2,4-Dihydro-3H-1,2,4-triazol-3-one P2X7 antagonists

Abstract

The present invention relates to novel 2,4-dihydro-3H-1,2,4-triazol-3-one compounds of formula (I) having P2X7 receptor (P2X7) antagonistic properties, pharmaceutical compositions containing these compounds, chemical processes for the preparation of these compounds and their use in the treatment or prevention of diseases associated with P2X7 receptor activity in animals, particularly in humans. JPEG2024535697000116.jpg3754

Description

[Technical field]

[0001] The present invention relates to novel 2,4-dihydro-3H-1,2,4-triazol-3-one compounds of formula (I) having P2X7 receptor (P2X7) antagonistic properties, pharmaceutical compositions containing these compounds, chemical processes for the preparation of these compounds and their use in the treatment or prevention of diseases associated with P2X7 receptor activity in animals, particularly in humans. [Background technology]

[0002] P2X7 belongs to the P2X ionotropic receptor family. P2X7 is activated by extracellular nucleotides, particularly adenosine triphosphate (ATP). P2X7 is distinguished from other P2X family members by its specific localization (especially in the CNS and immunocompetent cells), the high concentration 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 present on various cell types, specifically macrophages, mast cells and lymphocytes (T and B), known to be primarily involved in inflammatory and / or immune processes. Activation of the P2X7 receptor by extracellular nucleotides, e.g., ATP, results in the release of interleukin-1β (1L-1β) and giant cell formation (macrophages / microglial cells), granule loss (mast cells), and L-selectin release (lymphocytes). P2X7 receptors are also located on antigen-presenting cells (APCs), keratinocytes, salivary gland acinar cells (parotid cells), hepatocytes, erythrocytes, erythroleukemia cells, monocytes, fibroblasts, bone marrow cells, neurons, and renal mesangial cells. P2X7 receptors are also known to be pain sensors in the nervous system. In experiments using P2X7-deficient mice, we demonstrate the role of P2X7 in the development of pain, 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, such as 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 have an important function in neurotransmission within the CNS through its activation on postsynaptic and / or presynaptic neurons and glia. Using in situ hybridization, data revealed that P2X7 receptor mRNA is widely distributed throughout the rat brain.In particular, high expression areas of P2X7 mRNA 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 signals were also observed in the trigeminal motor nucleus, facial nucleus, hypoglossal nucleus, and motor neurons of the anterior horn of the spinal cord.

[0003] Therefore, there is therapeutic rationale for the use of P2X7 antagonist 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 disorder, mood and anxiety disorder, HIV-induced neuroinflammation, and chronic neuropathic and inflammatory pain. In addition, peripheral inflammatory 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, liver fibrosis, skin injury, emphysema, muscular dystrophy, fibrosis, atherosclerosis, burns, Crohn's disease, ulcerative colitis, age-related macular degeneration, malignant cell proliferation and metastasis, Sjogren's syndrome, myeloblastic leukemia, diabetes, osteoporosis, and ischemic heart disease, are all examples in which the involvement of P2X7 receptors 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: WO2004099146 discloses benzamide inhibitors of the P2X7 receptor and their use in the treatment of inflammatory diseases.

[0005] WO2009108551 discloses heteroaryl amide analogues and their use in P2X7 receptor mediated conditions. WO2009132000 discloses quinoline and isoquinoline substituted P2X7 receptor antagonists and their use in P2X7 receptor mediated conditions.

[0006] WO2015119018 discloses thiazole and oxazole derivatives as P2X7 receptor antagonists and their use in P2X7 receptor mediated conditions. WO2015 / 099107A1 discloses pyrimidinone substituted P2X7 receptor antagonists and their use in P2X7 receptor mediated conditions.

[0007] WO2018202694A1 discloses oxadiazolinone compound P2X7 receptor antagonists and their use in P2X7 receptor-mediated conditions. [Brief description of the drawings]

[0008] [Figure 1] FIG. 1 shows the application protocol. Summary of the Invention [Problem to be solved by the invention]

[0009] However, there is still an unmet need for compounds that can effectively antagonize P2X7 and can be delivered to different target organs that are the site of P2X7-mediated pathology, including the brain.Such compounds are presented herein. [Means for solving the problem]

[0010] Various aspects of the invention are presented below. The present invention relates to a 2,4-dihydro-3H-1,2,4-triazol-3-one compound represented by the following formula (I) or a pharma- ceutically acceptable salt thereof:

[0011] [ka]

[0012] including any stereochemically isomeric forms thereof, wherein R is an aromatic, aliphatic, heteroaromatic, or heteroaliphatic ring, optionally substituted with one or more substituents selected from: halogen; C1-C4 alkyl, the C1-C4 alkyl being optionally substituted with one or more halogens; R1 is a C3-C6 cycloalkyl, the C3-C6 cycloalkyl optionally substituted with one or more halogens, or a C1-C4 alkyl, the C1-C4 alkyl optionally substituted with one or more substituents selected from: halogen; OR3, where R3 is H or C1-C4 alkyl, the C1-C4 alkyl being optionally substituted with one or more halogens; NR4R5 group, where R4 and R5 are H or C1-C4 alkyl, the C1-C4 alkyl being optionally substituted with one or more halogens; C3-C6 cycloalkyl, the C3-C6 cycloalkyl optionally substituted with one or more halogens; a phenyl ring, the phenyl ring being optionally substituted with halogen; n is 1 or 2; preferably, n is 1; R2 is selected from aromatic, heteroaromatic, aliphatic and heteroaliphatic monocyclic or bicyclic rings, which are optionally substituted with one or more substituents selected from: halogen; C1-C4 alkyl, the C1-C4 alkyl being optionally substituted with one or more halogens; and a heteroaromatic ring, the heteroaromatic ring being optionally substituted with one or more halogens; Or R2 is -OH; a compound or a pharma- ceutically acceptable salt thereof, Regarding.

[0013] As used in the above definition, The terms "halo", "halogen" and "halide" may be used interchangeably and refer to a substituent fluoro, chloro, bromo, or iodo.

[0014] As used herein above, the term "stereochemically isomeric forms" defines all possible isomeric forms that the compounds of formula (I) may take. Unless otherwise stated or indicated, the chemical name of the compound denotes a mixture of all possible stereochemically isomeric forms, said mixture containing all diastereomers and enantiomers of the basic molecular structure. More specifically, the stereocenters can have R- or S-configuration, and the substituents on the divalent cyclic (partially) saturated groups can have either cis- or trans-configuration.

[0015] Stereochemically isomeric forms of the compounds of formula (I) are obviously intended to be embraced within the scope of the present invention. The absolute stereochemical configuration of the compounds of formula (I) and intermediates used in their preparation may be readily determined by those skilled in the art using well-known methods such as, for example, X-ray diffraction.

[0016] Furthermore, some of the compounds of formula (I) and some of the intermediates used in their preparation may exhibit polymorphism. It is to be understood that the invention encompasses any polymorphic form that has properties useful in the treatment of the above conditions.

[0017] The above pharmaceutically acceptable salts are meant to include the therapeutically active and non-toxic acid addition salt forms that the compounds of formula (I) can form. These pharmaceutically acceptable acid addition salts can be conveniently obtained by treating the base form with such a suitable acid. Suitable acids include, for example, inorganic acids, such as hydrohalic acids, for example 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.

[0018] Conversely, said salt forms can be converted by treatment with an appropriate base into the free base form. The compound of formula (I) may exist in both nonsolvated and solvated form.The term "solvate" is used herein to describe the molecular association of the compound of the present invention and one or more pharma-ceutically acceptable solvent molecules, such as water or ethanol.The term "hydrate" is used when said solvent is water.

[0019] Preferably, R is phenyl, pyridinyl, cyclohexyl, cycloheptyl, piperidinyl or piperazinyl, optionally substituted with one or more substituents selected from: halogens, preferably Cl and F; C1-C4 alkyl, the C1-C4 alkyl being optionally substituted with one or more halogens, preferably methyl, preferably methyl or trifluoromethyl.

[0020] n is 1 or 2, preferably n is 1. Preferably, R1 is a C1-C4 alkyl (preferably methyl or ethyl) optionally substituted with: one or more halogens (preferably F), C3-C4 cycloalkyl (preferably cyclopropyl), the cycloalkyl optionally substituted with halogen (preferably F), or Phenyl ring.

[0021] Preferably, R2 is selected from an aromatic, aliphatic, heteroaromatic or heteroaliphatic ring, which is selected from phenyl, C3-C7 cycloalkyl, C6-C8 bicycloalkanyl, pyridinyl, piperidinyl, tetrahydrofuranyl and morpholinyl, wherein the ring is optionally substituted with one or more substituents selected from halogen, a heteroaromatic ring, the heteroaromatic ring optionally substituted with halogen, and C1-C4 alkyl, the C1-C4 alkyl optionally substituted with one or more halogen atoms, or R2 is -OH.

[0022] A preferred embodiment of the present invention relates to compounds of formula (I) as defined above: R is selected from cycloheptyl, cyclohexyl or phenyl, which are optionally substituted with one or more halogens (preferably F or Cl), or C1-C4 alkyl (preferably methyl), wherein the C1-C4 alkyl is optionally substituted with halogens (preferably F); R1 is selected from C1-C4 alkyl (preferably methyl or ethyl), the C1-C4 alkyl being one or more halogens (preferably F), C3-C4 cycloalkyl (preferably cyclopropyl), the C3-C4 cycloalkyl being optionally substituted with halogen (preferably F), or Phenyl ring, Optionally substituted with n is 1 or 2, preferably n is 1; R2 is selected from the following: phenyl, said phenyl optionally substituted with one or more substituents selected from halogen (preferably F or Cl), C1-C4 alkyl, said C1-C4 alkyl optionally substituted with one or more halogen (preferably F), or pyrimidinyl, said pyrimidinyl optionally substituted with one or more halogen (preferably F); pyridinyl, the pyridinyl optionally substituted with one or more C1-C4 alkyl (preferably methyl), the C1-C4 alkyl optionally substituted with one or more halogen (preferably F); piperidinyl, the piperidinyl optionally substituted with C1-C4 alkyl (preferably methyl); cyclohexyl, said cyclohexyl being optionally substituted with one or more substituents selected from halogen (preferably F), C1-C4 alkyl (preferably methyl), said C1-C4 alkyl being optionally substituted with halogen (preferably F); cyclopropyl, cyclopentyl or cycloheptyl, which are optionally substituted with one or more halogens (preferably F); Tetrahydrofuranyl; morpholinyl, the morpholinyl optionally substituted with one or more C1-C4 alkyl (preferably methyl); bicyclo[3.1.0]hexan-3-yl, which is optionally substituted with one or more halogens; spiro[2.5]octan-6-yl, and -OH.

[0023] Another preferred embodiment of the present invention relates to compounds of formula (I) as defined above: R is selected from cyclohexyl, 4,4-difluorocyclohexyl, cycloheptyl, 2-chloro-6-fluorophenyl, 2-chloro-4-fluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, 2-trifluoromethylphenyl.

[0024] R1 is selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, benzyl, 3,3,3-trifluoropropyl, 2,2-difluoroethyl.

[0025] n is 1 or 2, preferably n is 1. R2 is selected from 4-fluorophenyl, 2-chloro-6-fluorophenyl, 2-trifluoromethylphenyl, 2-chloro-5-(5-fluoropyrimidin-2-yl)phenyl, 2-methylpyridin-3-yl, cyclohexyl, 4,4-difluorocyclohexyl, 3,3-difluorocyclopentyl, 6,6-difluorobicyclo[3.1.0]hexan-3-yl, 4-fluorocyclohexyl, 4-trifluoromethylcyclohexyl, cycloheptyl, 2-(trifluoromethyl)pyridin-4-yl, 4-spiro[2.5]octan-6-yl, 4,4-dimethylcyclohexyl, tetrahydrofuran-2-yl, 1-methylpiperidin-2-yl, morpholinyl, 2,2-dimethylcyclohexyl, 3,3-dimethylmorpholinyl, cycloheptylmethyl, and OH.

[0026] Most preferably, the compounds of formula (I) according to the invention are selected from the group consisting of the compounds described below:

[0027] [Table 1-1]

[0028] [Table 1-2]

[0029] [Table 1-3]

[0030] [Table 1-4]

[0031] Selected from: Compounds of formula (I) are generally prepared by reacting compounds of formula (II):

[0032] [ka]

[0033] (wherein R and R1 are as defined above), Compounds of formula (III):

[0034] [ka]

[0035] where R2 and n are as defined above and X is a suitable leaving group; and optionally converting the resulting compound of formula (I) into its addition salts and / or preparing its stereochemically isomeric forms.

[0036] X in the compound of formula (III) is a suitable leaving group, for example halo, e.g. chloro, bromo, and in some cases X may be a reactive leaving group, such as an alcohol. The reaction of the compound of formula (II) with the compound of formula (III) may be carried out in a reaction inert solvent, for example acetonitrile or DMF, and optionally in the presence of a suitable base, for example potassium carbonate or sodium methoxide. Stirring may enhance the reaction rate. The reaction may conveniently be carried out at a temperature ranging between room temperature and the reflux temperature of the reaction mixture.

[0037] Compounds of formula (III) are known in the art. Compounds of formula (II) may be prepared according to the following scheme:

[0038] [ka]

[0039] Compounds of formula (II), where R and R1 are as defined in formula (I), can be obtained by cyclization of the respective ethyl-N-(ethoxycarbonyl)imidate derivatives (VI).

[0040] The reaction is carried out in a suitable solvent such as 1,4-dioxane in the presence of a hydrazine derivative as a base and TEA, preferably at reflux temperature. Compounds of formula (VI), wherein R is as defined in formula (I), may be prepared from compounds of formula (V) by reaction with ethyl chloroformate in the presence of a tertiary amine, such as diisopropylethylamine, in an inert solvent, such as dichlormethane, preferably at 0-20° C.

[0041] Compounds of formula (V), where R is as defined in formula (I), may be prepared from the appropriate nitrile derivative (IV) by reaction with acetyl chloride using EtOH as solvent, preferably at room temperature.

[0042] The nitrile derivative (IV) is a known compound, commercially available, or can be prepared according to conventional reaction procedures generally known in the art. The compound of formula (I), its pharmaceutically acceptable salts, and their stereoisomeric forms have P2X7 receptor antagonistic properties, as demonstrated in the pharmacological examples. Other examples of group conversion reactions known in the art for converting the compound of formula (I) to other compounds of formula (I) include hydrolysis of carboxylic acid esters to the corresponding carboxylic acid or alcohol; hydrolysis of amides to the corresponding carboxylic acid or amine; alcohols can be converted to esters and ethers; primary amines can be converted to secondary or tertiary amines; double bonds can be hydrogenated to the corresponding single bonds. Some of the starting materials and intermediates are known compounds, commercially available, or can be prepared according to conventional reaction procedures generally known in the art. The compound of formula (I) prepared by the above method can be synthesized in the form of a racemic mixture of enantiomers, which can be separated from each other according to resolution procedures known in the art. The compound of formula (I) obtained in racemic form can be converted to the corresponding diastereomeric salt form by reaction with a suitable chiral acid. The diastereomeric salt forms are then separated, for example, by selective or fractional crystallization, and the enantiomers are liberated therefrom by alkali. Another method for separating the enantiomeric forms of the compounds of formula (I) involves liquid chromatography using a chiral stationary phase. The pure stereochemically isomeric forms can also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, when a specific stereoisomer is desired, the compound is synthesized by stereospecific preparation methods. These methods advantageously utilize enantiomerically pure starting materials. In the preparation of the compounds of formula (I) and the starting materials and / or intermediates described herein, it may be useful to protect certain groups that are sensitive to the reaction conditions. The evaluation of the usefulness of optional protection and the selection of appropriate protecting agents depending on the reactions to be performed and the functional groups to be protected in the preparation of the compounds of the invention are within the common knowledge of one of ordinary skill in the art. The removal of optional protecting groups is carried out according to conventional techniques.For a general review of 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.

[0043] The preparation of the salt of the compound of formula I is carried out according to known methods.Therefore, the compound of formula (I) of the present invention is useful as a medicament for treating the condition or disease mediated by P2X7 receptor, particularly P2X7 receptor antagonist activity.Then, this compound can be used for the manufacture of the medicament for treating the condition or disease mediated by P2X7 receptor activity, particularly P2X7 receptor antagonist activity.

[0044] The present invention also provides the use of a compound of formula (I) or a pharma- ceutically acceptable salt thereof for the manufacture of a medicament for the treatment of a condition or disease selected from conditions or diseases mediated by P2X7 receptors. In one aspect, the present invention provides a compound of formula (I) for use as a medicament or for use in the treatment of a condition or disease selected from conditions or diseases mediated by P2X7 receptors. Furthermore, the present invention also provides a method for the treatment of a condition mediated by P2X7 receptor activity in a mammalian subject, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of formula (I) or a pharma- ceutically acceptable salt thereof. In view of the above mechanism of action, the compounds of the present invention are useful for the treatment of neurodegenerative disorders of various origins, such as Alzheimer's disease and other dementia conditions, such as Lewy bodies, frontotemporal dementia and tauopathies; 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 invention are also useful for treating neurological conditions such as epilepsy, including simple partial seizures, complex partial seizures, secondarily generalized seizures, including absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures and atonic seizures.

[0045] The compounds of the present invention are also useful for treating cognitive disorders and psychiatric disorders.Psychiatric disorders include, but are not limited to, major depression, dysthymia, mania, bipolar disorder (such as bipolar disorder type I, bipolar disorder type II), cyclothymic disorder, rapid cycling, ultradian cycling, mania, hypomania, schizophrenia, schizophreniform disorder, schizoaffective disorder, personality disorder, attention disorder with or without hyperactivity, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorder due to general medical condition, substance-induced psychotic disorder or psychotic disorder not otherwise specified, anxiety disorder such as generalized anxiety disorder, panic disorder, post-traumatic stress disorder, impulse control disorder, phobic disorder, dissociative state, as well as smoking, drug addiction and alcoholism.In particular, bipolar disorder, psychosis, anxiety and addiction.

[0046] The compound of the present invention is useful for preventing or treating neuropathic pain.Neuropathy pain syndromes include but are not limited to diabetic neuropathy; sciatica; non-specific lower back pain; multiple sclerosis pain; fibromyalgia; HIV-related neuropathy; neuralgia, such as post-herpetic neuralgia and trigeminal neuralgia, Morton's neuralgia, causalgia; and pain from physical trauma, amputation, phantom limb, cancer, toxins or chronic inflammatory conditions; central pain, such as that observed in thalamic syndrome, mixed central pain and peripheral pain, such as complex regional pain syndrome (CRPS), also called reflex sympathetic dystrophy.

[0047] The compounds of the present invention are also useful for treating 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 or lower back pain (generalized, localized or primary spinal disease such as radiculopathy), bone pain (from osteoarthritis, osteoporosis, bone metastasis 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 headache pain, temporomandibular joint syndrome, gout, fibrosis or thoracic outlet syndrome pain, especially rheumatoid arthritis and osteoarthritis.

[0048] The compounds of the invention are also useful for treating acute pain caused by acute injury, illness, sports medicine injuries, carpal tunnel syndrome, burns, musculoskeletal sprains and muscle strains, muscle-tendon strains, cervicobrachial pain syndrome, dyspepsia, gastric ulcers, duodenal ulcers, dysmenorrhea, endometriosis or surgery (such as open heart or bypass surgery), post-operative pain, kidney stone pain, gallbladder pain, gallstone pain, labor pains or toothache.

[0049] The compounds of the invention are also useful in the treatment of headaches such as migraine, tension headache, transformed migraine or evolutionary headache, cluster headache, as well as secondary headache disorders such as those resulting from infection, metabolic disorders or other systemic diseases, and other acute headaches, paroxysmal headaches resulting from the exacerbation of the above primary and secondary headaches.

[0050] The compounds of the invention are also useful in diseases such as vertigo, tinnitus, muscle spasms, and other disorders including, but not limited to, cardiovascular diseases (such as cardiac arrhythmias, myocardial infarction or angina, hypertension, cardiac ischemia, cerebral ischemia), endocrine disorders (such as acromegaly or diabetes insipidus), diseases in which the pathophysiology involves excess or hypersecretion of endogenous substances (such as catecholamines, hormones or growth factors) or other inappropriate cellular secretion.

[0051] The compounds of the invention are also useful in the selective treatment of liver diseases such as inflammatory liver diseases, for example chronic hepatitis B, chronic hepatitis C, alcoholic liver disease, primary biliary cirrhosis, autoimmune hepatitis, liver fibrosis, non-alcoholic steatohepatitis and liver transplant rejection.

[0052] The compounds of the present invention inhibit inflammatory processes that affect all body tissues.Therefore, they are useful for treating inflammatory processes of the musculoskeletal system, including, but not limited to, arthritic conditions such as ankylosing spondylitis, cervical arthritis, fibromyalgia, gout, juvenile rheumatoid arthritis, lumbosacral arthritis, osteoarthritis, osteoporosis, psoriatic arthritis, and rheumatic diseases; diseases that affect the skin and related tissues: inflammatory conditions such as eczema, psoriasis, dermatitis, and sunburn; diseases of the respiratory system: asthma, allergic rhinitis, and respiratory distress syndrome, pulmonary disorders involving inflammation such as asthma and bronchitis; chronic obstructive pulmonary disease; disorders of the immune and endocrine system: nodular periarthritis, thyroiditis, aplastic anemia, scleroderma, myasthenia gravis, multiple sclerosis, and other demyelinating diseases, encephalomyelitis, sarcoidosis, nephritic syndrome, Behcet's syndrome, polymyositis, and gingivitis.

[0053] The compounds of the invention are useful for the treatment of gastrointestinal (GI) tract disorders such as, for example, inflammatory bowel disorders including, but not limited to, ulcerative colitis, Crohn's disease, ileitis, proctitis, celiac disease, enteropathy, microscopic or collagenous colitis, eosinophilic gastroenteritis, or pouchitis occurring after proctocolectomy and ileoanal anastomosis, and irritable bowel syndrome including any disorder associated with abdominal pain and / or discomfort such as pyloric spasm, nervous dyspepsia, spastic colitis, spastic colitis, spastic bowel, enteric neurosis, functional colitis, mucous colitis, laxative colitis, and functional dyspepsia, but also atrophic gastritis, verrucous gastritis, ulcerative colitis, peptic ulcers, heartburn, and other damage to the GI tract, for example, Helicobacter pylori. pylori; gastroesophageal reflux disease, gastroparesis, such as diabetic gastroparesis; and other functional bowel disorders, such as non-ulcer dyspepsia (NUD); vomiting, diarrhea, and visceral inflammation.

[0054] The compounds of the invention are also useful in the treatment of urogenital disorders such as overactive bladder, prostatitis (chronic bacterial and chronic nonbacterial prostatitis), prostatodynia, interstitial cystitis, urinary incontinence and benign prostatic hyperplasia, adnexitis, pelvic inflammation, Bartholinitis and vaginitis, in particular overactive bladder and urinary incontinence.

[0055] The compounds of the invention are also useful in treating ocular diseases such as retinitis, retinopathies, uveitis and acute injury to ocular tissue, age-related macular degeneration, chronic ocular hypertension, glaucoma, conjunctivitis, and the like. The compounds of the invention are also useful in the treatment of eating disorders such as, for example, anorexia nervosa, including the subtypes restrictive and binge / purging; bulimia nervosa, including the subtypes purging and non-purging; obesity; compulsive eating disorder; binge eating disorder; and eating disorder not otherwise specified.

[0056] The compounds of the invention are also useful in treating allergic dermatitis, airway hyperresponsiveness, chronic obstructive pulmonary disease (COPD), bronchitis, septic shock, Sjogren's syndrome, glomerulonephritis, atherosclerosis, malignant cell proliferation and metastasis, myeloblastic leukemia, diabetes, meningitis, osteoporosis, burns, ischemic heart disease, stroke, peripheral vascular disease, varicose veins, and glaucoma.

[0057] The terms "treat" and "treatment" as used herein refer to curative, palliative and prophylactic treatment, including reversing, alleviating, inhibiting, or preventing the progression of the disease, disorder, or condition to which such term applies, or one or more symptoms of such disease, disorder, or condition.

[0058] Additionally, the present invention provides pharmaceutical compositions comprising at least one pharma- ceutically 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 the specific compound, as the active ingredient, in base or acid addition salt form, is combined in an intimate mixture with at least one pharma- ceutically acceptable carrier, which may take a wide variety of forms depending on the form of preparation desired for administration. These pharmaceutical compositions are preferably in unit dosage form suitable for oral, rectal, transdermal or parenteral administration.

[0059] For example, when preparing compositions for oral dosage form, any of the usual liquid pharmaceutical carriers, such as water, glycols, oils, alcohols, etc., can be used for oral liquid preparations such as suspensions, syrups, elixirs and solutions; or solid pharmaceutical carriers, such as starch, sugar, kaolin, lubricants, binders, disintegrants, etc., can be used for powders, pills, capsules and tablets.Because of their easy administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously used.For parenteral injection compositions, pharmaceutical carriers mainly comprise sterile water, but other components can be included to improve the solubility of active ingredients.

[0060] Injectable solutions can be prepared by using pharmaceutical carriers including, for example, physiological saline, glucose solution or a mixture of both. Injectable suspensions can be prepared by using suitable liquid carriers, suspending agents, and the like. In compositions suitable for transdermal administration, pharmaceutical carriers can optionally include penetration enhancers and / or suitable wetting agents, optionally combined with small amounts of suitable additives that do not cause significant adverse effects on the skin. The additives can be selected to facilitate administration of the active ingredient to the skin and / or can be beneficial for preparing the desired composition. These topical compositions can be administered in various ways, for example, as a transdermal patch, spot-on, or ointment. It is clear that the addition salts of the compounds of formula (I) are more water-soluble than the corresponding base forms, and therefore more suitable for the preparation of aqueous compositions.

[0061] It is especially advantageous to formulate the pharmaceutical compositions of the invention in dosage unit form for ease of administration and uniformity of dosage. As used herein, "dosage unit form" refers to a physically separate unit suitable as a unitary dosage, each unit containing a predetermined amount of active ingredient calculated to produce a desired therapeutic effect in association with the required pharmaceutical carrier. Examples of such dosage unit forms are tablets (including scored or coated tablets), capsules, pills, powder packets, wafers, injectable solutions or suspensions, teaspoonfuls, tablespoons, etc., and separate multiples thereof.

[0062] 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 forms), capsules or gel capsules, and are prepared by conventional means using pharma- ceutically acceptable excipients and carriers, such as binders (e.g., pregelatinized maize starch, polyvinylpyrrolidone, hydroxypropylmethylcellulose, 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.), wetting agents (e.g., sodium lauryl sulfate), etc. Such tablets may also be coated by methods well known in the art.

[0063] Liquid preparations for oral administration may take the form of, for example, solution, syrup or suspension, or may be formulated as a dry product for mixing with water and / or other suitable liquid carriers before use.Such liquid preparations can be prepared by conventional means, optionally with other pharma- ceutically acceptable additives, for example, suspending agents (e.g., sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose or hydrogenated edible fats), emulsifying agents (e.g., lecithin or gum acacia), 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).

[0064] The pharma- ceutically acceptable sweeteners useful in the pharmaceutical compositions of the present invention preferably include at least one intense sweetener, such as aspartame, acesulfame potassium, sodium cyclamate, alitarne, dihydrochalcone sweetener, monellin, stevioside sucralose (4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose) or, preferably, saccharin, sodium saccharin or calcium saccharin, and optionally at least one bulk sweetener, such as sorbitol, mannitol, fructose, sucrose, maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol, caramel or honey. Intense sweeteners are conveniently used in low concentrations. For example, in the case of sodium saccharin, the concentration may range from 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 flavors that can mask bitter components in low-dose formulations preferably include fruit flavors, such as cherry, raspberry, blackcurrant or strawberry flavors. A combination of two flavors can give very good results. In high-dose formulations, stronger pharma-ceutically acceptable flavors, such as caramel chocolate, mint cool, fantasy, etc., may be required.

[0065] Each flavor may be present in the final composition at a concentration ranging from about 0.05% to 1% (weight / volume). Strong flavor combinations are advantageously used. Preferably, flavors are used that do not undergo any change or loss of taste and / or color in the environment of the formulation.

[0066] The compound of formula (I) can be formulated for parenteral administration by injection, conveniently intravenous, intramuscular or subcutaneous injection, for example, by bolus injection or continuous intravenous infusion.The preparations for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives.They can take the form of suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulating agents such as isotonicity agents, suspending agents, stabilizing agents and / or dispersing agents.Alternatively, the active ingredient can be in powder form, for mixing with a suitable vehicle, for example, sterile pyrogen-free water, before use.

[0067] The compounds of formula (I) may also be formulated in rectal compositions such as suppositories or retention enemas, eg, containing conventional suppository bases such as cocoa butter and / or other glycerides. Those skilled in the art in the treatment of diseases associated with ligand-gated ion channel mediation will easily determine the therapeutically effective amount of the compound of formula (I) from the test results shown below. In general, a 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 body weight of the patient to be treated. It may be appropriate to administer the therapeutically effective dose in the form of two or more subdoses at appropriate intervals throughout the day. The 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 active ingredient per unit dosage form.

[0068] As used herein, a "therapeutically effective amount" of a compound is an amount of the compound that, when administered to an individual or animal, results in a sufficiently high level of the compound to cause a discernible P2X7 receptor antagonist response in the individual or animal.

[0069] The exact dosage and frequency of administration depends on the specific compound of formula (I) used, the specific condition being treated, the severity of the condition being treated, the age, weight and general physical condition of the specific patient, and other drugs that the patient may be taking, as is well known to those skilled in the art.Furthermore, the "therapeutically effective amount" can be reduced or increased depending on the response of the patient being treated and / or depending on the evaluation of the physician who prescribes the compound of the present invention.Therefore, the effective daily dose ranges mentioned herein above are merely guidelines. Nomenclature and structure In general, the nomenclature used in this application is based on ChemOffice and is created according to IUPAC systematic nomenclature. The chemical structures depicted herein were created using ChemDraw version 18.2. 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. Nitrogen-containing heteroaryl rings are depicted with an open valence on the nitrogen atom, R 1 , R 2 , R 3 When a variable such as is shown on a heteroaryl ring, such a variable may be bonded or linked to the open valence nitrogen. When a chiral center is present in a structure, but no specific stereochemistry is shown for the chiral center, both enantiomers associated with the chiral center are encompassed by the structure. When a structure shown herein can exist in multiple tautomeric forms, all such tautomers are encompassed by the structure. The atoms depicted in the structures herein are intended to encompass all naturally occurring isotopes of such atoms. Thus, for example, hydrogen atoms depicted herein are meant to include deuterium and tritium, and carbon atoms are 13 C isotopes and 14 C isotope is included. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0070] Abbreviation Abbreviations that may be used in the description of the schemes and examples that follow are as follows: CC: column chromatography; DCM: dichloromethane, DMF: dimethylformamide; EtOAc: ethyl acetate EtOH: ethanol; hrs: time; ACN: acetonitrile; min: minutes (s); N: normal; NMR: nuclear magnetic resonance; rt: room temperature; THF: tetrahydrofuran; LC-MS: liquid chromatography mass spectrometry; K2CO3: Potassium carbonate; Na2SO4: sodium sulfate; HPLC: High performance liquid chromatography; on: overnight; CH3ONa: Sodium methoxide; NaCl: sodium chloride; HCl: Hydrochloric acid; Y: yield; DIPEA: N,N-diisopropylethylamine; Et2O: diethyl ether; LiAlH4: Lithium aluminum hydride. EXAMPLES

[0071] Experimental part The following examples illustrate the invention. Unless otherwise stated, all details (especially percentages and amounts) are by weight. Intermediates A. Nitrile derivatives Most of the substituted nitrile derivatives used as starting materials were purchased from commercial chemical companies:

[0072] [Table 2]

[0073] B. Halogen Derivatives Most halogen derivatives were purchased from chemical vendors:

[0074] [Table 3-1]

[0075] [Table 3-2]

[0076] General synthesis scheme

[0077] [ka]

[0078] Step 1. Acetyl chloride 2 (8.0 equiv.) was added dropwise to a cooled (0° C.) and stirred solution of nitrile derivative 1 (1.0 equiv.) in EtOH; the reaction flask was capped and the reaction mixture was allowed to warm to room temperature and stirred overnight. After completion of the reaction by LC-MS analysis, the volatiles were removed under reduced pressure and the product was isolated as the hydrochloride salt. The residue was used without further purification.

[0079] Step 2. To a cooled (0 °C) stirred solution of 3 (1.0 equiv.) in DCM under N2 flow, DIPEA (3.0 equiv.) was added and the reaction mixture was stirred at 0 °C for 30 min. Then, ethyl chloroformate (1.1 equiv.) was added dropwise to the reaction mixture within 30-45 min. The reaction mixture was stirred at room temperature for 3 h. After that, the mixture was filtered through a silica plug to remove salts and the filtrate was concentrated under reduced pressure. After purification of the crude product as reported in the specific examples, the desired product was obtained.

[0080] Step 3. To a solution of 5 (1.0 equiv.) in dioxane, the hydrazine derivative (2.5 equiv.) and TEA (2.5 equiv.) were added and the reaction mixture was heated at reflux for 16 h. After cooling, the reaction mixture was diluted with water and washed with EtOAc. Then, the pH was adjusted to 2 with 1M hydrochloric acid and the aqueous solution was extracted with EtOAc. The organic phase was then washed with brine, dried (Na2SO4) and evaporated under vacuum. After purification of the crude product as reported in the specific examples, the desired product was obtained.

[0081] Step 4. Method A. To a cooled (0° C.) stirred solution of 6 (1.0 equiv.) in DMF, CH3ONa (3 equiv.) was added and the reaction mixture was stirred at the same temperature for 10 min. Then, halide 7 (5 equiv.) was added and the reaction mixture was stirred at 70° C. overnight. The reaction was quenched by addition of water and extracted with EtOAc (×3). The organic layers were combined, washed with brine, dried (Na2SO4) and evaporated under reduced pressure. After purification of the crude product as reported in the specific examples, the desired product was obtained.

[0082] Method B. To a cooled (0° C.) stirred solution of 6 (1.0 equiv.) in ACN / DMF (5:1 v / v), K2CO3 (2.5 equiv.) was added and the reaction mixture was stirred at the same temperature for 10 min. Then, halide 7 (1.2 equiv.) was added and the reaction mixture was stirred overnight at rt. The reaction was quenched by addition of water and extracted with EtOAc (×3). The organic layers were combined, washed with brine, dried (Na2SO4) and evaporated under reduced pressure. After purification of the crude product as reported in the specific examples, the desired product was obtained.

[0083] Step 5. To a solution of benzoic acid derivative (9) (1.0 equiv.) in MeOH and DCM (3.5 ml + 1.5 ml) was added (trimethylsilyl)diazomethane (10) dropwise. The reaction was stirred at room temperature for 2 h. Then, another 2 equiv. of (trimethylsilyl)diazomethane was added and the reaction was stirred at room temperature for another 2 h. The solvent was then removed under reduced pressure and the remaining residue was taken up in EtOAc. The solution was washed with NaHCO3s.s. (2x10 mL), dried (Na2SO4) and filtered. The solvent was removed under reduced pressure and the residue was used in the next step without further purification.

[0084] Step 6. To a solution of 11 (1.0 equiv) in THF was added LiAlH4 (0.5 equiv) at 0° C. with vigorous stirring and the reaction was allowed to warm to rt. The mixture was stirred at rt for 2 h. Upon completion, the mixture was cooled to 0° C., quenched with H2O and diluted by adding Et2O. The reaction mixture was filtered under vacuum and the filtrate was dried (Na2SO4) and concentrated under vacuum. After purification of the crude product as reported in specific examples, the desired product was obtained.

[0085] Step 7. A mixture of 12 (1.0 equiv) and thionyl chloride (1.5 equiv) in DCM was heated overnight at 45° C. After cooling to rt, the solvent was removed in vacuo and the residue was used in the next step without further purification. Specific Examples Example 1 5-(2-chloro-6-fluorobenzyl)-4-(4-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0086] [ka]

[0087] Ethyl 2-(2-chloro-6-fluorophenyl)acetimidate hydrochloride (Intermediate 1). The title compound was prepared by the general procedure (Scheme 1, Step 1) starting from commercially available nitrile CAS: 75279-55-9.

[0088] Ethyl-2-(2-chloro-6-fluorophenyl)-N-(ethoxycarbonyl)acetimidate (Intermediate 2). The title compound was prepared by the general procedure (Scheme 1, Step 2) starting from Intermediate 1. Purification was carried out by flash silica gel column chromatography using hexane / EtOAc 4:1 v / v as eluent (Y=19%).

[0089] 5-(2-chloro-6-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 3). The title compound was prepared by the general procedure (Scheme 1, step 3) starting from Intermediate 2 and methylhydrazine CAS:60-34-4. Purification was carried out by flash silica gel column chromatography using hexane / AcOEt 1:4 v / v as eluent (Y=59%).

[0090] 5-(2-chloro-6-fluorobenzyl)-4-(4-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:459-46-1. Purified by HPLC (Y=64%).

[0091] Example 2 5-(2-chloro-6-fluorobenzyl)-4-(cyclohexylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one.

[0092] [ka]

[0093] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:2550-36-9. Purified by HPLC (Y=58%).

[0094] Example 3 5-(2-chloro-6-fluorobenzyl)-4-((4,4-difluorocyclohexyl)methyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0095] [ka]

[0096] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:858121-94-5. Purified by HPLC (Y=35%).

[0097] Example 4 5-(2-chloro-6-fluorobenzyl)-4-((3,3-difluorocyclopentyl)methyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0098] [ka]

[0099] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:1695914-13-6. Purified by HPLC (Y=73%).

[0100] Example 5 5-(2-chloro-6-fluorobenzyl)-4-((6,6-difluorobicyclo[3.1.0]hexan-3-yl)methyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0101] [ka]

[0102] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:1393569-74-8. Purified by HPLC (Y=65%).

[0103] Example 6 5-(2-chloro-6-fluorobenzyl)-4-((4-fluorocyclohexyl)methyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0104] [ka]

[0105] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:1784609-74-0. Purified by HPLC (Y=29%).

[0106] Example 7 5-(2-chloro-6-fluorobenzyl)-2-methyl-4-((4-(trifluoromethyl)cyclohexyl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0107] [ka]

[0108] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:858121-96-7. Purified by HPLC (Y=39%).

[0109] Example 8 5-(2-chloro-4-fluorobenzyl)-4-(4-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0110] [ka]

[0111] Ethyl 2-(2-chloro-4-fluorophenyl)acetimidate hydrochloride (Intermediate 4) The title compound was prepared by the general procedure (Scheme 1, Step 1) starting from commercially available nitrile CAS: 75279-56-0.

[0112] Ethyl-2-(2-chloro-4-fluorophenyl)-N-(ethoxycarbonyl)acetimidate (Intermediate 5). The title compound was prepared by the general procedure (Scheme 1, Step 2) starting from Intermediate 4. Purification was carried out by flash silica gel column chromatography using hexane / EtOAc 4:1 v / v as eluent (Y=64%).

[0113] 5-(2-chloro-4-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 6). The title compound was prepared by the general procedure (Scheme 1, step 3) starting from Intermediate 5 and methylhydrazine CAS:60-34-4. Purification was carried out by flash silica gel column chromatography using hexane / EtOAc 4:1 v / v as eluent (Y=91%).

[0114] 5-(2-chloro-4-fluorobenzyl)-4-(4-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 6 and bromide CAS:459-46-1. Purified by HPLC (Y=89%).

[0115] Example 9 5-(2-chloro-4-fluorobenzyl)-4-(cyclohexylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0116] [ka]

[0117] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 6 and bromide CAS:2550-36-9. Purified by HPLC (Y=66%).

[0118] Example 10 5-(2-chloro-4-fluorobenzyl)-4-((3,3-difluorocyclopentyl)methyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0119] [ka]

[0120] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 6 and bromide CAS:1695914-13-6. Purified by HPLC (Y=58%).

[0121] Example 11 5-(2-chloro-4-fluorobenzyl)-4-(cycloheptylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0122] [ka]

[0123] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 6 and bromide CAS:3814-32-2. Purified by HPLC (Y=57%).

[0124] Example 12 5-(2-chloro-6-fluorobenzyl)-4-(cycloheptylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0125] [ka]

[0126] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:3814-32-2. Purified by HPLC (Y=44%).

[0127] Example 13 5-(Cyclohexylmethyl)-2-methyl-4-((2-(trifluoromethyl)pyridin-4-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0128] [ka]

[0129] Ethyl 2-cyclohexylacetimidate hydrochloride (Intermediate 7) The title compound was prepared by the general procedure (Scheme 1, Step 1) starting from commercially available nitrile CAS: 4435-14-7.

[0130] Ethyl-2-cyclohexyl-N-(ethoxycarbonyl)acetimidate (Intermediate 8). The title compound was prepared by the general procedure (Scheme 1, Step 2) starting from Intermediate 7. Purification was performed by flash silica gel column chromatography using a linear gradient of 0-50% ethyl acetate in hexanes (Y=49%).

[0131] 5-(Cyclohexylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 9). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 8 and methylhydrazine CAS:60-34-4. Purification was performed by flash silica gel column chromatography using a linear gradient of 0-100% ethyl acetate in hexanes (Y=64%).

[0132] 5-(cyclohexylmethyl)-2-methyl-4-((2-(trifluoromethyl)pyridin-4-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method B) starting from intermediate 9 and chloride CAS:1027545-48-7. Purified by HPLC (Y=37%).

[0133] Example 14 5-(2-chloro-6-fluorobenzyl)-2-methyl-4-(spiro[2.5]octan-6-ylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0134] [ka]

[0135] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:1621225-50-0. Purified by HPLC (Y=53%).

[0136] Example 15 5-(2-chloro-6-fluorobenzyl)-4-(2-(4,4-difluorocyclohexyl)ethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0137] [ka]

[0138] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:2092565-10-9. Purified by HPLC (Y=31%).

[0139] Example 16 5-(2-chloro-6-fluorobenzyl)-4-(2-(4,4-dimethylcyclohexyl)ethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0140] [ka]

[0141] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:570398-26-4. Purified by HPLC (Y=57%).

[0142] Example 17 4-(Cyclohexylmethyl)-2-methyl-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0143] [ka]

[0144] Ethyl 2-(2-(trifluoromethyl)phenyl)acetimidate hydrochloride (Intermediate 10). The title compound was prepared by the general procedure (Scheme 1, Step 1) starting from commercially available nitrile CAS: 3038-47-9.

[0145] Ethyl-N-(ethoxycarbonyl)-2-(2-(trifluoromethyl)phenyl)acetimidate (Intermediate 11). The title compound was prepared by the general procedure (Scheme 1, Step 2) starting from Intermediate 10. Purification was performed by flash silica gel column chromatography using a linear gradient of 2-15% ethyl acetate in cyclohexane (Y=35%).

[0146] 2-Methyl-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 12). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 11 and methylhydrazine CAS:60-34-4. It was used in the next step without further purification (Y=97%).

[0147] 4-(cyclohexylmethyl)-2-methyl-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 12 and bromide CAS:2550-36-9. Purified by HPLC (Y=27%).

[0148] Example 18 4-((4,4-difluorocyclohexyl)methyl)-2-methyl-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0149] [ka]

[0150] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 12 and bromide CAS:858121-94-5. Purified by HPLC (Y=23%).

[0151] Example 19 4-((3,3-difluorocyclopentyl)methyl)-2-methyl-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0152] [ka]

[0153] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 12 and bromide CAS:1695914-13-6. Purified by HPLC (Y=24%).

[0154] Example 20 5-(2-chloro-6-fluorobenzyl)-2-methyl-4-((tetrahydrofuran-2-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0155] [ka]

[0156] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:1192-30-9. Purification was performed by flash silica gel column chromatography using a linear gradient of 0-100% ethyl acetate in cyclohexane (Y=23%).

[0157] Example 21 5-(2-chloro-6-fluorobenzyl)-2-methyl-4-((1-methylpiperidin-2-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0158] [ka]

[0159] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:1390654-84-8. Purification was performed by flash silica gel column chromatography using a linear gradient of 0-20% methanol in dichloromethane (Y=44%).

[0160] Example 22 5-(2-chloro-6-fluorobenzyl)-2-methyl-4-(2-morpholinoethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0161] [ka]

[0162] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method B) starting from intermediate 3 and bromide CAS:42802-94-8. Purified by HPLC (Y=20%).

[0163] Example 23 4-((2,2-dimethylcyclohexyl)methyl)-2-methyl-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0164] [ka]

[0165] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 12 and bromide CAS:1501249-61-1. Purified by HPLC (Y=11%).

[0166] Example 24 4-(2-chloro-6-fluorobenzyl)-5-(cyclohexylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0167] [ka]

[0168] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method B) starting from intermediate 9 and chloride CAS:55117-15-2. Purification was performed by flash silica gel column chromatography using a linear gradient of 0% to 100% ethyl acetate (containing 1% TEA) in hexanes (Y=50%).

[0169] Example 25 5-(Cyclohexylmethyl)-2-methyl-4-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0170] [ka]

[0171] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method B) starting from intermediate 9 and chloride CAS:21742-00-7. Purification was performed by flash silica gel column chromatography using a linear gradient of 0% to 100% ethyl acetate (containing 1% TEA) in hexanes (Y=17%).

[0172] Example 26 4-((4,4-difluorocyclohexyl)methyl)-5-(2-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0173] [ka]

[0174] Ethyl 2-(2-fluorophenyl)acetimidate hydrochloride (Intermediate 13) The title compound was prepared by the general procedure (Scheme 1, Step 1) starting from commercially available nitrile CAS:326-62-5.

[0175] Ethyl-N-(ethoxycarbonyl)-2-(2-fluorophenyl)acetimidate (Intermediate 14). The title compound was prepared by the general procedure (Scheme 1, Step 2) starting from Intermediate 13. Purification was performed by flash silica gel column chromatography using a linear gradient of 0-50% ethyl acetate in hexanes (Y=63%).

[0176] 5-(2-Fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 15). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 14 and methylhydrazine CAS:60-34-4. Purification was performed by flash silica gel column chromatography using a linear gradient of 0-100% ethyl acetate in hexanes (Y=17%).

[0177] 4-((4,4-difluorocyclohexyl)methyl)-5-(2-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 15 and bromide CAS:858121-94-5. Purification was performed by flash silica gel column chromatography using a linear gradient of 0% to 100% ethyl acetate (containing 1% TEA) in hexanes (Y=38%).

[0178] Example 27 4-(Cyclohexylmethyl)-5-(2-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0179] [ka]

[0180] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 15 and bromide CAS:2550-36-9. Purification was performed by flash silica gel column chromatography using a linear gradient of 0% to 100% ethyl acetate (containing 1% TEA) in hexanes (Y=41%).

[0181] Example 28 4-(Cycloheptylmethyl)-2-methyl-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0182] [ka]

[0183] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from Intermediate 12 and bromide CAS:3814-32-2. Purified by HPLC (Y=10%).

[0184] Example 29 4-(2-chloro-5-(5-fluoropyrimidin-2-yl)benzyl)-5-(4-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0185] [ka]

[0186] Ethyl 2-(4-fluorophenyl)acetimidate hydrochloride (Intermediate 16) The title compound was prepared by the general procedure (Scheme 1, Step 1) starting from commercially available nitrile CAS: 459-22-3.

[0187] Ethyl-N-(ethoxycarbonyl)-2-(4-fluorophenyl)acetimidate (Intermediate 17). The title compound was prepared by the general procedure (Scheme 1, Step 2) starting from Intermediate 16. Purification was performed by flash silica gel column chromatography using a linear gradient of 0-50% ethyl acetate in hexanes (Y=57%).

[0188] 5-(4-Fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 18). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 17 and methylhydrazine CAS:60-34-4. Purification was performed by flash silica gel column chromatography using a linear gradient of 0-100% ethyl acetate in hexanes (Y=23%).

[0189] Methyl 2-chloro-5-(5-fluoropyrimidin-2-yl)benzoate (Intermediate 19). The title compound was prepared by the general procedure (Scheme 2, Step 5) starting from the benzoic acid derivative CAS:1227807-75-1. Used in the next step without further purification.

[0190] (2-Chloro-5-(5-fluoropyrimidin-2-yl)phenyl)methanol (Intermediate 20). The title compound was prepared by the general procedure (Scheme 2, Step 6) starting from Intermediate 19. Purified by flash silica gel column chromatography using a linear gradient of 0-50% ethyl acetate in hexanes (Y=49%).

[0191] 2-(4-Chloro-3-(chloromethyl)phenyl)-5-fluoropyrimidine (Intermediate 21). The title compound was prepared by the general procedure (Scheme 2, Step 7) starting from Intermediate 20.

[0192] 4-(2-chloro-5-(5-fluoropyrimidin-2-yl)benzyl)-5-(4-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method B) starting from intermediate 18 and chloride (intermediate 21). Purification was performed by flash silica gel column chromatography using a linear gradient of 0% to 100% ethyl acetate (containing 1% TEA) in hexanes (Y=25%).

[0193] Example 30 5-(2-chloro-6-fluorobenzyl)-4-(2-(3,3-dimethylmorpholino)ethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0194] [ka]

[0195] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method B) starting from intermediate 3 and bromide CAS:1098202-59-5. Purified by HPLC (Y=20%).

[0196] Example 31 5-(Cyclohexylmethyl)-2-methyl-4-((2-methylpyridin-3-yl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0197] [ka]

[0198] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method B) starting from intermediate 9 and chloride CAS:120277-68-1. Purified by HPLC (Y=28%).

[0199] Example 32 4-((2,2-dimethylcyclohexyl)methyl)-5-(2-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0200] [ka]

[0201] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 15 and bromide CAS:1501249-61-1. Purification was performed by flash silica gel column chromatography using a linear gradient of 0% to 100% ethyl acetate (containing 1% TEA) in hexanes (Y=13%).

[0202] Example 33 5-(2-chloro-6-fluorobenzyl)-4-((2,2-dimethylcyclohexyl)methyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0203] [ka]

[0204] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:1501249-61-1. Purified by HPLC (Y=16%).

[0205] Example 34 5-(2-chloro-6-fluorobenzyl)-4-((4,4-difluorocyclohexyl)methyl)-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0206] [ka]

[0207] 5-[(2-chloro-6-fluorophenyl)methyl]-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 27). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 2 and ethyl hydrazine oxalate (1:1) CAS:6629-60-3 (Y=50%).

[0208] 5-[(2-chloro-6-fluorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, step 4, method A) starting from intermediate 27 and bromide CAS:858121-94-5. Purified by HPLC (Y=31%).

[0209] Example 35 5-(2-chloro-4-fluorobenzyl)-2-methyl-4-(spiro[2.5]octan-6-ylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0210] [ka]

[0211] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 6 and bromide CAS:1621225-50-0. Purified by HPLC (Y=33%).

[0212] Example 36 5-(2-chloro-4-fluorobenzyl)-4-(2-(4,4-difluorocyclohexyl)ethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0213] [ka]

[0214] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 6 and bromide CAS:2092565-10-9. Purified by HPLC (Y=39%).

[0215] Example 37 4-(Cycloheptylmethyl)-5-(2-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0216] [ka]

[0217] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from Intermediate 15 and bromide CAS:3814-32-2. Purified by HPLC (Y=17%).

[0218] Example 38 4-(2-chloro-5-(5-fluoropyrimidin-2-yl)benzyl)-5-(cyclohexylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0219] [ka]

[0220] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method B) starting from Intermediate 9 and the chloride (Intermediate 21). Purification was performed by flash silica gel column chromatography using a linear gradient of 0-100% ethyl acetate (containing 1% TEA) in hexanes (Y=48%).

[0221] Example 39 4-(2-(4,4-difluorocyclohexyl)ethyl)-2-methyl-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0222] [ka]

[0223] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 12 and bromide CAS:2092565-10-9. Purification was performed by flash silica gel column chromatography using a linear gradient of 0% to 100% ethyl acetate (containing 1% TEA) in hexanes (Y=33%).

[0224] Example 40 2-Methyl-5-(2-(trifluoromethyl)benzyl)-4-((4-(trifluoromethyl)cyclohexyl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0225] [ka]

[0226] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 12 and bromide CAS:858121-96-7. Purified by HPLC (Y=10%).

[0227] Example 41 5-(2-chloro-4-fluorobenzyl)-4-(2-(4,4-dimethylcyclohexyl)ethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0228] [ka]

[0229] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 6 and bromide CAS:570398-26-4. Purified by HPLC (Y=48%).

[0230] Example 42 5-(2-chlorobenzyl)-4-((4,4-difluorocyclohexyl)methyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0231] [ka]

[0232] Ethyl 2-(2-chlorophenyl)acetimidate hydrochloride (Intermediate 22) The title compound was prepared by the general procedure (Scheme 1, Step 1) starting from commercially available nitrile CAS: 2856-63-5.

[0233] Ethyl-2-(2-chlorophenyl)-N-(ethoxycarbonyl)acetimidate (Intermediate 23). The title compound was prepared by the general procedure (Scheme 1, Step 2) starting from Intermediate 22. Purification was performed by flash silica gel column chromatography using a 50-100% linear gradient of dichloromethane in hexanes (Y=34%).

[0234] 5-(2-Chlorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 24). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 23 and methylhydrazine CAS:60-34-4. Purification was performed by flash silica gel column chromatography using a linear gradient of 50-100% ethyl acetate in hexanes (Y=5%).

[0235] 5-(2-chlorobenzyl)-4-((4,4-difluorocyclohexyl)methyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 24 and bromide CAS:858121-94-5. Purified by HPLC (Y=43%).

[0236] Example 43 5-(2-chloro-6-fluorobenzyl)-2-(cyclopropylmethyl)-4-((4,4-difluorocyclohexyl)methyl)-2,4-dihydro-3H-1,2,4-triazol-one

[0237] [ka]

[0238] 5-(2-chloro-6-fluorobenzyl)-2-(cyclopropylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 25). The title compound was prepared by the general procedure (Scheme 1, step 3) starting from intermediate 2 and (cyclopropylmethyl)hydrazine CAS:809282-61-9 (Y=62%).

[0239] 5-(2-chloro-6-fluorobenzyl)-2-(cyclopropylmethyl)-4-((4,4-difluorocyclohexyl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, step 4, method A) starting from intermediate 25 and bromide CAS:858121-94-5. Purified by HPLC (Y=75%).

[0240] Example 44 5-(2-chloro-6-fluorobenzyl)-4-((4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0241] [ka]

[0242] 5-(2-chloro-6-fluorobenzyl)-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 26). The title compound was prepared by the general procedure (Scheme 1, step 3) starting from intermediate 2 and (2,2,2-trifluoroethyl)hydrazine CAS:5042-30-8 (Y=64%).

[0243] 5-(2-chloro-6-fluorobenzyl)-4-((4,4-difluorocyclohexyl)methyl)-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, step 4, method A) starting from intermediate 26 and bromide CAS:858121-94-5. Purified by HPLC (Y=48%).

[0244] Example 45 4-(2-(4,4-dimethylcyclohexyl)ethyl)-5-(2-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0245] [ka]

[0246] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 15 and bromide CAS:570398-26-4. Purified by HPLC (Y=19%).

[0247] Example 46 4-(2-(4,4-difluorocyclohexyl)ethyl)-5-(2-fluorobenzyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0248] [ka]

[0249] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 15 and bromide CAS:2092565-10-9. Purified by HPLC (Y=8%).

[0250] Example 47 5-(2-Fluorobenzyl)-2-methyl-4-(spiro[2.5]octan-6-ylmethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0251] [ka]

[0252] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 15 and bromide CAS:1621225-50-0. Purified by HPLC (Y=9%).

[0253] Example 48 2-Methyl-4-(spiro[2.5]octan-6-ylmethyl)-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0254] [ka]

[0255] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 12 and bromide CAS:1621225-50-0. Purified by HPLC (Y=43%).

[0256] Example 49 4-(2-(4,4-dimethylcyclohexyl)ethyl)-2-methyl-5-(2-(trifluoromethyl)benzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0257] [ka]

[0258] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 12 and bromide CAS:570398-26-4. Purified by HPLC (Y=31%).

[0259] Example 50 2-Benzyl-5-(2-chloro-6-fluorobenzyl)-4-((4,4-difluorocyclohexyl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0260] [ka]

[0261] 2-Benzyl-5-(2-chloro-6-fluorobenzyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 28). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 2 and benzylhydrazine dihydrochloride CAS:20570-96-1. Purification was performed by flash silica gel column chromatography using a linear gradient of 0% to 50% ethyl acetate in cyclohexane (Y=9%).

[0262] 2-benzyl-5-(2-chloro-6-fluorobenzyl)-4-((4,4-difluorocyclohexyl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method B) starting from intermediate 28 and bromide CAS:858121-94-5. Purified by HPLC (Y=5%).

[0263] Example 51 5-(2-Fluorobenzyl)-2-methyl-4-((4-(trifluoromethyl)cyclohexyl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0264] [ka]

[0265] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 15 and bromide CAS:858121-96-7. Purified by HPLC (Y=24%).

[0266] Example 52 5-(2-chloro-4-fluorobenzyl)-2-methyl-4-((4-(trifluoromethyl)cyclohexyl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0267] [ka]

[0268] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 6 and bromide CAS:858121-96-7. Purified by HPLC (Y=13%).

[0269] Example 53 5-(2-chloro-6-fluorobenzyl)-4-(2-hydroxyethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0270] [ka]

[0271] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:540-51-2. Purified by HPLC (Y=35%).

[0272] Example 54 5-[(2-chlorophenyl)methyl]-4-(cycloheptylmethyl)-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0273] [ka]

[0274] 5-[(2-chlorophenyl)methyl]-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 29). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 23 and (2,2,2-trifluoroethyl)hydrazine CAS:540-51-2. This product was used in the next step without purification (Y=41%).

[0275] 5-[(2-chlorophenyl)methyl]-4-(cycloheptylmethyl)-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 29 and bromide CAS:3814-32-2. Purified by HPLC (Y=16%).

[0276] Example 55 5-[(2-chlorophenyl)methyl]-4-(cycloheptylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0277] [ka]

[0278] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 24 and bromide CAS:3814-32-2. Purified by HPLC (Y=20%).

[0279] Example 56 5-[(2-chloro-6-fluorophenyl)methyl]-2-methyl-4-[(1-methylcycloheptyl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0280] [ka]

[0281] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 3 and bromide CAS:1936250-61-1. Purified by HPLC (Y=15%).

[0282] Example 57 5-[(2-chloro-6-fluorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-2-(3,3,3-trifluoropropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0283] [ka]

[0284] 5-[(2-chloro-6-fluorophenyl)methyl]-2-(3,3,3-trifluoropropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 30). The title compound was prepared by the general procedure (Scheme 1, step 3) starting from Intermediate 2 and (3,3,3-trifluoropropyl)hydrazine CAS:1446322-01-5. This product was used in the next step without purification (Y=67%).

[0285] 5-[(2-chloro-6-fluorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-2-(3,3,3-trifluoropropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, step 4, method A) starting from intermediate 30 and bromide CAS:858121-94-5. Purified by HPLC (Y=56%).

[0286] Example 58 5-[(2-chloro-6-fluorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-2-(2,2-difluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0287] [ka]

[0288] 5-[(2-chloro-6-fluorophenyl)methyl]-2-(2,2-difluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 31). The title compound was prepared by the general procedure (scheme 1, step 3) starting from intermediate 2 and (2,2-difluoroethyl)hydrazine CAS:1504582-53-9. This product was used in the next step without purification (Y=78%).

[0289] 5-[(2-chloro-6-fluorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-2-(3,3,3-trifluoropropyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, step 4, method A) starting from intermediate 31 and bromide CAS:858121-94-5. Purified by HPLC (Y=9%).

[0290] Example 59 4-[(2-chloro-6-fluorophenyl)methyl]-5-(cycloheptylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0291] [ka]

[0292] Ethyl 2-cycloheptylethaneimidate hydrochloride (Intermediate 32) The title compound was prepared by the general procedure (Scheme 1, Step 1) starting from the commercially available nitrile CAS: 5452-65-3.

[0293] Ethyl-2-cycloheptyl-N-(ethoxycarbonyl)ethaneimidate (Intermediate 33). The title compound was prepared by the general procedure (Scheme 1, Step 2) starting from Intermediate 32. Purification was carried out by flash silica gel column chromatography using hexane / EtOAc 4:1 v / v as eluent (Y=71%).

[0294] 5-(cycloheptylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 34). The title compound was prepared by the general procedure (scheme 1, step 3) starting from intermediate 33 and methylhydrazine CAS:302-15-8. It was used in the next step without purification (Y=90%).

[0295] 4-[(2-chloro-6-fluorophenyl)methyl]-5-(cycloheptylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, step 4, method B) starting from intermediate 34 and chloride CAS:55117-15-2. Purified by HPLC (Y=60%).

[0296] Example 60 4-[(2-chloro-6-fluorophenyl)methyl]-5-(cycloheptylmethyl)-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0297] [ka]

[0298] 5-(Cycloheptylmethyl)-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 35). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 33 and ethylhydrazine CAS:6629-60-3. It was used in the next step without purification (Y=90%).

[0299] 4-[(2-chloro-6-fluorophenyl)methyl]-5-(cycloheptylmethyl)-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, step 4, method A) starting from intermediate 35 and chloride CAS:55117-15-2. Purified by HPLC (Y=73%).

[0300] Example 61 4-[(2-chloro-6-fluorophenyl)methyl]-5-(cycloheptylmethyl)-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0301] [ka]

[0302] 5-(cycloheptylmethyl)-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 36). The title compound was prepared by the general procedure (scheme 1, step 3) starting from intermediate 33 and (2,2,2-trifluoroethyl)hydrazine CAS:5042-30-8. It was used in the next step without purification (Y=80%).

[0303] 4-[(2-chloro-6-fluorophenyl)methyl]-5-(cycloheptylmethyl)-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, step 4, method A) starting from intermediate 36 and chloride CAS:55117-15-2. Purified by HPLC (Y=88%).

[0304] Example 62 5-[(2-chlorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0305] [ka]

[0306] 5-[(2-chlorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 29 and bromide CAS:858121-94-5. Purified by HPLC (Y=12%).

[0307] Example 63 5-[(2-chlorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0308] [ka]

[0309] 5-[(2-chlorophenyl)methyl]-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 37). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 23 and ethyl hydrazine CAS:6629-60-3. It was used in the next step without purification (Y=38%).

[0310] 5-[(2-chlorophenyl)methyl]-4-[(4,4-difluorocyclohexyl)methyl]-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 37 and bromide CAS:858121-94-5. Purified by HPLC (Y=6%).

[0311] Example 64 5-[(2-chlorophenyl)methyl]-4-(cycloheptylmethyl)-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0312] [ka]

[0313] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 37 and bromide CAS:3814-32-2. Purified by HPLC (Y=7%).

[0314] Example 65 5-[(2-chloro-6-fluorophenyl)methyl]-4-[(3,3-difluorocyclopentyl)methyl]-2-ethyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0315] [ka]

[0316] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 27 and bromide CAS:1695914-13-6. Purified by HPLC (Y=75%).

[0317] Example 66 5-[(2-chloro-6-fluorophenyl)methyl]-2-(cyclopropylmethyl)-4-[(3,3-difluorocyclopentyl)methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one

[0318] [ka]

[0319] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 25 and bromide CAS:1695914-13-6. Purified by HPLC (Y=80%).

[0320] Example 67 5-[(2-chloro-6-fluorophenyl)methyl]-4-(cycloheptylmethyl)-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0321] [ka]

[0322] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 26 and bromide CAS:3814-32-2. Purified by HPLC (Y=99%).

[0323] Example 68 5-[(2-chloro-6-fluorophenyl)methyl]-4-[(1-methylpiperidin-2-yl)methyl]-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0324] [ka]

[0325] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 26 and bromide CAS:1390654-84-8. Purified by HPLC (Y=71%).

[0326] Example 69 5-(2-chloro-6-fluorobenzyl)-2-(cyclopropylmethyl)-4-((4-(trifluoromethyl)cyclohexyl)methyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0327] [ka]

[0328] The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 25 and bromide CAS:858121-96-7. Purified by HPLC (Y=78%).

[0329] Example 70 4-[(2-chloro-6-fluorophenyl)methyl]-5-[(4,4-difluorocyclohexyl)methyl]-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one

[0330] [ka]

[0331] Ethyl 2-(4,4-difluorocyclohexyl)ethaneimidate hydrochloride (Intermediate 38). The title compound was prepared by the general procedure (Scheme 1, Step 1) starting from commercially available nitrile CAS:959600-88-5.

[0332] Ethyl-2-(4,4-difluorocyclohexyl)-N-(ethoxycarbonyl)ethaneimidate (Intermediate 39). The title compound was prepared by the general procedure (Scheme 1, Step 2) starting from Intermediate 38. Purification was carried out by flash silica gel column chromatography using hexane / EtOAc 4:1 v / v as eluent (Y=45%).

[0333] 5-[(4,4-difluorocyclohexyl)methyl]-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (intermediate 40). The title compound was prepared by the general procedure (scheme 1, step 3) starting from intermediate 39 and (2,2,2-trifluoroethyl)hydrazine CAS:5042-30-8. It was used in the next step without purification (Y=81%).

[0334] 4-[(2-chloro-6-fluorophenyl)methyl]-5-[(4,4-difluorocyclohexyl)methyl]-2-(2,2,2-trifluoroethyl)-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, step 4, method A) starting from intermediate 40 and chloride CAS:55117-15-2. Purified by HPLC (Y=11%).

[0335] Example 71 4-[(2-chloro-6-fluorophenyl)methyl]-5-[(4,4-difluorocyclohexyl)methyl]-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one

[0336] [ka]

[0337] 5-[(4,4-difluorocyclohexyl)methyl]-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate 41). The title compound was prepared by the general procedure (Scheme 1, Step 3) starting from Intermediate 39 and methylhydrazine CAS:302-15-8. It was used in the next step without purification (Y=79%).

[0338] 4-[(2-chloro-6-fluorophenyl)methyl]-5-[(4,4-difluorocyclohexyl)methyl]-2-methyl-2,4-dihydro-3H-1,2,4-triazol-3-one. The title compound was prepared by the general procedure (Scheme 1, Step 4, Method A) starting from intermediate 41 and chloride CAS:55117-15-2. Purified by HPLC (Y=8%).

[0339] Table 1 lists the final compounds prepared according to the experimental procedures described in Example 1.

[0340] [Table 4-1]

[0341] [Table 4-2]

[0342] [Table 4-3]

[0343] [Table 4-4]

[0344] [Table 4-5]

[0345] [Table 4-6]

[0346] [Table 4-7]

[0347] [Table 4-8]

[0348] [Table 4-9]

[0349] [Table 4-10]

[0350] [Table 4-11]

[0351] [Table 4-12]

[0352] analysis part System purification HPLC preparative The HPLC system WATERS Quaternary Gradient Mobile 2535 was equipped with a WATERS UV / Visible Detector 2489, and dual wavelength UV detection was performed. Two types of mobile phase were used: Mobile Phase A: Water (MilliQ) 0.05% FA, Mobile Phase B: Acetonitrile (Chromasolv Sigma-Aldrich) 0.05% FA, and gradient conditions were set for each compound. Purification was performed with a Luna Phenomenex Column C18 5μm 19x150. The injection volume was 100-500μl, and the flow rate was 15ml / min. LCMS - Step 1 HPLC measurements were performed using a Dionex 3000 module including a quaternary pump with degasser, an autosampler, a column oven (set at 29 °C), a diode array detector DAD, and a column as specified for each method 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 acquired by scanning from 50 to 800 in 0.48 seconds. The capillary needle voltage was 5 kV in positive and negative ionization modes, and the source temperature was maintained at 275 °C. Nitrogen was used as the nebulizer gas with a flow rate of 8 l / min. Data acquisition was performed with a Thermo Xcalibur Qual Browser.

[0353] In addition to the general procedure: Reversed phase HPLC was performed on a Kinetex XB-C18 column Phenomenex (1.7 μm, 50x2.1 mm) at a flow rate of 0.300 ml / min. Two mobile phases were used: mobile phase A: ammonium formate buffer at pH 3.5; mobile phase B: acetonitrile (Chromasolv Sigma-Aldrich), with a gradient of 15% B to 50% for 15 min, 100% B for 0.9 min, 5% B for 0.1 min, and these conditions were held for 4 min to re-equilibrate the column. The injection volume was 5 μl. LCMS procedure 2 HPLC measurements were performed using a VANQUISH FLEX module including a quaternary pump with degasser, an autosampler, a column oven (set at 40°C), a diode array detector DAD, and a column as specified for each method below. The MS detector (ISQ Thermo Scientific) consisted of an electrospray ionization source. Mass spectra were acquired scanning from 100 to 700 in 0.2 seconds. The capillary needle voltage was 3 kV for positive ionization mode and 2 kV for negative ionization mode, and the source temperature was maintained at 250°C. Nitrogen was used as the nebulizer gas.

[0354] In addition to the general procedure: Reversed phase UHPLC was performed using a Luna Omega-C18 column Phenomenex (1,6 μm, 50x2.1 mm) at a flow rate of 0.600 ml / min. Two mobile phases were used: Mobile phase A: Water (LC-MS grade) 0.1% FA; Mobile phase B: Acetonitrile (LiChrosolv for LC-MS Merck) with a gradient of 15% B in 0.2 min, 15% to 95% in 1.6 min, 95% B in 0.60 min, 15% B in 0.10 min, and these conditions were held for 1.05 min to re-equilibrate the column (total run time 3.55 min). Injection volume was 0.8 μl. Data acquisition was performed on a Chromeleon 7.

[0355] [Table 5-1]

[0356] [Table 5-2]

[0357] NMR characterization 1 H NMR spectra were recorded on a Bruker NMR 400 MHz or 600 MHz spectrometer using CDCl3 as the solvent. Chemical shifts (δ) are reported in parts per million (ppm) relative to tetramethylsilane (TMS), which was used as the internal standard.

[0358] [Table 6-1]

[0359] [Table 6-2]

[0360] [Table 6-3]

[0361] [Table 6-4]

[0362] [Table 6-5]

[0363] [Table 6-6]

[0364] Pharmacological Examples Examples of the present invention were found to be active in the automated patch clamp human P2X7 channel assay.

[0365] To directly monitor the blockade of P2X7 channels, an electrophysiological assay was developed and performed on a QPatch16X automated electrophysiological instrument. HEK-293 cells expressing P2X7 channels were cultured in modified EMEM.

[0366] Five million cells were seeded into a T225 flask 72 hours prior to the experiment. Immediately prior to the experiment, the cells were washed twice, detached from the flask with trypsin-EDTA, resuspended in suspension, and placed on a QPatch16x.

[0367] Compounds (20 mM in 100% DMSO) stored at -20°C were prepared on the day of the experiment (initial dilution 1:20 in 100% DMSO to prepare a 1 mM stock solution, followed by a 1 microM solution in external solution + serial dilution 1:10).

[0368] Standard whole-cell voltage clamp experiments were performed at room temperature, and data from these experiments were sampled at 2 KHz using multihole technology. The intracellular solution contained (mM) 135 CsF, 10 NaCl, 1 EGTA, 10 HEPES, (pH 7.2 with CsOH), while the extracellular solution contained (mM) 145 NaCl, 4 KCl, 0.5 MgCl2, 1 CaCl2, 10 HEPES, 10 Glc (pH 7.4 with NaOH).

[0369] After establishing a seal and passing in the whole-cell configuration, cells were held at -80 mV. P2XR7 currents were evoked by adding 100 microM BzATP alone (four times) followed by the presence of increasing concentrations of the compound of interest (1, 10, 100, and 1000 nM).

[0370] Pre-incubation periods 5 to 8 contain steps of increasing concentrations of the compound of interest (1, 10, 100, and 1000 nM) as indicated in the figure (Application Protocol).

[0371] Figure: Application protocol. The maximal inward current evoked by BzATP was measured in the absence or presence of increasing concentrations of the compound of interest and normalized. Potential agonist effects were measured as % of control and IC50 determined by fitting the dose-response curve data to the following equation: Y=100 / (1+10^((LogIC50-X)*HillSlope)) During the ceremony: X = logarithm of concentration Y = normalized response, from 100% to 0%, decreasing as X increases.

[0372] LogIC 50 : Same logarithmic units as X. HillSlope: Slope coefficient or HS, unitless. Here, potency ranges are reported as A, B, C, and D, where A is less than 10 nM, B is 10 nM to 100 nM, C is 0.1 to 1 μM, and D is 1 to 10 μM.

[0373] [Table 7-1]

[0374] [Table 7-2]

[0375] Compounds of the invention were found to be active in the human P2X7 channel calcium influx assay. Extracellular binding of Bz-ATP to the P2X7 receptor opens the channel, allowing Ca 2+ This Ca influx was measured in HEK-293 cells stably transfected with the P2X7 receptor using the Screen Quest™ Fluo-8 No Wash Calcium Assay Kit (AAt Bioquest®, cat. 36316). 2+ Fluo-8 was then stimulated with Bz-ATP to measure calcium influx. Once inside the cells, the lipophilic protecting group of Fluo-8 is cleaved by nonspecific cellular esterases, resulting in a negatively charged fluorescent dye that remains intracellularly. Its fluorescence increases upon binding to calcium. When HEK-293 / P2X7 cells are stimulated with Bz-ATP, Ca 2+ enters the cells, increasing the fluorescence of Fluo-8 NW. This dye has an absorption spectrum that is compatible with excitation at 488 nm by an argon laser light source, and its emission wavelength is in the range of 515–575 nm.

[0376] HEK-293 cells stably transfected with P2X7 receptor were seeded overnight in growth medium at 10,000-20,000 cells / well in 384-well plates. After 24 hours, medium was removed and cells were preloaded with 20 μL / w Fluo-8 NW for 1 hour at room temperature. Then, 10 μL / w test compound and 3× concentration of control antagonist A438079 were injected by FLIPRTETRA and the kinetic response was monitored over 5 minutes. 15 μL / w 3× control activator (EC 80A second injection of 0.5 mM Bz-ATP was performed using the FLIPR TETRA and the emitted fluorescence signal was recorded for an additional 3 min. All experiments were performed in low divalent cation assay buffer (0.3 mM Ca). 2+ and 0 mM Mg 2+ The effect of the test compound was measured as a percentage of inhibition relative to the control antagonist and was expressed accordingly as IC 50 Potency ranges are reported here as A, B, C, and D, where A is less than 200 nM, B is 200 nM to 1 μM, C is 1 to 10 μM, and D is 10 to 30 μM.

[0377] [Table 8-1]

[0378] [Table 8-2]

Claims

1. A compound of formula (I) below, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 including any stereochemically isomeric forms thereof, wherein R is an aromatic, aliphatic, heteroaromatic, or heteroaliphatic ring; wherein R is optionally substituted with one or more substituents selected from: Halogens and C １ ~C ４ Alkyl, the C １ ~C ４ The alkyl is optionally substituted with one or more halogens; R １ is C ３ ~C ６ is cycloalkyl; wherein R 1 is optionally substituted with one or more substituents selected from: halogen or C 1 -C 4 alkyl, １ ~C ４ The alkyl is optionally substituted with one or more substituents selected from the following: halogen, OR 3 , NR 4 R 5 , C 3 -C 6 cycloalkyl, ３ ~C ６ cycloalkyl optionally substituted with one or more halogens; and phenyl rings, the phenyl rings optionally substituted with one or more halogens; n is 1 or 2, preferably n is 1; R ２ is selected from —OH, aromatic, heteroaromatic, aliphatic and heteroaliphatic monocyclic or bicyclic rings; wherein the aromatic, heteroaromatic, aliphatic and heteroaromatic monocyclic or bicyclic rings are optionally substituted with one or more substituents selected from: Halogen, C １ ~C ４ Alkyl, the C １ ~C ４ alkyl optionally substituted with one or more halogens, and heteroaromatic rings, the heteroaromatic rings optionally substituted with one or more halogens; R 3 is H or C 1 -C 4 alkyl, said C 1 -C 4 alkyl optionally substituted with one or more halogens; and R 4 and R 4 are independently H or C 1 -C 4 alkyl, wherein the C 1 -C 4 alkyl is optionally substituted with one or more halogens; The compound, or a pharmaceutically acceptable salt thereof.

2. 10. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, including any stereochemically isomeric forms thereof, wherein: R is phenyl, pyridinyl, cyclohexyl, cycloheptyl, piperidinyl, or piperazinyl; wherein R is optionally substituted with one or more substituents selected from: halogens, preferably Cl and F; and C １ ~C ４ Alkyl, preferably methyl, １ ~C ４ Alkyl is optionally substituted with one or more halogens, preferably methyl or trifluoromethyl. That is, The compound, or a pharmaceutically acceptable salt thereof.

3. 10. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, including any stereochemically isomeric forms thereof, wherein: R １ is C １ ~C ４ alkyl (preferably methyl or ethyl); wherein R 1 is optionally substituted with one or more substituents selected from: one or more halogens (preferably F); C ３ ~C ４ cycloalkyl (preferably cyclopropyl), wherein the C 3 -C 4 cycloalkyl is optionally substituted with one or more halogen atoms (preferably F); and phenyl ring; The compound, or a pharmaceutically acceptable salt thereof.

4. 10. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, including any stereochemically isomeric forms thereof, wherein: R ２ is —OH or an aromatic, aliphatic, heteroaromatic or heteroaliphatic ring; The aromatic, aliphatic, heteroaromatic or heteroaliphatic ring may be phenyl, C ３ ~C ７ Cycloalkyl, C ６ ~C ８ selected from bicycloalkanyl, pyridinyl, piperidinyl, tetrahydrofuranyl, and morpholinyl; wherein the aromatic, aliphatic, heteroaromatic or heteroaliphatic ring is: is optionally substituted with one or more substituents selected from: halogen; a heteroaromatic ring, the heteroaromatic ring being optionally substituted with one or more halogens; and C １ ~C ４ Alkyl, the C １ ~C ４ The alkyl is optionally substituted with one or more halogens. The compound, or a pharmaceutically acceptable salt thereof.

5. 10. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, including any stereochemically isomeric forms thereof, wherein: R is selected from cycloheptyl, cyclohexyl, or phenyl; wherein R is optionally substituted with one or more substituents selected from: halogen (preferably F or Cl); C 1 -C 4 alkyl (preferably methyl); １ ~C ４ The alkyl is optionally substituted with halogen (preferably F); R １ teeth, C １ ~C ４ alkyl (preferably methyl or ethyl); C ３ ~C ４ cycloalkyl (preferably cyclopropyl); or phenyl ring; is selected from The C 1 -C 4 alkyl or C ３ ~C ４ The cycloalkyl is optionally substituted with halogen (preferably F); n is 1 or 2, preferably n is 1; and R ２ is selected from: Phenyl, said phenyl being optionally substituted with one or more substituents selected from: halogen (preferably F or Cl); C １ ~C ４ Alkyl, the C １ ~C ４ The alkyl is optionally substituted with one or more halogens (preferably F), and pyrimidinyl, the pyrimidinyl optionally substituted with one or more halogens (preferably F); pyridinyl, the pyridinyl being one or more C １ ~C ４ Optionally substituted with alkyl (preferably methyl), １ ~C ４ The alkyl is optionally substituted with one or more halogens (preferably F); piperidinyl, the piperidinyl being one or more C １ ~C ４ optionally substituted with alkyl (preferably methyl); cyclohexyl, said cyclohexyl being optionally substituted with one or more substituents selected from: halogen (preferably F), and C １ ~C ４ Alkyl (preferably methyl), １ ~C ４ The alkyl is optionally substituted with one or more halogens (preferably F); cyclopropyl, cyclopentyl, or cycloheptyl; said cyclopropyl, cyclopentyl, or cycloheptyl optionally substituted with one or more halogens (preferably F); tetrahydrofuranyl; morpholinyl, the morpholinyl being one or more C １ ~C ４ optionally substituted with alkyl (preferably methyl); Bicyclo[3.1.0]hexan-3-yl; spiro[2.5]octan-6-yl, the spiro[2.5]octan-6-yl optionally substituted with one or more halogens (preferably F); and -OH, or a pharmaceutically acceptable salt thereof.

6. 10. A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, including any stereochemically isomeric forms thereof, wherein: R is independently selected from cyclohexyl, 4,4-difluorocyclohexyl, cycloheptyl, 2-chloro-6-fluorophenyl, 2-chloro-4-fluorophenyl, 2-fluorophenyl, 4-fluorophenyl, 2-chlorophenyl, and 2-trifluoromethylphenyl; R １ is independently selected from hydrogen, methyl, ethyl, 2,2,2-trifluoroethyl, cyclopropylmethyl, benzyl, 3,3,3-trifluoropropyl, and 2,2-difluoroethyl; n is 1 or 2, preferably n is 1; and R ２ is independently selected from 4-fluorophenyl, 2-chloro-6-fluorophenyl, 2-trifluoromethylphenyl, 2-chloro-5-(5-fluoropyrimidin-2-yl)phenyl, 2-methylpyridin-3-yl, cyclohexyl, 4,4-difluorocyclohexyl, 3,3-difluorocyclopentyl, 6,6-difluorobicyclo[3.1.0]hexan-3-yl, 4-fluorocyclohexyl, 4-trifluoromethylcyclohexyl, cycloheptyl, 2-(trifluoromethyl)pyridin-4-yl, 4-spiro[2.5]octan-6-yl, 4,4-dimethylcyclohexyl, tetrahydrofuran-2-yl, 1-methylpiperidin-2-yl, morpholinyl, 2,2-dimethylcyclohexyl, 3,3-dimethylmorpholinyl, cycloheptylmethyl, and —OH; The compound, or a pharmaceutically acceptable salt thereof.

7. The group consisting of: 【Table 1-1】 【Table 1-2】 【Table 1-3】 【Table 1-4】 2. The compound of formula (I) according to claim 1, selected from:

8. A process for preparing a compound of formula (I) according to claim 1, comprising the step of: Compound: 【Chemistry 2】 (Wherein R and R １ is as defined in claim 1 ), and Compounds of formula (III): 【Chemistry 3】 (In the formula, R ２ and n is as defined in claim 1 and X is a suitable leaving group), and optionally converting the resulting compound of formula (I) into its addition salts and / or preparing its stereochemically isomeric forms. A process involving:

9. A pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, in any stereochemically isomeric form, and a pharmaceutically acceptable diluent and / or carrier.

10. 10. A pharmaceutical composition for use as a medicament, said pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, said compound, or a pharmaceutically acceptable salt thereof, including any stereochemically isomeric form thereof.

11. 10. A pharmaceutical composition for use in the treatment of a condition or disease selected from P2X7 receptor mediated conditions or diseases, said pharmaceutical composition comprising a compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, said compound, or a pharmaceutically acceptable salt thereof, including any stereochemical isomer thereof.

12. The pharmaceutical composition for use according to claim 11, wherein the condition or disease is selected from neurodegenerative disorders, cognitive disorders, psychiatric disorders, neuropathic pain, chronic pain, inflammatory processes of the musculoskeletal system, liver fibrosis, gastrointestinal disorders, genitourinary tract disorders, eye diseases, chronic obstructive pulmonary disease (COPD), cancer and proliferative diseases.

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