JP2022503879A - Use of ENT family transporter inhibitors in the treatment of cancer and their combination with adenosine receptor antagonists - Google Patents

Abstract

The present invention relates to the use of ENT family transporter inhibitors for the treatment of cancer. The present invention further relates to the combined use of the ENT family transporter inhibitor and an adenosine receptor antagonist for the treatment of cancer. The present invention further relates to pharmaceutical compositions and parts kits comprising such combinations.

Description

The present invention relates to the use of ENT family transporter inhibitors for the treatment of cancer. The present invention further relates to the combined use of the ENT family transporter inhibitor and an adenosine receptor antagonist for the treatment of cancer. The present invention further relates to pharmaceutical compositions and parts kits comprising such combinations.

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

One of the endogenous substrates of ENT is adenosine, a potent physiological and pharmacological regulator of many functions. Cell signaling by adenosine occurs via four known G protein-coupled adenosine receptors A1, A2A, A2B, and A3. ENT plays an important regulatory role in various physiological processes, including regulation of coronary blood flow, inflammation, and neurotransmission by affecting the concentration of adenosine provided to these receptors (Griffith). DA and Jarvis SM, Biochim Biophyss Acta, 1996, 1286, 153-181; Shryock JC and Belardinelli L, Am J Cardiol, 1997, 79 (12A), 2-10; Anderson 99 (12A), 2-10; Anderson 99. , 867-873).

Various agents, such as dilazep, dipyridamole, and drafurazine, that interact with ENT and alter adenosine levels, have been developed for cardioprotective or vasodilatory effects.

Adenosine is also a potent immunosuppressive metabolite and is often elevated in the extracellular tumor microenvironment (TME) (Bray Jet al., Cancer Res, 1997, 57, 2602-265). Extracellular adenosine is primarily produced by the conversion of ATP by the ectonucleotidases CD39 and CD73 (Stag J and Smith MJ, Oncogene, 2010, 2, 5346-5358). Adenosine activates four G protein-coupled receptor subtypes (A1, A2A, A2B, and A3). In particular, activation of the A2A receptor is believed to be a major promoter of innate and acquired immune cell suppression leading to suppression of antitumor immune responses (Ohta and Sitkovsky, Nature, 2001, 414, 916). -920) (Stag and Smith, Oncogene, 2010, 2,5346-5358) (Antonioli L et al., Nature Reviews Cancer, 2013, 13, 842-857) (Cekic Cand LindenJ, N. , 16, 177-192) (Allard B et al., Curr Op Pharmacol, 2016, 29, 7-16) (Vijayan D et al., Nature Reviews Cancer, 2017, 17, 709-724).

To evaluate whether adenosine can reduce T cell vitality through intracellular uptake by ENT, ENT transporters localized to the plasma membrane in human primary lymphocytes (ENT1, ENT2, and ENT4). The mRNA expression level of the cells was confirmed in the public RNA-seq database (Monnal RJP et al., Nature, 2015, 2: 150051). B cells, CD4 ⁺ T cells, and CD8 ⁺ T cells expressed ENT1 (SLC29A1), ENT2 (SLC29A2), and ENT4 (SLC29A4) (FIGS. 1A, 1B, and 1C).

Applicants herein have demonstrated that adenosine and ATP significantly suppress T cell proliferation and cytokine secretion (IL-2) and significantly reduce T cell viability. Adenosine-mediated and ATP-mediated inhibition of T cell viability and proliferation was restored normally with the use of ENT inhibitors.

Furthermore, when an ENT inhibitor is used in combination with an adenosine receptor antagonist, not only can the adenosine-mediated and ATP-mediated suppression of T cell viability and proliferation be restored, but also the cytokine secretion of T cells can be restored. rice field.
Accordingly, the present invention provides the use of ENT family transporter inhibitors for the treatment of cancer. It also provides a combination of the ENT family transporter inhibitor and an adenosine receptor antagonist for the treatment of cancer.

Griffith DA and Jarvis SM, Biochim Biophys Acta, 1996, 1286, 153-181 Shryock JC and Belardinelli L, Am J Cardiol, 1997, 79 (12A), 2-10 Anderson CM et al. , J Neurochem, 1999, 73, 867-873 Bray J et al. , Cancer Res, 1997, 57, 2602-265 Stag J and Smith MJ, Oncogene, 2010, 2,5346-5358 Ohta and Sitkovsky, Nature, 2001, 414, 916-920 Antonioli L et al. , Nature Reviews Cancer, 2013, 13, 842-857 Celsius Cand Linden J, Nature Reviews, Immunology, 2016, 16, 177-192 Allard B et al. , Curr Op Subject, 2016, 29, 7-16 Vijayan D et al. , Nature Reviews Cancer, 2017, 17, 709-724 Bonnal RJP et al. , Nature, 2015, 2: 150051

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

In one embodiment, the ENT family transporter is ENT1 and the inhibitor is selected from the group consisting of small molecules, nucleic acids, peptides, and antibodies.

In one embodiment, the subject is treated with an additional therapeutic agent in combination with an ENT family transporter inhibitor or is given an additional therapeutic agent within approximately 14 days of administration of the ENT family transporter inhibitor. In one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist.

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

The present invention also provides a combination containing an effective amount of an ENT family transporter inhibitor for the treatment of cancer in a human subject.

In one embodiment, the ENT family transporter inhibitor is administered before, at the same time as, or after administration of an additional therapeutic agent comprising an adenosine receptor antagonist.

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

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

In one embodiment, the adenosine receptor antagonist is selected from:
5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine;
(S) -7- (5-Methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2-yl) methyl) -3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-amine;
6- (2-Chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine;
3- (2-Amino-6-(1-((6- (2-hydroxypropane-2-yl) pyridine-2-yl) methyl) -1H-1,2,3-triazole-4-yl) pyrimidine -4-yl) -2-methylbenzonitrile;
2- (2-Franyl) -7- (2- (4- (4- (2-Methoxyethoxy) phenyl) -1-piperazinyl) ethyl) -7H-pyrazolo (4,3-e) (1,2, 4) Triazolo (1,5-c) pyrimidine-5-amine;
3- (4-Amino-3-methylbenzyl) -7- (2-furyl) -3H- (1,2,3) triazolo (4,5-d) pyrimidine-5-amine; and 4-hydroxy-N -(4-Methoxy-7-morpholinobenzo [d] thiazole-2-yl) -4-methylpiperidine-1-carboxamide.

In one embodiment, the adenosine receptor antagonist is a compound of formula (I) as defined below.

In one embodiment, the ENT family member is ENT1.

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

The present invention further provides a formulation comprising an effective amount of an adenosine receptor antagonist in combination with an effective amount of an ENT family member inhibitor, as well as a pharmaceutically acceptable excipient.

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

In one embodiment, the adenosine receptor antagonist in the formulation is selected from:
5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine;
(S) -7- (5-Methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2-yl) methyl) -3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-amine;
6- (2-Chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine;
3- (2-Amino-6-(1-((6- (2-hydroxypropane-2-yl) pyridine-2-yl) methyl) -1H-1,2,3-triazole-4-yl) pyrimidine -4-yl) -2-methylbenzonitrile;
2- (2-Franyl) -7- (2- (4- (4- (2-Methoxyethoxy) phenyl) -1-piperazinyl) ethyl) -7H-pyrazolo (4,3-e) (1,2, 4) Triazolo (1,5-c) pyrimidine-5-amine;
3- (4-Amino-3-methylbenzyl) -7- (2-furyl) -3H- (1,2,3) triazolo (4,5-d) pyrimidine-5-amine; and 4-hydroxy-N -(4-Methoxy-7-morpholinobenzo [d] thiazole-2-yl) -4-methylpiperidine-1-carboxamide.

In one embodiment, the adenosine receptor in the pharmaceutical product is a compound of formula (I) as defined below.

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

In one embodiment, the pharmaceutical product further comprises an additional therapeutic agent.

Definitions In the present invention, the following terms have the following meanings.

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

The term "alkenyl" refers to an unsaturated hydrocarbyl group that may be linear or branched and contains 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 ethenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl and its isomers, 2-hexenyl and its isomers, 2,4-pentadienyl and the like.

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

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

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

The term "alkyl" refers to the hydrocarbyl radical of the formula C _n H _{2n + 1} (where n is a number greater than or equal to 1). In general, the alkyl group of the present invention contains 1 to 8 carbon atoms, more preferably the alkyl group of the present invention contains 1 to 6 carbon atoms. The alkyl group may be linear or branched. Suitable alkyl groups include methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, and octyl.

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

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

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

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

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

The term "alkyl heteroaryl" refers to any heteroaryl substituted with an alkyl group, as alkyl is as defined herein.

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

The term "alkylsulfonyl" refers to the group-SO2 _- alkyl, as alkyl is as defined herein.

The term "alkyl sulfone alkyl" refers to the group-alkyl-SO ₂ -alkyl, where alkyl is as defined herein.

The term "alkylsulfoneimideyl" refers to the group -S (= O) (= NH) -alkyl, as alkyl is as defined herein.

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

The term "alkylsulfoxide alkyl" refers to the group-alkyl-SO-alkyl, where alkyl is as defined herein.

The term "alkyne" refers to a class of monovalent unsaturated hydrocarbyl groups that are unsaturated due to the presence of one or more carbon-carbon triple bonds. The alkynyl group usually and preferably has the same number of carbon atoms as above with respect to the alkyl group. Non-limiting examples of alkynyl groups include ethynyl, 2-propynyl, 2-butynyl, 3-butynyl, 2-pentynyl and its isomers, 2-hexynyl and its isomers and the like.

The term "alkyne alkyl" refers to a group-alkyl-alkyne, as alkyl and alkyne are as defined herein.

The term "amino" refers to group-NH ₂ .

The term "aminoalkyl" refers to the group-alkyl-NH ₂ , where alkyl is as defined herein.

The term "aminoalkylaminocarbonyl" refers to the group-(C = O) -NH-alkyl-NH ₂ , where alkyl is as defined herein.

The term "aminoalkylcarbonylamino" refers to the group -NH- (C = O) -alkyl-NH ₂ , where alkyl is as defined herein.

The term "aminocarbonyl" refers to the group- (C = O) -NH ₂ .

The term "(aminocarbonylalkyl) (alkyl) amino" refers to the group -NR ¹ R ² , where in the formula R ¹ is an alkyl group and R ² is -alkyl- (C = O) -NH ₂ It is a group and alkyl is as defined herein.

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

The term "aminosulfonyl" refers to the group -SO ₂ -NH ₂ .

The term "aryl" is a polycycle having a monocycle (ie, phenyl) or an aromatic polycycle (eg, naphthyl) fused to each other, typically containing 5-12, preferably 5-10 atoms. It refers to a valent unsaturated aromatic hydrocarbyl group, more preferably a 5- or 6-membered aryl. Non-limiting examples of aryls include phenyl, naphthalenyl.

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

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

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

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

The term "dialkylamino" refers to the group -NR ¹ R ² , where R ¹ and R ² are both alkyl groups independently defined herein.

The term "dialkylaminoalkyl" refers to the group-alkyl-NR ¹ R ² , where R ¹ and R ² are both alkyl groups independently defined herein.

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

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

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

The term "halo" or "halogen" refers to fluoro, chloro, bromo, or iodine.

The term "heteroaryl" refers to an aryl group as defined herein in which at least one carbon atom is substituted with a heteroatom. In other words, an aromatic monocycle of 5-12 carbon atoms, or a ring system containing two fused rings, usually containing 5-6 atoms, one or more in the ring. The carbon atom of the above is substituted with an oxygen atom, a nitrogen atom, and / or a sulfur atom, in which case the nitrogen and sulfur of the heteroatom may be optionally oxidized, and the nitrogen of the heteroatom is optional. It may be quaternized by selection. Non-limiting examples of such heteroaryls include oxazolyl, thiazolyl, imidazolyl, furanyl, and pyrrolyl. Preferably, the heteroaryl is a 5- or 6-membered heteroaryl, and more preferably the 5- or 6-membered heteroaryl is a frill.

The term "heterocyclyl" refers to a non-aromatic cyclic group, a fully saturated cyclic group, or a partially unsaturated cyclic group (eg, 3-7 members) having at least one heteroatom in a ring containing at least one carbon atom. It refers to a monocyclic type, a 7 to 11 member bicyclic type, or a type containing a total of 3 to 10 ring atoms). Preferably, the heterocyclyl is a 5- or 6-membered heterocyclyl. Each ring of a heteroatom containing a heteroatom may have one, two, three, or four heteroatoms selected from a nitrogen atom, an oxygen atom, and / or a sulfur atom. In this case, the heteroatom nitrogen and sulfur may be optionally oxidized and the heteroatom nitrogen may be optionally quaternized. Heterocyclic groups can be attached to any heteroatom or carbon atom of the ring or ring system, as long as the valence allows. The ring of the polycyclic heterocycle may be condensed or crosslinked and / or bonded via one or more spiro atoms. Examples of non-limiting heterocyclic groups are aziridinyl, oxylanyl, thiylanyl, piperidinyl, azetidinyl, 2-imidazolinyl, pyrazolidinyl imidazolidinyl, isooxazolinyl, oxazolidinyl, isooxazolidinyl, thiazolidinyl, isothiazo. Ridinyl, piperidinyl, succinimidyl, 3H-indrill, indolinyl, isoindolinyl, 2H-pyrrolyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 4H-quinolinidinyl, 2-oxopiperazinyl, piperazinyl, homopiperazinyl, 2- Pyrazolinyl, 3-pyrazolinyl, tetrahydro-2H-pyranyl, 2H-pyranyl, 4H-pyranyl, 3,4-dihydro-2H-pyranyl, oxetanyl, thietanyl, 3-dioxolanyl, 1,4-dioxanyl, 2,5-dioxy Imidazolidinyl, 2-oxopiperidinyl, 2-oxopyrrodynyl, indolinyl, tetrahydropyranyl, tetrahydrofuranyl, tetrahydrothiophenyl, tetrahydroquinolinyl, tetrahydroisoquinoline-1-yl, tetrahydroisoquinoline-2-yl, Tetrahydroisoquinoline-3-yl, tetrahydroisoquinoline-4-yl, thiomorpholine-4-yl, 1-oxide-1-thiomorpholine-4-yl, 1-dioxide-1-thiomorpholine-4-yl, 1,3 -Dioxolanil, 1,4-oxathianyl, 1,4-dithianyl, 1,3,5-trioxanyl, 1H-pyrrolidinyl, tetrahydro-1,1-dioxothiophenyl, N-formylpiperazinyl, and morpholine-4- Il can be mentioned.

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

The term "(heterocyclyl) (alkyl) aminoalkyl" refers to the group-alkyl-NR ¹ R ² , where R ¹ is an alkyl group, R ² is a heterocyclyl group, and alkyl and heterocyclyl are herein. As defined in the book.

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

The term "heterocyclylalkyl" refers to group-alkyl-heterocyclyl, as alkyl and heterocyclyl are as defined herein.

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

The term "heterocyclyl sulfonyl" refers to the group-SO ₂ -heterocyclyl, which is as defined herein.

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

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

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

The term "oxo" refers to substituent = O.

The term "sulfonylamino" refers to the group -NH-SO ₂ .

The term "about" that precedes a number includes values 10% above and below that number. It should be understood that the values dictated by the term "about" should also be clearly disclosed in their own right.

The term "administration" or a variant thereof (eg, "administration") treats a pathological condition, symptom, or disease with an active agent or active ingredient, alone or as part of a pharmaceutically acceptable composition. Or it means giving to the patient trying to prevent.

The term "antagonist" refers to a natural or synthetic compound that binds to a protein and blocks the biological activation of the protein and the resulting action of the protein. A protein can be a receptor, a protein molecule that receives a chemical signal from outside the cell. Thus, "adenosine receptor antagonists" include any chemical that, when administered to a patient, results in inhibition or downregulation of biological activity associated with adenosine receptor activation. Biological activity includes any of the downstream biological effects that would otherwise result from binding of the natural ligand to the adenosine receptor. Such adenosine receptor antagonists include any agent capable of blocking either adenosine receptor activation or downstream biological effects of adenosine receptor activation.

The term "inhibitor" refers to a biological effect that inhibits or significantly reduces or downregulates the expression of a gene and / or protein, or inhibits or significantly reduces the biological activity of a protein. Refers to a natural or synthetic compound that has. Thus, "ENT inhibitor" or "ENT family transporter inhibitor" refers to a compound having a biological effect that inhibits, significantly reduces or downregulates the biological activity of the ENT family transporter.

As used herein, the term "antibody" includes monoclonal antibodies, polyclonal antibodies, multispecific antibodies (eg, bispecific antibodies), and antibody fragments as long as they exhibit the desired biological activity. do.

The term "chemotherapy" refers to a type of cancer treatment that uses one or more anticancer agents (chemotherapeutic agents) as part of a standard chemotherapy regimen. Chemotherapy may be given for cure, or it may be for life extension or relief of symptoms. Chemotherapeutic agents include, for example, anticancer alkylating agents, anticancer metabolic antagonists, anticancer antibiotics, plant-derived anticancer agents, anticancer platinum coordination compounds, and any of them. It is selected from the combination of.

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

The term "human" refers to an amphoteric subject at any stage of development (ie, newborn, infant, young, adolescent, adult).

The term "patient" refers to a mammal, more preferably a human, who is awaiting or receiving medical treatment, or is the subject of medical treatment, or is the subject of medical treatment.

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

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

The term "peptide" refers to a linear polymer of amino acids less than 50 amino acids bound to each other by peptide bonds.

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

The expression "pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant" causes side effects, allergic reactions, or other adverse reactions when administered to animals, preferably humans. Refers to substances that do not allow. These include, for example, solvents, co-solvents, antioxidants, surfactants, stabilizers, emulsifiers, buffers, pH regulators, preservatives (or preservatives), antibacterial and antifungal agents, isotonic agents, fabrications. Granules or binders, solvents, disintegrants, flow promoters, diluents or fillers, adsorbents, dispersants, suspensions, coatings, bulking agents, release agents, absorption retarders, sweeteners, flavors Contains all non-active substances such as agents. For human administration, the preparation must meet the criteria for sterility, exothermic properties, general safety, and purity required by regulatory agencies such as the FDA Bureau or EMA.

As used herein, the terms "prevent", "prevent", and "prevention" refer to a method of delaying or eliminating the onset of a condition or disease and / or its associated symptoms, in which the patient has the condition or disease. It refers to a method of preventing the disease or reducing the risk of the patient suffering from a condition or disease.

As used herein, the term "prodrug" is pharmacologically acceptable for compounds of formula (I), such as esters or amides, the in vivo in vivo conversion product of which produces a bioactive drug. Means the derivative to be. Prodrugs are generally characterized by increased bioavailability and are easily metabolized in vivo to become bioactive compounds.

The term "radiation therapy" refers to cancer treatments using various radiation sources such as X-rays, gamma rays, neutrons, electron beams, protons, and radiation sources. It is used to control or kill malignant cells as part of cancer treatment. Radiation therapy can cure many types of cancer if it is confined to one area of the body. It can also be used as part of adjuvant therapy to prevent recurrence of the tumor after surgery to remove the primary malignant tumor. Radiation therapy is broadly divided into three main categories: external beam radiation therapy (EBRT or XRT); small source therapy or sealed source radiation therapy; and systemic radioisotope therapy (RIT) or unsealed source radiation therapy. ..

The terms "therapeutically effective amount" or "effective amount" or "therapeutically effective dose" are used to (1) delay or prevent the development of cancer in a subject without causing significant negative effects or adverse side effects in the subject. (2) To reduce the severity or incidence of cancer; (3) To slow or stop the progression, aggravation, or worsening of one or more symptoms of the cancer that affect the subject; (4) Affecting a subject, resulting in amelioration of cancer symptoms; or (5) Amount or dose of an active ingredient that affects a subject and is intended to cure the cancer. As a prophylactic agent or treatment, a therapeutically effective amount may be administered prior to the onset of cancer. Alternatively, or in addition, as a therapeutic treatment, a therapeutically effective amount may be administered after the onset of the cancer.

The term "treating" or "treatment" refers to curative treatment, in which case it is intended to prevent or slow down the targeted pathological condition or disease. After the subject or mammal has been treated according to the present invention, i.e., a decrease in cancer cell count; and / or some relief of one or more symptoms associated with a particular disease or condition; morbidity and A subject or mammal is "treated" for a disease or abnormality or condition if it exhibits one or more observable and / or measurable reductions or disappearances of reduced mortality and improved quality of life problems. Is working. The above parameters for assessing the success and improvement of treatment of a disease can be easily measured by routine procedures familiar to physicians.

The term "stem cell transplantation" refers to a procedure in which healthy hematopoietic cells (stem cells) are given to a patient and replaced by autologous cells destroyed by radiation or high doses of anticancer drug given by the disease or as part of the procedure. Healthy stem cells can be derived from the patient's blood or bone marrow, donor, or neonatal umbilical cord blood. Stem cell transplantation can be autologous transplantation (using the patient's own stem cells collected and stored prior to treatment), allogeneic transplantation (using stem cells donated by others other than identical twins), or allogeneic transplantation (using stem cells donated by others other than identical twins). (Using stem cells donated by identical twins).

The term "subject" refers to mammals, preferably humans. In one embodiment, the subject has been diagnosed with cancer. In one embodiment, a subject is a patient, preferably a human, who is awaiting or receiving medical treatment, is subject to medical treatment, or is monitored for the development or progression of a disease such as cancer. I am a patient. In one embodiment, the subject is a human patient who is treated and / or monitored for the development or progression of cancer. In one embodiment, the subject is a man. In another embodiment, the subject is a female. In one embodiment, the subject is an adult. In another embodiment, the subject is a child.

ENT Inhibitors for Use in Cancer Treatment The present invention relates to the use of ENT family transporter inhibitors for cancer treatment.

Hereinafter, the ENT family transporter inhibitor is also referred to as an ENT inhibitor.

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

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

In one embodiment, the ENT inhibitor is an inhibitor selective for ENT1. In one embodiment, the ENT inhibitor is an inhibitor that is selective for ENT1 compared to other ENT inhibitors, especially compared to ENT2 and ENT4.

In one embodiment, the ENT inhibitor is selected from the group consisting of small molecules, nucleic acids, peptides, and antibodies.

Examples of ENT inhibitors are dilazep, dipyridamole, NBMPR (nitrobenzylthioinosine), drafurazine, STI-571 (Gleevec), ticagrelor, solfurazine, miofladine, decinium-22, lopinavir, quinidine, 8MDP, TC-T 6000, 5 -Iodotubercidin, cilostazol, salts thereof, and any mixture thereof. In a specific embodiment, the ENT inhibitor is selected from NaCl, dipyridamole, dilazep, ticagrelor, and salts thereof, including dilazep hydrochloride. In a specific embodiment, the ENT inhibitor is selected from dipyridamole, dilazep, ticagrelor, and salts thereof, including dilazep hydrochloride. In one embodiment, the ENT inhibitor is NBMP or a salt thereof. In one embodiment, the ENT inhibitor is dipyridamole or a salt thereof. In one embodiment, the ENT inhibitor is dilazep or a salt thereof, including dilazep hydrochloride. In one embodiment, the ENT inhibitor is ticagrelor or a salt thereof.

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

Accordingly, the present invention relates to ENT family transporter inhibitors used for the treatment of cancer in human subjects.

In one embodiment, the subject is treated with an additional therapeutic agent in combination with an ENT family transporter inhibitor or is given an additional therapeutic agent within approximately 14 days of administration of the ENT family transporter inhibitor. In one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist. In one embodiment, the ENT family transporter inhibitor is administered before, at the same time as, or after administration of an additional therapeutic agent comprising an adenosine receptor antagonist.

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

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

In one embodiment, in the methods of the invention, the subject is treated with an additional therapeutic agent in combination with an ENT family transporter inhibitor, or an additional therapeutic agent within approximately 14 days of administration of the ENT family transporter inhibitor. Given. In one embodiment, in the method of the invention, the additional therapeutic agent comprises an adenosine receptor antagonist. Further details regarding the adenosine receptor antagonist are described below.

In one embodiment, in the method of the invention, the subject has previously received at least one prior therapeutic treatment, after administration of at least one prior therapeutic treatment and prior to administration of the ENT family transporter inhibitor. Is progressing to. In one embodiment, in the methods of the invention, the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, hormone therapy, and surgery.

The present invention also relates to a combination drug comprising an effective amount of an ENT family transporter inhibitor for the treatment of cancer in a human subject.

In one embodiment, in the pharmaceutical product of the present invention, the ENT family transporter inhibitor is administered before, at the same time as, or after administration of an additional therapeutic agent containing an adenosine receptor antagonist.

Combination: ENT inhibitor and adenosine receptor antagonist The present invention further relates to a combination of an ENT inhibitor and an adenosine receptor antagonist.

Therefore, the present invention
(A) Effective amount of ENT inhibitor and
(B) Concerning combinations comprising, with, an effective amount of an adenosine receptor antagonist.

In the context of the present invention, the term "combination" preferably means that an ENT inhibitor and an A2AR antagonist are present in combination. Accordingly, combinations of the invention may be present as one composition (eg, a pharmaceutical composition) comprising all components in one same mixture, or different components may form different parts of a parts kit. It may exist as a parts kit. Administration of the ENT inhibitor and administration of the A2AR antagonist at the same or staggered time of administration (ie, the frequency of administration of each component is approximately the same or different), at the same site or at different sites. Either can be done in approximately the same or different dosage forms.

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

The above embodiments for ENT inhibitors also apply to the combinations of the invention. In particular, in one embodiment, in the combination of the invention, the ENT inhibitor is an inhibitor of ENT1.

The combination of the present invention comprises at least one adenosine receptor antagonist as the second component.

As defined above, "adenosine receptor antagonist" refers to a compound that, when administered to a patient, results in inhibition or downregulation of the biological activity associated with activation of the adenosine receptor. Biological activity includes any of the downstream biological effects that would otherwise result from binding of the natural ligand to the adenosine receptor. Such adenosine receptor antagonists include any agent capable of blocking either adenosine receptor activation or downstream biological effects of adenosine receptor activation.

Adenosine receptors (or P1 receptors) are a class of purinergic G protein-coupled receptors with adenosine as an endogenous ligand. There are four known types of adenosine receptors in humans, A1, A2A, A2B, and A3, each encoded by a different gene (ADOARA1, ADORA2A, ADORA2B, and ADORA3, respectively).

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

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

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

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

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

In a specific embodiment, the combination of the invention comprises at least one A2A receptor antagonist as defined herein and at least one as defined above, eg, at least one ENT1 inhibitor. Includes ENT inhibitors.

A2A Receptor Antagonist In one embodiment, the combination of the invention comprises at least one A2AR antagonist.

"A2AR antagonist" refers to a compound that, when administered to a patient, results in inhibition or downregulation of biological activity associated with activation of the A2A receptor. Biological activity includes any of the downstream biological effects that would otherwise result from binding of the natural ligand to the A2A receptor. Such A2AR antagonists include any agent capable of blocking either A2A receptor activation or downstream biological effects of A2A receptor activation.

Examples of A2AR antagonists are preladenant (SCH-420,814), bipadenant (BIIB-014), tozadenant (SYK-115), ATL-444, istradefylline (KW-6002), MSX-3, SCH-5621, SCH-412,348, SCH-442,416, ST-1535, caffeine, VER-6623, VER-6497, VER-7835, ZM-241,385, theophylline. Also included are A2AR antagonists disclosed in WO2018 / 178338, WO2011 / 121418, WO2009 / 156737, WO2011 / 09562, or WO2018 / 136700.

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

（式中、Ｒ^１及びＲ^２は以下に定義される通りである）のチオカルバメート誘導体またはその薬学的に許容される塩もしくは溶媒和物であるＡ２ＡＲアンタゴニストと、
を含む組み合わせを提供する。 Therefore, in a specific embodiment, the present invention comprises (a) an ENT inhibitor.
(B) Equation (I)

With A2AR antagonists, which are thiocarbamate derivatives of (where R ¹ and R ² are as defined below) or pharmaceutically acceptable salts or solvates thereof.
Provide combinations including.

の化合物、またはその薬学的に許容される塩もしくは溶媒和物であり、式中、
Ｒ^１は、５員もしくは６員のヘテロアリールまたは５員もしくは６員のアリールを表し、ヘテロアリール基またはアリール基は任意選択で、Ｃ１～Ｃ６アルキル（好ましくはメチル）及びハロ（好ましくはフルオロまたはクロロ）から選択される１つ以上の置換基で置換され、好ましくは、Ｒ^１は５員ヘテロアリールを表し、より好ましくは、Ｒ^１はフリルを表し；
Ｒ^２は、６員アリールまたは６員ヘテロアリールを表し、
ヘテロアリール基またはアリール基は任意選択で、ハロ、アルキル、ヘテロシクリル、アルコキシ、シクロアルキルオキシ、ヘテロシクリルオキシ、カルボニル、アルキルカルボニル、アミノカルボニル、ヒドロキシカルボニル、ヘテロシクリルカルボニル、アルキルスルホキシド、アルキルスルホニル、アミノスルホニル、ヘテロシクリルスルホニル、アルキルスルホンイミドイル、カルボニルアミノ、スルホニルアミノ、及びアルキルスルホンアルキルから選択される１つ以上の置換基で置換され；
上記置換基が任意選択で、オキソ、ハロ、ヒドロキシ、シアノ、アルキル、アルケニル、アルデヒド、ヘテロシクリルアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルキルアミノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、（ヘテロシクリル）（アルキル）アミノアルキル、ヘテロシクリル、ヘテロアリール、アルキルヘテロアリール、アルキン、アルコキシ、アミノ、ジアルキルアミノ、アミノアルキルカルボニルアミノ、アミノカルボニルアルキルアミノ、（アミノカルボニルアルキル）（アルキル）アミノ、アルケニルカルボニルアミノ、ヒドロキシカルボニル、アルキルオキシカルボニル、アミノカルボニル、アミノアルキルアミノカルボニル、アルキルアミノアルキルアミノカルボニル、ジアルキルアミノアルキルアミノカルボニル、ヘテロシクリルアルキルアミノカルボニル、（アルキルアミノアルキル）（アルキル）アミノカルボニル、アルキルアミノアルキルカルボニル、ジアルキルアミノアルキルカルボニル、ヘテロシクリルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホキシド、アルキルスルホキシドアルキル、アルキルスルホニル、及びアルキルスルホンアルキルから選択される１つ以上の置換基で置換されるか；
あるいは、ヘテロアリール基またはアリール基は任意選択で、それらが結合する原子とともに５員もしくは６員のアリール環、５員もしくは６員のヘテロアリール環、５員もしくは６員のシクロアルキル環、または５員もしくは６員のヘテロシクリル環を形成する２個の置換基で置換され、任意選択で、オキソ、ハロ、ヒドロキシ、シアノ、アルキル、アルケニル、アルデヒド、ヘテロシクリルアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルキルアミノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、（ヘテロシクリル）（アルキル）アミノアルキル、ヘテロシクリル、ヘテロアリール、アルキルヘテロアリール、アルキン、アルコキシ、アミノ、ジアルキルアミノ、アミノアルキルカルボニルアミノ、アミノカルボニルアルキルアミノ、（アミノカルボニルアルキル）（アルキル）アミノ、アルケニルカルボニルアミノ、ヒドロキシカルボニル、アルキルオキシカルボニル、アミノカルボニル、アミノアルキルアミノカルボニル、アルキルアミノアルキルアミノカルボニル、ジアルキルアミノアルキルアミノカルボニル、ヘテロシクリルアルキルアミノカルボニル、（アルキルアミノアルキル）（アルキル）アミノカルボニル、アルキルアミノアルキルカルボニル、ジアルキルアミノアルキルカルボニル、ヘテロシクリルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホキシド、アルキルスルホキシドアルキル、アルキルスルホニル、及びアルキルスルホンアルキルから選択される１つ以上の置換基で置換される。 In a preferred embodiment, the A2AR antagonist is the formula (I) :.

Compound, or a pharmaceutically acceptable salt or solvate thereof, in the formula,
^R1 represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, where the heteroaryl group or aryl group is optional and C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or or). Substituted with one or more substituents selected from (chloro), preferably R ¹ represents a 5-membered heteroaryl and more preferably R ¹ represents a frill;
R ² represents a 6-membered aryl or a 6-membered heteroaryl.
Heteroaryl group or aryl group is optional, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclyl. Substituted with one or more substituents selected from sulfonyl, alkylsulfonimideyl, carbonylamino, sulfonylamino, and alkylsulfonalkyl;
The above substituents are optional, oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl). (Alkyl) Aminoalkyl, Heterocyclyl, Heteroaryl, Alkyne Heteroaryl, Alkyne, Alkyne, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl) (Alkyl) Amino, Alkenylcarbonylamino, Hydroxycarbonyl , Alkyneoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylaminoalkylcarbonyl , Heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonalkyls substituted with one or more substituents selected from;
Alternatively, the heteroaryl group or aryl group is optionally a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, a 5- or 6-membered cycloalkyl ring, or a 5-membered ring with the atoms to which they are attached. Substituted with two substituents forming a member or 6-membered heterocyclyl ring, optionally oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl , Aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkin, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, ( Aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (Alkyl) with one or more substituents selected from aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxides, alkylsulfoxidealkyls, alkylsulfonyls, and alkylsulfonalkyls. Will be replaced.

のもの、またはその薬学的に許容される塩もしくは溶媒和物であり、式中、
Ｒ^１は、５員もしくは６員のヘテロアリールまたは５員もしくは６員のアリールを表し、ヘテロアリール基またはアリール基は任意選択で、Ｃ１～Ｃ６アルキル（好ましくはメチル）及びハロ（好ましくはフルオロまたはクロロ）から選択される１つ以上の置換基で置換され、好ましくは、Ｒ^１は５員ヘテロアリールを表し、より好ましくは、Ｒ^１はフリルを表し；
Ｘ^１及びＸ^２はそれぞれ独立してＣまたはＮを表し；
Ｒ^１’は、Ｘ^１がＮである場合に存在しないか、Ｘ^１がＣである場合に、Ｒ^１’は、Ｈ、ハロ、アルキル、ヘテロシクリル、アルコキシ、シクロアルキルオキシ、ヘテロシクリルオキシ、カルボニル、アルキルカルボニル、アミノカルボニル、ヒドロキシカルボニル、ヘテロシクリルカルボニル、アルキルスルホキシド、アルキルスルホニル、アミノスルホニル、ヘテロシクリルスルホニル、アルキルスルホンイミドイル、カルボニルアミノ、スルホニルアミノ、またはアルキルスルホンアルキルを表し、
上記置換基が任意選択で、オキソ、ハロ、ヒドロキシ、シアノ、アルキル、アルケニル、アルデヒド、ヘテロシクリルアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルキルアミノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、（ヘテロシクリル）（アルキル）アミノアルキル、ヘテロシクリル、ヘテロアリール、アルキルヘテロアリール、アルキン、アルコキシ、アミノ、ジアルキルアミノ、アミノアルキルカルボニルアミノ、アミノカルボニルアルキルアミノ、（アミノカルボニルアルキル）（アルキル）アミノ、アルケニルカルボニルアミノ、ヒドロキシカルボニル、アルキルオキシカルボニル、アミノカルボニル、アミノアルキルアミノカルボニル、アルキルアミノアルキルアミノカルボニル、ジアルキルアミノアルキルアミノカルボニル、ヘテロシクリルアルキルアミノカルボニル、（アルキルアミノアルキル）（アルキル）アミノカルボニル、アルキルアミノアルキルカルボニル、ジアルキルアミノアルキルカルボニル、ヘテロシクリルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホキシド、アルキルスルホキシドアルキル、アルキルスルホニル、及びアルキルスルホンアルキルから選択される１つ以上の置換基で置換され；
Ｒ^２’は、Ｈ、ハロ、アルキル、ヘテロシクリル、アルコキシ、シクロアルキルオキシ、ヘテロシクリルオキシ、カルボニル、アルキルカルボニル、アミノカルボニル、ヒドロキシカルボニル、ヘテロシクリルカルボニル、アルキルスルホキシド、アルキルスルホニル、アミノスルホニル、ヘテロシクリルスルホニル、アルキルスルホンイミドイル、カルボニルアミノ、スルホニルアミノ、またはアルキルスルホンアルキルを表し、
上記置換基が任意選択で、オキソ、ハロ、ヒドロキシ、シアノ、アルキル、アルケニル、アルデヒド、ヘテロシクリルアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルキルアミノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、（ヘテロシクリル）（アルキル）アミノアルキル、ヘテロシクリル、ヘテロアリール、アルキルヘテロアリール、アルキン、アルコキシ、アミノ、ジアルキルアミノ、アミノアルキルカルボニルアミノ、アミノカルボニルアルキルアミノ、（アミノカルボニルアルキル）（アルキル）アミノ、アルケニルカルボニルアミノ、ヒドロキシカルボニル、アルキルオキシカルボニル、アミノカルボニル、アミノアルキルアミノカルボニル、アルキルアミノアルキルアミノカルボニル、ジアルキルアミノアルキルアミノカルボニル、ヘテロシクリルアルキルアミノカルボニル、（アルキルアミノアルキル）（アルキル）アミノカルボニル、アルキルアミノアルキルカルボニル、ジアルキルアミノアルキルカルボニル、ヘテロシクリルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホキシド、アルキルスルホキシドアルキル、アルキルスルホニル、及びアルキルスルホンアルキルから選択される１つ以上の置換基で置換されるか；
あるいは、Ｒ^１’及びＲ^２’は、それらが結合する原子とともに５員もしくは６員のアリール環、５員もしくは６員のヘテロアリール環、５員もしくは６員のシクロアルキル環、または５員もしくは６員のヘテロシクリル環を形成し、任意選択で、オキソ、ハロ、ヒドロキシ、シアノ、アルキル、アルケニル、アルデヒド、ヘテロシクリルアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルキルアミノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、（ヘテロシクリル）（アルキル）アミノアルキル、ヘテロシクリル、ヘテロアリール、アルキルヘテロアリール、アルキン、アルコキシ、アミノ、ジアルキルアミノ、アミノアルキルカルボニルアミノ、アミノカルボニルアルキルアミノ、（アミノカルボニルアルキル）（アルキル）アミノ、アルケニルカルボニルアミノ、ヒドロキシカルボニル、アルキルオキシカルボニル、アミノカルボニル、アミノアルキルアミノカルボニル、アルキルアミノアルキルアミノカルボニル、ジアルキルアミノアルキルアミノカルボニル、ヘテロシクリルアルキルアミノカルボニル、（アルキルアミノアルキル）（アルキル）アミノカルボニル、アルキルアミノアルキルカルボニル、ジアルキルアミノアルキルカルボニル、ヘテロシクリルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホキシド、アルキルスルホキシドアルキル、アルキルスルホニル、及びアルキルスルホンアルキルから選択される１つ以上の置換基で置換され；
Ｒ^３’は、Ｘ^２がＮである場合に存在しないか、Ｘ^２がＣである場合に、Ｒ^３’は、Ｈまたはハロ、好ましくは、ＨまたはＦを表し；
Ｒ^４’は、Ｈまたはハロ、好ましくは、ＨまたはＦを表し；
Ｒ^５’は、Ｈまたはハロ、好ましくは、ＨまたはＦを表す。 In one embodiment, the preferred compound of formula (I) is formula (Ia) :.

Or a pharmaceutically acceptable salt or solvate thereof, in the formula,
^R1 represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, where the heteroaryl group or aryl group is optional and C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or or). Substituted with one or more substituents selected from (chloro), preferably R ¹ represents a 5-membered heteroaryl and more preferably R ¹ represents a frill;
X ¹ and X ² independently represent C or N;
R ^1'is absent when X ¹ is N, or when X ¹ is C, R ^1'is H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, Represents alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimideyl, carbonylamino, sulfonylamino, or alkylsulfonalkyl.
The above substituents are optional, oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl). (Alkyl) Aminoalkyl, Heterocyclyl, Heteroaryl, Alkyl Heteroaryl, Alkin, Alkine, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl) (Alkyl) Amino, Alkenylcarbonylamino, Hydroxycarbonyl , Alkyloxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylaminoalkylcarbonyl , Heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonalkyl substituted with one or more substituents selected from;
R ^2'is H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfone. Represents imideyl, carbonylamino, sulfonylamino, or alkylsulfonealkyl,
The above substituents are optional, oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl). (Alkyl) Aminoalkyl, Heterocyclyl, Heteroaryl, Alkyne Heteroaryl, Alkyne, Alkyne, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl) (Alkyl) Amino, Alkenylcarbonylamino, Hydroxycarbonyl , Alkyneoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylaminoalkylcarbonyl , Heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonalkyls substituted with one or more substituents selected from;
Alternatively, R ^1'and R ^2'are 5- or 6-membered aryl rings, 5- or 6-membered heteroaryl rings, 5- or 6-membered cycloalkyl rings, or 5-membered or 5-membered or 6-membered aryl rings with the atoms to which they are attached. Form a 6-membered heterocyclyl ring, optionally oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylamino Alkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkin, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenyl Carbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl , Dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonalkyl substituted with one or more substituents selected from;
R ^3'is absent if X ² is N, or if X ² is C, R ^3'represents H or halo, preferably H or F;
R ^4'represents H or halo, preferably H or F;
R ^5'represents H or halo, preferably H or F.

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

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

In one specific embodiment of the invention, R ^1'does not exist when X ¹ is N.

In another specific embodiment, where X ¹ is C, R ^1'is H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl. , Heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimideyl, carbonylamino, sulfonylamino, or alkylsulfonalkyl, the above substituents are optional, oxo, halo, hydroxy, cyano, Alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkin , Alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkyl Aminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) Aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylaminoalkylcarbonyl, Heterocyclylcarbonyl, Alkenylcarbonyl, Alkinylcarbonyl, Alkyl Sulfoxide, Alkyl Sulfoxide Alkyl , Alkylsulfonyl, and alkylsulfonalkyl substituted with one or more substituents selected from.

In a preferred embodiment, the R ^{1'substituted} group is optional, halo, hydroxy, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) amino. Alkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, heterocyclylalkylaminocarbonyl, (aminocarbonylalkyl) (alkyl) amino, hydroxycarbonyl, aminocarbonyl, amino Substituent with one or more substituents selected from alkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, heterocyclylcarbonyl, alkylsulfoxide, and alkylsulfonealkyl. To.

In one specific embodiment of the invention, R ^2'is H, halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, Represents alkylsulfonyl, aminosulfonyl, heterocyclylsulfonyl, alkylsulfonimideyl, carbonylamino, sulfonylamino, or alkylsulfonalkyl, the above substituents are optional, oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclyl. Alkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkyne, alkoxy, amino, dialkylamino , Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl) (alkyl) Amino, Alkenylcarbonylamino, Hydroxycarbonyl, Alkoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylamino Carbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxides, alkylsulfoxides, alkylsulfonyls, and alkylsulfones. Substituted with one or more substituents selected from alkyl.

In a preferred embodiment, the R ^{2'substituent} is optional, oxo, halo, hydroxy, cyano, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl, heteroaryl, alkyl heteroaryl, hydroxycarbonyl, alkyloxycarbonyl, amino. It is substituted with one or more substituents selected from carbonyl, heterocyclylalkylaminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxides, alkylsulfonealkyls.

In another specific embodiment of the invention, R ^1'and R ^2'are 5 or 6 membered aryl rings, 5 or 6 membered heteroaryl rings, 5 or 6 members together with the atoms to which they are attached. A membered cycloalkyl ring or a 5- or 6-membered heterocyclyl ring is formed and optionally oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl. , Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl, (Heterocyclyl) (Alkyl) Aminoalkyl, Heterocyclyl, Heteroaryl, Alkyl Heteroaryl, Alkin, Alkine, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, ( Aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) With one or more substituents selected from (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxides, alkylsulfoxidealkyls, alkylsulfonyls, and alkylsulfonalkyls. Will be replaced.

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

In one specific embodiment of the invention, ^{R4'represents} H or halo. In a preferred embodiment, R ^4'represents H or F.

In one specific embodiment of the invention, ^{R5'represents} H or halo. In a preferred embodiment, R ^5'represents H or F.

のもの、またはその薬学的に許容される塩もしくは溶媒和物であり、式中、Ｒ^１、Ｒ^１’、Ｒ^２’、Ｒ^３’、Ｒ^４’、及びＲ^５’は、式（Ｉａ）に定義される通りである。 In one embodiment, the preferred compound of formula (Ia) is Formula (Ia-1) :.

, Or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ^1' , R ^2' , R ^3' , R ^4' , and R ^5'are in the formula (Ia). ).

のもの、またはその薬学的に許容される塩もしくは溶媒和物であり、式中、
Ｒ^１及びＲ^３’は、式（Ｉａ）に定義される通りであり；
Ｒ^１’’は、オキソ、ハロ、ヒドロキシ、シアノ、アルキル、アルケニル、アルデヒド、ヘテロシクリルアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルキルアミノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、（ヘテロシクリル）（アルキル）アミノアルキル、ヘテロシクリル、ヘテロアリール、アルキルヘテロアリール、アルキン、アルコキシ、アミノ、ジアルキルアミノ、アミノアルキルカルボニルアミノ、アミノカルボニルアルキルアミノ、（アミノカルボニルアルキル）（アルキル）アミノ、アルケニルカルボニルアミノ、ヒドロキシカルボニル、アルキルオキシカルボニル、アミノカルボニル、アミノアルキルアミノカルボニル、アルキルアミノアルキルアミノカルボニル、ジアルキルアミノアルキルアミノカルボニル、ヘテロシクリルアルキルアミノカルボニル、（アルキルアミノアルキル）（アルキル）アミノカルボニル、アルキルアミノアルキルカルボニル、ジアルキルアミノアルキルカルボニル、ヘテロシクリルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホキシド、アルキルスルホキシドアルキル、アルキルスルホニル、及びアルキルスルホンアルキルから選択される１つ以上の基で置換されたアルキル基またはヘテロシクリル基を表す。 In one embodiment, the preferred compound of formula (Ia-1) is Formula (Ia-1a) :.

Or a pharmaceutically acceptable salt or solvate thereof, in the formula,
R ¹ and R ^3'as defined in equation (Ia);
R ^1'' refers to oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl). ) Aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyl Oxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclyl Represents an alkyl or heterocyclyl group substituted with one or more groups selected from carbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonalkyl.

In one specific embodiment of the invention, R ^{1 ″} is oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylamino. Alkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) ) Amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, An alkyl group or heterocyclyl substituted with one or more groups selected from alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonalkyl. Represents a group.

In a preferred embodiment, R ^{1 ″} is hydroxy, heterocyclyl, heteroaryl, alkyl heteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino. , Hydroxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, (Alkylaminoalkyl) (Alkyl) Aminocarbonyl, Heterocyclylcarbonyl, Alkyl Sulfoxide, Alkyl Sulfone Alkyl Represents an alkyl group or a heterocyclyl group substituted with the above groups.

のもの、またはその薬学的に許容される塩もしくは溶媒和物であり、式中、
Ｒ^１及びＲ^３’は、式（Ｉａ）に定義される通りであり；
Ｒ^１’は、Ｈまたはハロ、好ましくは、ＨまたはＦを表し；
Ｒ^２’’は、オキソ、ハロ、ヒドロキシ、シアノ、アルキル、アルケニル、アルデヒド、ヘテロシクリルアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルキルアミノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、（ヘテロシクリル）（アルキル）アミノアルキル、ヘテロシクリル、ヘテロアリール、アルキルヘテロアリール、アルキン、アルコキシ、アミノ、ジアルキルアミノ、アミノアルキルカルボニルアミノ、アミノカルボニルアルキルアミノ、（アミノカルボニルアルキル）（アルキル）アミノ、アルケニルカルボニルアミノ、ヒドロキシカルボニル、アルキルオキシカルボニル、アミノカルボニル、アミノアルキルアミノカルボニル、アルキルアミノアルキルアミノカルボニル、ジアルキルアミノアルキルアミノカルボニル、ヘテロシクリルアルキルアミノカルボニル、（アルキルアミノアルキル）（アルキル）アミノカルボニル、アルキルアミノアルキルカルボニル、ジアルキルアミノアルキルカルボニル、ヘテロシクリルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホキシド、アルキルスルホキシドアルキル、アルキルスルホニル、及びアルキルスルホンアルキルから選択される１つ以上の基で置換されたアルキル基またはヘテロシクリル基を表す。 In one embodiment, the preferred compound of formula (Ia-1) is Formula (Ia-1b) :.

Or a pharmaceutically acceptable salt or solvate thereof, in the formula,
R ¹ and R ^3'as defined in equation (Ia);
R ^1'represents H or halo, preferably H or F;
R ^2'' is oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl). ) Aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyl Oxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclyl Represents an alkyl or heterocyclyl group substituted with one or more groups selected from carbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonalkyl.

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

In one specific embodiment of the invention, R ^{2 ″} is oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylamino. Alkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkyne, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) ) Amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, An alkyl group or heterocyclyl substituted with one or more groups selected from alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonalkyl. Represents a group.

In a preferred embodiment, R ^2'' is hydroxy, cyano, heteroaryl, alkyl heteroaryl, alkyne, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, alkylsulfoxide, alkylsulfonealkyl. Represents an alkyl or heterocyclyl group substituted with one or more groups selected from.

のもの、またはその薬学的に許容される塩もしくは溶媒和物であり、式中、
Ｒ^１及びＲ^３’は、式（Ｉａ）に定義される通りであり；
Ｒ^１’は、Ｈまたはハロ、好ましくは、ＨまたはＦを表し；
Ｒ^２’は、Ｈまたはハロ、好ましくは、ＨまたはＦを表し；
Ｒ^１ｉ及びＲ^１ｉｉは、それぞれ独立して、水素、ヒドロキシ、アルキル、アルケニル、ヘテロシクリルアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルキルアミノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、（ヘテロシクリル）（アルキル）アミノアルキル、ヘテロシクリル、ヘテロアリール、アルキルヘテロアリール、アルキンアルキル、アルコキシ、アミノ、ジアルキルアミノ、アミノアルキルカルボニルアミノ、アミノカルボニルアルキルアミノ、（アミノカルボニルアルキル）（アルキル）アミノ、アルケニルカルボニルアミノ、ヒドロキシカルボニル、アルキルオキシカルボニル、アミノカルボニル、アミノアルキルアミノカルボニル、アルキルアミノアルキルアミノカルボニル、ジアルキルアミノアルキルアミノカルボニル、ヘテロシクリルアルキルアミノカルボニル、（アルキルアミノアルキル）（アルキル）アミノカルボニル、アルキルアミノアルキルカルボニル、ジアルキルアミノアルキルカルボニル、ヘテロシクリルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホキシドアルキル、またはアルキルスルホンアルキルを表し；
Ｒ^２ｉ及びＲ^２ｉｉは、それぞれ独立して、水素、ヒドロキシ、アルキル、アルケニル、ヘテロシクリルアルキル、ヒドロキシアルキル、ジヒドロキシアルキル、ヒドロキシアルキルアミノアルキル、アミノアルキル、アルキルアミノアルキル、ジアルキルアミノアルキル、（ヘテロシクリル）（アルキル）アミノアルキル、ヘテロシクリル、ヘテロアリール、アルキルヘテロアリール、アルキンアルキル、アルコキシ、アミノ、ジアルキルアミノ、アミノアルキルカルボニルアミノ、アミノカルボニルアルキルアミノ、（アミノカルボニルアルキル）（アルキル）アミノ、アルケニルカルボニルアミノ、ヒドロキシカルボニル、アルキルオキシカルボニル、アミノカルボニル、アミノアルキルアミノカルボニル、アルキルアミノアルキルアミノカルボニル、ジアルキルアミノアルキルアミノカルボニル、ヘテロシクリルアルキルアミノカルボニル、（アルキルアミノアルキル）（アルキル）アミノカルボニル、アルキルアミノアルキルカルボニル、ジアルキルアミノアルキルカルボニル、ヘテロシクリルカルボニル、アルケニルカルボニル、アルキニルカルボニル、アルキルスルホキシドアルキル、またはアルキルスルホンアルキルを表す。 In one embodiment, the preferred compound of formula (Ia-1) is formula (Ia-1c) or (Ia-1d) :.

Or a pharmaceutically acceptable salt or solvate thereof, in the formula,
R ¹ and R ^3'as defined in equation (Ia);
R ^1'represents H or halo, preferably H or F;
R ^2'represents H or halo, preferably H or F;
R ¹ⁱ and R ¹ⁱⁱ are independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl). ) Aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkynalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, Alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, Represents heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl, or alkylsulfonalkyl;
R ²ⁱ and R ²ⁱⁱ are independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl). ) Aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkynalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, Alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, Represents heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxidealkyl, or alkylsulfonalkyl.

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

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

In one specific embodiment of the invention, R ¹ⁱ and R ¹ⁱⁱ are independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylamino, respectively. Alkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkinalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) ( Alkyl) Amino, Alkenylcarbonyl Amino, Hydroxycarbonyl, Alkyloxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) Aminocarbonyl , Alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide alkyl, or alkylsulfonealkyl.

In a preferred embodiment, R ¹ⁱ and R ¹ⁱⁱ are independently hydrogen, alkyl, heterocyclylalkyl, hydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) amino. Represents an alkyl or heterocyclylalkylaminocarbonyl.

In one specific embodiment of the invention, R ²ⁱ and R ²ⁱⁱ are independently hydrogen, hydroxy, alkyl, alkenyl, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylamino, respectively. Alkyl, dialkylaminoalkyl, (heterocyclyl) (alkyl) aminoalkyl, heterocyclyl, heteroaryl, alkyl heteroaryl, alkinalkyl, alkoxy, amino, dialkylamino, aminoalkylcarbonylamino, aminocarbonylalkylamino, (aminocarbonylalkyl) ( Alkyl) Amino, Alkenylcarbonyl Amino, Hydroxycarbonyl, Alkyloxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) Aminocarbonyl , Alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide alkyl, or alkylsulfonealkyl.

In a preferred embodiment, R ²ⁱ and R ²ⁱⁱ independently represent hydrogen, alkyl, heterocyclylalkyl, dihydroxyalkyl, dialkylaminoalkyl, or heterocyclylalkylaminocarbonyl, respectively. In a preferred embodiment, R ²ⁱ and R ²ⁱⁱ independently represent hydrogen, alkyl, or dialkylaminoalkyl, respectively.

のもの、またはその薬学的に許容される塩もしくは溶媒和物であり、式中、式中、Ｒ^１、Ｒ^２’、Ｒ^３’、Ｒ^４’、及びＲ^５’は、式（Ｉａ）に定義される通りである。 In one embodiment, the preferred compound of formula (Ia) is formula (Ia-2) or (Ia-3) :.

, Or a pharmaceutically acceptable salt or solvate thereof, wherein R ¹ , R ^2' , R ^3' , R ^{4' ,} and R 5'in the formula, formula (Ia). As defined in.

Particularly preferred compounds of formula (I) of the present invention are those listed in Table 1 below and pharmaceutically acceptable salts and solvates thereof.
Table 1

In Table 1, the term "Cpd" means a compound.

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

In one embodiment, the A2AR antagonist is selected from:
(R, S) -5-amino-3- (2- (4- (2,4-difluoro-5-(2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-yl) ethyl) -8- ( Furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidine-2 (3H) -one (compound 7);
(+)-5-Amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-yl) ethyl) -8- (fran-) 2-yl) Thiazolo [5,4-e] [1,2,4] Triazolo [1,5-c] Piperazine-2 (3H) -one (Compound 8a) and (-)-5-Amino-3- (2- (4- (2,4-difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-yl) ethyl) -8- (fran-2-yl) thiazolo [5,4- e] [1,2,4] Triazolo [1,5-c] piperazine-2 (3H) -on (Compound 8b).

In a specific embodiment, the A2AR antagonist is selected from:
(R, S) -5-amino-3- (2- (4- (2,4-difluoro-5-(2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-yl) ethyl) -8- ( Fran-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] piperazine-2 (3H) -one (Compound 7); and (+) -5-amino -3- (2- (4- (2,4-difluoro-5- (2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-yl) ethyl) -8- (fran-2-yl) thiazolo [5 , 4-e] [1,2,4] triazolo [1,5-c] piperazine-2 (3H) -on (Compound 8a).

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

In another preferred embodiment, the A2AR antagonist is (-)-5-amino-3-(2-(4- (2,4-difluoro-5-(2- (methylsulfinyl) ethoxy) phenyl) piperazine-1). -Il) Ethyl) -8- (Fran-2-yl) Thiazolo [5,4-e] [1,2,4] Triazolo [1,5-c] Pyrimidine-2 (3H) -on (Compound 8b) Is. In one embodiment, the invention also relates to enantiomers, salts, solvates, polymorphs, polycomponent complexes, and liquid crystals of compounds of formula (I) and its subforms.

In one embodiment, the invention also comprises polymorphs and crystalline phases of compounds of formula (I) and its subforms, prodrugs and isomers thereof (optical isomers, geometric isomers, and tautomeric isomers). ), And isotopic-labeled compounds of formula (I) and its subforms.

Compounds of formula (I) and its subforms may exist in the form of different stereoisomers because they may contain asymmetric centers. Accordingly, the present invention includes all possible stereoisomers, not only racemic compounds, but also individual enantiomers and their non-racemic mixtures as well. If compounds as a single enantiomer are desired, chiral chromatography methods such as stereospecific synthesis, division of the final product or any convenient intermediate, or each known in the art. Can be obtained by. Division of the final product, intermediate or starting material can be carried out by any suitable method known in the art.

The compounds of the invention may be in the form of pharmaceutically acceptable salts. The pharmaceutically acceptable salts of the compound of formula (I) and its subforms include acid addition salts and base salts thereof. Suitable acid addition salts are formed from acids that form non-toxic salts. For example, acetate, adipate, asparagate, benzoate, besilate, bicarbonate / carbonate, bicarbonate / sulfate, borate, cansilate, citrate, cyclamic acid. Salts, edicates, esylates, formates, fumarates, gluceptates, gluconates, glucronates, hexafluorophosphates, hibenzates, hydrochlorides / chlorides, hydrides / Bromide, Hydroiodide / Iodide, Isothionate, Lactate, Napate, Maleate, Malonate, Mesilate, Methyl Sulfate, Naftylate, 2-Napsilate, Nicotin Acids, nitrates, orotates, oxalates, palmitates, pamoates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, sacchar phosphates, stearate, succinic acid. Examples include salts, tannates, tartrates, tosylates, trifluoroacetates, and xinafoates. Suitable base salts are formed from bases that form non-toxic salts. For example, aluminum salt, arginine salt, benzatin salt, calcium salt, choline salt, diethylamine salt, diolamine salt, glycine salt, lysine salt, magnesium salt, meglumin salt, olamine salt, potassium salt, sodium salt, tromethamine salt, 2- Examples thereof include (diethylamino) ethanol salt, ethanolamine salt, morpholin salt, 4- (2-hydroxyethyl) morpholin salt, and zinc salt. Hemi salts of acids and bases, such as hemi sulfates and hemicalcium salts, can also be formed. Preferred pharmaceutically acceptable salts include hydrochloride / chloride salt, hydrobromide / bromide salt, bicarbonate / sulfate, nitrate, citrate, tosylate, esylate, and acetate. Can be mentioned. In a particularly preferred embodiment, the compound of formula (I) is in the form of an HCl salt or esylate.

When the compound of the present invention contains a basic group in addition to the acidic group, the compound of the present invention can also form an internal salt, and such a compound is within the scope of the present invention. If the compound of the invention contains a hydrogen donating heteroatom (eg NH), the invention will also be a salt and / or a salt formed by the transfer of the hydrogen atom to a basic group or atom within the molecule. Includes isomers.

The pharmaceutically acceptable salt of the compound of formula (I) and its subforms is
(I) Reacting the compound of formula (I) with the desired acid;
(Ii) Reacting the compound of formula (I) with a desired base;
Remove protective groups that are unstable to acids or bases from suitable precursors of compounds of formula (iii), or use the desired acids to open rings of suitable cyclic precursors, such as lactones or lactams. That; or (iv) by one or more methods of converting one salt of the compound of formula (I) to another, either by reaction with a suitable acid or by using a suitable ion exchange column. Can be prepared.

All of these reactions are usually carried out in solution. The salt can be precipitated from the solution and collected by filtration or by evaporation of the solvent. The degree of salt ionization can vary from fully ionized to nearly non-ionized.

The compounds of the invention can be administered in the form of pharmaceutically acceptable salts. The term "pharmaceutically acceptable salt" refers to acetate, lactobionate, benzenesulfonate, laurate, benzoate, malate, bicarbonate, maleate, bicarbonate, Mandel. Acid salt, hydrogen tartrate, mesylate, borate, methyl bromide, bromide salt, methyl nitrate, calcium edetate, methyl sulfate, cansylate, mutinate, carbonate, napsilate, chloride Salt, nitrate, clavrate, N-methylglucamine, citrate, ammonium salt, dihydrochloride, oleate, edetate, oxalate, edicylate, pamoate (embonate) , Estolate, palmitate, esylate, pantothenate, fumarate, phosphate / diphosphate, gluceptate, polygalacturonate, gluconate, salicylate, glutamate, stea Hydrolate, Glycolyl alsanylate, sulfate, hexylresolcinate, basic acetate, hydrabamine, succinate, hydrobromide, tannate, hydrochloride, tartrate, hydroxynaphthoate As a dosage form for altering solubility or hydrolyzing properties, such as theocrate, iodide salt, tosylate, isothionate, trietioiodate, lactate, pamoate, and valerate. It is intended to contain all acceptable salts that can be used or used in sustained release or prodrug formulations. Depending on the particular function of the compounds of the invention, pharmaceutically acceptable salts of the compounds of the invention include those formed from cations such as sodium, potassium, aluminum, calcium, lithium, magnesium and zinc. And ammonia, ethylenediamine, N-methyl-glutamine, lysine, arginine, ornithine, choline, N, N'-dibenzylethylene-diamine, chloroprocine, diethanolamine, prokine, N-benzylphenetyl-amine, diethylamine, piperazine, tris ( It includes those formed from bases such as hydroxymethyl) aminomethane and tetramethylammonium hydroxide.

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

In addition, with respect to the salts of the compounds of the invention, pharmaceutically acceptable salts are generally preferred, but in the broadest sense, for example, non-pharmaceutically which can be used for isolation and / or purification of the compounds of the invention. It should be noted that acceptable salts are also included in the invention. For example, a salt formed of an optically active acid or base can be used to form a diastereoisomer salt that can facilitate the separation of the optically active isomer of the compound of formula (I) above. can.

The compounds of the invention may be in the form of pharmaceutically acceptable solvates. The pharmaceutically acceptable solvate of the compound of formula (I) and its subforms is one or more stoichiometric or quasi-stoichiometric pharmaceutically acceptable solvent molecules (such as ethanol or water). ) Is contained. The term "hydrate" refers to the case where the solvent is water.

Also, in the presence of alcohol groups, pharmaceutically acceptable esters such as acetic acid esters, maleic acid esters, pivaloyloxymethyl, etc. can be used, which have soluble or hydrolyzable properties. Is known in the art to be used as a sustained release formulation or a prodrug formulation.

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

In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2009 / 156737. In particular, the A2AR antagonist is a compound of Example 1S of WO2009 / 156737, ie, (S) -7- (5-methylfuran-2-yl) -3-((6-(((6-". [Tetrahydrofuran-3-yl] oxy)) Methyl) Pyridine-2-yl) Methyl) -3H- [1,2,3] Triazolo [4,5-d] Pyrimidine-5-amine:

In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2011 / 09566. In particular, the A2AR antagonist is a compound of WO2011 / 09566 (cxiv), i.e. 6- (2-chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1, also known as AZD4635. 2,4-Triazine-3-amine:

In another embodiment, the A2AR antagonist is an A2AR antagonist disclosed in WO2018 / 136700. In particular, the A2AR antagonist is the compound of Example 1 of WO2018 / 136700, ie 3- (2-amino-6- (1-((6- (2-hydroxypropane-2-yl) pyridine), also known as AB928. -2-Il) Methyl) -1H-1,2,3-triazole-4-yl) Pyrimidine-4-yl) -2-Methylbenzonitrile:

In another embodiment, the A2AR antagonist is a preladenant (SCH-420,814), ie 2- (2-furanyl) -7- (2- (4- (4- (2-methoxyethoxy) phenyl) -1). -Piperadinyl) ethyl) -7H-pyrazolo (4,3-e) (1,2,4) triazolo (1,5-c) pyrimidine-5-amine:

In another embodiment, the A2AR antagonist is bipadenant (BIIB-014), ie 3- (4-amino-3-methylbenzyl) -7- (2-furyl) -3H- (1,2,3) triazolo. (4,5-d) Pyrimidine-5-amine:

In another embodiment, the A2AR antagonist is tozadenant (SYK-115), ie 4-hydroxy-N- (4-methoxy-7-morpholinobenzo [d] thiazole-2-yl) -4-methylpiperidine-1. -Carboxamide:

Therefore, in one embodiment, the adenosine receptor antagonist is selected from:
5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine;
(S) -7- (5-Methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2-yl) methyl) -3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-amine;
6- (2-Chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine;
3- (2-Amino-6-(1-((6- (2-hydroxypropane-2-yl) pyridine-2-yl) methyl) -1H-1,2,3-triazole-4-yl) pyrimidine -4-yl) -2-methylbenzonitrile;
2- (2-Franyl) -7- (2- (4- (4- (2-Methoxyethoxy) phenyl) -1-piperazinyl) ethyl) -7H-pyrazolo (4,3-e) (1,2, 4) Triazolo (1,5-c) pyrimidine-5-amine;
3- (4-Amino-3-methylbenzyl) -7- (2-furyl) -3H- (1,2,3) triazolo (4,5-d) pyrimidine-5-amine; and 4-hydroxy-N -(4-Methoxy-7-morpholinobenzo [d] thiazole-2-yl) -4-methylpiperidine-1-carboxamide.

In one embodiment, the adenosine receptor antagonist is 5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine. In one embodiment, the adenosine receptor antagonist is (S) -7- (5-methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2). -Il) Methyl) -3H- [1,2,3] triazolo [4,5-d] pyrimidin-5-amine. In one embodiment, the adenosine receptor antagonist is 6- (2-chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine. .. In one embodiment, the adenosine receptor antagonist is 3-(2-amino-6- (1-((6- (2-hydroxypropan-2-yl) pyridin-2-yl) methyl) -1H-1, 2,3-Triazole-4-yl) pyrimidin-4-yl) -2-methylbenzonitrile.

A2B Receptor Antagonist In one embodiment, the combination of the invention comprises at least one A2BR antagonist.

"A2BR antagonist" refers to a compound that, when administered to a patient, results in inhibition or downregulation of biological activity associated with activation of the A2B receptor. Biological activity includes any of the downstream biological effects that would otherwise result from binding of the natural ligand to the A2B receptor. Such A2BR antagonists include any agent capable of blocking either A2B receptor activation or a biological effect downstream of A2B receptor activation.

Examples of A2BR antagonists are Vipadenant (BIIB-014), CVT-6883, MRS-1706, MRS-1754, PSB-603, PSB-0788, PSB-1115, OSIP-339,391, ATL-801, Theophylline, Caffeine. The inn is mentioned.

Specific Combinations In one embodiment, the combinations of the present invention are
(A) An effective amount of an ENT inhibitor, preferably an ENT1 inhibitor, preferably selected from NBMPR, dipyridamole, dilazep, ticagrelor, and salts thereof (including dilazep hydrochloride).
(B) preferably
(+)-5-Amino-3-(2- (4- (2,4-difluoro-5-(2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-yl) ethyl) -8- (furan-) 2-Il) Thiazolo [5,4-e] [1,2,4] Triazolo [1,5-c] Pyrimidine-2 (3H) -on;
(-)-5-Amino-3- (2- (4- (2,4-difluoro-5-(2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-yl) ethyl) -8- (furan-) 2-Il) Thiazolo [5,4-e] [1,2,4] Triazolo [1,5-c] Pyrimidine-2 (3H) -on;
5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine;
(S) -7- (5-Methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2-yl) methyl) -3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-amine;
6- (2-Chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine;
3- (2-Amino-6-(1-((6- (2-hydroxypropane-2-yl) pyridine-2-yl) methyl) -1H-1,2,3-triazole-4-yl) pyrimidine -4-yl) -2-methylbenzonitrile;
And an effective amount of an adenosine receptor antagonist, preferably an A2AR antagonist, selected from pharmaceutically acceptable salts thereof.

In one embodiment, the combination of the invention is
(A) An effective amount of dipyridamole as an ENT inhibitor,
(B) preferably
(+)-5-Amino-3-(2- (4- (2,4-difluoro-5-(2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-yl) ethyl) -8- (furan-) 2-Il) Thiazolo [5,4-e] [1,2,4] Triazolo [1,5-c] Pyrimidine-2 (3H) -on;
(-)-5-Amino-3- (2- (4- (2,4-difluoro-5-(2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-yl) ethyl) -8- (furan-) 2-Il) Thiazolo [5,4-e] [1,2,4] Triazolo [1,5-c] Pyrimidine-2 (3H) -on;
5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine;
(S) -7- (5-Methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2-yl) methyl) -3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-amine;
6- (2-Chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine;
3- (2-Amino-6-(1-((6- (2-hydroxypropane-2-yl) pyridine-2-yl) methyl) -1H-1,2,3-triazole-4-yl) pyrimidine -4-yl) -2-methylbenzonitrile;
And an effective amount of an adenosine receptor antagonist, preferably an A2AR antagonist, selected from pharmaceutically acceptable salts thereof.

In one embodiment, the combination of the invention is
(A) An effective amount of an ENT inhibitor, preferably an ENT1 inhibitor, preferably selected from NBMPR, dipyridamole, dilazep, ticagrelor, and salts thereof (including dilazep hydrochloride).
(B) As an A2AR antagonist, an effective amount of (+)-5-amino-3-(2-(4- (2,4-difluoro-5-(2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-) Il) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidine-2 (3H) -on.

In one embodiment, the combination of the invention is
(A) An effective amount of an ENT inhibitor, preferably an ENT1 inhibitor, preferably selected from NBMPR, dipyridamole, dilazep, ticagrelor, and salts thereof (including dilazep hydrochloride).
(B) As an A2AR antagonist, an effective amount of (-)-5-amino-3-(2-(4- (2,4-difluoro-5-(2- (methylsulfinyl) ethoxy) phenyl) piperazine-1-) Il) ethyl) -8- (furan-2-yl) thiazolo [5,4-e] [1,2,4] triazolo [1,5-c] pyrimidine-2 (3H) -on.

Formulations and Pharmaceutical Compositions The present invention further relates to a formulation comprising a combination of the present invention. In particular, the present invention provides a formulation comprising an effective amount of an adenosine receptor antagonist in combination with an effective amount of an ENT family member inhibitor, as well as a pharmaceutically acceptable excipient.

Specific embodiments for adenosine receptor antagonists and ENT family transporter inhibitors listed above also apply in the context of the pharmaceuticals of the invention.

The invention further relates to pharmaceutical compositions comprising the combinations of the invention.

In one embodiment, the pharmaceutical composition is
(A) Effective amount of ENT inhibitor and
(B) With an effective amount of adenosine receptor antagonist,
(C) Containing at least one pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant.

The above embodiments for ENT inhibitors and adenosine receptor antagonists also apply to the pharmaceutical compositions of the present invention.

のチオカルバメート誘導体、またはその薬学的に許容される塩もしくは溶媒和物である、有効量のＡ２ＡＲアンタゴニストと、
（ｃ）少なくとも１種の薬学的に許容される担体、希釈剤、賦形剤、及び／またはアジュバントと、を含む医薬組成物を提供する。 In a preferred embodiment, the invention
(A) With an effective amount of an ENT inhibitor, such as an ENT1 inhibitor,
(B) Thiocarbamate derivative, more preferably the formula (I) as defined above.

With an effective amount of an A2AR antagonist, which is a thiocarbamate derivative of, or a pharmaceutically acceptable salt or solvate thereof.
(C) Provided is a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant.

In one embodiment, the pharmaceutical or pharmaceutical composition of the invention further comprises an additional therapeutic agent.

At least one pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant used to prepare the dosage form will be apparent to those of skill in the art and will be available in the latest version of Remington's Pharmaceutical Sciences. See.

In particular, the pharmaceutical composition of the present invention can optionally contain such inactive substances commonly used in pharmaceutical formulations, such as co-solvents, lipid carriers, antioxidants, surfactants. , Wetting agents, emulsifiers, buffers, pH adjusters, preservatives (or preservatives), isotonic agents, stabilizers, granulators or binders, precipitation inhibitors, lubricants, disintegrants, flow promoters, Diluents or fillers, adsorbents, dispersants, suspending agents, bulking agents, release agents, sweeteners, flavoring agents and the like.

In a preferred embodiment, the pharmaceutical composition of the invention comprises one or more pharmaceutically acceptable cosolvents. Preferably, the co-solvent is selected from capric acid, polyethylene glycol (PEG), propylene glycol, ethanol, dimethyl sulfoxide, dimethylacetamide, dimethylisosorbide, and mixtures thereof. In a specific embodiment, the pharmaceutical composition of the invention comprises caprylic acid and / or PEG. Advantageously, if the composition comprises PEG as a co-solvent, the PEG has a low molecular weight, preferably the PEG is PEG400. In an alternative embodiment, if the composition comprises PEG, the PEG is of medium molecular weight, preferably PEG3350.

In a specific embodiment, the pharmaceutical composition of the invention comprises one or more pharmaceutically acceptable lipid carriers. In a preferred embodiment, the lipid carrier is lauroylpolyoxyl-32 glyceride. This excipient corresponds to Glucire® 44/14 manufactured by Gattefose (Saint-Priest-France). This excipient includes the following lauroylpolyoxyl-32 glyceride NF / USP (NF: National Pharmacopoeia; USP: United States Pharmacopeia); lauroyl macrogol-32 glyceride EP (European Pharmacopoeia); hydride coconut PEG-32. Esther (INCI); also known by the reference name CAS number 57107-95-6. Glyceride® 44/14 corresponds to a well-defined multi-component substance consisting of lauric acid (C ₁₂ ) monoglycerides, diglycerides and triglycerides, as well as PEG-32 monoesters and diesters. Glucire® 44/14 has a melting point in the range of 42.5 ° C to 47.5 ° C (44 ° C average) and a hydrophilic / lipophilic balance (HLB) value of 14.

In another embodiment, the lipid carrier is Vitamin E TPGS. This excipient includes the following D-α-tocopherol polyethylene glycol-1000 succinate; Tocophersolan; Tocophersolan; 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-ethandyl); Vitamin E Also known as PEG succinate, formed from vitamin E complexed with polyethylene glycol 1000 via a succinate linker. Will be done. Vitamin E TPGS has a melting point in the range of 37 to 41 ° C. and a hydrophilic / lipophilic balance (HLB) value of 13.

In one embodiment, the pharmaceutical composition of the present invention further comprises one or more antioxidants, preferably the antioxidants are butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), citric acid. , Sodium metabisulfate, ascorbic acid, methionine, and vitamin E, more preferably the antioxidant is BHT.

In some embodiments, surfactants such as polyethylene glycol, polyoxyethylene sorbitan fatty acid ester, sorbitan ester, doxart sodium, sodium lauryl sulfate, polysorbate (20, 80, etc.), poroxamer (188, 407, etc.), Pluronic® polyol, polyoxyethylene sorbitan monoether (TWEEN®-20, TWEEN®-80, etc.), Vitamin E TPGS (Vitamin E polyethylene glycol succinate), Cremofol RH40 (Polyoxyl) 40 hydrogenated castor oil), Cremofol EL (polyoxyl 35 hydrogenated castor oil), polyethylene glycol 660 12-monostearate, sorbol HS15 (polyoxyethylated 12-hydroxystearic acid), labrasol (caprilocaproyl polyoxyl) -8 glyceride), labrafil M1944 (oleoyl polyoxyl-6 glyceride), polylactide-polyethylene glycol copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus®) and the like are added.

In some embodiments, wetting agents such as sodium lauryl sulfate, vitamin E TPGS, sodium doxart, polysorbate 80, poloxamer 407 and the like are added. A preferred wetting agent is poloxamer 407.

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

In some embodiments, buffers are used to help maintain pH in a range close to physiological conditions. Suitable buffers include organic and inorganic acids as well as salts thereof, eg, citrate buffers (eg, monosodium citrate-disodium citrate mixture, citrate-trisodium citrate mixture, citrus). Acid-monosodium citrate mixture, etc.), succinate buffer (eg, succinic acid-monosodium succinate mixture, succinic acid-sodium hydroxide mixture, succinic acid-disodium succinate mixture, etc.), tartrate buffer (For example, tartrate-sodium tartrate mixture, tartrate-potassium tartrate mixture, tartrate-sodium hydroxide mixture, etc.), fumarate buffer (eg, fumarate-monosodium fumarate mixture, fumarate-disodium fumarate mixture, etc.) Monosodium fumarate-disodium fumarate mixture, etc.), gluconate buffer (eg, gluconic acid-sodium gluconate mixture, gluconic acid-sodium hydroxide mixture, gluconic acid-potassium gluconate mixture, etc.), oxalate Buffers (eg, oxalic acid-sodium oxalate mixture, oxalic acid-sodium hydroxide mixture, oxalic acid-potassium oxalate mixture, etc.), lactate buffers (eg, lactic acid-sodium lactate mixture, lactic acid-sodium hydroxide mixture). , Lactic acid-potassium lactate mixture, etc.), and acetate buffers (eg, acetic acid-sodium acetate mixture, acetic acid-sodium hydroxide mixture, etc.). In addition, trimethylamine salts such as phosphate buffer, histidine buffer, and Tris can be used.

In some embodiments, pH regulators such as sodium hydroxide, sodium bicarbonate, magnesium oxide, potassium hydroxide, meglumin, sodium carbonate, citric acid, tartaric acid, ascorbic acid, fumaric acid, succinic acid, and malic acid. Etc. are added.

In some embodiments, preservatives are added to prevent the growth of microorganisms. Suitable preservatives for use with the present disclosure include phenol, benzyl alcohol, metacresol, methylparaben, propylparaben, octadecyldimethylbenzylammonium chloride, benzalkonium halides (eg, chlorides, bromides, and iodides), hexa. Included are methonium chloride and alkylparabens such as methylparaben or propylparaben, catechol, resorcinol, cyclohexanol, and 3-pentanol.

In some embodiments, isotonic agents, sometimes referred to as "stabilizers," are added, which include polyhydric sugar alcohols, such as trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol. , Xylitol, sorbitol, and mannitol. Stabilizers refer to a wide range of excipients, the scope of their function from bulking agents to additives that solubilize therapeutic agents, or additives that help prevent denaturation or adhesion to the vessel wall, or activity. It can even extend to additives that help inhibit component precipitation, particle growth, or aggregation. Typical stabilizers are polysaccharide alcohols (listed above); amino acids such as arginine, lysine, glycine, glutamine, asparagine, histidine, alanine, ornithine, L-leucine, 2-phenylalanine, glutamate, treonine; inositol, etc. Organic sugars or sugar alcohols such as lactose, trehalose, stachiose, mannitol, sorbitol, xylitol, ribitol, myoinitol, galactitol, glycerol; polyethylene glycol; amino acid polymers; urea, glutathione, thioctic acid, thioglycolic acid, including cyclitol. Sulfur-containing reducing agents such as sodium, thioglycerol, α-monothioglycerol, and sodium thiosulfate; low molecular weight polypeptides (eg, peptides with 10 residues or less); human serum albumin, bovine serum albumin, gelatin, or immunoglobulin. Proteins such as; hydrophilic polymers such as polyvinylpyrrolidone; poroxamar 407; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulosephthalate, or hydroxypropylmethylcelluloseacetate succinate; carboxymethylcellulose (Na / Ca); xylose, mannose, fructose. , Monosaccharides such as 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) It can be methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methylmethacrylate) 1: 2: 1. Preferred stabilizers are, for example, glycerol; polyethylene glycol; polyvinylpyrrolidone; cellulose derivatives such as hydroxypropylmethylcellulose, hydroxypropylmethylcellulosephthalate, or hydroxypropylmethylcellulose acetate succinate; carboxymethylcellulose (Na / Ca); polyethylene glycol methyl ether-. Block-poly (DL-lactide) copolymer; and poly (butyl methacrylate-co- (2-dimethylaminoethyl) methacrylate-co-methyl methacrylate) 1: 2: 1; polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft Copolymer, polyvinylpyrrolidone-polyvinyl acetate copolymer.

In some embodiments, for example, polymers such as starch, gum (including natural, semi-synthetic, and synthetic), microcrystalline cellulose, ethyl cellulose, methyl cellulose, hydroxypropyl cellulose, povidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, etc. Granulators / binders (s) such as are added. Preferred granulators are, for example, methyl cellulose, hydroxypropyl cellulose, povidone, and polyvinylpyrrolidone-polyvinyl acetate copolymer.

In some embodiments, precipitation inhibitors, such as water-soluble derivatives of cellulose, including hydroxypropylmethylcellulose and methylcellulose, and polyvinylpyrrolidone, polyvinylpyrrolidone-polyvinyl acetate copolymer, polyvinylcaprolactam-polyvinyl acetate-polyethylene glycol graft copolymer, and the like. Alternatively, a water-soluble polymer such as poloxamer 407 is added. A preferred precipitation inhibitor is hydroxypropylmethylcellulose.

In some embodiments, lubricants such as, for example, magnesium stearate, glyceryl ester, behenoyle polyoxyl-8 glyceride Nf (Complitol HD5 ATO), stearyl sodium fumarate, etc. are added.

In some embodiments, disintegrants such as, for example, synthetics such as sodium starch glycolate, crospovidone, croscarmellose sodium, corridon CL, and naturally derived products such as locust bean gum are added.

In some embodiments, flow promoters such as talc, magnesium stearate, colloidal silicon dioxide, starch and the like are added.

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

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

In some embodiments, the pharmaceutical composition of the invention is in the form of tablets, such as granulators, binders, lubricants, disintegrants, flow promoters, diluents, adsorbents and the like. Excipients are added.

In some embodiments, the pharmaceutical compositions of the invention are in the form of capsules, the capsule shell being made from gelatin or from non-animal products such as cellulose and derivatives thereof such as hydroxypropylmethylcellulose. Polyethylene glycol acting as a plasticizer; pigments such as titanium dioxide or iron oxide that allow impermeableness and color distinction; lubricants such as carnauba wax; gelling agents such as carrageenan, and wetting agents such as sodium lauryl sulfate. Other ingredients such as can be contained in a capsule shell. In one embodiment, the pharmaceutical composition of the invention is formulated as a capsule, in which case the capsule shell is composed of gelatin and optionally contains additional ingredients such as polyethylene glycol and sodium lauryl sulfate. Is done.

According to non-limiting examples, the pharmaceutical composition can be administered orally, parenterally (by intravenous, intramuscular or subcutaneous injection, or intravenous injection, etc.), topical administration (including eyeballs), rectal administration, etc. It may be in a form suitable for administration by inhalation, skin patch, implantation, suppository or the like. Such suitable dosage forms (which can be solid, semi-solid, or liquid, depending on the method of administration), and methods for use in their preparation, as well as carriers, diluents, and excipients are those of skill in the art. See the latest version of Remington's Pharmaceutical Sciences.

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

According to one embodiment, the pharmaceutical composition is in a form suitable for oral administration. Suitable forms for oral administration can be solid, semi-solid, or liquid. Some preferred but non-limiting examples of such forms are liquid compositions, paste compositions, or solid compositions, more specifically tablets, formulated for long-term or sustained release. Tablets, capsules (including soft and hard gelatin capsules), pills, sugar-coated tablets, lozenges, sachets, cashews, powders, liquids, gels, syrups, slurrys, elixirs, emulsions, solutions, And suspensions.

According to another embodiment, the pharmaceutical composition is a form suitable for injection, particularly targeted by intravenous injection, intramuscular injection, intraperitoneal injection, intrathoracic injection, subcutaneous injection, transdermal injection, or infusion. It is to be injected.

Sterile injection forms of the pharmaceutical composition of the present invention include sterile injectable solutions and sterile packaging powders (usually reconstituted prior to use) for administration as a bolus and / or continuous administration.

The sterile injection form of the pharmaceutical composition of the present invention can be a solution or an aqueous suspension or an oily suspension. Such suspensions can be formulated according to techniques known in the art using suitable dispersants or wetting and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic, pharmaceutically acceptable diluent or solvent. Acceptable vehicles and solvents that can be used include water, Ringer's solution, and isotonic sodium chloride solution. In addition, sterile non-volatile oils have traditionally been used as solvents or suspension media. Any non-irritating non-volatile oil may be used for this purpose, including synthetic monoglycerides or synthetic diglycerides. Fatty acids such as oleic acid and its glyceride derivatives are particularly useful in the preparation of injections, as well as naturally pharmaceutically acceptable oils such as polyoxyethylated olive oil or castor oil. Such oily solutions or suspensions also include long chains such as carboxymethyl cellulose or similar dispersants commonly used in pharmaceutically acceptable dosage form formulations including emulsions and suspensions. It may also contain an alcohol diluent or dispersant. Others such as Tween®, Span®, and other emulsifiers or bioavailability enhancers commonly used in the production of pharmaceutically acceptable solids, liquids, or other dosage forms. Commonly used surfactants can also be used for pharmaceutical purposes.

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

According to another embodiment, the pharmaceutical composition 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, small enemas, enemas, gels, rectal foams, creams, ointments and the like.

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

The pharmaceutical preparations of the invention are preferably in unit dosage form, eg, boxes, blisters, vials, bottles, leaflets, ampoules, or any other suitable single or multiple dose holder or container. (They may be labeled appropriately) may optionally be packaged with one or more leaflets containing product information and / or instructions for use.

Parts Kit The present invention further relates to a parts kit comprising the combination of the present invention.

In one embodiment, the parts kit of the present invention is
(A) With the first moiety containing an effective amount of ENT inhibitor;
(B) Containing a second portion comprising an effective amount of adenosine receptor antagonist.

The above embodiments for ENT inhibitors and adenosine receptor antagonists also apply to the parts kits of the present invention.

のチオカルバメート誘導体、またはその薬学的に許容される塩もしくは溶媒和物である、有効量のＡ２ＡＲアンタゴニストを含む第２の部分と、を含むパーツキットを提供する。 In a preferred embodiment, the invention comprises (a) a first portion comprising an effective amount of an ENT inhibitor, such as, for example, an ENT1 inhibitor;
(B) Thiocarbamate derivative, more preferably the formula (I) as defined above.

Provided is a parts kit comprising a second portion comprising an effective amount of an A2AR antagonist, which is a thiocarbamate derivative of, or a pharmaceutically acceptable salt or solvate thereof.

Depending on the type of ENT inhibitor and adenosine receptor antagonist, the first and second parts of the kit may be in the form of a pharmaceutical composition. Excipients, dosage forms, and routes of administration of such pharmaceutical compositions are apparent to those of skill in the art (see the latest version of Remington's Pharmaceutical Sciences), especially with respect to the pharmaceutical compositions of the invention described above. It can be enumerated.

In one embodiment, the second portion of the kit comprises an A2AR antagonist, preferably a thiocarbamate derivative of formula (I) as defined above, and at least one pharmaceutically acceptable carrier, diluent, excipient. Included are pharmaceutical compositions comprising a form and / or an adjuvant. The pharmaceutically acceptable carrier, diluent, excipient, and / or adjuvant of the pharmaceutical composition of the second part of the parts kit may be those listed above with respect to the pharmaceutical composition of the invention.

Administration of different parts of the kit can be performed simultaneously or staggered to either the same site or different sites, in approximately the same or different dosage forms, as defined below.

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

Dosage Regimen In the context of the present invention, administration of ENT inhibitors and adenosine receptor antagonists simultaneously or staggered to either the same or different sites of administration, either approximately the same or different, as further outlined below. It can be done in dosage form.

In one embodiment, the ENT inhibitor is administered before, at the same time as, or after administration of the adenosine receptor antagonist.

In order to prevent the individual mechanisms induced by the ENT inhibitor and the adenosine receptor antagonist from being negatively influenced by each other, the adenosine receptor antagonist and the ENT inhibitor are separated by time (staggered). That is, they may be administered sequentially and / or to different administration sites. This means that the adenosine receptor antagonist may be administered, for example, before, at the same time, or after the ENT inhibitor, or vice versa. Alternatively or additionally, the adenosine receptor antagonist and the ENT inhibitor may be administered at different sites of administration or at the same site of administration, preferably staggered.

In one embodiment, the adenosine receptor antagonist is to be administered before and / or at the same time as the ENT inhibitor. In one embodiment, the adenosine receptor antagonist is to be administered before or on the same day that the ENT inhibitor is administered.

In another embodiment, the ENT inhibitor shall be administered before and / or at the same time as the adenosine receptor antagonist. In one embodiment, the ENT inhibitor shall be administered before or on the same day that the adenosine receptor antagonist is administered.

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

In another embodiment, the ENT inhibitor shall be administered prior to and / or simultaneously with the adenosine receptor antagonist and continued thereafter.

Dosage The ENT inhibitor and adenosine receptor antagonist may be administered in divided doses of once-daily into at least once-daily doses, depending on the condition and mode of administration to be prevented or treated.

It is understood that the total daily dose of adenosine receptor antagonist and ENT inhibitor will be determined by the attending physician within the bounds of sound medical judgment. Specific doses for a particular subject depend on a variety of factors such as the cancer being treated, the patient's age, weight, overall health, gender, and diet, as well as similar factors well known in the medical field. Will be different.

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

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

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

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

In one embodiment, the subject is a mammal, preferably a human, and the dose of the adenosine receptor antagonist, preferably the therapeutically effective dose, is from about 1 mg to about 500 mg, preferably from about 5 mg to about 200 mg, more preferably about 10 mg. Daily doses ranging from ~ 100 mg.

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

In one embodiment, the subject is a mammal, preferably a human, and the dose of the ENT inhibitor, preferably the therapeutically effective dose, ranges from about 0.01 mg (mg / kg) to about 5 mg / kg per kg of body weight. The dose of.

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

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

In one embodiment, the subject is a mammal, preferably a human, and the dose of the ENT inhibitor, preferably the therapeutically effective dose, ranges from about 1 mg to about 500 mg per dose.

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

In one embodiment, the subject is a mammal, preferably a human, and the dose of the ENT inhibitor, preferably the therapeutically effective dose, is administered once, twice, three times, or more. It is a daily dose. In one embodiment, the subject is a mammal, preferably a human, and the dose of the ENT inhibitor, preferably the therapeutically effective dose, is a daily dose administered in one or two ingestions.

Uses Another object of the present invention is the use of a combination of pharmaceuticals, i.e., medical uses. Accordingly, in one embodiment, the use of the combination of the invention in the manufacture of a pharmaceutical product is provided. In particular, the invention provides the use of the pharmaceutical compositions of the invention or the kits of the invention in the manufacture of pharmaceuticals.

In particular, the invention provides combinations, pharmaceutical compositions, or parts kits of the invention for use in the treatment and / or prevention of cancer.

The invention further provides the use of combinations, pharmaceutical compositions, or parts kits of the invention in the manufacture of pharmaceuticals for treating and / or preventing cancer.

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

In particular, the present invention provides a method of treating cancer, comprising administering a combination of an adenosine receptor antagonist and an ENT family transporter inhibitor to a patient in need thereof. Specific embodiments for adenosine receptor antagonists and ENT family transporter inhibitors listed above also apply in the context of the therapeutic methods of the invention.

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

Various cancers are known in the art. Cancers that can be treated using the methods of the invention include solid and non-solid tumors, in particular benign and malignant solid tumors, as well as benign and malignant non-solid tumors. Cancer can be metastatic or non-metastatic. Cancer can be familial or idiopathic.

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

Examples of solid tumors include biliary tract cancer, brain tumors (including glioblastoma and medullary blastoma), breast cancer, cartinoids, cervical cancer, villous cancer, colon cancer, colon cancer, endometrial cancer, esophageal cancer, gastric cancer, Glioglioma, head and neck cancer, intraepithelial neoplasia (including Bowen's disease and Paget's disease), liver cancer, lung cancer, neuroblastoma, oral cancer (including squamous epithelial cancer), ovarian cancer (epithelial cells, stroma) (Including those originating from cells, germ cells, and mesenchymal cells), pancreatic cancer, prostate cancer, rectal cancer, kidney cancer (including adenocarcinoma and Wilms tumor), sarcoma (smooth myoma, rhizome myoma, fat) Sperm epithelium including sarcoma, fibrosarcoma, and osteosarcoma), skin cancer (including melanoma, caposic sarcoma, basal cell cancer, and squamous cell carcinoma), testicular cancer including germ cell tumor (spiral epithelium such as malformation and chorionic villus cancer) Tumors and nonseptic epithelioma), interstitial tumors, germ cell tumors, thyroid cancers (including, but not limited to, thyroid adenocarcinoma and medullary carcinoma), and urinary tract epithelial cancers.

In another embodiment, the cancer treated according to the present invention is non-solid cancer. Examples of non-solid tumors include, but are not limited to, blood neoplasms. As used herein, blood neoplasm is a technical term that includes lymphatic disorders, myeloid disorders, and AIDS-related leukemias.

Lymphocytic disorders include, but are not limited to, acute lymphocytic leukemia and chronic lymphoproliferative disorders (eg, lymphoma, myeloma, and chronic lymphocytic leukemia). Lymphomas include, for example, Hodgkin's disease, non-Hodgkin's lymphoma, and lymphocytic lymphoma. Examples of chronic lymphocytic leukemia include T-cell chronic lymphocytic leukemia and B-cell chronic lymphocytic leukemia.

In a specific embodiment, the cancer is breast cancer, cartinoid, cervical cancer, colorectal cancer, endometrial cancer, glioma, head and neck cancer, liver cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, It is selected from prostate cancer, kidney cancer, gastric cancer, thyroid cancer, and urinary tract epithelial cancer.

In a specific embodiment, the cancer is breast cancer. In a specific embodiment, the cancer is a carcinoid cancer. In a specific embodiment, the cancer is cervical cancer. In a specific embodiment, the cancer is colorectal cancer. In a specific embodiment, the cancer is endometrial cancer. In a specific embodiment, the cancer is 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 cancer.

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

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

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

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

The present invention also relates to a pharmaceutical preparation for use in the treatment of cancer, wherein the pharmaceutical preparation is administered to a human subject in an amount effective for the treatment of cancer.
(A) With ENT family transporter inhibitors;
(B) Optionally include one or more pharmaceutically acceptable carriers, diluents, excipients, and / or adjuvants.

In one embodiment, in the pharmaceutical formulation for use of the present invention, the ENT family transporter is ENT1 and the inhibitor is selected from the group consisting of small molecules, nucleic acids, peptides and antibodies.

In one embodiment, in a pharmaceutical formulation for use of the present invention, the pharmaceutical formulation further comprises an additional therapeutic agent. In one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist.

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

In one embodiment, in a pharmaceutical product for use of the present invention, the pharmaceutical product is administered before, at the same time as, or after administration of an additional therapeutic agent containing an adenosine receptor antagonist.

The present invention also provides a pharmaceutical formulation for use in the treatment of cancer, wherein the pharmaceutical formulation is administered to a human subject in an amount effective for the treatment of cancer.
(A) ENT family transporter inhibitors and (b) adenosine receptor antagonists;
(C) Optionally include one or more pharmaceutically acceptable carriers, diluents, excipients, and / or adjuvants.

In one embodiment, in a pharmaceutical formulation for use of the invention comprising an adenosine receptor antagonist, the adenosine receptor antagonist comprises an A2A or A2B receptor antagonist. In one embodiment, the adenosine receptor antagonist is selected from:
5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine;
(S) -7- (5-Methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2-yl) methyl) -3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-amine;
6- (2-Chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine;
3- (2-Amino-6-(1-((6- (2-hydroxypropane-2-yl) pyridine-2-yl) methyl) -1H-1,2,3-triazole-4-yl) pyrimidine -4-yl) -2-methylbenzonitrile;
2- (2-Franyl) -7- (2- (4- (4- (2-Methoxyethoxy) phenyl) -1-piperazinyl) ethyl) -7H-pyrazolo (4,3-e) (1,2, 4) Triazolo (1,5-c) pyrimidine-5-amine;
3- (4-Amino-3-methylbenzyl) -7- (2-furyl) -3H- (1,2,3) triazolo (4,5-d) pyrimidine-5-amine; and 4-hydroxy-N -(4-Methoxy-7-morpholinobenzo [d] thiazole-2-yl) -4-methylpiperidine-1-carboxamide.

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

The present invention also provides a method of treating a cancer, comprising administering the pharmaceutical formulation to a human subject in an amount effective for the treatment of cancer.
(A) With ENT family transporter inhibitors;
(B) Optionally include one or more pharmaceutically acceptable carriers, diluents, excipients, and / or adjuvants.

In one embodiment, in the method of the invention, the ENT family transporter is ENT1 and the inhibitor is selected from the group consisting of small molecules, nucleic acids, peptides, and antibodies.

In one embodiment, in the method of the invention, the pharmaceutical formulation further comprises an additional therapeutic agent. In one embodiment, the additional therapeutic agent comprises an adenosine receptor antagonist.

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

In one embodiment, in the method of the invention, the pharmaceutical product is administered before, simultaneously with, or after administration of an additional therapeutic agent containing an adenosine receptor antagonist.

The present invention also provides a method of treating a cancer, comprising administering the pharmaceutical formulation to a human subject in an amount effective for the treatment of cancer.
(A) ENT family transporter inhibitors and (b) adenosine receptor antagonists,
(C) Optionally include one or more pharmaceutically acceptable carriers, diluents, excipients, and / or adjuvants.

In one embodiment, in the method of the invention in which the pharmaceutical formulation comprises an adenosine receptor antagonist, the adenosine receptor antagonist comprises an A2A or A2B receptor antagonist. In one embodiment, the adenosine receptor antagonist is selected from:
5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine;
(S) -7- (5-Methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2-yl) methyl) -3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-amine;
6- (2-Chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine;
3- (2-Amino-6-(1-((6- (2-hydroxypropane-2-yl) pyridine-2-yl) methyl) -1H-1,2,3-triazole-4-yl) pyrimidine -4-yl) -2-methylbenzonitrile;
2- (2-Franyl) -7- (2- (4- (4- (2-Methoxyethoxy) phenyl) -1-piperazinyl) ethyl) -7H-pyrazolo (4,3-e) (1,2, 4) Triazolo (1,5-c) pyrimidine-5-amine;
3- (4-Amino-3-methylbenzyl) -7- (2-furyl) -3H- (1,2,3) triazolo (4,5-d) pyrimidine-5-amine; and 4-hydroxy-N -(4-Methoxy-7-morpholinobenzo [d] thiazole-2-yl) -4-methylpiperidine-1-carboxamide.

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

It is a graph which shows the expression of ENT1 in a human primary lymphocyte. FPKM: Fragment per kilobase of 1 million. Source: Bonnal RJP, Nature 2015. It is a graph which shows the expression of ENT2 in a human primary lymphocyte. FPKM: Fragment per kilobase of 1 million. Source: Bonnal RJP, Nature 2015. It is a graph which shows the expression of ENT4 in a human primary lymphocyte. FPKM: Fragment per kilobase of 1 million. Source: Bonnal RJP, Nature 2015. 2A and 2B are graphs showing the viability of CD3 + T cells treated differently, showing that ENT inhibitors reverse the decline in adenosine / ATP-mediated T cell viability. Human primary CD3 + T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 25 μM adenosine (FIG. 2A) or 200 μM ATP (FIG. 2B). T cell viability was analyzed by flow cytometry after a 3-day incubation period. The average +/- SD of biological replication is shown. Representative data for one healthy donor are shown. Similar data were obtained for two healthy donors. 3A, 3B, 3C, and 3D are graphs showing the proliferation of CD4 + T cells and CD8 + T cells treated differently, and the ENT inhibitor suppresses adenosine / ATP-mediated T cell proliferation. Indicates that it will be rescued. Human primary CD3 + T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 25 μM adenosine (FIGS. 3A and 3C) or 200 μM ATP (FIGS. 3B and 3D). After a 3-day incubation period, flow cytometry was used to analyze the proliferation of CD4 + (FIGS. 3A and 3B) and CD8 + (FIGS. 3C and 3D) T cells. The average +/- SD of biological replication is shown. Representative data for one healthy donor are shown. Similar data were obtained for two healthy donors. 3A, 3B, 3C, and 3D are graphs showing the proliferation of CD4 + T cells and CD8 + T cells treated differently, and the ENT inhibitor suppresses adenosine / ATP-mediated T cell proliferation. Indicates that it will be rescued. Human primary CD3 + T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 25 μM adenosine (FIGS. 3A and 3C) or 200 μM ATP (FIGS. 3B and 3D). After a 3-day incubation period, flow cytometry was used to analyze the proliferation of CD4 + (FIGS. 3A and 3B) and CD8 + (FIGS. 3C and 3D) T cells. The average +/- SD of biological replication is shown. Representative data for one healthy donor are shown. Similar data were obtained for two healthy donors. 4A and 4B are graphs showing IL-2 secretion of differently treated CD3 + T cells, which are adenosine / ATP-mediated T cells treated with a combination of an ENT inhibitor and the _A2AR antagonist compound 8a. It shows that suppression of cellular cytokine secretion is rescued. CD3 + T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 25 μM adenosine (FIG. 4A) or 200 μM ATP (FIG. 4B). IL-2 secretion in the supernatant was analyzed by AlphaLISA after a 3-day incubation period. The average +/- SD of biological replication is shown. Representative data for one healthy donor are shown. Similar data were obtained for two healthy donors. FIG. 5A shows the viability of CD3 + T cells determined by staining with a fixable life-and-death determination dye. FIG. 5B shows the proliferation rate of CD8 + T cells determined by the CFSE dilution method. FIG. 5C shows the concentration of TNFα present in the cell culture supernatant. Human primary CD3 + T cells were stimulated with anti-CD3 / anti-CD28 coated microbeads and treated with 100 μM ATP or control medium. After a 3-day incubation period, flow cytometry was used to analyze CD3 + T cell viability (FIG. 5A) and CD8 + T cell proliferation (FIG. 5B). TNFα secretion in the supernatant was analyzed by AlphaLISA. Gray shaded bars indicate wells treated with A2AR antagonists and clear bars indicate wells treated with comparable concentrations of DMSO. Results are shown as mean ± standard deviations obtained from 6-series (DMSO) or 2-series (A2AR antagonist) wells. The data shown are representative of the data obtained from 3 healthy individuals in 4 independent experiments. In vivo LPS-induced TNF alpha production in mice when pretreated with compound 8b (A2AR antagonist) or NBMPR (ENT1 inhibitor) or a combination thereof. BALB / c mice were pretreated with NBMPR (20 mg / kg, po) or vehicle for 1 hour prior to LPS (1 mg / kg, IV) injection. Thirty minutes prior, mice were treated with a single dose of compound 8b (3 mg / kg, po) or vehicle. Serum was collected from mice 1 hour after LPS treatment. The level of TNF alpha was determined by ELISA (n = 5). The P-value is shown using the Mann-Whitney test and ns = no significant difference. Shows MCA205 tumor growth upon treatment with compound 8b (A2AR antagonist) in combination with NBMPR (ENT1 inhibitor). FIG. 7A is a graph showing the median value of tumor volume over time after subcutaneous inoculation of tumor cells. 7B-D are treated with vehicle (FIG. 7B), 20 mg / kg, BIDx22 (day 11) NBMPR alone (FIG. 7C) or in combination with 3 mg / kg, compound 8b of BIDx22 (FIG. 7D). The individual tumor growth volume of the mice. (N = 10, * P = 0.0043, ** P = 0.0015, *** P <0.0001, linear mixed model statistical analysis). Shows MCA205 tumor growth upon treatment with compound 8b (A2AR antagonist) in combination with NBMPR (ENT1 inhibitor). FIG. 7A is a graph showing the median value of tumor volume over time after subcutaneous inoculation of tumor cells. 7B-D are treated with vehicle (FIG. 7B), 20 mg / kg, BIDx22 (day 11) NBMPR alone (FIG. 7C) or in combination with 3 mg / kg, compound 8b of BIDx22 (FIG. 7D). The individual tumor growth volume of the mice. (N = 10, * P = 0.0043, ** P = 0.0015, *** P <0.0001, linear mixed model statistical analysis).

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

Use the following abbreviations:
ATP: Adenosine Triphosphate BSA: Bovine Serum Albumin CFSE: Carboxyfluorescein Succinimidyl Ester DMSO: Dimethylsulfoxide EDTA: Ethylenediaminetetraacetate FACS: Fluorescent Activated Cell Selection FBS: Bovine Fetal Serum mL: Millimole μL: Microliter mM: mmol nM: Nanomol μM: Micromol PBS: Phosphate buffered saline rpm: Rotations per minute RPMI: Roswell Park Memorial Institute medium

Example 1. ENT1 inhibitors in combination with A2AR antagonists restore TNFalpha production in T cells Materials The reagents and compounds used in the following assays are available at:

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

Human primary T cell culture. Purified human CD3 ⁺ T cells were thawed and washed twice with RPMI1640 medium containing 10% hiFBS, UltraGlutamine (Lonza) supplemented with 1x non-essential amino acids, and 1 mM sodium pyruvate (Gibco) (complete medium). After the final wash, cells were resuspended in PBS containing 10% FBS, labeled with 3 μM CFSE at room temperature for 5 minutes and then washed twice in complete medium. After the final wash, cells were suspended in X-Vivo15 medium at 1.6 × ¹⁰⁶ cells / mL. 50 μL of cell suspension (8 × 10 ⁴ T cells) was added to the wells of a sterile round bottom 96-well plate. Cells were activated by adding 50 μL of anti-CD3 anti-CD28 coated microbeads (Dynabeads, human T activator CD3 / CD28) suspended in X-Vivo15 medium at a ratio of 1 microbead per 2 cells. Adenosine (75 mM stock solution in DMSO) and ATP (powder) were diluted with X-Vivo15 medium and 25 μL or 50 μL was added to the wells to reach a final assay concentration of 25 μM adenosine or 200 μM ATP. From 100 mM stock solution (DMSO solution or aqueous solution), serial dilutions of the ENT inhibitors dilazep dihydrochloride, dipyridamole, and ticagrelol were prepared in X-Vivo15 medium and 25 μL was added to the wells. _A 2AR antagonist compound 8a (10 mM stock in DMSO) was diluted with X-Vivo15 medium and 25 μL was added to the wells to reach a final assay concentration of 300 nM. In tests involving different A2AR antagonists, either or match A2AR antagonist compound 8a with a final concentration of 300 nM, NIR178 with a final concentration of 5 μM, CPI-444 with a final concentration of 5 μM, AZD4635 with a final concentration of 1 μM, or AB928 with a final concentration of 1 μM. A concentration of DMSO was placed in the well. In addition, some wells were populated with a final concentration of 1 μM ENT-1 inhibitor dipyridamole, or a combination of dipyridamole and an A2AR antagonist. The final DMSO concentration for this assay was 0.05% and the final assay volume was 200 μL. The experiment was biologically performed in 2 stations and DMSO controls were added in 4 stations. The cells were allowed to stand in a humidified tissue culture incubator at 37 ° C. for 72 hours while flowing 5% CO ₂ . After 72 hours, cells were centrifuged at 1600 rpm for 5 minutes and pelleted, and the supernatant was transferred to a V-bottom 96-well plate to quantify cytokines. For flow cytometric analysis, the cell pellet was resuspended in FACS buffer (see below).

Cytokine quantification. The supernatant was centrifuged at 4000 rpm for 10 minutes, IL-2 was quantified using the IL-2 (human) AlphaLISA biotin-free detection kit, and the AlphaLISA human TNFα biotin-free detection kit was used according to the manufacturer's instructions. TNFα was quantified.

Flow cytometry. The cells were washed with FACS buffer (PBS containing 2 mM EDTA and 0.1% BSA) and stained on ice for 20 minutes with a surface marker antibody and a dye for life or death determination. Cells were washed twice with FACS buffer and data were obtained using LSRFortessa (BD biosciences). Analysis was performed using FlowJo software (Treestar).

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

Adenosine-mediated and ATP-mediated inhibition of T cell viability, proliferation, and IL-2 secretion is not restored by the potent and selective A2AR antagonist compound 8a, an A2AR-independent mechanism of T cell inhibition. Was suggested (Figs. 2-4).

Extracellular adenosine is taken up by cells by an equilibrium nucleoside transporter (ENT).

Primary T cells were treated with adenosine or ATP and incubated with three different structurally unrelated ENT inhibitors, dipyridamole, dilazep hydrochloride, and ticagrelor. All of the ENT inhibitors tested restored T cell proliferation and viability (FIGS. 2 and 3), indicating the adverse effects of ENT cell uptake of adenosine on T cell metabolism. However, none of the ENT inhibitors rescued T cell-derived IL-2 secretion as a single agent.

Complete rescue of adenosine-mediated and ATP-mediated suppression of T cell cytokine secretion was achieved during combination therapy with the A2A receptor antagonist compound 8a and an ENT inhibitor (FIGS. 4A and 4B). These results show that adenosine suppresses T cell function and vitality by both extracellular and intracellular mechanisms, but in combination with A2AR antagonists (not limited to compound 8a, as further shown below) and ENT inhibitors. It shows that treatment can reverse this.

5A-C show that the combination of the ENT-1 inhibitor dipyridamole with the A2A receptor antagonist compounds 8a, AB928, CPI-444, NIR178, and AZD4635 can reverse the inhibition of T cells in the presence of ATP. Is shown. More specifically, ATP significantly inhibited the proliferation of CD8 + T cells and reduced T cell viability, which was completely reversed by the ENT-1 inhibitor dipyridamole. ATP also significantly inhibited the production of TNFα. Both A2AR and ENT-1 inhibitors were able to partially restore cytokine production individually. The combination of both inhibitors further increased the recovery of cytokine secretion compared to either treatment alone. Overall, these data are for the treatment of cancer with Compounds 8a, AB928, AZD4635, NIR178, or CPI-444 for the complete recovery of T cell function and survival in ATP / adenosine-rich tumor microenvironments. It has been shown that the combination with ENT-1 inhibitors is beneficial.

Example 2. ENT1 inhibitors in combination with A2AR antagonists restore TNF alpha production in the LPS model of endotoxinemia The most prominent targets for adenosine transport are the equilibrium nucleoside transporters, ENT1, ENT2, ENT3, and ENT4. ENT inhibitors regulate adenosine across the cell membrane to reduce intracellular adenosine levels and allow extracellular adenosine accumulation by inhibiting intracellular and extracellular transport of nucleosides, eg, equilibrium nucleoside transport. High intracellular adenosine has been shown to result in suppression of immune cell proliferation, survival, and function. On the other hand, extracellular adenosine reduces activation and function of immune cells, such as pro-inflammatory cytokine production and cytotoxicity, by binding to the adenosine receptor 2A (A2AR). Thus, inhibition of equilibrium transporters aims to reduce intracellular adenosine, thereby enhancing the survival, proliferation, and function of immune cells, while inhibition of A2AR by inhibiting extracellular adenosine. Aims to restore pro-inflammatory activity, cytotoxicity, and immune cell activation.

NBMPR (6-S-[(4-nitrophenyl) methyl] -6-thioinosin) is a specific ENT1 inhibitor and has similar activity in humans and mice. Therefore, the use of NBMPR in a mouse model specifically inhibits the activity of ENT1.

The TNFalpha-mediated inhibition observed in the presence of the ENT1 inhibitor NBMPR using a lipopolysaccharide (LPS) model known to induce the secretion of the pro-inflammatory cytokine TNFalpha is an A2AR antagonist. It was evaluated whether the rescue could be achieved by adding the compound 8b.

BALB / c mice _were p. o. Treated. After 30 minutes, NBMPR 20 mg / kg p. o. The mice were treated with. After 60 minutes, mice were treated with LPS and blood was collected, and TNF alpha in serum was measured by ELISA.

Treatment with LPS significantly increased TNF alpha levels in serum. The A2AR antagonist, compound 8b, had no effect on TNF alpha levels after LPS treatment, but treatment with NBMPR alone significantly suppressed TNF alpha production almost 2-fold (p = 0.008). Pretreatment of mice with compound 8b reversed the effect of NBMPR and rescued TNF alpha production more than 2-fold (p = 0.016) (FIG. 6).

Example 3. ENT1 inhibitor in combination with A2AR antagonist demonstrates antitumor effect in mouse syngeneic MCA205 experimental fibrosarcoma model Anti-A2AR antagonist, compound 8b in combination with ENT1 inhibitor NBMPR in established mouse syngeneic MCA205 fibrosarcoma tumor model The tumor effect was evaluated.

MCA205 tumor cells were subcutaneously inoculated into the right abdomen of C57BL / 6 mice. Mice were randomly assigned to groups when the average tumor size reached about 50 mm ³ . A vehicle as a control (2.5% DMSO, 10% Solutol HS15 in _dH2O , pH 3) was p. o. Or, NBMPR at 20 mg / kg, p. o. , BIDx22 (7th to 29th days) as a single agent, or compound 8b, p. o. , 3 mg / kg, QDx22 (7th to 29th days) was administered to mice in combination.

20 mg / kg, p. o. NBMPR, which was administered as a single agent twice daily (BID) for 22 consecutive days, showed a significant delay in tumor growth (p = 0.0043) compared to vehicle (FIGS. 7A, 7B, and). FIG. 7C).

3 mg / kg of compound 8b p. o. In combination with 20 mg / kg of NBMPR, when administered twice daily (BID) for 22 consecutive days, there was a significant delay in tumor growth (p <0.0001) compared to the vehicle, and NBMPR alone. It showed a significant delay in tumor growth (p = 0.0015) when compared to therapy (FIGS. 7A-7D).

Claims (29)

An ENT family transporter inhibitor for use in the treatment of cancer in human subjects. The ENT family transporter inhibitor for use according to claim 1, wherein the ENT family transporter is ENT1 and the inhibitor is selected from the group consisting of small molecules, nucleic acids, peptides and antibodies. Claimed that the subject is treated with an additional therapeutic agent in combination with the ENT family transporter inhibitor or is given the additional therapeutic agent within about 14 days of administration of the ENT family transporter inhibitor. The ENT family transporter inhibitor for use according to any one of 1 or 2. The ENT family transporter inhibitor for use according to claim 3, wherein the additional therapeutic agent comprises an adenosine receptor antagonist. Claim 1 that the subject has previously received at least one prior therapeutic treatment and has progressed since administration of the at least one prior therapeutic treatment and prior to administration of the ENT family transporter inhibitor. ENT family transporter inhibitor for use according to any one of 4 to 4. The ENT family transporter inhibitor for use according to claim 5, wherein the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, hormone therapy, and surgery. The ENT family transporter inhibitor for use according to claim 4, wherein the ENT family transporter inhibitor is administered before, at the same time as, or after administration of the additional therapeutic agent containing an adenosine receptor antagonist. .. (A) With an effective amount of ENT family transporter inhibitor;
(B) A combination comprising, with, an effective amount of an adenosine receptor antagonist. (A) With an effective amount of ENT family transporter inhibitor;
(B) With an effective amount of adenosine receptor antagonist;
(C) A pharmaceutical composition comprising at least one pharmaceutically acceptable excipient. (A) With the first moiety containing an effective amount of the ENT family transporter inhibitor;
(B) A parts kit comprising a second portion comprising an effective amount of an adenosine receptor antagonist. The combination, pharmaceutical composition, or parts kit according to any one of claims 8 to 10, wherein the adenosine receptor antagonist is an A2A or A2B receptor antagonist. The adenosine receptor antagonist
5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine;
(S) -7- (5-Methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2-yl) methyl) -3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-amine;
6- (2-Chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine;
3- (2-Amino-6-(1-((6- (2-hydroxypropane-2-yl) pyridine-2-yl) methyl) -1H-1,2,3-triazole-4-yl) pyrimidine -4-yl) -2-methylbenzonitrile;
2- (2-Franyl) -7- (2- (4- (4- (2-Methoxyethoxy) phenyl) -1-piperazinyl) ethyl) -7H-pyrazolo (4,3-e) (1,2, 4) Triazolo (1,5-c) pyrimidine-5-amine;
3- (4-Amino-3-methylbenzyl) -7- (2-furyl) -3H- (1,2,3) triazolo (4,5-d) pyrimidine-5-amine; and 4-hydroxy-N -(4-Methoxy-7-morpholinobenzo [d] thiazole-2-yl) -4-methylpiperidine-1-carboxamide, the combination according to any one of claims 8 to 11, the pharmaceutical composition. Things or parts kits. The adenosine receptor antagonist is the formula (I).

Compound, or a pharmaceutically acceptable salt or solvate thereof, in the formula,
^R1 represents a 5- or 6-membered heteroaryl or a 5- or 6-membered aryl, where the heteroaryl group or aryl group is optional and C1-C6 alkyl (preferably methyl) and halo (preferably fluoro or or). Substituted with one or more substituents selected from (chloro), preferably R ¹ represents a 5-membered heteroaryl and more preferably R ¹ represents a frill;
R ² represents a 6-membered aryl or a 6-membered heteroaryl.
The heteroaryl group or the aryl group is optionally halo, alkyl, heterocyclyl, alkoxy, cycloalkyloxy, heterocyclyloxy, carbonyl, alkylcarbonyl, aminocarbonyl, hydroxycarbonyl, heterocyclylcarbonyl, alkylsulfoxide, alkylsulfonyl, aminosulfonyl. , Heterocyclylsulfonyl, alkylsulfonimideyl, carbonylamino, sulfonylamino, and substituted with one or more substituents selected from alkylsulfonalkyl;
The substituent is optional, oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkylaminoalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (heterocyclyl). (Alkyl) Aminoalkyl, Heterocyclyl, Heteroaryl, Alkyne Heteroaryl, Alkyne, Alkyne, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino, (Aminocarbonylalkyl) (Alkyl) Amino, Alkenylcarbonylamino, Hydroxycarbonyl , Alkyneoxycarbonyl, Aminocarbonyl, Aminoalkylaminocarbonyl, Alkylaminoalkylaminocarbonyl, Dialkylaminoalkylaminocarbonyl, Heterocyclylalkylaminocarbonyl, (alkylaminoalkyl) (alkyl) aminocarbonyl, Alkylaminoalkylcarbonyl, Dialkylaminoalkylcarbonyl , Heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidealkyl, alkylsulfonyl, and alkylsulfonalkyls substituted with one or more substituents selected from;
Alternatively, the heteroaryl group or the aryl group is optionally a 5- or 6-membered aryl ring, a 5- or 6-membered heteroaryl ring, or a 5- or 6-membered cycloalkyl ring, together with the atoms to which they are attached. Alternatively, it is substituted with two substituents forming a 5- or 6-membered heterocyclyl ring, optionally oxo, halo, hydroxy, cyano, alkyl, alkenyl, aldehyde, heterocyclylalkyl, hydroxyalkyl, dihydroxyalkyl, hydroxyalkyl. Aminoalkyl, Aminoalkyl, Alkylaminoalkyl, Dialkylaminoalkyl, (Heterocyclyl) (Alkyl) Aminoalkyl, Heterocyclyl, Heteroaryl, Alkyl Heteroaryl, Alkin, Alkine, Amino, Dialkylamino, Aminoalkylcarbonylamino, Aminocarbonylalkylamino , (Aminocarbonylalkyl) (alkyl) amino, alkenylcarbonylamino, hydroxycarbonyl, alkyloxycarbonyl, aminocarbonyl, aminoalkylaminocarbonyl, alkylaminoalkylaminocarbonyl, dialkylaminoalkylaminocarbonyl, heterocyclylalkylaminocarbonyl, (alkylamino) One or more substitutions selected from alkyl) (alkyl) aminocarbonyl, alkylaminoalkylcarbonyl, dialkylaminoalkylcarbonyl, heterocyclylcarbonyl, alkenylcarbonyl, alkynylcarbonyl, alkylsulfoxide, alkylsulfoxidoalkyl, alkylsulfonyl, and alkylsulfonalkyl. The combination, pharmaceutical composition, or parts kit according to any one of claims 8 to 11, which is substituted with a group. The combination, pharmaceutical composition, or parts kit according to any one of claims 8 to 13, wherein the ENT family transporter is ENT1. The combination, pharmaceutical composition, or parts kit according to any one of claims 8 to 14, further comprising an additional therapeutic agent. The combination, pharmaceutical composition, or parts kit according to any one of claims 8 to 15, which is for medical use. The combination, pharmaceutical composition, or parts kit according to any one of claims 8 to 15, for use in the treatment of cancer. The combination, pharmaceutical composition, or parts kit according to any one of claims 8 to 15, wherein the ENT family transporter inhibitor is administered before, simultaneously with, or after administration of the adenosine receptor antagonist. .. A pharmaceutical product for use in cancer treatment, wherein the pharmaceutical product is administered to a human subject in an amount effective for the cancer treatment, and the product is a pharmaceutical product.
(A) With ENT family transporter inhibitors;
(B) The pharmaceutical formulation comprising, optionally, one or more pharmaceutically acceptable carriers, diluents, excipients, and / or adjuvants. 19. The pharmaceutical formulation for use according to claim 19, wherein the ENT family transporter is ENT1 and the inhibitor is selected from the group consisting of small molecules, nucleic acids, peptides, and antibodies. The pharmaceutical product for use according to any one of claims 19 or 20, wherein the pharmaceutical product further comprises an additional therapeutic agent. The pharmaceutical formulation for use according to claim 21, wherein the additional therapeutic agent comprises an adenosine receptor antagonist. The pharmaceutical formulation for use according to any one of claims 19-22, wherein the subject has previously received at least one prior therapeutic treatment. 23. The pharmaceutical formulation for use according to claim 23, wherein the prior therapeutic treatment is selected from the group consisting of chemotherapy, immunotherapy, radiation therapy, stem cell transplantation, hormone therapy, and surgery. The pharmaceutical preparation for use according to any one of claims 21 to 24, wherein the pharmaceutical product is administered before, at the same time as, or after the administration of the additional therapeutic agent containing an adenosine receptor antagonist. A pharmaceutical product for use in cancer treatment, wherein the pharmaceutical product is administered to a human subject in an amount effective for cancer treatment.
(A) With ENT family transporter inhibitors;
(B) With an adenosine receptor antagonist;
(C) The pharmaceutical formulation comprising, optionally, one or more pharmaceutically acceptable carriers, diluents, excipients, and / or adjuvants. The pharmaceutical preparation for use according to any one of claims 22 to 26, wherein the adenosine receptor antagonist comprises an A2A or A2B receptor antagonist. The adenosine receptor antagonist
5-bromo-2,6-di- (1H-pyrazole-1-yl) pyrimidine-4-amine;
(S) -7- (5-Methylfuran-2-yl) -3-((6-(([tetrahydro-3-yl] oxy) methyl) pyridin-2-yl) methyl) -3H- [1, 2,3] Triazolo [4,5-d] pyrimidin-5-amine;
6- (2-Chloro-6-methylpyridine-4-yl) -5- (4-fluorophenyl) -1,2,4-triazine-3-amine;
3- (2-Amino-6-(1-((6- (2-hydroxypropane-2-yl) pyridine-2-yl) methyl) -1H-1,2,3-triazole-4-yl) pyrimidine -4-yl) -2-methylbenzonitrile;
2- (2-Franyl) -7- (2- (4- (4- (2-Methoxyethoxy) phenyl) -1-piperazinyl) ethyl) -7H-pyrazolo (4,3-e) (1,2, 4) Triazolo (1,5-c) pyrimidine-5-amine;
3- (4-Amino-3-methylbenzyl) -7- (2-furyl) -3H- (1,2,3) triazolo (4,5-d) pyrimidine-5-amine; and 4-hydroxy-N -(4-Methoxy-7-morpholinobenzo [d] thiazole-2-yl) -4-methylpiperidine-1-carboxamide for use according to any one of claims 22-27. Pharmaceutical preparation. The pharmaceutical preparation for use according to any one of claims 22 to 27, wherein the adenosine receptor antagonist comprises a compound of formula (I) as defined in claim 13.

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