Thiocarbamate derivatives as A2A inhibitors, pharmaceutical compositions thereof, and combinations with anticancer agents

Abstract

The present invention relates to thiocarbamate derivatives of formula (I), which are suitable for use as A2A adenosine receptor (A2AR) inhibitors (I). The present invention particularly relates to a pharmaceutical composition comprising an A2A inhibitor of formula (I) and a lipid carrier, such as lauroyl polyethylene glycol-32 glyceride, D-α-tocopherol-polyethylene glycol-1000 succinate or a mixture thereof. The pharmaceutical composition of the present invention is particularly suitable for oral administration in the treatment of cancer. The present invention also relates to a combination comprising an A2A receptor inhibitor of formula (I) and an anticancer agent. The anticancer agent is, for example, an immunotherapeutic agent, such as a checkpoint inhibitor. The present invention further relates to a pharmaceutical composition and a component kit comprising the combination. In addition, the combination of the present invention is particularly suitable for the treatment and / or prevention of cancer.

Description

[0001] This application is a divisional application of the Chinese invention patent application with application number 201980073376.6, invention name “Thiocarbamate derivatives as A2A inhibitors, pharmaceutical compositions thereof and combinations with anticancer agents” and application date September 11, 2019 (PCT application number PCT / EP2019 / 074208). Field of the Invention

[0002] The present invention relates to thiocarbamate derivatives which are useful as A2A adenosine receptor (A2AR) inhibitors.

[0003] The present invention particularly relates to a pharmaceutical composition comprising a thiocarbamate derivative as an adenosine A2A receptor inhibitor. The pharmaceutical composition of the present invention is particularly suitable for oral administration in the treatment of cancer.

[0004] The present invention also relates to a combination comprising an A2A adenosine receptor (A2AR) inhibitor and an anticancer agent. The A2AR inhibitor is a thiocarbamate derivative of formula (I) as defined below. The anticancer agent is, for example, an immunotherapeutic agent, such as, for example, a checkpoint inhibitor. The present invention further relates to a pharmaceutical composition and a kit of ingredients comprising the combination. The combination of the present invention is particularly suitable for treating and / or preventing cancer. Background of the Invention

[0006] Many immunosuppressive mechanisms in tumors are common to physiological immunoregulation in normal tissues. This immunoregulation is very important for keeping the immune system under control to prevent autoreactive immune responses and prevent ongoing immune responses from causing severe tissue damage. Lack of physiological immunoregulation often leads to overwhelming immune activation associated with autoimmunity. For example, CTLA-4 is a physiological mechanism that negatively regulates T cell activity by blocking co-stimulatory signals that interact via CD28-B7. Lack of CTLA4 can cause nonspecific T cell activation, and CTLA-4-deficient mice die within weeks due to massive lymphocyte tissue infiltration. PD-1 also provides T cell inhibitory signals when interacting with its ligands PD-L1 and PD-L2. It is known that the lack of PD-1 in mice can lead to various types of autoimmune disorders, depending on the genetic strain.

[0007] In addition to cell surface transducers of immunosuppressive signals (e.g., CTLA-4 and PD-1), immunosuppression in the tumor microenvironment also involves anti-inflammatory cytokines (IL-10, TGF-β), enzymes (indoleamine-2,3-dioxygenase), and professional immunoregulatory cells (regulatory T cells, myeloid-derived suppressor cells MDSC). These immunosuppressive mechanisms play an important role in controlling the immune response of normal tissues. Since tumors exploit this physiological immunoregulatory mechanism to protect their tissues from immune attack, these mechanisms aimed at preventing inflammatory complications have now proven to be a major obstacle to spontaneous cancer regression and immune cancer therapy. The identification of immunosuppressive mechanisms in tumors points to molecular targets for restoring antitumor immune responses. Therefore, these negative immunoregulatory mechanisms, the so-called immune checkpoints, have become a focus in drug development. Antibodies directed against PD1, PDL1, or CTLA4 have been approved as anticancer therapies for a variety of indications, such as metastatic melanoma, non-small cell lung cancer, renal cell carcinoma, Hodgkin's lymphoma, head and neck cancer, urothelial carcinoma, hepatocellular carcinoma, and for the treatment of patients with solid tumors that have one of two specific genetic characteristics, namely, mismatch repair deficiency and high microsatellite instability, regardless of cancer type.

[0008] Extracellular adenosine is known to be an inhibitor of immune function. Although intracellular adenosine is involved in energy metabolism, nucleic acid metabolism, and methionine cycling, extracellular adenosine plays an important role in intercellular signaling. Its signals are transmitted through G protein-coupled adenosine receptors on the cell surface and affect a variety of physiological functions, including the nervous system, cardiovascular system, and immune system.

[0009] Tumors contain high levels of extracellular adenosine, suggesting that tumor cells may benefit from its immunosuppressive effects and catabolic energy production (Allard et al., Curr. Opin. Pharmacol., 2016, 29, 7-16; Otta A., Frontiers in Immunology, 2016, 7: 109). This high level of extracellular adenosine may be due to overexpression of the CD73 enzyme, which is responsible for the production of extracellular adenosine. CD73 is overexpressed by many tumors, and all of the following tumors express moderate or high levels of CD73 in >50% of the tumor surface as measured by immunohistochemistry (www.proteinatlas.org): breast cancer, carcinoid tumor, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer, urothelial cancer.

[0010] Of the four known types of adenosine receptors, the A2A adenosine receptor (A2AR) is the predominant subtype expressed in most immune cells. Stimulation of the A2AR typically provides an immunosuppressive signal that inhibits the activity of T cells (proliferation, cytokine production, cytotoxicity), NK cells (cytotoxicity), NKT cells (cytokine production, CD40L upregulation), macrophages / dendritic cells (antigen presentation, cytokine production), and neutrophils (oxidative burst). The presence of high levels of extracellular adenosine in tumors has been found to play an important role in evading antitumor immune responses. In particular, A2AR-deficient mice have been shown to spontaneously regress inoculated tumors, whereas wild-type mice did not show similar tumor regression. A2AR antagonists are also beneficial in wild-type animals bearing tumors. Importantly, depletion of T cells and NK cells attenuates the blocking effect of A2AR antagonists on tumor growth, suggesting that antitumor cellular immune responses are improved. The effector functions of T cells and NK cells are sensitive to A2AR stimulation. Furthermore, when activated in the presence of an A2AR agonist, the effector function of T cells remained impaired even after the A2AR agonist was removed, suggesting that the adenosine-rich environment in tumors may induce T cells that are anergic to tumor cells.

[0011] Therefore, given that the A2A receptor is expressed in most immune cells, and in particular effector immune cells such as T cells and NK cells, and given that the A2A receptor is involved in tissues that produce adenosine, it is believed that A2A inhibitors may play a role in all cancer indications.

[0012] Therefore, there is a need for A2A inhibitors that can restore immune function in the tumor environment.

[0013] Adenosine is known to be an endogenous regulator of many other physiological functions. For example, at the level of the central nervous system (CNS), adenosine is known to induce levels of sedative, anxiolytic, and anti-epileptic effects.

[0014] Therefore, A2A inhibitors have been previously developed for the treatment of depression and neurodegenerative diseases such as Parkinson's disease or Alzheimer's disease (Pinna A., CNS Drugs, 2014, 28, 455). One of the most advanced A2A inhibitors developed for the treatment of CNS diseases is Preladenant (Hodgson RA et al., J. Pharmacol. Exp. Ther., 2009, 330 (1), 294-303; Hauser RA et al., JAMA Neurol., 2015, 72 (12), 1491-500).

[0015] However, in order to target A2A receptors in the CNS, such previously developed A2A inhibitors have been designed to cross the blood-brain barrier.

[0016] Given the higher levels of adenosine in tumors compared to the brain, much higher amounts of the compound would be required to achieve the desired effect of restoring immune function for cancer treatment. Therefore, in order to avoid deleterious side effects, in contrast to all previously developed A2A inhibitors, an A2A inhibitor with limited, if any, CNS penetration should be provided.

[0017] The applicant provides in international patent application PCT / EP2018 / 058301 a series of non-brain penetrant A2A inhibitors, which are thiocarbamate derivatives, suitable for restoring immune function in the tumor environment.

[0018] However, these compounds have very low solubility in aqueous buffers, low solubility in the intestine, and therefore low oral bioavailability. Therefore, there is a need for pharmaceutical formulations of these compounds suitable for oral administration.

[0019] As demonstrated in the following experimental section, applicants hereby provide pharmaceutical compositions that impart suitable oral bioavailability to thiocarbamate A2A inhibitors.

[0020] Furthermore, the anti-cancer effects of anti-cancer agents such as, for example, immunotherapeutics, chemotherapeutics or anti-angiogenic agents or combinations thereof may still be insufficient. This may be due, at least in part, to the tumor immune escape mechanisms described above.

[0021] A2AR inhibitors (particularly thiocarbamate derivatives disclosed in WO2018 / 178338) and specific combinations of other anticancer agents have not been reported. In this article, the applicant provides a combination comprising an adenosine A2A receptor inhibitor as disclosed in WO2018 / 178338 and another anticancer agent, such as an immunosuppressant such as a checkpoint inhibitor. Summary of the invention

[0022] Therefore, the present invention relates to a pharmaceutical composition comprising:

[0023] (a) a compound of formula (I) as defined below, or a pharmaceutically acceptable salt or solvate thereof;

[0024]

[0025] (b) a liquid carrier selected from lauroyl polyoxyl-32 glyceride, D-α-tocopheryl-polyethylene glycol-1000 succinate, and mixtures thereof; and

[0026] (c) optionally one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants.

[0027] In one embodiment, the compound of formula (I) has a sub-formula as defined below, in particular formula (Ia), (Ia-1), (Ia-1a), (Ia-1b), (Ia-1c) or (Ia-1d). In one embodiment, the compound of formula (I) is one of those listed in Table 1 below. In a specific embodiment, the compound of formula (I) is selected from:

[0028] (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;

[0029] (+)-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;

[0030] and pharmaceutically acceptable salts or solvates thereof.

[0031] In one embodiment, the compound of formula (I) is in the form of a salt, wherein the salt is a hydrochloride or ethanesulfonate salt.

[0032] In one embodiment, the pharmaceutical composition of the present invention further comprises PEG 400 and / or PEG 3350. In one embodiment, the pharmaceutical composition of the present invention further comprises caprylic acid.

[0033] In one embodiment, the pharmaceutical composition of the present invention further comprises an antioxidant, which may be, for example, butylated hydroxytoluene (BHT).

[0034] In one embodiment, the pharmaceutical composition of the present invention further comprises a wetting agent; preferably, the wetting agent is selected from sodium lauryl sulfate, vitamin E TPGS, docusate sodium, polysorbate 80 and poloxamer 407; more preferably, the wetting agent is sodium lauryl sulfate.

[0035] In one embodiment, the pharmaceutical composition of the present invention further comprises a precipitation inhibitor; preferably, the precipitation inhibitor is selected from hydroxypropyl methylcellulose, methylcellulose, polyvinyl pyrrolidone, polyvinyl pyrrolidone-polyvinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and poloxamer 407; more preferably hydroxypropyl methylcellulose.

[0036] In one embodiment, in the pharmaceutical composition of the invention, the compound of formula (I) is present in an amount ranging from 1% to 20% w / w, preferably 5% to 15% w / w, more preferably about 10% w / w.

[0037] In one embodiment, in the pharmaceutical composition of the invention, the lipid carrier is present in an amount ranging from 55% to 99% w / w, preferably 60% to 95% w / w, more preferably 70% to 90% w / w.

[0038] In one embodiment, the pharmaceutical composition of the present invention can be formulated into capsules, tablets or granules. In one embodiment, when the pharmaceutical composition of the present invention is formulated into capsules, the capsule shell is composed of gelatin, and wherein additional components are optionally included in the capsule shell, such as, for example, polyethylene glycol and sodium lauryl sulfate.

[0039] The present invention further relates to a method for treating cancer, comprising administering to a patient in need thereof a therapeutically acceptable effective amount of a pharmaceutical composition according to the present invention. In one embodiment, the cancer is selected from breast cancer, carcinoid tumor, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer and urothelial cancer.

[0040] The present invention therefore relates to a combination comprising:

[0041] (a) at least one compound of formula (I):

[0042]

[0043] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 as defined below; and

[0044] (b) at least one anticancer agent.

[0045] In one embodiment, the compound of formula (I) has formula (Ia), (Ia-1) or (Ia-1b) as defined below. In one embodiment, the compound of formula (I) is one of those listed in Table 1 below.

[0046] In one embodiment, the anti-cancer agent is selected from an immunotherapeutic agent, a chemotherapeutic agent, an anti-angiogenic agent, a multidrug resistance-associated protein inhibitor, a radiotherapeutic agent, and any combination thereof.

[0047] In one embodiment, the immunotherapeutic agent is selected from a checkpoint inhibitor, a checkpoint agonist, an IDO inhibitor, a PI3K inhibitor, an adenosine receptor inhibitor, an adenosine-producing enzyme inhibitor, a CD40 agonist, an IL2 variant, an immune cell, a therapeutic vaccine, or any combination thereof.

[0048] In one embodiment, the checkpoint inhibitor is an inhibitor of a checkpoint protein selected from PD-1, PD-L1, CTLA-4, and TIGIT.

[0049] In one embodiment, the PD-1 inhibitor is an anti-PD-1 antibody; the PD-L1 inhibitor is an anti-PD-L1 antibody; the CTLA-4 inhibitor is an anti-CTLA-4 antibody and the TIGIT inhibitor is an anti-TIGIT antibody.

[0050] In one embodiment, the chemotherapeutic agent is selected from the group consisting of anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, Parp inhibitors, anti-hormone sensitive cancer agents, and any combination thereof. In one embodiment, the anticancer antibiotic is doxorubicin. In one embodiment, the anticancer platinum coordination compound is oxaliplatin. In one embodiment, the combination of chemotherapeutic agents is selected from the group consisting of: (i) a combination consisting of folinic acid, fluorouracil, and oxaliplatin; (ii) a combination consisting of carboplatin and paclitaxel; and (iii) a combination consisting of gemcitabine and nab-paclitaxel.

[0051] In one embodiment, the combination of the invention comprises at least one compound of formula (I) as defined herein and at least two anticancer agents as defined herein.

[0052] The present invention also relates to a pharmaceutical composition comprising:

[0053] (a) at least one compound of formula (I) as defined herein; and

[0054] (b) at least one anticancer agent as defined herein.

[0055] The present invention further relates to a kit of parts comprising:

[0056] (a) a first component comprising at least one compound of formula (I) as defined herein; and

[0057] (b) a second component comprising at least one anticancer agent as defined herein.

[0058] In one embodiment, the combination, pharmaceutical composition or kit of parts according to the invention is for medical use.

[0059] In one embodiment, the combination, pharmaceutical composition or kit of parts according to the invention is used for the treatment and / or prevention of cancer.

[0060] In one embodiment, the cancer is selected from breast cancer, carcinoid tumor, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer and urothelial carcinoma.

[0061] In one embodiment, the components of the combination or kit of parts according to the invention are to be administered sequentially and / or simultaneously to a patient in need thereof.

[0062] In one embodiment, the components of the combination or kit of parts according to the invention are to be administered to a patient in need thereof via different routes of administration.

[0063] definition

[0064] In the present invention, the following terms have the following meanings:

[0065] The term "aldehyde" refers to the group -CHO.

[0066] The term "alkenyl" refers to an unsaturated hydrocarbon radical which may be linear or branched, containing one or more carbon-carbon double bonds. 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 vinyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and isomers thereof, 2-hexenyl and isomers thereof, 2,4-pentadienyl, and the like.

[0067] The term "alkenylcarbonyl" refers to the group -(C=O)-alkenyl, wherein alkenyl is as defined herein.

[0068] The term "alkenylcarbonylamino" refers to the group -NH-(C=O)-alkenyl, wherein alkenyl is as defined herein.

[0069] The term "alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined herein.

[0070] The term "alkyl" refers to a group of the formula C n H 2n+1 wherein n is a number greater than or equal to 1. Typically, 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 straight or branched. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl and octyl.

[0071] The term "alkylaminoalkyl" refers to the group -alkyl-NH-alkyl wherein alkyl is as defined herein.

[0072] The term "alkylaminoalkylaminocarbonyl" refers to the group -(C=O)-NH-alkyl-NH-alkyl, wherein alkyl is as defined herein.

[0073] The term "(alkylaminoalkyl)(alkyl)aminocarbonyl" refers to the group -(C=O)-NR 1 R 2 , where R 1 is an alkyl group and R 2 is -alkyl-NH-alkyl, wherein alkyl is as defined herein.

[0074] The term "alkylaminoalkylcarbonyl" refers to the group -(C=O)-alkyl-NH-alkyl, wherein alkyl is as defined herein.

[0075] The term "alkylcarbonyl" refers to the group -(C=O)-alkyl, wherein alkyl is as defined herein.

[0076] The term "alkylheteroaryl" refers to any heteroaryl group substituted with an alkyl group, wherein alkyl is as defined herein.

[0077] The term "alkoxycarbonyl" refers to the group -(C=O)-O-alkyl, wherein alkyl is as defined herein.

[0078] The term "alkylsulfonyl" refers to the group -SO2-alkyl wherein alkyl is as defined herein.

[0079] The term "alkylsulfonealkyl" refers to the group -alkyl-SO2-alkyl, wherein alkyl is as defined herein.

[0080] The term "alkylsulfonimido" refers to the group -S(=O)(=NH)-alkyl, wherein alkyl is as defined herein.

[0081] The term "alkyl sulfoxide" refers to the group -(S=O)-alkyl, wherein alkyl is as defined herein.

[0082] The term "alkylsulfoxidealkyl" refers to the group -alkyl-SO-alkyl, wherein alkyl is as defined herein.

[0083] The term "alkyne" refers to a class of monovalent unsaturated hydrocarbon groups in which the unsaturation is 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 the above-mentioned alkyl groups. Non-limiting examples of alkynyl groups are ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and isomers thereof, 2-hexynyl and isomers thereof, and the like.

[0084] The term "alkynylalkyl" refers to the group -alkyl-alkynyl wherein alkyl and alkynyl are as defined herein.

[0085] The term "amino" refers to the group -NH2.

[0086] The term "aminoalkyl" refers to the group -alkyl-NH2, wherein alkyl is as defined herein. The term "aminoalkylaminocarbonyl" refers to the group -(C=O)-NH-alkyl-NH2, wherein alkyl is as defined herein.

[0087] The term "aminoalkylcarbonylamino" refers to the group -NH-(C=O)-alkyl-NH2 wherein alkyl is as defined herein.

[0088] The term "aminocarbonyl" refers to the group -(C=O)-NH2.

[0089] The term "(aminocarbonylalkyl)(alkyl)amino" refers to the group -NR 1 R 2 , where R 1 is an alkyl group and R 2 is an -alkyl-(C=O)-NH2 group, wherein alkyl is as defined herein.

[0090] The term "aminocarbonylalkylamino" refers to the group -NH-alkyl-(C=O)-NH2 wherein alkyl is as defined herein.

[0091] The term "aminosulfonyl" refers to the group -SO2-NH2.

[0092] The term "antioxidant" refers to an agent that reduces or prevents oxidation of other substances.

[0093] The term "aryl" refers to a polyunsaturated aromatic hydrocarbon group having a single ring (i.e., phenyl) or multiple aromatic rings fused together (e.g., naphthyl), which generally contains 5 to 12 atoms; preferably 5 to 10; more preferably, the aryl group is a 5- or 6-membered aryl group. Non-limiting examples of aryl groups include phenyl, naphthyl.

[0094] The term "carbonyl" refers to the group -(C=O)-.

[0095] The term "carbonylamino" refers to the group -NH-(C=O)-.

[0096] The term "cycloalkyl" refers to a cyclic alkyl group, i.e., a monovalent, saturated or unsaturated hydrocarbon group having 1 or 2 ring structures. Cycloalkyl groups include monocyclic or bicyclic hydrocarbon groups. Cycloalkyl groups may contain 3 or more carbon atoms in the ring, and according to the present invention, typically contain 3 to 10, more preferably 3 to 8 carbon atoms; more preferably, the cycloalkyl group is a 5- or 6-membered cycloalkyl group. Examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl.

[0097] The term "cycloalkoxy" refers to the group -O-cycloalkyl, wherein cycloalkyl is as defined herein.

[0098] The term "dialkylamino" refers to the group -NR 1 R 2 , where R 1 and R 2 are each independently alkyl as defined herein.

[0099] The term "dialkylaminoalkyl" refers to the group -alkyl-NR 1 R 2 , where R 1 and R 2 are each independently alkyl as defined herein.

[0100] The term "dialkylaminoalkylaminocarbonyl" refers to the group -(C=O)-NH-alkyl-NR 1 R 2 , where R 1 and R 2 are all alkyl as defined herein.

[0101] The term "dialkylaminoalkylcarbonyl" refers to the group -(C=O)-alkyl-NR 1 R 2 , where R 1 and R 2 are all alkyl as defined herein.

[0102] The term "dihydroxyalkyl" refers to an alkyl group, as defined herein, substituted with two hydroxy (-OH) groups.

[0103] The term "halo" or "halogen" refers to fluorine, chlorine, bromine or iodine.

[0104] The term "heteroaryl" refers to an aryl group as defined herein, wherein at least one carbon atom is replaced by a heteroatom. In other words, it refers to an aromatic monocyclic ring of 5 to 12 carbon atoms or a ring system comprising 2 rings fused together, typically containing 5 to 6 atoms; wherein one or more carbon atoms are replaced by oxygen, nitrogen and / or sulfur atoms, wherein nitrogen and sulfur heteroatoms may be optionally oxidized, and nitrogen heteroatoms may be optionally quaternized. Non-limiting examples of such heteroaryls include: oxazolyl, thiazolyl, imidazolyl, furanyl and pyrrolyl. Preferably, heteroaryl is a 5- or 6-membered heteroaryl, more preferably, a 5- or 6-membered heteroaryl is a furanyl.

[0105] The term "heterocyclic radical" refers to a non-aromatic, fully saturated or partially unsaturated cyclic group (e.g., 3 to 7-membered monocyclic, 7 to 11-membered bicyclic, or containing a total of 3 to 10 ring atoms) having at least one heteroatom in at least one carbon-containing ring. Preferably, the heterocyclic radical is a 5- or 6-membered heterocyclic radical. Each ring of the heterocyclic radical containing heteroatoms may have 1, 2, 3 or 4 heteroatoms selected from nitrogen atoms, oxygen atoms and / or sulphur atoms, wherein nitrogen and sulphur heteroatoms may be optionally oxidized and nitrogen heteroatoms may be optionally quaternized. The heterocyclic radical may be attached to any heteroatom or carbon atom of the ring or ring system as valence permits. The ring of a polycyclic heterocycle may be fused, bridged and / or connected by one or more spiral atoms. Non-limiting exemplary heterocyclic groups include aziridinyl, oxiranyl, thiiranyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinylimidazolidinyl, isoxazolinyl, oxazolidinyl, isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl, succinimidyl, 3H-indolyl, indolinyl, isoindolyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolizinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2-pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thiocyclyl, butane, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioxaimidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, indolyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothienyl, tetrahydroquinolinyl, tetrahydroisoquinolin-1-yl, tetrahydroisoquinolin-2-yl, tetrahydroisoquinolin-3-yl, tetrahydroisoquinolin-4-yl, thiomorpholin-4-yl, 1-oxo-1-thiomorpholin-4-yl, 1-dioxo-1-thiomorpholin-4-yl, 1,3-dioxolanyl, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolazinyl, tetrahydro-1,1-dioxothiphenyl, N-formylpiperazinyl and morpholin-4-yl.

[0106] The term "heterocyclylalkylaminocarbonyl" refers to the group -(C=O)-NH-alkyl-heterocyclyl wherein alkyl and heterocyclyl are as defined herein.

[0107] The term "(heterocyclyl)(alkyl)aminoalkyl" refers to the group -alkyl-NR 1 R 2 , where R 1 is an alkyl group and R 2 is heterocyclyl, wherein alkyl and heterocyclyl are as defined herein.

[0108] The term "heterocyclylcarbonyl" refers to the group -(C=O)-heterocyclyl, wherein heterocyclyl is as defined herein.

[0109] The term "heterocyclylalkyl" refers to the group -alkyl-heterocyclyl wherein alkyl and heterocyclyl are as defined herein.

[0110] The term "heterocyclyl" refers to the group -O-heterocyclyl, wherein heterocyclyl is as defined herein.

[0111] The term "heterocyclylsulfonyl" refers to the group -SO2-heterocyclyl, wherein heterocyclyl is as defined herein.

[0112] The term "hydroxyalkyl" refers to the group -alkyl-OH wherein alkyl is as defined herein.

[0113] The term "hydroxyalkylaminoalkyl" refers to the group -alkyl-NH-alkyl-OH wherein alkyl is as defined herein.

[0114] The term "hydroxycarbonyl" refers to the group -C(=O)-OH, wherein carbonyl is as defined herein. In other words, "hydroxycarbonyl" corresponds to a carboxylic acid group.

[0115] The term "oxo" refers to a =0 substituent.

[0116] The term "sulfonylamino" refers to the group -NH-SO2.

[0117] The term "about" preceding a number encompasses plus or minus 10% or less (such as plus or minus 1%) of the value of the number. It is to be understood that the value to which the term "about" refers is itself also specifically and preferably disclosed.

[0118] The term "administration" or variations thereof (e.g., "administering") refers to providing an active agent or active ingredient (e.g., an A2AR inhibitor or an anticancer agent) alone or as part of a pharmaceutically acceptable composition to a patient whose condition, symptom, or disease is to be treated or prevented.

[0119] The term "autologous" refers to any material derived from the same individual into which the material is later reintroduced.

[0120] The term "allogeneic" refers to any material derived from a different individual of the same species as the individual into which the material is introduced. Two or more individuals are said to be allogeneic to one another when the genes at one or more loci are not identical.

[0121] In some aspects, allogeneic material from an individual of the same species may be sufficiently genetically distinct from the antigen to allow for antigenic interaction.

[0122] The term "IC 50” or “half maximal inhibitory concentration” means the concentration of an inhibitor required for 50% inhibition in vitro.

[0123] The term "inhibitor" refers to a natural or synthetic compound that has a biological effect of inhibiting or significantly reducing or down-regulating gene and / or protein expression or a biological effect of inhibiting or significantly reducing the biological activity of a protein. Therefore, an "A2AR inhibitor" refers to a compound that has a biological effect of inhibiting or significantly reducing or down-regulating the biological activity of an A2A receptor.

[0124] The term "human" refers to subjects of both sexes and at any stage of development (ie, newborn, infant, toddler, adolescent, adult).

[0125] The term "patient" refers to a warm-blooded animal or mammal, more preferably a human, who is awaiting or receiving medical care, or is / will be the subject of a medical procedure.

[0126] The expression "pharmaceutically acceptable" means that the ingredients of the pharmaceutical composition are compatible with each other and not deleterious to the subject to which they are administered.

[0127] The expression "pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant" refers to a substance that does not produce adverse, allergic or other untoward reactions when administered to animals, preferably humans. It includes any and all inactive substances, such as, for example, solvents, co-solvents, antioxidants, surfactants, stabilizers, emulsifiers, buffers, pH adjusters, preserving agents / preservating agents, antibacterial and antifungal agents, isotonic agents, granulating agents or binders, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersants, suspending agents, coating agents, bulking agents, release agents, absorption delaying agents, sweeteners, flavoring agents, etc. For human administration, the formulation should meet the sterility, pyrogenicity, general safety and purity standards required by regulatory authorities (such as, for example, FDA or EMA).

[0128] As used herein, the term "prodrug" refers to any compound that will be modified to form a drug species, wherein the modification can be performed in vivo or in vitro and can be performed before or after the prodrug reaches the area of ​​the body when administration of the drug is indicated.

[0129] As used herein, the terms "prevent," "preventing," and "prevention" refer to a method of delaying or preventing the onset of a condition or disease and / or its attendant symptoms, preventing a patient from developing a condition or disease, or reducing a patient's risk of developing a condition or disease.

[0130] As used herein, the term "prodrug" refers to a pharmacologically acceptable derivative of a compound of formula (I), such as an ester or amide, whose in vivo biotransformation product generates a biologically active drug. Prodrugs are generally characterized by increased bioavailability and are easily metabolized into biologically active compounds in vivo.

[0131] The term "therapeutically effective amount" or "therapeutically effective dose" refers to an amount or dose of an active ingredient that is intended to achieve the following goals without causing significant negative or adverse side effects to the subject: (1) delaying or preventing the onset of cancer in the subject; (2) reducing the severity or incidence of cancer; (3) slowing or stopping the progression, aggravation, or worsening of one or more symptoms of cancer affecting the subject; (4) ameliorating the symptoms of cancer affecting the subject; or (5) curing the cancer affecting the subject. A therapeutically effective amount can be administered prior to the onset of cancer for a preventive or prophylactic effect. Alternatively or additionally, a therapeutically effective amount can be administered after the onset of cancer for a therapeutic effect.

[0132] The term "treating" or "treatment" refers to therapeutic treatment; wherein the purpose is to prevent or slow down the target pathological condition or disease. A subject or mammal is successfully "treated" for a disease or disorder or condition if, after receiving treatment of the invention, the subject or mammal shows an observable and / or measurable decrease in the presence or absence of one or more of the following: a reduction in the number of cancer cells; and / or a relief to some extent of one or more symptoms associated with a particular disease or condition; a reduction in morbidity and mortality and an improvement in quality of life issues. The above parameters for assessing successful treatment and improvement of the disease can be readily measured by routine procedures familiar to physicians.

[0133] The term "subject" refers to a mammal, preferably a human. In one embodiment, the subject is diagnosed with cancer. In one embodiment, the subject is a patient, preferably a human patient, who is waiting to receive or is receiving medical care, or has been / is / will be a subject of a medical procedure, or is being monitored for the development or progression of a disease (such as cancer). In one embodiment, the subject is a human patient receiving treatment and / or monitoring the development or progression of cancer. In one embodiment, the subject is a male. In another embodiment, the subject is a female. In one embodiment, the subject is an adult. In another embodiment, the subject is a child.

[0134] The term "tumor-specific antigen" or "tumor-associated antigen" refers to an antigen that is specifically and / or abundantly expressed by cancer cells or tumor cells. T cells expressing T cell receptors that recognize and bind to the antigen may be referred to as T cells that recognize tumor-specific or tumor-associated antigens, T cells that are specific for tumor-specific or tumor-associated antigens, T cells that are specific for tumor-specific or tumor-associated antigens, or T cells that are directed against tumor-specific or tumor-associated antigens.

[0135] The term "vaccine" refers to a preparation (i.e., a vaccine) comprising a substance or a group of substances, which is intended to induce and / or enhance a targeted immune response to an infectious agent (such as a virus, bacteria, fungus, or parasite) or a cancer cell in a subject. Preventive vaccination is used to prevent a subject from having a specific disease or only having a mild disease. Therapeutic vaccination is intended to treat a specific disease in a subject. For example, a therapeutic anti-cancer vaccine may comprise one or more tumor-associated antigens, which are intended to induce and / or enhance a cell-mediated immune response, particularly a T cell immune response, against cancer cells expressing the tumor-associated antigen. DETAILED DESCRIPTION

[0136] A2AR inhibitors

[0137] The present invention relates to a combination of a pharmaceutical composition comprising at least one A2A adenosine receptor (A2AR) inhibitor and an anticancer agent. The A2AR inhibitor is a thiocarbamate derivative, in particular those thiocarbamate derivatives disclosed in PCT / EP2018 / 058301. More preferably, the A2AR inhibitor is a thiocarbamate derivative of formula (I) as described below.

[0138] In one embodiment, the thiocarbamate derivative A2AR inhibitor has formula (I):

[0139]

[0140] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0141] R 1 represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluorine or chlorine); preferably, R 1 represents a 5-membered heteroaryl group; more preferably, R 1 represents a furanyl group;

[0142] R 2 represents a 6-membered aryl group or a 6-membered heteroaryl group,

[0143] wherein the heteroaryl or aryl is optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonylimino, carbonylamino, sulfonylamino and alkylsulfonealkyl;

[0144] The substituents are optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl;

[0145] or heteroaryl or aryl is optionally substituted with two substituents which, together with the atoms to which they are attached, form a 5- or 6-membered aromatic ring, a 5- or 6-membered heteroaromatic ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, Alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclocarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0146] In one embodiment, preferred compounds of formula (I) have formula (la):

[0147]

[0148] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0149] R 1 represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluorine or chlorine); preferably, R 1 represents a 5-membered heteroaryl group; more preferably, R 1 represents a furanyl group;

[0150] X 1 and X 2 Each independently represents C or N;

[0151] When X 1 When N, R 1’ does not exist; or when X 1 When C, R 1’ represents H, halogen, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonylimide, carbonylamino, sulfonylamino or alkylsulfonealkyl;

[0152] The substituents are optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl;

[0153] R 2’ represents H, halogen, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonylimide, carbonylamino, sulfonylamino or alkylsulfonealkyl;

[0154] The substituents are optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl;

[0155] or R 1’ and R 2’ together with the atoms to which they are attached, form a 5- or 6-membered aromatic ring, a 5- or 6-membered heteroaromatic ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclocarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl;

[0156] When X 2 When N, R 3’ does not exist; or when X 2 When C, R 3’ represents H or halogen, preferably H or F;

[0157] R 4’ represents H or halo, preferably H or F; and

[0158] R 5’ represents H or halogen, preferably H or F.

[0159] In a particular embodiment of the invention, R 1represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from C1-C6 alkyl (preferably methyl) and halogen (preferably fluorine or chlorine). In a preferred embodiment, R 1 represents a 5-membered heteroaryl group; more preferably, R 1 represents a furanyl group;

[0160] In a particular 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 mean C.

[0161] In a particular embodiment of the present invention, when X 1 When N, R 1’ Does not exist.

[0162] In another specific embodiment, when X 1 When C, R 1’ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimide, carbonylamino, sulfonylamino or alkylsulfonealkyl; the substituent is optionally substituted by one or more substituents 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, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0163] In a preferred embodiment, R 1’The substituents are optionally substituted with one or more substituents selected from the group consisting of halo, hydroxy, alkyl, heterocycloalkyl, 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.

[0164] In a particular embodiment of the invention, R 2’ represents H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimide, carbonylamino, sulfonylamino or alkylsulfonealkyl; the substituent is optionally substituted by one or more substituents 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, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0165] In a preferred embodiment, R 2’ The substituents are optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, heterocycloalkyl, dihydroxyalkyl, dialkylaminoalkyl, heteroaryl, alkylheteroaryl, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, heterocycloalkylaminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl.

[0166] In another specific embodiment of the present invention, R 1’ and R 2’together with the atoms to which they are attached, form a 5- or 6-membered aromatic ring, a 5- or 6-membered heteroaromatic ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, Aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclocarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0167] In a particular embodiment of the present invention, when X 2 When N, R 3’ In another specific embodiment of the present invention, when X 2 When C, R 3’ In a preferred embodiment, when X 2 When C, R 3’ Indicates H or F.

[0168] In a particular embodiment of the invention, R 4’ In a preferred embodiment, R 4’ Indicates H or F.

[0169] In a particular embodiment of the invention, R 5’ In a preferred embodiment, R 5’ Indicates H or F.

[0170] In one embodiment, preferred compounds of formula (Ia) are those of formula (Ia-1):

[0171]

[0172] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 1’ , R 2’ , R 3’ , R 4’ and R 5’ As defined in formula (Ia).

[0173] In one embodiment, preferred compounds of formula (Ia-1) are those of formula (Ia-1a):

[0174]

[0175] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0176] R 1 and R 3’ As defined in formula (Ia); and

[0177] R 1” represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclic alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclic)(alkyl)aminoalkyl, heterocyclic, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclic alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclic carbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0178] In a particular embodiment of the invention, R 1” represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclic alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclic)(alkyl)aminoalkyl, heterocyclic, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclic alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclic carbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0179] In a preferred embodiment, R 1”It represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of hydroxy, heterocyclic, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, hydroxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, heterocyclic carbonyl, alkyl sulfoxide, and alkyl sulfonealkyl.

[0180] In one embodiment, preferred compounds of formula (Ia-1) are those of formula (Ia-1b):

[0181]

[0182] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0183] R 1 and R 3’ As defined in formula (Ia);

[0184] R 1’ represents H or halo, preferably H or F; and

[0185] R 2” represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclic alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclic)(alkyl)aminoalkyl, heterocyclic, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclic alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclic carbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0186] In a particular embodiment of the invention, R 1’ In a preferred embodiment, R 1’ Indicates H or F.

[0187] In a particular embodiment of the invention, R 2”represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclic alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclic)(alkyl)aminoalkyl, heterocyclic, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclic alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclic carbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[0188] In a preferred embodiment, R 2” represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of hydroxy, cyano, heteroaryl, alkylheteroaryl, alkyne, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, and alkylsulfonealkyl.

[0189] In one embodiment, preferred compounds of formula (Ia-1) are those of formula (Ia-1c) or (Ia-1d):

[0190]

[0191] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[0192] R 1 and R 3’ As defined in formula (Ia);

[0193] R 1’ represents H or halogen, preferably H or F;

[0194] R 2’ represents H or halogen, preferably H or F;

[0195] R 1i and R 1iieach independently represents hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynylalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl; and

[0196] R 2i and R 2ii Each independently represents hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynylalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl.

[0197] In a particular embodiment of the invention, R 1’ In a preferred embodiment, R 1’ Indicates H or F.

[0198] In a particular embodiment of the invention, R 2’ In a preferred embodiment, R 2’ Indicates H or F.

[0199] In a particular embodiment of the 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, alkynylalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl.

[0200] 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.

[0201] In a particular embodiment of the invention, R 2i and R 2ii R is independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynylalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl. 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.

[0202] In one embodiment, preferred compounds of formula (Ia) are those of formula (Ia-2) or (Ia-3):

[0203]

[0204] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 2’ , R 3’ , R 4’ and R 5’ As defined in formula (Ia).

[0205] Particularly preferred compounds of formula (I) according to the invention are those listed in Table 1 below.

[0206] Table 1

[0207]

[0208]

[0209]

[0210]

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218]

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228] and pharmaceutically acceptable salts and solvates thereof.

[0229] In Table 1, the term "Cpd" means compound.

[0230] The compounds in Table 1 were used Ultra version 12.0 (PerkinElmer).

[0231] In one embodiment, the compound of formula (I) is selected from:

[0232] (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);

[0233] (+)-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

[0234] (-)-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).

[0235] In a particular embodiment, the compound of formula (I) is selected from:

[0236] (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

[0237] (+)-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).

[0238] In a preferred embodiment, the compound of formula (I) 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).

[0239] In one embodiment, the present invention also relates to the enantiomers, salts, solvates, polymorphs, multi-component complexes and liquid crystals of the compounds of formula (I) and its subformulae.

[0240] In one embodiment, the present invention also relates to compounds of formula (I) and its subformulae, their prodrugs and isomers (including optical, geometric and tautomers) and isotopically labeled polymorphs and crystal habits of compounds of formula (I) and its subformulae.

[0241] The compounds of formula (I) and its subformulae may contain asymmetric centers and therefore may exist in different stereoisomeric forms. Therefore, the present invention includes all possible stereoisomers and includes not only racemic compounds but also individual enantiomers and non-racemic mixtures thereof. When a compound as a single enantiomer is required, this type of compound may be synthesized by stereospecificity as known in the art or by splitting the final product or any suitable intermediate or by chiral chromatography. The splitting of the final product, intermediate or starting material may be carried out by any suitable method known in the art.

[0242] The compounds of the present invention may be in the form of pharmaceutically acceptable salts. Pharmaceutically acceptable salts of compounds of formula (I) and its subformulas include acid addition salts and basic salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples include acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camsylate, citrate, cyclamate, edisylate, ethanesulfonate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, hyaluronate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, methanesulfonate, methosulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, saccharate, stearate, succinate, tannate, tartrate, toluenesulfonate, trifluoroacetate, and xinofoate. Suitable base salts are formed from bases which form non-toxic salts. Examples include aluminum, arginine, benzathine penicillin, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, tromethamine, 2-(diethylamino)ethanol, ethanolamine, morpholine, 4-(2-hydroxyethyl)morpholine and zinc salts. Hemi-salts of acids and bases can also be formed, such as hemisulphates and hemicalcium salts. Preferred pharmaceutically acceptable salts include hydrochlorides / chlorides, hydrobromides / bromides, bisulfates / sulfates, nitrates, citrates, toluenesulfonates, ethanesulfonates and acetates. In particularly preferred embodiments, the compound of formula (I) is in the form of HCl salts or ethanesulfonates.

[0243] When the compounds of the present invention contain both acidic and basic groups, the compounds of the present invention may also form internal salts, and such compounds are within the scope of the present invention. When the compounds of the present invention contain heteroatoms (e.g., NH) that donate hydrogen, the present invention also encompasses salts and / or isomers formed by transferring the hydrogen atom to a basic group or atom within the molecule.

[0244] Pharmaceutically acceptable salts of compounds of formula (I) and its subformulae may be prepared by one or more of the following methods:

[0245] (i) by reacting a compound of formula (I) with a desired acid;

[0246] (ii) by reacting a compound of formula (I) with a desired base;

[0247] (iii) by removing an acid- or base-labile protecting group from a suitable precursor of a compound of formula (I), or by ring-opening a suitable cyclic precursor such as a lactone or lactam using the desired acid; or

[0248] (iv) converting one salt of a compound of formula (I) into another salt by reaction with an appropriate acid or with the aid of a suitable ion exchange column.

[0249] All of these reactions are usually carried out in solution. The salt may precipitate from solution and may be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionization in the salt may range from fully ionized to almost non-ionized.

[0250] The compounds of the present invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" is intended to include all acceptable salts, such as acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bisulfate, mandelate, bitartrate, methanesulfonate, borate, methyl bromide, bromide, methylnitrate, calcium edetate, methylsulfate, camphorsulfonate, mucate, carbonate, naphthylsulfonate, chloride, nitrate, clavulanate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edisylate, pamoate (spicate), propionate, dodecane The invention also includes but is not limited to hydroxyl sulfate, palmitate, ethanesulfonate, pantothenate, fumarate, phosphate / diphosphate, glucoheptonate, polygalacturonate, gluconate, salicylate, glutamate, stearate, glycolyl p-aminophenylarsonic acid salt, sulfate, hexylresorcinate, basic acetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate, theoclate, iodide, toluenesulfonate, isothiosulfate, triethyl iodide, lactate, panoate, valerate and the like, which can be used as a dosage form for improving solubility or hydrolysis characteristics or can be used for sustained release or prodrug preparations. Depending on the specific functionality of the compounds of the invention, pharmaceutically acceptable salts of the compounds of the invention include those formed with cations such as sodium, potassium, aluminum, calcium, lithium, magnesium, zinc, and with bases such as ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N,N'-dibenzylethylenediamine, chloroprocaine, diethanolamine, procaine, N-benzylphenethylamine, diethylamine, piperazine, tris(hydroxymethyl)aminomethane and tetramethylammonium hydroxide.

[0251] 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 an amino group is present, acid salts, i.e., hydrochlorides, hydrobromides, acetates, palmitates, ethanesulfonates, toluenesulfonates, etc., can be used as dosage forms.

[0252] In addition, although generally with respect to the salts of the compounds of the present invention, pharmaceutically acceptable salts are preferred, it should be noted that the present invention also includes non-pharmaceutically acceptable salts in the broadest sense, which can be used, for example, for the separation and / or purification of the compounds of the present invention. For example, salts formed with optically active acids or bases can be used to form diastereomeric salts, which can facilitate the separation of optically active isomers of the compounds of formula (I) above.

[0253] The compounds of the present invention may be in the form of pharmaceutically acceptable solvates. Pharmaceutically acceptable solvates of compounds of formula (I) and its subformulae 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.

[0254] The present invention also generally encompasses all pharmaceutically acceptable prodrugs and prodrugs of the compounds of formula (I) and subformulae thereof.

[0255] Likewise, where an alcohol group is present, pharmaceutically acceptable esters such as acetate, maleate, pivaloyloxymethyl and the like may be employed, as well as those esters known in the art to improve solubility or hydrolysis characteristics for use as sustained release or prodrug formulations.

[0256] Pharmaceutical composition

[0257] Therefore, the present invention relates to a pharmaceutical composition comprising an A2A inhibitor as a pharmaceutically active ingredient, preferably a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I) as described above; and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0258] In one embodiment, the pharmaceutical composition of the present invention comprises an A2A inhibitor, such as a thiocarbamate derivative of formula (I) as described above, and at least one lipid carrier. In one embodiment, the lipid carrier is selected from lauroyl polyoxyl-32 glyceride, D-α-tocopheryl-polyethylene glycol-1000 succinate, and mixtures thereof. In one embodiment, the lipid carrier is lauroyl polyoxyl-32 glyceride. In another embodiment, the lipid carrier is -α-tocopheryl-polyethylene glycol-1000 succinate. In another embodiment, the lipid carrier is a mixture of lauroyl polyoxyl-32 glyceride and D-α-tocopheryl-polyethylene glycol-1000 succinate.

[0259] In one embodiment, the present invention therefore provides a pharmaceutical composition comprising:

[0260] (a) a compound of formula (I);

[0261]

[0262] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 As defined above;

[0263] (b) a lipid carrier selected from lauroyl polyoxyl-32 glyceride, D-α-tocopheryl-polyethylene glycol-1000 succinate, and mixtures thereof; and

[0264] (c) optionally one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants.

[0265] In one embodiment, the present invention provides a pharmaceutical composition comprising:

[0266] (a) a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 As defined above;

[0267] (b) lauroyl polyoxyl-32 glyceryl; and

[0268] (c) optionally one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants.

[0269] In another embodiment, the present invention provides a pharmaceutical composition comprising:

[0270] (a) a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 As defined above;

[0271] (b) D-α-tocopheryl-polyethylene glycol-1000 succinate; and

[0272] (c) optionally one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants.

[0273] Active ingredients

[0274] The pharmaceutical composition of the present invention therefore comprises a compound of formula (I) or a pharmaceutically acceptable salt or solvate thereof as a pharmaceutically active ingredient, wherein R 1 and R 2 As defined above.

[0275] All embodiments detailed above regarding the A2AR inhibitors are applicable to the pharmaceutical compositions of the present invention.

[0276] Lipid carrier

[0277] The pharmaceutical composition of the present invention comprises a lipid carrier, preferably lauroyl polyoxyl-32 glyceride, D-α-tocopheryl-polyethylene glycol-1000 succinate or a mixture thereof.

[0278] In one embodiment, the pharmaceutical composition of the invention comprises lauroyl polyoxyl-32 glyceride. This excipient corresponds to the glycerol manufactured by Gattefossé (Saint-Priest-France). 44 / 14. This excipient is also known from the following references:

[0279] - Lauroyl polyoxyl-32 glyceride NF / USP (NF: National Formulary; USP: US Pharmacopeia);

[0280] - Lauroyl Macrogol-32 Glyceride EP (European Pharmacopeia);

[0281] - Hydrogenated Coconut PEG-32 Esters (INCI);

[0282] -CAS No. 57107-95-6.

[0283] 44 / 14 corresponds to the monoglyceride, diglyceride and triglyceride and lauric acid (C 12 ) is a well-defined multi-component material composed of PEG-32 monoesters and diesters. The melting point of 44 / 14 ranges from 42.5°C to 47.5°C (average 44°C) and has a hydrophile / lipophile balance (HLB) value of 14.

[0284] To enhance the wetting, dissolution, solubility and bioavailability of active ingredients, use 44 / 14.

[0285] In another embodiment, the pharmaceutical composition of the invention comprises D-α-tocopherol-polyethylene glycol-1000 succinate. This excipient corresponds to vitamin E TPGS and is also known according to the following references:

[0286] -D-α-Tocopheryl polyethylene glycol 1000 succinate;

[0287] - Tocophersolan;

[0288] - Tocofersolan;

[0289] -VEGS;

[0290] -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);

[0291] - Vitamin E PEG succinate;

[0292] -CAS No. 9002-96-4.

[0293] Vitamin E TPGS corresponds to a well-defined substance consisting of D-α-tocopherol (vitamin E) conjugated to polyethylene glycol 1000 via a succinic acid linker and has a melting point in the range of 37° C. to 41° C. and a hydrophilic / lipophilic balance (HLB) value of 13.

[0294] Vitamin E TPGS is used to enhance the wetting, dissolution, solubility and bioavailability of active ingredients.

[0295] Additionally or as an alternative to lauroyl polyoxyl-32 glyceride, the pharmaceutical composition may further comprise Vitamin E TPGS.

[0296] Other Ingredients

[0297] The pharmaceutical composition of the present invention may optionally contain one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants. Such suitable carriers, diluents, excipients and / or adjuvants for preparing administration forms are obvious to the skilled artisan; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0298] The pharmaceutical composition of the present invention may optionally contain such inactive substances commonly used in pharmaceutical preparations, such as, for example, solubilizers, antioxidants, surfactants, wetting agents, emulsifiers, buffers, pH regulators, preservatives (preserving agents / preservating agents), isotonicity agents, stabilizers, granulating agents or binders, precipitation inhibitors, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersants, suspending agents, leavening agents, release agents, sweeteners, flavoring agents, etc.

[0299] According to one embodiment, the pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable inactive ingredients selected from the group consisting of caprylic acid, polyethylene glycol, propylene glycol, ethanol, glycerol, dimethyl sulfoxide, dimethylacetamide, dimethyl isosorbide, cellulose derivatives (including hydroxypropyl methylcellulose, methylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate and hydroxypropyl methylcellulose acetate succinate), cremophor RH40 (polyoxyl 40 hydrogenated castor oil), cremophor EL (polyoxyl 35 hydrogenated castor oil), polysorbate 20 (polyoxyethylene sorbitan monolaurate), polysorbate 80 (polyoxyethylene sorbitan monooleate), poloxamer 188 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)), poloxamer 407 (poly(ethylene glycol)-block-poly(propylene glycol)-block-poly(ethylene glycol)), vitamin E TPGS (Vitamin E polyethylene glycol succinate), Solutol HS15 (polyoxyethylene 12-hydroxystearic acid), Labrasol (octylcanoyl polyoxy-8 glyceride), Labrafil M1944 (oleoyl polyoxy-6 glyceride), Polyvinyl pyrrolidone (also known as povidone, preferably polyvinyl pyrrolidone K17, K19, K29-K32, K90), Polyvinyl pyrrolidone polyvinyl acetate copolymer, Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer Polylactic acid-polyethylene glycol block copolymer, carboxymethyl cellulose (Na / Ca), polyethylene glycol methyl ether-block-poly (DL-lactide) copolymer, sodium lauryl sulfate, docusate sodium, propylene glycol monolaurate, propylene glycol dilaurate, propylene glycol monocaprylate, polyethylene glycol 660 12-monostearate, poly (butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1, sodium dodecyl sulfate.

[0300] In a preferred embodiment, the pharmaceutical composition of the present invention comprises one or more pharmaceutically acceptable cosolvents. Preferred cosolvents are selected from caprylic acid, polyethylene glycol (PEG), propylene glycol, ethanol, dimethyl sulfoxide, dimethylacetamide, dimethyl isosorbide 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 cosolvent, PEG is a low molecular weight, and PEG is preferably PEG 400. In an alternative embodiment, when the composition comprises PEG, it has a medium molecular weight, preferably PEG 3350.

[0301] 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.

[0302] In some embodiments, a surfactant is added, such as polyethylene glycol, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, docusate sodium, sodium lauryl sulfate, polysorbate (20, 80, etc.), poloxamer (188, 407, etc.), complex polyols, polyoxyethylene sorbitan monoether ( 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 (polyoxyethylene 12-hydroxystearic acid), labrasol (octylcanoyl polyoxyl-8 glyceride), labrafil M1944 (oleoyl polyoxyl-6 glyceride), polylactic acid polyethylene glycol block copolymer, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer

[0303] In some embodiments, a wetting agent is added, such as, for example, sodium lauryl sulfate, Vitamin E TPGS, docusate sodium, polysorbate 80, poloxamer 407. A preferred wetting agent is poloxamer 407.

[0304] In some embodiments, an emulsifier is added, such as, for example, 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. Preferred emulsifiers are, for example, poloxamer, propylene glycol monolaurate, propylene glycol dilaurate, and propylene glycol monocaprylate.

[0305] In some embodiments, buffers are used to help maintain pH within a range close to physiological conditions. Suitable buffers include organic and inorganic acids and salts thereof, such as citrate buffers (e.g., mixtures of monosodium citrate-disodium citrate, mixtures of citric acid-trisodium citrate, mixtures of citric acid-monosodium citrate, etc.), succinate buffers (e.g., mixtures of succinic acid-monosodium succinate, mixtures of succinic acid-sodium hydroxide, mixtures of succinic acid-disodium succinate, etc.), tartrate buffers (e.g., mixtures of tartaric acid-sodium tartrate, mixtures of tartaric acid-potassium tartrate, mixtures of tartaric acid-sodium hydroxide, etc.), fumarate buffers (e.g., mixtures of fumaric acid-monosodium fumarate, fumaric acid-sodium tartrate, etc.). In some embodiments, the present invention provides a buffer solution containing a plurality of buffers, such as a mixture of gluconic acid-disodium fumarate, a mixture of monosodium fumarate-disodium fumarate, etc.), a gluconate buffer (e.g., a mixture of gluconic acid-sodium gluconate, a mixture of gluconic acid-sodium hydroxide, a mixture of gluconic acid-potassium gluconate, etc.), an oxalate buffer (e.g., a mixture of oxalic acid-sodium oxalate, a mixture of oxalic acid-sodium hydroxide, a mixture of oxalic acid-potassium oxalate, etc.), a lactate buffer (e.g., a mixture of lactic acid-sodium lactate, a mixture of lactic acid-sodium hydroxide, a mixture of lactic acid-potassium lactate, etc.), and an acetate buffer (e.g., a mixture of acetic acid-sodium acetate, a mixture of acetic acid-sodium hydroxide, etc.). In addition, a phosphate buffer, a histidine buffer, and a trimethylamine salt such as Tris can be used.

[0306] In some embodiments, a pH adjuster is added, such as, for example, sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, meglumine, sodium carbonate, citric acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid, and malic acid.

[0307] In some embodiments, preservatives are added to slow the growth of microorganisms. Suitable preservatives for the present disclosure include phenol, benzyl alcohol, metacresol, methylparaben, propylparaben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides (e.g., benzalkonium chloride, benzalkonium bromide, and benzalkonium iodide), hexamethonium chloride, and alkylparabens such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, and 3-pentanol.

[0308] In some embodiments, isotonic agents, sometimes referred to as "stabilizers," are added, which include polyols, for example trivalent or higher sugar alcohols, such as glycerol, erythritol, arabitol, xylitol, sorbitol, and mannitol. Stabilizers refer to a large class of excipients whose functions range from bulking agents to additives that dissolve therapeutic agents or help prevent denaturation or adhesion to the walls of containers or help inhibit precipitation, particle growth, or agglomeration of active ingredients. Typical stabilizers can be polyols (listed above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, myoinisitol, galactitol, glycerol, etc., including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur-containing reducing agents such as urea, glutathione, lipoic acid, sodium thioacetate, thioglycerol, α-monothioglycerol and sodium thiosulfate; low molecular weight polypeptides (e.g., having 10 or fewer residues); peptides); proteins such as human serum albumin, bovine serum albumin, gelatin or immunoglobulins; hydrophilic polymers such as polyvinyl pyrrolidone; poloxamer 407; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate; carboxymethyl cellulose (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; polyvinyl pyrrolidone; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate; carboxymethyl cellulose (Na / Ca); polyethylene glycol methyl ether-block-poly(DL-lactide) copolymer; poly(butyl methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1:2:1; polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0309] In some embodiments, granulating agents / binders are added, such as starches, gums (including natural, semi-synthetic and synthetic), microcrystalline cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polymers such as povidone, polyvinyl pyrrolidone polyvinyl acetate copolymers, etc. Preferred granulating agents are, for example, methyl cellulose, hydroxypropyl cellulose, povidone and polyvinyl pyrrolidone polyvinyl acetate copolymers.

[0310] In some embodiments, precipitation inhibitors are added, such as, for example, water-soluble derivatives of cellulose, including hydroxypropyl methylcellulose and methylcellulose; and water-soluble polymers, such as polyvinyl pyrrolidone, polyvinyl pyrrolidone polyvinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or poloxamer 407. Preferred precipitation inhibitors are, for example, hydroxypropyl methylcellulose and polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0311] In some embodiments, lubricants are added, such as, for example, magnesium stearate, glyceryl esters, behenyl polyoxyl-8 glyceride Nf (Compritol HD5 ATO), sodium stearyl fumarate, and the like.

[0312] In some embodiments, disintegrants are added, for example synthetic ones like sodium starch glycolate, crospovidone, croscarmellose sodium, kollidon CL, as well as natural sources such as locust bean gum and the like.

[0313] In some embodiments, glidants are added, such as, for example, talc, magnesium stearate, colloidal silicon dioxide, starch, and the like.

[0314] In some embodiments, diluents (or fillers) are added, such as, for example, dextrose, lactose, mannitol, microcrystalline cellulose, sorbitol, sucrose, dibasic calcium phosphate, dehydrated calcium sulfate, starch, and the like.

[0315] In some embodiments, adsorbents are added, such as, for example, silica, purified aluminum silicate, and the like.

[0316] In some embodiments, the pharmaceutical composition of the present invention is in the form of a tablet, and tableting excipients such as, for example, granulating agents, binders, lubricants, disintegrants, glidants, diluents, adsorbents, etc. are added.

[0317] In some embodiments, the pharmaceutical composition of the present invention is in the form of a capsule, wherein the capsule shell is made of gelatin or a product of non-animal origin such as cellulose and its derivatives such as hydroxypropyl methylcellulose. Other ingredients may be included in the capsule shell, such as polyethylene glycol to act as a plasticizer; pigments such as titanium dioxide or iron oxide to provide opacity and color difference; 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 into a capsule, wherein the capsule shell is composed of gelatin, and wherein additional components are optionally contained in the capsule shell, such as, for example, polyethylene glycol and sodium lauryl sulfate.

[0318] quantity

[0319] In one embodiment, the pharmaceutical composition of the present invention comprises a compound of formula (I) in an amount ranging from 1% to 20% by weight based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises a compound of formula (I) in an amount ranging from 5% to 15% w / w, preferably from 8% to 12% w / w, more preferably from 9% to 11% w / w, more preferably about 10% w / w.

[0320] In one embodiment, the pharmaceutical composition of the present invention comprises a lipid carrier in an amount ranging from 55 wt% to 90 wt% based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises a lipid carrier in an amount within the range of 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w.

[0321] In one embodiment, the pharmaceutical composition of the present invention comprises lauroyl polyoxyl-32 glyceride in an amount ranging from 55 wt% to 90 wt% based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises lauroyl polyoxyl-32 glyceride in an amount within the range of 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w.

[0322] In one embodiment, the pharmaceutical composition of the present invention comprises D-α-tocopherol-polyethylene glycol-1000 succinate measured in the range of 55 wt % to 90 wt % based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises D-α-tocopherol-polyethylene glycol-1000 succinate in an amount within the range of 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w.

[0323] In one embodiment, the pharmaceutical composition of the present invention may comprise PEG 400 in an amount ranging from 0% to 30% by weight, based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises PEG 400 in an amount ranging from 5% to 30% w / w, preferably from 10% to 25% w / w, more preferably from 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w.

[0324] In one embodiment, the pharmaceutical composition of the present invention may comprise PEG 3350 in an amount ranging from 0% to 30% by weight, based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises PEG 3350 in an amount ranging from 5% to 30% w / w, preferably from 10% to 25% w / w, more preferably from 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w.

[0325] In one embodiment, the pharmaceutical composition of the present invention may comprise caprylic acid in an amount ranging from 0% to 20% by weight, based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises caprylic acid in an amount ranging from 1% to 20% w / w, preferably from 3% to 15% w / w, more preferably from 5% to 10% w / w, more preferably about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, more preferably about 9% w / w.

[0326] In one embodiment, the pharmaceutical composition of the present invention may comprise an antioxidant, preferably BHT, measured in the range of 0% to 5% by weight, based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises BHT in an amount in the following range: 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w.

[0327] In one embodiment, the pharmaceutical composition of the present invention may comprise a wetting agent, preferably sodium lauryl sulfate (SLS), measured in the range of 0% to 10% by weight, based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises SLS in an amount in the following range: 0.5% to 5% w / w, preferably 0.5% to 2% w / w, more preferably 0.5% to 1.5% w / w, more preferably about 1.0% w / w.

[0328] In one embodiment, the pharmaceutical composition of the present invention may comprise a precipitation inhibitor, preferably hydroxypropyl methylcellulose, measured in the range of 0% to 10% by weight, based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises hydroxypropyl methylcellulose in an amount in the range of 0.5% to 5% w / w, preferably 0.5% to 2% w / w, more preferably 0.5% to 1.5% w / w, more preferably about 1% w / w.

[0329] In one embodiment, the pharmaceutical composition of the present invention may comprise an alternative precipitation inhibitor, preferably a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, in an amount ranging from 0% to 10% by weight, based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer in an amount ranging from 0.5% to 5% w / w, preferably from 0.5% to 2% w / w, more preferably from 0.5% to 1.5% w / w, more preferably about 1.0% w / w.

[0330] In one embodiment, the pharmaceutical composition of the present invention may comprise an alternative precipitation inhibitor in the range of 0% to 10% by weight, preferably poloxamer 407, based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises poloxamer 407 in an amount in the range of 0.5% to 5% w / w, preferably 0.5% to 2% w / w, more preferably 0.5% to 1.5% w / w, more preferably about 1.0% w / w.

[0331] In one embodiment, the pharmaceutical composition of the present invention may comprise an alternative precipitation inhibitor, preferably a polyvinyl pyrrolidone polyvinyl acetate copolymer, in an amount ranging from 0% to 10% by weight, based on the total weight (w / w) of the composition. Preferably, the pharmaceutical composition of the present invention comprises polyvinyl pyrrolidone polyvinyl acetate in an amount ranging from 0.5% to 5% w / w, preferably from 0.5% to 2% w / w, more preferably from 0.5% to 1.5% w / w, more preferably about 1.0% w / w.

[0332] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0333] a) 1% to 20% by weight of a compound of formula (I), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w; and

[0334] b) 55 to 99% w / w of lauroyl polyoxyl-32 glyceride, preferably 60 to 95% w / w, preferably 65 to 90% w / w, more preferably 70 to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w.

[0335] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0336] a) 1% to 20% by weight of a compound of formula (I), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0337] b) 55% to 99% w / w lauroyl polyoxyl-32 glyceride, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0338] c) 0% to 30% w / w PEG 400, preferably 5% to 30% w / w, preferably 10% to 25% w / w, more preferably 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w; and

[0339] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0340] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0341] a) 1% to 20% by weight of a compound of formula (I), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0342] b) 55% to 99% w / w lauroyl polyoxyl-32 glyceride, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0343] c) 0% to 30% w / w PEG 3350, preferably 5% to 30% w / w, preferably 10% to 25% w / w, more preferably 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w; and

[0344] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0345] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0346] a) 1% to 20% by weight of a compound of formula (I), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0347] b) 55% to 99% w / w lauroyl polyoxyl-32 glyceride, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0348] c) 0% to 20% w / w caprylic acid, preferably 1% to 20% w / w, preferably 3% to 15% w / w, more preferably 5% to 10% w / w, more preferably about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, more preferably about 9% w / w; and

[0349] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0350] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0351] a) 1% to 20% by weight of a compound of formula (I) (in salt form, preferably as an HCl salt or an ethanesulfonate salt), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0352] b) 55% to 99% w / w lauroyl polyoxyl-32 glyceride, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0353] c) 0% to 30% w / w PEG400, preferably 5% to 30% w / w, preferably 10% to 25% w / w, more preferably 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w; and

[0354] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0355] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0356] a) 1% to 20% by weight of a compound of formula (I) (in salt form, preferably as an HCl salt or an ethanesulfonate salt), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0357] b) 55% to 99% w / w lauroyl polyoxyl-32 glyceride, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0358] c) 0% to 30% w / w PEG3350, preferably 5% to 30% w / w, preferably 10% to 25% w / w, more preferably 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w; and

[0359] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0360] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0361] a) 1% to 20% by weight of a compound of formula (I), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w; and

[0362] b) 55% to 99% w / w Vitamin E TPGS, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w.

[0363] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0364] a) 1% to 20% by weight of a compound of formula (I), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0365] b) 55% to 99% w / w Vitamin E TPGS, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0366] c) 0% to 30% w / w PEG 400, preferably 5% to 30% w / w, preferably 10% to 25% w / w, more preferably 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w; and

[0367] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0368] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0369] a) 1% to 20% by weight of a compound of formula (I), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0370] b) 55% to 99% w / w Vitamin E TPGS, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0371] c) 0% to 30% w / w PEG 3350, preferably 5% to 30% w / w, preferably 10% to 25% w / w, more preferably 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w; and

[0372] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0373] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0374] a) 1% to 20% by weight of a compound of formula (I), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0375] b) 55% to 99% w / w Vitamin E TPGS, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0376] c) 0% to 20% w / w caprylic acid, preferably 1% to 20% w / w, preferably 3% to 15% w / w, more preferably 5% to 10% w / w, more preferably about 5% w / w, about 6% w / w, about 7% w / w, about 8% w / w, about 9% w / w, more preferably about 9% w / w; and

[0377] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0378] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0379] a) 1% to 20% by weight of a compound of formula (I) (in salt form, preferably as an HCl salt or an ethanesulfonate salt), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0380] b) 55% to 99% w / w Vitamin E TPGS, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0381] c) 0% to 30% w / w PEG400, preferably 5% to 30% w / w, preferably 10% to 25% w / w, more preferably 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w; and

[0382] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0383] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0384] a) 1% to 20% by weight of a compound of formula (I) (in salt form, preferably as an HCl salt or an ethanesulfonate salt), based on the total weight (w / w) of the composition; preferably 5% to 15% w / w, more preferably 8% to 12% w / w, more preferably 9% to 11% w / w, more preferably about 10% w / w;

[0385] b) 55% to 99% w / w Vitamin E TPGS, preferably 60% to 95% w / w, preferably 65% ​​to 90% w / w, more preferably 70% to 90% w / w, more preferably about 70% w / w, about 71% w / w, about 72% w / w, about 73% w / w, about 74% w / w, about 75% w / w, about 76% w / w, about 77% w / w, about 78% w / w, about 79% w / w, about 80% w / w, about 81% w / w, about 82% w / w, about 83% w / w, about 84% w / w, about 85% w / w, about 86% w / w, about 87% w / w, about 88% w / w, about 89% w / w, about 90% w / w;

[0386] c) 0% to 30% w / w PEG3350, preferably 5% to 30% w / w, preferably 10% to 25% w / w, more preferably 15% to 20% w / w, more preferably about 15% w / w, about 16% w / w, about 17% w / w, about 18% w / w, about 19% w / w, about 20% w / w, more preferably about 18% w / w; and

[0387] d) 0% to 5% w / w BHT, preferably 0.001% to 5% w / w, preferably 0.005% to 1% w / w, more preferably 0.01% to 0.5% w / w, more preferably about 0.01% w / w, about 0.05% w / w, about 0.10% w / w, about 0.15% w / w, about 0.20% w / w, about 0.25% w / w, about 0.30% w / w, about 0.40% w / w, about 0.50% w / w, more preferably about 0.10% w / w, based on the total weight (w / w) of the composition.

[0388] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0389] a) 5% to 15% w / w of a compound of formula (I);

[0390] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0391] c) 10% to 25% w / w PEG400; and

[0392] d) Optionally 0.01% to 0.5% w / w BHT.

[0393] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0394] a) 5% to 15% w / w of a compound of formula (I);

[0395] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0396] c) 10% to 25% w / w PEG 400;

[0397] d) optionally 0.01% to 0.5% w / w BHT;

[0398] e) optionally 0.5% to 10% w / w SLS; and

[0399] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0400] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0401] a) 5% to 15% w / w of a compound of formula (I);

[0402] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0403] c) 10% to 25% w / w PEG 400;

[0404] d) optionally 0.01% to 0.5% w / w BHT; and

[0405] e) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0406] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0407] a) 5% to 15% w / w of a compound of formula (I);

[0408] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0409] c) 10% to 25% w / w PEG 400;

[0410] d) optionally 0.01% to 0.5% w / w BHT; and

[0411] e) Optionally 0.5% to 10% w / w Poloxamer 407.

[0412] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0413] a) 5% to 15% w / w of a compound of formula (I);

[0414] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0415] c) 10% to 25% w / w PEG 400;

[0416] d) optionally 0.01% to 0.5% w / w BHT; and

[0417] e) Optionally 0.5% to 10% w / w of a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0418] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0419] a) 5% to 15% w / w of a compound of formula (I);

[0420] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0421] c) 10% to 25% w / w PEG 400;

[0422] d) optionally 0.01% to 0.5% w / w BHT; and

[0423] e) Optionally 0.5% to 10% w / w of polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0424] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0425] a) 5% to 15% w / w of a compound of formula (I);

[0426] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0427] c) 10% to 25% w / w PEG3350; and

[0428] d) Optionally 0.01% to 0.5% w / w BHT.

[0429] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0430] a) 5% to 15% w / w of a compound of formula (I);

[0431] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0432] c) 10% to 25% w / w PEG3350;

[0433] d) optionally 0.01% to 0.5% w / w BHT;

[0434] e) optionally 0.5% to 10% w / w SLS; and

[0435] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0436] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0437] a) 5% to 15% w / w of a compound of formula (I);

[0438] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0439] c) 10% to 25% w / w PEG3350;

[0440] d) optionally 0.01% to 0.5% w / w BHT; and

[0441] e) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0442] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0443] a) 5% to 15% w / w of a compound of formula (I);

[0444] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0445] c) 10% to 25% w / w PEG3350;

[0446] d) optionally 0.01% to 0.5% w / w BHT; and

[0447] e) optionally 0.5% to 10% w / w of Poloxamer 407 /

[0448] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0449] a) 5% to 15% w / w of a compound of formula (I);

[0450] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0451] c) 10% to 25% w / w PEG3350;

[0452] d) optionally 0.01% to 0.5% w / w BHT; and

[0453] e) Optionally 0.5% to 10% w / w of a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0454] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0455] a) 5% to 15% w / w of a compound of formula (I);

[0456] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0457] c) 10% to 25% w / w PEG3350;

[0458] d) optionally 0.01% to 0.5% w / w BHT; and

[0459] e) Optionally 0.5% to 10% w / w of polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0460] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0461] a) 5% to 15% w / w of a compound of formula (I);

[0462] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0463] c) 5% to 10% w / w caprylic acid; and

[0464] d) Optionally 0.01% to 0.5% w / w BHT.

[0465] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0466] a) 5% to 15% w / w of a compound of formula (I);

[0467] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0468] c) 5% to 10% w / w caprylic acid;

[0469] d) optionally 0.01% to 0.5% w / w BHT;

[0470] e) optionally 0.5% to 10% w / w SLS; and

[0471] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0472] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0473] a) 5% to 15% w / w of a compound of formula (I);

[0474] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0475] c) 5% to 10% w / w caprylic acid;

[0476] d) optionally 0.01% to 0.5% w / w BHT; and

[0477] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0478] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0479] a) 5% to 15% w / w of a compound of formula (I);

[0480] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0481] c) 5% to 10% w / w caprylic acid;

[0482] d) optionally 0.01% to 0.5% w / w BHT; and

[0483] e) Optionally 0.5% to 10% w / w Poloxamer 407.

[0484] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0485] a) 5% to 15% w / w of a compound of formula (I);

[0486] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0487] c) 5% to 10% w / w caprylic acid;

[0488] d) optionally 0.01% to 0.5% w / w BHT; and

[0489] e) Optionally 0.5% to 10% w / w of a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0490] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0491] a) 5% to 15% w / w of a compound of formula (I);

[0492] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0493] c) 5% to 10% w / w caprylic acid;

[0494] d) optionally 0.01% to 0.5% w / w BHT; and

[0495] e) Optionally 0.5 to 10% w / w of polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0496] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0497] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0498] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0499] c) 10% to 25% w / w PEG 400;

[0500] d) optionally 0.01% to 0.5% w / w BHT;

[0501] e) optionally 0.5% to 10% w / w SLS; and

[0502] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0503] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0504] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0505] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0506] c) 10% to 25% w / w PEG 400;

[0507] d) optionally 0.01% to 0.5% w / w BHT; and

[0508] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0509] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0510] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0511] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0512] c) 10% to 25% w / w PEG 400;

[0513] d) optionally 0.01% to 0.5% w / w BHT; and

[0514] e) Optionally 0.5% to 10% w / w Poloxamer 407.

[0515] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0516] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0517] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0518] c) 10% to 25% w / w PEG 400;

[0519] d) optionally 0.01% to 0.5% w / w BHT; and

[0520] e) Optionally 0.5% to 10% w / w of a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0521] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0522] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0523] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0524] c) 10% to 25% w / w PEG 400;

[0525] d) optionally 0.01% to 0.5% w / w BHT; and

[0526] e) Optionally 0.5% to 10% w / w of polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0527] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0528] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0529] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0530] c) 10% to 25% w / w PEG3350;

[0531] d) optionally 0.01% to 0.5% w / w BHT;

[0532] e) optionally 0.5% to 10% w / w SLS; and

[0533] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0534] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0535] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0536] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0537] c) 10% to 25% w / w PEG3350;

[0538] d) optionally 0.01% to 0.5% w / w BHT; and

[0539] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0540] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0541] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0542] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0543] c) 10% to 25% w / w PEG3350;

[0544] d) optionally 0.01% to 0.5% w / w BHT; and

[0545] e) Optionally 0.5% to 10% w / w Poloxamer 407.

[0546] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0547] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0548] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0549] c) 10% to 25% w / w PEG3350;

[0550] d) optionally 0.01% to 0.5% w / w BHT; and

[0551] e) Optionally 0.5% to 10% w / w of a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0552] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0553] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0554] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0555] c) 10% to 25% w / w PEG3350;

[0556] d) optionally 0.01% to 0.5% w / w BHT; and

[0557] e) Optionally 0.5% to 10% w / w of polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0558] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0559] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0560] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0561] c) 5% to 10% w / w caprylic acid;

[0562] d) optionally 0.01% to 0.5% w / w BHT;

[0563] e) optionally 0.5% to 10% w / w SLS; and

[0564] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0565] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0566] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0567] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0568] c) 5% to 10% w / w caprylic acid;

[0569] d) optionally 0.01% to 0.5% w / w BHT; and

[0570] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0571] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0572] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0573] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0574] c) 5% to 10% w / w caprylic acid;

[0575] d) optionally 0.01% to 0.5% w / w BHT; and

[0576] e) Optionally 0.5% to 10% w / w Poloxamer 407.

[0577] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0578] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0579] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0580] c) 5% to 10% w / w caprylic acid;

[0581] d) optionally 0.01% to 0.5% w / w BHT; and

[0582] e) Optionally 0.5% to 10% w / w of a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0583] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0584] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0585] b) 70% to 90% w / w lauroyl polyoxyl-32 glyceride;

[0586] c) 5% to 10% w / w caprylic acid;

[0587] d) optionally 0.01% to 0.5% w / w BHT; and

[0588] e) Optionally 0.5% to 10% w / w of polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0589] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0590] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0591] b) 70% to 90% w / w Vitamin E TPGS;

[0592] c) 10% to 25% w / w PEG 400;

[0593] d) optionally 0.01% to 0.5% w / w BHT;

[0594] e) optionally 0.5% to 10% w / w SLS; and

[0595] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0596] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0597] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0598] b) 70% to 90% w / w Vitamin E TPGS;

[0599] c) 10% to 25% w / w PEG 400;

[0600] d) optionally 0.01% to 0.5% w / w BHT; and

[0601] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0602] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0603] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0604] b) 70% to 90% w / w Vitamin E TPGS;

[0605] c) 10% to 25% w / w PEG 400;

[0606] d) optionally 0.01% to 0.5% w / w BHT; and

[0607] e) Optionally 0.5% to 10% w / w of Poloxamer 407

[0608] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0609] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0610] b) 70% to 90% w / w Vitamin E TPGS;

[0611] c) 10% to 25% w / w PEG 400;

[0612] d) optionally 0.01% to 0.5% w / w BHT; and

[0613] e) Optionally 0.5% to 10% w / w of a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0614] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0615] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0616] b) 70% to 90% w / w Vitamin E TPGS;

[0617] c) 10% to 25% w / w PEG 400;

[0618] d) optionally 0.01% to 0.5% w / w BHT; and

[0619] e) Optionally 0.5% to 10% w / w of polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0620] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0621] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0622] b) 70% to 90% w / w Vitamin E TPGS;

[0623] c) 10% to 25% w / w PEG3350;

[0624] d) optionally 0.01% to 0.5% w / w BHT;

[0625] e) optionally 0.5% to 10% w / w SLS; and

[0626] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0627] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0628] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0629] b) 70% to 90% w / w Vitamin E TPGS;

[0630] c) 10% to 25% w / w PEG3350;

[0631] d) optionally 0.01% to 0.5% w / w BHT; and

[0632] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0633] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0634] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0635] b) 70% to 90% w / w Vitamin E TPGS;

[0636] c) 10% to 25% w / w PEG3350;

[0637] d) optionally 0.01% to 0.5% w / w BHT; and

[0638] e) Optionally 0.5% to 10% w / w Poloxamer 407.

[0639] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0640] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0641] b) 70% to 90% w / w Vitamin E TPGS;

[0642] c) 10% to 25% w / w PEG3350;

[0643] d) optionally 0.01% to 0.5% w / w BHT; and

[0644] e) Optionally 0.5% to 10% w / w of a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0645] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0646] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0647] b) 70% to 90% w / w Vitamin E TPGS;

[0648] c) 10% to 25% w / w PEG3350;

[0649] d) optionally 0.01% to 0.5% w / w BHT; and

[0650] e) Optionally 0.5% to 10% w / w of polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0651] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0652] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0653] b) 70% to 90% w / w Vitamin E TPGS;

[0654] c) 5% to 10% w / w caprylic acid;

[0655] d) optionally 0.01% to 0.5% w / w BHT;

[0656] e) optionally 0.5% to 10% w / w SLS; and

[0657] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0658] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0659] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0660] b) 70% to 90% w / w Vitamin E TPGS;

[0661] c) 5% to 10% w / w caprylic acid;

[0662] d) optionally 0.01% to 0.5% w / w BHT; and

[0663] f) Optionally 0.5% to 10% w / w hydroxypropyl methylcellulose.

[0664] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0665] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0666] b) 70% to 90% w / w Vitamin E TPGS;

[0667] c) 5% to 10% w / w caprylic acid;

[0668] d) optionally 0.01% to 0.5% w / w BHT; and

[0669] e) Optionally 0.5% to 10% w / w Poloxamer 407.

[0670] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0671] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0672] b) 70% to 90% w / w Vitamin E TPGS;

[0673] c) 5% to 10% w / w caprylic acid;

[0674] d) optionally 0.01% to 0.5% w / w BHT; and

[0675] e) Optionally 0.5% to 10% w / w of a polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer.

[0676] In one embodiment, the pharmaceutical composition of the present invention comprises:

[0677] a) 5% to 15% w / w of a compound of formula (I) in salt form, preferably as an HCl salt or an ethanesulfonate salt;

[0678] b) 70% to 90% w / w Vitamin E TPGS;

[0679] c) 5% to 10% w / w caprylic acid;

[0680] d) optionally 0.01% to 0.5% w / w BHT; and

[0681] e) Optionally 0.5% to 10% w / w of polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0682] Dosage form

[0683] In one embodiment, the pharmaceutical composition of the invention is in a form suitable for oral administration. Such suitable administration forms may be solid, semisolid or liquid. Such suitable administration forms will be known to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0684] Some preferred but non-limiting examples of such forms include capsules (including soft and hard gelatin capsules), tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions and syrups.

[0685] The pharmaceutical composition of the present invention is preferably in unit dosage form and can be suitably packaged, for example in a box, blister, vial, bottle, sachet, ampoule or in any other suitable single-dose or multi-dose holder or container (which can be appropriately labeled); optionally with one or more loose-leafs containing product information and / or instructions for use. Such a unit dosage form may contain, for example, about 5 mg to about 200 mg of the active pharmaceutical ingredient, preferably about 10 mg to about 100 mg.

[0686] The pharmaceutical compositions of the invention may also be formulated so as to provide quick, sustained or delayed release of one or more active compounds contained therein.

[0687] Manufacturing of pharmaceutical compositions

[0688] The pharmaceutical composition of the present invention can be produced by methods known to those skilled in the art.

[0689] In one embodiment, the pharmaceutical composition of the present invention is in solid or semi-solid form. Solid dispersions can be routinely prepared using, for example, melting (melting), melt granulation, solvent evaporation, spray drying, freeze drying (freeze drying), hot melt extrusion, electrostatic spinning methods, using fluidized bed coating systems or supercritical fluid technology to coat sugar beads.

[0690] In one embodiment, the pharmaceutical composition of the present invention is in the form of a capsule, preferably a hard gelatin capsule. In this case, the capsule can be manufactured from a common blend using conventional mixing and capsule filling processes according to Good Manufacturing Practice.

[0691] In one embodiment, the capsule manufacturing process comprises the following steps:

[0692] i) melting lauroyl polyoxyl-32 glyceride at a temperature not lower than 50° C. but not higher than 80° C.;

[0693] ii) optional other excipients such as, for example, caprylic acid, sodium lauryl sulfate, hydroxypropyl methylcellulose, PEG, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl pyrrolidone polyvinyl acetate copolymer, poloxamer 407 and / or BHT are then added to the lauroyl polyoxyl-32 glyceride and mixed together using a suitable mixer;

[0694] iii) then gradually adding the compound of formula (I) in free base or suitable salt form, preferably HCl salt or ethanesulfonate salt form, using a suitable mixer with continuous mixing to produce a visually uniform distribution of the drug substance with no observable lumps or agglomerates;

[0695] iv) mixing is then continued for at least 30 minutes to ensure uniform distribution of the drug substance as determined by visual inspection;

[0696] v) The blend is then maintained in a molten state with continuous mixing and filled into appropriately sized gelatin capsule shells to achieve the target capsule fill weight.

[0697] As mentioned above, the gelatin capsule shell may optionally contain additional components, such as, for example, polyethylene glycol and sodium lauryl sulfate.

[0698] Capsule filling is carried out using conventional capsule filling methods and equipment suitable for molten semisolid dosage forms.

[0699] In another embodiment, the capsule manufacturing process comprises the following steps:

[0700] i) melting the vitamin E TPGS at a temperature not lower than 50° C. but not higher than 80° C.;

[0701] ii) optional other excipients such as, for example, caprylic acid, sodium lauryl sulfate, hydroxypropyl methylcellulose, PEG, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl pyrrolidone polyvinyl acetate copolymer, poloxamer 407 and / or BHT are then added to the lauroyl polyoxyl-32 glyceride and mixed together using a suitable mixer;

[0702] iii) then gradually adding the compound of formula (I) in free base or suitable salt form, preferably HCl salt or ethanesulfonate salt form, using a suitable mixer with continuous mixing to produce a visually uniform distribution of the drug substance with no observable lumps or agglomerates;

[0703] iv) mixing is then continued for at least 30 minutes to ensure uniform distribution of the drug substance as determined by visual inspection;

[0704] v) The blend is then maintained in a molten state with continuous mixing and filled into appropriately sized gelatin capsule shells to achieve the target capsule fill weight.

[0705] dose

[0706] Depending on the condition to be prevented or treated and the form of administration, the pharmaceutical composition of the present invention can be administered in the form of a single daily dose, divided into one or more daily doses.

[0707] In one embodiment, the pharmaceutical compositions of the invention are administered at a dosage such that it corresponds to administration of about 5 mg to about 200 mg of the pharmaceutically active ingredient (free base equivalent), preferably about 10 mg to about 100 mg, to the subject per administration.

[0708] In one embodiment, the effective dosage of the pharmaceutically active ingredient may be in the range of about 0.08 to about 3.3 mg / kg, preferably in the range of about 0.15 to about 1.7 mg / kg.

[0709] use

[0710] Another object of the present invention is a medicament comprising the pharmaceutical composition according to the invention.

[0711] The present invention further relates to the use of the pharmaceutical composition of the present invention for inhibiting A2A receptors.

[0712] According to another feature of the invention, there is provided a method of modulating A2A activity in a patient in need of such treatment, preferably in a warm-blooded animal and even more preferably in a human, said method comprising administering to said patient an effective amount of a pharmaceutical composition of the invention.

[0713] According to another feature of the invention, there is provided the use of a pharmaceutical composition of the invention for the manufacture of a medicament for modulating A2A activity in a patient in need of such treatment, the method comprising administering to the patient an effective amount of the pharmaceutical composition of the invention.

[0714] In one embodiment, the present invention relates to the use of the pharmaceutical composition of the present invention for enhancing immune recognition and destruction of cancer cells.

[0715] The pharmaceutical composition of the present invention is therefore suitable for preventing and / or treating cancer, in particular for treating cancer.

[0716] The present invention further relates to a method of treating cancer comprising administering to a mammalian species in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention.

[0717] The present invention further provides use of the pharmaceutical composition of the present invention for manufacturing a medicament for treating and / or preventing cancer.

[0718] The present invention also provides a method for delaying the onset of cancer in a patient, comprising administering a pharmaceutically effective amount of the pharmaceutical composition of the present invention to a patient in need thereof.

[0719] Preferably, the patient is a warm-blooded animal, more preferably a human.

[0720] Various cancers are known in the art. Cancer can be metastatic or non-metastatic. Cancer can be familial or sporadic. In some embodiments, the cancer is selected from the group consisting of: leukemia and multiple myeloma. Additional cancers that can be treated using the methods of the present invention include, for example, benign and malignant solid tumors and benign and malignant non-solid tumors. In a specific embodiment, the cancer is selected from breast cancer, carcinoid tumors, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer and urothelial cancer. In a specific embodiment, the cancer is breast cancer. In a specific embodiment, the cancer is carcinoid tumors. 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 kidney cancer. In a specific embodiment, the cancer is stomach cancer. In a specific embodiment, the cancer is thyroid cancer. In a specific embodiment, the cancer is urothelial carcinoma.

[0721] Examples of solid tumors include, but are not limited to, bile duct cancer, brain cancer (including glioblastoma and medulloblastoma), breast cancer, carcinoid tumors, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including those derived from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, kidney cancer (including adenocarcinoma and Wilms tumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, leukemia, and osteosarcoma), sarcoma), basal cell carcinoma, and squamous cell carcinoma), testicular cancer including germinal tissue tumors (seminomas and nonseminomas such as teratomas and choriocarcinomas), stromal tumors, germ cell tumors, thyroid cancer (including adenocarcinoma and medullary carcinoma), and urothelial carcinoma.

[0722] Examples of solid tumors include, but are not limited to, bile duct cancer, brain cancer (including glioblastoma and medulloblastoma), breast cancer, cervical cancer, choriocarcinoma, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including those derived from epithelial cells, stromal cells, germ cells and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, kidney cancer (including adenocarcinoma and Wilms' tumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma and squamous cell carcinoma), testicular cancer including germ tissue tumors (seminoma and non-seminoma, such as teratoma and choriocarcinoma), stromal tumors, germ cell tumors, and thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma).

[0723] Examples of non-solid tumors include, but are not limited to, hematological tumors. As used herein, hematological tumors are a term of art that includes lymphoid disorders, bone marrow diseases, and AIDS-related leukemias.

[0724] Lymphatic disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphocytic leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphomas, and lymphocytic lymphomas). Chronic lymphocytic leukemias include, for example, T-cell chronic lymphocytic leukemia and B-cell chronic lymphocytic leukemia.

[0725] The present invention further relates to the use of the pharmaceutical composition according to the invention for the prevention and / or treatment of radiation-induced fibrosis, connective tissue diseases (such as, for example, Sjögren's syndrome, i.e., scleroderma), chronic bacterial infections (such as, for example, Helicobacter pylori), abnormal scarring (keloids) and polymicrobial sepsis.

[0726] The present invention further relates to a method for treating or preventing radiation-induced fibrosis, connective tissue diseases (such as, for example, Sjögren's syndrome, i.e., scleroderma), chronic bacterial infections (such as, for example, Helicobacter pylori), abnormal scarring (keloids) and polymicrobial sepsis, which comprises administering to a mammalian species in need thereof a therapeutically effective amount of a pharmaceutical composition of the present invention.

[0727] The present invention further provides the use of a pharmaceutical composition according to the invention for the manufacture of a medicament for the treatment and / or prevention of radiation-induced fibrosis, connective tissue diseases (such as, for example, Sjögren's syndrome, i.e., scleroderma), chronic bacterial infections (such as, for example, Helicobacter pylori), abnormal scarring (keloids) and polymicrobial sepsis.

[0728] The present invention also provides a method for delaying the onset of radiation-induced fibrosis, connective tissue diseases (such as, for example, Sjögren's syndrome, i.e., scleroderma), chronic bacterial infections (such as, for example, Helicobacter pylori), abnormal scarring (keloids), and polymicrobial sepsis in a patient, comprising administering to a patient in need thereof a pharmaceutically effective amount of a pharmaceutical composition of the present invention.

[0729] combination

[0730] The present invention also relates to a combination comprising:

[0731] (a) at least one A2A adenosine receptor (A2AR) inhibitor, and

[0732] (b) at least one anticancer agent.

[0733] In a preferred embodiment, the present invention provides a combination comprising:

[0734] (a) at least one A2AR inhibitor which is a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I)

[0735]

[0736] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 as defined above; and

[0737] (b) at least one anticancer agent.

[0738] As described in detail below, the anti-cancer agent may be selected from an immunotherapeutic agent, a chemotherapeutic agent, an anti-angiogenic agent, a multidrug resistance associated protein inhibitor, a radiotherapeutic agent, and any combination thereof.

[0739] In the context of the present invention, the term "combination" preferably means that the A2AR inhibitor and the anticancer agent appear in combination. Thus, the combination of the present invention may appear as a composition, including all components in one and the same mixture (e.g., a pharmaceutical composition), or may appear as a kit of parts, wherein different components form different parts of such a kit of parts. The administration of the A2AR inhibitor and the anticancer agent may be carried out simultaneously or staggered in time, at the same administration site or at different administration sites, at similar or different administration times (i.e., similar or different administration times of each component), in similar or different dosage forms.

[0740] The present invention is based on the surprising discovery that the combination of A2AR inhibitors and anticancer agents (such as immunotherapeutics, especially checkpoint inhibitors) shows extremely favorable tumor growth inhibition and / or reduction in the number of cancer cells, thereby improving survival, which is not expected by the prior art. Therefore, the combination therapy of A2AR inhibitors and anticancer agents can greatly reduce the harmful effects of the disease to be treated, such as the growth rate of tumors. These effects are shown in the examples below.

[0741] A2AR inhibitors

[0742] The combination of the present invention comprises an A2AR inhibitor as a first component. Preferably, the A2AR inhibitor is a thiocarbamate derivative, in particular a thiocarbamate derivative as disclosed in PCT / EP2018 / 058301. More preferably, the A2AR inhibitor is a thiocarbamate derivative of formula (I) as described above.

[0743] In a preferred embodiment, the combination according to the invention therefore comprises a compound of formula (I):

[0744]

[0745] or a pharmaceutically acceptable salt or solvate thereof as an A2AR inhibitor, wherein R 1 and R 2 As defined above.

[0746] All embodiments detailed above with respect to A2AR inhibitors apply to the combinations of the present invention.

[0747] Anticancer Agents

[0748] The combination of the present invention comprises at least one anticancer agent as a second component.

[0749] In one embodiment, the anti-cancer agent is selected from an immunotherapeutic agent, a chemotherapeutic agent, an anti-angiogenic agent, a multidrug resistance-associated protein inhibitor, a radiotherapeutic agent, and any combination thereof.

[0750] In one embodiment, the combination of the invention comprises a single anticancer agent. In another embodiment, the combination of the invention comprises multiple anticancer agents; preferably two, three or four anticancer agents as defined below. In the case of a combination of anticancer agents used in the combination of the invention, the anticancer agents may be agents of the same class or agents of different classes. For example, a combination of an immunotherapeutic agent and a chemotherapeutic agent may be used with an A2AR inhibitor.

[0751] Immunotherapeutic agents

[0752] In one embodiment, the combination of the invention comprises an immunotherapeutic agent as the anti-cancer agent.

[0753] In this context, the present invention relates to a combination comprising:

[0754] (a) at least one A2A adenosine receptor (A2AR) inhibitor, and

[0755] (b) at least one immunotherapeutic agent.

[0756] In a preferred embodiment, the present invention provides a combination comprising:

[0757] (a) at least one A2AR inhibitor which is a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I) or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 and R 2 as defined above; and

[0758] (b) at least one immunotherapeutic agent.

[0759] In the present invention, "immunotherapy" refers to a therapy aimed at inducing and / or enhancing an immune response against a specific target, such as against cancer cells. In this latter case, it is called cancer immunotherapy.

[0760] Immunotherapeutic agents are, for example, selected from checkpoint inhibitors, checkpoint agonists (also known as T cell agonists), IDO inhibitors, PI3K inhibitors, adenosine receptor inhibitors, adenosine-producing enzyme inhibitors, CD40 agonists, IL2 variants, immune cells (for adoptive transfer), therapeutic vaccines, and combinations thereof. In a specific embodiment, the immunotherapeutic agent is a checkpoint inhibitor.

[0761] In one embodiment, the immunotherapeutic agent to be combined with the A2AR inhibitor of formula (I) as described above comprises or consists of a checkpoint inhibitor, a checkpoint agonist, an IDO inhibitor, a PI3K inhibitor, an adenosine receptor inhibitor, an adenosine-producing enzyme inhibitor, a CD40 agonist, an IL2 variant, an immune cell (for adoptive transfer), a therapeutic vaccine, or any mixture thereof.

[0762] In the context of the present invention, the term "combination" preferably means that the A2AR inhibitor and the immunotherapeutic agent appear in combination. Therefore, the combination of the present invention may appear as a composition, including all components in one and the same mixture (e.g., a pharmaceutical composition), or may appear as a component kit, wherein different components form different parts of this component kit. The administration of the A2AR inhibitor and the immunotherapeutic agent may be performed simultaneously or staggered in time, at the same administration site or at different administration sites, at similar or different administration times (i.e., similar or different administration times of each component), in similar or different dosage forms. This combination can induce an active immune response, thereby preventing, for example, tumor growth or inducing tumor regression.

[0763] Checkpoint inhibitors

[0764] In one embodiment, the combination of the invention comprises at least one checkpoint inhibitor as immunotherapeutic agent.

[0765] Checkpoint inhibitors (CPIs), also known as immune checkpoint inhibitors (ICIs), block the interaction between inhibitory receptors expressed on T cells and their ligands. As a cancer treatment, the use of checkpoint inhibitors is intended to prevent ligands expressed by tumor cells from activating inhibitory receptors expressed on T cells. Thus, the use of checkpoint inhibitors is intended to prevent the inhibition of T cells present in the tumor, i.e., tumor-infiltrating T cells, and thus enhance the subject's immune response to tumor cells.

[0766] Thus, the combination of the present invention can restore immune function in the tumor environment by using an A2AR inhibitor as a first component and antagonize signaling of the checkpoint pathway by inhibiting or suppressing signal transduction using preferably a checkpoint inhibitor as a second component of the immunotherapeutic agent.

[0767] Examples of checkpoint inhibitors include, but are not limited to:

[0768] - inhibitors of the cell surface receptor PD-1 (programmed cell death protein 1), also known as CD279 (cluster of differentiation 279);

[0769] - inhibitors of the ligand PD-L1 (programmed death ligand 1), also known as CD274 (cluster of differentiation 274) or B7-H1 (B7 homolog 1);

[0770] - inhibitor of the cell surface receptor CTLA4 or CTLA-4 (cytotoxic T-lymphocyte-associated protein 4), also known as CD152 (cluster of differentiation 152);

[0771] - LAG-3 (lymphocyte activation gene 3), also known as an inhibitor of CD223 (cluster of differentiation 223);

[0772] - TIM-3 (T cell immunoglobulin and mucin domain-3), also known as inhibitor of HAVCR2 (hepatitis A virus cellular receptor 2) or CD366 (cluster of differentiation 366);

[0773] - inhibitor of TIGIT (T-cell immunoreceptor with Ig and ITIM domains), also known as VSIG9 (V-Set and immunoglobulin domain protein 9) or VSTM3 (V-Set and transmembrane domain protein 3);

[0774] - BTLA (B and T lymphocyte attenuator), also known as an inhibitor of CD272 (cluster of differentiation 272);

[0775] - an inhibitor of CEACAM-1 (carcinoembryonic antigen-related cell adhesion molecule 1), also known as CD66a (cluster of differentiation 66a); and

[0776] -Inhibitors of GITR (glucocorticoid-induced TNFR-related protein), also known as TNFRSF18 (tumor necrosis factor receptor superfamily member 18) or AITR (activation-inducible TNFR family receptor).

[0777] In one embodiment, the checkpoint inhibitor is selected from the group comprising or consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA4 inhibitor, a LAG-3 inhibitor, a TIM-3 inhibitor, a TIGIT inhibitor, a BTLA inhibitor, a CEACAM-1 inhibitor, a GITR inhibitor, and any mixture thereof.

[0778] In one embodiment, the checkpoint inhibitor is selected from the group comprising or consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, a TIGIT inhibitor, and any mixture thereof.

[0779] In one embodiment, the checkpoint inhibitor is selected from the group comprising or consisting of a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor, and any mixture thereof.

[0780] In one embodiment, the checkpoint inhibitor is a PD-1 inhibitor, also known as anti-PD-1. PD-1 inhibitors may include antibodies, particularly monoclonal antibodies, that target PD-1, as well as non-antibody inhibitors, such as small molecule inhibitors.

[0781] Examples of PD-1 inhibitors include, but are not limited to, pembrolizumab, nivolumab, cemiplimab, tislelizumab, spartalizumab, ABBV-181, JNJ-63723283, BI 754091, MAG012, TSR-042, AGEN2034. Pembrolizumab is also known as MK-3475, MK03475, lambrolizumab, or SCH-900475. The trade name of pembrolizumab is Nivolumab is also known as ONO-4538, BMS-936558, MDX1106, or GTPL7335. The trade name of nivolumab is Cemiplizumab is also known as REGN2810 or REGN-2810. Tislelizumab is also known as BGB-A317. Spartalizumab is also known as PDR001 or PDR-001.

[0782] In one embodiment, the checkpoint inhibitor is selected from the group comprising or consisting of pembrolizumab, nivolumab, cemiplizumab, tislelizumab, spartalizumab, ABBV-181, JNJ-63723283, BI754091, MAG012, TSR-042, AGEN2034, and any mixture thereof.

[0783] In one embodiment, the checkpoint inhibitor is an inhibitor of PD-L1, also referred to as anti-PD-L1. PD-L1 inhibitors may include antibodies, particularly monoclonal antibodies, that target PD-L1, as well as non-antibody inhibitors, such as small molecule inhibitors.

[0784] Examples of PD-L1 inhibitors include, but are not limited to, avelumab, atezolizumab, durvalumab, and LY3300054. Avelumab is also known as MSB0010718C, MSB-0010718C, MSB0010682, or MSB-0010682. The trade name of avelumab is Atezolizumab is also known as MPDL3280A (clone YW243.55.S70), MPDL-3280A, RG-7446, or RG7446. The trade name of Atezolizumab is Durvalumab is also known as MEDI4736 or MEDI-4736. The trade name for Durvalumab is

[0785] In one embodiment, the checkpoint inhibitor is selected from the group comprising or consisting of avelumab, atezolizumab, durvalumab, LY3300054, and any mixture thereof.

[0786] In one embodiment, the checkpoint inhibitor is an inhibitor of CTLA-4, also known as anti-CTLA-4.

[0787] CTLA-4 inhibitors may include antibodies, particularly monoclonal antibodies, that target CTLA-4, as well as non-antibody inhibitors, such as small molecule inhibitors.

[0788] Examples of CTLA-4 inhibitors include, but are not limited to, ipilimumab and tesimumab. Ipilimumab is also known as BMS-734016, MDX-010, or MDX-101. The trade name of ipilimumab is Tisitumumab is also known as ticilimumab, CP-675, or CP-675,206.

[0789] In one embodiment, the at least one checkpoint inhibitor is selected from the group comprising or consisting of ipilimumab, tesimumab, and any mixture thereof.

[0790] In one embodiment, the checkpoint inhibitor is an inhibitor of TIGIT, also known as anti-TIGIT.

[0791] In one embodiment of the various methods, pharmaceutical compositions, kits, or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof is BMS-986207 (Bristol-Myers Squibb, New York, NY).

[0792] In another embodiment of the various methods, pharmaceutical compositions, kits, or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof is OMP-313M32 (OncoMed Pharmaceuticals, Redwood city, CA).

[0793] In another embodiment of the various methods, pharmaceutical compositions, kits or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof is MK-7684 (Merck & Co., Kenilworth, NJ).

[0794] In yet another embodiment of the various methods, pharmaceutical compositions, kits, or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof is MTIG7192A (also known as RG6058, U.S. Publication No. 2017 / 0088613).

[0795] In yet another embodiment of the various methods, pharmaceutical compositions, kits, or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof is PTZ-201 (Potenza Therapeutics, Cambridge, MA; also known as ASP8374, Astellas Pharma, Tokyo, Japan).

[0796] In another embodiment of the various methods, pharmaceutical compositions, kits, or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof is COM902 (Compugen LTD, Holon, IL).

[0797] In another embodiment of the various methods, pharmaceutical compositions, kits, or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof is as described in WO2018 / 160704 (Seattle Genetics, Seattle, WA).

[0798] In another embodiment of the various methods, pharmaceutical compositions, kits or uses provided herein, the anti-human TIGIT monoclonal antibody or antigen-binding fragment thereof is as described in WO2019 / 023504 (Iteos Therapeutics). In certain preferred embodiments, the anti-human TIGIT antibody or antigen-binding fragment comprises a combination of HCDR1, HCDR2, HCDR3, LCDR1, LCDR2 and LCDR3, wherein:

[0799] HCDR1 comprises or consists of: SEQ ID NO: 1 (YTFTSYYMH),

[0800] HCDR2 comprises or consists of: SEQ ID NO: 2 (VIGPSGASTSYAQKFQG),

[0801] HCDR3 comprises or consists of: SEQ ID NO: 3 (ARDHSDYWSGIMEV),

[0802] LCDR1 comprises or consists of: SEQ ID NO:4 (RASQSVRSSYLA),

[0803] LCDR2 comprises or consists of: SEQ ID NO: 5 (GASSRAT), and

[0804] LCDR3 comprises or consists of SEQ ID NO: 6 (QQYFSPPWT).

[0805] Checkpoint agonists (T cell agonists)

[0806] In one embodiment, the combination of the invention comprises at least one checkpoint agonist (also called T cell agonist) as immunotherapeutic agent.

[0807] T cell agonists work by activating stimulatory receptors expressed on immune cells (such as T cells). As used herein, the term "stimulatory receptor" refers to a receptor that induces a stimulatory signal when activated and thus causes an enhanced immune response. As a cancer treatment, T cell agonist therapy is intended to activate stimulatory receptors expressed on immune cells present in tumors. Specifically, T cell agonist therapy is intended to enhance the activation of T cells (i.e., tumor-infiltrating T cells) present in tumors, and thus enhance the immune response of the subject to tumor cells.

[0808] Examples of T cell agonists include, but are not limited to:

[0809] - agonists of CD137 (cluster of differentiation 137), also known as 4-1BB or TNFRS9 (tumor necrosis factor receptor superfamily, member 9);

[0810] - Agonists of the OX40 receptor, also known as CD134 (Cluster of Differentiation 134) or TNFRSF4 (Tumor Necrosis Factor Receptor Superfamily, Member 4).

[0811] In one embodiment, the checkpoint agonist is selected from the group comprising or consisting of a CD137 agonist, an OX40 agonist, and any mixture thereof.

[0812] Examples of CD137 agonists include, but are not limited to, utomilumab and urelumab.

[0813] IDO inhibitors

[0814] In one embodiment, the combination of the invention comprises at least one inhibitor of indoleamine-2,3-dioxygenase (IDO) as immunotherapeutic agent.

[0815] Indoleamine 2,3-dioxygenase catalyzes the first and rate-limiting step in the catabolism of L-tryptophan (Trp). IDO participates in immune regulation by limiting T cell function and participating in immune tolerance mechanisms. IDO activity in tumor cells can weaken antitumor responses. Therefore, inhibition of IDO can restore tumor immune surveillance.

[0816] Examples of IDO inhibitors include β-carboline (also known as norharmane), rosmarinic acid, 1-methyl-L-tryptophan (also known as L-1-MT), epacadostat, navoximod or those disclosed in WO2015 / 173764, and more preferably those of formula II, II' or II".

[0817] In a preferred embodiment, the IDO inhibitor is selected from those disclosed in WO2015 / 173764, and more preferably those of formula II, II' or II".

[0818] PI3Kγ inhibitors

[0819] In one embodiment, the combination of the invention comprises at least one PI3K inhibitor as immunotherapeutic agent.

[0820] Phosphoinositide 3-kinase inhibitors (PI3K inhibitors) are a class of medical drugs that work by inhibiting one or more phosphoinositide 3-kinases, which are components of the PI3K / AKT / mTOR pathway, an important signaling pathway for many cellular functions such as growth control, metabolism, and translation initiation. Many types of cancer activate the PI3K pathway, thereby preventing cell death in tumor cells.

[0821] There are many different classes and isoforms of PI3K. Class 1 PI3K has a catalytic subunit called p110, which has 4 types (isoforms) - p110α, p110β, p110γ and p110δ.

[0822] In a preferred embodiment, the PI3K inhibitor is a PI3K-γ inhibitor.

[0823] Examples of PI3K inhibitors include Wortmannin, LY294002, Demethoxyviridon, Hibiscone C, Edaracipib, Copanlisib, Duvelisib, Taselisib, Buparlisib, Alpelisib, Umbralisib, Dactolisib, Voxtalisib, IPI-549, RP6530, IC87114, and TG100-115.

[0824] Examples of PI3K-γ inhibitors include Copanlisib, Duvelisib, IPI-549, RP6530, IC87114, and TG100-115.

[0825] Adenosine receptor inhibitors

[0826] In one embodiment, the combination of the invention comprises at least one additional adenosine receptor inhibitor as immunotherapeutic agent.

[0827] As mentioned in the introduction, adenosine receptors are a class of purinergic G protein-coupled receptors that use adenosine as an endogenous ligand. There are four known types of adenosine receptors in humans: A1, A2A, A2B, and A3.

[0828] The combination of the present invention comprises as a first component an A2A receptor inhibitor of formula (I) as defined above. The second component of the combination may be another inhibitor of adenosine receptors, in particular an inhibitor of A1, A2A, A2B or A3 receptors. Preferably, the second component of the combination of the present invention is an inhibitor of A2B receptors or an inhibitor of A3 receptors.

[0829] Examples of A2B receptor inhibitors include ATL-801, CVT-6883, MRS-1706, MRS-1754, OSIP-339,391, PSB-603, PSB-0788, and PSB-1115.

[0830] Examples of A3 receptor inhibitors include KF-26777, MRS-545, MRS-1191, MRS-1220, MRS-1334, MRS-1523, MRS-3777, MRE-3005-F20, MRE-3008-F20, PSB-11, OT-7999, VUF-5574, and SSR161421.

[0831] Adenosine-producing enzyme inhibitors

[0832] In one embodiment, the combination of the invention comprises at least one adenosine-producing enzyme inhibitor as immunotherapeutic agent.

[0833] Ecto-nucleotidases are a family of nucleotide metabolizing enzymes that metabolize nucleotides to nucleosides. Subfamilies of ecto-nucleotidases include: CD39 / NTPDases (ecto-nucleotide triphosphate diphosphohydrolases), nucleotide pyrophosphatase / phosphodiesterase (NPP)-type ectophosphodiesterases, alkaline phosphatases, and ecto-5'-nucleotidase / CD73.

[0834] Among other functions, ectonucleotidases generate extracellular adenosine, the first step involving the conversion of ATP / ADP to AMP performed by ENTPD1 (also known as CD39). The second step involves the conversion of AMP to adenosine. It is performed by NT5E (also known as CD73). Thus, ectonucleotidases are enzymes that produce adenosine.

[0835] As mentioned in the introduction, high levels of extracellular adenosine play an important role in the escape of anti-tumor immune responses. Therefore, the use of inhibitors of adenosine-producing enzymes would be beneficial in cancer therapy by being able to reduce extracellular adenosine levels.

[0836] Examples of adenosine-producing enzyme inhibitors include:

[0837] - CD39, also known as ENTPD1 or inhibitor of ectonucleoside triphosphate diphosphohydrolase (EC 3.6.1.5, adenosine triphosphatase diphosphatase),

[0838] - CD73, also known as inhibitor of 5'-nucleotidase (5'-NT) or ecto-5'-nucleotidase or NT5E,

[0839] - inhibitors of ectonucleotide pyrophosphatase / PDE (EC 3.6.1.9 and EC 3.1.4.1), and

[0840] - inhibitors of alkaline phosphatase (AP; EC 3.1.3.1),

[0841] -CD38, also known as inhibitor of cyclic ADP ribose hydrolase or ADP ribosyl cyclase / cyclic ADP-ribose (cADPR) hydrolase).

[0842] Examples of adenosine-producing enzyme inhibitors include IPH5201, A001485, SRF617, ARL67156, POM-1, IPH5301, A000830, A001190, A001421, SRF373 / NZV930, and Darutumumab. More specifically, examples of CD39 inhibitors include IPH5201, A001485, SRF617, ARL67156, and POM-1; examples of CD73 inhibitors include IPH5301, A000830, A001190, A001421, and SRF373 / NZV930; and examples of CD38 inhibitors include Darutumumab.

[0843] CD40 agonists

[0844] In one embodiment, the combination of the invention comprises at least one CD40 agonist as immunotherapeutic agent.

[0845] CD40 is a cell surface receptor member of the tumor necrosis factor (TNF) receptor superfamily. It mediates indirect tumor cell killing and direct tumor cell apoptosis by activating the immune system. Similar to the endogenous CD40 ligand (CD40L or CD154), CD40 agonists bind to CD40 on a variety of immune cell types. This triggers cell proliferation and activation of antigen presenting cells (APCs) and activates B cells, effector T cells, and memory T cells. This results in an enhanced immune response against tumor cells.

[0846] Examples of CD40 agonists include CD40 agonistic antibodies and recombinant CD40 agonists (i.e., proteins, not antibodies). Examples of CD40 agonistic antibodies include selicrelumab (formerly known as RO7009789 and CP-870,893), APX005M, JNJ-64457107 (formerly known as ADC-1013), SEA-CD40, ChiLob 7 / 4, CDX-1140H, dacetuzumab (SGN-40), and ABBV-428. Examples of recombinant CD40 agonists include MEDI5083 and HERA-CD40L.

[0847] IL2 variants

[0848] In one embodiment, the combination of the invention comprises at least one IL2 variant as immunotherapeutic agent.

[0849] Interleukin-2 (IL-2) is a powerful immune growth factor that plays an important role in maintaining T cell responses. The potential of IL-2 to expand T cells without loss of functionality has led to its early use in cancer immunotherapy.

[0850] Examples of IL2 variants include recombinant, PEGylated and / or mutated IL2 variants, such as, for example, aldesleukin, monomethoxy PEG IL2, NKTR-214, MDNA-109, RO6874281, and ALKS-4230.

[0851] Immune Cells - Adoptive Cell Transfer

[0852] According to one embodiment, the immunotherapeutic agent is an immune cell used in the adoptive transfer of cells, also known as adoptive cell therapy (both also known as ACT), in particular the adoptive transfer of T cells, also known as adoptive T cell therapy.

[0853] As used herein, adoptive transfer of cells or adoptive cell therapy is defined as the transfer, e.g., infusion, of immune cells to a subject. As a cancer treatment, adoptive transfer of immune cells to a subject is intended to enhance the subject's immune response to cancer cells.

[0854] In one embodiment, the immune cell is a T cell, in particular an effector T cell. Examples of effector T cells include CD4 + T cells and CD8 + T cells.

[0855] In one embodiment, the transferred T cells are cytotoxic cells. Examples of cytotoxic T cells include CD8 + T cells and natural killer (NK) cells, especially natural killer (NK) T cells.

[0856] In one embodiment, the transferred immune cells as described above are antigen-specific cells. In one embodiment, the transferred immune cells as described above are antigen-specific immune cells, wherein the antigen is specifically and / or abundantly expressed by cancer cells. In one embodiment, the transferred immune cells as described above are cancer-specific immune cells, in other words, the transferred immune cells as described above specifically recognize cancer cells by antigens specifically and / or abundantly expressed by the cancer cells. In one embodiment, the transferred immune cells as described above are cancer-specific effector T cells. In one embodiment, the transferred immune cells as described above are cancer-specific CD8 + Effector T cells, especially cancer-specific cytotoxic CD8 + T cells. In one embodiment, the transferred immune cells as described above are cancer-specific cytotoxic cells. In one embodiment, the transferred immune cells as described above are cancer-specific NK cells. In one embodiment, the transferred immune cells as described above are tumor-specific immune cells, in other words, the transferred immune cells as described above specifically recognize tumor cells by antigens specifically and / or abundantly expressed by the tumor cells. In one embodiment, the transferred immune cells as described above are tumor-specific effector T cells. In one embodiment, the transferred immune cells as described above are tumor-specific CD8 + Effector T cells, especially tumor-specific cytotoxic CD8 + T cells. In one embodiment, the transferred immune cells as described above are tumor-specific cytotoxic cells. In one embodiment, the transferred immune cells as described above are tumor-specific NK cells.

[0857] In one embodiment, the transferred immune cells as described above are autologous immune cells, in particular autologous T cells. In another embodiment, the transferred immune cells as described above are allogeneic (or allogeneic) immune cells, in particular allogeneic NK cells.

[0858] Methods for isolating T cells (particularly antigen-specific T cells, such as tumor-specific T cells) from a subject are well known in the art (see, e.g., Rosenberg and Restifo, 2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs and Rosenberg, 2014, Immunol Rev 257, 56-71). Methods for ex vivo expansion of T cells are well known in the art (see, e.g., Rosenberg and Restifo, 2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs and Rosenberg, 2014, Immunol Rev 257, 56-71). Protocols for infusing T cells in a subject, including pre-infusion conditioning regimens, are well known in the art (see, e.g., Rosenberg and Restifo, 2015, Science 348, 62-68; Prickett et al., 2016, Cancer Immunol Res 4, 669-678; or Hinrichs and Rosenberg, 2014, Immunol Rev 257, 56-71).

[0859] In one embodiment, in the respective contexts of CAR immune cell therapy and CAR T cell therapy, the immune cell is a CAR immune cell, in particular a CAR T cell.

[0860] As used herein, CAR immune cell therapy is adoptive cell therapy, wherein the cells transferred are immune cells as described above, such as T cells or NK cells, which are genetically engineered to express chimeric antigen receptors (CAR). As a cancer treatment, the adoptive transfer of CAR immune cells to subjects is intended to enhance the subject's immune response to cancer cells.

[0861] CAR is a synthetic receptor consisting of a targeting portion associated with one or more signaling domains in a single fusion molecule or several molecules. Typically, the binding portion of CAR consists of an antigen binding domain of a single-chain antibody (scFv), which contains a light fragment and a variable fragment of a monoclonal antibody connected by a flexible linker. Binding portions based on receptor or ligand domains have also been successfully used. The signaling domain of the first generation of CARs is usually derived from the cytoplasmic region of CD3ζ or the Fc receptor γ chain. The first generation of CARs has been shown to successfully redirect the cytotoxicity of T cells, however, they were unable to provide prolonged expansion and anti-tumor activity in vivo. Therefore, signaling domains from co-stimulatory molecules including CD28, OX-40 (CD134) and 4-1BB (CD137) are added alone (second generation) or in combination (third generation) to increase the survival rate of CAR-modified T cells and enhance their proliferation.

[0862] Therefore, in one embodiment, the T cells transferred as described above are CAR T cells. The expression of CAR enables T cells to be redirected to selected antigens (such as antigens expressed on the surface of cancer cells). In one embodiment, the transferred CAR T cells recognize tumor-specific antigens.

[0863] In another embodiment, the NK cells transferred as described above are CAR NK cells. CAR expression enables NK cells to redirect to selected antigens (such as antigens expressed on the surface of cancer cells). In one embodiment, the transferred CAR NK cells recognize tumor-specific antigens.

[0864] In one embodiment, the CAR immune cell as described above is an autologous CAR immune cell, particularly an autologous CAR T cell. In another embodiment, the CAR immune cell as described above is an allogeneic (or allogeneic) CAR immune cell, particularly an allogeneic CAR NK cell.

[0865] Therapeutic vaccines

[0866] According to one embodiment, the immunotherapeutic agent is a therapeutic vaccine (also sometimes referred to as a therapeutic vaccine).

[0867] As used herein, a therapeutic vaccine is defined as the administration of at least one tumor-specific antigen (e.g., a synthetic long peptide or SLP) or a nucleic acid encoding the tumor-specific antigen; the administration of a recombinant viral vector that selectively enters and / or replicates in tumor cells; the administration of tumor cells; and / or the administration of immune cells (e.g., dendritic cells) that are engineered to present tumor-specific antigens and trigger an immune response against these antigens.

[0868] As a cancer treatment, therapeutic vaccines are designed to enhance a subject's immune response against tumor cells.

[0869] Examples of therapeutic vaccines intended to enhance a subject's immune response to tumor cells include, but are not limited to, therapeutic vaccines based on viral vectors, such as adenovirus (e.g., oncolytic adenovirus), vaccinia virus (e.g., modified vaccinia Ankara (MVA)), alphavirus (e.g., Semliki Forrest Virus (SFV)), measles virus, herpes simplex virus (HSV), and coxsackievirus; synthetic long peptide (SLP) vaccines; and dendritic cell vaccines.

[0870] Chemotherapeutic agents

[0871] In one embodiment, the combination of the invention comprises at least one chemotherapeutic agent as anticancer agent.

[0872] The chemotherapeutic agent is, for example, selected from anticancer alkylating agents, anticancer antimetabolites, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, Parp inhibitors, anti-hormone sensitive cancer agents, and any combination thereof.

[0873] In one embodiment, the chemotherapeutic agent to be combined with the A2AR inhibitor of formula (I) as described above comprises or consists of an anticancer alkylating agent, an anticancer antimetabolite, an anticancer antibiotic, a plant-derived anticancer agent, an anticancer platinum coordination compound, a Parp inhibitor, an anti-hormone-sensitive cancer agent, and any combination thereof.

[0874] Anticancer alkylating agents

[0875] In one embodiment, the combination of the invention comprises at least one anticancer alkylating agent as chemotherapeutic agent.

[0876] The anticancer alkylating agent refers to an alkylating agent having anticancer activity, and the term "alkylating agent" herein generally refers to an agent that gives an alkyl group in an alkylation reaction in which a hydrogen atom of an organic compound is replaced by an alkyl group.

[0877] Examples of anticancer alkylating agents include nitrogen mustard N-oxide, cyclophosphamide, ifosfamide, melphalan, busulfan, dibromomannitol, carboquinone, thiotepa, rammustine, nimustine, temozolomide, and carmustine.

[0878] Anticancer antimetabolites

[0879] In one embodiment, the combination of the invention comprises at least one anticancer antimetabolite as chemotherapeutic agent.

[0880] Anticancer antimetabolites refer to antimetabolites having anticancer activity, and the term "antimetabolite" herein broadly includes substances that interfere with normal metabolism and substances that inhibit the electron transfer system to prevent the production of high-energy intermediates due to their structural or functional similarities to metabolites important to living organisms (such as vitamins, coenzymes, amino acids and sugars).

[0881] Examples of anticancer antimetabolites include methotrexate, 6-mercaptopurine riboside, mercaptopurine, 5-fluorouracil (also known as "5-FU"), tegafur, doxifluridine, canoflurane, cytarabine, cytarabine alkylphosphoesters, enocitabine, S-1, gemcitabine, fludarabine and pemetrexed disodium. Preferably, the anticancer antimetabolite is selected from 5-FU, gemcitabine and pemetrexed.

[0882] anticancer antibiotics

[0883] In one embodiment, the combination of the invention comprises at least one anticancer antibiotic as chemotherapeutic agent.

[0884] "Anticancer antibiotics" refer to antibiotics having anticancer activity, and "antibiotics" herein include substances produced by microorganisms or by partial or complete synthesis and their derivatives; and inhibit cell growth and other functions of microorganisms and other living organisms.

[0885] Examples of anticancer antibiotics include actinomycin D, doxorubicin, daunorubicin, neocarzinostatin, bleomycin, pelocycin, mitomycin C, aclarubicin, pirarubicin, epirubicin, zestradiol, idarubicin, rapamycin and valrabicin. Preferably, the anticancer antibiotic is doxorubicin.

[0886] Plant-derived anticancer agents

[0887] In one embodiment, the combination of the invention comprises at least one anticancer agent of plant origin as chemotherapeutic agent.

[0888] The "plant-derived anticancer agent" used in the specification includes compounds having anticancer activity derived from plants, or compounds prepared by chemically modifying the above compounds.

[0889] Examples of plant-derived anticancer agents include vincristine, vinblastine, vindesine, etoposide, sobuzoxane, docetaxel, paclitaxel, nab-paclitaxel, and vinorelbine. Preferably, the plant-derived anticancer agent is docetaxel.

[0890] Anticancer platinum coordination compounds

[0891] In one embodiment, the combination of the invention comprises at least one anticancer platinum coordination compound as chemotherapeutic agent.

[0892] An "anticancer platinum coordination compound" refers to a platinum coordination compound having anticancer activity, and the term "platinum coordination compound" herein refers to a platinum coordination compound that provides platinum in ionic form.

[0893] Preferred platinum compounds include cisplatin; cis-diaminedihydrate platinum (O)-ion; chloro(diethylenetriamine)-platinum (II) chloride; dichloro(ethylenediamine)-platinum (II); diamine(1,1-cyclobutanedicarboxylic acid) platinum (II) (carboplatin); spiroplatin; isopropylplatin; diamine(2-ethylmalonate) platinum (II); ethylenediaminemalonate platinum (H); hydrated (1,2-diaminodicyclohexane) sulfate platinum (II); ); hydrated (1,2-diaminodicyclohexane) malonate platinum (II); (1,2-diaminocyclohexane) malonate platinum (II); (4-carboxyphthalate) (1,2-diaminocyclohexane) platinum (II); (1,2-diaminocyclohexane)-(isocitrate) platinum (II); (1,2-diaminocyclohexane) oxalate platinum (II); ormaplatin; tetraplatin; carboplatin; nedaplatin and oxaliplatin. Preferably, the anticancer platinum coordination compound is selected from carboplatin and oxaliplatin.

[0894] Parp inhibitors

[0895] In one embodiment, the combination of the invention comprises at least one Parp inhibitor as chemotherapeutic agent.

[0896] "Parp inhibitors" refers to inhibitors of poly ADP ribose polymerase (PARP). This enzyme is important for repairing single-strand breaks in DNA. If such breaks are not repaired before the DNA is replicated, the replication will result in the formation of double-strand breaks. Therefore, PARP inhibitors can cause the formation of multiple double-strand breaks in tumors, leading to the death of tumor cells.

[0897] Examples of Parp inhibitors include olaparib, rucaparib, niraparib, veliparib, pamiparib, iniparib, and talazoparib.

[0898] Anti-hormone sensitive cancer agents

[0899] In one embodiment, the combination of the invention comprises at least one anti-hormone-sensitive cancer agent as chemotherapeutic agent.

[0900] "Anti-hormone-sensitive cancer agent" refers to an anti-cancer agent that is active against hormone-sensitive cancers. Examples of anti-hormone-sensitive cancer agents include anti-androgens, GnRH agonists, and GnRH antagonists.

[0901] "Antiandrogens" refers to a class of drugs that prevent androgens, such as testosterone and dihydrotestosterone (DHT), from mediating their biological effects in the body. Antiandrogens can be used, for example, to treat prostate cancer. Examples of antiandrogens include bicalutamide, flutamide, nilutamide, apalutamide, enzalutamide, and abiraterone.

[0902] "Gonadotropin-releasing hormone agonists" (GnRH agonists) refer to a class of drugs that affect gonadotropins and sex hormones. They can be used to lower the levels of sex hormones in the treatment of hormone-sensitive cancers (such as prostate cancer and breast cancer). Examples of GnRH agonists include goserelin, leuprolide, and triptorelin.

[0903] "Gonadotropin-releasing hormone antagonists" (GnRH antagonists) refer to a class of drugs that antagonize the action of gonadotropin-releasing hormone (GnRH). They can be used, for example, to treat prostate cancer. An example of a GnRH antagonist is degarelix.

[0904] Combinations of chemotherapeutic agents

[0905] Combinations of chemotherapeutic agents may be used as the second component of the combination of the invention.

[0906] For example, a combination known as folfox may be used. Folfox includes the combined use of fluorouracil (an antimetabolite), oxaliplatin (a platinum compound), and folinic acid (a chemoprotectant).

[0907] Alternatively, a combination consisting of carboplatin (a platinum compound) and paclitaxel (a plant-derived agent) may be used. Another example is a combination consisting of gemcitabine (an antimetabolite) and nab-paclitaxel (a plant-derived agent).

[0908] In one embodiment, the combination of chemotherapeutic agents is selected from:

[0909] (i) a combination consisting of folinic acid, fluorouracil and oxaliplatin (folfox);

[0910] (ii) a combination consisting of carboplatin and paclitaxel; and

[0911] (iii) Combination consisting of gemcitabine and nab-paclitaxel.

[0912] Anti-angiogenic agents

[0913] In one embodiment, the combination of the invention comprises at least one anti-angiogenic agent as anti-cancer agent.

[0914] Angiogenesis, the growth of new blood vessels, plays an important role in the development of tumors and the progression of malignancies. Inhibition of angiogenesis has been shown to inhibit tumor growth and metastasis. The most prominent target of anti-angiogenic agents is vascular endothelial growth factor (VEGF) and its receptors.

[0915] Several other factors have also received attention, including integrins, matrix metalloproteinases, and endogenous antiangiogenic factors.

[0916] Thus, anti-angiogenic agents include VEGF inhibitors, integrin inhibitors, and matrix metalloproteinase inhibitors.

[0917] Examples of anti-angiogenic agents include ramucirumab, IMC-18F1, bevacizumab, Ziv-aflibercept, sorafenib, sunitinib, axitinib, nintedanib, regorafenib, pazobanib, cabozantinib, vandetanib and thalidomide. In a specific embodiment, the anti-angiogenic agent is a VEGF inhibitor, such as ramucirumab.

[0918] Multidrug resistance-associated protein inhibitors

[0919] In one embodiment, the combination of the invention comprises at least one multidrug resistance-associated protein inhibitor as anticancer agent.

[0920] Multidrug resistance-associated proteins (MRP / ABCC) are a subfamily of ATP-binding cassette transporters that can actively pump a variety of organic anionic compounds across the plasma membrane against their concentration gradient. These proteins are involved in multidrug resistance by transporting a variety of drugs outside the cell, including anticancer drugs. Inhibition of multidrug resistance-associated proteins can therefore improve the efficacy of anticancer drugs.

[0921] Examples of multidrug resistance-associated protein inhibitors include inhibitors of MRP4 / ABCC4, inhibitors of MRP5 / ABCC5, and inhibitors of MRP8 / ABCC11.

[0922] Radiotherapeutic agents - radiation therapy

[0923] In one embodiment, the combination of the invention comprises at least one radiotherapeutic agent as anticancer agent.

[0924] "Radiation therapy" refers to the use of various types of radiation, such as X-rays, gamma rays, neutron rays, electron beams, proton beams, and radioactive sources, to treat cancer. It is used as part of cancer treatment to control or kill malignant cells. Radiation therapy may be curative for many types of cancer if it is targeted to one area of ​​the body. It may also be used as part of adjuvant therapy to prevent the recurrence of a tumor after surgical removal of a primary malignancy.

[0925] The three main parts of radiation therapy are: external beam radiation therapy (EBRT or XRT); brachytherapy or sealed source radiation therapy; and systemic radioisotope therapy (RIT) or unsealed source radiation therapy. The difference has to do with the location of the radiation source; external is outside the body, brachytherapy uses a sealed radiation source precisely placed in the treatment area, and systemic radioisotopes are given by infusion or oral ingestion. Particle therapy is a special case of external beam radiation therapy in which the particles are protons or heavy ions. Radiation can be delivered by linear accelerators.

[0926] Systemic radioisotope therapy (RIT) is a form of targeted therapy. The targeting effect may be due to the chemical properties of the isotope, such as radioiodine, which is specifically taken up by the thyroid gland a thousand times better than other body organs. Targeting can also be achieved by attaching the radioisotope to another molecule or antibody to direct it to the target tissue, thus forming a radiopharmaceutical.

[0927] To enhance the radiosensitivity of cancer, radiosensitizers can be administered during radiotherapy. Examples of radiosensitizers include: cisplatin, nimorazole, and cetuximab.

[0928] Thus, in one embodiment, the radiotherapeutic agent is selected from sealed radioactive sources, radioisotopes, radiopharmaceuticals, radiosensitizers, and the like useful in radiotherapy procedures.

[0929] In another embodiment, the present invention also provides the use of an A2AR inhibitor as described above in combination with radiation therapy, including radiation therapy by external beam radiation or X-ray radiation; brachytherapy; and whole body radioisotope therapy.

[0930] combination

[0931] In one embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above and at least one anticancer agent as defined above.

[0932] In a particular embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above and at least one immunotherapeutic agent as defined above.

[0933] In a particular embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above and at least one checkpoint inhibitor as defined above, preferably a PD-1 inhibitor, a PD-L1 inhibitor, a CTLA-4 inhibitor or a TIGIT inhibitor, or any mixture thereof.

[0934] In a particular embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above and at least one adenosine-producing enzyme inhibitor as defined above, preferably at least one CD39 inhibitor, such as, for example, ARL67156 and POM-1.

[0935] In a particular embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above and at least one chemotherapeutic agent as defined above.

[0936] In a particular embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above and at least one anticancer antibiotic as defined above, such as, for example, doxorubicin.

[0937] In a particular embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above and at least one anticancer platinum coordination compound as defined above, such as, for example, oxaliplatin.

[0938] In a particular embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above, at least one immunotherapeutic agent as defined above and at least one chemotherapeutic agent as defined above.

[0939] In a particular embodiment, the combination of the present invention comprises at least one A2AR inhibitor as defined above, at least one checkpoint inhibitor as defined above, and at least one chemotherapeutic agent as defined above. In a particular embodiment, the combination of the present invention comprises at least one A2AR inhibitor as defined above, at least one PD-L1 inhibitor, CTLA-4 inhibitor or TIGIT inhibitor as defined above, and at least one chemotherapeutic agent. In a particular embodiment, the combination of the present invention comprises at least one A2AR inhibitor as defined above, at least one checkpoint inhibitor as defined above, and at least one. In a particular embodiment, the combination of the present invention comprises at least one A2AR inhibitor as defined above, at least one PD-L1 inhibitor as defined above, CTLA-4 inhibitor or TIGIT inhibitor, and at least one anticancer antibiotic as defined above, such as, for example, doxorubicin.

[0940] In a particular embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above and at least two checkpoint inhibitors as defined above. In a particular embodiment, the combination of the invention comprises at least one A2AR inhibitor as defined above, at least one PD-L1 inhibitor as defined above and at least one TIGIT inhibitor as defined above.

[0941] Pharmaceutical composition

[0942] The invention further relates to a pharmaceutical composition comprising the combination according to the invention.

[0943] In one embodiment, the pharmaceutical composition comprises:

[0944] (a) at least one A2AR inhibitor,

[0945] (b) at least one anticancer agent, and

[0946] (c) at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant. In a preferred embodiment, the present invention provides a pharmaceutical composition comprising:

[0947] (a) at least one A2AR inhibitor as defined above, which is a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I), or a pharmaceutically acceptable salt or solvate thereof;

[0948] (b) at least one anti-cancer agent as defined above, such as, for example, an immunotherapeutic agent, a chemotherapeutic agent, an anti-angiogenic agent, a multidrug resistance-associated protein inhibitor, a radiotherapeutic agent, or any combination thereof, and

[0949] (c) at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0950] The at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant used to prepare the administration form will be apparent to the skilled artisan; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0951] The pharmaceutical composition comprising the combination of the present invention may optionally contain inactive substances of the type commonly used in pharmaceutical preparations, such as, for example, solubilizers, lipid carriers, antioxidants, surfactants, wetting agents, emulsifiers, buffers, pH regulators, preservatives (preserving agents / preservating agents), isotonicity agents, stabilizers, granulating agents or binders, precipitation inhibitors, lubricants, disintegrants, glidants, diluents or fillers, adsorbents, dispersants, suspending agents, leavening agents, release agents, sweeteners, flavoring agents, etc.

[0952] In a preferred embodiment, the pharmaceutical composition comprising the combination of the present invention comprises one or more pharmaceutically acceptable cosolvents. Preferred cosolvents are selected from caprylic acid, polyethylene glycol (PEG), propylene glycol, ethanol, dimethyl sulfoxide, dimethylacetamide, dimethyl isosorbide 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 cosolvent, PEG is a low molecular weight, and PEG is preferably PEG 400. In an alternative embodiment, when the composition comprises PEG, it has a medium molecular weight, preferably PEG3350.

[0953] In a particular embodiment, the pharmaceutical composition comprising the combination of the invention comprises one or more pharmaceutically acceptable lipid carriers. In a preferred embodiment, the lipid carrier is lauroyl polyoxyl-32 glyceride. This excipient corresponds to the excipient manufactured by Gattefossé (Saint-Priest-France). 44 / 14. This excipient is also known according to the following references: Lauroyl Polyoxyl-32 Glycerides NF / USP (NF: National Formulary; USP: US Pharmacopeia); Lauroyl Polyoxyl-32 Glycerides EP (European Pharmacopeia); Hydrogenated Coconut PEG-32 Esters (INCI); CAS No. 57107-95-6. 44 / 14 corresponds to the monoglyceride, diglyceride and triglyceride and lauric acid (C 12 ) is a well-defined multi-component material composed of PEG-32 monoesters and diesters. The melting point of 44 / 14 ranges from 42.5°C to 47.5°C (average 44°C) and has a hydrophile / lipophile balance (HLB) value of 14.

[0954] In another embodiment, the lipid carrier is vitamin E TPGS. This excipient is also known according to the following references: D-α-tocopheryl 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 and is formed from vitamin E conjugated 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.

[0955] In one embodiment, the pharmaceutical composition comprising the combination 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.

[0956] In some embodiments, a surfactant is added, such as polyethylene glycol, polyoxyethylene sorbitan fatty acid esters, sorbitan esters, docusate sodium, sodium lauryl sulfate, polysorbate (20, 80, etc.), poloxamer (188, 407, etc.), complex polyols, polyoxyethylene sorbitan monoether ( 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 (polyoxyethylene 12-hydroxystearic acid), labrasol (octylcanoyl polyoxyl-8 glyceride), labrafil M1944 (oleoyl polyoxyl-6 glyceride), polylactic acid polyethylene glycol block copolymer, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer

[0957] In some embodiments, a wetting agent is added, such as, for example, sodium lauryl sulfate, Vitamin E TPGS, docusate sodium, polysorbate 80, poloxamer 407. Preferably, the wetting agent is poloxamer 407.

[0958] In some embodiments, an emulsifier is added, such as, for example, 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. Preferred emulsifiers are, for example, poloxamer, propylene glycol monolaurate, propylene glycol dilaurate, and propylene glycol monocaprylate.

[0959] In some embodiments, buffers are used to help maintain pH within a range close to physiological conditions. Suitable buffers include organic and inorganic acids and salts thereof, such as citrate buffers (e.g., mixtures of monosodium citrate-disodium citrate, mixtures of citric acid-trisodium citrate, mixtures of citric acid-monosodium citrate, etc.), succinate buffers (e.g., mixtures of succinic acid-monosodium succinate, mixtures of succinic acid-sodium hydroxide, mixtures of succinic acid-disodium succinate, etc.), tartrate buffers (e.g., mixtures of tartaric acid-sodium tartrate, mixtures of tartaric acid-potassium tartrate, mixtures of tartaric acid-sodium hydroxide, etc.), fumarate buffers (e.g., mixtures of fumaric acid-monosodium fumarate, fumaric acid-sodium tartrate, etc.). In some embodiments, the present invention provides a buffer solution containing a plurality of buffers, such as a mixture of gluconic acid-disodium fumarate, a mixture of monosodium fumarate-disodium fumarate, etc.), a gluconate buffer (e.g., a mixture of gluconic acid-sodium gluconate, a mixture of gluconic acid-sodium hydroxide, a mixture of gluconic acid-potassium gluconate, etc.), an oxalate buffer (e.g., a mixture of oxalic acid-sodium oxalate, a mixture of oxalic acid-sodium hydroxide, a mixture of oxalic acid-potassium oxalate, etc.), a lactate buffer (e.g., a mixture of lactic acid-sodium lactate, a mixture of lactic acid-sodium hydroxide, a mixture of lactic acid-potassium lactate, etc.), and an acetate buffer (e.g., a mixture of acetic acid-sodium acetate, a mixture of acetic acid-sodium hydroxide, etc.). In addition, a phosphate buffer, a histidine buffer, and a trimethylamine salt such as Tris can be used.

[0960] In some embodiments, a pH adjuster is added, such as, for example, sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, meglumine, sodium carbonate, citric acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid, and malic acid;

[0961] In some embodiments, preservatives are added to slow the growth of microorganisms. Suitable preservatives for the present disclosure include phenol, benzyl alcohol, metacresol, methylparaben, propylparaben, octadecyldimethylbenzyl ammonium chloride, benzalkonium halides (e.g., benzalkonium chloride, benzalkonium bromide, and benzalkonium iodide), hexamethonium chloride, and alkylparabens such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, and 3-pentanol.

[0962] In some embodiments, isotonic agents, sometimes referred to as "stabilizers," are added, which include polyols, for example trivalent or higher sugar alcohols, such as glycerol, erythritol, arabitol, xylitol, sorbitol, and mannitol. Stabilizers refer to a large class of excipients whose functions range from bulking agents to additives that dissolve therapeutic agents or help prevent denaturation or adhesion to the walls of containers or help inhibit precipitation, particle growth, or agglomeration of active ingredients. Typical stabilizers can be polyols (listed above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamic acid, threonine, etc.; organic sugars or sugar alcohols, such as lactose, trehalose, stachyose, mannitol, sorbitol, xylitol, ribitol, inositol, galactitol, glycerol, etc., including cyclitols such as inositol; polyethylene glycol; amino acid polymers; sulfur-containing reducing agents such as urea, glutathione, lipoic acid, sodium thioacetate, thioglycerol, α-monothioglycerol and sodium thiosulfate; low molecular weight polypeptides (e.g., peptides with 10 or fewer residues); proteins, such as Human serum albumin, bovine serum albumin, gelatin or immunoglobulin; hydrophilic polymers such as polyvinyl pyrrolidone; poloxamer 407; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate; carboxymethyl cellulose (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; polyvinyl pyrrolidone; cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl methylcellulose phthalate or hydroxypropyl methylcellulose acetate succinate; carboxymethyl cellulose (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, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, polyvinyl pyrrolidone polyvinyl acetate copolymer.

[0963] In some embodiments, granulating agents / binders are added, such as starches, gums (including natural, semi-synthetic and synthetic), microcrystalline cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, polymers such as povidone, polyvinyl pyrrolidone polyvinyl acetate copolymers, etc. Preferred granulating agents are, for example, methyl cellulose, hydroxypropyl cellulose, povidone and polyvinyl pyrrolidone polyvinyl acetate copolymers.

[0964] In some embodiments, precipitation inhibitors are added, such as, for example, water-soluble derivatives of cellulose, including hydroxypropyl methylcellulose and methylcellulose; and water-soluble polymers, such as polyvinyl pyrrolidone, polyvinyl pyrrolidone polyvinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, or poloxamer 407. A preferred precipitation inhibitor is hydroxypropyl methylcellulose.

[0965] In some embodiments, lubricants are added, such as, for example, magnesium stearate, glyceryl esters, behenyl polyoxyl-8 glyceride Nf (Compritol HD5 ATO), sodium stearyl fumarate, and the like.

[0966] In some embodiments, disintegrants are added, for example synthetic ones like sodium starch glycolate, crospovidone, croscarmellose sodium, kollidon CL, as well as natural sources such as locust bean gum and the like.

[0967] In some embodiments, glidants are added, such as, for example, talc, magnesium stearate, colloidal silicon dioxide, starch, and the like.

[0968] In some embodiments, diluents (or fillers) are added, such as, for example, dextrose, lactose, mannitol, microcrystalline cellulose, sorbitol, sucrose, dibasic calcium phosphate, dehydrated calcium sulfate, starch, and the like.

[0969] In some embodiments, adsorbents are added, such as, for example, silica, purified aluminum silicate, and the like.

[0970] In some embodiments, the pharmaceutical composition comprising the combination of the present invention is in the form of a tablet, and tableting excipients such as, for example, granulating agents, binders, lubricants, disintegrants, glidants, diluents, adsorbents, etc. are added.

[0971] In some embodiments, the pharmaceutical composition comprising the combination of the present invention is in the form of a capsule, wherein the capsule shell is made of gelatin or a product of non-animal origin such as cellulose and its derivatives such as hydroxypropyl methylcellulose. Other ingredients may be included in the capsule shell, such as polyethylene glycol to act as a plasticizer; pigments such as titanium dioxide or iron oxide to provide opacity and color difference; lubricants such as carnauba wax; gelling agents such as carrageenan and wetting agents such as sodium lauryl sulfate. In one embodiment, the pharmaceutical composition comprising the combination of the present invention is formulated into a capsule, wherein the capsule shell is composed of gelatin, and wherein additional components are optionally contained in the capsule shell, such as, for example, polyethylene glycol and sodium lauryl sulfate.

[0972] By way of non-limiting example, the pharmaceutical composition comprising the combination may be in an administration form suitable for oral administration, parenteral administration (such as by intravenous, intramuscular or subcutaneous injection or intravenous infusion), topical administration (including ophthalmic), rectal administration, by inhalation, by skin patch, by implant, by suppository, etc. Such suitable administration forms may be solid, semisolid or liquid, depending on the mode of administration, and the administration forms as well as methods and carriers, diluents and excipients for their preparation will be clear to the skilled person; reference is made to the latest edition of Remington's Pharmaceutical Sciences.

[0973] The compositions may be formulated so as to provide quick, sustained or delayed release of the active compound or compounds contained therein.

[0974] According to one embodiment, the pharmaceutical composition comprising the combination of the present invention is in a form suitable for oral administration. Suitable forms for oral administration may be solid, semisolid or liquid. Some preferred but non-limiting examples of such forms include liquids, pastes or solid compositions, and more specifically tablets, tablets formulated for extended 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.

[0975] According to another embodiment, the pharmaceutical composition comprising the combination is in a form suitable for injection, especially for injection into a subject by intravenous, intramuscular, intraperitoneal, intrapleural, subcutaneous, transdermal injection or infusion.

[0976] Sterile injectable forms of the pharmaceutical compositions of the invention include sterile injectable solutions and sterile packaged powders (which generally are reconstituted prior to use) for bolus administration and / or continuous administration.

[0977] The sterile injectable form of the pharmaceutical composition of the present invention can be a solution or an aqueous or oily suspension. These suspensions can be prepared according to techniques known in the art using suitable dispersants or wetting agents and suspending agents. Sterile injectable preparations can also be sterile injectable solutions or suspensions in pharmaceutically acceptable diluents or solvents. Among acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution can be used. In addition, sterile fixed oils are conventionally used as solvents or suspension media. For this purpose, any less irritating fixed oils can be used, including synthetic monoglycerides or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are suitable for preparing injectables, as are natural pharmaceutically acceptable oils such as olive oil or castor oil, particularly their polyoxyethylene forms. These oil solutions or suspensions may also contain long-chain alcohol diluents or dispersants, such as carboxymethyl cellulose or similar dispersants commonly used in the preparation of pharmaceutically acceptable dosage forms (including emulsions and suspensions). Other commonly used surfactants such as Tweens, Spans and other emulsifying agents or bioavailability enhancers commonly used in the manufacture of pharmaceutically acceptable solid, liquid, or other dosage forms may also be used for the purposes of formulation.

[0978] According to another embodiment, the pharmaceutical composition comprising the combination 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, liquids, pastes or solid compositions, and more specifically aqueous solutions, drops, dispersants, sprays, ointments, creams, lotions, microcapsules, micron or nanoparticles, polymeric patches or controlled release patches, etc.

[0979] According to another embodiment, the pharmaceutical composition comprising the combination of the present invention is in a form suitable for rectal administration. Examples of forms suitable for rectal administration include, but are not limited to, suppositories, mini-enemas, enemas, gels, rectal foams, creams, ointments, etc.

[0980] According to another embodiment, the pharmaceutical composition comprising the combination of the invention is in a form suitable for administration by inhalation. Examples of forms suitable for administration by inhalation include, but are not limited to, aerosols.

[0981] The pharmaceutical formulations of the present invention are preferably in unit dosage form and may be suitably packaged, for example in boxes, blisters, vials, bottles, sachets, ampoules or in 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.

[0982] Ingredients Kit

[0983] The invention further relates to a kit of parts comprising the combination according to the invention.

[0984] In one embodiment, the kit of parts of the present invention comprises:

[0985] (a) a first component comprising at least one A2AR inhibitor, and

[0986] (b) a second component comprising at least one anticancer agent.

[0987] In a preferred embodiment, the present invention provides a kit of parts comprising:

[0988] (a) a first component comprising at least one A2AR inhibitor as defined above which is a thiocarbamate derivative, more preferably a thiocarbamate derivative of formula (I)

[0989]

[0990] or a pharmaceutically acceptable salt or solvate thereof; and

[0991] (b) a second component comprising at least one anti-cancer agent as defined above, such as, for example, an immunotherapeutic agent, a chemotherapeutic agent, an anti-angiogenic agent, a multidrug resistance-associated protein inhibitor, a radiotherapeutic agent or any combination thereof.

[0992] In one embodiment, the first component comprises a pharmaceutical composition comprising an A2AR inhibitor as defined above, preferably a thiocarbamate derivative of formula (I); and at least one pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant.

[0993] The pharmaceutically acceptable carrier, diluent, excipient and / or adjuvant of the pharmaceutical composition of the first component of the kit of components may be those listed above in relation to the pharmaceutical composition of the present invention.

[0994] Similarly, the dosage form and administration route of the pharmaceutical composition of the first component of the kit of components may be those listed above with respect to the pharmaceutical composition of the present invention.

[0995] In one embodiment, the second component comprises at least one anticancer agent as defined above. Depending on the type of anticancer agent, the second component of the kit may be in the form of a pharmaceutical composition. The excipients, dosage forms and routes of administration of such pharmaceutical compositions will be clear to the skilled person (with reference to the latest edition of Remington's Pharmaceutical Sciences), and may in particular be those listed above for the pharmaceutical compositions of the invention.

[0996] According to one embodiment, the kit of the present invention may include one or more other components, including one or more other anticancer agents. For example, the kit may include (a) a first component comprising an A2AR inhibitor of formula (I); (b) a second component comprising an immunotherapeutic agent; and (c) a third component comprising a chemotherapeutic agent. In another embodiment, the kit may include (a) a first component comprising an A2AR inhibitor of formula (I); (b) a second component comprising a checkpoint inhibitor; and (c) a third component comprising a chemotherapeutic agent. In another embodiment, the kit may include (a) a first component comprising an A2AR inhibitor of formula (I); (b) a second component comprising a checkpoint inhibitor; and (c) a third component comprising a different checkpoint inhibitor.

[0997] As shown below, administration of the different components of the kit can be carried out simultaneously or staggered in time, at the same administration site or at different administration sites, at similar or different administration times (i.e., similar or different administration times for each component), in similar or different dosage forms.

[0998] Regimen and dosage

[0999] In the context of the present invention, administration of the A2AR inhibitor and the anticancer agent can be performed simultaneously or staggered in time, at the same administration site or at different administration sites, at similar or different administration times (i.e., similar or different administration times for each component), in similar or different dosage forms, as further outlined below.

[1000] In order to ensure that the separate mechanisms caused by the A2AR inhibitor and the anticancer agent do not negatively affect each other, the anticancer agent and the A2AR inhibitor are preferably administered separately in time (in a time-staggered manner), i.e., sequentially and / or at different administration sites. This means that the A2AR inhibitor can be administered, for example, before, at the same time or after the anticancer agent, or vice versa. Alternatively or in addition, the A2AR inhibitor and the anticancer agent can be administered at different administration sites or at the same administration site, preferably when administered in a time-staggered manner.

[1001] In one embodiment, the A2AR inhibitor will be administered prior to and / or concurrently with an immunotherapeutic as described above. In one embodiment, the immunotherapeutic is a checkpoint inhibitor, and the A2AR inhibitor will be administered prior to or on the same day as the checkpoint inhibitor as described above.

[1002] In one embodiment, the A2AR inhibitor will be administered prior to and / or concurrently with an immunotherapeutic as described above, and sequentially thereafter.

[1003] In one embodiment, the A2AR inhibitor will be administered before or concurrently with the immunotherapeutic agent described above, and then continue for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 days thereafter. In another embodiment, the A2AR inhibitor will be administered before or concurrently with the immunotherapeutic agent described above, and then continue for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks thereafter. In another embodiment, the A2AR inhibitor will be administered before or concurrently with the immunotherapeutic agent described above, and then continue for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 months thereafter.

[1004] In one embodiment, the immunotherapeutic agent is a check point inhibitor, and the A2AR inhibitor will be administered before or simultaneously with the check point inhibitor. In one embodiment, the immunotherapeutic agent is a check point inhibitor, and the A2AR inhibitor will be administered before or simultaneously with the check point inhibitor and continuously thereafter. In one embodiment, the immunotherapeutic agent is a check point inhibitor, and the A2AR inhibitor will be administered before or simultaneously with the check point inhibitor, and then continue thereafter for at least 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 weeks.

[1005] Depending on the condition to be prevented or treated and the form of administration, the combination of the invention can be administered in the form of a single daily dose, divided into one or more daily doses.

[1006] According to one embodiment, a therapeutically effective dose of an A2AR inhibitor as described above is administered for the treatment of cancer in a subject in need thereof, wherein the A2AR inhibitor is used in combination with an anticancer agent, such as an immunotherapeutic agent. Thus, in one embodiment, the pharmaceutical combination or kit of parts of the present invention comprises a therapeutically effective dose of an A2AR inhibitor as described above and a therapeutically effective dose of an anticancer agent as described above.

[1007] It should be understood that the total daily dosage of the A2AR inhibitor and anticancer agent will be determined by the attending physician within the scope of sound medical judgment. The specific dosage for any particular subject will depend on a variety of factors, such as the cancer to be treated; the patient's age, weight, general health, sex and diet; and similar factors well known in the medical field.

[1008] In one embodiment, the subject is a mammal, preferably a human, and the dose (preferably a therapeutically effective dose) of the A2AR inhibitor is a dose in the range of about 0.01 milligrams per kilogram of body weight (mg / kg) to about 5 mg / kg, preferably about 0.08 mg / kg to about 3.3 mg / kg, more preferably about 0.15 mg / kg to about 1.7 mg / kg.

[1009] In one embodiment, the subject is a mammal, preferably a human, and the dose (preferably a therapeutically effective dose) of the A2AR inhibitor is a dose in the range of about 0.01 milligrams 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, more preferably about 0.15 mg / kg / day to about 1.7 mg / kg / day.

[1010] In one embodiment, the subject is a mammal, preferably a human, and the dose (preferably a therapeutically effective dose) of the A2AR inhibitor is a 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.

[1011] In one embodiment, the subject is a mammal, preferably a human, and the dose (preferably a therapeutically effective dose) of the A2AR inhibitor is a dose 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.

[1012] In one embodiment, the subject is a mammal, preferably a human, and the dose (preferably a therapeutically effective dose) of the A2AR inhibitor 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.

[1013] In one embodiment, the subject is a mammal, preferably a human, and the dose of the A2AR inhibitor (preferably a therapeutically effective dose) is a daily dose to be administered once, twice, three times or more. In one embodiment, the subject is a mammal, preferably a human, and the dose of the A2AR inhibitor (preferably a therapeutically effective dose) is a daily dose to be administered once or twice.

[1014] use

[1015] Another object of the present invention is the use of the combination of the present invention as a medicament. Therefore, in one embodiment, the present invention provides the use of the combination of the present invention for 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 for the manufacture of a medicament.

[1016] 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.

[1017] In one embodiment, the invention relates to the treatment and / or prevention of cancer comprising administering to a mammalian species in need thereof a therapeutically effective amount of a combination, pharmaceutical composition or kit of parts of the invention.

[1018] The present invention further provides the use of the combination, pharmaceutical composition or kit of parts of the present invention for the manufacture of a medicament for treating and / or preventing cancer.

[1019] The present invention also provides a method of delaying the onset of cancer in a patient, comprising administering to a patient in need thereof a pharmaceutically effective amount of the combination, pharmaceutical composition or kit of parts of the present invention.

[1020] Various cancers are known in the art. Cancers that can be treated using the methods of the present invention include solid cancers 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.

[1021] In one embodiment, the cancer to be treated according to the present invention is a solid cancer. As used herein, the term "solid cancer" encompasses any cancer (also called a malignant tumor) that forms a discrete tumor mass, as opposed to a cancer (or malignant tumor) that diffusely infiltrates tissue without forming a mass.

[1022] Examples of solid tumors include, but are not limited to, bile duct cancer, brain cancer (including glioblastoma and medulloblastoma), breast cancer, carcinoid tumors, cervical cancer, choriocarcinoma, colon cancer, colorectal cancer, endometrial cancer, esophageal cancer, gastric cancer, glioma, head and neck cancer, intraepithelial neoplasms (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous cell carcinoma), ovarian cancer (including those derived from epithelial cells, stromal cells, germ cells and mesenchymal cells ... These include pancreatic cancer, prostate cancer, colorectal cancer, renal cancer (including adenocarcinoma and Wilms' tumor), sarcomas (including leiomyosarcoma, rhabdomyosarcoma, liposarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, Kaposi's sarcoma, basal cell carcinoma, and squamous cell carcinoma), testicular cancer including germinal tissue tumors (seminoma and non-seminoma such as teratoma and choriocarcinoma), stromal tumors, germ cell tumors, thyroid cancer (including thyroid adenocarcinoma and medullary carcinoma), and urothelial carcinoma.

[1023] In another embodiment, the cancer to be treated according to the present invention is a non-solid cancer. Examples of non-solid tumors include, but are not limited to, blood tumors. As used herein, blood tumors are a term of the art that includes lymphatic disorders, bone marrow diseases, and leukemias associated with AIDS.

[1024] Lymphatic disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphoproliferative disorders (e.g., lymphomas, myelomas, and chronic lymphocytic leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphomas, and lymphocytic lymphomas). Chronic lymphocytic leukemias include, for example, T-cell chronic lymphocytic leukemia and B-cell chronic lymphocytic leukemia.

[1025] In a specific embodiment, the cancer is selected from breast cancer, carcinoid tumor, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer and urothelial carcinoma.

[1026] In a specific embodiment, the cancer is breast cancer. In a specific embodiment, the cancer is a carcinoid tumor. 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 a 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 kidney cancer. In a specific embodiment, the cancer is gastric cancer. In a specific embodiment, the cancer is thyroid cancer. In a specific embodiment, the cancer is urothelial carcinoma.

[1027] In another specific embodiment, the cancer is selected from the group consisting of leukemia and multiple myeloma.

[1028] In one embodiment, the present invention relates to a combination, a pharmaceutical composition or a kit of parts as defined above for use in immunotherapy, preferably for use as cancer immunotherapy.

[1029] In one embodiment, the invention relates to a method of immunotherapy, preferably cancer immunotherapy, comprising administering to a mammalian species in need thereof a therapeutically effective amount of a combination, pharmaceutical composition or kit of parts of the invention.

[1030] The present invention further provides the use of the combination, pharmaceutical composition or kit of parts of the present invention for the manufacture of a medicament for performing immunotherapy, preferably cancer immunotherapy.

[1031] In one embodiment, the invention relates to the use of the combination, pharmaceutical composition or kit of parts of the invention for enhancing immune recognition and destruction of cancer cells.

[1032] In one embodiment, the invention relates to a method for enhancing immune recognition and destruction of cancer cells, comprising administering to a mammalian species in need thereof a therapeutically effective amount of a combination, pharmaceutical composition or kit of parts of the invention.

[1033] The present invention further provides the use of the combination, pharmaceutical composition or kit of parts of the present invention for the manufacture of a medicament for enhancing immune recognition and destruction of cancer cells.

[1034] Preferably, the patient is a warm-blooded animal, more preferably a human.

[1035] In one embodiment, a patient receiving an A2AR inhibitor as described herein also receives immunotherapy, chemotherapy, radiation therapy, or a combination thereof.

[1036] In one embodiment, the subject is resistant to immunotherapy. In one embodiment, the subject is resistant to cancer immunotherapy.

[1037] In one embodiment, the subject is resistant to chemotherapy. In one embodiment, the subject is resistant to cancer chemotherapy.

[1038] In one embodiment, the subject is resistant to radiation therapy. In one embodiment, the subject is resistant to cancer radiation therapy.

[1039] The present invention also relates to compounds of formula (I) as defined above for use in therapy in combination with an anticancer agent as defined above, in particular an immunotherapeutic agent, a chemotherapeutic agent, an anti-angiogenic agent, a multidrug resistance associated protein inhibitor, a radiotherapeutic agent or any combination thereof.

[1040] The present invention also relates to a compound of formula (I) as defined above for use in a patient treated by immunotherapy, chemotherapy, radiotherapy or a combination thereof.

[1041] Therefore, the present invention also relates to a method for treating cancer in a subject resistant to an anticancer agent, comprising administering to the patient a compound of formula (I) as defined above and the anticancer agent. In one embodiment, the anticancer agent is immunotherapy, chemotherapy, radiotherapy or a combination thereof.

[1042] The present invention further relates to a method for enhancing a subject's therapeutic response to an anticancer agent, comprising further administering to the patient a compound of formula (I) as defined above. In one embodiment, the anticancer agent is immunotherapy, chemotherapy, radiotherapy or a combination thereof.

[1043] The invention also relates to an anticancer agent as defined above for use in therapy in combination with a compound of formula (I) as defined above. BRIEF DESCRIPTION OF THE DRAWINGS

[1044] Figure 1 shows the effect of A administered as a single agent in the liver Hepa 1-6 syngeneic tumor model. 2A Antitumor efficacy of R inhibitor compound 7. Figure 1A It is a graph showing the tumor volume over time after inoculation. Figure 1B Tumor volume distribution on day 22 is shown.

[1045] FIG2 shows A20 tumor growth after compound 7 used as a single agent or in combination with anti-PD-L1 treatment. Figure 2A It is a graph showing the tumor volume over time after inoculation. Figure 2B Tumor volume distribution on day 23 is shown.

[1046] Figure 3 shows the growth of EMT6 tumors after treatment with compound 8a in combination with antagonist anti-CTLA4 mAb. The number of complete responders (CR) in each group of 10 mice is indicated. Tumor growth over time: median ( Figure 3A ),vehicle( Figure 3B ) and aCTLA-4, 3 mg / kg Q3Dx2 (Day 9, Day 12), independent ( Figure 3C ) or with D) Compound 8, 0.1 mg / kg QDx25 ( Figure 3D ) or compound 8, 0.6 mg / kg QDx25 ( Figure 3E )combination.

[1047] Figure 4 shows that the A2AR inhibitor compound 8a combined with anti-PD-L1 mAb modulates T cell infiltration in the A20 tumor microenvironment. Figure 4A ) and CD8+ T cells ( Figure 4B Absolute quantification of the number of ) was calculated by calculating the mean of 10 high power fields / section (10 HPF) from independent tumors (symbols represent individual mice; n=5 to 7 mice / group). Medians and interquartile ranges are shown, with p values ​​calculated using the Mann Whitney nonparametric t-test.

[1048] Figure 5 shows MCA205 tumor growth after treatment with Compound 8b as a single agent or in combination with oxaliplatin. Figure 5A is a graph showing the median tumor volume over time after subcutaneous inoculation of tumor cells. Figure 5B -E is the medium ( Figure 5B ) treated mice. Compound 8b, 0.6 mg / kg QDx25 ( Figure 5C ) and oxaliplatin, 10 mg / kg QDx1 (day 11), independent ( Figure 5D) or with compound 8b, 0.6 mg / kg QDx25 ( Figure 5E )combination.

[1049] Figure 6 shows the growth of CT26 tumors after treatment with compound 8b, 0.6 mg / kg QDx32; anti-TIGIT mAb, 1 mg / kg Q3Dx3 (days 9, 12, and 15); doxorubicin 6 mg / kg Q3Dx2 (days 10 and 14) and different combinations thereof. Fig. 6A is a graph showing the median tumor volume over time after subcutaneous inoculation of tumor cells. Figure 6B -D is the medium ( Figure 6B )、Adriamycin( Figure 6C ) or anti-TIGIT mAb ( Fig.6D ) Individual tumor growth volumes of mice treated with . Fig. 6E -G is a combination of doxorubicin and anti-TIGIT ( Fig. 6E ), the combination of compound 8b and doxorubicin ( Fig. 6F ) and the triple combination of compound 8b, doxorubicin and anti-TIGIT ( Figure 6G ) Individual tumor growth volumes of mice treated with .

[1050] Fig. 7A Proliferation of CD4 determined by CFSE dilution is shown. + The proportion of cells. Figure 7B The concentration of TNFα present in the cell culture supernatant is shown. CD39i represents the combination of the CD39 inhibitor ARL67156 and POM-1. Dark grey bars show wells treated with compound 8a, while light grey bars represent concentration-matched DMSO-treated wells. Results are shown as mean ± standard deviation from replicate wells.

[1051] Example

[1052] The present invention will be better understood with reference to the following examples. These examples are intended to represent specific embodiments of the present invention and are not intended to limit the scope of the invention.

[1053] The following abbreviations are used:

[1054] BHT: Butylated Hydroxytoluene

[1055] BID: 2 times a day (twice a day)

[1056] ca.: approximately

[1057] CR: Complete responder

[1058] DMSO: dimethyl sulfoxide

[1059] EDTA: Ethylenediaminetetraacetic acid

[1060] HPLC: High Performance Liquid Chromatography

[1061] LC-MS: Liquid chromatography-mass spectrometry

[1062] mAb: monoclonal antibody

[1063] mg: milligram

[1064] MS: mass spectrometry

[1065] PBS: Phosphate buffered saline

[1066] PEG: polyethylene glycol

[1067] QD: Daily (i.e. once a day)

[1068] Q3D: Every 3 days (i.e. once every 3 days)

[1069] rpm: revolutions per minute

[1070] TGI: tumor growth inhibition

[1071] TIL: tumor infiltrating lymphocytes

[1072] UV: Ultraviolet

[1073] μL: microliter

[1074] % v / v: percentage of the total volume of the composition by volume

[1075] %w / w: percentage by weight of the total weight of the composition

[1076] I. Compounds

[1077] Compounds of formula (I) were prepared as described in PCT / EP2018 / 058301.

[1078] II. Pharmaceutical Compositions

[1079] II.1. Preparation of pharmaceutical compositions

[1080] Two compositions according to the invention were prepared in capsule form comprising the following ingredients (Table 2):

[1081] Table 2. Capsule composition (% w / w).

[1082]

[1083]

[1084] Capsule 2A is prepared from a common blend using conventional mixing and capsule filling processes in accordance with good manufacturing practices. Lauroyl polyoxyl-32 glyceride is melted at a product temperature of not less than 50°C but not more than 80°C. Caprylic acid and butylated hydroxytoluene (BHT) are then added to lauroyl polyoxyl-32 glyceride in sequence and mixed together using a suitable mixer. Compound 8a is then gradually added to the lauroyl polyoxyl-32 glyceride / caprylic acid / BHT mixture and continuously mixed together using a suitable mixer to produce a visually uniform drug distribution without observable lumps or agglomerates. Mixing is then continued for at least 30 minutes to ensure that the drug substance is evenly distributed as determined by visual inspection. The blend is then maintained in a molten state under continuous mixing and filled into a gelatin capsule shell of an appropriate size to achieve the target capsule fill weight. Capsule filling is performed using conventional capsule filling methods and equipment suitable for molten semisolid preparations.

[1085] A similar process was performed for making all other capsule examples, where lauroyl polyoxyl-32 glyceride was replaced with vitamin E TPGS. Polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and hydroxypropyl methylcellulose were added to the molten lauroyl polyoxyl-32 glyceride or vitamin TPGS as required.

[1086] II.2. Pharmacological Examples

[1087] II.2.i Thermodynamic solubility in shake flasks - HPLC

[1088] This example is intended to demonstrate that compounds of formula (I) are poorly soluble in water or aqueous buffers and therefore it is desirable to provide formulations of said compounds.

[1089] Compound 8a (2.0 mg, crystalline solid) was weighed into the lower chamber of a Whatman miniuniprep vial. 450 μL of test medium was added to each chamber. After addition, the filter piston of the miniuniprep vial was placed and compressed to the liquid level so that the medium and compound were in contact with the filter during incubation. The sample was vortexed for 2 minutes and then incubated for 24 hours at room temperature (about 22-25° C.) with shaking at 880 rpm. The miniuniprep was compressed to prepare a filtrate for injection into an HPLC system. The supernatant was diluted 50 times with medium to prepare a diluent. Three UV standard solutions were injected into the HPLC from low to high concentrations, and the diluents and supernatants were then tested. The test sample was injected in duplicate.

[1090] The results are shown in Table 3:

[1091] Table 3. Solubility of compound 8a in the aqueous media tested.

[1092]

[1093] In all aqueous media tested, the solubility was very low, and testing in FaSSIF (Fasted State Simulated Intestinal Fluid) was representative of the low intestinal solubility.

[1094] II.2.ii. Exposure after oral administration in dogs

[1095] The purpose of this assay is to determine the exposure in dogs following oral administration of the pharmaceutical composition of the invention. To stimulate gastric acid secretion, pentagastrin was administered to dogs just prior to administration of the capsule formulation.

[1096] Five male beagle dogs (>6 months old, weighing 7-9 kg) were fed in the afternoon (3:30 to 4:00 pm) the day before oral dosing, and the remaining food was removed at approximately 7:00 pm. Food was not retained until after the four-hour blood collection.

[1097] Pentagastrin (Sigma, 1 mg) was dissolved in 200 μL (0.200 mL) of 10% (v / v) ammonium hydroxide (NH4OH) / 90% (v / v) phosphate buffered saline (PBS). 0.12 mL of this stock solution was then diluted by adding 4.88 mL of PBS solution, followed by vortexing of the vial. The solution was filtered (under a laminar flow hood) into a sterile amber glass serum bottle through a 0.22 μm syringe filter. Before capsule administration, 6 μg / kg of pentagastrin was administered to the animal by intramuscular injection of approximately 30 minutes (± 2 minutes).

[1098] The dosage capsule formulation (80 mg / dog, i.e., about 10 mg / kg animal) is administered by placing the capsule behind the dog's throat and pushing it into the pharynx with the thumb or index finger. The capsule is moistened with water to facilitate administration. After the dose is administered, swallowing can be induced by gently stroking the dog's throat or tapping the dog under the dog's chin if necessary. Immediately after the capsule is administered, water (4 mL / kg) or a pH 2.5 HCl aqueous solution (4 mL / kg) is injected into the animal's mouth to help swallow the capsule. After administration, the animal's mouth is checked to ensure that the dose has been swallowed.

[1099] Blood was collected into tubes containing potassium (K2) EDTA*2H2O (0.85-1.15 mg) on ​​wet ice (Jiangsu Kangjian medical suppliesco.,LTD) at the time points shown in Table 4, and plasma was processed by centrifugation (3,000 x g for 10 minutes at 2 to 8°C) within one hour of collection. Plasma samples (0.2 mL) were transferred to labeled polypropylene microcentrifuge tubes and stored frozen at -60°C or lower until bioanalysis.

[1100] The concentration of compound 8a in plasma was quantified by LC-MS / MS. The measured concentrations (mean values ​​of five dogs) are shown in Table 4, and the main pharmacokinetic parameters are shown in Table 5.

[1101] Table 4. Concentration of compound 8a in plasma.

[1102] Time point (h) Concentration of Preparation 1 (ng / mL) Concentration of Formulation 2A (ng / mL) 0.25 94.7 94.4 0.50 431 292 1.0 242 384 2.0 161 108 4.0 9.91 10.5 8.0 3.42 3.45 12 4.68 <1

[1103] Table 5. Pharmacokinetic parameters.

[1104]

[1105]

[1106] C max : Maximum plasma concentration of active ingredient obtained after administration; T max : Reach C max time; AUC: area under the curve, corresponding to the integral of the concentration-time curve (AUC last : AUC until the last sample drawn; AUC inf : AUC until infinite time)

[1107] The above results clearly demonstrate that the use of the pharmaceutical composition of the present invention can provide thiocarbamate A2A inhibitors with suitable oral bioavailability.

[1108] III. Combination with anticancer agents - in vivo studies

[1109] Summary of results:

[1110] Compound 7 at 3 mg / kg BID significantly delayed the growth of HEPA-1-6 tumors compared to vehicle controls in syngeneic hosts.

[1111] In combination with anti-PD-L1, compound 7 showed anti-tumor activity at 0.3 mg / kg BID and 3 mg / kg BID, significantly delaying tumor growth in the A20 syngeneic mouse lymphoma model compared with the anti-PD-L1 control.

[1112] In combination with anti-CTLA-4, compound 8a showed antitumor activity at 0.1 mg / kg and significantly delayed tumor growth in a dose-dependent manner starting from 0.6 mg / kg in the EMT6 syngeneic mouse breast cancer model. Moreover, in cured mice, growth was arrested after re-vaccination, suggesting that a specific memory response was induced.

[1113] Further illustrating the mechanism of action, in combination with anti-PD-L1, compound 8a at 3 mg / kg BID significantly increased the infiltration of CD3+ and CD8+ cells, without an effect on FOXP3-expressing cells.

[1114] In combination with oxaliplatin, compound 8b showed significant antitumor activity at 0.6 mg / kg by delaying tumor growth in the MCA205 syngeneic mouse fibrosarcoma cancer model.

[1115] In combination with doxorubicin, compound 8b showed significant antitumor activity at 0.6 mg / kg by delaying tumor growth in the CT26 syngeneic mouse colon cancer model. In the same example, the triple combination of doxorubicin, 1 mg / kg of anti-TIGIT mAb and 0.6 mg / kg of compound 8b showed significantly improved antitumor activity in the CT26 syngeneic mouse colon cancer model compared to the double combination of doxorubicin and compound 8b or doxorubicin and anti-TIGIT mAb.

[1116] III.1. Syngeneic HEPA1-6 Mouse Liver Tumor Model

[1117] This study evaluated the antitumor activity of compound 7 in a mouse HCC model (NCR-A2A-032).

[1118] C57BL / 6 female mice (8 weeks old) were inoculated subcutaneously with Hepa 1-6 tumor cells in the right flank region (day 0). When the tumor size reached approximately 50 mm 3 (Day 4), mice were randomized into experimental groups and treated from Day 4 until Day 25. Mice were orally administered with vehicle (10% DMSO, 10% Solutol HS15 in dH2O pH 3) or Compound 7 (0.3 and 3 mg / kg, orally, BIDx21).

[1119] Compound 7 showed significant antitumor efficacy at 3 mg / kg, with a tumor growth inhibition (TGI) of 44% calculated on day 22 (p=0.024). Figure 1A and 1B ).

[1120] III.2. Syngeneic A20 Experimental Lymphoma Model in Combination with Anti-PD-L1

[1121] In this study, the antitumor efficacy of compound 7 was evaluated in a B-cell lymphoma model as a single agent (monotherapy) or in combination with an antagonist anti-programmed death-ligand 1 (anti-PD-L1) monoclonal antibody (10F.9G2, BioXcell) (NCR-A2A-031).

[1122] BALB / c female mice (8 weeks old) were inoculated subcutaneously with A20 mouse B cell tumor cells in the right lower flank region (day 0). When the tumor size reached approximately 50 mm 3 (Day 7), mice were randomized into groups and treatment was started. Mice were orally administered vehicle (10% DMSO, 10% Solutol HS15 in dH2O pH3) as a control or compound 7, 0.3 and 3 mg / kg orally BID x 21 (Day 7 to Day 28) or anti-PD-L1 mAb, 5 mg / kg i.p. Q3D x 3 (Day 9, Day 12, Day 15) as a single dose or combination.

[1123] Compound 7 administered orally at 0.3 mg / kg BID in combination with anti-PD-L1 mAb showed anti-tumor activity (TGI = 76%, measured on day 23), although it did not reach statistical significance (p = 0.106) compared with anti-PD-L1 monotherapy (TGI = 49%).

[1124] Compound 7 administered at 3 mg / kg BID in combination with anti-PD-L1 mAb showed significant improvement in antitumor activity (p=0.039 for TGI and p=0.0008 for overall inhibition of tumor growth) compared to single-agent anti-PD-L1 mAb (TGI=82% and 49%, respectively, observed on day 23) ( Figure 2A and 2B ).

[1125] Statistical analysis also revealed that compound 7 synergized with anti-PD-L1 mAb to significantly inhibit the growth of established A20 syngeneic tumors (p=0.017).

[1126] III.3. Syngeneic EMT6 breast cancer model in combination with anti-CTLA-4

[1127] The antitumor efficacy of compound 8a in combination with anti-cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) antagonist mAb (9H10, BioXcell) was evaluated in a triple-negative breast cancer model.

[1128] EMT6 breast tumor cells were orthotopically inoculated into the right lower mammary fat pad of 8-week-old female BALB / c mice (day 0). 3Mice were randomly assigned to groups at 9 days (day 9). Mice were orally administered control vehicle (10% DMSO, 10% Solutol HS15 in dH2O pH 3) or anti-CTLA-4 mAb, 3 mg / kg ip Q3Dx2 (day 9, day 12) either alone or in combination with compound 8a (0.1 mg / kg orally QDx25 or 0.6 mg / kg orally QDx25).

[1129] The combination of compound 8a and anti-CTLA-4 significantly reduced tumor growth (p=0.0153, mean TGI=99% measured on day 31 - complete responders (CR)=7 / 10) when administered at 0.6 mg / kg compared to anti-CTLA4 alone (CR=3, mean TGI=72% measured on day 31) ( Figure 3A , 3B Although compound 8a at 0.1 mg / kg in combination with anti-CTLA-4 mAb (as above) did not reach statistical significance (p=0.8665) compared with anti-CTLA4 mAb as a single agent, it resulted in CR=5 (n=10 mice per group) and mean TGI=85% ( Figure 3A and 3D ). In addition, there was no statistically significant difference between the doses. This indicates that compound 8a showed in vivo activity starting from 0.1 mg / kg when combined with anti-CTLA4 mAb (Figure 1).

[1130] When complete responders (cured mice) were re-challenged with EMT6 tumor cells (specific antigen) or irrelevant colon CT26 cells (non-specific antigen), mice previously treated with 0.1 and 0.6 mg / kg of compound 8a in combination with anti-CTLA-4 mAb were unable to resist challenge with irrelevant CT26 cells (100% tumor incidence), but completely rejected EMT6 cells (no tumor formation) in 66% (0.1 mg / kg) and 100% (0.6 mg / kg) of the mice, respectively.

[1131] Thus, compound 8a combined with an anti-CTLA-4 antagonist mAb significantly inhibited the growth of established EMT6 syngeneic tumors and induced long-term memory responses, resulting in a durable and specific antitumor response.

[1132] III.4. Mechanism of action of compound 8A in reducing tumor growth in the A20 lymphoma model

[1133] Having established that compound 8a (or its racemic mixture, compound 7) exhibited antitumor activity at well-tolerated doses in several experimental tumor models, this study evaluated the mechanism of action responsible for this effect.

[1134] Compound 8a was evaluated as a single agent and in combination with an antagonist anti-PD-L1 mAb in a B-cell lymphoma tumor model. Mice bearing A20 tumors (tumor size of approximately 70 mm 3 , day 12 after inoculation) were treated with control vehicle orally (10% DMSO, 10% Solutol HS15 in dH2O pH3) or with anti-PD-L1 mAb, 1 mg / kg i.p. Q3Dx3 (days 14, 17 and 20) and compound 8a, 3 mg / kg orally BIDx10 as a single agent or in combination with anti-PD-L1 mAb. Semi-quantitative techniques were used to analyze the total CD3 + T cells, CD8 + T cells and FOXP3 + Treg cells and tumor-infiltrating lymphocytes (TIL) were characterized and compared.

[1135] Compound 8a at 3 mg / kg as a single dose had an effect on CD3 + and CD8 + There was a modest effect on TILs, but the increase in invasiveness did not reach significance. The combination of compound 8a (3 mg / kg) with anti-PDL-1 mAb showed a significant increase in CD3 + T cells (p = 0.0068) and CD8 + There was a significant increase in T cell infiltration (p = 0.0035) Figure 4A and 4B ). None of the treatments, either as single agents or in combination, showed statistically significant changes in Treg infiltration.

[1136] These results strongly suggest that the combination of compound 8a and aPDL-1 mAb significantly modulated the immunosuppressive properties of the tumor microenvironment by increasing TIL infiltration.

[1137] III.5. Syngeneic MCA205 Experimental Fibrosarcoma Model in Combination with Oxaliplatin

[1138] The antitumor efficacy of compound 8b in combination with oxaliplatin was evaluated in an established murine syngeneic MCA205 fibrosarcoma tumor model.

[1139] MCA205 tumor cells were subcutaneously inoculated into the right flank of C57BL / 6 mice. 3The mice were randomly divided into groups when the average size of the mice reached . The mice were orally administered with vehicle (10% DMSO, 10% Solutol HS15 in dH2O pH 3) as a control or compound 8b, 0.6 mg / kg QDx25 (days 11-36) or oxaliplatin, 10 mg / kg ip QDx1 (day 11) as a single dose or combination.

[1140] Oxaliplatin given as a single administration ip on D11 showed a significant delay in tumor growth compared to vehicle (p=0.0202) (Figure 5).

[1141] Compound 8b administered orally at 0.6 mg / kg once daily (QD) for 25 consecutive days in combination with oxaliplatin showed a significant delay in tumor growth compared to vehicle (p<0.0001) and also compared to oxaliplatin monotherapy (p=0.0284) (Figure 5).

[1142] III.6. Syngeneic CT26 Experimental Colon Cancer Model in Combination with Doxorubicin and / or Anti-TIGIT MAb

[1143] In this study, the antitumor efficacy of compound 8b in combination with the chemotherapeutic agent doxorubicin and with an anti-TIGIT mAb was evaluated in a colon tumor model (CT26).

[1144] BALB / c female mice (8 weeks old) were inoculated subcutaneously with CT26 mouse tumor cells in the right lower flank region (day 0). When the tumor size reached approximately 90 mm 3 (Day 9), mice were randomized into groups and treatment was started. Mice were orally administered vehicle (10% DMSO, 10% Solutol HS15 in dH2O pH3) as a control or administered doxorubicin 6 mg / kg iv Q4Dx2 (Day 10 and Day 14) or anti-TIGIT mAb, 29527 (see US10329349), 1 mg / kg ip Q3Dx3 (Days 9, 12 and 15) as a single agent or in combination with compound 8b 0.6 mg / kg orally QDx 32 (Days 9 to 41).

[1145] Compared with mice treated with vehicle, intraperitoneal injection of 1 mg / kg anti-TIGIT mAb 29527 (see US10329349) on days 9, 12, and 15 after tumor cell inoculation significantly inhibited tumor growth (p=0.0009, Figure 6)

[1146] Doxorubicin administered twice at 6 mg / kg on days 10 and 14 had no significant effect on tumor growth (p=0.14, Figure 6), while improved anti-tumor efficacy when combined with anti-TIGIT mAb (p=0.008 and p=0.0002, respectively, when compared to anti-TIGIT mAb or doxorubicin stand-alone therapy (Figure 6).

[1147] Administration of compound 8b at 0.6 mg / kg QD starting from day 9, in combination with doxorubicin at 6 mg / kg on days 10 and 14, achieved significant anti-tumor effects compared to doxorubicin alone (p=0.0003, Figure 6). Anti-tumor growth efficacy was significantly higher in mice treated with the triple combination of compound 8b, doxorubicin, and anti-TIGIT when compared to doxorubicin + compound 8b (p<0.0001) or anti-TIGIT + doxorubicin (p=0.003), and there were 5 complete responders (CR) in the 8 mice in this triple combination treatment group, compared to 0 CR and 1 CR in 10 mice in the doxorubicin + compound 8b and anti-TIGIT + doxorubicin combination, respectively (Figure 6).

[1148] III.7. Restoration of human T cell function in combination with CD39 inhibitors

[1149] Purpose. When T cells are activated, they proliferate and produce proinflammatory cytokines. Adding adenosine triphosphate (ATP) to the culture provides a source of adenosine, as ATP is first converted to adenosine monophosphate by CD39 and then to adenosine by CD73. Adenosine is converted in part by binding to A 2A Therefore, this assay aims to show that A 2A The combination of the receptor antagonist compound 8a with the CD39 inhibitors ARL67156 and POM-1 could reverse the inhibitory effects on T cell proliferation and inflammatory cytokine production in the presence of ATP.

[1150] PBMC and CD3 +T cell isolation. Venous blood from healthy volunteers was obtained via ImmuneHealth (Centre Hospitalier Universitaire Tivoli, La Louviere, Belgium). Peripheral blood mononuclear cells (PBMCs) were collected by density gradient centrifugation using SepMate-50 tubes (StemCell Technologies, Grenoble, France) and Lymphoprep (Axis-shield, Oslo, Norway) according to the manufacturer's instructions. PBMCs were stored in heat-inactivated fetal bovine serum (hiFBS; Gibco, ThermoFisher Scientific, Merelbeke, Belgium) containing 10% DMSO in liquid nitrogen until needed. PBMCs were thawed and washed into PBS (containing 10% hiFBS) and labeled with 1 μM CFSE (Life Technologies) for 5 minutes at room temperature. Cells were washed into StemCell isolation buffer and CD3 T cells were isolated by immunomagnetic negative selection using the EasySep Human T Cell Isolation Kit (StemCell Technologies) according to the manufacturer's instructions. + T cells.

[1151] Human T cell activation assay. Human CD3 + T cells were washed into X-VIVO15 medium (LONZA) and plated at 8×10 per well. 4 The cells were distributed into 96-well plates. The wells received A at a final concentration of 100 nM. 2A Receptor antagonist compound 8a or matching concentration of DMSO (Sigma-Aldrich). In addition, some wells received a combination of CD39 inhibitor ARL67156 (Tocris Bioscience, 100 μM) and POM-1 (Tocris Bioscience, 10 μM), or a combination of CD39 inhibitor and compound 8a. Cells were cultured in the presence or absence of ATP (Sigma-Aldrich) at a final concentration of 100 μM and activated by adding anti-CD3 and anti-CD28 coated microbeads (Dynabeads Human T Activator CD3 / CD28; Life Technologies).

[1152] The cells were placed in a humidified tissue culture incubator at 37°C with 5% CO2 for 72 hours. After 72 hours, the supernatant was sampled and stored at -20°C. CD4 was assessed by determining CFSE dilution via flow cytometry using BD LSRFortessa (BD Biosciences). + Proliferation of T cells The supernatants were subsequently thawed and quantified using the AlphaLISA human TNFα biotin-free detection kit (AL325; Perkin-Elmer, Zaventem, Belgium) according to the manufacturer's instructions.

[1153] Results: The presence of ATP significantly inhibited CD4 + T cell proliferation, while the CD39 inhibitors ARL67156 and POM-1 almost completely rescued CD4 + T cell proliferation ( Fig. 7A The presence of compound 8a contributed little to the increased proliferation of these cells. ATP also significantly inhibited TNFα production. Both compound 8a and the CD39 inhibitor alone restored approximately 50% of TNFα production, and in combination completely rescued ( Figure 7B Overall, these data illustrate the value of combining compound 8a with a CD39 inhibitor for cancer immunotherapy with the goal of fully restoring T cell function in the ATP-rich tumor microenvironment.

[1154] In summary, this application involves the following aspects:

[1155] 1. A pharmaceutical composition comprising:

[1156] (a) Compounds of formula (I):

[1157]

[1158] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1159] R 1 represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluorine or chlorine); preferably, R 1 represents a 5-membered heteroaryl group; more preferably, R 1 represents a furanyl group;

[1160] R 2 represents a 6-membered aryl group or a 6-membered heteroaryl group,

[1161] wherein the heteroaryl or aryl is optionally substituted with one or more substituents selected from the group consisting of halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonylimino, carbonylamino, sulfonylamino and alkylsulfonealkyl;

[1162] The substituents are optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl;

[1163] or heteroaryl or aryl is optionally substituted with two substituents which, together with the atoms to which they are attached, form a 5- or 6-membered aromatic ring, a 5- or 6-membered heteroaromatic ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclocarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl;

[1164] (b) a lipid carrier selected from lauroyl polyoxyl-32 glyceride, D-α-tocopheryl-polyethylene glycol-1000 succinate, and mixtures thereof; and

[1165] (c) optionally one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants.

[1166] 2. The pharmaceutical composition according to item 1, wherein the compound has formula (Ia)

[1167]

[1168] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1169] R 1 As defined in item 1;

[1170] X 1 and X 2 Each independently represents C or N;

[1171] When X 1 When N, R 1’ does not exist; or when X 1 When C, R 1’ represents H, halogen, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonylimide, carbonylamino, sulfonylamino or alkylsulfonealkyl;

[1172] The substituents are optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl;

[1173] R 2’ represents H, halogen, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimide, carbonylamino, sulfonylamino or alkylsulfonealkyl;

[1174] The substituents are optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonealkyl;

[1175] or R 1’ and R 2’ together with the atoms to which they are attached, form a 5- or 6-membered aromatic ring, a 5- or 6-membered heteroaromatic ring, a 5- or 6-membered cycloalkyl ring, or a 5- or 6-membered heterocyclyl ring; optionally substituted with one or more substituents selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocycloalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocycloalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclocarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl;

[1176] When X 2 When N, R 3’ does not exist; or when X 2 When C, R 3’ represents H or halogen, preferably H or F;

[1177] R 4’ represents H or halo, preferably H or F; and

[1178] R 5’ represents H or halogen, preferably H or F.

[1179] 3. The pharmaceutical composition according to item 1 or item 2, wherein the compound has the formula (Ia-1)

[1180]

[1181] or a pharmaceutically acceptable salt or solvate thereof, wherein R 1 , R 1’ , R 2’ , R 3’ , R 4’ and R 5’ As defined in item 2.

[1182] 4. A pharmaceutical composition according to any one of items 1 to 3, wherein the compound has the formula (Ia-1a)

[1183]

[1184] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1185] R 1 and R 3’ as defined in item 2; and

[1186] R 1” represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclic alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclic)(alkyl)aminoalkyl, heterocyclic, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclic alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclic carbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[1187] 5. The pharmaceutical composition according to any one of items 1 to 3, wherein the compound has the formula (Ia-1b)

[1188]

[1189] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1190] R 1 and R 3’ As defined in item 2;

[1191] R 1’ represents H or halo, preferably H or F; and

[1192] R 2” represents an alkyl or heterocyclic group substituted by one or more groups selected from the group consisting of oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclic alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclic)(alkyl)aminoalkyl, heterocyclic, heteroaryl, alkylheteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclic alkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclic carbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl and alkylsulfonealkyl.

[1193] 6. The pharmaceutical composition according to any one of items 1 to 3, wherein the compound has the formula (Ia-1c) or (Ia-1d)

[1194]

[1195] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1196] R 1 and R 3’ As defined in item 2;

[1197] R 1’ represents H or halogen, preferably H or F;

[1198] R 2’ represents H or halogen, preferably H or F;

[1199] 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, alkynylalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl; and

[1200] R 2i and R 2ii Each independently represents hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl)(alkyl)aminoalkyl, heterocyclyl, heteroaryl, alkylheteroaryl, alkynylalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl)(alkyl)amino, alkenylcarbonylamino, hydroxycarbonyl, alkoxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl)(alkyl)aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl or alkylsulfonealkyl.

[1201] 7. A pharmaceutical composition according to any one of items 1 to 6, wherein the compound of formula (I) is selected from the group consisting of:

[1202] 3-(2-(4-(4-((1H-1,2,3-triazolo-4-yl)methoxy-2-fluorophenyl)piperazin-1-yl)ethyl)-5-amino-(8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1203] 5-((4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)methyl)-1,3,4-oxadiazol-2(3H)-one;

[1204] 5-amino-3-(2-(4-(3-fluoropyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1205] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetamide;

[1206] (S)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1207] (R)-5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfinyl)ethoxy)phenyl)-piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1208] (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;

[1209] (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;

[1210] (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;

[1211] 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1212] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)acetic acid;

[1213] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)phenoxy)acetamide;

[1214] 5-amino-3-(2-(4-(4-(2,3-dihydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1215] 5-amino-3-(2-(4-(4-(2-aminoethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1216] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide;

[1217] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-methylbenzamide;

[1218] 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(2-morpholinoethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1219] 5-amino-3-(2-(4-(4-(2-(dimethylamino)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1220] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzenesulfonamide;

[1221] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-methylbenzenesulfonamide;

[1222] 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1223] 5-amino-8-(furan-2-yl)-3-(2-(4-(4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1224] 3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)benzamide;

[1225] 5-amino-8-(furan-2-yl)-3-(2-(4-(3-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1226] 5-amino-3-(2-(4-(2-fluoro-4-(2-oxo-2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1227] 5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1228] 5-amino-3-(2-(4-(2-fluoro-4-(piperazine-1-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1229] 5-amino-3-(2-(4-(2-fluoro-4-(2-(piperazin-1-yl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1230] 5-amino-3-(2-(4-(2-fluoro-4-(piperazin-1-ylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1231] 5-amino-3-(2-(4-(2-fluoro-4-(methylsulfonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1232] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-aminoethyl)-3-fluorobenzamide;

[1233] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylamino)ethyl)benzamide;

[1234] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluorobenzamide;

[1235] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-hydroxyethyl)benzamide;

[1236] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-3-fluorobenzamide;

[1237] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetic acid;

[1238] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3,5-difluorophenoxy)acetic acid;

[1239] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid;

[1240] (S)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid;

[1241] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-2-methylpropanoic acid;

[1242] 3-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenyl)propanoic acid;

[1243] 4-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)butanoic acid;

[1244] 2-(3-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,6-difluorophenoxy)acetic acid;

[1245] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetic acid;

[1246] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorobenzoic acid;

[1247] 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)amino)acetamide;

[1248] 2-((2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)(methyl)amino)acetamide;

[1249] 5-amino-3-(2-(4-(2-fluoro-4-(piperidin-4-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1250] 5-amino-3-(2-(4-(2-fluoro-4-(pyrrolidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1251] 3-(2-(4-(4-((1H-1,2,4-triazol-3-yl)methoxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1252] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(methylamino)ethyl)acetamide;

[1253] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-(dimethylamino)ethyl)acetamide;

[1254] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-aminoethyl)acetamide;

[1255] (R)-2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)propanoic acid;

[1256] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)acetamide;

[1257] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-methyl-N-(2-(methylamino)ethyl)benzamide;

[1258] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-3-fluoro-N-methylbenzamide;

[1259] (R)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(1-(dimethylamino)propan-2-yl)-3-fluorobenzamide;

[1260] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-methyl-N-(2-(methylamino)ethyl)acetamide;

[1261] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-2-methylpropanoic acid;

[1262] (S)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoic acid;

[1263] (R)-2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)propanoic acid;

[1264] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(methylamino)ethyl)acetamide;

[1265] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-(dimethylamino)ethyl)acetamide;

[1266] 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluoro-N-methylbenzamide;

[1267] 4-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)butanoic acid;

[1268] 3-(2-(4-(5-((1H-tetrazol-5-yl)methoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-5-amino-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1269] 5-amino-3-(2-(4-(2-fluoro-4-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1270] 5-amino-3-(2-(4-(2,4-difluoro-5-((1-methyl-1H-1,2,4-triazol-3-yl)methoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1271] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methyl(oxetan-3-yl)amino)ethyl)benzamide;

[1272] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-((2-hydroxyethyl)amino)ethyl)benzamide;

[1273] 2-amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)acetamide;

[1274] (S)-2-amino-N-(2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)ethyl)-3-methylbutanamide;

[1275] Ethyl 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetate;

[1276] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)acetonitrile;

[1277] 5-amino-8-(furan-2-yl)-3-(2-(4-(pyridin-4-yl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1278] 5-amino-8-(furan-2-yl)-3-(2-(4-(pyrimidin-4-yl)piperazin-1-yl)ethyl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1279] 5-amino-3-(2-(4-(2,4-difluoro-5-(2-(methylsulfonyl)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;

[1280] 5-amino-3-(2-(4-(2-fluoro-4-(2-(methylsulfonyl)ethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1281] 5-amino-3-(2-(4-(6-fluoro-2-oxoindolin-5-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1282] 5-amino-3-(2-(4-(2-fluoro-4-(S-methylsulfonylimino)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1283] 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2-(dimethylamino)ethyl)-2,4-difluorobenzamide;

[1284] 5-amino-3-(2-(4-(5-fluoro-2-methylpyridin-4-yl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1285] 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1286] 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-hydroxytetrahydrofuran-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1287] 5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxy-2-methylpropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1288] 5-amino-3-(2-(4-(2-fluoro-4-(2-hydroxypropan-2-yl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1289] 5-amino-3-(2-(4-(2-fluoro-4-(3,3,3-trifluoro-2-hydroxypropoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1290] 5-amino-3-(2-(4-(2-fluoro-5-(2-hydroxyethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1291] 5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1292] 5-amino-3-(2-(4-(2,4-difluoro-5-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1293] 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1294] 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1295] 5-amino-3-(2-(4-(2,4-difluoro-5-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1296] 5-amino-3-(2-(4-(2,4-difluoro-5-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1297] (S)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1298] (R)-5-amino-3-(2-(4-(2,4-difluoro-5-((2-oxopyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1299] 2-(5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluorophenoxy)-N-(2-morpholinoethyl)acetamide;

[1300] 5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(morpholin-3-ylmethyl)benzamide;

[1301] 5-amino-3-(2-(4-(2-fluoro-4-(morpholin-3-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1302] 5-amino-3-(2-(4-(2-fluoro-4-(morpholin-2-ylmethoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1303] 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1304] 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1305] 5-amino-3-(2-(4-(2-fluoro-4-(((3R,4S)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1306] 5-amino-3-(2-(4-(2-fluoro-4-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1307] 2-(4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluorophenoxy)-N-(2-morpholinoethyl)acetamide;

[1308] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-morpholinoethyl)benzamide;

[1309] 4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(morpholin-3-ylmethyl)benzamide;

[1310] 5-amino-3-(2-(4-(4-(azetidin-3-yloxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1311] (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1312] (R)-5-amino-3-(2-(4-(2,4-difluoro-5-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1313] 5-amino-3-(2-(4-(2,4-difluoro-5-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1314] 5-amino-3-(2-(4-(2,4-difluoro-5-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1315] (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide;

[1316] (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-(2-(methylsulfinyl)ethyl)benzamide;

[1317] (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2-(methylsulfinyl)ethyl)benzamide;

[1318] (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-2,4-difluoro-N-methyl-N-(2-(methylsulfinyl)ethyl)benzamide;

[1319] 5-amino-3-(2-(4-(2,4-difluoro-5-(1-oxothiomorpholine-4-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1320] 5-amino-3-(2-(4-(2,4-difluoro-5-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1321] (R)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1322] (S)-5-amino-3-(2-(4-(2-fluoro-4-(methylsulfinyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1323] 5-amino-3-(2-(4-(2-fluoro-4-(((1s,4s)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1324] 5-amino-3-(2-(4-(2-fluoro-4-(((1r,4r)-1-oxidotetrahydro-2H-thiopyran-4-yl)oxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1325] (S)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide;

[1326] (R)-4-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-3-fluoro-N-(2-(methylsulfinyl)ethyl)benzamide;

[1327] 5-amino-3-(2-(4-(2-fluoro-4-(1-oxothiomorpholine-4-carbonyl)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1328] 5-amino-3-(2-(4-(2-fluoro-4-(1-oxidothiomorpholino)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1329] (S)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1330] (R)-5-amino-3-(2-(4-(5-(2,3-dihydroxypropoxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1331] (S)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide;

[1332] (R)-5-(4-(2-(5-amino-8-(furan-2-yl)-2-oxothiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-3(2H)-yl)ethyl)piperazin-1-yl)-N-(2,3-dihydroxypropyl)-2,4-difluorobenzamide;

[1333] 5-amino-3-(2-(4-(4-(azetidin-3-yloxy)-2-fluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1334] 5-amino-3-(2-(4-(5-(azetidin-3-yloxy)-2,4-difluorophenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1335] (S)-5-amino-3-(2-(4-(2,4-difluoro-5-(3-(methylsulfinyl)propoxy)phenyl)piperazin-1-yl)ethyl)-8-(furan-2-yl)thiazolo[5,4-e][1,2,4]triazolo[1,5-c]pyrimidin-2(3H)-one;

[1336] and pharmaceutically acceptable salts or solvates thereof.

[1337] 8. A pharmaceutical composition according to any one of items 1 to 7, wherein the compound of formula (I) is selected from:

[1338] (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;

[1339] (+)-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;

[1340] and pharmaceutically acceptable salts or solvates thereof.

[1341] 9. The pharmaceutical composition according to any one of items 1 to 8, wherein the salt of the compound is a hydrochloride or an ethanesulfonate.

[1342] 10. The pharmaceutical composition according to any one of items 1 to 9, further comprising PEG 400, PEG 3350 and / or caprylic acid.

[1343] 11. A pharmaceutical composition according to any one of items 1 to 10, further comprising an antioxidant; preferably, the antioxidant is selected from butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid, sodium metabisulfite, ascorbic acid, methionine and vitamin E; more preferably, the antioxidant is BHT.

[1344] 12. The pharmaceutical composition according to any one of items 1 to 11, further comprising a wetting agent; preferably, the wetting agent is selected from sodium lauryl sulfate, vitamin E TPGS, docusate sodium, polysorbate 80 and poloxamer 407; more preferably, the wetting agent is sodium lauryl sulfate.

[1345] 13. The pharmaceutical composition according to any one of items 1 to 12, further comprising a precipitation inhibitor; preferably, the precipitation inhibitor is selected from hydroxypropyl methylcellulose, methylcellulose, polyvinyl pyrrolidone, polyvinyl pyrrolidone-polyvinyl acetate copolymer, polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer and poloxamer 407; more preferably, the precipitation inhibitor is hydroxypropyl methylcellulose.

[1346] 14. A pharmaceutical composition according to any one of items 1 to 13, wherein the compound of formula (I) is present in an amount ranging from 1% to 20% w / w, preferably from 5% to 15% w / w, more preferably about 10% w / w.

[1347] 15. A pharmaceutical composition according to any one of items 1 to 14, wherein the lipid carrier is present in an amount ranging from 55% to 99% w / w, preferably from 60% to 95% w / w, more preferably from 70% to 90% w / w.

[1348] 16. The pharmaceutical composition according to any one of items 1 to 15, wherein the composition can be formulated into different dosage forms, such as capsules, tablets or granules.

[1349] 17. A pharmaceutical composition according to any one of items 1 to 16, formulated as a capsule, wherein the capsule shell consists of gelatin, and wherein additional components are optionally included in the capsule shell, such as, for example, polyethylene glycol and sodium lauryl sulfate.

[1350] 18. The pharmaceutical composition according to any one of items 1 to 17, for use in the treatment and / or prevention of cancer.

[1351] 19. A pharmaceutical composition for use according to claim 18, wherein the cancer is selected from breast cancer, carcinoid tumor, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer and urothelial carcinoma.

[1352] 20. A combination comprising:

[1353] (a) at least one compound of formula (I):

[1354]

[1355] or a pharmaceutically acceptable salt or solvate thereof, wherein:

[1356] R 1 represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, wherein the heteroaryl or aryl is optionally substituted by one or more substituents selected from C1-C6 alkyl (preferably methyl) and halo (preferably fluorine or chlorine); preferably, R 1 represents a 5-membered heteroaryl group; more preferably, R 1 represents a furanyl group;

[1357] R 2 represents a 6-membered aryl or 6-membered heteroaryl group, wherein the heteroaryl or aryl group is optionally substituted by one or more substituents selected from the group consisting of a halo, an alkyl, a heterocyclyl, an alkoxy, a cycloalkyloxy, a heterocyclyloxy, a carbonyl, an alkylcarbonyl, an aminocarbonyl, a hydroxycarbonyl, a heterocyclylcarbonyl, an alkylsulfoxide, an alkylsulfonyl, an aminosulfonyl, a heterocyclylsulfonyl, an alkylsulfonimide, a carbonylamino, a sulfonylamino and an alkylsulfonealkyl group; [1...

Claims

1. The hydrochloride salt of the compound having the following structure:

2. The hydrochloride according to claim 1, wherein the hydrochloride 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 hydrochloride.

3. The hydrochloride according to claim 1, wherein the hydrochloride 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 hydrochloride.

4. A pharmaceutical composition comprising: a) the hydrochloride salt according to any one of claims 1 to 3; and b) Polyethylene glycol. The pharmaceutical composition according to claim 4 , further comprising lauroyl polyoxyl-32 glyceride.

6. The pharmaceutical composition according to claim 5, wherein the lauroyl polyoxyl-32 glyceride is 44 / 14.

7. The pharmaceutical composition according to claim 4, 5 or 6, further comprising butylated hydroxytoluene.

8. The pharmaceutical composition according to any one of claims 4 to 7, further comprising a polyvinyl pyrrolidone-polyvinyl acetate copolymer.

9. The pharmaceutical composition according to any one of claims 4 to 7, further comprising one or more additional pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants.

10. A pharmaceutical composition comprising: (a) A compound having the following structure or a pharmaceutically acceptable salt or solvate thereof; (b) a lipid carrier selected from lauroyl polyoxyl-32 glyceride, D-α-tocopheryl-polyethylene glycol-1000 succinate, and mixtures thereof; and (c) optionally one or more other pharmaceutically acceptable carriers, diluents, excipients and / or adjuvants.

11. The pharmaceutical composition according to claim 10, wherein the lauroyl polyoxyl-32 glyceride is 44 / 14.

12. The pharmaceutical composition according to claim 10 or 11, wherein the compound 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; (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; and Its pharmaceutically acceptable salt or solvate.

13. The pharmaceutical composition according to any one of claims 10-12, wherein the compound is a hydrochloride salt.

14. The pharmaceutical composition according to claim 13, wherein the hydrochloride 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 hydrochloride; or (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 hydrochloride.

15. The pharmaceutical composition according to any one of claims 10-14, further comprising polyethylene glycol.

16. The pharmaceutical composition according to any one of claims 10 to 15, further comprising butylated hydroxytoluene, butylated hydroxyanisole, citric acid, sodium metabisulfite, ascorbic acid, methionine or vitamin E; preferably butylated hydroxytoluene.

17. The pharmaceutical composition according to any one of claims 10 to 16, further comprising sodium lauryl sulfate, vitamin E TPGS, docusate sodium, polysorbate 80 or poloxamer 407; preferably sodium lauryl sulfate.

18. The pharmaceutical composition according to any one of claims 10-17, further comprising hydroxypropyl methylcellulose, methylcellulose, polyvinyl pyrrolidone, polyvinyl pyrrolidone-polyvinyl acetate copolymer, polyvinyl caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer or poloxamer 407; preferably polyvinyl pyrrolidone-polyvinyl acetate copolymer.

19. The pharmaceutical composition according to any one of claims 4-18, wherein the compound has the structure or a pharmaceutically acceptable salt or solvate thereof, The compound is present in an amount ranging from 1% to 20% w / w, or from 5% to 15% w / w.

20. The pharmaceutical composition of any one of claims 5-19, wherein lauroyl polyoxyl-32 glyceride is present in an amount ranging from 55% to 99% w / w, or from 60% to 95% w / w, or from 70% to 90% w / w.

21. The pharmaceutical composition according to any one of claims 4 to 20, wherein the composition is suitable for oral administration.

22. The pharmaceutical composition according to any one of claims 4-21, wherein the composition is formulated as a capsule, tablet or pill.

23. Use of a compound according to any one of claims 1 to 3 or a pharmaceutical composition according to any one of claims 4 to 22 for the preparation of a medicament for the treatment and / or prevention of cancer.

24. The use according to claim 23, wherein the cancer is selected from breast cancer, carcinoid tumor, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, prostate cancer, kidney cancer, gastric cancer, thyroid cancer and urothelial carcinoma.

25. The use according to claim 23, wherein the cancer is selected from breast cancer, prostate cancer, melanoma and solid tumors.

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