embodiments, pH adjusters are added, such as sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, meglumine, sodium carbonate, citric acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid, and malic acid.

[0218] In some embodiments, preservatives are added to prevent microbial growth.Preservatives suitable for use with the present disclosure include phenol, benzyl alcohol, metacresol, methylparaben, propylparaben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides (e.g., chloride, bromide, and iodide), hexamethonium chloride, and alkylparaben such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, and 3-pentanol.

[0219] In some embodiments, isotonicity agents, sometimes referred to as "stabilizers," are added and include polyhydric sugar alcohols, such as trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol, and mannitol. Stabilizers refer to a broad category of excipients whose function can range from bulking agents to additives that solubilize the therapeutic agent or help prevent denaturation or adhesion to container walls, or help inhibit precipitation, particle growth, or aggregation of the active ingredient. Exemplary stabilizers include polyhydric sugar alcohols (listed above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, and the like; organic sugars or sugar alcohols such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myo-inositol, galactitol, glycerol, and the like, including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur-containing reducing agents such as urea, glutathione, thioctic acid, sodium thioglycolate, thioglycerol, α-monothioglycerol, and sodium thiosulfate; low molecular weight polypeptides (e.g., peptides of 10 residues or less); human serum albumin, bovine serum albumin, and the like. the hydrophilic polymer such as polyvinylpyrrolidone; poloxamer 407; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose 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 methyl ether-block-poly(DL-lactide) copolymer; poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1.Preferred stabilizers are, for example, glycerol; polyethylene glycol; polyvinylpyrrolidone; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate, or hydroxypropyl methylcellulose acetate succinate; carboxymethylcellulose (Na / Ca); polyethylene glycol methyl ether-block-poly(DL-lactide) copolymer; and poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1; polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer.

[0220] In some embodiments, granulating / binder(s) are added such as, for example, starches, gums (including natural, semi-synthetic, and synthetic), microcrystalline cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polymers such as povidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, etc. Preferred granulating agents are, for example, methyl cellulose, hydroxypropyl cellulose, povidone, and polyvinylpyrrolidone-polyvinyl acetate copolymer.

[0221] In some embodiments, a precipitation inhibitor is added, such as water-soluble derivatives of cellulose including hydroxypropyl methylcellulose and methylcellulose, and water-soluble polymers such as polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or poloxamer 407. A preferred precipitation inhibitor is hydroxypropyl methylcellulose.

[0222] In some embodiments, lubricants are added, such as, for example, magnesium stearate, glyceryl esters, behenoyl polyoxyl-8 glyceride Nf (Compritol HD5 ATO), sodium stearyl fumarate, and the like.

[0223] In some embodiments, disintegrants are added, such as synthetics such as sodium starch glycolate, crospovidone, croscarmellose sodium, Kollidon CL, and natural origins such as locust bean gum.

[0224] In some embodiments, glidants are added such as, for example, talc, magnesium stearate, colloidal silicon dioxide, starch, and the like.

[0225] In some embodiments, diluents (or fillers) are added, such as, for example, dextrose, lactose, mannitol, microcrystalline cellulose, sorbitol, sucrose, dicalcium phosphate, calcium sulfate dehydrate, starch, and the like.

[0226] In some embodiments, adsorbents are added, such as, for example, silicon dioxide, purified aluminum silicate, and the like.

[0227] In some embodiments, the pharmaceutical compositions of the present invention are in the form of a tablet and include tabletting excipients such as granulating agents, binders, lubricants, disintegrants, glidants, diluents, adsorbents, and the like.

[0228] In some embodiments, the pharmaceutical composition of the present invention is in the form of a capsule, and the capsule shell is made of gelatin or non-animal products such as cellulose and its derivatives such as hydroxypropylmethylcellulose. Other ingredients can be included in the capsule shell, such as polyethylene glycol, which acts as a plasticizer; pigments such as titanium dioxide or iron oxide, which allow impermeability and color differentiation; lubricants such as carnauba wax; gelling agents such as carrageenan, and wetting agents such as sodium lauryl sulfate. In one embodiment, the pharmaceutical composition of the present invention is formulated as a capsule, in which the capsule shell is made of gelatin, and optionally additional ingredients, such as polyethylene glycol and sodium lauryl sulfate, are included in the capsule shell.

[0229] By way of non-limiting examples, the pharmaceutical compositions may be in a form suitable for administration orally, parenterally (such as by intravenous, intramuscular, or subcutaneous injection, or intravenous infusion), topically (including ocularly), rectally, by inhalation, skin patch, implant, suppository, etc. Such suitable dosage forms (which may be solid, semi-solid, or liquid, depending on the method of administration), as well as methods for use in their preparation, and carriers, diluents, and excipients, will be apparent to those skilled in the art, who may consult the latest edition of Remington's Pharmaceutical Sciences.

[0230] The compositions can be formulated so as to permit quick, sustained, or delayed release of the active compound(s) contained therein.

[0231] According to one embodiment, the pharmaceutical composition is in a form suitable for oral administration.The form suitable for oral administration can be solid, semi-solid or liquid.Some preferred but non-limiting examples of such forms include liquid compositions, paste compositions or solid compositions, more specifically tablets, tablets formulated for extended release or sustained release, capsules (including soft and hard gelatin capsules), pills, dragees, lozenges, sachets, cachets, powders, liquids, gels, syrups, slurries, elixirs, emulsions, solutions and suspensions.

[0232] According to another embodiment, the pharmaceutical composition is in a form suitable for injection, in particular for injection into a subject by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection, or infusion.

[0233] Sterile injectable forms of the pharmaceutical compositions of the invention include sterile injectable solutions and sterile packaged powders, typically reconstituted before use, for administration as a bolus and / or continuous administration.

[0234] The sterile injectable form of the pharmaceutical composition of the present invention may be a solution or an aqueous or oily suspension. Such a suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic pharmaceutically acceptable diluent or solvent. Acceptable vehicles and solvents that can be used include 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 may be used, including synthetic mono- or diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are useful for the preparation of injectables, as are natural pharmaceutically acceptable oils, such as olive oil or castor oil, particularly in polyoxyethylated form. Such oily solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethylcellulose or similar dispersants, which are commonly used in the formulation of pharmaceutically acceptable dosage forms, including emulsions and suspensions. Other commonly used surfactants, such as Tween®, Span®, and other emulsifiers or bioavailability enhancers commonly used in the manufacture of pharma- ceutically acceptable solid, liquid, or other dosage forms, may also be used for formulation purposes.

[0235] According to another embodiment, the pharmaceutical composition of the present invention is in a form suitable for topical administration.Examples of forms suitable for topical administration include, but are not limited to, liquid compositions, paste compositions, or solid compositions, more specifically aqueous solutions, droplets, dispersions, sprays, ointments, creams, lotions, microcapsules, microparticles or nanoparticles, polymeric patches, or controlled release patches.

[0236] According to another embodiment, the pharmaceutical composition of the present invention is in a form suitable for rectal administration, including, but not limited to, suppositories, mini enemas, enemas, gels, rectal foams, creams, ointments, etc.

[0237] According to another embodiment, the pharmaceutical composition of the present invention is in a form suitable for administration via inhalation. Examples of forms suitable for administration via inhalation include, but are not limited to, aerosols.

[0238] The pharmaceutical preparations of the invention are preferably in unit dosage form and may be suitably packaged, for example, in boxes, blisters, vials, bottles, sachets, ampoules, or any other suitable single-dose or multi-dose holders or containers, which may be appropriately labeled, optionally with one or more leaflets containing product information and / or instructions for use.

[0239] Parts Kits The present invention further relates to a kit-of-parts comprising the combination of the invention.

[0240] In one embodiment, the kit of parts of the invention comprises: (a) a first portion comprising an effective amount of an ENT inhibitor; (b) a second portion comprising an effective amount of an adenosine receptor antagonist.

[0241] The above embodiments relating to the ENT inhibitors and adenosine receptor antagonists also apply to the kit-of-parts of the present invention.

[0242] In a preferred embodiment, the present invention (a) a first portion comprising an effective amount of an ENT inhibitor, such as an ENT1 inhibitor; (b) thiocarbamate derivatives, more preferably those of formula (I) as defined above [ka] and a second part comprising an effective amount of an A2AR antagonist, which is a thiocarbamate derivative of the formula:

[0243] Depending on the type of ENT inhibitor and adenosine receptor antagonist, the first and second parts of the kit may be in the form of pharmaceutical compositions. The excipients, dosage forms and administration routes of such pharmaceutical compositions will be clear to those skilled in the art (see Remington's Pharmaceutical Sciences, latest edition), and may in particular be those listed above for the pharmaceutical compositions of the present invention.

[0244] In one embodiment, the second part of the kit comprises a pharmaceutical composition comprising an A2AR antagonist, preferably a thiocarbamate derivative of formula (I) as defined above, and at least one pharma- ceutically acceptable carrier, diluent, excipient, and / or adjuvant. The pharma- ceutically acceptable carrier, diluent, excipient, and / or adjuvant of the pharmaceutical composition of the second part of the kit of parts may be those listed above for the pharmaceutical composition of the present invention.

[0245] As formulated below, administration of the different parts of the kit can be done simultaneously or staggered, either at the same administration site or at different administration sites, and in substantially the same or different dosage forms.

[0246] In one embodiment, the kit-of-parts of the invention further comprises an additional therapeutic agent.

[0247] Dosing regimen In the context of the present invention, administration of the ENT inhibitor and the adenosine receptor antagonist can be simultaneous or staggered, either at the same administration site or at different administration sites, and in substantially the same or different dosage forms, as further outlined below.

[0248] In one embodiment, the ENT inhibitor is administered before, simultaneously with, or after administration of the adenosine receptor antagonist.

[0249] In order to prevent the individual mechanisms induced by ENT inhibitors and adenosine receptor antagonists from being negatively affected by each other, adenosine receptor antagonists and ENT inhibitors can be administered at different times (staggered), i.e. sequentially, and / or at different administration sites.This means that adenosine receptor antagonists can be administered, for example, before, at the same time, or after ENT inhibitors, or vice versa.Alternatively or in addition, adenosine receptor antagonists and ENT inhibitors can be administered at different administration sites or at the same administration site, and in this case, staggered administration is preferred.

[0250] In one embodiment, the adenosine receptor antagonist is administered prior to and / or simultaneously with the ENT inhibitor. In one embodiment, the adenosine receptor antagonist is administered prior to or on the same day that the ENT inhibitor is administered.

[0251] In another embodiment, the ENT inhibitor is administered prior to and / or simultaneously with the adenosine receptor antagonist, hi one embodiment, the ENT inhibitor is administered prior to or on the same day that the adenosine receptor antagonist is administered.

[0252] In one embodiment, the adenosine receptor antagonist is administered prior to and / or simultaneously with the ENT inhibitor and continuously thereafter.

[0253] In another embodiment, the ENT inhibitor is administered prior to and / or simultaneously with the adenosine receptor antagonist and continuously thereafter.

[0254] dose Depending on the condition to be prevented or treated and the form of administration, the ENT inhibitors and adenosine receptor antagonists may be administered in a single daily dose divided into one or more administrations per day.

[0255] It is understood that the total daily dosage of adenosine receptor antagonist and ENT inhibitor will be determined by the attending physician within the scope of sound medical judgment. The specific dosage for a particular subject will vary depending on a variety of factors, such as the cancer being treated, the patient's age, weight, general health, sex, and diet, as well as similar factors well known in the medical arts.

[0256] In one embodiment, the subject is a mammal, preferably a human, and the dose of the adenosine receptor antagonist, preferably a therapeutically effective dose, is in the range of about 0.01 mg / kg to about 5 mg / kg of body weight, preferably about 0.08 mg / kg to about 3.3 mg / kg, and more preferably about 0.15 mg / kg to about 1.7 mg / kg.

[0257] In one embodiment, the subject is a mammal, preferably a human, and the dose of the adenosine receptor antagonist, preferably a therapeutically effective dose, is in the range of about 0.01 mg per kilogram of body weight per day (mg / kg / day) to about 5 mg / kg / day, preferably about 0.08 mg / kg / day to about 3.3 mg / kg / day, and more preferably about 0.15 mg / kg / day to about 1.7 mg / kg / day.

[0258] In one embodiment, the subject is a mammal, preferably a human, and the dose of the adenosine receptor antagonist, preferably a therapeutically effective dose, is in the range of about 1 mg to about 500 mg, preferably about 5 mg to about 200 mg, more preferably about 10 mg to about 100 mg.

[0259] In one embodiment, the subject is a mammal, preferably a human, and the dose of the adenosine receptor antagonist, preferably a therapeutically effective dose, is in the range of about 1 mg to about 500 mg per administration, preferably about 5 mg to about 200 mg per administration, more preferably about 10 mg to about 100 mg per administration.

[0260] In one embodiment, the subject is a mammal, preferably a human, and the dose of the adenosine receptor antagonist, preferably a therapeutically effective dose, is a daily dose in the range of about 1 mg to about 500 mg, preferably about 5 mg to about 200 mg, more preferably about 10 mg to about 100 mg.

[0261] In one embodiment, the subject is a mammal, preferably a human, and the dose of the adenosine receptor antagonist, preferably a therapeutically effective dose, is a daily dose administered in one, two, three or more ingestions. In one embodiment, the subject is a mammal, preferably a human, and the dose of the adenosine receptor antagonist, preferably a therapeutically effective dose, is a daily dose administered in one or two ingestions.

[0262] In one embodiment, the subject is a mammal, preferably a human, and the dose of the ENT inhibitor, preferably a therapeutically effective dose, is in the range of about 0.01 mg per kilogram (mg / kg) to about 5 mg / kg of body weight.

[0263] In one embodiment, the subject is a mammal, preferably a human, and the dose of the ENT inhibitor, preferably a therapeutically effective dose, is a dose in the range of about 0.01 mg per kilogram of body weight per day (mg / kg / day) to about 5 mg / kg / day.

[0264] In one embodiment, the subject is a mammal, preferably a human, and the dose of the ENT inhibitor, preferably a therapeutically effective dose, is a dose in the range of about 1 mg to about 500 mg.

[0265] In one embodiment, the subject is a mammal, preferably a human, and the dose of the ENT inhibitor, preferably a therapeutically effective dose, is in the range of about 1 mg to about 500 mg per administration.

[0266] In one embodiment, the subject is a mammal, preferably a human, and the dose, preferably a therapeutically effective dose, of the ENT inhibitor is a daily dose ranging from about 1 mg to about 500 mg.

[0267] In one embodiment, the subject is a mammal, preferably a human, and the dose, preferably a therapeutically effective dose, of the ENT inhibitor is a daily dose administered in one, two, three or more ingestions. In one embodiment, the subject is a mammal, preferably a human, and the dose, preferably a therapeutically effective dose, of the ENT inhibitor is a daily dose administered in one or two ingestions.

[0268] Purpose Another object of the present invention is the use of the combination as a medicament, i.e. for medical use.Accordingly, in one embodiment, the present invention provides the use of the combination of the present invention in the manufacture of a medicament.In particular, the present invention provides the use of the pharmaceutical composition of the present invention or the kit of the present invention in the manufacture of a medicament.

[0269] In particular, the present invention provides a combination, a pharmaceutical composition or a kit-of-parts according to the invention for use in the treatment and / or prevention of cancer.

[0270] The present invention further provides the use of a combination, pharmaceutical composition or kit-of-parts according to the invention in the manufacture of a medicament for treating and / or preventing cancer.

[0271] The present invention further provides a method of cancer treatment comprising administering a therapeutically effective amount of the combination, pharmaceutical composition or kit-of-parts of the invention to a mammalian species in need thereof.

[0272] In particular, the present invention provides a method for treating cancer, comprising administering to a patient in need thereof a combination of an adenosine receptor antagonist and an ENT family transporter inhibitor. The specific embodiments of the adenosine receptor antagonist and the ENT family transporter inhibitor listed above also apply in the context of the treatment method of the present invention.

[0273] The present invention also provides a method for delaying the onset of cancer in a patient, comprising administering to a patient in need thereof a pharma- ceutical effective amount of the combination, pharmaceutical composition or kit-of-parts of the present invention.

[0274] Various cancers are known in the art.Cancers that can be treated using the method of the present invention include solid and non-solid cancers, particularly benign and malignant solid tumors, and benign and malignant non-solid tumors.Cancers can be metastatic or non-metastatic.Cancers can be familial or sporadic.

[0275] In one embodiment, the cancer treated according to the present invention is a solid cancer. As used herein, the term "solid cancer" includes any cancer (also called a malignant tumor) that forms a discrete mass, as opposed to a cancer (or malignant tumor) that diffusely infiltrates tissue without forming a mass.

[0276] Examples of solid tumors include biliary tract cancer, brain tumors (including glioblastoma and medulloblastoma), breast cancer, carcinoid, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasia (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including those arising from epithelial cells, stromal cells, germ cells, and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, and rectal cancer. Cancer, including, but not limited to, renal cancer (including adenocarcinoma and Wilms' tumor), sarcoma (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), testicular cancer, including germ cell tumors (seminomas and non-seminomas, such as teratomas and choriocarcinomas), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma), and urothelial carcinoma.

[0277] In another embodiment, the cancer treated according to the present invention is a non-solid cancer. Examples of non-solid tumors include, but are not limited to, hematological neoplasms. As used herein, hematological neoplasms is a term of art that includes lymphoid disorders, myeloid disorders, and AIDS-related leukemia.

[0278] Lymphatic disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphoma, myeloma, and chronic lymphocytic leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphoma, and lymphocytic lymphoma. Chronic lymphocytic leukemias include, for example, T-cell chronic lymphocytic leukemia and B-cell chronic lymphocytic leukemia.

[0279] In specific embodiments, the cancer is selected from breast cancer, carcinoid, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, renal cancer, gastric cancer, thyroid cancer, and urothelial cancer.

[0280] 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 cervical cancer. 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 glioma. In a specific embodiment, the cancer is head and neck cancer. In a specific embodiment, the cancer is liver cancer. In a specific embodiment, the cancer is lung cancer. In a specific embodiment, the cancer is 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 renal 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 carcinoma.

[0281] In another specific embodiment, the cancer is selected from the group consisting of leukemia and multiple myeloma.

[0282] Preferably, the patient is a warm-blooded animal, more preferably a human.

[0283] In one embodiment, the subject receiving an ENT family transporter inhibitor is treated with an additional therapeutic agent in combination with the ENT family transporter inhibitor or has received the additional therapeutic agent within about 14 days of administration of the ENT family transporter inhibitor. In one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist.

[0284] In one embodiment, the subject has previously undergone at least one prior therapeutic treatment and has progressed since administration of the at least one prior therapeutic treatment prior to administration of the ENT family transporter inhibitor, in one embodiment, the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, hormone therapy, and surgery.

[0285] The present invention also relates to a pharmaceutical formulation for use in the treatment of cancer, the pharmaceutical formulation being administered to a human subject in an amount effective to treat cancer, the formulation comprising: (a) ENT family transporter inhibitors; (b) optionally, one or more pharma- ceutically acceptable carriers, diluents, excipients, and / or adjuvants.

[0286] In one embodiment, in the pharmaceutical formulation for use according to the invention, the ENT family transporter is ENT1 and the inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a peptide, and an antibody.

[0287] In one embodiment, in the pharmaceutical formulation for use according to the invention, the pharmaceutical formulation further comprises an additional therapeutic agent, hi one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist.

[0288] In one embodiment, in the pharmaceutical preparation for use of the present invention, the subject has previously undergone at least one prior therapeutic treatment, in one embodiment, the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, hormone therapy, and surgery.

[0289] In one embodiment, in the pharmaceutical formulation for use according to the invention, the pharmaceutical formulation is administered prior to, concurrently with, or following administration of an additional therapeutic agent, including an adenosine receptor antagonist.

[0290] The invention also provides a pharmaceutical formulation for use in the treatment of cancer, the pharmaceutical formulation being administered to a human subject in an amount effective to treat cancer, the formulation comprising: (a) ENT family transporter inhibitors (b) adenosine receptor antagonists; (c) optionally, one or more pharma- ceutically acceptable carriers, diluents, excipients, and / or adjuvants.

[0291] In one embodiment, in the pharmaceutical formulation for use according to the invention comprising an adenosine receptor antagonist, the adenosine receptor antagonist comprises an A2A or A2B receptor antagonist. In one embodiment, the adenosine receptor antagonist is selected from the following: 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide.

[0292] In another embodiment, the adenosine receptor antagonist comprises a compound of formula (I) as defined above.

[0293] The invention also provides a method of treating cancer comprising administering to a human subject a pharmaceutical formulation in an amount effective to treat the cancer, the formulation comprising: (a) ENT family transporter inhibitors; (b) optionally, one or more pharma- ceutically acceptable carriers, diluents, excipients, and / or adjuvants.

[0294] In one embodiment, in the methods of the invention, the ENT family transporter is ENT1 and the inhibitor is selected from the group consisting of a small molecule, a nucleic acid, a peptide, and an antibody.

[0295] In one embodiment, in the methods of the invention, the pharmaceutical formulation further comprises an additional therapeutic agent, hi one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist.

[0296] In one embodiment, in the method of the present invention, the subject has previously undergone at least one prior therapeutic treatment, hi one embodiment, the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, hormone therapy, and surgery.

[0297] In one embodiment, in the methods of the invention, the pharmaceutical preparation is administered prior to, concurrently with, or following administration of an additional therapeutic agent, including an adenosine receptor antagonist.

[0298] The invention also provides a method of treating cancer comprising administering to a human subject a pharmaceutical formulation in an amount effective to treat the cancer, the formulation comprising: (a) ENT family transporter inhibitors (b) an adenosine receptor antagonist; and (c) optionally, one or more pharma- ceutically acceptable carriers, diluents, excipients, and / or adjuvants.

[0299] In one embodiment, in the method of the invention where the pharmaceutical formulation comprises an adenosine receptor antagonist, the adenosine receptor antagonist comprises an A2A or A2B receptor antagonist. In one embodiment, the adenosine receptor antagonist is selected from the following: 5-Bromo-2,6-di-(1H-pyrazol-1-yl)pyrimidin-4-amine; (S)-7-(5-methylfuran-2-yl)-3-((6-(([tetrahydrofuran-3-yl]oxy)methyl)pyridin-2-yl)methyl)-3H-[1,2,3]triazolo[4,5-d]pyrimidin-5-amine; 6-(2-chloro-6-methylpyridin-4-yl)-5-(4-fluorophenyl)-1,2,4-triazin-3-amine; 3-(2-amino-6-(1-((6-(2-hydroxypropan-2-yl)pyridin-2-yl)methyl)-1H-1,2,3-triazol-4-yl)pyrimidin-4-yl)-2-methylbenzonitrile; 2-(2-furanyl)-7-(2-(4-(4-(2-methoxyethoxy)phenyl)-1-piperazinyl)ethyl)-7H-pyrazolo(4,3-e)(1,2,4)triazolo(1,5-c)pyrimidin-5-amine; 3-(4-amino-3-methylbenzyl)-7-(2-furyl)-3H-(1,2,3)triazolo(4,5-d)pyrimidin-5-amine; and 4-Hydroxy-N-(4-methoxy-7-morpholinobenzo[d]thiazol-2-yl)-4-methylpiperidine-1-carboxamide.

[0300] In another embodiment, the adenosine receptor antagonist comprises a compound of formula (I) as defined above. [Brief description of the drawings]

[0301] [Figure 1A] Graph showing ENT1 expression in human primary lymphocytes. FPKM: Fragments per kilobase million. Source: Bonnal RJP, Nature 2015. [Figure 1B] Graph showing ENT2 expression in human primary lymphocytes. FPKM: Fragments per kilobase million. Source: Bonnal RJP, Nature 2015. [Figure 1C] Graph showing ENT4 expression in human primary lymphocytes. FPKM: Fragments per kilobase million. Source: Bonnal RJP, Nature 2015. [Diagram 2] Figures 2A and 2B are graphs showing the viability of differently treated CD3+ T cells and show that ENT inhibitors reverse the adenosine / ATP-mediated decrease in T cell viability. Human primary CD3+ T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 25 μM adenosine (Figure 2A) or 200 μM ATP (Figure 2B). T cell viability was analyzed by flow cytometry after a 3-day incubation period. Mean + / - SD of biological replicates is shown. Representative data from one healthy donor is shown. Similar data were obtained in two healthy donors. [Figure 3-1]Figures 3A, 3B, 3C, and 3D are graphs showing proliferation of differently treated CD4+ and CD8+ T cells, showing that ENT inhibitors rescue adenosine / ATP-mediated suppression of T cell proliferation. Human primary CD3+ T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 25 μM adenosine (Figures 3A and 3C) or 200 μM ATP (Figures 3B and 3D). Proliferation of CD4+ (Figures 3A and 3B) and CD8+ (Figures 3C and 3D) T cells was analyzed by flow cytometry after a 3-day incubation period. Means + / - SD of biological replicates are shown. Representative data from one healthy donor are shown. Similar data were obtained in two healthy donors. [Figure 3-2] Figures 3A, 3B, 3C, and 3D are graphs showing proliferation of differently treated CD4+ and CD8+ T cells, showing that ENT inhibitors rescue adenosine / ATP-mediated suppression of T cell proliferation. Human primary CD3+ T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 25 μM adenosine (Figures 3A and 3C) or 200 μM ATP (Figures 3B and 3D). Proliferation of CD4+ (Figures 3A and 3B) and CD8+ (Figures 3C and 3D) T cells was analyzed by flow cytometry after a 3-day incubation period. Means + / - SD of biological replicates are shown. Representative data from one healthy donor are shown. Similar data were obtained in two healthy donors. [Figure 4]Figures 4A and 4B are graphs showing IL-2 secretion of differently treated CD3+ T cells, showing that combined treatment with an ENT inhibitor and an A2AR antagonist, compound 8a, rescues adenosine / ATP-mediated suppression of T cell cytokine secretion. CD3+ T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 25 μM adenosine (Figure 4A) or 200 μM ATP (Figure 4B). IL-2 secretion was analyzed in the supernatants by AlphaLISA after a 3-day incubation period. Mean + / - SD of biological replicates is shown. Representative data from one healthy donor is shown. Similar data were obtained in two healthy donors. [Diagram 5] Figure 5A shows the viability of CD3+ T cells as determined by staining with fixable viability dye. Figure 5B shows the proliferation of CD8+ T cells as determined by the CFSE dilution method. Figure 5C shows the concentration of TNFα present in the cell culture supernatant. Human primary CD3+ T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 100 μM ATP or control medium. CD3+ T cell viability (Figure 5A) and CD8+ T cell proliferation (Figure 5B) were analyzed by flow cytometry after a 3-day incubation period. TNFα secretion in the supernatant was analyzed by AlphaLISA. Grey shaded bars indicate wells treated with A2AR antagonists and clear bars indicate wells treated with DMSO at an equivalent concentration. Results are shown as mean ± standard deviation from sextuplicate (DMSO) or duplicate (A2AR antagonist) wells. Data shown are representative of data obtained in three healthy individuals in four independent experiments. [Figure 6]Figure 1 shows in vivo LPS-induced TNF-alpha production in mice when pretreated with compound 8b (A2AR antagonist) or NBMPR (ENT1 inhibitor) or their combination. BALB / c mice were pretreated with NBMPR (20 mg / kg, po) or vehicle 1 h prior to LPS (1 mg / kg, IV) injection. 30 min prior, mice were treated with a single dose of compound 8b (3 mg / kg, po) or vehicle. One hour after LPS treatment, serum was collected from mice. Levels of TNF-alpha were determined by ELISA (n=5). P values ​​are shown using the Mann-Whitney test, ns=not significant. [Figure 7-1] Figure 7 shows MCA205 tumor growth upon treatment with compound 8b (A2AR antagonist) in combination with NBMPR (ENT1 inhibitor). Figure 7A is a graph depicting the median tumor volume over time following subcutaneous inoculation of tumor cells. Figures 7B-D are individual tumor growth volumes for mice treated with vehicle (Figure 7B), NBMPR at 20 mg / kg, BIDx22 (day 11) alone (Figure 7C), or in combination with compound 8b at 3 mg / kg, BIDx22 (Figure 7D). (n=10, *P=0.0043, **P=0.0015, ***P<0.0001, linear mixed model statistical analysis). [Figure 7-2] Figure 7 shows MCA205 tumor growth upon treatment with compound 8b (A2AR antagonist) in combination with NBMPR (ENT1 inhibitor). Figure 7A is a graph depicting the median tumor volume over time following subcutaneous inoculation of tumor cells. Figures 7B-D are individual tumor growth volumes for mice treated with vehicle (Figure 7B), NBMPR at 20 mg / kg, BIDx22 (day 11) alone (Figure 7C), or in combination with compound 8b at 3 mg / kg, BIDx22 (Figure 7D). (n=10, *P=0.0043, **P=0.0015, ***P<0.0001, linear mixed model statistical analysis). EXAMPLES

[0302] The present invention may be better understood by reference to the following examples, which are intended to represent specific embodiments of the invention and are not intended to limit the scope of the invention.

[0303] The following abbreviations are used: ATP: Adenosine triphosphate BSA: bovine serum albumin CFSE: carboxyfluorescein succinimidyl ester DMSO: Dimethyl sulfoxide EDTA: Ethylenediaminetetraacetic acid FACS: Fluorescence-activated cell sorting FBS: Fetal bovine serum mL: milliliter μL: microliter mM: millimolar nM: nanomolar μM: micromolar PBS: Phosphate-buffered saline rpm: Revolutions per minute RPMI: Roswell Park Memorial Institute medium

[0304] Example 1. ENT1 inhibitors in combination with A2AR antagonists restore TNF-alpha production in T cells material Reagents and compounds used in the following assays were obtained from the following sources: [Table 2-1] [Table 2-2]

[0305] method PBMC and CD3 +Isolation of T cells. Venous blood from healthy volunteers was obtained from the Unite d'Investigation Clinique (Centre Hospitalier Universitaire de Tivoli, La Louviere, Belgium). All volunteers signed an informed consent approved by the ethical committee (FOR-UIC-BV-050-01-01 ICF_HBS_HD Version 5.0). Mononuclear cells were harvested by density gradient centrifugation using SepMate-50 tubes and Lymphoprep according to the manufacturer's instructions. CD3 T cells were isolated by negative selection in immunomagnetic separation using the EasySep Human T Cell Isolation Kit according to the manufacturer's instructions. + T cells were isolated. CD3 + T cells were stored in heat-inactivated FBS and 10% DMSO in liquid nitrogen.

[0306] Human primary T cell culture. Human purified CD3 + T cells were thawed and washed twice with RPMI1640 medium containing 10% hiFBS, UltraGlutamine (Lonza) supplemented with 1x non-essential amino acids, and 1 mM sodium pyruvate (Gibco) (complete medium). After the final wash, cells were resuspended in PBS containing 10% FBS and labeled with 3 μM CFSE for 5 min at room temperature, then washed twice with complete medium. After the final wash, cells were resuspended at 1.6 × 10 6 The cell suspension (8 × 10 450 μL of 100 mM T cells (Dynabeads, human T activator CD3 / CD28) were added to wells of a sterile round-bottom 96-well plate. Cells were activated by adding 50 μL of anti-CD3 anti-CD28 coated microbeads (Dynabeads, human T activator CD3 / CD28) suspended in X-Vivo15 medium at a ratio of 1 microbead per 2 cells. Adenosine (75 mM stock solution in DMSO) and ATP (powder) were diluted in X-Vivo15 medium and 25 μL or 50 μL were added to the wells to reach a final assay concentration of 25 μM adenosine or 200 μM ATP. Serial dilutions of the ENT inhibitors dilazep dihydrochloride, dipyridamole, and ticagrelor were prepared in X-Vivo15 medium from 100 mM stock solutions (in DMSO or water) and 25 μL were added to the wells. A 2A The R antagonist compound 8a (10 mM stock in DMSO) was diluted in X-Vivo15 medium and 25 μL was added to the wells to reach a final assay concentration of 300 nM. In studies involving different A2AR antagonists, wells received either the A2AR antagonist compound 8a at a final concentration of 300 nM, NIR178 at a final concentration of 5 μM, CPI-444 at a final concentration of 5 μM, AZD4635 at a final concentration of 1 μM, or AB928 at a final concentration of 1 μM, or a matching concentration of DMSO. In addition, some wells received the ENT-1 inhibitor dipyridamole at a final concentration of 1 μM, or a combination of dipyridamole and an A2AR antagonist. The final DMSO concentration in this assay was 0.05% and the final assay volume was 200 μL. Experiments were performed in biological duplicates and DMSO controls were added in quadruplicates. Cells were placed in a humidified tissue culture incubator at 37°C with 5% CO2 for 72 hours. After 72 hours, cells were pelleted by centrifugation at 1600 rpm for 5 minutes and supernatants were transferred to V-bottom 96-well plates for cytokine quantification. For flow cytometry analysis, cell pellets were resuspended in FACS buffer (see below).

[0307] Cytokine quantification. Supernatants were centrifuged at 4000 rpm for 10 min and IL-2 was quantified using the IL-2 (human) AlphaLISA biotin-free detection kit and TNFα was quantified using the AlphaLISA human TNFα biotin-free detection kit according to the manufacturer's instructions.

[0308] Flow cytometry. Cells were washed with FACS buffer (PBS containing 2 mM EDTA and 0.1% BSA) and stained with surface marker antibodies and viability dyes for 20 min on ice. Cells were washed twice with FACS buffer and data were acquired using an LSRFortessa (BD biosciences). Analysis was performed using FlowJo software (Treestar).

[0309] result To evaluate the effect of adenosine on human primary T cells, CD3 + T cells were stimulated with anti-CD3 / CD28-coated microbeads and treated with adenosine or ATP. Adenosine and ATP significantly suppressed T cell proliferation and cytokine secretion (IL-2), and significantly reduced T cell viability (Figures 2-4).

[0310] Adenosine- and ATP-mediated inhibition of T cell viability, proliferation, and IL-2 secretion was not rescued by compound 8a, a potent and selective A2AR antagonist, suggesting an A2AR-independent mechanism of T cell inhibition (Figures 2–4).

[0311] Extracellular adenosine is taken up into cells by equilibrative nucleoside transporters (ENT).

[0312] Primary T cells were treated with adenosine or ATP and incubated with three different structurally unrelated ENT inhibitors, dipyridamole, dilazep hydrochloride, and ticagrelor. All ENT inhibitors tested restored T cell proliferation and viability (Figures 2 and 3), indicating a deleterious effect of ENT-induced cellular uptake of adenosine on T cell metabolism. However, none of the ENT inhibitors as single agents rescued T cell-derived IL-2 secretion.

[0313] Upon combination treatment of the A2A receptor antagonist compound 8a with an ENT inhibitor, adenosine- and ATP-mediated suppression of T cell cytokine secretion was completely rescued (FIGS. 4A and 4B). These results indicate that adenosine suppresses T cell function and vitality through both extracellular and intracellular mechanisms, but this can be reversed by combination treatment of an A2AR antagonist (including but not limited to compound 8a, as further shown below) with an ENT inhibitor.

[0314] Figure 5A-C shows that the combination of the ENT-1 inhibitor dipyridamole with the A2A receptor antagonists compounds 8a, AB928, CPI-444, NIR178, and AZD4635 can reverse the inhibition of T cells in the presence of ATP. More specifically, ATP significantly inhibited CD8+ T cell proliferation and reduced T cell viability, which was fully reversed by the ENT-1 inhibitor dipyridamole. ATP also significantly inhibited TNFα production. Both A2AR and ENT-1 inhibitors were able to partially restore cytokine production individually. The combination of both inhibitors further increased the recovery of cytokine secretion compared to either treatment alone. Collectively, these data indicate that the combination of compounds 8a, AB928, AZD4635, NIR178, or CPI-444 with ENT-1 inhibitors for cancer therapy is beneficial for the complete restoration of T cell function and viability in the ATP / adenosine-rich tumor microenvironment.

[0315] Example 2. ENT1 inhibitors in combination with A2AR antagonists restore TNF-alpha production in the LPS model of endotoxemia The most prominent targets of adenosine transport are the equilibrative nucleoside transporters, ENT1, ENT2, ENT3, and ENT4. ENT inhibitors regulate the transport of nucleosides in and out, e.g., adenosine across the cell membrane, so as to reduce the intracellular adenosine concentration by inhibiting equilibrative nucleoside transport and allow the accumulation of adenosine outside the cell. High intracellular adenosine has been shown to result in suppression of immune cell proliferation, survival, and function. On the other hand, extracellular adenosine reduces the activation and function, e.g., proinflammatory cytokine production and cytotoxicity, of immune cells by binding to adenosine receptor 2A (A2AR). Thus, inhibition of equilibrative transporters aims to reduce intracellular adenosine and thereby enhance immune cell survival, proliferation, and function, while inhibition of A2AR aims to restore proinflammatory activity, cytotoxicity, and immune cell activation by inhibiting extracellular adenosine.

[0316] NBMPR (6-S-[(4-nitrophenyl)methyl]-6-thioinosine) is a specific ENT1 inhibitor with similar activity in humans and mice. Thus, the use of NBMPR in mouse models specifically blocks ENT1 activity.

[0317] Using a lipopolysaccharide (LPS) model, known to induce secretion of the proinflammatory cytokine TNF-alpha, we assessed whether the TNF-alpha-mediated suppression observed in the presence of the ENT1 inhibitor NBMPR could be rescued by the addition of the A2AR antagonist, compound 8b.

[0318] BALB / c mice were treated po with vehicle (2.5% DMSO, 10% Solutol HS15 in dH2O, pH 3) as a control or 3mg / kg of compound 8b. After 30 minutes, mice were treated po with NBMPR 20mg / kg. After 60 minutes, mice were treated with LPS and bled to measure TNF-alpha in serum by ELISA.

[0319] Treatment with LPS significantly increased TNF-alpha levels in serum. The A2AR antagonist, compound 8b, had no effect on TNF-alpha levels after LPS treatment, whereas treatment with NBMPR alone significantly inhibited TNF-alpha production by nearly two-fold (p=0.008). Pretreatment of mice with compound 8b reversed the effect of NBMPR and rescued TNF-alpha production by more than two-fold (p=0.016) (Figure 6).

[0320] Example 3. ENT1 inhibitors in combination with A2AR antagonists demonstrate antitumor efficacy in a murine syngeneic MCA205 experimental fibrosarcoma model The antitumor efficacy of the A2AR antagonist, compound 8b, in combination with the ENT1 inhibitor NBMPR was evaluated in an established mouse syngeneic MCA205 fibrosarcoma tumor model.

[0321] MCA205 tumor cells were inoculated subcutaneously into the right flank of C57BL / 6 mice. The average tumor size was approximately 50 mm 3 At the time of reaching 100 mg / kg, mice were randomly assigned to groups. Mice were administered vehicle (2.5% DMSO, 10% Solutol HS15 in dH2O, pH 3) as a control, po, or NBMPR at 20 mg / kg, po, BIDx22 (days 7-29) as a single agent or in combination with compound 8b, po, 3 mg / kg, QDx22 (days 7-29).

[0322] NBMPR administered as a single agent at 20 mg / kg, po, twice daily (BID) for 22 consecutive days demonstrated a significant delay (p=0.0043) in tumor growth compared to vehicle (FIGS. 7A, 7B, and 7C).

[0323] Compound 8b at 3 mg / kg po in combination with NBMPR at 20 mg / kg, both administered twice daily (BID) for 22 consecutive days, demonstrated significant tumor growth delay compared to vehicle (p<0.0001) and also significantly delayed tumor growth when compared to NBMPR monotherapy (p=0.0015) (Figures 7A-7D).

Claims

1. 1. A combination pharmaceutical for use in the treatment of cancer, comprising: (a) an effective amount of an ENT family transporter inhibitor selected from dilazep, dipyridamole, nitrobenzylthioinosine and ticagrelor; (b) an effective amount of: (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; or A pharma- ceutically acceptable salt or solvate thereof and an adenosine receptor antagonist selected from the group consisting of

2. 1. A pharmaceutical composition for use in the treatment of cancer, comprising: (a) an effective amount of an ENT family transporter inhibitor selected from dilazep, dipyridamole, nitrobenzylthioinosine and ticagrelor; (b) an effective amount of: (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; or A pharma- ceutically acceptable salt or solvate thereof Selected from an adenosine receptor antagonist; (c) at least one pharma- ceutically acceptable excipient.

3. 1. A kit of parts for use in cancer treatment, comprising: (a) a first portion comprising an effective amount of an ENT family transporter inhibitor selected from dilazep, dipyridamole, nitrobenzylthioinosine, and ticagrelor; (b) an effective amount of: (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; or A pharma- ceutically acceptable salt or solvate thereof Selected from and a second part comprising an adenosine receptor antagonist.

4. The adenosine receptor antagonist is (+)-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 4. The pharmaceutical combination, pharmaceutical composition or kit-of-parts according to any one of claims 1 to 3, wherein the compound is triazolo[1,5-c]pyrimidin-2(3H)-one or a pharma- ceutically acceptable salt or solvate thereof.

5. The pharmaceutical combination, pharmaceutical composition or kit-of-parts according to any one of claims 1 to 3, wherein the adenosine receptor antagonist is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharma- ceutically acceptable salt or solvate thereof.

6. The pharmaceutical combination, pharmaceutical composition or kit-of-parts according to any one of claims 1 to 3, wherein the adenosine receptor antagonist is (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharma- ceutically acceptable salt or solvate thereof.

7. The pharmaceutical combination, pharmaceutical composition or kit-of-parts according to any one of claims 1 to 3, wherein the adenosine receptor antagonist is (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharma- ceutically acceptable salt or solvate thereof.

8. The pharmaceutical combination or kit-of-parts according to any one of claims 1, 3 to 7, wherein the ENT family transporter inhibitor is administered before, simultaneously with, or after administration of an adenosine receptor antagonist.

9. 1. A pharmaceutical formulation for use in the treatment of cancer, said pharmaceutical formulation being administered to a human subject in an amount effective for treating cancer, said formulation comprising: (a) an ENT family transporter inhibitor, wherein the ENT family transporter is ENT1, and the ENT family transporter inhibitor is selected from dilazep, dipyridamole, nitrobenzylthioinosine and ticagrelor; (b) Below: (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2 -yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one; or A pharma- ceutically acceptable salt or solvate thereof Selected from an adenosine receptor antagonist; (c) optionally, one or more pharma- ceutically acceptable carriers, diluents, excipients, and / or adjuvants.

10. 10. The pharmaceutical formulation for use according to claim 9, wherein the adenosine receptor antagonist is (+)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharma- ceutically acceptable salt or solvate thereof.

11. 10. The pharmaceutical formulation for use according to claim 9, wherein the adenosine receptor antagonist is (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharma- ceutically acceptable salt or solvate thereof.

12. 10. The pharmaceutical formulation for use according to claim 9, wherein the adenosine receptor antagonist is (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharma- ceutically acceptable salt or solvate thereof.

13. 10. The pharmaceutical formulation for use according to claim 9, wherein the adenosine receptor antagonist is (R,S)-5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one or a pharma- ceutically acceptable salt or solvate thereof.

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