Heterocyclic derivatives as P2X7 receptor antagonists

Abstract

The present invention relates to novel 1,4-substituted piperidine compounds of formula (I) having P2X7 receptor (P2X7) antagonistic properties, pharmaceutical compositions containing these compounds, chemical processes for preparing these compounds, and their use in the treatment or prevention of diseases associated with P2X7 receptor activity in animals, particularly humans.

Description

[Technical Field]

[0001] The present invention relates to novel substituted heterocyclic compounds of formula (I) having P2X7 receptor (P2X7) antagonistic properties, pharmaceutical compositions comprising these compounds, chemical processes for preparing these compounds, and their use in the treatment or prevention of diseases related to P2X7 receptor activity in animals, particularly humans. [Background technology]

[0002] P2X7 belongs to the P2X ion channel receptor family. P2X7 is activated by extracellular nucleotides, particularly adenosine triphosphate (ATP). P2X7 is distinguished from other members of the P2X family by its specific localization (particularly to CNS and immune cells), the high concentrations of ATP (in the mM range) required to activate it, and its ability to form large pores upon prolonged or repeated stimulation. P2X7 is a ligand-gated ion channel and is found on various cell types, specifically macrophages, mast cells, and lymphocytes (T and B), which are known to be primarily involved in inflammatory and / or immune processes. Activation of the P2X7 receptor by extracellular nucleotides, such as ATP, results in the release of interleukin-1β (IL-1β) and giant cell formation (macrophages / microglia cells), granule disappearance (mast cells), and L-selectin release (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APCs), keratin-producing cells, salivary gland acinar cells (parotid cells), hepatocytes, erythrocytes, erythroleukemia cells, monocytes, fibroblasts, myeloid cells, neurons, and renal mesangial cells. P2X7 receptors are also known to be pain sensors in the nervous system. Experiments using P2X7-deficient mice demonstrate the role of P2X7 in pain development, as these mice were protected from the development of both adjuvant-induced inflammatory pain and partial nerve ligation-induced neuropathic pain. There is also growing evidence that P2X7 or its downstream effectors, such as IL-1β, are involved in the pathophysiology of several neurological disorders, including Alzheimer's disease (JI Diaz-Hernandez et al., Neurobiol. Aging 2012, 1816-1828: In vivo P2X7 inhibition reduces Aβ plaques in AD through GSK3β). P2X7 is thought to play a crucial role in neurotransmission within the CNS through its activation on postsynaptic and / or presynaptic neurons and glial cells. In situ hybridization revealed that P2X7 receptor mRNA is widely distributed throughout the rat brain.In particular, regions of high P2X7 mRNA expression were found in the anterior olfactory nucleus, cerebral cortex, piriform cortex (Pir), lateral septal nucleus (LS), hippocampal pyramidal cell layer (CA1, CA3, CA4), pontine nuclei, lateral cuneate nucleus, and medial vestibular nucleus. P2X7 hybridization signaling was also observed in motor neurons of the trigeminal motor nucleus, facial nerve nucleus, hypoglossal nerve nucleus, and spinal anterior horn.

[0003] Therefore, there is a therapeutic rationale for the use of P2X7 antagonists in the treatment of various disease conditions. These conditions include, but are not limited to, CNS-related diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, spinal cord injury, cerebral ischemia, head trauma, meningitis, sleep disorders, mood and anxiety disorders, HIV-induced neuroinflammation, and chronic neuropathic and inflammatory pain. Furthermore, peripheral inflammatory diseases and autoimmune diseases, including but not limited to rheumatoid arthritis, osteoarthritis, psoriasis, allergic dermatitis, asthma, chronic obstructive pulmonary disease, airway hyperresponsiveness, septic shock, bronchitis, glomerulonephritis, irritable bowel syndrome, fatty liver disease, hepatic fibrosis, skin injuries, emphysema, muscular dystrophy, fibrosis, atherosclerosis, burns, Crohn's disease, ulcerative colitis, age-related macular degeneration, malignant cell proliferation and metastasis, Sjögren's syndrome, myeloblastic leukemia, diabetes mellitus, osteoporosis, and ischemic heart disease, are all examples in which the involvement of the P2X7 receptor has been suggested. Given the clinical importance of P2X7, the identification of compounds that modulate P2X7 receptor function represents an attractive avenue for the development of new therapeutic agents.

[0004] P2X7 inhibitors are described in various patent applications, such as the following: WO2004 / 099146 discloses benzamide inhibitors of the P2X7 receptor and their use in the treatment of inflammatory diseases.

[0005] WO2009 / 108551 discloses heteroarylamide analogs and their use in P2X7 receptor-mediated states. WO2009 / 132000 discloses quinoline and isoquinoline-substituted P2X7 receptor antagonists and their use in P2X7 receptor-mediated conditions.

[0006] WO2015 / 119018 discloses thiazole and oxazole derivatives as P2X7 receptor antagonists, and their use in P2X7 receptor-mediated conditions. WO2018 / 041563 discloses substituted N-[2-(4-phenoxypiperidine-1-yl)-2-(1,3-thiazole-5-yl)ethyl]benzamide and N-[2-(4-benzyloxypiperidine-1-yl)-2-(1,3-thiazole-5-yl)ethyl]benzamide derivatives as P2X7 receptor antagonists. [Overview of the project] [Problems that the invention aims to solve]

[0007] However, there remains an unmet need for compounds that can efficiently antagonize P2X7 in both humans and rodent species, possess appropriate drug-like properties, and be optimally delivered to different target organs, including the brain, which are sites of P2X7-mediated pathology. Such compounds are shown herein. [Means for solving the problem]

[0008] Various aspects of the present invention are presented below. The present invention relates to a heterocyclic compound of the following formula (I) or a pharmaceutically acceptable salt thereof:

[0009] [ka]

[0010] This includes any stereochemical isomer forms thereof, in the formula, W is oxygen, O-C1~C4 alkyl Ren ;C1~C4 Alki Ren -O-, R 1is one or more groups selected from C1-C4 alkyl (optionally substituted with halogen), C1-C4 alkoxy, halogen, cyano, C3-C6 cycloalkyl, or a monocyclic or bicyclic 5- to 10-member heterocycle optionally substituted with a benzo-fused heterocycle, relates to.

[0011] As used in the above definitions, the terms "halo", "halogen", and "halide" can be used interchangeably and refer to the substituents fluoro, chloro, bromo or iodo.

[0012] As used herein, the term "stereochemical isomeric form" defines all possible isomeric forms that the compounds of formula (I) can assume. Unless otherwise mentioned or indicated, the chemical name of a compound denotes a mixture of all possible stereochemical isomeric forms, which mixture contains all diastereomers and enantiomers of the basic molecular structure. More specifically, a stereocenter can have an R- or S-configuration and substituents on bivalent cyclic (partially) saturated groups can have either a cis- or trans-configuration.

[0013] The stereochemical isomeric forms of the compounds of formula (I) are intended to be clearly embraced within the scope of the present invention. The absolute stereochemical configuration of the compounds of formula (I) and of the intermediates used in their preparation can be readily determined by those skilled in the art using well-known methods such as, for example, X-ray diffraction.

[0014] Furthermore, some of the compounds of formula (I) and some of the intermediates used in their preparation may exhibit polymorphism. The present invention is to be understood as encompassing any polymorphic form having useful properties in the treatment of the above conditions.

[0015] The above pharmaceutically acceptable salts mean that the compound of formula (I) includes therapeutically active and non-toxic acid addition salt forms that can be formed. These pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the basic form with such appropriate acids. Appropriate acids include, for example, inorganic acids such as hydrohalic acids such as hydrochloric acid or hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc.; or organic acids such as acetic acid, propanoic acid, hydroxyacetic acid, lactic acid, pyruvic acid, oxalic acid (i.e., ethanedioic acid), malonic acid, succinic acid (i.e., butanedioic acid), maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, methanesulfonic acid, trifluoromethanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, cyclamic acid, salicylic acid, p-aminosalicylic acid, pamoic acid, etc.

[0016] Conversely, the salt form can be converted to the free base form by treatment with an appropriate base. The compound of formula (I) may exist in both non-solvated and solvated forms. The term "solvate" is used herein to describe a molecular aggregate comprising a compound of the invention and one or more pharmaceutically acceptable solvent molecules such as water or ethanol. The term "hydrate" is used when the solvent is water.

[0017] A preferred embodiment of the present invention relates to the compound of formula (I) defined above. W is oxygen, O-C1-C4 alkyl Ren ; C1-C4 alkyl Ren -O-, and R 1Pyridines monosubstituted or disubstituted with cyano, methyl, halogen, trifluoromethyl groups and / or C3-C7 cycloalkyl groups; pyrimidines monosubstituted or disubstituted with cyano, methyl, trifluoromethyl groups, C3-C7 alkoxy, C3-C7 cycloalkoxy and / or halogen groups; oxazoles monosubstituted or disubstituted with C3-C7 cycloalkyl, methyl and / or halogen groups; thiazoles monosubstituted or disubstituted with C3-C7 cycloalkyl, cyano, methyl and / or halogen groups; benzothiazoles; benzoxazoles; methyl, halogen, These include thiadiazoles monosubstituted or disubstituted with phenyl and / or C1-C4 alkoxys; tetrazoles substituted or unsubstituted with phenyl; benzodiazoles substituted or unsubstituted with halogens, phenyl, or other halogens; pyridazines substituted with methyl and / or halogens; pyrazolo[1,5-a]pyrazines; [1,2,4]triazolo[4,3-a]pyrazines; naphthyridines; pyrazolo[3,4-d]pyrimidines; pyrazines monosubstituted or disubstituted with C3-C7 cycloalkyl, methyl, heterocyclic, and / or halogens; [1,2]oxazolo[5,4-b]pyridines; or phthalazines.

[0018] Another aspect of the present invention is a compound of formula (I) as defined above, In the formula, W is oxygen, -CH2O- or -OCH2-, R 1These include pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, 5-fluoropyridine-3-yl, 3-fluoropyridine-4-yl, 3-fluoropyridine-2-yl, 1,5-methyl-1,2-oxazole-3-yl, dimethyl-1,2-oxazole-4-yl, 1,3-thiazole-2-yl, 3-methyl-1,2,4-thiadiazole-5-yl, 4-chloro-1,3-thiazole-2-yl, 3-cyclopropyl-1,2,4-thiadiazole-5-yl, 6-methylpyridine-2-yl, and 4-methylpyridine-2-yl. Zin-2-yl, 5-cyanopyridine-3-yl, 3-cyanopyrazine-2-yl, 2-cyanopyrazine-3-yl, 2-chloropyridine-3-yl, 1,3-benzothiazole-2-yl, 1,2-benzoxazole-3-yl, 1,3-benzoxazole-2-yl, 3-(2-methoxyethyl)-1,2,4-thiadiazole-5-yl, 3-phenyl-1,2,4-oxadiazole-5-yl, 1-phenyl-1H-1,2,3,4-tetrazole-5-yl, 4-fluoro-1-methyl-1H-1,3-benzodiazole-2-yl, 3-methylpyridin-2-yl, 5-methylpyrimidine-2-yl, 6-methylpyridazine-3-yl, 5-fluoropyridin-2-yl, 6-fluoropyrimidine-4-yl, 6-fluoropyridazine-3-yl, 6-fluoropyrazine-2-yl, 3-fluoropyrazine-2-yl, 2-fluoropyrimidine-4-yl, 3-cyanopyridin-2-yl, 6-cyanopyridin-2-yl, 4-cyanopyridin-3-yl, 6-fluoro-2-methylpyrimidine-4-yl, 6-fluoro-5-methylpyrimidine-4-yl, 6-cyclopropylpyrimidine Zin-2-yl, 4-(trifluoromethyl)pyrimidine-2-yl, 6-(trifluoromethyl)pyrimidine-4-yl, pyrazolo[1,5-a]pyrazine-4-yl, [1,2,4]triazolo[4,3-a]pyrazine-5-yl, [1,2,4]triazolo[4,3-a]pyrazine-8-yl, 3-chloropyridine-2-yl, 1,5-naphthyridine-4-yl, 1,6-naphthyridine-5-yl, 3-cyanopyridine-4-yl, -methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 3-methyl-[1,2,4]triazolo[4,3-a] Pyrazine-8-yl, 4-cyano-3-methyl-1,2-thiazole-5-yl, -fluoro-6-methylpyrimidine-4-yl, 2-fluoro-5-methylpyrimidine-4-yl, 5-fluoro-6-methylpyrimidine-4-yl, 3-(difluoromethoxy)pyridine-2-yl, 3-(difluoromethoxy)pyridine-2-yl, 6-(1H-pyrazole-1-yl)pyrazine-2-yl, 3-(trifluoromethyl)pyridine-2-yl, 6-(trifluoromethyl)pyridine-2-yl, 2-(trifluoromethyl)pyridine-4-yl, 3,6-dimethyl-[1,2]oxazolo[5,4-b]pyridine-4-yl, 2-methoxypyrimidine-4-yl, 4-methoxypyrimidine-2-yl, 6-methoxypyrimidine-4-yl, cyclobutoxypyrazine-2-yl, 5-fluoro-2,6-dimethylpyrimidine-4-yl, 4-chloropyridine-3-yl, pyrazine-2-yl, pyridazine-3-yl, 6-fluoropyridine-2-yl, 2-methylpyridine-4-yl, 2-chloropyridine Midine-4-yl, 4-chloropyrimidine-2-yl, 6-chloropyrazine-2-yl, 6-chloropyridine-2-yl, pyrimidine-4-yl, 2-fluoropyridine-4-yl, 4-fluoropyridine-2-yl, 1,3-thiazole-2-yl, 4-chloro-1,3-thiazole-2-yl, 4-methyl-1,3-thiazole-2-yl, 3-methyl-1,2,4-thiadiazole-5-yl, 4-cyano-1-methyl-1H-pyrazole-5-yl, 3-cyclopropyl-1,2,4-thiadiazole Lu-5-yl, 6-methylpyridine-2-yl, 4-methylpyridine-2-yl, 2-cyanopyridine-3-yl, 5-cyanopyridine-3-yl, 3-cyanopyrazine-2-yl, 1,3-benzothiazole-2-yl, 1,2-benzoxazole-3-yl, 3-(2-methoxyethyl)-1,2,4-thiadiazole-5-yl, 4-phenyl-4H-1,2,4-triazole-3-yl, 1-phenyl-1H-1,2,3,4-tetrazole-5-yl, 4-fluoro-1-methyl-1H-1,3-Benzodiazole-2-yl, 3-methylpyridine-2-yl, 5-methylpyrimidine-2-yl, 6-methylpyridazine-3-yl, 5-fluoropyrididine-2-yl, 6-fluoropyrimidine-4-yl, 6-fluoropyridazine-3-yl, 6-fluoropyrazine-2-yl, 3-fluoropyrazine-2-yl, 2-fluoropyrimidine-4-yl, 3-cyanopyridine-2-yl, 6-cyanopyridine-2-yl, 2-cyanopyridine-4-yl, 4-cyanopyridine-3-yl, 6-fluoro-2-methylpyrimidine-4-yl, 6-fluoro-5-methylpyrimidine-4-yl, 4-(trifluoromethyl) These are pyrimidine-2-yl, 6-(trifluoromethyl)pyrimidine-4-yl, pyrazolo[1,5-a]pyrazine-4-yl, pyrazolo[1,5-a]pyrimidine-5-yl, [1,2,4]triazolo[4,3-a]pyrazine-5-yl, [1,2,4]triazolo[4,3-a]pyrazine-8-yl, 3-chloropyridine-2-yl, 1,6-naphthyridine-5-yl, 3-cyanopyridine-4-yl, 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 6-fluoropyridine-2-yl, 2-fluoropyridine-4-yl, 4-fluoropyridine-2-yl, or 2-cyanopyridine-4-yl.

[0019] Most preferably, the compound of formula (I) according to the present invention is selected from the group consisting of the compounds listed in the following table.

[0020] [Table 1-1]

[0021] [Table 1-2]

[0022] [Table 1-3]

[0023] [Table 1-4]

[0024] [Table 1-5]

[0025] [Table 1-6]

[0026] [Table 1-7]

[0027] [Table 1-8]

[0028] Compounds of formula (I) are generally the same as compounds of formula (II),

[0029] [ka]

[0030] (In the formula, W and R 1 (The meaning is as defined above.) Compound of formula (III) and

[0031] [ka]

[0032] It can be prepared by reacting them. The reaction between the compound of formula (II) and the compound of formula (III) may be carried out in a reaction-inert solvent such as acetonitrile, dimethylacetamide, N-methylpyrrolidone, or DMF, and optionally in the presence of a suitable base such as sodium carbonate, potassium carbonate, or triethylamine. Stirring may increase the reaction rate. The reaction may be conveniently carried out at temperatures in the range between room temperature and the reflux temperature of the reaction mixture.

[0033] Compounds of formula (III) can be prepared by general procedures known in the art or reported in the literature. The compound of formula (II) can be prepared according to the following scheme.

[0034] [ka]

[0035] Primary amines (II) can be obtained by reduction of their respective nitrile derivatives (IV) in nitrogen-hydrogen bond formation reactions. Non-limiting examples of such reactions include reductions with the following: Hydrogen or a hydrogen source in the presence of metals such as nickel, platinum, palladium, and cobalt as catalysts, or derivatives thereof such as Raney Ni, platinum oxide, palladium oxide, or Raney cobalt; Hydrides such as lithium aluminum hydride, DIBAL, boron hydride, or their functional derivatives.

[0036] The reaction can be carried out in a suitable solvent such as methanol, tetrahydrofuran, acetic acid, diethyl ether, toluene, or methanolic ammonia solution, preferably at a temperature of -78°C to room temperature.

[0037] Compound of formula (IV) (wherein the formula, linker and R 1The compounds (as defined by formula (I)) can be prepared by Strecker condensation reaction of the respective heterocycle intermediate (V) with the aldehyde (VI) in the presence of a cyanide (VII) source, such as TMSCN or a functional derivative thereof, in a solvent such as AcOH or MeCN, preferably at a temperature of 0°C to room temperature. Stirring can increase the rate of the Strecker condensation reaction.

[0038] Some of the starting materials and intermediates are known compounds, commercially available, or can be prepared according to conventional reaction procedures commonly known in the art. Heterocycle intermediates (V) are generally known in the art.

[0039] The compound of formula (I) can be prepared for a reaction between the compound of formula (VIIIa) or formula (VIIIb) and a suitable commercially available halide R1-X.

[0040] [ka]

[0041] The reaction of the compound of formula (VIIIa or VIIIb) with the halide can be carried out in a reaction-inert solvent such as THF. The reaction was carried out in oven-dried vials using a stock solution of alkoxide VIII in an inert solvent such as THF under an argon atmosphere, and the appropriate halide was added to these vials all at once by syringe as a solution in anhydrous THF. Stirring may increase the reaction rate. The reaction can be carried out at room temperature if convenient.

[0042] The compound of formula VIII can be prepared according to the following scheme.

[0043] [ka]

[0044] The compound of formula (VIII) can be prepared by reacting the corresponding compound of formula (IX) with NaH, and the reaction was carried out under an argon atmosphere in an inert solvent such as THF, preferably at room temperature.

[0045] The compound of formula (IX) can be prepared from the corresponding compound of formula (X) by hydrolysis with concentrated HCl in MeOH, thereby removing the protecting group from the alcohol functional group.

[0046] Compound (X), compound (XI), and compound (XII) can be prepared according to the methods reported in the examples. The compound of formula (I) prepared by the above process can be synthesized in the form of a racemic mixture of enantiomers, which can be separated from each other by separation procedures known in the art. The compound of formula (I) obtained in racemic form can be converted to the corresponding diastereomer salt form by reaction with a suitable chiral acid. This diastereomer salt form can then be separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom with alkali. Another method for separating the enantiomer forms of the compound of formula (I) involves liquid chromatography using a chiral stationary phase. This pure stereochemical isomer form can also be derived from the corresponding pure stereochemical isomer form of a suitable starting material, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound is synthesized by a stereospecific preparation method. These methods advantageously utilize enantiomerically pure starting materials.

[0047] The compounds of formula (I), their pharmaceutically acceptable salts, and their stereoisomer forms possess P2X7 receptor antagonistic properties, as demonstrated in pharmacological examples. Other examples of group conversion reactions known in the art for converting compounds of formula (I) to other compounds of formula (I) include hydrolysis of carboxylic acid esters to corresponding carboxylic acids or alcohols; hydrolysis of amides to corresponding carboxylic acids or amines; alcohols can be converted to esters and ethers; primary amines can be converted to secondary or tertiary amines; and double bonds can be hydrogenated to corresponding single bonds. Some of the starting materials and intermediates are known compounds, commercially available, or can be prepared according to conventional reaction procedures commonly known in the art. The compounds of formula (I) prepared in the above methods can be synthesized in the form of a racemic mixture of enantiomers, which can be separated from each other according to separation procedures known in the art. The compounds of formula (I) obtained in racemic form can be converted to the corresponding diastereomer salt forms by reaction with a suitable chiral acid. These diastereomer salt forms can then be separated, for example, by selective or fractional crystallization, and the enantiomers can be liberated therefrom with alkali. Another method for separating the enantiomer forms of the compound of formula (I) involves liquid chromatography using a chiral stationary phase. This pure stereochemical isomer can also be derived from the corresponding pure stereochemical isomer of a suitable starting material, provided the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, the compound is synthesized by a stereospecific preparation method. These methods advantageously utilize enantiomerically pure starting materials. In the preparation of the compound of formula (I) and the starting materials and / or intermediates described herein, it may be useful to protect certain groups sensitive to reaction conditions. Evaluating the usefulness of optional protection, and selecting an appropriate protective agent depending on the reaction performed in the preparation of the compounds of the present invention and the functional group being protected, is common sense for those skilled in the art. Removal of optional protecting groups is carried out according to the prior art.For general literature on the use of protecting groups in organic chemistry, see Theodora W. Greene and Peter GM Wuts, “Protective groups in organic synthesis”, John Wiley & Sons, Inc., II Ed., 1991.

[0048] The preparation of salts of the compound of formula I is carried out according to known methods. Therefore, the compound of the present invention of formula (I) is useful as a pharmacopoeia in the treatment of conditions or diseases mediated by P2X7 receptors, particularly P2X7 receptor antagonist activity. Subsequently, the compound may be used for the manufacture of pharmacopoeias for the treatment of conditions or diseases mediated by P2X7 receptor activity, particularly P2X7 receptor antagonist activity.

[0049] The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof for the manufacture of a pharmaceutical for the treatment of a condition or disease selected from a condition or disease mediated by the P2X7 receptor. In one embodiment, the present invention provides a compound of formula (I) for use as a pharmaceutical or for use in the treatment of a condition or disease selected from a condition or disease mediated by the P2X7 receptor. Furthermore, the present invention also provides a method for treating a condition mediated by P2X7 receptor activity in a mammalian subject, comprising the step of administering a therapeutically effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof to a mammal in need of such treatment. In consideration of the above mechanism of action, the compounds of the present invention are useful in the treatment of neurodegenerative disorders of various origins, e.g., Alzheimer's disease and other dementias, e.g., Lewy body dementia, frontotemporal dementia and tauopathy; amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease and other Parkinsonian syndromes; HIV-induced neuroinflammation; essential tremor; other spinocerebellar degenerations and Charcot-Marie-Tooth neuropathy. The compounds of the present invention are also useful in treating neurological conditions such as epilepsy, including simple partial seizures, complex partial seizures, secondary generalized seizures, and further including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures.

[0050] The compounds of the present invention are also useful in the treatment of cognitive and psychiatric disorders. Psychiatric disorders include, but are not limited to, major depression, dysthymia, mania, bipolar disorder (including type I and type II bipolar disorder), cyclothymic disorder, rapid cycling, ultraradian cycling, mania, hypomania, schizophrenia, schizophrenia-like disorder, schizoaffective disorder, personality disorders, attention disorders with or without hyperactivity, delusional disorders, brief psychotic disorders, shared psychotic disorders, psychotic disorders due to systemic conditions, substance-induced psychotic disorders or other psychotic disorders not otherwise specified, anxiety disorders such as generalized anxiety disorder, panic disorder, post-traumatic stress disorder, impulse control disorders, phobic disorders, dissociative states, and even smoking, drug addiction and alcoholism. In particular, bipolar disorder, psychosis, anxiety, and addiction are included.

[0051] The compounds of the present invention are useful for the prevention or treatment of neuropathic pain. Neuropathic pain syndromes include, but are not limited to, diabetic neuropathy; sciatica; nonspecific low back pain; multiple sclerotic pain; fibromyalgia; HIV-related neuropathy; neuralgia, e.g., postherpetic neuralgia and trigeminal neuralgia, Morton's neuralgia, burning pain; and pain resulting from physical trauma, amputation, phantom limb, cancer, toxins or chronic inflammatory conditions; central pain, e.g., as observed in thalamic syndromes; mixed central and peripheral pain, e.g., complex regional pain syndrome (CRPS), also known as reflex sympathetic dystrophy.

[0052] The compounds of the present invention are also useful in the treatment of chronic pain. Chronic pain includes, but is not limited to, chronic pain caused by inflammation or inflammation-related conditions, osteoarthritis, rheumatoid arthritis, acute injury or trauma, upper back pain or lower back pain (resulting from primary spinal diseases such as systemic, localized or radicular disorders), bone pain (due to osteoarthritis, osteoporosis, bone metastases or unknown reasons), pelvic pain, spinal cord injury-related pain, cardiac chest pain, non-cardiac chest pain, central post-stroke pain, myofascial pain, sickle cell pain, cancer pain, Fabry disease, AIDS pain, geriatric pain or pain due to headache, temporomandibular joint syndrome, gout, pain caused by fibrosis or thoracic outlet syndrome, particularly rheumatoid arthritis and osteoarthritis.

[0053] The compounds of the present invention are also useful in treating acute pain caused by acute injuries, diseases, sports medicine injuries, carpal tunnel syndrome, burns, musculoskeletal sprains and muscle tension, muscle and tendon tension, cervicobrachial pain syndrome, indigestion, gastric ulcers, duodenal ulcers, dysmenorrhea, endometriosis, or surgery (such as cardiac incision or bypass surgery), postoperative pain, kidney stone pain, gallbladder pain, gallstone pain, labor pains, or toothaches.

[0054] The compounds of the present invention are also useful for treating headaches such as migraines, tension headaches, transformative migraines or evolutive headaches, cluster headaches, as well as secondary headache disorders such as those resulting from infections, metabolic disorders or other systemic diseases, and other acute headaches, paroxysmal headaches, etc., resulting from the exacerbation of the primary and secondary headaches mentioned above.

[0055] The compounds of the present invention are useful for diseases such as dizziness, tinnitus, and muscle spasms, as well as other disorders including but not limited to cardiovascular diseases (cardiac arrhythmias, myocardial infarction or angina pectoris, hypertension, myocardial ischemia, cerebral ischemia, etc.) and endocrine disorders (acromegaly or diabetes insipidus, etc.), and for diseases in which the pathophysiology of the disorder involves an excess or over-secretion of endogenous substances (catecholamines, hormones or growth factors, etc.) or other inappropriate cellular secretion.

[0056] The compounds of the present invention are also useful in the selective treatment of inflammatory liver diseases, such as chronic hepatitis B, chronic hepatitis C, alcoholic liver disease, primary biliary cirrhosis, autoimmune hepatitis, hepatic fibrosis, non-alcoholic steatohepatitis, and liver transplant rejection.

[0057] The compounds of the present invention inhibit inflammatory processes that affect all body tissues. Therefore, they are useful in treating inflammatory processes in the musculoskeletal system, including arthritis conditions such as ankylosing myelitis, cervical arthritis, fibromyalgia, gout, juvenile rheumatoid arthritis, sacroiliac arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, and rheumatic diseases; diseases affecting the skin and related tissues: inflammatory conditions such as eczema, psoriasis, dermatitis, and sunburn; respiratory system diseases: lung disorders involving inflammation such as asthma, allergic rhinitis, and respiratory distress syndrome, asthma, and bronchitis; chronic obstructive pulmonary disease; and immune and endocrine system disorders: periarthritis nodosa, thyroiditis, aplastic anemia, scleroderma, myasthenia gravis, multiple sclerosis, and other demyelinating diseases, encephalomyelitis, sarcomatoid arthritis, nephritis, Behçet's syndrome, polymyositis, and gingivitis, although this does not encompass all target diseases.

[0058] The compounds of the present invention are useful in treating gastrointestinal (GI) tract disorders such as inflammatory bowel disorders, including, but not limited to, irritable bowel syndrome, including any disorders associated with abdominal pain and / or abdominal discomfort, such as ulcerative colitis, Crohn's disease, ileitis, proctitis, celiac disease, intestinal diseases, microscopic or collagenous colitis, eosinophilic gastroenteritis, or sac inflammation resulting after colectomy and ileostomy, as well as irritable bowel syndrome, which includes any disorders associated with abdominal pain and / or abdominal discomfort, such as pylorus spasm, nervous dyspepsia, spastic colitis, spastic colitis, spastic bowel, enteroneurosis, functional colitis, mucinous colitis, laxative colitis and functional dyspepsia, but are not useful in treating atrophic gastritis, verrucous gastritis, ulcerative colitis, peptic ulcers, heartburn, and other damage to the GI tract, such as Helicobacter pylori. It is also useful in treating gastroesophageal reflux disease, diabetic gastroparesis and other gastroparesis caused by pylori, as well as other functional bowel disorders such as non-ulcerative dyspepsia (NUD); vomiting, diarrhea, and visceral inflammation.

[0059] The compounds of the present invention are also useful in treating urogenital disorders such as overactive bladder, prostatitis (chronic bacterial and chronic nonbacterial prostatitis), prostatic pain, interstitial cystitis, urinary incontinence and benign prostatic hyperplasia, adnexitis, pelvic inflammation, Bartholin's gland inflammation and vaginitis. They are particularly useful for overactive bladder and urinary incontinence.

[0060] The compounds of the present invention are also useful in treating eye diseases such as retinitis, retinopathy, uveitis, acute injury to eye tissue, age-related macular degeneration, glaucoma, and conjunctivitis. The compounds of the present invention are also useful in the treatment of eating disorders, such as anorexia nervosa including the restrictive and binge / purgative subtypes; bulimia nervosa including the purging and non-purging subtypes; obesity; obsessive-compulsive eating disorder; binge eating disorder; and eating disorders not otherwise specified.

[0061] The compounds of the present invention are also useful for allergic dermatitis, airway hyperreactivity, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, Sjögren's syndrome, glomerulonephritis, atherosclerosis, proliferation and metastasis of malignant cells, myeloblastic leukemia, diabetes, meningitis, osteoporosis, burns, ischemic heart disease, stroke, peripheral vascular disease, varicose veins, and glaucoma.

[0062] As used herein, the terms “to treat” and “treatment” refer to curative, temporary palliative and preventive treatments, including reversing, mitigating, inhibiting or preventing the progression of a disease, disorder or condition, or one or more symptoms of such disease, disorder or condition, to which such terms apply.

[0063] In addition, the present invention provides a pharmaceutical composition comprising at least one pharmaceutically acceptable carrier and a therapeutically effective amount of a compound of formula (I). To prepare the pharmaceutical compositions of the present invention, an effective amount of a specific compound in the form of a base or acid addition salt is combined as an active ingredient in a tight mixture with at least one pharmaceutically acceptable carrier, which can take a wide variety of forms depending on the desired form of preparation for administration. These pharmaceutical compositions are preferably unit dosage forms suitable for oral administration, rectal administration, transdermal administration, or parenteral injection.

[0064] For example, when preparing oral dosage forms, in the case of oral liquid formulations such as suspensions, syrups, elixirs, and solutions, any of the usual liquid pharmaceutical carriers such as water, glycol, oil, or alcohol may be used; or in the case of powders, pills, capsules, and tablets, solid pharmaceutical carriers such as starch, sugar, kaolin, lubricants, binders, and disintegrants may be used. For their easy administration, tablets and capsules represent the most advantageous oral dosing unit forms, in which case solid pharmaceutical carriers are obviously used. For parenteral injection compositions, the pharmaceutical carrier mainly consists of sterile water, but other components may be included to improve the solubility of the active ingredient.

[0065] Injectable solutions can be prepared, for example, by using a pharmaceutical carrier containing physiological saline, glucose solution, or a mixture of both. Injectable suspensions can be prepared by using a suitable liquid carrier, suspending agent, etc. In compositions suitable for transdermal administration, the pharmaceutical carrier may optionally contain a penetration enhancer and / or a suitable wetting agent, optionally combined with a small amount of suitable additives that do not cause significant adverse effects on the skin. These additives may be selected to facilitate the administration of the active ingredient to the skin and / or may be beneficial for preparing the desired composition. These topical compositions can be administered in various ways, for example, as transdermal patches, spot-ons, or ointments. The addition salts of the compounds of formula (I) are more water-soluble than their corresponding base forms and are therefore clearly more suitable for the preparation of aqueous compositions.

[0066] For ease of administration and uniformity of dosage, it is particularly advantageous to formulate the pharmaceutical composition of the present invention in dosage unit form. As used herein, “medication unit form” refers to a physically distinct unit suitable as a unit dose, each unit containing a predetermined amount of the active ingredient calculated to produce the desired therapeutic effect in relation to the required pharmaceutical carrier. Examples of such medication unit forms include tablets (including split or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoons, and separate portions thereof.

[0067] For oral administration, the pharmaceutical compositions of the present invention may take the form of solid dosage forms, such as tablets (both swallowable and chewable), capsules, or gel capsules, and may be prepared by conventional means using pharmaceutically acceptable excipients and carriers such as binders (e.g., pregelatinized corn starch, polyvinylpyrrolidone, hydroxypropyl methylcellulose, etc.), fillers (e.g., lactose, microcrystalline cellulose, calcium phosphate, etc.), lubricants (e.g., magnesium stearate, talc, silica, etc.), disintegrants (e.g., potato starch, sodium starch glycolate, etc.), and wetting agents (e.g., sodium lauryl sulfate). Such tablets may also be coated by methods well known in the art.

[0068] Liquid formulations for oral administration may take the form of solutions, syrups, or suspensions, or may be formulated as dry products for mixing with water and / or another suitable liquid carrier before use. Such liquid formulations may be prepared by conventional means with optional other pharmaceutically acceptable additives, such as suspending agents (e.g., sorbitol syrup, methylcellulose, hydroxypropyl methylcellulose, or hydrogenated edible fats), emulsifiers (e.g., lecithin or acacia gum), non-aqueous carriers (e.g., almond oil, oily esters, or ethyl alcohol), sweeteners, flavorings, masking agents, and preservatives (e.g., methyl p-hydroxybenzoate or propyl p-hydroxybenzoate, or sorbic acid).

[0069] A useful pharmaceutically acceptable sweetener in the pharmaceutical composition of the present invention preferably includes at least one strong sweetener, such as aspartame, acesulfame potassium, sodium cyclamate, Alitarm, dihydrochalcone sweetener, monelin, steviosidosucralose (4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose), or preferably saccharin, sodium saccharin, or calcium, and optionally at least one bulk sweetener, such as sorbitol, mannitol, fructose, sucrose, maltose, isomaltose, glucose, hydrogenated glucose syrup, xylitol, caramel, or honey. The strong sweetener is conveniently used at low concentrations. For example, in the case of sodium saccharin, its concentration may be in the range of about 0.04% to 0.1% (weight / volume) of the final formulation. Bulk sweeteners can be effectively used at higher concentrations ranging from about 10% to about 35%, preferably about 10% to 15% (weight / volume). pharmaceutically acceptable flavorings that can mask bitter components in low-dose formulations preferably include fruit flavorings, such as cherry, raspberry, blackcurrant, or strawberry flavorings. Combinations of two flavorings can yield very good results. In high-dose formulations, stronger pharmaceutically acceptable flavorings, such as caramel chocolate, mint cool, or fantasy, may be required.

[0070] Each flavoring may be present in the final composition at a concentration ranging from approximately 0.05% to 1% (weight / volume). Combinations of strong flavorings are advantageous. Preferably, flavorings are used that do not undergo any change or loss of taste and / or color under the formulation environment.

[0071] Compounds of formula (I) can be formulated for injection, preferably intravenous, intramuscular, or subcutaneous injection, for parenteral administration by rapid intravenous injection or continuous intravenous infusion. Injectable formulations can be provided in unit dosage forms, such as ampoules or multi-dose containers, containing added preservatives. They can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles and may contain formulation agents such as isotonic agents, suspending agents, stabilizers, and / or dispersants. Alternatively, the active ingredient may be present in powder form for mixing with a suitable vehicle, such as sterile water free of pyrogens, before use.

[0072] The compound of formula (I) can also be formulated into rectal compositions such as suppositories or retained enemas, which contain conventional suppository bases such as cocoa butter and / or other glycerides. Those skilled in the art in treating diseases associated with ligand-dependent ion channel mediation will readily determine the therapeutically effective dose of the compound of formula (I) from the test results shown below. Generally, the therapeutically effective dose is considered to be about 0.001 mg / kg to about 50 mg / kg, more preferably about 0.01 mg / kg to about 10 mg / kg, of the patient's body weight. It may be appropriate to administer the therapeutically effective dose in the form of two or more subdose doses at appropriate intervals throughout the day. Subdoses can be formulated, for example, as unit dosage forms, each containing about 0.1 mg to about 1000 mg, more specifically about 1 to about 500 mg, of the active ingredient per unit dosage form.

[0073] As used herein, the “therapeutic effective dose” of a compound is the amount of the compound that, when administered to an individual or animal, results in a level of the compound sufficiently high to elicit a recognizable P2X7 receptor antagonist response in that individual or animal.

[0074] As is well known to those skilled in the art, the exact dosage and frequency of administration depend on the particular compound of formula (I) being used, the particular condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the particular patient, and other drugs the patient may be taking. Further, the "therapeutically effective amount" can be decreased or increased depending on the response of the patient being treated and / or the evaluation of the physician prescribing the compounds of the present invention. Accordingly, the ranges of effective daily amounts recited above herein are merely guidelines. Nomenclature and Structure Generally, the nomenclature used in this application is based on ChemSketch™ (ACD Labs) and is created in accordance with IUPAC systematic nomenclature. The chemical structures shown herein were created using ChemDraw® version 19.1. Any open valence appearing on a carbon, oxygen, sulfur, or nitrogen atom in the structures herein indicates the presence of a hydrogen atom, unless otherwise indicated. A nitrogen-containing heteroaryl ring is shown with an open valence on a nitrogen atom, and variables such as R 1 、R 2 、R 3 etc. are shown on the heteroaryl ring, such variables may be bonded or linked to the open valence nitrogen. When a chiral center is present in the structure but no specific stereochemistry is indicated for the chiral center, both enantiomers associated with the chiral center are included in the structure. When structures shown herein can exist in multiple tautomeric forms, all such tautomers are included by the structure. The atoms represented in the structures herein are intended to include all naturally occurring isotopes of such atoms. Thus, for example, a hydrogen atom represented herein means including deuterium and tritium, and a carbon atom means including 13 C isotope and 14 C isotope.

Mode for Carrying Out the Invention

[0075] Abbreviations The following abbreviations may be used in the following description of schemes and examples: AcOH: Acetic acid; Anh: Anhydrous; AcONa: Sodium acetate; DCM: Dichloromethane; DHP: Dihydropyran DIBAL: Diisobutylaluminum hydride; DMF: Dimethylformamide; DMSO: Dimethyl sulfoxide; æ: ethyl acetate; ESI: Electrospray ionization; HCl: hydrochloric acid; h: time; Hrs: time; KHCO3: Potassium bicarbonate; M: Mole; MeCN: Acetonitrile; MeOH: methanol; MgSO4: Magnesium sulfate; Min: minutes; NaH: Sodium hydride; NaHCO3: Sodium bicarbonate; Na2SO3: Sodium sulfite; Ni-Lanay: Nickel-Lanay; NMR: nuclear magnetic resonance; ON: overnight; PPTS: Pyridinium p-toluenesulfonate; RT: room temperature; TFA trifluoroacetic acid; THF: Tetrahydrofuran; TLC: Thin-layer chromatography.

[0076] TMSCN: Trimethylsilylcyanide; UPLC-MS: Ultra-high performance liquid chromatography-mass spectrometry; Y: Yield. The present invention includes, but is not limited to, the following embodiments. [Aspect 1] Compounds of the following formula (I), or pharmaceutically acceptable salts thereof: [ka] Including any of those stereochemical isomer forms, In the formula, W is oxygen, O-C1~C4 alkyl;C1~C4 alkyl-O-, R 1 This is a monocyclic or bicyclic 5-10 membered heterocycle that is optionally substituted with one or more groups selected from C1-C4 alkyl (optionally substituted with halogens), C1-C4 alkoxy, halogen, cyano, or C3-C6 cycloalkyl, or a benzo-condensed heterocycle. [Aspect 2] R 1 Pyridines monosubstituted or disubstituted with one or more groups selected from cyano, methyl, halogen, trifluoromethyl, and / or C3-C7 cycloalkyl groups; pyrimidines monosubstituted or disubstituted with cyano, methyl, trifluoromethyl, C3-C7 alkoxy, C3-C7 cycloalkoxy, and / or halogen groups; oxazoles monosubstituted or disubstituted with C3-C7 cycloalkyl, methyl, and / or halogen groups; thiazoles monosubstituted or disubstituted with C3-C7 cycloalkyl, cyano, methyl, and / or halogen groups; benzothiazoles; benzoxazoles; methyl, halogen, phenyl, and / or C1-C4 A compound according to Embodiment 1, or a pharmaceutically acceptable salt thereof comprising any stereochemical isomer thereof, is a thiadiazole monosubstituted or disubstituted with lucoxy; a tetrazole substituted or unsubstituted with phenyl; a halogenated, phenylated or unsubstituted benzodiazole; a pyridazine substituted with methyl and / or halogen; a pyrazolo[1,5-a]pyrazine; a [1,2,4]triazolo[4,3-a]pyrazine; a naphthyridine; a pyrazolo[3,4-d]pyrimidine; a pyrazine monosubstituted or disubstituted with C3-C7 cycloalkyl, methyl, heterocyclic and / or halogen; a [1,2]oxazolo[5,4-b]pyridine; or a phthalazine. [Aspect 3] W is oxygen, -CH2O- or -OCH2-, and R 1 These include pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, 5-fluoropyridine-3-yl, 3-fluoropyridine-4-yl, 3-fluoropyridine-2-yl, 1,5-methyl-1,2-oxazole-3-yl, dimethyl-1,2-oxazole-4-yl, 1,3-thiazole-2-yl, 3-methyl-1,2,4-thiadiazole-5-yl, 4-chloro-1,3- Thiazol-2-yl, 3-cyclopropyl-1,2,4-thiadiazole-5-yl, 6-methylpyridine-2-yl, 4-methylpyridine-2-yl, 5-cyanopyridine-3-yl, 3-cyanopyrazine-2-yl, 2-cyanopyrazine-3-yl, 2-chloropyridine-3-yl, 1,3-benzothiazole-2-yl, 1,2-benzoxazole-3-yl, 1,3-benzoxazole-2-yl, 3 -(2-methoxyethyl)-1,2,4-thiadiazole-5-yl, 3-phenyl-1,2,4-oxadiazole-5-yl, 1-phenyl-1H-1,2,3,4-tetrazol-5-yl, 4-fluoro-1-methyl-1H-1,3-benzodiazole-2-yl, 3-methylpyridine-2-yl, 5-methylpyrimidine-2-yl, 6-methylpyridazine-3-yl, 5-fluoropyrididine-2-yl, 6-fluoropyrimidine-4-yl, 6-fluoropyridazine-3-yl, 6-fluoropyrazine-2-yl, 3-fluoropyrazine -2-yl, 2-fluoropyrimidine-4-yl, 3-cyanopyridine-2-yl, 6-cyanopyridine-2-yl, 4-cyanopyridine-3-yl, 6-fluoro-2-methylpyrimidine-4-yl, 6-fluoro-5-methylpyrimidine-4-yl, 6-cyclopropylpyridine-2-yl, 4-(trifluoromethyl)pyrimidine-2-yl, 6-(trifluoromethyl)pyrimidine-4-yl, pyrazolo[1,5-a]pyrazine-4-yl, [1,2,4]triazolo[4,3-a]pyrazine-5-yl, [1,2,4]triazolo[4, 3-a]pyrazine-8-yl, 3-chloropyridine-2-yl, 1,5-naphthyridine-4-yl, 1,6-naphthyridine-5-yl, 3-cyanopyridine-4-yl, -methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 3-methyl-[1,2,4]triazolo[4,3-a]pyrazine-8-yl, 4-cyano-3-methyl-1,2-thiazole-5-yl, -fluoro-6-methylpyrimidine-4-yl, 2-fluoro-5-methylpyrimidine-4-yl, 5-fluoro-6-methylpyrimidine-4-yl, 3-(difluorometh Xy)pyridine-2-yl, 3-(difluoromethoxy)pyridine-2-yl, 6-(1H-pyrazole-1-yl)pyrazine-2-yl, 3-(trifluoromethyl)pyridine-2-yl, 6-(trifluoromethyl)pyridine-2-yl, 2-(trifluoromethyl)pyridine-4-yl, 3,6-dimethyl-[1,2]oxazolo[5,4-b]pyridine-4-yl, 2-methoxypyrimidine-4-yl, 4-methoxypyrimidine-2-yl, 6-methoxypyrimidine-4-yl, -cyclobutoxypyrazine-2-yl, 5-fluoro-2,6-dimethylpyrimidine-4-yl, 4-chloropyridine-3-yl, pyrazine-2-yl, pyridazine-3-yl, 6-fluoropyridine-2-yl, 2-methylpyridine-4-yl, 2-chloropyrimidine-4-yl, 4-chloropyrimidine-2-yl, 6-chloropyrazine-2-yl, 6-chloropyridine-2-yl, pyrimidine-4-yl, 2-fluoropyridine-4-yl, 4-fluoropyridine-2-yl, 1,3-thiazole-2-yl, 4-chloro-1,3-thiazole-2-yl, 4-methyl-1,3-thiazole-2-yl 3-methyl-1,2,4-thiadiazole-5-yl, 4-cyano-1-methyl-1H-pyrazole-5-yl, 3-cyclopropyl-1,2,4-thiadiazole-5-yl, 6-methylpyridine-2-yl, 4-methylpyridine-2-yl, 2-cyanopyridine-3-yl, 5-cyanopyridine-3-yl, 3-cyanopyrazine-2-yl, 1,3-benzothiazole-2-yl, 1,2-benzoxazole-3-yl, 3-(2-methoxyethyl)-1,2,4-thiadiazole-5-yl, 4-phenyl-4H-1,2,4-thiadiazole Zol-3-yl, 1-phenyl-1H-1,2,3,4-tetrazol-5-yl, 4-fluoro-1-methyl-1H-1,3-benzodiazole-2-yl, 3-methylpyridine-2-yl, 5-methylpyrimidine-2-yl, 6-methylpyridazine-3-yl, 5-fluoropyrididine-2-yl, 6-fluoropyrimidine-4-yl, 6-fluoropyridazine-3-yl, 6-fluoropyrazine-2-yl, 3-fluoropyrazine-2-yl, 2-fluoropyrimidine-4-yl, 3-cyanopyridine-2-yl, 6-cyanopyridine-2 -yl, 2-cyanopyridine-4-yl, 4-cyanopyridine-3-yl, 6-fluoro-2-methylpyrimidine-4-yl, 6-fluoro-5-methylpyrimidine-4-yl, 4-(trifluoromethyl)pyrimidine-2-yl, 6-(trifluoromethyl)pyrimidine-4-yl, pyrazolo[1,5-a]pyrazine-4-yl, pyrazolo[1,5-a]pyrimidine-5-yl, [1,2,4]triazolo[4,3-a]pyrazine-5-yl, [1,2,4]triazolo[4,3-a]pyrazine-8-yl, 3-chloropyridine-2-yl, 1,6-Naphthyridine-5-yl, 3-Cyanopyridine-4-yl, 1-Methyl- The compound described in Embodiment 1, which is 1H-pyrazolo[3,4-d]pyrimidine-4-yl, 6-fluoropyridine-2-yl, 2-fluoropyridine-4-yl, or 4-fluoropyridine-2-yl, 2-cyanopyridine-4-yl, or a pharmaceutically acceptable salt thereof comprising any stereochemical isomer thereof. [Aspect 4] A compound according to Embodiment 1, selected from the group consisting of the compounds listed in the table below, or a pharmaceutically acceptable salt thereof, comprising any stereochemical isomer thereof. [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] [Aspect 5] A process for preparing the compound of formula (I) described in Embodiment 1, The compound of formula (II) and [ka] (In the formula, W and R 1 (The meaning is as defined in Embodiment 1.) Compound of formula (III) and [ka] The step includes reacting the following: A process comprising the steps of optionally converting the obtained compound of formula (I) to its salt, and / or preparing its stereochemical isomer form. [Aspect 6] A process for preparing a compound of formula (I) as described in Embodiment 1, comprising the step of reacting a compound of formula (VIIIa) or (VIIIb) with a halide of formula R1-X. [ka] (In the formula, R 1 A process comprising the steps of optionally converting the obtained compound of formula (I) to a salt thereof (as defined in Embodiment 1), and / or preparing its stereochemical isomer form. [Aspect 7] A compound of formula (I) as described in any one of embodiments 1 to 4, or a pharmaceutically acceptable salt thereof including any stereochemical isomer thereof, and a pharmaceutically acceptable diluent. A pharmaceutical preparation including and / or a carrier. [Aspect 8] A pharmaceutically acceptable salt thereof comprising a compound of formula (I) as described in any one of embodiments 1 to 4, or any stereochemical isomer thereof, for use as a pharmaceutical. [Aspect 9] Compounds of formula (I) as described in any one of embodiments 1 to 4, or pharmaceutically acceptable salts thereof, comprising any stereochemical isomer thereof, for use in the prevention and / or treatment of conditions or diseases selected from P2X7 receptor-mediated conditions or diseases. [Aspect 10] Compounds of formula (I) as described in embodiment 9, or pharmaceutically acceptable salts thereof comprising any stereochemical isomer thereof, for use in the prevention and / or treatment of neuropathy, neurodegenerative disorders, neuroinflammatory disorders, cognitive impairment, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headache, musculoskeletal inflammatory processes, gastrointestinal disorders, urogenital disorders, eye diseases, cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, and allergic diseases. [Examples]

[0077] Experimental section The following examples illustrate the present invention. Unless otherwise specified, all details (especially percentages and quantities) relate to weight. A. Synthesis of intermediates Preparation of nitrile derivatives (IV) (typical procedure) A suitable commercial amine (1.0 equivalent) and anhydrous NaOAc (3.8 equivalents) were stirred in glacial acetic acid (1.3 mL, 0.9 M) at room temperature for 2 hours. Separately, a solution of 4-(difluoromethyl)thiazole-5-carbaldehyde CAS:1803203-56-6 (1 equivalent) in glacial acetic acid (1.5 mL, 0.4 M) was cooled to 13°C, followed by dropwise addition of TMSCN (12 equivalents), and maintained for another 30 minutes before being mixed with the above AcOH solution of the corresponding amine. The resulting reaction mixture was stirred overnight at room temperature. Volatile substances were removed under vacuum. The oily residue was dissolved in DCM (20 mL) and washed with saturated NaHCO3 solution (3 × 5 mL), 10% Na2SO3 solution (5 mL), water, and brine. The organic phase was dried over MgSO4 and evaporated under vacuum to obtain a crude nitrile derivative, which was used in the next step without further purification. (y = 36-71%) Use this procedure: Intermediate 1a (y=55%) was prepared using 4-[(3,5-dimethyl-1,2-oxazol-4-yl)methoxy]piperidine hydrochloride (CAS: 1097797-73-3); Intermediate 1b (y=67%) was prepared using 42-(piperidine-4-yloxy)pyridine hydrochloride (CAS 313490-36-7); Intermediate 1c (y=64%) was prepared using 3-(piperidine-4-yloxy)pyridine (CAS: 310881-48-2); Intermediate 1d (y=55%) was prepared using 4-(piperidine-4-yloxy)pyridine (CAS:224178-65-8); Intermediate 1e (y=56%) was prepared using 2-(piperidine-4-yloxy)pyrimidine (CAS: 499240-48-1); Intermediate 1f (y=71%) was prepared using 3-fluoro-5-(piperidine-4-yloxy)pyridine (CAS: 1189578-46-8); One g of the intermediate (y=48%) was prepared using 3-fluoro-4-(piperidine-4-yloxy)pyridine hydrochloride (CAS:2013099-11-9). Intermediate 1h (y=58%) was prepared using 3-fluoro-2-(piperidine-4-yloxy)pyridine (CAS: 1189578-05-9); Intermediate 1i (y=49%) was prepared using 4-[(5-methyl-1,2-oxazol-3-yl)methoxy]piperidine hydrochloride (CAS: 883537-12-0).

[0078] Intermediate 1j (y=66%) was prepared using 4-hydroxypiperidine (CAS: 5382-16-1). Intermediate 1k (y=60%) was prepared using 4-hydroxymethylpiperidine (CAS: 6457-49-4).

[0079] [Table 2-1]

[0080] [Table 2-2]

[0081] Preparation of oxan-2-yloxynitrile derivative (XII) (typical procedure) A 1.0 equivalent of a 4-hydroxy / acetonitrile derivative was dissolved in 180 mL of anhydrous DCM (0.1 M). 5.0 equivalents of DHP were added, followed by 0.02 equivalents of PPTS. The reaction mixture was stirred overnight at room temperature and then quenched with 50 mL of saturated NaHCO3 aqueous solution. The phases were separated, the organic phase was washed with brine, dehydrated with MgSO4, and concentrated under vacuum to obtain the crude product, which was used without further purification.

[0082] Use this procedure: Intermediate 2a (y=61%) was prepared starting from intermediate 1j. Intermediate 2b (y=67%) was prepared starting from intermediate 1k.

[0083] [Table 3]

[0084] Preparation of amine derivative (II) (typical procedure) A suitable nitrile intermediate 1 (1.0 equivalent) was dissolved in anhydrous DCM (2-3 mL) under an inert atmosphere. The solution was cooled to -65°C, and a 1 M solution of DIBAL in DCM (3.5 equivalents) was added dropwise. The reaction mixture was stirred at -65°C for 1 hour, then the reaction mixture was raised to -40°C and quenched with 10% Rochelle salt. The two-phase mixture was stirred at room temperature for 30 minutes. The phases were separated, and the aqueous phase was extracted with DCM (3 × 10 mL). The combined organic phases were dried over MgSO4 and concentrated under vacuum. The crude product was purified by column chromatography to obtain the title compound (y = 31-63%).

[0085] Use this procedure: Intermediate 3a (y=51%) was prepared starting from intermediate 1a. Intermediate 3b (y=38%) was prepared starting from intermediate 1b. Intermediate 3c (y=49%) was prepared starting from intermediate 1c. Intermediate 3d (y=46%) was prepared starting from intermediate 1d. Intermediate 3e (y=41%) was prepared starting from intermediate 1e. Intermediate 3f (y=54%) was prepared starting from intermediate 1f. 3 g of the intermediate (y=31%) was prepared starting from 1 g of the intermediate. Intermediate 3h (y=63%) was prepared starting from intermediate 1h. Intermediate 3i (y=39%) was prepared starting from intermediate 1i. Intermediate 3j (y=62%) was prepared starting from intermediate 2a. Intermediate 3k (y=59%) was prepared starting from intermediate 2b.

[0086] [Table 4-1]

[0087] [Table 4-2]

[0088] Preparation of oxan-2-yloxybenzamide derivative (X) (typical procedure) A suitable amine (1.0 equivalent) was dissolved in anhydrous MeCN (5 mL) under an inert atmosphere. The solution was cooled to -15°C, and KHCO3 (2 equivalents), followed by pure 2-chloro-6-fluorobenzoyl chloride (CAS: 79455-63-3; 1.15 equivalents), was added. The reaction mixture was heated overnight to room temperature. Volatile substances were then removed under vacuum, the solid residue was dissolved in DCM, and insoluble substances were filtered off. The filtrate was concentrated under vacuum to obtain the crude product, which was used further without further purification.

[0089] Use this procedure: Intermediate 4a was prepared starting from intermediate 3j; Intermediate 4b was prepared starting from intermediate 3k.

[0090] [Table 5]

[0091] Preparation of hydroxybenzamide derivatives (IX) (typical procedure) Crude intermediate 4, an oxan-2-yloxybenzamide derivative (1.0 equivalent), was dissolved in MeOH (22 mL, 0.6 M) and cooled to 10°C. Concentrated aqueous HCl (7 mL) was added, and the reaction mixture was stirred at room temperature for 30 minutes. Volatile substances were removed under vacuum to obtain a wet residue, which was dissolved in saturated aqueous NaHCO3 and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over MgSO4, and concentrated. The crude product was purified by column chromatography (hexane / ethyl acetate 1 / 1, followed by pure ethyl acetate) to obtain the title compound. (y = 88-96%) Use this procedure: Intermediate 5a (y=96%) was prepared starting from intermediate 4a. Intermediate 5b (y=88%) was prepared starting from intermediate 4b.

[0092] [Table 6]

[0093] Preparation of disodium alkoxide derivative (VIII) (typical procedure) A suitable intermediate 5, a hydroxybenzamide derivative (1.0 equivalent), was dissolved in anhydrous THF (0.046 M) under an argon atmosphere. NaH (60% dispersion in mineral oil, 2.1 equivalents) was added in several portions at room temperature, and the reaction mixture was stirred for a further 2 to 12 hours (preferably overnight) to obtain a pale yellow solution of the disodium salt, which was then used. The prepared solutions of known concentrations were stored in sealed vials at room temperature and remained viable for at least one month. 1 No evidence of degradation was shown by 1H-NMR and UPLC. When stored in the refrigerator, a partial precipitate of the disodium salt formed, which dissolved back during sonication at room temperature.

[0094] Use this procedure: Intermediate 6a was prepared starting from intermediate 5a; Intermediate 6b was prepared starting from intermediate 5b.

[0095] [Table 7]

[0096] General procedure for the synthesis of the final compound Method A Preparation of Examples 1-9 Solid KHCO3 (2.0 equivalents) was added all at once at -10°C to a stirred solution of a suitable amine and intermediate 3 (1.0 equivalent) in anhydrous MeCN (6 mL, 0.05 M). A suitable 2-chloro-6-fluorobenzoyl chloride CAS:79455-63-3 (1.15 equivalents) was added to the reaction mixture. After stirring for a further 30 minutes at -10°C, the volatile substances were evaporated. The residue was ground through DCM (10 mL), filtered, and concentrated to obtain the crude residue, which was purified by column chromatography (SiO2; hexane / siRNA 2:1) to obtain the title compound (y = 32-98%).

[0097] Using this procedure, compound: Example 1 (y=67%) was prepared starting from intermediate 3b; Example 2 (y=50%) was prepared starting from intermediate 3c; Example 3 (y=54%) was prepared starting from intermediate 3d; Example 4 (y=85%) was prepared starting from intermediate 3e; Example 5 (y=72%) was prepared starting from intermediate 3f; Example 6 (y=98%) was prepared starting from 3 g of the intermediate; Example 7 (y=32%) was prepared starting from intermediate 3h; Example 8 (y=43%) was prepared starting from intermediate 3i; Example 9 (y=68%) was prepared starting from intermediate 3a. Method B Preparation of Examples 10-127 A stock solution (1.0 equivalent) of the appropriate alkoxide intermediate 6, prepared as described above, was placed in an oven-dried vial (7 mL, screw cap with septum) under an argon atmosphere. A suitable commercial halide (1.0 equivalent) was added all at once by syringe as a solution in anhydrous THF (1 mL). The reaction mixture was maintained at room temperature. 1 The reaction was monitored by 1H-NMR and UPLC. Once an acceptable conversion level (preferably greater than 50%) was achieved, the reaction mixture was quenched with a stock solution of diglycolic anhydride (approximately 0.25 M, 1 mL, 1.1 equivalents), shaken, and maintained at room temperature for a further 2–12 hours (preferably overnight). After evaporating volatile substances under vacuum, the residue was partitioned between RINKAN (5 mL) and water (2 mL). The organic phase was washed with water (2 mL), dried over MgSO4, concentrated under vacuum to obtain the crude residue, which was purified by column chromatography (SiO2; Hex / EA 1:2) to obtain the title compound (y = 7–71%). Using this procedure, compound: Example 10 (y=60%) was prepared starting from intermediate 6a and 2-fluoro-1,3-thiazole (CAS 27225-14-5); Example 11 (y=54%) was prepared starting from intermediate 6a and 5-chloro-3-methyl-1,2,4-thiadiazole (CAS 21734-85-0); Example 12 (y=35%) was prepared starting from intermediate 6a and 2,4-dichlorothiazole (CAS 4175-76-2); Example 13 (y=46%) was prepared starting from intermediate 6a and 5-chloro-3-cyclopropyl-1,2,4-thiadiazole (CAS 122684-54-2); Example 14 (y=12%) was prepared starting from intermediate 6a and 2-fluoro-6-methylpyridine (CAS 407-22-7); Example 15 (y=18%) was prepared starting from intermediate 6a and 2-fluoro-4-methylpyridine (CAS 461-87-0); Example 16 (y=19%) was prepared starting from intermediate 6a and 5-fluoropyridine-3-carbonitrile (CAS 696-42-4); Example 17 (y=26%) was prepared starting from intermediate 6a and 3-chloropyrazine-2-carbonitrile (CAS 55557-52-3); Example 18 (y=60%) was prepared starting from intermediate 6a and 2-cyano-3-fluoropyridine (CAS 97509-75-6); Example 19 (y=11%) was prepared starting from intermediate 6a and 2-chloro-3-fluoropyridine (CAS 17282-04-1); Example 20 (y=43%) was prepared starting from intermediate 6a and 2-fluoro-1,3-benzothiazole (CAS 1123-98-4); Example 21 (y=12%) was prepared starting from intermediate 6a and 3-chloro-1,2-benzoxazole (CAS 16263-52-8); Example 22 (y=16%) was prepared starting from intermediate 6a and 2-chloro-1,3-benzoxazole (CAS 615-18-9); Example 23 (y=42%) was prepared starting from intermediate 6a and 5-chloro-3-(2-methoxyethyl)-1,2,4-thiadiazole (CAS 89180-91-6); Example 24 (y=11%) was prepared starting from intermediate 6a and 5-chloro-3-phenyl-1,2,4-oxadiazole (CAS 827-44-1); Example 25 (y=54%) was prepared starting from intermediate 6a and 5-chloro-1-phenyl-1H-tetrazole (CAS 14210-25-4); Example 26 (y=58%) was prepared starting from intermediate 6a and 2-chloro-4-fluoro-1-methyl-1H-1,3-benzodiazole (CAS 1283719-98-1); Example 27 (y=28%) was prepared starting from intermediate 6a and 2-fluoro-3-methylpyridine (CAS 2369-18-8); Example 28 (y=35%) was prepared starting from intermediate 6a and 2-fluoro-5-methylpyrimidine (CAS 62802-36-2); Example 29 (y=47%) was prepared starting from intermediate 6a and 3-fluoro-6-methylpyridazine (CAS 65202-56-4); Example 30 (y=36%) was prepared starting from intermediate 6a and 2,5-difluoropyridine (CAS 84476-99-3); Example 31 (y=28%) was prepared starting from intermediate 6a and 4,6-difluoropyrimidine (CAS 2802-62-2); Example 32 (y=54%) was prepared starting from intermediate 6a and 3,6-difluoropyridazine (CAS 33097-39-1); Example 33 (y=42%) was prepared starting from intermediate 6a and 2,6-difluoropyrazine (CAS 33873-09-5); Example 34 (y=57%) was prepared starting from intermediate 6a and 2,3-difluoropyrazine (CAS 52751-15-2); Example 35 (y=22%) was prepared starting from intermediate 6a and 2,4-difluoropyrimidine (CAS 2802-61-1); Example 36 (y=67%) was prepared starting from intermediate 6a and 2-fluoropyridine-3-carbonitrile (CAS 3939-13-7); Example 37 (y=65%) was prepared starting from intermediate 6a and 2-cyano-6-fluoropyridine (CAS 3939-15-9); Example 38 (y=59%) was prepared starting from intermediate 6a and 3-fluoropyridine-4-carbonitrile (CAS 113770-88-0); Example 39 (y=51%) was prepared starting from intermediate 6a and 4,6-difluoro-2-methylpyrimidine (CAS 18382-80-4); Example 40 (y=71%) was prepared starting from intermediate 6a and 4,6-difluoro-5-methylpyrimidine (CAS 18260-64-5); Example 41 (y=19%) was prepared starting from intermediate 6a and 2-fluoro-6-(cyclopropyl)pyridine (CAS 1563529-53-2); Example 42 (y=29%) was prepared starting from intermediate 6a and 2-chloro-4-(trifluoromethyl)pyrimidine (CAS 33034-67-2); Example 43 (y=59%) was prepared starting from intermediate 6a and 4-chloro-6-(trifluoromethyl)pyrimidine (CAS 37552-81-1); Example 44 (y=47%) was prepared starting from intermediate 6a and 4-chloropyrazolo[1,5-a]pyrazine (CAS 1260665-84-6); Example 45 (y=16%) was prepared starting from intermediate 6a and 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (CAS 63744-34-3); Example 46 (y=24%) was prepared starting from intermediate 6a and 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (CAS 68774-77-6); Example 47 (y=33%) was prepared starting from intermediate 6a and 3-chloro-2-fluoropyridine (CAS 1480-64-4); Example 48 (y=15%) was prepared starting from intermediate 6a and 4-chloro-1,5-naphthyridine (CAS 7689-63-6); Example 49 (y=58%) was prepared starting from intermediate 6a and 5-chloro-1,6-naphthyridine (CAS 23616-32-2); Example 50 (y=29%) was prepared starting from intermediate 6a and 4-chloropyridine-3-carbonitrile (CAS 89284-61-7); Example 51 (y=42%) was prepared starting from intermediate 6a and 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (CAS 23000-43-3); Example 52 (y=11%) was prepared starting from intermediate 6a and 8-chloro-3-methyl-[1,2,4]triazolo[4,3-a]pyrazine (CAS 68774-78-7); Example 53 (y=54%) was prepared starting from intermediate 6a and 5-chloro-3-methyl-1,2-thiazole-4-carbonitrile (CAS 25069-00-5); Example 54 (y=14%) was prepared starting from intermediate 6a and 2,4-difluoro-6-methylpyrimidine (CAS 696-80-0); Example 55 (y=37%) was prepared starting from intermediate 6a and 2,4-difluoro-5-methylpyrimidine (CAS 96548-89-9); Example 56 (y=59%) was prepared starting from intermediate 6a and 4-chloro-5-fluoro-6-methylpyrimidine (CAS 898044-55-8); Example 57 (y=8%) was prepared starting from intermediate 6a and 2-chloro-3-(difluoromethoxy)pyridine (CAS 1206977-80-1); Example 58 (y=30%) was prepared starting from intermediate 6a and 2-chloro-6-(1H-pyrazole-1-yl)pyrazine (CAS 642459-09-4); Example 59 (y=33%) was prepared starting from intermediate 6a and 2-chloro-3-(trifluoromethyl)pyridine (CAS 65753-47-1); Example 60 (y=25%) was prepared starting from intermediate 6a and 2-chloro-6-(trifluoromethyl)pyridine (CAS 39890-95-4); Example 61 (y=11%) was prepared starting from intermediate 6a and 4-chloro-2-(trifluoromethyl)pyridine (CAS 131748-14-6); Example 62 (y=32%) was prepared starting from intermediate 6a and 4-chloro-3,6-dimethyl-[1,2]oxazolo[5,4-b]pyridine (CAS 2126161-62-2); Example 63 (y=29%) was prepared starting from intermediate 6a and 4-chloro-2-methoxypyrimidine (CAS 51421-99-9); Example 64 (y=32%) was prepared starting from intermediate 6a and 2-chloro-4-methoxypyrimidine (CAS 22536-63-6); Example 65 (y=13%) was prepared starting from intermediate 6a and 4-chloro-6-methoxypyrimidine (CAS 26452-81-3); Example 66 (y=25%) was prepared starting from intermediate 6a and 2-chloro-3-cyclobutoxypyrazine (CAS 1250943-13-5); Example 67 (y=38%) was prepared starting from intermediate 6a and 4-chloro-5-fluoro-2,6-dimethylpyrimidine (CAS 1240622-52-9); Example 68 (y=28%) was prepared starting from intermediate 6a and 1-chlorophthalazine (CAS 5784-45-2); Example 69 (y=10%) was prepared starting from intermediate 6a and 4-chloro-3-fluoropyridine (CAS 2546-56-7); Example 70 (y=62%) was prepared starting from intermediate 6a and 2-fluoropyrazine (CAS 4949-13-7); Example 71 (y=42%) was prepared starting from intermediate 6a and 3-chloropyridazine (CAS 1120-95-2); Example 72 (y=65%) was prepared starting from intermediate 6a and 2,6-difluoropyridine (CAS 1513-65-1); Example 73 (y=15%) was prepared starting from intermediate 6a and 4-chloro-2-methylpyridine (CAS 3678-63-5); Example 74 (y=19%) was prepared starting from intermediate 6a and 2,4-dichloropyrimidine (CAS 3934-20-1); Example 75 (y=24%) was prepared starting from intermediate 6a and 2,4-dichloropyrimidine (CAS 3934-20-1); Example 76 (y=28%) was prepared starting from intermediate 6a and 2,6-dichloropyrazine (CAS 4774-14-5); Example 77 (y=33%) was prepared starting from intermediate 6a and 2,6-dichloropyridine (CAS 2402-78-0); Example 78 (y=25%) was prepared starting from intermediate 6a and 4-chloropyrimidine (CAS 17180-93-7); Example 79 (y=29%) was prepared starting from intermediate 6a and 2-chloro-4-cyanopyridine (CAS 33252-30-1); Example 80 (y=52%) was prepared starting from intermediate 6a and 2,4-difluoropyridine (CAS 34941-90-7); Example 81 (y=29%) was prepared starting from intermediate 6a and 2,4-difluoropyridine (CAS 34941-90-7); Example 82 (y=44%) was prepared starting from intermediate 6b and 2-fluoro-1,3-thiazole (CAS 27225-14-5); Example 83 (y=41%) was prepared starting from intermediate 6b and 2,4-dichlorothiazole (CAS 4175-76-2); Example 84 (y=7%) was prepared starting from intermediate 6b and 2-chloro-4-methyl-1,3-thiazole (CAS 26847-01-8); Example 85 (y=36%) was prepared starting from intermediate 6b and 5-chloro-3-methyl-1,2,4-thiadiazole (CAS 21734-85-0); Example 86 (y=10%) was prepared starting from intermediate 6b and 5-chloro-1-methyl-1H-pyrazole-4-carbonitrile (CAS 111493-52-8); Example 87 (y=43%) was prepared starting from intermediate 6b and 5-chloro-3-cyclopropyl-1,2,4-thiadiazole (CAS 122684-54-2); Example 88 (y=39%) was prepared starting from intermediate 6b and 2-fluoro-6-methylpyridine (CAS 407-22-7); Example 89 (y=32%) was prepared starting from intermediate 6b and 2-fluoro-4-methylpyridine (CAS 461-87-0); Example 90 (y=57%) was prepared starting from intermediate 6b and 2-cyano-3-fluoropyridine (CAS 97509-75-6); Example 91 (y=50%) was prepared starting from intermediate 6b and 5-fluoropyridine-3-carbonitrile (CAS 696-42-4); Example 92 (y=21%) was prepared starting from intermediate 6b and 3-chloropyrazine-2-carbonitrile (CAS 55557-52-3); Example 93 (y=48%) was prepared starting from intermediate 6b and 2,2-fluoro-1,3-benzothiazole (CAS 1123-98-4); Example 94 (y=19%) was prepared starting from intermediate 6b and 3-chloro-1,2-benzoxazole (CAS 16263-52-8); Example 95 (y=51%) was prepared starting from intermediate 6b and 5-chloro-3-(2-methoxyethyl)-1,2,4-thiadiazole (CAS 89180-91-6); Example 96 (y=9%) was prepared starting from intermediate 6b and 3-chloro-4-phenyl-4H-1,2,4-triazole (CAS 90002-02-1); Example 97 (y=60%) was prepared starting from intermediate 6b and 5-chloro-1-phenyl-1H-tetrazole (CAS 14210-25-4); Example 98 (y=7%) was prepared starting from intermediate 6b and 2-chloro-4-fluoro-1-methyl-1H-1,3-benzodiazole (CAS 1283719-98-1); Example 99 (y=21%) was prepared starting from intermediate 6b and 2-fluoro-3-methylpyridine (CAS 2369-18-8); Example 100 (y=59%) was prepared starting from intermediate 6b and 2-fluoro-5-methylpyrimidine (CAS 62802-36-2); Example 101 (y=62%) was prepared starting from intermediate 6b and 3-fluoro-6-methylpyridazine (CAS 65202-56-4); Example 102 (y=34%) was prepared starting from intermediate 6b and 2,5-difluoropyridine (CAS 84476-99-3); Example 103 (y=39%) was prepared starting from intermediate 6b and 4,6-difluoropyrimidine (CAS 2802-62-2); Example 104 (y=53%) was prepared starting from intermediate 6b and 3,6-difluoropyridazine (CAS 33097-39-1); Example 105 (y=53%) was prepared starting from intermediate 6b and 2,6-difluoropyrazine (CAS 33873-09-5); Example 106 (y=44%) was prepared starting from intermediate 6b and 2,3-difluoropyrazine (CAS 52751-15-2); Example 107 (y=14%) was prepared starting from intermediate 6b and 2,4-difluoropyrimidine (CAS 2802-61-1); Example 108 (y=65%) was prepared starting from intermediate 6b and 2-fluoropyridine-3-carbonitrile (CAS 3939-13-7); Example 109 (y=53%) was prepared starting from intermediate 6b and 2-cyano-6-fluoropyridine (CAS 3939-15-9); Example 110 (y=53%) was prepared starting from intermediate 6b and 4-fluoropyridine-2-carbonitrile (CAS 847225-56-3); Example 111 (y=64%) was prepared starting from intermediate 6b and 3-fluoropyridine-4-carbonitrile (CAS 113770-88-0); Example 112 (y=11%) was prepared starting from intermediate 6b and 4,6-difluoro-2-methylpyrimidine (CAS 18382-80-4); Example 113 (y=30%) was prepared starting from intermediate 6b and 4,6-difluoro-5-methylpyrimidine (CAS 18260-64-5); Example 114 (y=33%) was prepared using 2-chloro-4-(trifluoromethyl)pyrimidine (CAS 33034-67-2), starting from intermediate 6b; Example 115 (y=43%) was prepared starting from intermediate 6b and 4-chloro-6-(trifluoromethyl)pyrimidine (CAS 37552-81-1); Example 116 (y=34%) was prepared starting from intermediate 6b and 4-chloropyrazolo[1,5-a]pyrazine (CAS 1260665-84-6); Example 117 (y=18%) was prepared starting from intermediate 6b and 5-chloropyrazolo[1,5-a]pyrimidine (CAS 29274-24-6); Example 118 (y=8%) was prepared starting from intermediate 6b and 5-chloro-[1,2,4]triazolo[4,3-a]pyrazine (CAS 63744-34-3); Example 119 (y=12%) was prepared starting from intermediate 6b and 8-chloro-[1,2,4]triazolo[4,3-a]pyrazine (CAS 68774-77-6); Example 120 (y=56%) was prepared starting from intermediate 6b and 3-chloro-2-fluoropyridine (CAS 1480-64-4); Example 121 (y=31%) was prepared starting from intermediate 6b and 5-chloro-1,6-naphthyridine (CAS 23616-32-2); Example 122 (y=37%) was prepared starting from intermediate 6b and 4-chloropyridine-3-carbonitrile (CAS 89284-61-7); Example 123 (y=65%) was prepared starting from intermediate 6b and 4-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine (CAS 23000-43-3); Example 124 (y=67%) was prepared starting from intermediate 6b and 2,6-difluoropyridine (CAS 1513-65-1); Example 125 (y=18%) was prepared starting from intermediate 6b and 2,4-difluoropyridine (CAS 34941-90-7); Example 126 (y=8%) was prepared starting from intermediate 6b and 2,4-difluoropyridine (CAS 34941-90-7); Example 127 (y=50%) was prepared starting from intermediate 6a and 4-fluoropyridine-2-carbonitrile (CAS 847225-56-3).

[0098] [Table 8-1]

[0099] [Table 8-2]

[0100] [Table 8-3]

[0101] [Table 8-4]

[0102] [Table 8-5]

[0103] [Table 8-6]

[0104] Table 8-7

[0105] Table 8-8

[0106] Table 8-9

[0107] Table 8-10

[0108] Table 8-11

[0109] Table 8-12

[0110] Table 8-13

[0111] Table 8-14

[0112] Table 8-15

[0113] Table 8-16

[0114] Table 8-17

[0115] Table 8-18

[0116] Table 8-19

[0117] Table 8-20

[0118] Table 8-21

[0119] Table 8-22

[0120] Table 8-23

[0121] Table 8-24

[0122] Table 8-25

[0123] Table 8-26

[0124] Table 8-27

[0125] Table 8-28

[0126] Table 8-29

[0127] Table 8-30

[0128] Table 8-31

[0129] Table 8-32

[0130] Table 8-33

[0131] Analytical methods LC_MS HPLC measurements were performed using a Dionex 3000 module containing a quaternary pump with degasser, autosampler, column oven (set to 29°C), diode array detector DAD, and a column as specified below. The flow from the column was split to an MS spectrometer. The MS detector (LCQ Fleet Thermo Scientific) consisted of an electrospray ionization source. Mass spectra were obtained by scanning from 50 to 800 over 0.48 seconds. The capillary needle voltage was 5 kV in both positive and negative ionization modes, and the source temperature was maintained at 275°C. Nitrogen was used as the nebulizer gas, and the flow rate was 8 l / min. Data acquisition was performed using Thermo Xcalibur Qual Browser.

[0132] Several methods have been used for LC_MS analysis of the patented examples. (Method A) HPLC conditions: Wavelength range: (190~340) nm ± 4 nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Injection volume: 2.0μl Analysis time: 6 minutes Dissolution: Gradient

[0133] [Table 9]

[0134] (Method B) HPLC conditions: Wavelength range: (190~340) nm ± 4 nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Injection volume: 2.0μl Analysis time: 6 minutes Dissolution: Gradient

[0135] [Table 10]

[0136] (Method C) HPLC conditions: Wavelength range: (190~340) nm ± 4 nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Injection volume: 2.0μl Analysis time: 7 minutes Dissolution: Gradient

[0137] [Table 11]

[0138] (Method D) HPLC conditions: Wavelength range: (190~340) nm ± 4 nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Injection volume: 2.0μl Analysis time: 6 minutes Dissolution: Gradient

[0139] [Table 12]

[0140] (Method E) HPLC conditions: Wavelength range: (190~340) nm ± 4 nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Injection volume: 2.0μl Analysis time: 7 minutes Dissolution: Gradient

[0141] [Table 13]

[0142] (Method F) HPLC conditions: Wavelength range: (190~340) nm ± 4 nm Flow rate: 1.0ml / min Column temperature: 25℃ Autosampler temperature: 20℃ Injection volume: 2.0μl Analysis time: 6 minutes Dissolution: Gradient

[0143] [Table 14]

[0144] [Table 15]

[0145] [Table 16-1]

[0146] [Table 16-2]

[0147] Characterization by NMR 1 1H NMR and 13 ¹¹C-NMR spectra were recorded using a Bruker Avance III HD 400 MHz NMR spectrometer with CDCl3 as the solvent. Chemical shifts (δ) are reported in parts per million (ppm) compared to the residual signal of a selected, not fully deuterated solvent for the ¹H NMR spectrum, to which 7.26 ppm was assigned for CHCl3.

[0148] [Table 17-1]

[0149] Table 17-2

[0150] Table 17-3

[0151] Table 18-1

[0152] Table 18-2

[0153] Table 18-3

[0154] Table 18-4

[0155] Table 18-5

[0156] Table 18-6

[0157] Table 18-7

[0158] Table 18-8

[0159] Table 18-9

[0160] Table 18-10

[0161] Table 18-11

[0162] Table 18-12

[0163] Table 18-13

[0164] Table 18-14

[0165] Table 18-15

[0166] Table 18-16

[0167] Table 18-17

[0168] Table 18-18

[0169] Table 18-19

[0170] Table 18-20

[0171] Table 18-21

[0172] Table 18-22

[0173] Table 18-23

[0174] Table 18-24

[0175] Table 18-25

[0176] Table 18-26

[0177] Table 18-27

[0178] Table 18-28

[0179] [Table 18-29]

[0180] [Table 18-30]

[0181] [Table 18-31]

[0182] Pharmacological examples The compound of the present invention was found to be active in a human P2X7 channel calcium influx assay. Extracellular binding of Bz-ATP to the P2X7 receptor opens a channel and allows Ca to enter the cell. 2+ Enables inflow. Using Screen Quest® Fluo-8 No Wash Calcium Assay Kit (AAt Bioquest®, cat. 36316), in HEK-293 cells stably transfected with the P2X7 receptor, this Ca 2+ Influx was measured. Upon entering the cell, the lipophilic protecting group of Fluo-8 is cleaved by nonspecific cell esterases, producing a negatively charged fluorescent dye that remains in the cell. This fluorescence increases when it binds to calcium. When HEK-293 / P2X7 cells are stimulated with Bz-ATP, Ca 2+ Upon entering the cell, the fluorescence of Fluo-8 NW increases. This dye has an absorption spectrum suitable for excitation at 488 nm by an argon laser light source, and its emission wavelength is in the range of 515–575 nm.

[0183] HEK-293 cells stably transfected with the P2X7 receptor were seeded overnight in growth medium at 10,000–20,000 cells / well in 384-well plates. After 24 hours, the medium was removed and the cells were pre-inoculated with 20 μL / w of Fluo-8 NW at room temperature for 1 hour. Subsequently, 10 μL / w of the test compound and 3× concentration of the reference antagonist A438079 were injected by FLIPRTETRA, and the kinetic response was monitored over 5 minutes. 15 μL / w of 3× reference activator (EC) was also injected. 80 A second injection of Bz-ATP was performed using FLIPR TETRA, and the emitted fluorescence signal was recorded for a further 3 minutes. All experiments were performed using low divalent cation assay buffer (0.3 mM Ca). 2+ and 0 mM Mg 2+ The test was conducted in [a specific environment]. The effect of the test compound was measured as the percentage of inhibition against the reference antagonist, and IC was performed accordingly. 50 The value was calculated.

[0184] [Table 19-1]

[0185] [Table 19-2]

[0186] [Table 19-3]

[0187] In vitro evaluation of test compounds for inducing CYP4503A4 metabolism using human liver cells. CYP induction was evaluated using human cryopreserved hepatocytes for adherent culture. Test compounds were evaluated in two series at three or six different concentrations.

[0188] Sandwich culture of cryopreserved hepatocytes suitable for adherent culture was performed simultaneously with a one-day recovery period after adherent culture. Cell morphology and colonization density were evaluated in representative wells using a phase-contrast microscope. To ensure a maximum induced response, the experiment proceeded only when the colonization density exceeded 75%.

[0189] Adherent cultured hepatocyte monolayers were treated with the test compound, negative control, and positive control for two days, with the culture medium changed every 24 hours. On the fourth day, cell morphology and density were repeated to ensure the integrity of the cell monolayer. Cell morphology and density were evaluated in representative wells using a phase-contrast microscope.

[0190] Cytotoxicity of the test compound to the cell monolayer was evaluated by an adenosine triphosphate (ATP) content assay in a separate plate. mRNA expression levels for CYP1A2, CYP2B6, and CYP3A4 were evaluated using the QuantiGene® Plex 2.0 method. For induction experiments to be acceptable, the mRNA expression induction ratio for CYP3A4-positive controls must be at least 4 times higher than that of negative vehicle controls.

[0191] As illustrated below, the compounds of the present invention have unexpected advantages over prior art compounds in that they are less susceptible to, or far less susceptible to, metabolic induction mediated by CYP4503A4.

[0192] [Table 20]

Claims

1. Compounds of the following formula (I), or pharmaceutically acceptable salts thereof: 【Chemistry 1】 Including any of those stereochemical isomer forms, In the formula, W is oxygen, O-C1-C4 alkylene; C1-C4 alkylene-O-, R １ This is a monocyclic or bicyclic 5-10 membered heterocycle that is optionally substituted with one or more groups selected from C1-C4 alkyl (optionally substituted with halogens), C1-C4 alkoxy, halogen, cyano, or C3-C6 cycloalkyl, or a benzo-condensed heterocycle.

2. R １ This includes pyridines monosubstituted or disubstituted with one or more groups selected from cyano, methyl, halogen, trifluoromethyl, and / or C3-C6 cycloalkyl groups; pyrimidines monosubstituted or disubstituted with cyano, methyl, trifluoromethyl, C1-C4 alkoxy, and / or halogen groups; oxazoles monosubstituted or disubstituted with C3-C6 cycloalkyl, methyl, and / or halogen groups; thiazoles monosubstituted or disubstituted with C3-C6 cycloalkyl, cyano, methyl, and / or halogen groups; benzothiazoles; benzoxazoles; and methyl, halogen, and / or C1-C4 alkoxy groups. The compound according to claim 1, or any pharmaceutically acceptable salt thereof comprising any stereochemical isomer thereof, is a monosubstituted or disubstituted thiadiazole; tetrazole; optionally halogen-substituted benzodiazole; methyl and / or halogen-substituted pyridazine; pyrazolo[1,5-a]pyrazine; [1,2,4]triazolo[4,3-a]pyrazine; naphthyridine; pyrazolo[3,4-d]pyrimidine; pyrazine monosubstituted or disubstituted with C3-C6 cycloalkyl, methyl, benzo-condensed heterocycle and / or halogen; [1,2]oxazolo[5,4-b]pyridine; or phthalazine.

3. W is oxygen, -CH ２ O- or -OCH ２ - and R １ These include pyridine-2-yl, pyridine-3-yl, pyridine-4-yl, pyrimidine-2-yl, 5-fluoropyridine-3-yl, 3-fluoropyridine-4-yl, 3-fluoropyridine-2-yl, 1,5-methyl-1,2-oxazole-3-yl, dimethyl-1,2-oxazole-4-yl, 1,3-thiazole-2-yl, 3-methyl-1,2,4-thiadiazole-5-yl, 4-chloro-1,3-thiazole-2-yl, 3-cyclopropyl-1,2,4-thiadiazole-5-yl, and 6-methylpy Lysine-2-yl, 4-methylpyridine-2-yl, 5-cyanopyridine-3-yl, 3-cyanopyrazine-2-yl, 2-cyanopyrazine-3-yl, 2-chloropyridine-3-yl, 1,3-benzothiazole-2-yl, 1,2-benzoxazole-3-yl, 1,3-benzoxazole-2-yl, 4-fluoro-1-methyl-1H-1,3-benzodiazole-2-yl, 3-methylpyridine-2-yl, 5-methylpyrimidine-2-yl, 6-methylpyridazine-3-yl, 5-fluoropyridine-2 -yl, 6-fluoropyrimidine-4-yl, 6-fluoropyridazine-3-yl, 6-fluoropyrazine-2-yl, 3-fluoropyrazine-2-yl, 2-fluoropyrimidine-4-yl, 3-cyanopyridine-2-yl, 6-cyanopyridine-2-yl, 4-cyanopyridine-3-yl, 6-fluoro-2-methylpyrimidine-4-yl, 6-fluoro-5-methylpyrimidine-4-yl, 6-cyclopropylpyridine-2-yl, 4-(trifluoromethyl)pyrimidine-2-yl, 6-(trifluoromethyl ) Pyrimidine-4-yl, pyrazolo[1,5-a]pyrazine-4-yl, [1,2,4]triazolo[4,3-a]pyrazine-5-yl, [1,2,4]triazolo[4,3-a]pyrazine-8-yl, 3-chloropyridine-2-yl, 1,5-naphthyridine-4-yl, 1,6-naphthyridine-5-yl, 3-cyanopyridine-4-yl, 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 3-methyl-[1,2,4]triazolo[4,3-a]pyrazine-8-yl, 4-cyano-3-methyl-1,2-thiazole-5-yl, 2-fluoro-6-methylpyrimidine-4-yl, 2-fluoro-5-methylpyrimidine-4-yl, 5-fluoro-6-methylpyrimidine-4-yl, 6-(1H-pyrazole-1-yl)pyrazine-2-yl, 3-(trifluoromethyl)pyridine-2-yl, 6-(trifluoromethyl)pyridine-2-yl, 2-(trifluoromethyl)pyridine-4-yl, 3,6-dimethyl-[1,2]oxazolo[5,4-b]pyridine-4-yl, 2-methoxypyrimidine-4-yl, 4-methoxypyrimidine-2-yl, 6-methoxypyrimidine-4-yl, 5-fluoro-2,6-dimethylpyrimidine-4-yl, 4-chloropyridine-3-yl, pyrazine-2-yl, pyridazine-3-yl, 6-fluoropyridine-2-yl, 2-methylpyridine-4-yl, 2-chloropyridine Midine-4-yl, 4-chloropyrimidine-2-yl, 6-chloropyrazine-2-yl, 6-chloropyridine-2-yl, pyrimidine-4-yl, 2-fluoropyridine-4-yl, 4-fluoropyridine-2-yl, 1,3-thiazole-2-yl, 4-chloro-1,3-thiazole-2-yl, 4-methyl-1,3-thiazole-2-yl, 3-methyl-1,2,4-thiadiazole-5-yl, 4- Cyano-1-methyl-1H-pyrazole-5-yl, 3-cyclopropyl-1,2,4-thiadiazole-5-yl, 6-methylpyridine-2-yl, 4-methylpyridine-2-yl, 2-cyanopyridine-3-yl, 5-cyanopyridine-3-yl, 3-cyanopyrazine-2-yl, 1,3-benzothiazole-2-yl, 1,2-benzoxazole-3-yl, 4-fluoro-1-methyl-1H-1,3-benzodiazole-2-yl, 3-methylpyridine-2-yl, 5-methylpyrimidine-2-yl, 6-methylpyridazine-3-yl, 5-fluoropyridine-2-yl, 6-fluoropyrimidine-4-yl, 6-fluoropyridazine-3-yl, 6-fluoropyrazine-2-yl, 3-fluoropyrazine-2-yl, 2-fluoropyrimidine-4-yl, 3-cyanopyridine-2-yl, 6-cyanopyridine-2-yl, 2-cyanopyridine-4-yl, 4-cyanopyridine-3-yl, 6-fluoro-2-methylpyrimidine-4-yl, 6-fluoro-5-methylpyrimidine-4-yl, 4-(trifluoromethyl)pyrimidine-2-yl, 6-(trifluoromethyl) The compound according to claim 1, which is pyrimidine-4-yl, pyrazolo[1,5-a]pyrazine-4-yl, pyrazolo[1,5-a]pyrimidine-5-yl, [1,2,4]triazolo[4,3-a]pyrazine-5-yl, [1,2,4]triazolo[4,3-a]pyrazine-8-yl, 3-chloropyridine-2-yl, 1,6-naphthyridine-5-yl, 3-cyanopyridine-4-yl, 1-methyl-1H-pyrazolo[3,4-d]pyrimidine-4-yl, 6-fluoropyridine-2-yl, 2-fluoropyridine-4-yl, or 4-fluoropyridine-2-yl, 2-cyanopyridine-4-yl, or a pharmaceutically acceptable salt thereof comprising any stereochemical isomer thereof.

4. Compounds selected from the group consisting of the compounds listed in the table below, or pharmaceutically acceptable salts thereof, including any stereochemical isomer thereof. Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8

5. A process for preparing a compound of formula (I) as described in claim 1, The compound of formula (II) and 【Chemistry 2】 (W and R in the formula) １ (The meaning is as defined in claim 1.) Compound of formula (III) and 【Transformation 3】 The step includes reacting the following: A process comprising the steps of optionally converting the obtained compound of formula (I) to a salt thereof, and / or preparing its stereochemical isomer form.

6. A process for preparing a compound of formula (I) according to claim 1, comprising a compound of formula (VIIIa) or (VIIIb) and formula R １ The process includes the step of reacting with a halogen of -X. 【Chemistry 4】 (In the formula, R １ A process comprising the steps of (i) being as defined in claim 1), where X is a halogen, and optionally converting the resulting compound of formula (I) to a salt thereof, and / or preparing its stereochemical isomer form.

7. A pharmaceutical formulation comprising a compound of formula (I) as described in any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof including any stereochemical isomer thereof, and a pharmaceutically acceptable diluent and / or carrier.

8. A pharmaceutical preparation according to claim 7, for use as a pharmaceutical.

9. A pharmaceutical formulation according to claim 7, for use in the prevention and / or treatment of a condition or disease selected from P2X7 receptor-mediated conditions or diseases.

10. The pharmaceutical formulation according to claim 9, wherein the P2X7 receptor-mediated condition or disease is selected from neurological disorders, neurodegenerative disorders, neuroinflammatory disorders, cognitive impairments, psychiatric disorders, neuropathic pain, chronic pain, acute pain, headaches, musculoskeletal inflammatory processes, gastrointestinal disorders, urogenital disorders, eye diseases, cardiovascular diseases, endocrine disorders, liver diseases, eating disorders, and allergic diseases.

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