RU2534804C1 - SUBSTITUTED [1,2,4]TRIAZOLO[4,3-a]PYRIDINES, DEMONSTRATING PROPERTIES OF ANTAGONISTS OF ADENOSINE A2A RECEPTORS, AND THEIR APPLICATION - Google Patents

Abstract

FIELD: chemistry.SUBSTANCE: in general formulaA represents optionally substituted aminocarbonyl group -N-C(O)-, in which amino group can be substituted and substituents can be selected from hydrogen, C-Calkyl, possibly substituted with C-Calkoxy, C-Ccycloalkyl, 5-6-membered heteroaryl, in which heteroatoms are selected from oxygen or nitrogen; aryl, selected from phenyl, possibly substituted with hydroxy, C-Calkyl, C-Calkoxy, halogen, C-Cacylamino group, or naphthyl; or amino group is selected from C-Cheterocyclyl, containing 1-2 heteroatoms in cycle, selected from nitrogen, oxygen or sulphur, possibly substituted with hydroxy, C-Calkyl, benzyl, phenyl, which can be substituted with halogen, and said heterocyclyl can be condensed with benzene ring; acylamino group, in which acyl is selected from C-Calkylcarbonyl, where alkyl can be substituted with phenyl, substituted with phenyl, in which substituents are selected from C-Calkoxy; 5-membered heteroaryl with heteroatom, selected from atom of oxygen or sulphur; benzoyl, possibly substituted with C-Calkyl, C-Calkoxy, C-Calkylthio or halogen, methylenedioxy; heterocyclylcarbonyl, in which heterocyclyl is selected from 5-6-membered heterocyclyl, with 1-2 heteroatoms, selected from nitrogen, oxygen or sulphur, possibly condensed with benzene ring and possibly substituted with C-Calkyl, halogen; or ureido group, in which one of substituents of terminal amido group represents hydrogen, and the second substituent is selected from: C-Calkyl, substituted with phenyl, 5-membered saturated or aromatic heterocyclyl, in which heteroatoms are selected from oxygen or sulphur; C-Calkenyl; aryl, selected from phenyl, substituted with C-Calkyl, C-Calkoxy, ethylenedioxy, methylenedioxy, halogen, C-Calkylcarbonyl; 5-membered heterocyclyl, in which heteroatoms are selected from sulphur or oxygen atom, and possibly substituted with alkyloxycarbonyl group; B represents non-aromatic cyclic substituent, selected from C-Ccycloalkyl; and has other values, given in the invention formula. Values R1a R1b R1c are given in the invention formula.EFFECT: increased efficiency of application of compounds.12 cl, 8 tbl, 13 ex

Description

This invention relates to new compounds - substituted [1,2,4] triazolo [4,3-a] pyridines exhibiting antagonistic activity against adenosine A2A receptors, and to their use as a drug substance, pharmaceutical compositions, drugs and adjuvants. The invention also relates to methods for treating disorders of the central nervous system (CNS), neurodegenerative, inflammatory, infectious and oncological diseases.

Adenosine regulates many physiological functions, in particular, acts as a cytoprotector in normal and pathophysiological conditions in response to stress in organs and tissues [Haskó G, Linden J, Cronstein B, Pacher P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Discov. 2008; 7: 759-770]. This protective response can manifest itself as increased blood supply (vasodilation or angiogenesis), ischemic preconditioning [Akaiwa K, Akashi H, Harada H, Sakashita H, Hiromatsu S, Kano T, Aoyagi S. Moderate cerebral venous congestion induces rapid cerebral protection via adenosine A1 receptor activation. Brain Res. 2006; 1122: 47-55], and / or anti-inflammatory effect (activation and infiltration of inflammatory cells, production of cytokines and free radicals) [Ohta A, Sitkovsky M. Role of G-protein-coupled adenosine receptors in downregulation of inflammation and protection from tissue damage . Nature. 2001; 41: 916-920]. Extracellular adenosine acts on receptors located on the cell membrane, activating the corresponding intracellular signaling cascades.

There are four subtypes of adenosine receptors, designated A1, A2A, A2B, and A3 (Table 1), each of which has a unique pharmacological profile, tissue distribution, and binding to effector molecules [Fredholm BB, IJzerman AP, Jacobson KA, Klotz KN, Linden J International Union of Pharmacology. Xxv. Nomenclature and classification of adenosine receptors. Pharmacol Rev. 2001; 53: 527-552]. All adenosine receptors belong to the family of receptors associated with G-proteins (GPCRs), structurally resembling receptors for biogenic amines.

Table 1 Properties of adenosine GPCR receptors Receptor subtype A1 A2A A2B A3 G protein Gi go Gs golf Gs, gq Gi gq Signal transmission mechanism Inhibition of adenylate cyclase (↓ AC) Phospholipase C activation (↑ PLC) (↑ AC) (↓ chCa ⁺² ) (↑ AC) (↑ PLC) (↓ AC) (↑ PLC) Blockade of calcium channels (↓ chCa ⁺² ) Activation of potassium channels (↑ chK ⁺ ) Effector molecules (secondary messengers) ↓ cAMP ↑ cAMP ↑ cAMP ↑ cAMP ↑ IP3 ↑ IP3 ↑ IP3 ↑ IP3 ↓ chCa ⁺² ↑ chCa ⁺² ↑ chCa ⁺² ↑ chCa ⁺² ↑ chK ⁺ Receptor adenosine affinity (radioligand binding ^a ) Kd, nM 10 (rA1) 30 (rA2A) > 100000 (hA2B) 1000 (hA3) Receptor adenosine affinity (functional testing ^b ) EC50, nM 310 (hA1) 700 (hA2A) 24000 (hA2B) 290 (hA3)

Table 1 Tissue distribution (high expression) CNS (cortex, hippocampus, cerebellum, spinal cord); adrenal glands; atria Spleen; thymus white blood cells (lymphocytes, granulocytes); platelets; GABA neurons; olfactory bulbs Cecum and colon; bladder Mast cells; testes a) [J Med Chem. 2000; 43: 2196]; b) [Bioorg Med Chem Lett. 2011; 21 (7): 1933]

Activation of A1 receptors leads to inhibition of adenylate cyclase via A1 / Gi / o receptor-bound proteins [Londos C, Cooper DM, Wolff J. Subclasses of external adenosine receptors. PNAS USA. 1980; 77: 2551-2554], and also increases the activity of phospholipase C PLC [Rogel A, Bromberg Y, Sperling O, Zoref-Shani E. Phospholipase C is involved in the adenosine activated signal transduction pathway conferring protection against iodoacetic acid-induced injury in primary rat neuronal cultures. Neurosci Lett. 2005; 373: 218-221]. A1 receptors activate potassium channels, including KATP channels, and block Q-, P- and N-types of calcium Ca2 + channels.

Activation of A2A receptors increases adenylate cyclase activity. In the peripheral system, the main proteins conjugated to A2A receptors are Gs proteins. In the striatum, where the content of A2A receptors is maximum, they are coupled with Golf proteins [Kull B, Svenningsson P, Fredholm BB. Adenosine A2A receptors are colocalized with and activate Golf in rat striatum. Mol Pharmacol. 2000; 58: 771-777], which, like Gs proteins, are associated with adenylate cyclase. A2A receptors are able to incorporate a PLC signaling cascade, induce inositol phosphate synthesis and increase intracellular calcium concentration, and also activate protein kinase C.

A2B receptors are positively associated with adenylate cyclase and phospholipase C. Many functions of A2B receptors are determined by phospholipase C, which is activated by Gq proteins [Linden J, Thai T, Figler H, Jin X, Robeva AS. Characterization of human A2B adenosine receptors: radioligand binding, western blotting, and coupling to Gq in human embryonic kidney 293 cells and HMC-1 mast cells. Mol Pharmacol. 1999; 56: 705-713]. These receptors are also involved in the signaling cascade of arachidonic acid [Donoso MV, Lopez R, Miranda R, Briones R, Huidobro-Toro JP. A2B adenosine receptor mediates human chorionic vasoconstriction and signals through the arachidonic acid cascade. Am J Physiol Heart Circ Physiol. 2005; 288: H2439-H2449].

A3 receptors are involved in classical signaling pathways by inhibiting adenylate cyclase, stimulating phospholipase C, and causing mobilization of calcium ions [Zhou QY, et al. Molecular cloning and characterization of an adenosine receptor: the A3 adenosine receptor. PNAS USA. 1992; 89: 7432-7436]. A3 receptor agonists inhibit melanoma cell growth by participating in the WNT signaling cascade [Fishman P, et al. Evidence for involvement of Wnt signaling pathway in IB-MECA mediated suppression of melanoma cells. Oncogene. 2002; 21: 4060-4064].

Small molecules - modulators of adenosine receptors can be widely used in pharmacology and medicine. Currently, a large number of substances with affinity for adenosine receptors are known, but most of them are not selective. Non-selective ligands of adenosine receptors (for example, some analogues of adenine and xanthines) have a very complex pharmacological profile, therefore they have extremely limited clinical use (with the exception of non-selective weakly affinity caffeine). Therefore, the search for selective adenosine ligands is an urgent task. Of particular importance are selective A2A receptor antagonists.

A large number of scientific papers and patents are devoted to the use of A2A receptor antagonists as drug candidates for the treatment of central nervous system diseases, which include, but are not limited to:

- Parkinson's disease [Pinna A. Novel investigational adenosine A2A receptor antagonists for Parkinson's disease. Expert Opin Invest Drugs. 2009; 18 (11): 1619-1631];

- Alzheimer's disease and other cognitive impairment [Takahashi RN, Pamlona FA, Prediger RD. Adenosine receptor antagonists for cognitive dysfunction: a review of animal studies. Front Biosci. 2008; 13: 2614-32];

brain ischemia and stroke [Monopoli A, Lozza G, Forlani A, Mattavelli A, Ongini E. Blockade of adenosine A2A receptors by SCH 58261 results in neuroprotective effects in cerebral ischaemia in rats. Neuroreport. 1998; 9 (17): 3955-3959];

- mental disorders [Wardas J. Potential role of adenosine A2A receptors in the treatment of schizophrenia. Front Biosci., 2008; 13: 4071-4096];

- other neurodegenerative diseases and addictions [Ribeiro JA, Sebastião AM, de Mendonça A. Adenosine receptors in the nervous system: pathophysiological implications. Prog Neurobiol. 2002; 68 (6): 377-392].

The prospect of searching for selective adenosine A2A ligands is confirmed by a series of CNS drug candidates that are currently at different stages of clinical trials (Table 2) [http://www.integrity.prous.com]:

Table 2. A2A antagonists of adenosine receptors at different stages of testing Connections Developer Structure Test phase Appointment Link Istradefylline KW-6002 Kyowa Hakko Kirin

Phase 3 Registration Parkinson's disease KW-6002 Drugs Future 2001, 26 (1): 21 Preladenant SCH-420814 MK-3814 Schering-Plow (Merck & Co.)

Phase 3 Parkinson's disease J Med Chem 2011, 54 (13): 4,312

Table 2. Tozadenant RO-449351 SYN-115 Roche Biotie Therapies NIDA

Phase 2/3 Parkinson's disease J Neurosci 2010, 30 (48): 16284 Phase 0/1 Cocaine addiction Vipadenant BIIB-014 V-2006 VR-2006 Biogen Idec Vernalis

Phase 2 Test Discontinued Parkinson's disease J Med Chem 2009, 52 (1): 33

Table 2. ST-1535 Sigma-tau

Phase 1 Parkinson's disease Eur J Pharmacol 2008, 579 (1-3): 149 V-81444 Vernalis Structure not disclosed Phase 1 Parkinson's disease Successful outcome for V81444 in phase I study. Vernalis Press Release 2012, May 02 PBF-509 Palobiofarma Structure not disclosed Phase 1 Parkinson's disease Palobiofarma Web Site 2012, Novemb. 16

Table 2. Almirall Almirall neurocrine biosciences

Preclinical trials Parkinson's disease J Med Chem 2008, 51 (22): 7099 DT-1133 Domain therapeutics Structure not disclosed Preclinical trials Parkinson's disease Domain Therapeutics SA Web Site 2013, February 19

table 2 SCH-442416 Merck & Co.

Preclinical trials Diagnostic agent J Med Chem 2000; 43 (23): 4359

It was previously shown that adenosine, which accumulates near tumor tissue [BIay J, White TD, Oskin DW. The Extracellular Fluid of Solid Carcinomas Contains immunosuppressive Concentrations of Adenosine. Cancer Research. 1997; 57: 2602-2605], significantly inhibits the ability of activated T-lymphocytes and natural killer cells to bind to and kill tumor cells [Hoskin DW, Reynolds T, Blay J. Adenosine as a possible inhibitor of killer T-cell activation in the microenvironment of solid tumours. Int J Cancer. 1994; 59: 854-855]. Hypoxia, developing in conditions of solid tumors, leads to an increase in the concentration of adenosine near the tumor tissue. Adenosine, by binding to type A2A adenosine receptors located on the cell membrane of lymphocytes, transmits an adenosine signal into cells, which reduces the ability of lymphocytes to attack tumor tissue [Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-Adenosinergic Immunosuppression: Tumor Protection Tumor Protection: Tumor Protection Regulatory Cells and Cancerous Tissue Hypoxia. Clin Cancer Res. 2008; 14 (19): 5947-5952]. On this basis, a new approach has been proposed to enhance the effectiveness of antitumor therapy (in particular, vaccines) using an adjuvant that antagonizes A2A receptors [Ohta A, Sitkovsky M. Methods and composition for improving immune responses. WO 2008/147482 12/04/2008].

Studies have shown that agonists of A2A adenosine receptors are important regulators of inflammatory processes. A2A agonists have been shown to have anti-inflammatory properties in vitro and in vivo. Adenosine, interacting with surface receptors A1, A2A, A2B and A3, has a different biological effect. Of all four receptors, A2A is the most common and closely associated with the inflammatory response. The studies revealed the ability of A2A to inhibit the phosphorylation of Zap-70 tyrosine kinase, the secretion of eosinophils and monocytes, weaken the perforin and cytotoxicity of lymphokine-activated killer cells. Activation of the A2A adenosine receptor suppresses the inflammatory signaling system in cytokines and accelerates the healing process. [M.A. Trevethick, S.J. Mantell, E.F. Stuart, A. Barnard, K.N. Wright, M Yeadon, Pfizer Global R&D, “Treatment of Inflammatory Airways with Adenosine A2A Receptor Agonists,” Journal of the Pharmacist, 2009, Issue No. 3, http://www.provisor.com.ua/].

Thus, the search for effective and selective A2A receptor antagonists seems to be an extremely important and promising task.

In order to develop new highly effective A2A ligands, the authors of this invention performed a wide screening of a variety of low molecular weight compounds, determining the effectiveness of their interaction with adenosine receptors. Surprisingly, hit compounds were discovered, which are some derivatives of [1,2,4] triazolo [4,3-a] pyridines. Then, directed modifications of the detected structures and testing of new compounds were carried out, and the “structure – activity” relationship was established and the most promising series and leader compounds were selected. As a result, a series of new derivatives of [1,2,4] triazolo [4,3-a] pyridines, previously not described in the literature, which are original and highly effective A2A receptor antagonists, was synthesized.

An object of the present invention is to provide novel selective A2A receptor antagonists.

This goal is achieved by new antagonists of adenosine A2A receptors, which are substituted [1,2,4] triazolo- [4,3-a] pyridines of the general formula I, as well as their pharmaceutically acceptable salts.

The subject of the present invention is substituted [1,2,4] triazolo [4,3-a] pyridines of the general formula I, as well as their pharmaceutically acceptable salts:

where A represents an optionally substituted aminocarbonyl group —N — C (O) -, in which the amino group may be substituted and substituents may be selected from

hydrogen, C ₁ -C ₅ alkyl optionally substituted with C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, a 5-6 membered heteroaryl in which the heteroatoms are selected from oxygen or nitrogen;

an aryl selected from phenyl, optionally substituted with hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halogen, C ₁ -C ₅ acylamino group, or naphthyl;

or an amino group is selected from a C ₃ -C ₇ heterocyclyl containing 1-2 heteroatoms in a ring selected from nitrogen, oxygen or sulfur, optionally substituted with hydroxy, C ₁ -C ₅ alkyl, benzyl, phenyl, which may be substituted with halogen, wherein said heterocyclyl may be fused to a benzene ring;

an acylamino group in which the acyl is selected from

C ₁ -C ₆ alkylcarbonyl, wherein the alkyl may be substituted with phenyl substituted with phenyl, wherein the substituents are selected from C ₁ -C ₅ alkoxy; A 5-membered heteroaryl with a heteroatom selected from an oxygen or sulfur atom;

benzoyl, optionally substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio or halogen, methylenedioxy;

heterocyclylcarbonyl, in which heterocyclyl is selected from a 5-6 membered heterocyclyl, with 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, optionally fused to a benzene ring and optionally substituted with C ₁ -C ₅ alkyl, halogen;

or a ureido group in which one of the substituents on the terminal amido group is hydrogen, and the second substituent is selected from:

C ₁ -C ₃ alkyl substituted with phenyl, a 5-membered saturated or aromatic heterocyclyl, in which the heteroatoms are selected from oxygen or sulfur;

C ₂ -C ₆ alkenyl;

aryl selected from phenyl substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, ethylenedioxy, methylenedioxy, halogen, C ₁ -C ₃ alkylcarbonyl;

A 5-membered heterocyclyl in which the heteroatoms are selected from a sulfur or oxygen atom, and optionally substituted with an alkyloxycarbonyl group;

B is a non-aromatic cyclic substituent selected from C ₄ -C ₆ cycloalkyl;

an aromatic cyclic substituent selected from phenyl, which may be substituted with halogen, C ₁ -C ₃ alkoxy;

a non-aromatic 5-6 membered heterocyclic substituent with a nitrogen atom as a heteroatom, and optionally N-substituted with C ₁ -C ₃ alkyl;

an aromatic 5-6 membered heterocyclic substituent in which the heteroatoms are selected from nitrogen, oxygen or sulfur, and which may be substituted with C ₁ -C ₆ alkyl;

or an aromatic 5-6 membered heterocyclic substituent in which the heteroatom is selected from nitrogen condensed with a benzene ring;

R1a, R1b and R1c independently represent hydrogen, C ₁ -C ₃ alkoxy;

excluding the compounds shown in Table 3.

The following are definitions of terms that are used in the description of the present invention.

″ Aminocarbonyl ″ means a —C (= O) NR ₂ group, each R independently of one another is hydrogen, alkyl, alkenyl (see substituents of the aminocarbonyl group, see ″ carbamoyl substituent ″). Preferably carbamoyl, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl or butylaminocarbonyl. Aminocarbonyl may have substituents, see ″ carbamoyl substituent ″ defined in this section.

“Aminothiocarbonyl ″ means RC (= S) NH ₂ , aminothiocarbonyl may have substituents, see ″ carbamoyl substituent ″, ″ substituted aminothiocarbonyl group ″ defined in this section.

″ Substituted aminothiocarbonyl group ″ (aminothiocarbonyl) means R′R ″ NC (= S) is a group in which the substituents R ′ and R ″ may be optionally substituted with alkyl, cycloalkyl, aryl, hetaryl and heterocyclyl, as defined in this section . Preferred aminocarbonyl groups are optionally substituted C ₁ -C ₅ alkyl, C ₁ -C ₅ cycloalkyl, optionally substituted aryl (see cyclic substituent), optionally substituted hetaryl (see cyclic substituent), optionally substituted heterocyclyl (see heterocyclyl substituent ) or an amino group R′R ″ N.

“Amino group” means a radical of the formula —NR ₂ in which each R independently of one another is hydrogen, alkyl, alkenyl or cycloalkyl, for example, —NH ₂ , methylamino, diethylamino, cyclohexylamino, tert-butylamino or ethylamino.

“Azaheterocycle” means an aromatic or non-aromatic monocyclic or polycyclic system containing at least one nitrogen atom in a ring. Preferably piperidine, piperazine, pyrrolidine, morpholine, thiomorpholine, azacyclooctane. The azaheterocycle may have substituents (see cyclic system substituents).

"Aryl" means an aromatic monocyclic or polycyclic system containing from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms. Aryl may contain one or more ″ cyclic system substituents ″ which may be the same or different. Preferably phenyl or naphthyl.

"Alkenyl" means a linear or branched hydrocarbon group containing from 2 to 7 carbon atoms and including at least one carbon-carbon double bond.

Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkenyl chain. Preferred alkenyl groups are ethenyl, propenyl, n-butenyl, iso-butenyl, 3-methylbut-2-enyl, n-pentenyl, and cyclohexylbutenyl.

An alkenyl group may have one or more substituents, see ″ Alkenyl Substituents ″.

"Alkenyl group substituents" can be halogen, alkenyloxy, cycloalkyl, cyano, hydroxy, alkoxy, carboxy, alkynyloxy, aralkoxy, aryloxy, aryloxycarbonyl, alkylthio, heteroaralkyloxy, heterocyclyl, heterocyclylalkyloxy, alkoxycarbonyloxycarbonylcarbonyl.

"Alkynyl" means a linear or branched hydrocarbon group containing from 2 to 12 carbon atoms and including at least one carbon-carbon triple bond.

Branched means that one or more lower alkyl groups, such as methyl, ethyl or propyl, are attached to the linear alkynyl chain. An alkynyl group may have one or more substituents, see ″ Alkenyl Substituents ″. Preferred alkynyl groups are ethynyl, propynyl, n-butynyl, isobutynyl, 3-methylbut-2-ynyl, n-pentynyl, buta-1,3-diine and hexa-1,3,5-triine.

"Alkyl" means an aliphatic hydrocarbon linear or branched group with 1-6 carbon atoms in the chain. A branched group means that a C ₁ -C ₆ alkyl group, such as methyl, ethyl or propyl, is attached to the linear alkyl chain. Preferred straight or branched alkyl groups are groups representing alkyl groups having from 1 to 10 carbon atoms. Most preferred lower alkyl groups have from 1 to 8 carbon atoms. Preferred alkyl groups are C ₁ -C ₆ alkyl, more preferred are methyl, ethyl, n-propyl, 2-iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, n-pentyl, 2-pentyl, 3-pentyl, neo-pentyl, n-hexyl. Alkyl may have substituents, see ″ Substituted alkyl ″.

"Alkylcycloalkyl" means cycloalkyl substituted with alkyl. Preferably 1-, 2-, 3- or 4-methyl or ethylcyclohexyl.

"Alkylcycloalkylalkyl" means alkyl substituted with alkylcycloalkyl. Preferably 2-, 3- or 4-methyl- or ethylcyclohexylmethyl or 2-, 3- or 4-methyl- or ethylcyclohexylethyl.

“Aralkyl” means alkyl substituted with aryl. Preferred aralkyl groups include benzyl, naphth-1-ylmethyl, naphth-2-ylmethyl and phenethyl.

″ Alkyloxy ″ or ″ Alkoxy ″ means a C ₁ -C ₆ Alkyl O— group in which alkyl is defined in this section. Preferred alkoxy groups are methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy and tert-butoxy.

″ Aromatic cycle ″ (aromatic system) means a planar cyclic system in which all atoms of the cycle participate in the formation of a single conjugation system including, according to the Hückel rule, (4n + 2) π-electrons (n is a non-negative integer). Examples of aromatic cycles are benzene, naphthalene, anthracene, and the like. In the case of “heteroaromatic rings”, π-electrons and p-electrons of heteroatoms participate in the conjugation system; their total number is also equal to (4n + 2). Examples of such cycles are pyridine, thiophene, pyrrole, furan, thiazole and the like. The aromatic cycle may have one or more ″ substituents of the cyclic system ″ and may be anelated with a non-aromatic cycle, heteroaromatic or heterocyclic system.

″ Acyl group ″ (Acyl) means RC (= O) -, (preferably C ₁ -C ₆ acyl) optionally substituted with C ₁ -C ₅ alkyl-C (= O) -, C ₁ -C ₅ cycloalkyl-C ( = O) -, (preferably cyclopropyl-C (= O) -, cyclobutyl-C (= O) -); heterocyclyl-C (= O) -, (preferably 2-methylfuran), aryl-C (= O) - (aroyl), aralkyl-C (= O) -, (preferably 3-phenylpentane-C (= O) -) , heteroaryl-C (= O) - (heteroaroyl), heteroarylalkyl-C (= O) are groups in which C ₁ -C ₆ alkyl-, C ₁ -C ₅ alkenyl-, C ₁ -C ₆ cycloalkyl-, heterocyclyl -, aryl-, aralkyl, heteroaryl-, heteroarylalkyl, methoxy group, these groups may have substituents, see ″ substituents of the cyclic system ″, ″ substituted alkyl ″, ″ substituted alkenyl ″, ″ substituents of the heterocyclic system ″ defined in this section.

″ Α-aminoacyl group ″ (α-aminoacyl) means C (= O) CH (R ² _k ) NR ² _{k + 1} R ² _{k + 2} ,

where R ² _k , R ² _{k + 1} and R ² _{k + 2} can be hydrogen, C ₁ -C ₅ alkyl, aryl, saturated or unsaturated heterocyclyl, or NR ² _k R ² _{k + 2} is 5-6 member heterocycle, these groups may have substituents, see ″ substituents of the cyclic system ″, ″ substituted alkyl ″, ″ substituents of the heterocyclic system ″, ″ substituted aryl ″ defined in this section.

"Acyloxy group" means an R (= O) -O group.

A “hydrazinocarbonyl group” means a —C (═O) —NH — NH ₂ group. The hydrazinocarbonyl group may have substituents, see ″ carbamoyl substituent ″ defined in this section.

“Heteroaryl ″ (hetaryl) means an aromatic monocyclic or polycyclic system comprising from 5 to 14 carbon atoms, preferably from 5 to 10, in which one or more carbon atoms are replaced by heteroatoms or heteroatoms such as nitrogen, sulfur or oxygen. The prefix "aza", "oxa" or "thia" before "heteroaryl" means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. The nitrogen atom in the heteroaryl can be oxidized to N-oxide. Heteroaryl may have one or more ″ substituents on the cyclic system ″, which may be the same or different. Preferably pyrrolyl, furanyl, thienyl, pyridinyl. Heteroaryl may have substituents (see cyclic system substituents).

"Heterocycle" means an aromatic or non-aromatic saturated or partially saturated monocyclic or polycyclic system containing from 3 to 10 carbon atoms, mainly from 4 to 6 carbon atoms, in which one or more carbon atoms are replaced by a heteroatom such as nitrogen, oxygen, sulfur phosphorus. The prefix "aza", "oxa" or "thia" before heterocyclyl means the presence in the cyclic system of a nitrogen atom, an oxygen atom or a sulfur atom, respectively. Heterocyclyl may have one or more substituents, which may be the same or different. The nitrogen and sulfur atoms in the heterocyclyl can be oxidized to N-oxide, S-oxide or S-dioxide. Representative heterocyclyls are piperidinyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxan-2-yl, tetrahydrofuryl, tetrahydrothienyl, etc. Heterocyclyl may have substituents. Compounds are preferred: piperidinyl substituted with methyl; piperidinyl substituted with an optionally substituted hydroxy group; piperidinyl substituted with phenyl; piperazinyl substituted with C ₁ -C ₅ alkyl.

″ Hydroxy group ″ (Hydroxyl group) means —OH group.

″ Halogen ″ means fluorine, chlorine, bromine and iodine. Fluorine, chlorine are preferred.

"Cycloalkyl" means a saturated carbocyclic group having one or more rings having 3-10 carbon atoms. Preferred cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and decahydronaphthyl.

“Cycloalkylalkyl” means an alkyl group substituted with a cycloalkyl group. Preferred cycloalkylalkyls include cyclopentylmethyl, cyclohexylmethyl, cyclohexylethyl, decahydronaft-1-ylmethyl and decahydronaphth-2-ylmethyl.

″ Cyano group ″ means a group -C -N.

"Substituted alkyl" substituted alkyl may have one or more, same or different substituents, including halogen, alkenyloxy, cycloalkyl, aryl, heteroaryl, heterocyclyl, hydroxy. Preferred alkyl substituents are: acyl, acylamino, acyloxy, alkenyl, alkoxy, alkyl, alkynyl, amino, aryl, aryloxy, carbamoyl, carboalkoxy, carboxy, carboxyamido, carboxyamino, cyano, disubstituted amino, formyl, guanidino, halogeno, hetero, hetero, hetero, hetero hydroxy, iminoamino, nitro, oxo, phosphonamine, sulfinyl, sulfonamine, sulfonyl, thio, thioacylamine, thioureido or ureido.

"Substituted aryl" means phenyl or naphthyl substituted with one or more substituents of the aryl group, which may be the same or different, where the "substituent of the aryl group" includes alkyl, alkenyl, alkynyl, aryl, aralkyl, hydroxy, alkoxy, aryloxy, aralkoxy , hydroxyalkyl, acyl, formyl, carboxy, alkenoyl, aroyl, halogen, nitro, trihalomethyl, cyano, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, acylamino, aroylamino, carbamoyl, alkylcarbamoyl lkilkarbamoil, arylcarbamoyl, aralkilkarbamoil, alkylsulfonyl, alkylsulfinyl, arylsulfonyl, arylsulfinyl, aralkylsulfonyl, aralkylsulfinyl, or - NR _a R _b, where R _a and R _b are independently hydrogen, alkyl, aryl or aralkyl.

Preferably phenyl substituted with hydroxy; C ₁ -C ₅ alkyl (preferably methyl); halogen (preferably chlorine, fluorine); aminocarbonyl group; sulfo group. Preferably, naphthyl substituted with C ₁ -C ₅ alkyl. Aryl can be anelated with a non-aromatic ring system or heterocycle.

″ Substituents of the amino group ″ substituents of the amino group R ′ and R ″ are hydrogen, optionally substituted C ₁ -C ₅ alkyl, optionally substituted C ₃ -C ₅ cycloalkyl (see the Deputy of the cyclic system), optionally substituted aryl (see the Deputy of the cyclic system) optionally substituted heteroaryl (see cyclic substituent), optionally substituted heterocyclyl (see cyclic substituent), alkoxycarbonyl substituted with linear or non-linear C ₁ -C ₅ alkyl, halogen, heterocyclyl; alkylaminocarbonyl, arylaminocarbonyl, heteroarylaminocarbonyl, heterocyclylaminocarbonyl.

″ Substituents of the cyclic system ″ may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Preferably phenyl substituted with hydroxy; C ₁ -C ₅ alkyl; halogen; aminocarbonyl group.

Aryl can be annelated with a non-aromatic ring system or heterocycle. Preferred cyclic moieties are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, hydroxy-group, C ₁ -C ₅ alkyloxy group (methoxy, ethoxy, propoxy), carboxy group, aminocarbonyl (see ″ aminocarbonyl ″ ) phenylannelated with a 5-7 membered saturated ring containing 1-3 heteroatoms (nitrogen, oxygen and sulfur atoms are preferred).

“Substituent ″ means a chemical radical that attaches to a molecular skeleton (scaffold, fragment), for example ″ substituent alkyl ″, ″ substituent of an amino group ″, ″ substituent of carbamoyl ″, ″ substituent of a cyclic system ″, the meanings of which are defined in this section.

″ Substituted aminocarbonyl group ″ (aminocarbonyl) means R′R ″ N — C (= O) is a group in which the substituents R ′ and R ″ may be optionally substituted with alkyl, cycloalkyl, aryl, hetaryl and heterocyclyl, as defined in this section. Preferred aminocarbonyl groups are optionally substituted C ₁ -C ₅ alkyl, C ₁ -C ₅ cycloalkyl, optionally substituted aryl (see cyclic substituent), optionally substituted hetaryl (see cyclic substituent), optionally substituted heterocyclyl (see heterocyclyl substituent ) or an amino group R′R ″ N.

“Carbamoyl substituent” means a substituent attached to an aminocarbonyl group, the meaning of which is defined in this section. The carbamoyl substituent is hydrogen, alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkyl, heteroarylcycloalkenyl, annelated heteroarylcycloalkyl, annelated heteroarylheterocyclenyl, annelated heteroarylheterocyclyl, annelated arylcycloalkenyl, annelated arylcycloalkyl, annelated arylheterocyclenyl, annelated aryl Preferred carbamoyl substituents are alkyl, cycloalkyl, aryl, heteroaryl, heterocyclyl, alkoxycarbonylalkyl, aralkoxycarbonylalkyl, heteroaralkyloxycarbonylalkyl or R _k ^a R _{k + 1} ^a N-, R _k ^a R _{k + 1} ^a NC (= O) -alkyl annelated arylheterocyclenyl; annelated arylheterocyclyl.

“Heterocycle substituents” may be representatives of aryl groups, preferably phenyl or naphthyl, substituted phenyl or substituted naphthyl. Aryl can be anelated with a non-aromatic ring system or heterocycle. Preferred cyclic moieties are hydrogen, halogens (chlorine, fluorine, bromine), optionally substituted C ₁ -C ₅ alkyl, optionally substituted cyclo C ₁ -C ₅ alkyl, C ₁ -C ₅ alkene, hydroxy-group, C ₁ -C ₅ alkyloxy (methoxy, ethoxy, propoxy, ethylene glycol diester, methanediol diester), cyano group, C ₁ -C ₅ alkyloxycarbonyl (methyl, ethyl), alkylthio group (methylthio), carboxy group, aminocarbonyl (see “aminocarbonyl”), phenylated with 5-7 saturated membered ring containing 1-3 heteroatoms (nitrogen, oxygen and sulfur atoms are preferred tion).

″ Medicinal product (preparation) ″ - a substance (or a mixture of substances in the form of a pharmaceutical composition) in the form of tablets, capsules, injections, ointments and other formulations designed to restore, correct or alter physiological functions in humans and animals, as well as for treatment and disease prevention, diagnosis, anesthesia, contraception, cosmetology and more.

″ Nitro group ″ means a group —NO ₂ .

″ Trifluoromethyl ″ means an R-CF ₃ group;

"Ureido" means a group of NH ₂ —CO — NH—.

More preferred are substituted [1,2,4] triazolo [4,3-a] pyridines represented by the general formulas I-1, I-2, I-3, as well as their pharmaceutically acceptable salts:

where B has the meanings defined above;

R2a, R2b and R2c independently represent H, C ₁ -C ₃ alkoxy; R3a and R3b independently represent hydrogen, C ₁ -C ₅ alkyl optionally substituted with C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, 5-6 membered heteroaryl in which the heteroatoms are selected from oxygen or nitrogen; aryl selected from phenyl optionally substituted with hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halogen, C ₁ -C ₅ acylamino group, or naphthalene;

R3a and R3b may together form cyclic substituents, with the group R3a-N-R3b being a C ₃ -C ₇ heterocyclyl containing 1-2 heteroatoms in the ring selected from nitrogen, oxygen or sulfur, optionally substituted with hydroxy, C ₁ -C ₅ alkyl, benzyl, phenyl, which may be substituted by halogen, wherein said heterocyclyl may be fused to a benzene ring;

R4 is C ₁ -C ₅ alkyl, where the alkyl may be substituted with phenyl, substituted with phenyl, wherein the substituents are selected from C ₁ -C ₅ alkoxy; A 5-membered heteroaryl with a heteroatom selected from an oxygen or sulfur atom; aryl selected from phenyl optionally substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio or halogen, methylenedioxy; heterocyclyl, in which heterocyclyl is selected from a 5-6 membered heterocyclyl, with 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, possibly fused to a benzene ring and optionally substituted with C ₁ -C ₅ alkyl, halogen;

R5 is hydrogen;

R6a and R6b independently represent hydrogen, C ₁ -C ₃ alkyl substituted with phenyl, a 5-membered saturated or aromatic heterocyclyl, in which the heteroatoms are selected from oxygen or sulfur; C ₂ -C ₆ alkenyl, aryl selected from phenyl substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, ethylenedioxy, methylenedioxy, halogen, C ₁ -C ₃ alkylcarbonyl;

R6a and R6b may together form cyclic substituents, wherein the R6a-N-R6b group is a 5 membered heterocycle in which the heteroatoms are selected from a sulfur or oxygen atom, and optionally substituted with an alkyloxycarbonyl group;

The most preferred derivatives of [1,2,4] triazolo [4,3-a] pyridines are:

3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methoxyphenylamide (I-1-01);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methoxyphenylamide (I-1-02);

3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid naphthyl-1-amide (I-1-03);

3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methylphenylamide (I-1-04);

3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methylphenylamide (I-1-05);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid phenylamide (I-1-06);

3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-propylamide (I-1-07);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 4-methylphenylamide (I-1-08);

3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 4-fluorophenylamide (I-1-09);

3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid (2-methoxyphenyl) methylamide (I-1-10);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid (2-methoxyphenyl) methylamide (I-1-11);

3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-fluorophenylamide (I-1-12);

3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-chlorophenylamide (I-1-13);

3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-chlorophenylamide (I-1-14);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-chlorophenylamide (I-1-15);

3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methylphenylamide (I-1-16);

3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methylphenylamide (I-1-17);

3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-hydroxy-6-methylphenylamide (I-1-19);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid (cyclohexyl) methylamide (I-1-20);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2,3-dimethylphenylamide (I-1-21);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3,4-dimethylphenylamide (I-1-23);

3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3,5-dimethylphenylamide (I-1-24);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-ethylphenylamide (I-1-25);

3- (pyrid-4-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 3-methylphenylamide (I-1-26);

3- (pyrid-4-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methylphenylamide (I-1-27);

3- (pyrid-3-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methylphenylamide (I-1-28);

3- (pyrid-3-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methoxyphenylamide (I-1-29);

3- (5-methylfuryl-2) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methoxyphenylamide (I-1-30);

3- (thienyl-2) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methoxyphenylamide (I-1-31);

3- (indol-2-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methoxyphenylamide (I-1-32);

3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-ethylphenylamide (I-1-33);

3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methoxyphenylamide (I-1-34);

3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methoxyphenylamide (I-1-35);

3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid (furan-2-yl) methylamide (I-1-36);

3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid (furan-2-yl) methylamide (I-1-37);

3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid heptamethylene amide (I-1-38);

N- {3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -3,5-dimethylpiperidine (I-1-39);

N- {3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -4-hydroxy-4- (4-chlorophenyl) piperidine (I-1 -40);

N- {3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -4-benzylpiperidine (I-1-41);

N- {3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -1,2,3,4-tetrahydroquinoline (I-1-42);

N- {3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -4-hydroxy-4- (4-chlorophenyl) piperidine (I-1 -43);

3-phenyl- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methyl4-chloro-phenylamide (I-1-44)

3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-naphthylamide (I-1-47);

3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-propylamide (I-1-48);

3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methylphenylamide (I-1-49);

3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-fluorophenylamide (I-1-50);

3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methylphenylamide (I-1-51);

3- (2-fluorophenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid (furan-2-yl) methylamide (I-1-52);

N- {3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} piperazine (I-1-53);

N- {3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -N′-methylpiperazine (I-1-54);

N- {3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -2-hydroxyethylamine (I-1-55);

8 - [(2-ethoxybenzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-01);

8 - {[(2-methoxyphenyl) acetyl] amino} -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-02);

8 - [(thien-3-yl) acetylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-03);

8 - [(2-chloro-5-methylthio-benzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-04);

8 - [(thien-3-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-05);

8 - [(3-methylthien-2-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-06);

8 - [(indol-2-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-07);

8 - [(3-fluoro-4-methoxy-benzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-08);

8 - [(2,3-dihydrobenzo [1,4] dioxin-2-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-09) ;

8 - [(5-chlorothien-2-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-10);

8 - [(3,4-methylenedioxybenzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-11);

8 - [(5-methylisoxazol-3-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-12);

8 - [(2-methoxybenzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-13);

8 - [(2-methoxybenzoyl) amino] -3-cyclopentyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-14);

8 - [(2-ethoxybenzoyl) amino] -3-cyclopentyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-15);

8 - [(2-methoxybenzoyl) amino] -3-cyclohexyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-16);

8 - [(2-methoxybenzoyl) amino] -3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-17);

8- (benzoylamino] -3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-18);

8- (benzoylamino] -3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-19);

8- (2-methoxybenzoylamino] -3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-20);

8- (2-ethoxybenzoylamino] -3-phenyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-21);

8 - [(2-fluorobenzoyl) amino] -3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-22);

8 - [(2-fluorobenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-23);

8 - [(2-methoxybenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-24);

8 - [(2-methoxybenzoyl) amino] -3- (pyridin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-25);

8 - [(2-methoxybenzoyl) amino] -3- (pyridin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-26);

8 - [(2-chlorobenzoyl) amino] -3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-27);

8 - [(2-chlorobenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-28);

8 - [(2,6-dichlorobenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-29);

8 - [(2,6-dimethylbenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-30);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (3,4-dimethoxyphenyl) urea (I-3-01);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (2-methoxy-5-methylphenyl) urea (I-3-02);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (3,4-ethylenedioxyphenyl) urea (I-3-03);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (2-phenylethyl) urea (I-3-04);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (3,4-methylenedioxyphenyl) urea (I-3-05);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-06);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (tetrahydrofuryl-2-methyl) urea (I-3-07);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (2-methoxycarbonylthienyl-3) urea (I-3-08);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (3-acetylphenyl) urea (I-3-09);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (4-methoxy-2-methylphenyl) urea (I-3-10);

1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (4-methoxy-3-fluorophenyl) urea (I-3-11);

1- (3-cyclopentyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-12);

1- (3-cyclohexyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-13);

1- {3-N-methylpiperidin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (furyl-2-methyl) urea (I-3 -fourteen);

1- {3-N-methylpiperidin-3-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (furyl-2-methyl) urea (I-3 -fifteen);

1- {3- (N-methylpiperidin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (2-methoxyphenyl) urea (I-3- 16);

1- {3- (N-methylpiperidin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (3,4-dimethoxyphenyl) urea (I- 3-17);

1- {3- (N-methylpiperidin-3-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (2-methoxyphenyl) urea (I-3- eighteen);

1- {3- (N-methylpiperidin-3-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (3,4-dimethoxyphenyl) urea (I- 3-19);

1- (3-pyrid-4-yl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-20 );

1- (3-pyrid-3-yl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-21 );

1- (3-pyrid-4-yl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-22 );

1- (3-pyrid-3-yl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-23 );

1- {3- (N-methylpiperidin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3-allylurea (I-3-24);

1- {3- (N-methylpiperidin-3-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3-allylurea (I-3-25);

The subject of this invention is the pharmaceutically acceptable salts of the compounds of general formula I. A portion of the compounds of this invention contains ionic groups (secondary, tertiary amines) and can form salts which have been prepared by methods known in the art.

The subject of this invention is a method for producing derivatives of [1,2,4] triazolo [4,3-a] pyridines of the general formula I-2 and I-3 (Scheme 2):

For this, the corresponding 2-hydrazino-3-nitropyridines b2 were obtained from 2-chloro-3-nitropyridines b1. Hydrazines b2 were cyclocondensed with a suitable acyl derivative to give [1,2,4] triazolo [4,3-a] pyridines b3. Next, b3 nitropyridines were reduced with hydrogen over palladium on carbon and a series of b4 heterocyclic amines was obtained. Acylation of amines b4 with suitable acyl halides (acyl chloride, acyl fluoride, acyl bromide) in an aprotic neutral solvent (dichloromethane, dioxane, chloroform and the like) in the presence of a base (triethylamine, DABCO, pyridine and the like) upon cooling led to a series of substances I-2. The interaction of amines b4 with isothiocyanates in a neutral solvent (ethanol, dichloromethane, dioxane, chloroform and the like) led to a series of substances I-3.

The substituents R2, R3a and R3b, R4, R6 and B in Schemes 1 and 2 are defined above, X = Cl.

The subject of this invention is an active component having the properties of an A2A receptor antagonist, which is a (substance) for the preparation of pharmaceutical compositions and finished dosage forms for the prevention and treatment of disorders of the central nervous system, neurodegenerative, inflammatory, infectious and oncological diseases and is a compound of general formula I.

The subject of this invention is new compounds of general formula I, which are an agent (adjuvant) for enhancing the immune response or action of drugs in the combined treatment of disorders of the central nervous system, neurodegenerative, inflammatory, infectious and oncological diseases.

The subject of this invention is a pharmaceutical composition having antagonistic activity towards the adenosine A2A receptor, comprising, as an active component (substance) or agent (adjuvant), compounds of general formula I or their pharmaceutically acceptable salts in a therapeutically effective amount.

The subject of this invention is any of the aforementioned pharmaceutical compositions in the form of tablets, capsules and injections, ointments, gels and other formulations placed in a pharmaceutically acceptable package.

Pharmaceutical compositions may include pharmaceutically acceptable excipients, namely, diluents, auxiliary agents, and / or carriers used in the pharmaceutical field. The pharmaceutical composition, along with the compound of general formula I or a pharmaceutically acceptable salt thereof, of the present invention, may include other active substances, provided that they do not cause undesirable effects.

If it is necessary to use the pharmaceutical compositions of the present invention in clinical practice, they can be mixed for the manufacture of various forms, while they can include traditional pharmaceutical carriers; for example, oral forms (such as tablets, gelatine capsules, pills, solutions or suspensions); injection forms (such as solutions or suspensions for injection, or dry powder for injection, which requires only the addition of water for injection before use); local forms (such as ointments or solutions).

The carriers used in the pharmaceutical compositions of the present invention are carriers that are used in the pharmaceutical field to obtain common forms, including: in oral forms, binders, lubricants, disintegrants, solvents, diluents, stabilizers, suspending agents, colorless are used agents, flavoring agents of taste; antiseptic agents, solubilizers, stabilizers are used in injection forms; in local forms, bases, diluents, lubricants, antiseptic agents are used.

The subject of this invention is a method for preparing a pharmaceutical composition by mixing with an inert excipient, auxiliary agent, carrier and / or solvent of at least one active component (substance) of the general formula I or a pharmaceutically acceptable salt thereof in a therapeutically effective amount.

The subject of this invention is a method for selectively inhibiting the activity of an adenosine A2A receptor, which consists in the action of the active component (substance) of the general formula I on biological objects or samples whose functions are regulated by A2A adenosine receptors.

The subject of this invention is a medicament having antagonistic activity with respect to the adenosine A2A receptor, in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package intended for the prevention and treatment of disorders of the central nervous system, neurodegenerative, inflammatory, infectious and oncological diseases in humans and warm-blooded animals, which includes in its composition a new active component (substance) of the general formula I or a pharmaceutical composition in ter pevticheski effective amount.

Medicines can be administered orally or parenterally (for example, intravenously, subcutaneously, intraperitoneally or topically). The clinical dosage of an agent of general formula I in patients can be adjusted depending on the therapeutic efficacy and bioavailability of the active ingredients in the body, their metabolic rate and excretion from the body, as well as on the patient’s age, gender and stage of illness. In this case, the daily dose in adults is usually 10 ~ 500 mg, preferably 50 ~ 300 mg. In accordance with the instructions of a doctor or pharmacist, these drugs can be taken several times during certain periods of time (preferably from one to six times a day).

The subject of the present invention is a method for the prevention and treatment of disorders of the central nervous system, neurodegenerative, inflammatory, infectious and oncological diseases in animals and humans, which consists in administering in an effective amount to a patient a medicament or pharmaceutical composition comprising a new active component (substance) of a common formula I, in a therapeutically effective amount.

The invention is illustrated, but not limited to the following examples.

Initial reagents and physicochemical methods for proving the structure of synthesized substances and their purity.

All solvents and reagents were obtained from commercial sources such as Acros (Belgium), Sigma-Aldrich (USA), Lancaster (England) and ChemDiv (USA). Solvents and reagents were used without further purification. ¹ H-NMR spectra were recorded on a Bruker DPX-400 spectrometer (400 MHz, 27 ° C). Chemical shifts are given on a scale of δ (ppm), the internal standard is tetramethylsilane.

LC-MS characteristics of the claimed compounds (Tables 5-7) were determined using a Shimadzu HPLC apparatus equipped with a Waters XBridge C ₁₈ 3.5 mm column (4.6 mm × 150 mm), a PE SCIEX API 150 EX mass detector, or a Shimadzu detector spectrophotometric detector (λ , 220 and 254 nm). According to LC-MS data, all synthesized compounds had a basic substance content above 95%.

Analytical TLC was performed on silica gel on Silufol UV ₂₅₄ aluminum plates (5 cm × 15 cm) (Kavalier, Czech Republic) or on glass plates with a 0.25 mm layer of silica gel 60 F ₂₅₄ (Merck, Germany). Visualization was carried out using UV light at a wavelength of 254 nm. Silica gel 5-40 μm (Chemapol, Czech Republic) and 63 μm (EM Science, USA) were used for chromatographic purification.

Methods of obtaining and NMR characteristics of the claimed compounds

Example 1. Synthesis of ethyl ester of 2-hydrazinyl-nicotinic acid a2-1

A solution of ethyl 2-chloronicotinate a1-1 (10 g, 53.9 mmol) and anhydrous hydrazine (4.08 g, 127.6 mmol) in 200 ml of dioxane was stirred at 60 ° C for 12 hours. The mixture was cooled, concentrated in vacuo and dissolved in 35 ml of absolute methanol, removing the precipitate. The methanol was evaporated, the product a2-1 crystallized under absolute ether. Yield: 5.4 g (55%). MB 181; LC MS m / z 182 (M + H).

Example 2. General method for the synthesis of ethyl esters of 2 - [(2-acyl-substituted) hydrazinyl] -nicotinic acids.

A suspension of carboxylic acid (45.8 mmol), hydroxybenzotriazole HOBt (6.25 g, 46 mmol) and N-ethyl-N′-3-dimethylaminopropylcarbodiimide EDC (8.74 g, 46 mmol) in dry dichloromethane (200 ml) was stirred at room temperature for 10 minutes, then a solution of hydrazine a2-1 (9.5 g, 52.4 mmol) in 150 ml of dichloromethane was added to the mixture. The reaction mixture was stirred at room temperature from 2.0 to 16 hours, the precipitate was removed, and then washed with water (3 × 100 ml). The organic layer was dried over MgSO ₄ and evaporated. The resulting solid residue was used further without further purification. Yield: 50-85%.

Example 3. General method for the synthesis of ethyl esters of 3-substituted [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acids a3 (see Scheme 1).

К раствору 3.0 ммоль этилового эфира 2-[(2-ацил-замещенной)гидразинил]-никотиновой кислоты в 150 мл дихлорметана добавляли 15 мл POCI3, затем смесь кипятили 2.5-20 часов, контролируя протекание реакции с помощью ТСХ. Смесь охлаждали и концентрировали в вакууме. Остаток растворяли в 200 мл этилацетата, полученную смесь обрабатывали водным раствором NaHCO₃ и сушили над сульфатом магния. После упаривания этилацетата получали гетероциклические эфиры а3 с выходами 70-90%.

To a solution of 3.0 mmol of 2 - [(2-acyl-substituted) hydrazinyl] nicotinic acid ethyl ester in 150 ml of dichloromethane was added 15 ml of POCI3, then the mixture was boiled for 2.5-20 hours, monitoring the reaction using TLC. The mixture was cooled and concentrated in vacuo. The residue was dissolved in 200 ml of ethyl acetate, the resulting mixture was treated with an aqueous solution of NaHCO ₃ and dried over magnesium sulfate. Evaporation of ethyl acetate gave a3 heterocyclic esters in 70-90% yields.

Scheme 1

where R2, R ₃ a and R ₃ b, B have the above meanings, X = OH.

Example 4. General method for the synthesis of 3-substituted [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acids a4 (see Scheme 1).

К охлажденному (0°С) раствору 1.5 ммоль эфира а3 в 10 мл этанола добавляли при перемешивании 1.5 мл 2.5 н водного раствора NaOH. Смесь нагревали до комнатной температуры в течение 3 часов, реакцию останавливали, добавляя концентрированную соляную кислоту (до рН=2-3). Смесь упаривали, остаток промывали водой и высушивали. Выход кислот а4: 70-95%.

To a cooled (0 ° С) solution of 1.5 mmol of a3 ether in 10 ml of ethanol, 1.5 ml of a 2.5 N aqueous NaOH solution was added with stirring. The mixture was warmed to room temperature for 3 hours, the reaction was stopped by adding concentrated hydrochloric acid (to pH = 2-3). The mixture was evaporated, the residue was washed with water and dried. A4 acid yield: 70-95%.

Example 5. General method for the synthesis of amides of 3-substituted [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acids I-1 /

The synthesis was carried out in accordance with Scheme 1.

A mixture of a4 acid (1.0 mmol), amine (1.1 mmol), carbodiimide EDC (1.0 mmol) and 1-hydroxybenzotriazole (1.0 mmol) in 10 ml of DMF was stirred for 2-20 hours at room temperature, monitoring the progress of the reaction using LS-MS. At the end of the reaction, the mixture was diluted with 30 ml of water and extracted with methylene chloride (3 × 30 ml). The organic layer was dried over magnesium sulfate and evaporated. The product was purified by chromatography on silica gel (eluent CH ₂ Cl ₂ / MeOH 19: 1). The yields of amides I-1 25-85%.

Thus, the compounds of general formula I-1-01-I-1-55 were obtained, which are shown in Table 4.

Below are the NMR spectral data of some of the obtained amides of the compounds of general formula I-1:

I-1-01. 1H NMR (400 MHz, DMSO-d6) δ 3.83 (s, 3H), 6.74 (dt, J = 7.6, 2.1 Hz, 1H), 7.25-7.36 (m, 3H), 7.47 (t, J = 8.8 Hz, 2H), 7.56 (t, J = 2.1 Hz, 1H), 8.00 (dd, J = 8.8, 5.4 Hz, 2H), 8.27 (d, J = 7.0 Hz, 1H), 8.76 (d, J = 6.9 Hz, 1H), 11.71 (s, 1H)

I-1-02. 1H NMR (400 MHz, DMSO-d6) δ 3.84 (s, 3H), 6.74 (dt, J = 7.1, 2.4 Hz, 1H), 7.30 (m, 3H), 7.51 (m, 2H), 7.57 (m, 1H), 7.75 (m, 1H), 7.84 (td, J = 7.4, 2.0 Hz, 1H), 8.31 (d, J = 7.0 Hz, 1H), 8.48 (dd, J = 7.0.3.1 Hz, 1H), 11.65 (s, 1H)

I-1-03. 1H NMR (400 MHz, DMSO-d6) δ 3.88 (s, 3H), 7.25 (m, 2H), 7.33 (d, J = 8.5 Hz, 1H), 7.60 (m, 2H), 7.70 (m, 3H) , 7.79 (d, J = 8.2 Hz, 1H), 7.99 (d, J = 8.1 Hz, 1H), 8.33 (d, 6.9 Hz, 1H), 8.38 (d, 7.0 Hz, 1H), 8.50 (d, J = 7.5 Hz, 1H), 8.58 (d, J = 8.5 Hz, 1H), 12.27 (s, 1H)

I-1-04. 1H NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 3.86 (s, 3H), 6.99 (d, J = 7.6 Hz, 1H), 7.21 (m, 2H), 7.30 (m, 2H) , 7.65 (m, 4H), 8.27 (m, 2H), 11.68 (s, 1H)

I-1-05. 1H NMR (400 MHz, DMSO-d6) δ 2.40 (s, 3H), 3.91 (s, 3H), 6.98 (d, J = 7.8 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 7.24 (t, J = 7.0 Hz, 1H), 7.28 (t, J = 7.8 Hz, 1H), 7.63 (bs, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.86 (d, J = 8.7 Hz , 2H), 8.25 (d, J = 7.0 Hz, 1H), 8.72 (d, J = 7.0 Hz, 1H), 11.71 (s, 1H)

I-1-06. 1H NMR (400 MHz, DMSO-d6) δ 7.17 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.0 Hz, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.52 (m , 2H), 7.75 (m, 1H), 7.84 (m, 3H), 8.31 (d, J = 7.0 Hz, 1H), 8.48 (dd, J = 6.9, 3.1 Hz, 1H), 11.67 (s, 1H)

I-1-07. 1H NMR (400 MHz, DMSO-d6) δ 1.34 (d, J = 6.5 Hz, 6H), 4.24 (m, 1H), 7.14 (t, J = 7.0 Hz, 1H), 7.19 (t, J = 7.5 Hz , 1H), 7.29 (d, J = 8.3 Hz, 1H), 7.58 (d, J = 7.5 Hz, 1H), 7.64 (t, J = 8.3 Hz, 1H), 8.15 (m, 2H), 9.51 (d , J = 7.6 Hz, 1H)

I-1-08. 1H NMR (400 MHz, DMSO-d6) δ 2.35 (s, 3H), 7.22 (d, J = 8.1 Hz, 2H), 7.29 (t, J = 7.0 Hz, 1H), 7.51 (m, 2H), 7.72 (m, 3H), 7.84 (td, J = 7.4, 1.7 Hz, 1H), 8.30 (d, J = 7.0 Hz, 1H), 8.46 (dd, J = 7.0, 3.1 Hz, 1H), 11.59 (s, 1H)

I-1-09. 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 7.21 (m, 4H), 7.31 (d, J = 8.5 Hz, 1H), 7.65 (m, 2H), 7.86 (m, 2H) , 8.27 (m, 2H), 11.72 (s, 1H)

I-1-10. 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 3.93 (s, 3H), 4.66 (d, J = 5.8 Hz, 2H), 6.91 (t, J = 7.4 Hz, 1H), 7.00 (d, J = 8.1 Hz, 1H), 7.17 (m, 3H), 7.27 (t, J = 7.4 Hz, 1H), 7.31 (d, J = 7.4 Hz, 1H), 7.81 (d, J = 8.6 Hz , 2H), 8.14 (d, J = 7.0 Hz, 1H), 8.65 (d, J = 7.0 Hz, 1H), 10.04 (t, J = 5.8 Hz, 1H)

I-1-11. 1H NMR (400 MHz, DMSO-d6) δ 3.93 (s, 3H), 4.67 (d, J = 5.9 Hz, 2H), 6.91 (t, J = 7.3 Hz, 1H), 7.01 (d, J = 8.1 Hz , 1H), 7.25 (m, 2H), 7.32 (d, J = 7.4 Hz, 1H), 7.49 (m, 2H), 7.73 (m, 1H), 7.80 (t, J = 7.4 Hz, 1H), 8.20 (d, J = 6.9 Hz. 1H), 8.39 (dd, J = 7.1, 3.2 Hz, 1H), 9.99 (t, J = 5.9 Hz, 1H)

I-1-12. 1H NMR (400 MHz, DMSO-d6) δ 3.86 (s, 3H), 6.95 (m, 1H), 7.21 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.46 (m, 2H) , 7.65 (m, 2H), 7.89 (dt, J = 11.4,2.2 Hz, 1H), 8.28 (d, J = 7.0 Hz, 2H), 11.86 (s, 1H)

I-1-13. 1H NMR (400 MHz, DMSO-d6) δ 3.90 (s, 3H), 7.18 (m, 3H), 7.24 (t, J = 7.0 Hz, 1H), 7.43 (t, J = 8.1 Hz, 1H), 7.64 (d, J = 8.1 Hz, 1H), 7.85 (d, J = 8.8 Hz, 2H), 8.06 (t, J = 2.1 Hz, 1H), 8.25 (d, J = 7.0 Hz, 1H), 8.73 (d , J = 7.0 Hz, 1H), 11.85 (s, 1H)

I-1-14. 1H NMR (400 MHz, DMSO-d6) δ 7.19 (dd, J = 7.9, 2.1 Hz, 1H), 7.27 (t, J = 7.0 Hz, 1H), 7.45 (m, 3H), 7.63 (d, J = 8.3 Hz, 1H), 7.99 (dd, J = 8.7, 5.3 Hz, 2H), 8.06 (t, J = 2.1 Hz, 1H), 8.27 (d, J = 7.0 Hz, 1H), 8.77 (d, J = 7.0 Hz, 1H), 11.81 (s, 1H)

I-1-15. 1H NMR (400 MHz, DMSO-d6) δ 7.20 (dd, J = 8.0, 2.0 Hz, 1H), 7.30 (t, J = 7.0 Hz, 1H), 7.44 (t, J = 8.1 Hz, 1H), 7.52 (m, 2H), 7.66 (d, J = 8.2 Hz, 0H), 7.75 (m, 1H), 7.84 (t, J = 7.4 Hz, 1H), 8.08 (t, J = 2.0 Hz, 1H), 8.31 (d, J = 7.0 Hz, 1H), 8.49 (dd, J = 7.0, 3.1 Hz, 1H), 11.75 (s, 1H)

I-1-16. 1H NMR (400 MHz, DMSO-d6) δ 2.56 (s, 3H), 3.86 (s, 3H), 7.10 (t, J = 7.4 Hz, 1H), 7.22 (m, 3H), 7.30 (m, 2H) , 7.65 (m, 2H), 8.27 (m, 2H), 8.31 (d, J = 7.0 Hz, 1H), 11.54 (s, 1H)

I-1-17. 1H NMR (400 MHz, DMSO-d6) δ 2.56 (s, 3H), 3.91 (s, 3H), 7.09 (t, J = 7.4 Hz, 1H), 7.19 (d, J = 8.7 Hz, 2H), 7.26 (m, 3H), 7.86 (d, J = 8.7 Hz, 2H), 8.29 (d, J = 7.5 Hz, 2H), 8.74 (d, J = 7.0 Hz, 1H), 11.56 (s, 1H)

I-1-19. 1H NMR (400 MHz, DMSO-d6) δ 2.29 (s, 3H), 3.87 (s, 3H), 6.76 (d, J = 7.5 Hz, 1H), 6.80 (d, J = 7.7 Hz, 1H), 7.04 (t, J = 7.8 Hz, 1H), 7.21 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H), 7.65 (m, 2H), 8.26 (m, 2H), 9.37 (s, 1H) , 10.99 (s, 1H)

I-1-20. 1H NMR (400 MHz, DMSO-d6) δ 1.00-1.35 (m, 5H), 1.57-1.89 (m, 6H), 3.37 (t, J = 6.3 Hz, 2H), 7.23 (t, J = 7.0 Hz, 1H), 7.49 (m, 2H), 7.72 (m, 1H), 7.80 (t, J = 7.4 Hz, 1H), 8.18 (d, J = 7.0 Hz, 1H), 8.39 (dd, J = 7.0, 3.3 Hz, 1H), 9.59 (t, J = 5.9 Hz, 1H)

I-1-21. 1H NMR (400 MHz, DMSO-d6) δ 2.37 (s, 3H), 2.43 (s, 3H), 7.03 (d, J = 7.4 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 7.30 (t, J = 7.0 Hz, 1H), 7.51 (m, 2H), 7.75 (m, 1H), 7.85 (t, J = 7.3 Hz, 1H), 7.95 (d, J = 8.5 Hz, 1H), 8.34 (d, J = 7.0 Hz, 1H), 8.48 (dd, J = 7.0, 3.3 Hz, 1H), 11.42 (s, 1H)

I-1-23. 1H NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3H), 2.30 (s, 3H), 7.15 (d, J = 8.0 Hz, 1H), 7.29 (t, J = 7.0 Hz, 1H), 7.51 (m, 2H), 7.58 (m, 2H), 7.75 (m, 1H), 7.84 (t, J = 7.4 Hz, 1H), 8.29 (d, J = 7.0 Hz, 1H), 8.46 (dd, J = 7.0, 3.2 Hz, 1H), 11.54 (s, 1H)

I-1-24. 1H NMR (400 MHz, DMSO-d6) δ 2.36 (s, 6H), 3.86 (s, 3H), 6.81 (s, 1H), 7.21 (m, 2H), 7.31 (d, J = 8.4 Hz, 1H) , 7.46 (s, 2H), 7.65 (m, 2H), 8.26 (m, 2H), 11.63 (s, 1H)

I-1-25. 1H NMR (400 MHz, DMSO-d6) δ 1.34 (t, J = 7.5 Hz, 3H), 2.94 (q, J = 7.5 Hz, 2H), 7.14 (t, J = 7.5 Hz, 1H), 7.29 (m , 3H), 7.52 (m, 2H), 7.75 (m, 1H), 7.86 (t, J = 7.4 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.35 (d, J = 7.0 Hz , 1H), 8.49 (dd, J = 6.9.3.2 Hz, 1H), 11.53 (s, 1H)

I-1-36. 1H NMR (400 MHz, DMSO-d6) δ 4.71 (d, J = 5.5 Hz, 2H), 6.38 (m, 2H), 7.20 (t, J = 6.9 Hz, 1H), 7.44 (t, J = 8.5 Hz , 2H), 7.55 (s, 1H), 7.95 (dd, J = 8.5, 5.3 Hz, 2H), 8.18 (d, J = 6.9 Hz, 1H), 8.69 (d, J = 6.9 Hz, 1H), 9.91 (t, J = 5.5 Hz, 1H)

I-1-37. 1H NMR (400 MHz, DMSO-d6) δ 4.72 (d, J = 5.8 Hz, 2H), 6.39 (m, 2H), 7.23 (t, J = 7.0 Hz, 1H), 7.49 (m, 2H), 7.55 (d, J = 1.8 Hz, 1H), 7.73 (m, 1H), 7.79 (t, J = 7.4 Hz, 1H), 8.22 (d, J = 7.0 Hz, 1H), 8.41 (dd, J = 7.0, 3.2 Hz, 1H), 9.88 (t, J = 5.8 Hz, 1H)

I-1-38. 1H NMR (400 MHz, DMSO-d6) δ 1.57 (m, 4H), 1.68 (m, 4H), 1.85 (m, 2H), 3.28 (m, 2H), 3.65 (t, J = 6.2 Hz, 2H) , 7.07 (t, J = 6.8 Hz, 1H), 7.33 (d, J = 6.7 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.96 (dd, J = 8.8, 5.3 Hz, 2H) 8.55 (d, J = 7.1 Hz, 1H)

I-1-39. 1H NMR (400 MHz, DMSO-d6) δ 0.74 (d, J = 6.5 Hz, 3H), 0.86 (m, 1H), 0.99 (d, J = 6.5 Hz, 3H), 1.42-2.09 (m, 3H) , 2.31 (m, 1H), 2.55-2.91 (m, 1H), 3.24-3.69 (m, 1H), 4.59 (m, 1H), 7.06 (t, J = 6.9 Hz, 1H), 7.36 (d, J = 6.8 Hz, 1H), 7.43 (t, J = 8.8 Hz, 2H), 7.97 (m, 2H), 8.56 (d, J = 7.1 Hz, 1H)

I-1-40. 1H NMR (400 MHz, DMSO-d6) δ 1.74 (d, J = 13.7 Hz, 2H), 2.32 (m, 2H), 3.30 (m, 4H), 3.89 (s, 3H), 5.43 (s, 1H) , 7.04 (t, J = 6.9 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.33 (d, J = 8.6 Hz, 2H), 7.51 (d, J = 8.6 Hz, 2H), 7.79 (d, J = 8.4 Hz, 2H), 7.91 (m, 1H), 8.48 (d, J = 6.9 Hz, 1H), 9.43 (s, 1H)

I-1.41. 1H NMR (400 MHz, DMSO-d6) δ 1.31 (m, 2H), 1.52 (m, 1H), 1.77 (d, J = 14.3 Hz, 1H), 1.84 (m, 1H), 2.58 (d, J = 7.1 Hz, 2H), 2.81 (t, J = 12.5 Hz, 1H), 3.03 (t, J = 12.6 Hz, 1H), 3.42 (d, J = 13.1 Hz, 1H), 4.60 (d, J = 12.9 Hz , 1H), 7.06 (t, J = 6.9 Hz, 1H), 7.16 (m, 3H), 7.25 (m, 2H), 7.36 (d, J = 6.7 Hz, 1H), 7.42 (t, J = 8.7 Hz , 2H), 7.95 (dd, J = 8.7, 5.5 Hz, 2H), 8.54 (d, J = 7.1 Hz, 1H)

I-1-42. 1H NMR (400 MHz, DMSO-d6) δ 2.05 (m, 2H), 2.90 (t, J = 6.7 Hz, 2H), 3.78 (s, 2H), 7.02 (m, 4H), 7.17 (d, J = 8.0 Hz, 1H), 7.41 (t, J = 8.8 Hz, 2H), 7.45 (m, 1H), 7.94 (dd, J = 8.8, 5.4 Hz, 2H), 8.55 (d, J = 7.0 Hz, 1H)

I-1-43. 1H NMR (400 MHz, DMSO-d6) δ 1.50 (d, J = 13.0 Hz, 1H), 1.78 (d, J = 13.8 Hz, 1H), 2.04 (m, 2H), 3.30 (m, 2H), 3.53 (t, J = 13.0 Hz, 1Н), 4.58 (d, J = 12.7 Hz, 1Н), 5.22 (s, 1Н), 7.08 (t, J = 6.9 Hz, 1Н), 7.35 (d, J = 8.6 Hz , 2H), 7.43 (m, 3H), 7.53 (d, J = 8.6 Hz, 2H), 7.96 (dd, J = 8.8, 5.3 Hz, 2H), 8.55 (d, J = 7.1 Hz, 1H)

I-1-44. 1Н NMR (400 MHz, DMSO-d6) δ 2.26 (s, 3Н), 7.01 (t, J = 7.0 Hz, 1H), 7.15 (dd, J = 8.6, 2.4 Hz, 1H), 7.21 (d, J = 2.4 Hz, 1H), 7.60 (m, 3H), 7.84 (d, J = 7.1 Hz, 2H), 7.89 (d, J = 6.7 Hz, 1H), 7.97 (d, J = 8.6 Hz, 1H), 8.48 (d, J = 6.9 Hz, 1H), 9.93 (s, 1H)

Example 6. Synthesis of 3-nitropyridyl-2-hydrazine b2-1 (Scheme 2, b2, R2 = H).

(see Scheme 2)

в 2 литрах этанола и прибавляли по порциям 2,5 моля гидразингидрата. Смесь перемешивали при комнатной температуре в течение двух часов. Выпавший осадок отфильтровывали, промывали водой и холодным этанолом, сушили на воздухе. Выход продукта b2-1: 95%.A solution of 0.6 mol of chloropyridine b1 was placed in a conical flask

in 2 liters of ethanol and 2.5 moles of hydrazine hydrate was added in portions. The mixture was stirred at room temperature for two hours. The precipitate was filtered off, washed with water and cold ethanol, and dried in air. Yield b2-1: 95%.

Example 7. General method for the synthesis of 3-substituted 8-nitro [1,2,4] triazolo [4,3-a] pyridines b3 (see Scheme 2)

5.5 mmol of the corresponding orthoester was added to a suspension of 5 mmol of hydrazine b2-1 in 50 ml of ethanol and boiled for 1-2 hours with stirring. The mixture was cooled, the precipitate was filtered off, washed with ether and dried. Yield b3: 50-80%.

Example 8. General method for the synthesis of 3-substituted 8-amino [1,2,4] triazolo [4,3-a] pyridines b4 (Scheme 2)

0.05 mol of compound b3 in 100 ml of methanol, 1 g of 10% Pd / C was placed in a 250 ml autoclave and hydrogenated at room temperature until the calculated amount of hydrogen was completely absorbed. The mixture was filtered, the organics were evaporated, the precipitate was washed with acetonitrile, dried. Yield b4: 50-70%.

Example 9. General method for the synthesis of 3-substituted 8-acylamino [1,2,4] triazolo [4,3-a] pyridines I-2

The synthesis was carried out in accordance with Scheme 2.

Amine b4 (0.001 mol) was dissolved in 3 ml of dichloromethane, triethylamine (0.002 mol, 0.202 g) was added and cooled to 0 ° C. With vigorous stirring, 0.0012 mol of R4C (O) X chloride was carefully added and the mixture was warmed to room temperature. After three hours, the reaction mass was diluted with dichloromethane (30 ml), washed with 2.0 N hydrochloric acid (2 × 15 ml), dried over sodium sulfate and chromatographed with CH ₂ C _l2 / EtOH (column height 5 cm, width 1 cm). Received pure products 1-2 with yields of 60-90%.

Thus, the compounds I-2-01-I-2-30, shown in Table 5, were obtained.

Below are the NMR spectral data of some of the obtained amides I-2:

I-2-04. 1H NMR (400 MHz, DMSO-d6) δ 1.75 (t, J = 7.0 Hz, 3H), 2.06 (m, 1H), 2.19 (m, 1H), 2.54 (m, 4H), 4.02 (p, J = 8.5 Hz, 1H), 4.42 (q, J = 7.0 Hz, 2H), 6.90 (t, J = 7.1 Hz, 1H), 7.13 (t, J = 7.4 Hz, 1H), 7.27 (d, J = 8.4 Hz , 1H), 7.58 (td, J = 7.2, 1.9 Hz, 1H), 7.94 (d, J = 7.1 Hz, 1H), 8.13 (dd, J = 7.9, 1.9 Hz, 1H), 8.25 (d, J = 7.1 Hz, 1H), 11.09 (s, 1H)

I-2-07. 1H NMR (400 MHz, DMSO-d6) δ 2.05 (m, 1H), 2.21 (m, 1H), 2.55 (m, 4H), 4.05 (d, J = 8.0 Hz, 1H), 6.94 (t, J = 7.1 Hz, 1H), 7.06 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H), 7.48 (m, 2H), 7.67 (d, J = 8.1 Hz, 1H), 8.02 (m, 2H), 9.99 (s, 1H), 11.92 (s, 1H)

I-2-10. 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 1H), 2.19 (m, 1H), 2.52 (m, 4H), 4.04 (p, J = 8.4 Hz, 1H), 6.93 (t, J = 7.1 Hz, 1H), 7.18 (m, 1H), 7.83 (d, J = 7.1 Hz, 1H), 8.04 (d, J = 7.1 Hz, 1H), 8.11 (d, J = 4.1 Hz, 1H), 10.43 (s, 1H).

Example 10. General method for the synthesis of 3-substituted 8-ureido [1,2,4] triazolo [4,2-a] pyridines 1-3

The synthesis was carried out in accordance with Scheme 2.

Amine b4 (0.001 mol) was dissolved in 3 ml of dichloromethane, triethylamine (0.002 mol, 0.202 g) was added and cooled to 0 ° C. With vigorous stirring, 0.0012 mol of R6NCO isothiocyanate was added and the mixture was warmed to room temperature. After 1-3 hours, the reaction mass was diluted with dichloromethane (30 ml), washed with 2.0 N hydrochloric acid (2 × 15 ml), dried over sodium sulfate and chromatographed with CH ₂ C _l2 / EtOH (column height 5 cm, width 1 cm) . Received pure products 1-3 with yields of 60-90%.

Thus, the compounds I-3-01-I-3-25 were obtained, which are shown in Table 6.

Below are the NMR spectral data of some of the obtained urea 1-3:

I-3.03. 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 1H), 2.18 (m, 1H), 2.53 (m, 4H), 4.00 (p, J = 8.3 Hz, 1H), 4.20 (m, 4H) , 6.74 (m, 2H), 6.84 (t, J = 7.1 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.79 (d, J = 6.8 Hz, 1H), 7.88 (d, J = 7.3 Hz, 1H), 9.13 (s, 1H), 9.26 (s, 1H)

I-3-06. 1H NMR (400 MHz, DMSO-d6) δ 2.03 (m, 1H), 2.17 (m, 1H), 2.50 (m, 4H), 3.98 (p, J = 8.4 Hz, 1H), 4.33 (d, J = 5.5 Hz, 2H), 6.25 (d, J = 3.1 Hz, 1H), 6.36 (dd, J = 3.1, 1.8 Hz, 1H), 6.80 (t, J = 7.1 Hz, 1H), 7.46 (t, J = 5.5 Hz, 1H), 7.51 (d, J = 1.8 Hz, 1H), 7.75 (d, J = 6.9 Hz, 1H), 7.84 (d, J = 7.2 Hz, 1H), 9.07 (s, 1H)

I-3-08. 1H NMR (400 MHz, DMSO-d6) δ 2.05 (m, 1H), 2.18 (m, 1H), 2.54 (m, 4H), 3.86 (s, 3H), 4.01 (p, J = 8.2 Hz, 1H) , 6.85 (t, J = 7.1 Hz, 1H), 7.73 (d, J = 5.5 Hz, 1H), 7.84 (d, J = 6.9 Hz, 1H), 7.92 (d, J = 7.5 Hz, 1H), 7.97 (d, J = 5.5 Hz, 1H), 10.11 (s, 1H), 10.74 (s, 1H)

I-3-10. 1H NMR (400 MHz, DMSO-d6) δ 2.04 (m, 1H), 2.19 (m, 1H), 2.24 (s, 3H), 2.51 (m, 4H), 3.74 (s, 3H), 4.00 (p, J = 8.4 Hz, 1H), 6.70 (m, 2H), 6.82 (t, J = 7.1 Hz, 1H), 7.59 (d, J = 8.7 Hz, 1H), 7.78 (d, J = 6.8 Hz, 1H) , 7.89 (d, J = 7.4 Hz, 1H), 8.61 (s, 1H), 9.52 (s, 1H).

The antagonistic activity of the new compounds of general formula I and their pharmaceutically acceptable salts with respect to the adenosine A2A receptor was carried out ex vitro in a functional test on cells. In the experiment, cells of the ValiScreen cell line line (PerkinElmer, USA) expressing the recombinant human A2A type adenosine receptor were used.

Tables 4-6 show activity data for some of the compounds of general formula I, confirming their high antagonistic activity with respect to the adenosine A2A receptor: A means the inhibition of A2A receptors by the compound at a concentration of 10 μM by more than 75%, B by more than 50%, C - more than 25%, D - more than 10%.

Example 11. General method for the synthesis of salts of compounds of General formula I.

A portion of the compounds of this invention contains ionic groups (secondary, tertiary amines) and can form salts that have been prepared by methods known in the art.

For this, for example, to a solution of a base in an inert solvent (alcohol, acetone, chloroform, ether, ethyl acetate), a solution of an equivalent amount (sometimes excess) of an organic or inorganic acid in an inert solvent was added and precipitation of the desired salt was achieved. The inorganic acid may be hydrochloric acid, phosphoric acid, sulfuric acid, nitric acid, hydrobromic acid or hydroiodic acid. The organic acid may be methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, citric acid, lactic acid, lactic acid gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carboxylic acid or vanillic acid, n o not limited to them. Table 7 presents examples of the obtained pharmaceutically acceptable salts and some of their properties.

Biological tests and the activity of synthesized compounds.

Example 11. The study of the antagonistic activity of the compounds of General formula I and their pharmaceutically acceptable salts with respect to the adenosine A2A receptor.

The antagonistic activity of the new compounds of general formula I and their pharmaceutically acceptable salts with respect to the adenosine A2A receptor was carried out ex vitro in a functional test on cells. In the experiment, cells of the ValiScreen cell line line (PerkinElmer, USA) expressing the recombinant human A2A type adenosine receptor were used. When receptors are stimulated in these cells, a CGS-21680 agonist (Tocris) activates adenylate cyclase, which leads to an increase in the synthesis of intracellular cyclic adenosine monophosphate (cAMP or cAMP). The amount of cAMP was determined using LANCE technology (LANCE Ultra cAMP kit, PerkinElmer). By the ability of the test compounds to reduce the amount of cAMP synthesized in the presence of CGS-21680, their antagonistic activity was evaluated. The KW-6002 antagonist (Axon Medchem, Netherlands) described in the literature was used as a standard (comparison compound).

Cells were cultured in DMEM (PanEco, Russia) supplemented with 10% FBS (Biological Industries), a mixture of penicillin / streptomycin (PanEco) and G418 (Sigma) at a temperature of 37 ° C in an atmosphere of 5% CO ₂ . Before the experiment, cells were removed from the culture vial with Versen's solution (PanEco) and suspended in SB2 buffer (Hanks + 5 mM HEPES (pH 7.4) + 0.1% BSA + 200 uM Ro-20-1734 + 2U / mL ADA (adenosine deaminase)) to a density of 0.2 million cells per milliliter. ULight ™ -anti-cAMP Antibody (PerkinElmer) was added 1: 150 (v / v) to the cell suspension and the mixture was poured into white 384-well plates (PerkinElmer) 5 μl (1000 cells) per well.

Test compounds were dissolved in DMSO to a concentration of 6.32 mM and 3.16-fold serial dilutions in DMSO were prepared. The prepared serial dilutions were diluted 50 times with SB1 buffer solution (Hanks medium + 5 mM HEPES (pH 7.4) + 0.1% BSA). The resulting solutions of compounds in SB1 buffer were mixed in a 1: 1 ratio with a solution of CGS-21680 (12.64 nM), previously prepared in SB3 buffer (SB1 + 0.1% Pluronic F127). The resulting mixtures of test compounds with an agonist were added (5 μl in duplicates) to plate wells containing 5 μl of cells (as described above) and the plates were incubated for 30 minutes at room temperature. Each plate also contained 16 holes for each control (MAX and MIN). MAX - cells with 3.16 nM CGS 21680 (agonist concentration corresponding to EC ₉₀ , that is, a concentration that causes 90% cell activity); the signal from these wells was used in the calculations as 100% activity (0% inhibition). MIN - cells with a mixture of 3.16 nM CGS-21680 and 2 μM KW-6002 (antagonist concentration corresponding to IC ₁₀₀ , that is, a concentration that causes 100% inhibition of cell activity); the signal from these wells was used in the calculations as 0% activity (100% inhibition). In addition, each plate contained wells (in 4 repetitions), where the cells were treated with an agonist (CGS-21680) at different concentrations. The final concentration of DMSO in all wells was 1%.

The cAMP formed in the cells was quantified using the LANCE Ultra cAMP kit (PerkinElmer, USA), in accordance with the procedure recommended by the manufacturer. The fluorescent signal was measured on a Victor3V instrument (PerkinElmer) equipped with a built-in LANCE High Count software.

The apparent affinity of the test compounds was determined by the formula:

K _i = IC ₅₀ / (1 + L / K _D ),

where IC ₅₀ is the concentration of the antagonist at which adenylate cyclase activity is 50% of the maximum, L is the concentration of CGS-21680, at which measurements (3.16 nM) are carried out, and K _D is the apparent affinity constant of CGS-21680, quantitatively corresponding to the value of EC ₅₀ (concentration half-maximal cell stimulation) for CGS-21680 and determined from the curves of stimulation of cAMP accumulation in cells at different agonist concentrations. Tables 5-7 provide activity data for the compounds of general formula I.

Example 12. Radioligand analysis of the interaction of compounds of General formula I with adenosine A1, A2A, A2B and A3 receptors.

A radioligand analysis of the interaction of compounds of general formula I with adenosine A1, A2A, A2B and A3 receptors was performed to determine the selectivity of the interaction of compounds of general formula I with adenosine A2A receptor. When determining the interaction of the studied compounds with the adenosine A2A receptor, membrane preparations were used, obtained from human kidney embryonic cells expressing the recombinant human A2A receptor. Receptor expression was 7 pmol / mg protein. [ ³ H] CGS 21680 at a concentration of 0.05 μM was used as a radioligand. Solutions of the test compounds were prepared as described in the functional test procedure, with the difference that instead of SB1, a buffer of the following composition was used: 50 mM Tris-HCl, pH 7.4, 10 tM MgCl ₂ , I mM EDTA, 2 U / mL Adenosine Deaminase Membrane preparations were incubated in the presence of a mixture of the test compounds and [ ³ H] CGS 21680 for 90 min at 25 ° C and the mixtures were filtered on GF glass fiber filters (Millipor, USA). The radioactivity on the filters was determined using a MicroBeta liquid-oscillation counter (PerkinElmer, USA). Nonspecific binding was measured in the presence of 50 μM NECA, which was not more than 15% of the total binding. The affinity of the tested compounds was determined by the formula:

K _i = IC ₅₀ / (1 + L / K _D ),

where IC ₅₀ is the concentration of the antagonist at which the binding of [ ³ H] CGS-21680 is reduced to 50% of the maximum, L is the concentration of [ ³ H] CGS-21680 at which measurements (50 nM) and K _D is the affinity constant [ ³ H] CGS-21680, quantitatively corresponding to the EC ₅₀ value (half-maximum binding concentration) for [ ³ H] CGS-21680, and determined from the radioactive binding curves at different concentrations of [ ³ H] CGS-21680 (K _D = 64 nM).

Similarly investigated the interaction of new compounds of General formula I with adenosine A1, A2B and A3 receptors.

The radioligand analysis of the interaction of some compounds of the general formula I with adenosine A1, A2A, A2B and A3 receptors showed their high selectivity with respect to the adenosine A _2A receptor (Table 8).

Example 13. Obtaining a pharmaceutical composition.

The pharmaceutical composition according to the invention is prepared using methods generally accepted in the art and includes a pharmacologically effective amount of a drug substance representing a compound of formula I or a pharmaceutically acceptable salt thereof, usually from 5 to 30% by weight, in combination with one or more pharmaceutically acceptable adjuvants additives, such as diluents, binders, disintegrating agents, adsorbents, flavoring agents, flavoring agents. In accordance with known methods, pharmaceutical compositions may be in various liquid or solid forms.

Examples of solid dosage forms include, for example, tablets, pills, gelatine capsules, etc.

Examples of liquid dosage forms for injection and parenteral administration include solutions, emulsions, suspensions, etc.

Compositions, as a rule, are obtained using standard procedures involving the mixing of the active compound with a liquid or finely divided solid carrier.

Example. 100 mg of a composition containing 15.0 mg of the compound 3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methylphenylamide (compound I-1-16)

Compound I-1-16 15.0 mg Lactose 40.0 mg Alginic acid 20.0 mg Lemon acid 5.0 mg Tragacanth 20.0 mg

According to the invention, pharmaceutical compositions containing other compounds of the general formula I as a drug substance are likewise prepared.

Claims (12)

1. Substituted [1,2,4] triazolo [4,3-a] pyridines of the general formula I, as well as their pharmaceutically acceptable salts

where A represents an optionally substituted aminocarbonyl group —N — C (O) -, in which the amino group may be substituted and substituents may be selected from
hydrogen, C ₁ -C ₅ alkyl optionally substituted with C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, a 5-6 membered heteroaryl in which the heteroatoms are selected from oxygen or nitrogen;
an aryl selected from phenyl, optionally substituted with hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halogen, C ₁ -C ₅ acylamino group, or naphthyl;
or an amino group is selected from a C ₃ -C ₇ heterocyclyl containing 1-2 heteroatoms in a ring selected from nitrogen, oxygen or sulfur, optionally substituted with hydroxy, C ₁ -C ₃ alkyl, benzyl, phenyl, which may be substituted with halogen, wherein said heterocyclyl may be fused to a benzene ring;
an acylamino group in which the acyl is selected from
C ₁ -C ₆ alkylcarbonyl, wherein the alkyl may be substituted with phenyl substituted with phenyl, wherein the substituents are selected from C ₁ -C ₅ alkoxy; A 5-membered heteroaryl with a heteroatom selected from an oxygen or sulfur atom;
benzoyl, optionally substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio or halogen, methylenedioxy;
heterocyclylcarbonyl, in which heterocyclyl is selected from a 5-6 membered heterocyclyl, with 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, optionally fused to a benzene ring and optionally substituted with C ₁ -C ₅ alkyl, halogen;
or a ureido group in which one of the substituents on the terminal amido group is hydrogen, and the second substituent is selected from:
C ₁ -C ₃ alkyl substituted with phenyl, a 5-membered saturated or aromatic heterocyclyl, in which the heteroatoms are selected from oxygen or sulfur;
C ₂ -C ₆ alkenyl;
aryl selected from phenyl substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, ethylenedioxy, methylenedioxy, halogen, C ₁ -C ₃ alkylcarbonyl;
A 5-membered heterocyclyl in which the heteroatoms are selected from a sulfur or oxygen atom, and optionally substituted with an alkyloxycarbonyl group;
B is a non-aromatic cyclic substituent selected from C ₄ -C ₆ cycloalkyl;
an aromatic cyclic substituent selected from phenyl, which may be substituted with halogen, C ₁ -C ₃ alkoxy;
a non-aromatic 5-6 membered heterocyclic substituent with a nitrogen atom as a heteroatom, and optionally N-substituted with C ₁ -C ₃ alkyl;
an aromatic 5-6 membered heterocyclic substituent in which the heteroatoms are selected from nitrogen, oxygen or sulfur, and which may be substituted with C ₁ -C ₆ alkyl;
or an aromatic 5-6 membered heterocyclic substituent in which the heteroatom is selected from nitrogen condensed with a benzene ring;
R1a, R1b and R1c independently represent H, C ₁ -C ₃ alkoxy, excluding compounds:

n is 1.2; R = H, Hal, Me, MeO, CMe ₃ , CF ₃

n is 1.2; R = H, Hal, Me, MeO, CMe ₃ , CF ₃

n is 1.2; R = H, Hal, Me, MeO, CMe ₃ , CF ₃

2. Substituted [1,2,4] triazolo [4,3-a] pyridines according to claim 1 of the general formulas I-1, I-2, I-3, as well as their pharmaceutically acceptable salts:

Where:
B has the meanings defined in claim 1;
R2a, R2b and R2c independently represent H, C ₁ -C ₃ alkoxy;
R3a and R3b independently represent hydrogen, C ₁ -C ₅ alkyl optionally substituted with C ₁ -C ₃ alkoxy, C ₃ -C ₆ cycloalkyl, 5-6 membered heteroaryl in which the heteroatoms are selected from oxygen or nitrogen; aryl selected from phenyl optionally substituted with hydroxy, C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, halogen, C ₁ -C ₅ acylamino group, or naphthalene;
R3a and R3b may together form cyclic substituents, with the group R3a-N-R3b being a C ₃ -C ₇ heterocyclyl containing 1-2 heteroatoms in the ring selected from nitrogen, oxygen or sulfur, optionally substituted with hydroxy, C ₁ -C ₅ alkyl, benzyl, phenyl, which may be substituted by halogen, wherein said heterocyclyl may be fused to a benzene ring;
R4 is C ₁ -C ₅ alkyl, where the alkyl may be substituted with phenyl, substituted with phenyl, in which the substituents are selected from C ₁ -C ₅ alkoxy; A 5-membered heteroaryl with a heteroatom selected from an oxygen or sulfur atom; aryl selected from phenyl optionally substituted with C ₁ -C ₅ alkylene, C ₁ -C ₅ alkoxy, C ₁ -C ₅ alkylthio or halogen, methylenedioxy; heterocyclyl, in which heterocyclyl is selected from a 5-6 membered heterocyclyl, with 1-2 heteroatoms selected from nitrogen, oxygen or sulfur, possibly fused to a benzene ring and optionally substituted with C ₁ -C ₅ alkyl, halogen;
R5 is hydrogen;
R6a and R6b independently represent hydrogen, C ₁ -C ₃ alkyl substituted with phenyl, a 5-membered saturated or aromatic heterocyclyl, in which the heteroatoms are selected from oxygen or sulfur; C ₂ -C ₆ alkenyl, aryl selected from phenyl substituted with C ₁ -C ₅ alkyl, C ₁ -C ₅ alkoxy, ethylenedioxy, methylenedioxy, halogen, C ₁ -C ₃ alkylcarbonyl;
R6a and R6b may together form cyclic substituents, wherein the R6a-N-R6b group is a 5 membered heterocycle in which the heteroatoms are selected from a sulfur or oxygen atom, and optionally substituted with an alkyloxycarbonyl group; 3. Derivatives of [1,2,4] triazolo [4,3-a] pyridines according to claim 1, which are
3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methoxyphenylamide (I-1-01);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methoxyphenylamide (I-1-02);
3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid naphthyl-1-amide (I-1-03);
3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methylphenylamide (I-1-04);
3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methylphenylamide (I-1-05);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid phenylamide (I-1-06);
3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-propylamide (I-1-07);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 4-methylphenylamide (I-1-08);
3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 4-fluorophenylamide (I-1-09);
3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid (2-methoxyphenyl) methylamide (I-1-10);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid (2-methoxyphenyl) methylamide (I-1-11);
3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-fluorophenylamide (I-1-12);
3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-chlorophenylamide (I-1-13);
3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-chlorophenylamide (I-1-14);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-chlorophenylamide (I-1-15);
3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methylphenylamide (I-1-16);
3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methylphenylamide (I-1-17);
3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-hydroxy-6-methylphenylamide (I-1-19);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid (cyclohexyl) methylamide (I-1-20);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2,3-dimethylphenylamide (I-1-21);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3,4-dimethylphenylamide (I-1-23);
3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3,5-dimethylphenylamide (I-1-24);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-ethylphenylamide (I-1-25);
3- (pyrid-4-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 3-methylphenylamide (I-1-26);
3- (pyrid-4-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methylphenylamide (I-1-27);
3- (pyrid-3-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methylphenylamide (I-1-28);
3- (pyrid-3-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methoxyphenylamide (I-1-29);
3- (5-methylfuryl-2) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methoxyphenylamide (I-1-30);
3- (thienyl-2) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methoxyphenylamide (I-1-31);
3- (indol-2-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methoxyphenylamide (I-1-32);
3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-ethylphenylamide (I-1-33);
3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid 2-methoxyphenylamide (I-1-34);
3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methoxyphenylamide (I-1-35);
3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid (furan-2-yl) methylamide (I-1-36);
3- (2-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carboxylic acid (furan-2-yl) methylamide (I-1-37);
3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid heptamethylene amide (I-1-38);
N- {3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -3,5-dimethylpiperidine (I-1-39);
N- {3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -4-hydroxy-4- (4-chlorophenyl) piperidine (I-1 -40);
N- {3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -4-benzylpiperidine (I-1-41);
N- {3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -1,2,3,4-tetrahydroquinoline (I-1-42);
N- {3- (4-fluorophenyl) - [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -4-hydroxy-4- (4-chlorophenyl) piperidine (I-1 -43);
3-phenyl- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methyl-4-chloro-phenylamide (I-1-44)
3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-naphthylamide (I-1-47);
3- (4-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-propylamide (I-1-48);
3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-methylphenylamide (I-1-49);
3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 2-fluorophenylamide (I-1-50);
3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid 3-methylphenylamide (I-1-51);
3- (2-fluorophenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridine-8-carboxylic acid (furan-2-yl) methylamide (I-1-52);
N- {3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} piperazine (I-1-53);
N- {3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -N'-methylpiperazine (I-1-54);
N- {3- (2-methoxyphenyl) -5-methoxy- [1,2,4] triazolo [4,3-a] pyridin-8-carbonyl} -2-hydroxyethylamine (I-1-55);
8 - [(2-ethoxybenzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-01);
8 - {[(2-methoxyphenyl) acetyl] amino} -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-02);
8 - [(thien-3-yl) acetylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-03);
8 - [(2-chloro-5-methylthio-benzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-04);
8 - [(thien-3-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-05);
8 - [(3-methylthien-2-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-06);
8 - [(indol-2-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-07);
8 - [(3-fluoro-4-methoxy-benzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-08);
8 - [(2,3-dihydrobenzo [1,4] dioxin-2-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-09) ;
8 - [(5-chlorothien-2-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-10);
8 - [(3,4-methylenedioxybenzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-11);
8 - [(5-methylisoxazol-3-yl) carbonylamino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-12);
8 - [(2-methoxybenzoyl) amino] -3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-13);
8 - [(2-methoxybenzoyl) amino] -3-cyclopentyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-14);
8 - [(2-ethoxybenzoyl) amino] -3-cyclopentyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-15);
8 - [(2-methoxybenzoyl) amino] -3-cyclohexyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-16);
8 - [(2-methoxybenzoyl) amino] -3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-17);
8- (benzoylamino] -3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-18);
8- (benzoylamino] -3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-19);
8- (2-methoxybenzoylamino] -3- (2-methoxyphenyl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-20);
8- (2-ethoxybenzoylamino] -3-phenyl- [1,2,4] triazolo [4,3-a] pyridine (I-2-21);
8 - [(2-fluorobenzoyl) amino] -3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-22);
8 - [(2-fluorobenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-23);
8 - [(2-methoxybenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-24);
8 - [(2-methoxybenzoyl) amino] -3- (pyridin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-25);
8 - [(2-methoxybenzoyl) amino] -3- (pyridin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-26);
8 - [(2-chlorobenzoyl) amino] -3- (N-methylpiperidin-4-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-27);
8 - [(2-chlorobenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-28);
8 - [(2,6-dichlorobenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-29);
8 - [(2,6-dimethylbenzoyl) amino] -3- (N-methylpiperidin-3-yl) - [1,2,4] triazolo [4,3-a] pyridine (I-2-30);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (3,4-dimethoxyphenyl) urea (I-3-01);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (2-methoxy-5-methylphenyl) urea (I-3-02);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (3,4-ethylenedioxyphenyl) urea (I-3-03);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (2-phenylethyl) urea (1-3-04);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (3,4-methylenedioxyphenyl) urea (I-3-05);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-06);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (tetrahydrofuryl-2-methyl) urea (I-3-07);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (2-methoxycarbonylthienyl-3) urea (I-3-08);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (3-acetylphenyl) urea (I-3-09);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (4-methoxy-2-methylphenyl) urea (I-3-10);
1- (3-cyclobutyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (4-methoxy-3-fluorophenyl) urea (I-3-11);
1- (3-cyclopentyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-12);
1- (3-cyclohexyl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-13);
1- {3- (N-methylpiperidin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (furyl-2-methyl) urea (I- 3-14);
1- {3- (N-methylpiperidin-3-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (furyl-2-methyl) -urea (I- 3-15);
1- {3- (N-methylpiperidin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (2-methoxyphenyl) urea (I-3- 16);
1- {3- (N-methylpiperidin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (3,4-dimethoxyphenyl) urea (I- 3-17);
1- {3- (N-methylpiperidin-3-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (2-methoxyphenyl) urea (I-3- eighteen);
1- {3- (N-methylpiperidin-3-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3- (3,4-dimethoxyphenyl) urea (I- 3-19);
1- (3-pyrid-4-yl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-20 );
1- (3-pyrid-4-yl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-22 );
1- (3-pyrid-3-yl- [1,2,4] triazolo [4,3-a] pyridin-8-yl) -3- (furyl-2-methyl) urea (I-3-23 );
1- {3- (N-methylpiperidin-4-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3-allylurea (I-3-24);
1- {3- (N-methylpiperidin-3-yl) [1,2,4] triazolo [4,3-a] pyridin-8-yl} -3-allylurea (I-3-25). 4. The method of obtaining [1,2,4] triazolo [4,3-a] pyridines of the general formulas I-2 and I-3:

where R2, R4, R6 and B have the above meanings, X = Cl,
consisting in sequential cyclocondensation of the orthoester B-C (OMe) ₃ with compound b2 obtained by the reaction of 2-chloro-3-nitropyridine b1 with hydrazine; reduction of nitropyridine b3 with hydrogen over palladium on carbon; acylating the resulting amine b4 with a suitable acyl halide in the presence of a strong base to give compound I-2, or reacting the amine b4 with a suitable isocyanate in a neutral solvent to give compounds I-3. 5. The active component having the property of an antagonist of A2A receptors, which is a compound of General formula I according to any one of claims 1 to 3. 6. The active component with the properties of a selective antagonist of A2A receptors for the manufacture of a medicament suitable for the prophylaxis and treatment of disorders of the central nervous system, neurodegenerative, inflammatory, and oncological diseases, which is a compound of general formula I according to any one of claims 1 to 3. 7. A pharmaceutical composition having antagonistic activity with respect to the adenosine A2A receptor, comprising, as an active component or compound of general formula I according to any one of claims 1 to 3, or pharmaceutically acceptable salts thereof in a therapeutically effective amount. 8. The pharmaceutical composition according to claim 7 in the form of tablets, capsules and injections, ointments, gels and other finished forms, placed in a pharmaceutically acceptable package. 9. The method of obtaining the pharmaceutical composition according to any one of paragraphs 7-8 by mixing with an inert excipient, auxiliary agent, carrier and / or solvent, at least one active component (substance) of the General formula I according to claims 1 to 3 or its pharmaceutically acceptable salt in a therapeutically effective amount. 10. A method for selectively inhibiting the activity of an adenosine A2A receptor, which consists in the action of the active component (substance) of the general formula I according to claims 1-3, or a pharmaceutically acceptable salt thereof, on biological objects or samples whose functions are regulated by A2A adenosine receptors. 11. A drug suitable for the prevention and treatment of disorders of the central nervous system, neurodegenerative, inflammatory, oncological diseases, which contains the active ingredient according to claim 6 of general formula I or the pharmaceutical composition according to claim 7 in a therapeutically effective amount. 12. The drug according to claim 11 in the form of tablets, capsules or injections, placed in a pharmaceutically acceptable package.