Bicyclic amine derivatives as gabaa α5 receptor modulators

Abstract

This invention provides compounds of formula (I) having affinity and selectivity for γ-aminobutyric acid A receptor subunit α5 and serving as positive allosteric modulators of GABAA α5, and / or their salts and / or their stereoisomers and / or their mirror-image isomers and / or their racemic derivatives and / or their non-mirror-image isomers and / or their bioactive metabolites and / or their prodrugs and / or their solvates and / or their hydrates and / or their polymorphs, thereby enabling their use in the treatment or prevention of diseases related to the GABAA α5 receptor, methods for their preparation and intermediates of their preparation, pharmaceutical compositions comprising one or a combination of the other with one or more other active ingredients, and their use as pharmaceutical agents.

Description

Technical field

[0001] []

[0002] The present invention provides compounds of formula (I) that have affinity and selectivity for γ-aminobutyric acid A receptor subunit α5 (GABA Aα5) and serve as GABA Aα5 positive allosteric modulators (GABA Aα5 PAM), so that they can be used For the treatment or prevention of diseases related to GABA Aα5 receptors, preparation methods and intermediates thereof, pharmaceutical compositions containing them and their use as pharmaceuticals. prior art

[0003] []

[0004] Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the central nervous system. GABA-sensitive receptors are divided into two main families, ligand-gated GABA A receptors and G-protein-coupled GABA B receptors.

[0005] Ligand-gated GABA A receptors mediate the majority of inhibitory neurotransmission in the adult mammalian brain. The receptor is composed of a pentameric assembly of multiple subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3) that form a ligand-gated chloride channel ( Olsen and Sieghart, Pharmacol Rev2008, 60:243-260). Subunit distribution varies across development and region in the brain. This high variability leads to widespread changes in inhibitory and, under certain conditions, excitatory neural mechanisms and offers the possibility for specific therapeutic interventions (Fritschy and Möhler, J Comp Neurol1995, 359:154-194; Jacob, Front Mol Neurosci2019 , 12: Art 179). The physiological role and pharmacological profile of GABA A receptors are strongly dependent on subunit composition. Studies in genetically engineered mice have shown that receptor subunit composition, particularly with respect to the alpha isoform, largely determines the response to benzodiazepine-sensitive allosteric regulatory sites (BDZ sites). Pharmacology of compounds (Rudolph and Knflach, Nat Rev Drug Discov2011, 10:685-697). Widely distributed α1-containing receptors mediate sedation and amnesia effects, while α2 and α3-containing receptors produce anxiolytic, antiepileptic, and muscle relaxant effects (Sieghart and Sperk, Curr Top Med Chem2002, 2:795-816 ;Whiting et al., Drug Discov Today2003, 8:445-450). Receptors containing α5 subunits (α5GABA AR) are preferentially expressed in the hippocampus, prefrontal cortex, amygdala and dependent nucleus (Olsen and Sieghart, Neuropharmacology2009, 56:141-148; Sur et al., Brain Res1999, 822: 265-270;Martin et al., Biochem Soc Trans2009, 37:1334-1337), and is considered to be related to a variety of CNS diseases.

[0006] α5-containing receptors are primarily extrasynaptic and mediate tonic inhibition (Caraiscos et al., Proc Natl Acad SciUSA 2004, 101:3662-3667). In contrast to its inhibitory role in the mature nervous system, α5GABA AR can trigger excitation in early hippocampal circuit development (Marchionni et al., J Physiol. 2007, 581:515-528). Its regulatory effect on the excitability of main neurons in the hippocampus and cortex can explain the significant effects of α5GABA AR on neuronal development, cognition, learning and memory, as well as its effects on stroke, mild cognitive impairment, and schizophrenia. , depression, conditions related to dementia or disorders associated with social cognitive impairment or neurodevelopmental disorders (such as Down syndrome or autism spectrum disorder (ASD)) (Jacob, Front Mol Neurosci2019 , 12: Art 179; Mohamad and Tarmizi Che Has, J Mol Neurosci2019, 67:343-351; Soh and Lynch, Curr Drug Targets2015, 16:735-746).

[0007] Through enhanced neuronal plasticity (Martin et al., J Neurosci2010, 30:5269-5282) and network oscillatory activity (Towers et al, J Physiol2004, 559:721-728; Glykis and Mody, Neurophysiol2008, 95:2796-2807 ), genetic and pharmacological reduction of α5-mediated sustained suppression improves learning and memory (Möhler and Rudolph, F1000Res2017 Feb 3;6. pii: F1000 Faculty Rev-101). However, high activity in the hippocampus and cortex caused by reduced α5GABA AR function may also lead to hyperkinesis and impaired sensorimotor gating (Hauser et al., Mol Psychiatry2005, 10:201-207), and social behavioral deficits (Zurek et al. ., Ann Clin Transl Neurol2016, 3:392-398) and cognitive deficits in rodents (Engin et al., J Neurosci2015, 35:13698-13712; Martin et al., J Neurosci2010, 30:5269-5282; Prut et al., Genes Brain Behav2010, 9:478-488), whose behavioral changes are characteristic of various CNS disorders. In such pathological conditions, promoting rather than blocking α5GABA AR function may be a promising approach to treat the positive, negative, and cognitive symptoms associated with these diseases. In support of this notion, virus-induced overexpression of the α5 subunit of GABA A receptors in the ventral hippocampus normalizes physiological and behavioral deficits in a rat model of schizophrenia (Donegan et al., Nature Communications 2019, 10 :2819).

[0008] The University of Wisconsin-Milwaukee describes certain 4H-benzo[f]imidazo[1,5-a][1,4]diazepine derivatives (WO 2017 / 161370 A1) as α5-preferring PAM compounds. , such as, SH-053-2'F-R-CH3, MP-III-022 or GL-II-73 (Stamenić et al. Eur J Pharmacol2016, 791:433-433; Savic et al., Neuropsychopharmacology2008, 33:332- 339; Prevot et al., ACS Chem. Neurosci. 2019, 10:2088-2090), which shows pro-cognitive, anxiolytic and antidepressant effects in mouse stress models and aged mice (Prevot et al., Mol Neuropsychiatry 2019, 5:84-97). MP-III-022 and 6,7-dihydro-2-benzothiophene-4(5 H)-one α5 PAM compound 44 (Chambers et al., J Med Chem2003, 46:2227-2240) respectively improved youth and Cognitive performance in aged rats (Poe, Michael M., These and Dissertations.1301 (2016) https: / / dc.uwm.edu / etd / 1301; Koh et al. Neuropharmacology2013, 64:145:152). Acute treatment with GL-II-73 rescued chemically induced behavioral deficits in a mouse model of depression (Fee et al., Int J Neuropsychopharmacol 2021, 24:505-518), while long-term treatment with GL-II-73 Treatment also reversed age-related neuronal atrophy and working memory deficits in adult mice (Sibille et al., Biol Psychiatry2020, 87:Suppl1, page S85). In addition, SH-053-2'F-R-CH3 and MP-III-022 attenuated pathological changes in motor activity in rats with developmental patterns of schizophrenia (Gill et al., Neuropsychopharmacology 2011, 36:1903-1911; Batinic et al. Int J Dev Neurosci2017, 61:31-39).

[0009] AgeneBio Inc. describes the imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine derivative as GABA Aα5 PAM, and in Preclinical evidence from biological studies of age-related cognitive impairment found that these compounds occupy GABA Aα5 receptors in the hippocampus in the context of excessive hippocampal activity (Press release, AgeneBio, 11 Sep 2019; https: / / www.agenebio.com / agenebio-announces-additional-funding-to-advance-novel-gaba-a-therapeutic-program-to-address-alzheimers-and-other-cns-conditions / ), because of its pilot series Potent and selective compound with good in vivo efficacy in age-impaired rats (https: / / grantome.com / grant / NIH / R44-AG063607-01).

[0010] According to the present invention, the best indication is autism spectrum disorder (ASD). ASD is a complex heterogeneous neurodevelopmental disorder characterized by deterioration of social relationships, reduced communication, typical repetitive behaviors, and impairment of executive functions (Anagnostou et al., CMAJ2014, 186:509-519; Diagnostic and statistical manual of mental disorders. 5th ed. Arlington, VA: American Psychiatric Association; 2013 - Diagnostic Criteria for 299.00 Autism Spectrum Disorder). There are no drugs approved to treat the core symptoms of ASD. Current pharmacological treatments are limited to the atypical antipsychotics risperidone and aripiprazole, which are approved for the treatment of aggression and irritability associated with ASD (Anagnostou et al., Curr Opin Neurol 2018, 31:119-125). Antidepressants are prescribed off-label for the relief of obsessive-compulsive symptoms in ASD; the efficacy and tolerability of these treatments are modest (Carrasco et al., Pediatrics 2012, 129:e1301-e1310), so more information is needed for these conditions. There is an unmet need for selective, pathophysiologically based treatments.

[0011] ASD may be related to genomic alterations coupled to the GABA AR subunit. A chromosomal abnormality has been reported in patients with ASD, namely, duplication of copy number variations in the q11.2-13 region on chromosome 15. In humans, this region contains genes encoding the α5, β3, and γ3 subunits of GABA A receptors (Coghlan et al., Neurosci Biobehav Rev2012, 36:2044-2055). Exosome studies in autism patients identified missense mutations in Gabra5 - / - and RDX, the genes for the α5GABA AR and its anchoring protein radixin, further supporting α5GABA AR deficiency in ASD (Zurek et al., Ann Clin Transl Neurol 2016 , 3:392-398). Increasing evidence demonstrates the excitatory / inhibitory (E / I) imbalance caused by the deterioration of GABA function in ASD. Decreased expression of GABA synthases GAD65 and GAD67 and reduced GABA A receptor density have been reported in postmortem ASD brains (Fatemi et al., Biol Psychiatry2002 52:805-810; Oblak et al., Autism Res2009, 2:205 -219). In imaging studies using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS), reduced GABA concentration and GABA A receptor availability have been reported in patients with ASD (Mori et al. , Brain Dev2011, 34:648-654;Puts et al., Autism Res2016, 10:608-619;Robertson et al., Curr Biol2016, 26:80-85). A pilot PET study showed that the binding of the α5GABA AR selective tracer [11C]Ro154513 was reduced in multiple brain regions, suggesting that α5GABA AR levels were reduced in ASD (Mendez et al., Neuropharmacology 2013, 68:195-201). Another study showed changes in GABA sensitivity in perceptual tasks in patients with ASD (Horder et al., Sci Transl Med2018, pii:eaam8434). In line with these observations, postmortem analysis revealed reduced α5GABA AR expression (Blatt et al., J Autism Dev Disord, 2001, 31:537-54; Fatemi et al., J Autism Dev Disord, 2010, 40:743- 750). It can be considered that patients with ASD have impaired GABA function, so promoting cortical inhibition and restoring E / I balance through α5 PAM may be a feasible therapeutic strategy for the treatment of this disease.

[0012] Increased neuronal excitability in the cortex may contribute to autism-like behavioral deficits in rodents (Yizhar et al., Nature2011, 477:171-178). Genetic reduction of α5GABA AR supports clinical findings in Gabra5 − / − mice showing reduced persistence of current and increased excitability of primary hippocampal neurons (Bonin et al., J Neurophysiol 2007, 98:2244-2254). In addition to impaired executive functions, strong autism-like behaviors and pathology are observed in Gabra5 - / - mice (Zurek et al., Ann Clin Transl Neurol2016, 3:392-398; Mesbah-Oskui et al. , Neurotoxicol Teratol2017, 61:115-122). Likewise, Fragile Oostra, Cytogenet Genome Res2003, 100:111-123).

[0013] The prenatal valproate model has excellent construct and face validity, so it is a widely accepted disease model for ASD (Christensen et al., JAMA2013, 309:1696-1703; Roullet et al., Neurotox Teratol . 2013, 36:45-56). In this method, a single dose of valproic acid is administered to timed-mated female Wistar rats on gestation day 12.5. Following study drug treatment, offspring were behaviorally examined in a social preference assay on postpartum day 59. The social preference test is a highly accepted assay for assessing autistic behavior in rodents (Nadler et al., Genes Brain Behav2007, 3:303-314; Bambini-Junior et al., Brain Res2011, 1408:8-16 ). Briefly, in this assay, test animals are allowed to study conspecifics separated by a dividing perforated wall or similar area, however, there is no target conspecific. Autistic animals (such as rats prenatally exposed to valproate) spend little time engaging in social investigation during testing. It is believed that the reduced social behavior of animals treated with VPA can be reversed to normal levels by restoring inhibitory synaptic transmission mediated by α5GABA A receptors (Wang et al., Front Neurol2018, 9:Article 1052). Therefore, embodiments of the present invention may have substantial behavioral benefits in this preclinical disease model that recapitulates core symptoms of ASD. Therefore, it can be proposed that the compounds of the present invention (specifically GABA Aα5 PAM) may have therapeutic potential for the core symptoms of autism spectrum disorder in humans.

[0014] Positive modulators of GABA-A receptors, such as low-dose non-selective clonazepam, have also been shown to improve symptoms in preclinical models of ASD (Han et al., Nature2012,489:385- 390;Okamoto et al., J Neuroimmunol2018, 321:92-96), increasing expectations that clinically used benzodiazepines can be used to treat this disease at very low doses. In addition to this strategy, subunit-selective compounds, such as α2 / 3 modulators (AZD7325; https: / / www.clinicaltrials.gov / ct2 / show / NCT03678129) or α5 forward allosteric modulators, may provide novel therapeutic options for the treatment of ASD. Alternative approaches to improved therapeutic windows. Accordingly, the α5-selective PAM compound RG7816 (RO7017773) is in Phase II clinical development for the treatment of ASD (https: / / www.clinicaltrials.gov / ct2 / show / NCT04299464).

[0015] Therefore, compounds with high affinity and selectivity for α5GABA AR and GABAAα5 PAM respectively can be used alone or in combination with one or more other active ingredients for the treatment or prevention of one of the symptoms and / or syndromes of the disease. Central nervous system diseases that may be related to GABA Aα5 receptors. These include, but are not limited to, neurodevelopmental disorders such as autism spectrum disorder (ASD) (Mendez et al., Neuropharmacology2013, 68:195-201), fragile X disease (Curia et al., Cereb. Cortex2009, 19: 1515-1520), Prader-Willi syndrome (Bittel et al., J Med Genet2003, 40:568-574) or Down syndrome (Braudeau et al., J Psychopharmacology2011, 25:1030- 1042;Martinez-Cue et al., J Neurosci2013, 33: 953-966), neurocognitive diseases (Collinson et al., J Neurosci2002, 22:5572-5580), such as Alzheimer's disease, AD ) (Kwakowsky et al., J Neurochem 2018, 145:374-392; Solas et al., Curr Pharm Des2015; 21:4960-4971; Wu et al., Nat Commun2014, 4159), prodromal AD and mild Cognitive impairment (Maubach, Curr Drug Targets CNS Neurol Disord2003, 2: 233-239), vascular cognitive impairment and vascular dementia (Gacsályi et al., Eur J Pharmacol2018, 834:118-125), frontotemporal Lobar degeneration, including frontotemporal dementia, progressive superior ophthalmic nerve nucleus palsy and corticobasal syndrome (Murley and Rowe, Brain2018, 5:1263-1285), dementia with Lewy bodies (Khundakar et al., Acta Neuropathol Commun2016, 4:66), age-related memory impairment and cognitive decline (Koh et al., Neuropharmacology2013, 64:142-152), cognitive impairment associated with brain cancer, including but not Limited to medulloblastoma (Sengupta et al., CNS Oncol2014, 3:245-247), postoperative dementia (Cheng et al., J Neurosci2006, 26:3713-3720), and inflammation-induced dementia ( Wang et al., Cell Rep2012, 2: 488-496), HIV-related neurocognitive disorders (Green and Thayer, Neuropharmacology2019, 149:161-168), disease-related cognitive impairments, including but not limited to bias Headache and tension headache (Russo et al., Am J Hum Genet2005, 76:327-333), multiple sclerosis (Kammel et al., Neuroscience2018, 395:89-100), Parkinson's disease (Blaszczyk, Front Neurosci 2016, 10:269-277), epilepsy (McGinnity et al., Brain Commun2021, 3(1):fcaa190; Schipper et al., Mol Neurobiol2016, 53:5252-5265), attention deficit hyperactivity disorder and Adult attention deficit disorder (Bollmann et al., Transl Psychiatry2015, 8:e589; Edden et al., Arch Gen Psychiatry2014, 69: 750-753) or other CNS disorders, including but not limited to post-traumatic stress disorder (Lu et al. , Neuronal Plast2017, 2017:5715816 ), schizophrenia (Guidotti et al., Psychopharmacology2005, 180:191-205), positive, negative and / or cognitive symptoms related to schizophrenia (Asai et al ., Schizophrenia Res2008, 99:333 -340;Donegan et al., Nature Communications2019, 10:Article number 2819;Gill et al., Neuropsychopharmacology2011, 36:1903-1911;Hauser et al., Mol Psychiatry2005, 10:201- 207;Marques et al., Mol Psychiatry2021, 26:2616-2625;Redrobe et al., Psychopharmacology2012, 221: 451-468), bipolar disorder (Otani et al., Neurosci Lett2005, 381:108-113), hepatitis Tinton's disease (Du et al., Front Mol Neurosci.2017, 10:198), neurofibromatosis type I (Ribeiro et al., Cortex2015, 64:194-208), sleep disorders (Mesbah-Oskui et al. al., Neurotoxicol Teratol2017, 61:115-122), substance-related and addictive disorders, including but not limited to alcohol use disorder or gambling disorder (Mick et al., Addict Biol2017, 22:1601-1609; Stephens et al., Addict Biol2017, 22:1601-1609; al., Eur J Pharmacol2005, 526: 240-250), fetal alcohol cluster disorder (Toso et al., Am J Obstet Gynecol2006, 195:522-527), affective disorders (Bugay et al., Neuropsychopharmacology2020, 45:2289- 2298;Carreno et al., Int J Neuropsychopharmacology2017, 20:504-509;Choudary et al., Proc Natl Acad Sci USA2005, 102:15653-15658;Fischell et al., Neuropsychopharmacology2015; 40:2499-2509), psychiatric disorders (Wearne et al., Neuropharmacology2016, 111:107-118), substance-induced psychiatric disorders (Neugebauer et al., Behav Brain Res2018, 342:11-18), anxiety disorders (Behlke et al., Neuropsychopharmacology2016, 41:2492 -2501;Botta et al., Nat Neuroscience2015, 18:1493-1500), fear-related disorders (Botta et al., Nat Neuroscience2015, 18:1493-1500; Crestani et al., Proc Natl Acad Sci USA2002, 99 :8980-8985), stress disorders (Fischell et al., Neuropsychopharmacology2015; 40:2499-2509), neuropsychiatric symptoms related to Alzheimer's disease (Xu et al., Psychopharmacology2018, 235:1151-1161), stroke (Clarkson et al., Nature2010, 468:305-309; Lake et al., J Cereb Blood Flow Metab2015, 35:1601-1609), traumatic brain injury (Khodaei et al., Crit Care Med2020, 48:533- 544), neuropathic pain (Hérnandez-Reyes et al., Pain2019, 160:1448-1458) and inflammatory pain (Bravo-Hernández et al., Eur J Pharmacol.2014, 734:91-97; Munro et al., Neuropharmacology2011, 61:121-132). Modulation of α5GABA AR may also be beneficial in treating diseases and conditions, including, but not limited to, bronchoconstrictive diseases such as, but not limited to, asthma, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia (Gallos et al., Am J Physiol Lung Cell Mol Physiol 2015 , 308:L931-942;Mizuta et al., Am J Physiol Lung Cell Mol Physiol2008, 294:L1206-1216) and obesity (Xia et al., Mol Psychiatry2021, doi: 10.1038 / s41380-021-01053-w) . Compounds that modulate the α5GABA AR are particularly expected to be useful candidates for the treatment of neurodevelopmental disorders, neurocognitive disorders, affective disorders, and schizophrenia.

[0016] Many structurally different compounds active on the α5 subunit of the GABA A receptor are known in the technical field to which the invention belongs (Guerrini et al., Expert Opin Ther Patents 2013, 23(7):843-866), including heterogeneous compounds. Azoles (for example, WO 2009 / 071477 A1, WO 2018 / 104419 A1, WO 2019 / 238633 A1) and triazole derivatives (for example, WO 2012 / 062687 A1, WO 2014 / 001278 A1, WO 2014 / 001279 A1, WO 2014 / 0010282 A1, WO 2020 / 016443 A1).

[0017] Despite extensive research and modulators of GABA Aα5 receptors, there remains an unmet need to provide compounds that can be used to treat or prevent diseases associated with GABA Aα5 receptors. Contents of the invention

[0018] The present invention relates to a compound of formula (I), in A is expressed as base or base; R 1 is alkyl, alkoxy or haloalkyl; R 2 is hydrogen; alkyl optionally substituted with -S(O) 2-alkyl, cycloalkyl or heterocycle; cycloalkyl; heterocyclyl optionally substituted with alkyl; or heteroaryl ; X is CH or N; and / or its salts and / or its stereoisomers and / or its enantiomers and / or its racemates or its diastereomers and / or its biologically active metabolites or its prodrugs or its solvents compound or its hydrates and / or its polymorphs.

[0019] The present invention provides compounds of formula (I) as defined above for use as medicaments.

[0020] The present invention provides compounds of formula (I) as defined above for use in the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0021] The present invention provides the use of a compound of formula (I) as defined above in the manufacture of a medicament for the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0022] The present invention provides a method for treating or preventing diseases associated with GABA Aα5 receptors, which comprises administering an effective amount of at least one compound of formula (I) as defined above to a subject (including a human) in need of such treatment or prevention. compound.

[0023] The present invention provides the use of a compound of formula (I) as defined above in combination with one or more other active ingredients for the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0024] The present invention provides pharmaceutical compositions containing a compound of formula (I) as defined above as an active ingredient.

[0025] The present invention provides medicaments (combination pharmaceutical compositions) comprising a compound of formula (I) as defined above in combination with one or more other active ingredients.

[0026] The present invention provides pharmaceutical compositions containing a compound of formula (I) as defined above alone as an active ingredient or in combination with one or more other active ingredients for the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0027] The present invention provides methods for the preparation of compounds of formula (I) as defined above as well as intermediates for the preparation methods.

[0028] The present invention also provides for the preparation of pharmaceutical compositions containing a compound of formula (I) as defined above alone or in combination with one or more other active ingredients. Implementation

[0029] The present invention provides a formula (I) that has affinity and selectivity for γ-aminobutyric acid A receptor (GABA Aα5) containing α5 subunits and serves as a GABA Aα5 receptor positive allosteric modulator (GABA Aα5 PAM). Compounds that can be used to treat or prevent diseases associated with GABA Aα5 receptors, methods for their preparation, pharmaceutical compositions containing them alone or in combination with one or more other active ingredients, and their use as medicaments.

[0030] The present invention relates to a compound of formula (I) in A is expressed as base or base; R 1 is alkyl, alkoxy or haloalkyl; R 2 is hydrogen; alkyl optionally substituted with -S(O) 2-alkyl, cycloalkyl or heterocycle; cycloalkyl; heterocyclyl optionally substituted with alkyl; or heteroaryl ; X is CH or N; and / or its salts and / or its stereoisomers and / or its enantiomers and / or its racemates or its diastereomers and / or its biologically active metabolites or its prodrugs or its solvents compound or its hydrates and / or its polymorphs.

[0031] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, suitable methods and materials are described below.

[0032] Unless otherwise stated, the nomenclature used is based on the IUPAC systematic nomenclature.

[0033] Unless otherwise stated, the presence of any open valence on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of hydrogen.

[0034] Definitions of common terms used in this article, whether presented alone or in combination with other groups, are described below.

[0035] "As appropriate" or "as appropriate" means that the subsequently described event or circumstance may but does not necessarily occur, and the description includes circumstances in which the event or circumstance occurs and circumstances in which it does not occur.

[0036] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom on the parent molecule.

[0037] The term "substituted" means that the specified group carries one or more substituents.

[0038] Where any group may bear multiple substituents and a variety of possible substituents are provided, the substituents are independently selected and are not necessarily identical.

[0039] The term "unsubstituted" means that the specified group carries no substituents.

[0040] The term "optionally substituted" means that any atom of the specified group is unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When indicating the number of substituents, the term "one or more" means from one substituent up to the highest possible number of substitutions, i.e., one hydrogen is replaced by a substituent up to all hydrogens are replaced by a substituent. Possible substituents include, but are not limited to, C 1-4 alkyl groups, pendant oxy groups, and the like.

[0041] The term "alkyl" alone or in combination with other groups refers to a straight or branched chain, single or multi-branched hydrocarbon group, and is composed of 1 to 6 carbon atoms. Preferably, the alkyl group consists of 1 to 4 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, i-propyl (isopropyl), n-butyl, 2-butyl (secondary butyl) or tertiary butyl (t-butyl) (tert-butyl) group. More preferably, it is a C 1-2 alkyl group. Most preferred is methyl.

[0042] The term "alkoxy" alone or in combination with other groups refers to -O-alkyl, where alkyl is as defined above. Preferably, the alkoxy group is -O-alkyl, wherein the alkyl group consists of 1 to 4 carbon atoms. Examples include, but are not limited to, methoxy, ethoxy, isopropoxy, n-propoxy or tertiary butoxy. More preferably, it is C 1-2 alkoxy group. Most preferred is methoxy.

[0043] The terms "halogen", "halo" or "halide" alone or in combination with other groups refer to fluoro (fluorine), chloro (chlorine), bromo (bromo) (bromine) or iodo (iodine). Preferably, the halogen is fluorine.

[0044] The term "haloalkyl" alone or in combination with other groups means an alkyl group as defined above and which is substituted on any carbon atom of the alkyl group by one or more identical or different halogens, including adjacent and / or twin (germinal) Halo substitution, such as perhaloalkyl. The term "perhaloalkyl" refers to an alkyl group in which all hydrogen atoms have been replaced by the same or different halogen atoms. Examples include, but are not limited to, trihaloalkyl, dihaloalkyl or monohaloalkyl, for example, 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, Fluoromethyl, difluoromethyl or trifluoromethyl. Preferably, the haloalkyl group is halo-C 1-2 alkyl, more preferably difluoromethyl or trifluoromethyl, most preferably trifluoromethyl.

[0045] The term "cycloalkyl" refers to a monovalent monocyclic saturated carbocyclic group containing 3 to 7 carbon ring atoms. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane. Preferably, the cycloalkyl group contains 4 to 6 carbon ring atoms. Most preferably, the cycloalkyl group is cyclobutane or cyclopentane.

[0046] The term "heterocycle" alone or in combination with other groups means having 3 to 10 ring atoms containing 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S and the remaining ring atoms are Monovalently saturated or partially unsaturated monocyclic, bicyclic, fused, bridged or spiro ring systems of carbon atoms. Examples of monocyclic heterocycles are acridine , 2 H-acridine, oxygen ,sulfur , acridine, oxetane, thioxine, acridine-2-one, pyrrolidine, pyrrolone, dihydropyrrole, pyrazolidine, imidazoline, pyrazoline, tetrahydrofuran, dihydrofuran, dioxa Cyclopentane, tetrahydrothiophene, Azolidine, dihydrogen Azole, iso Azolidine, oxathiolane, tetrahydrothiazole, tetrahydrothiazodione, succinimide, Azolidinone, hydantoin, piperidine, pyridone, piperazine , tetrahydropyran, tetrahydrothiopyran, dihydropyran, tetrahydropyridine, dioxane, thiane, dithiocyclohexane, 1,1-dilateral oxy-sulfide Heterocyclohexane, morphine, thiomorphine, 1,1-di-oxy-thiomorphine, nitrogen ,two , high pipe , oxazepanyl, etc. Preferably, heterocycle alone or in combination with other groups refers to 3 to 7 ring atoms containing 1 or 2 ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon. Saturated single ring. More preferably, heterocycle alone or in combination with other groups refers to a monovalent saturated monocyclic ring having 3 to 7 ring atoms containing one ring heteroatom independently selected from O and S, and the remaining ring atoms are carbon. Most preferably, heterocycle alone or in combination with other groups refers to a monovalent saturated monocyclic ring having 3 to 6 ring atoms containing one ring heteroatom independently selected from O and S and the remaining ring atoms being carbon, such as , oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran.

[0047] The term "heteroaryl" alone or in combination with other groups means having 5 to 10 ring atoms containing 1, 2, and 3 ring heteroatoms independently selected from N, O, and S and the remaining ring atoms are carbon A monovalent heterocyclic aromatic monocyclic or bicyclic ring system. Examples of heteroaryl groups are pyrrole, furan, thiophene, imidazole, Azole, iso Azole, thiazole, isothiazole, triazole, tetrazole, Diazole, thiadiazole, tetrazole, pyridine, pyridine , pyrazole, da , pyrimidine, tri , diazepam, diazepam, benzofuran, benzothiophene, indole, isoindole, isobenzofuran, benzimidazole, benzo Azole, benzoiso Azole, benzothiazole, benzisothiazole, benzo Oxidazole, benzothiadiazole, benzotriazole, purine, quinoline, isoquinoline, quinazoline, quinoline pholine, carbazole or acridine. Preferably, heteroaryl alone or in combination with other groups means having 5 to 6 ring atoms containing 1 or 2 heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon. Heterocyclic aromatic monocyclic ring system. More preferably, heteroaryl alone or in combination with other groups refers to a monovalent heterocyclic ring having 6 ring atoms containing 1 or 2 heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon. Aromatic single ring system. Most preferably, heteroaryl, alone or in combination with other groups, refers to a monovalent heterocyclic aromatic monovalent monovalent heterocyclic aromatic group having 6 ring atoms containing 1 and 2 heteroatoms independently selected from N and the remaining ring atoms being carbon. Ring systems such as pyridine, pyridine , pyrimidine, pyrimidine .

[0048] The terms "compound(s) of this invention", "compound(s) of the present invention", and "compound of formula (I) as defined above" refer to compounds of formula (I) and / or its salts and / or its stereoisomers and / or its enantiomers and / or its racemates or its diastereomers and / or its biologically active metabolites or its prodrugs or its solvates Or its hydrates and / or its polymorphs.

[0049] The term "salt" refers to either pharmaceutically acceptable salt or pharmaceutically unacceptable salt.

[0050] The term "pharmaceutically acceptable salts" refers to traditional acid addition salts or base addition salts which retain the biological efficacy and properties of the compounds of formula (I) and which can be combined with a suitable non-toxic organic or inorganic acid or organic or Inorganic base formation. Examples of acid addition salts include salts derived from inorganic acids such as, but not limited to, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and perchloric acid, as well as salts derived from various organic acids. Acids such as, but not limited to, acetic acid, propionic acid, benzoic acid, glycolic acid, phenylacetic acid, salicylic acid, malonic acid, maleic acid, oleic acid, parapeptic acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid , methanesulfonic acid, oxalic acid, tartaric acid, naphthalenedisulfonic acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid, etc. Examples of base addition salts are salts derived from ammonium hydroxide, potassium hydroxide, sodium hydroxide and quaternary ammonium hydroxide (such as tetramethylammonium hydroxide).

[0051] "Pharmaceutically unacceptable salts" can be preferably used for the purification or isolation of compounds of formula (I) and are therefore also within the scope of the present invention.

[0052] The term "prodrug" refers to a derivative of a compound of formula (I) according to the present invention, which itself has no therapeutic effect, but contains a "prodrug" which upon chemical or metabolic degradation (biotransformation) in vivo becomes responsible for the therapeutic effect. Such groups of "biologically active metabolites".

[0053] Optical isomers can be prepared by resolving racemic mixtures by known methods, for example, by forming diastereomeric salts using optically active acids or optically active bases or by forming covalent diastereomeric salts. Suitable acids include, for example, tartaric acid, diethyltartaric acid, dibenzoyltartaric acid, xyloyltartaric acid, and camphorsulfonic acid. Diastereomer mixtures can be separated into individual diastereomers based on their physical and / or chemical differences by methods known to those skilled in the art, such as chromatography or fractional crystallization. . Subsequently, the optically active base or optically active base acid is released from the separated diastereomer salt. Various methods of separating optical isomers include chiral chromatography (eg, chiral HPLC columns), optionally followed by derivatization to maximize separation of the enantiomers. A suitable chiral HPLC column can be selected routinely as desired. Where applicable, enzymatic separation by derivatization can also be used. Optically active compounds of general formula (I) can also be prepared using chiral synthesis (but without racemization reaction conditions) using optically active starting materials.

[0054] The absolute configuration of a chiral compound can be determined, for example, by optical rotation of diastereomer pairs of compounds synthesized from the chiral compound, VCD (vibrational circular dichroism spectroscopy) and / or single crystal X-ray diffraction analysis, or 1H NMR Spectrometry.

[0055] Compounds of formula (I) may exist in a variety of polymorphic forms. As is known in the art to which this invention belongs, polymorphism is the ability of a compound to crystallize in more than one crystalline form (ie, polymorphic form). Polymorphs of a particular compound may be defined by the same chemical formula or composition, and their chemical structures differ as a result of the crystal structures of two different compounds.

[0056] The compounds of formula (I) and their salts may also exist as solvates or hydrates, which are also within the scope of the present invention. The term "solvate" refers to a non-covalent stoichiometric or non-stoichiometric combination of solvent and solute. The term "hydrate" refers to a non-covalent stoichiometric or non-stoichiometric combination of water and solute.

[0057] The present invention provides pharmaceutical compositions comprising as active ingredient at least one compound of formula (I) as defined above.

[0058] The present invention provides pharmaceutical compositions comprising a compound of formula (I) as defined above in combination with one or more other active ingredients. Pharmaceutical compositions may contain at least one compound of the invention and one or more other active ingredients in a single dosage form or separately. The combination compositions may be administered simultaneously, separately, or sequentially.

[0059] The term "pharmaceutical composition" (or "composition") refers to a mixture or solution containing a therapeutically effective amount of an active ingredient together with pharmaceutically acceptable excipients intended for administration to a subject (e.g., a human in need thereof).

[0060] The invention also relates to the preparation of pharmaceutical compositions.

[0061] The pharmaceutical compositions of the present invention may be formulated into a variety of pharmaceutical formulations, such as, but not limited to, solid oral dosage forms, such as tablets (e.g., buccal, sublingual, effervescent, chewable, orodispersible ), capsules, pills, orodispersible films, granules, powders; liquid formulations, such as solutions, emulsions, suspensions, syrups, elixirs, drops; parenteral dosage forms, such as intravenous injection, intramuscular injection, subcutaneous injection ;Other forms of drugs, such as eye drops, semisolid ophthalmic preparations, semisolid dermal preparations (such as ointments, creams, pastes), transdermal therapeutic systems, suppositories, rectal capsules, rectal solutions, emulsions, and suspensions wait.

[0062] The pharmaceutical composition of the present invention can be administered in various ways, such as, but not limited to, oral, rectal, mucus, transdermal or enteral administration; parenteral administration, including intramuscular, subcutaneous, intravenous, intramedullary injection and joint Intrathecal, intrathecal, direct intravenous, intraperitoneal, intranasal or intraocular injections and eye drops.

[0063] Alternatively, the compound can be administered locally rather than systemically, for example, by injecting the compound directly into the kidneys or heart, typically in a modified release formulation. Additionally, drugs can be administered in targeted carrier systems, for example, in liposomes encapsulated by tissue-specific antibodies.

[0064] Pharmaceutical compositions can be administered in a variety of ways and in a variety of pharmaceutical forms. The compounds of the invention may be administered in single or multiple doses, alone or in combination with pharmaceutically acceptable excipients.

[0065] For simple administration, it is preferable that the pharmaceutical composition is composed of dosage units containing the amount of active ingredients to be administered once, or in small amounts multiple times, or half, one-third, or one-quarter (multiple) of the active ingredients. Such dosage units are, for example, tablets, which may be provided with half or quarter grooves to facilitate splitting of the tablet in halves or quarters, thereby weighing out the desired amount of active ingredient(s).

[0066] Pharmaceutical compositions containing active ingredient(s) according to the invention typically contain 0.001 to 500 mg of active ingredient(s) per dosage unit. Of course, it is also possible for the amount of active ingredient(s) in each formulation to exceed the upper or lower limits stated above.

[0067] The present invention also relates to pharmaceutical compositions for pediatric use, such as, but not limited to, solutions, syrups, elixirs, suspensions, powders for preparing suspensions, dispersible or effervescent tablets, chewable tablets, orally disintegrating tablets or Granules, tablets or coated tablets, foaming powder or granules, capsules.

[0068] The pharmaceutical composition of the present invention can be prepared by methods known per se, such as conventional mixing, dissolution, emulsification, suspension, microencapsulation, freeze-drying, extrusion and spheroidization, lamination, film coating, granulation, Encapsulation, pelletization or compression.

[0069] The pharmaceutical compositions of the present invention may be formulated in a conventional manner using one or more physiologically or pharmaceutically acceptable excipients which facilitate incorporation of the active ingredients into a pharmaceutically acceptable pharmaceutical form. The term "physiologically or pharmaceutically acceptable excipient" means any ingredient used in the formulation of a pharmaceutical product that has no therapeutic activity and is non-toxic. Appropriate formulation depends on the mode of administration chosen. Any technique and excipient well known in the art to which the invention pertains may be used.

[0070] Excipients suitable for preparations may be selected from the following categories, such as, but not limited to, fillers for tablets and capsules, binders for tablets and capsules, drug release modifiers, disintegrants, glidants, lubricants, Sweeteners, taste masking agents, flavorings, coating materials, surfactants, stabilizers, preservatives or antioxidants, buffers, complexing agents, wetting agents or emulsifiers, salts to adjust osmotic pressure, freeze-dried excipients Forming agents, microencapsulation agents, ointment materials, penetration enhancers, solubilizers, solvents, suppository materials, and suspending agents.

[0071] The excipients and various preparation methods described above are only representative examples. Other materials and process techniques known in the technical field to which the invention belongs may also be used.

[0072] The term "other active ingredients" refers to therapeutic agents, including but not limited to 5-HT 1A antagonists or agonists (such as lecozotan, NLX 101, sarizotan); 5-HT 1B and 5-HT 1D agonists (such as rizatriptan, zolmitriptan, naratriptan, and sumatriptan); 5-HT 2 antagonists ; 5-HT 4 agonists (such as, PRX-03140); 5-HT 6 antagonists (such as, GSK 742467, SGS-518, FK-962, SL-65.0155, SRA-333, and xaliproden )); A2a adenosine receptor antagonists; acetylcholinesterase inhibitors (such as galantamine, rivastigmine, donepezil, tacrine, fen phenserine, ladostigil, and ABT-089); ADAM-10 ligands; alpha adrenergic receptor agonists; AMPA agonists or modulators (such as, CX-717, LY 451395, LY404187 and S-18986); androgen receptor modulators (such as, SFX 01); anti-amyloid antibodies, including anti-amyloid humanized monoclonal antibodies (such as, bapineuzumab) , ACCO1, CAD 106, AZD3102, H12A11V1); anticholinergics (such as biperiden); antispasmodics (such as acetazolamide, carbamazepine, escilide acetate) Eslicarbazepine acetate, ethosuximide, lacosamide, nitrazepam, oxcarbazepine, perampanel, phenobarbital ), phenytoin, primidone, rufinamide, stiripentol, topiramate, valproate); anti-inflammatory compounds (e.g. (R)-fluoride Flurbiprofen, nitroflurbiprofen, ND-1251, VP-025, HT-0712 and EHT-202); ApoE4 conformational modulators; atypical antipsychotics (such as aripiprazole, Asenapine, brexpiprazole, brilaroxazine, carbimide (cariprazine), iloperidone (iloperidone), loxapine (loxapine), lumateperone tosylate (lumateperone tosylate), lurasidone hydrochloride (lurasidone hydrochloride), molindone (molindone), olanzapine, paliperidone, quetiapine, risperidone, sulpiride, and ziprasidone); barbiturates; beta-secretase inhibitors (such as verubecestat and AZD3293) and γ-secretase inhibitors (such as LY450139 and TAK070) or modulators; blockers of Aβ oligomer formation; bradykinin B1 receptor antagonists (Such as, SSR240612, NVPSAA164 or any of the compounds described in WO 2007 / 072092 A2, WO 2008 / 068540 A1, WO 2008 / 050167 A1, WO 2008 / 050168 A1); phenylbutanone (such as, fluorine Haloperidol); Calcium channel blockers (such as ziconotide and NMED160); CB-1 receptor antagonists or inverse agonists (such as drinabant, cannabis cannabidiol); CB-2 agonists (such as GW-842166X and SAB378) or CB modulators (cannabidivarin, T1 / C20, THC conjugate, ZYN-002); Cholinergic agonists; phenothiazines class (such as, chloropropyl (chlorpromazine), fluphenazine (fluphenazine), mesodar (mesoridazine), perphenazine, thioridazine (thioridazine), triflurazine (trifluoperazine)); sulfur classes (such as chlorprothixene and thiothixene); COMT inhibitors (such as entacapone); ciclopyrrolidone; sedatives such as diphenylbutylpiperidine (such as pimozide) and indolone (such as molindolone) classes; DNA-guided DNA polymerase inhibitors (such as suramin sodium); Dopamine agonists and some agonists (such as pramipexole, ropinirole); dopamine precursors (such as carbidopa, levodopa); dopamine transport inhibition Agents; enzyme modulators or substitutes (such as, CM-AT, CM-4612 and CM-182); fatty acid amide hydrolase inhibitors (such as, JNJ 42165279); fatty acid or triglyceride substitutes (such as, triglyceride Glyceryl enanthate); fenamate derivatives (such as ASD-002); GABA A blockers (such as S44819, NGD 97-1, α5IA, α5IA-II, MRK-016, Bami basmisanil or any of those compounds described in PCT / IB2019 / 058208); GABA A receptor agonists (such as acamprosate); GABA A signal enhancers (such as, AZD-7325, PF-06372865, L-838,417, TPA-023, brexanolone, zuranolone, alphaxalone, ganaxolone, gaboxadol ( gaboxadol), tiagabine, vigabatrine, bumetanide); GABA B receptor agonists (such as arbaclofen or others WO 2018 / 167629 A1 or any of the compounds described in WO 2018 / 167630 A1); gabapentinoid (such as pregabalin, gabapentin); glutamate modulators (such as AMO 04); Glycine transport inhibitors; Glycogen synthase kinase 3β inhibitors (such as tideglusib (tideglusib), AZD1080, SAR502250 and CEP16805); Growth hormone secretagogues (such as butamoren ( ibutamoren, butamoren mesylate, and capromorelin); HDAC inhibitors; heterocyclic dibenzazepines (such as clozapine); histamine H3 receptor antagonists and inverse agonists (such as, S38093, ABT-834, ABT 829, GSK 189254, CEP16795 or any of the compounds described in WO 2014 / 136075 A1); HMG-CoA reductase inhibitors; Imidazopyridines (such as zolpidem); immunomodulators (such as, IMM-124E); KCNQ antagonists; lithium; LRRK2 inhibitors; LXR beta agonists; lysine-specific demethylation Chlorase 1 inhibitors (such as vafidemstat); M1 or M4 mAChR agonists or PAMs; MARK ligands; melatonin agents; melatonin agonists and antagonists; methyl-CpG Binding protein 2 (MECP2) gene replacement therapy (such as, AVXS 201); mGluR2 antagonists or modulators; mGluR4 positive allosteric modulators (such as, ADX-88178, foliglurax); mGluR5 antagonists ( Such as, HTL-14242, AZD9272, mavoglurant); Microbial community modulators (such as, AB-2004, CP-101, SB-121); Mild sedatives; MMP inhibitors; α7 nAChR agonists or Positive allosteric modulators (such as, ABT-126, AZD0328, EVP-6124, AVL-3288, PNU-120596 or those described in WO 2020 / 012422 A1, WO 2020 / 012423 A1 or WO 2020 / 012424 A1 any of the compounds) or antagonists (such as mecamylamine hydrochloride); neuropeptide receptor modulators (such as trofinetide, davunetide, NNZ- 2591); Neutrophil inhibitory factor; NK1 / NK3 receptor antagonist; NMDA receptor agonist or antagonist (such as memantine, neramexane, EVT101, AZD4282, BHV 5000) ; Norepinephrine transport inhibitors; Norepinephrine modulators; NOS inhibitors (such as, SD6010 and 274150); NQO1 modulators (such as, vatiquinone); NR2B antagonists (such as, Ladipotide) (radiprodil); NSAIDs (such as ibuprofen); Opioid analgesics (such as codeine, fentanyl, hydromorphone, levorphanol (levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene); Appetite Hormone antagonists and agonists; oxytocin; p25 / CDK5 inhibitors; PDE10 inhibitors; PDE4 inhibitors (such as, HT0712); PDE9 inhibitors (such as, BI40936); PI3KB inhibitors (such as, BBP-472); Potassium channel activators; PPARγ agonists (such as pioglitazone and rosiglitazone); prokineticin agonists and antagonists; pyrazolopyrimidines; modulates cholinergic / metabolic Glutamate receptor-type pyrrolidone compounds (such as fasoracetam, levetiracetam, bivaracetam, piracetam); σ-1 Receptor agonists (such as blarcamesine); sodium channel blockers and antagonists (such as lamotrine (lamotrigine, VX409, and SPI860); sphingosine phosphate 1 receptor modulators (such as fingolimod, ozanimod, siponimod, ponimod) ponesimod); SSRI or SNRI (such as fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline; or desvenlafaxine, duloxetine, venlafaxine); sulfonamides (such as zonisamide); tau phosphate Chemistry inhibitors; thrombolytic agents; triazolopyridines; dibenzazepines; tricyclic antidepressants; T-type calcium channel blockers; tyrosine hydroxylase inhibitors (such as, L1-79) ; Vasopressin; Vla receptor antagonist (such as balovaptan, BTRX-323511 or any of the compounds described in WO 2019 / 116324 A1 or WO 2019 / 116325 A1) ; Vitamin E; VR-1 antagonists (such as, AMG517, 705498, 782443, PAC20030, VI 14380, and A425619) may increase efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the compounds of the invention. other drugs for the body or enzymes.

[0073] In a specific example, the other active ingredients refer to 5-HT 1A antagonists or agonists (such as raczotan, NLX 101, sariszotan); atypical antipsychotics (such as aripiprazole, aripiprazole, Xenapine, Pixabay, Brilasazine, Carbimid , iloperidone, loxapine, lumepirone tosylate, lurasidone hydrochloride, morpholinindone, olanzapine, paliperidone, quetiapine, risperidone, sulpiride and zila CB-1 receptor antagonists or inverse agonists (such as dronaban, cannabidiol); CB-2 agonists (such as GW-842166X and SAB378) or CB modulators (such as Cannabidiol, T1 / C20, THC conjugate, ZYN-002); DNA-guided DNA polymerase inhibitors (such as suramin sodium); fatty acid amide hydrolase inhibitors (such as, JNJ 42165279 ); fatty acid or triglyceride substitutes (such as triheptanoin); GABA A receptor agonists (such as acamprosate); GABA A signal enhancers (such as AZD-7325, PF-06372865 , L-838,417, TPA-023, brenolon, zulanolone, alfaxalone, ganaxolone, gaboxadol, tigabine, aminebacetin, bumetanide); GABA B receptor Agonist (such as arbaclofen or any of the compounds described in WO 2018 / 167629 A1 or WO 2018 / 167630 A1); Glutamate modulator (such as AMO 04); Glycogen Synthetase kinase 3β inhibitors (such as tidaloxib, AZD1080, SAR502250, and CEP16805); lysine-specific demethylase 1 inhibitors (such as vaderestat); methyl-CpG binding proteins 2 (MECP2) gene replacement therapy (such as, AVXS 201); microbial community modulators (such as, AB-2004, CP-101, SB-121); neuropeptide receptor modulators (such as, Zofineti, Dafu NNZ-2591); NMDA receptor agonists or antagonists (such as memantine, nelamethane, EVT101, AZD4282, BHV 5000); NQO1 modulators (such as farticinone); oxytocin; Pyrrolidone compounds that modulate cholinergic / metabotropic glutamate receptors (such as fasoracetam, levetiracetam, brivaracetam, piracetam); sigma-1 receptor agonists ( Sphingosine phosphate 1 receptor modulators (such as fingolimod, ozanimod, siponimod, ponimod); SSRIs or SNRIs (such as , fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline; or desvenlafaxine, duloxetine, venlafaxine); tyrosine hydroxylation enzyme inhibitors (such as, L1-79); vasopressin; or V1a receptor antagonists (such as, balovatan, BTRX-323511, or those described in WO 2019 / 116324 A1 or WO 2019 / 116325 A1 any of the compounds).

[0074] The term "modulator" refers to a molecule that interacts with a target receptor, where the interaction may be, for example, agonistic, antagonistic, or inversely agonistic.

[0075] The term "inhibitor" refers to a molecule that competes with, reduces or prevents the binding of a specific ligand to a specific receptor or reduces or prevents inhibition of the function of a specific protein.

[0076] The term "agonist" refers to a compound that has affinity for a receptor binding site and enhances the activity of a receptor-mediated reaction. "Full agonists" produce a complete response, "partial agonists" produce less than complete activation (even when occupying the total receptor population).

[0077] The term "reverse agonist" refers to a compound that produces the opposite effect of the agonist by binding to the same binding site of the agonist, or that reduces the agonist effect by binding at a different allosteric binding site. Compounds with agent-like effects.

[0078] The term "antagonist" refers to a compound that reduces or prevents the action of another compound or receptor site or attenuates the action of an agonist. "Competitive antagonists" bind to the same site as the agonist but inactivate it, thus blocking the effect of the agonist. "Noncompetitive antagonists" bind to allosteric sites on the receptor to prevent receptor activation. The binding of "reversible antagonists" to the receptor is non-covalent (can be washed away), while the binding of "irreversible antagonists" is covalent (cannot be washed away).

[0079] The term "allosteric modulator" refers to a compound that binds to a receptor at a site different from the binding site of the agonist (i.e., the allosteric site), which changes by inducing a conformational change in the receptor. The affinity and / or activity of a receptor for endogenous ligands or agonists. "Positive allosteric modulators" or "PAMs" increase affinity and / or activity, while "negative allosteric modulators" or "NAMs" decrease receptor affinity and / or activity. Compounds of formula (I) as defined above are forward allosteric modulators.

[0080] The term "inhibition constant" (Ki) refers to the absolute binding affinity of a specific inhibitor for a receptor. Inhibition constants were measured using a competitive binding assay and, if no competing ligand was present, using the Cheng Prusoff relationship (K i= IC 50 / [1+([L] / K D) ], where [L] is the radioligand concentration and K D is the affinity of the labeled ligand for the receptor binding site) is calculated from the concentration at which a specific inhibitor will occupy half of the receptor (IC 50). Ki values ​​can be converted logarithmically to pK i values ​​(-logK i), where higher values ​​represent exponentially increasing potency.

[0081] The term "submaximal effective concentration" refers to the concentration of a specific compound required to obtain 10% of the maximum value of a specific effect.

[0082] The terms "condition", "defect", "deficiency", "disability", "disease", "disease" or "disease state" are used interchangeably to mean any disease, condition, symptom, syndrome, disorder or indication.

[0083] The term "GABA Aα5 receptor-associated disease" refers to a disease, disorder or condition of the central nervous system in which one of the symptoms and / or syndromes of the disease may be associated with the GABA Aα5 receptor. Such disorders include, but are not limited to, neurodevelopmental disorders, neurodegenerative disorders, neurocognitive disorders, schizophrenia, affective disorders, pain disorders, substance-related and addiction disorders or other disorders.

[0084] Disorders associated with GABA Aα5 receptors may show comorbidity with each other. A comorbidity is a medical condition that exists simultaneously but independently of another medical condition in a patient, or a medical condition that causes or results from another medical condition in the same patient or is related to another medical condition in the same patient. However, in psychiatric, mental or mental health disorders, comorbidity does not necessarily mean the presence of multiple disorders, but may reflect our current inability to provide a single diagnosis to explain all symptoms.

[0085] The term "neurodevelopmental disorder" includes, but is not limited to, autism spectrum disorder (ASD), Angelman syndrome, fragile X, Prader-Willi syndrome, Rett syndrome ( Rett syndrome) or Down syndrome.

[0086] The term "neurodegenerative disease" includes, but is not limited to, Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS).

[0087] The term "neurocognitive disorder" includes, but is not limited to, cognitive deficit disorder, memory deficit, age-related memory impairment or cognitive decline, dementia (or its different forms, such as Alzheimer's disease, Niemann-Pick disease Niemann Pick-disease, Parkinson's disease or Huntington's disease, dementia with Lewy body (DLB), frontotemporal dementia, vascular disease type of dementia (VaD), subcortical dementia, mixed vascular and subcortical dementia, multi-infarct dementia, postoperative dementia or inflammation-induced dementia), and Alzheimer’s disease Neuropsychiatric symptoms associated with Alzheimer's disease, mild cognitive impairment (MCI), vascular cognitive impairment (VCI), CNS conditions occurring after stroke, and cognitive impairment associated with brain cancer (including but not limited to medulloblastoma), cognitive degeneration in Down syndrome (DS), cognitive impairment in major depressive disorder (MDD) or neurocognitive disorders related to HIV. The term "schizophrenia" includes, but is not limited to, different forms of schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, schizotypal disorders and delusions.

[0088] The term "pain disorder" includes, but is not limited to, nociceptive pain, neuropathic pain, or inflammatory pain.

[0089] The term "affective disorder" includes, but is not limited to, disorders related to depression (such as major depressive disorder (MDD), minor depression, cyclothymia, seasonal affective disorder / seasonal depression, traumatic brain injury). Depression after brain injury (TBI), postpartum depression, premenstrual dysphoric disorder, menopausal-related depressive symptoms, depression after substance abuse / withdrawal, bipolar disorder (remitted bipolar disorder or bipolar disorder) Depressive phase), substance (alcohol or drug) induced or affective disorder not classified (MD-NOS).

[0090] The term "other disorders" includes, but is not limited to, attention deficit hyperactivity disorder and adult attention deficit disorder, other stress-related conditions, stroke, neurofibromatosis type I, multiple sclerosis, acute meningitis, alcohol use disorder, Fetal alcohol cluster disorder, bronchoconstrictive disease (such as asthma, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia), or obesity.

[0091] In a specific example, the diseases related to GABA Aα5 receptors refer to autism spectrum disorder (ASD), Angelman syndrome, fragile X disease, Prader-Willi syndrome, Rett syndrome, Down syndrome, Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease, amyotrophic lateral sclerosis (ALS), cognitive deficiency disorder, memory deficiency, age-related memory impairment or cognitive impairment cognitive decline, dementia (or its different forms, such as Alzheimer's disease, Niemann-Pick disease, Parkinson's disease or Huntington's disease), dementia with Lewy bodies (DLB), Frontotemporal dementia, vascular dementia (VaD), subcortical dementia, mixed vascular and subcortical dementia, multi-infarct dementia, postoperative dementia or inflammation-induced dementia dementia), neuropsychiatric symptoms associated with Alzheimer's disease, mild cognitive impairment (MCI), vascular cognitive impairment (VCI), CNS conditions occurring after stroke, cognition associated with brain cancer defects (including but not limited to medulloblastoma), cognitive impairment in Down syndrome (DS), major depressive disorder (MDD), HIV-related neurocognitive disorders, various forms of schizophrenia, and Positive, negative and / or cognitive symptoms associated with schizophrenia, schizotypal disorders and delusions; disorders associated with depression (such as major depressive disorder (MDD), minor depression, cyclothymia, Seasonal affective disorder / seasonal depression, post-traumatic brain injury (TBI) depression, postpartum depression, premenstrual dysphoric disorder, menopausal-related depressive symptoms, substance abuse / post-withdrawal depression, mania Depression (remitted bipolar disorder or depressive phase of bipolar disorder), substance (alcohol or drug) induced, affective disorder not classified (MD-NOS), attention deficit hyperactivity disorder and adult attention deficit disorder, other and stress related conditions, stroke, neurofibromatosis type I, multiple sclerosis, acute meningitis, alcohol use disorder, fetal alcohol cluster disorder, bronchoconstrictive disease (such as asthma, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia), or Obesity.

[0092] In a preferred specific example, the diseases related to GABA Aα5 receptors refer to autism spectrum disorder (ASD), Angelman syndrome, fragile X disease, Prader-Willi syndrome, Rett syndrome, Alzheimer's syndrome, Alzheimer's disease (AD), cognitive deficit disorder, memory deficiency, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, schizophrenia-related disorder negative and / or cognitive symptoms, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis.

[0093] The present invention provides a method for treating or preventing diseases related to GABA Aα5 receptors, which comprises administering only a therapeutically effective amount of as defined above to a subject (preferably a mammal, more preferably a human) in need of such treatment or prevention. A compound of formula (I) or a pharmaceutically acceptable excipient thereof in the form of a pharmaceutical formulation.

[0094] The present invention provides a method for treating or preventing diseases related to GABA Aα5 receptors, which includes administering a therapeutically effective amount of a substance as defined above to a subject (preferably a mammal, more preferably a human) in need of such treatment or prevention. A combination of a compound of formula (I) and one or more other active ingredients.

[0095] The present invention provides a method for the treatment or prevention of neurodevelopmental disorders, neurodegenerative diseases, neurocognitive disorders, schizophrenia, affective disorders, pain disorders, substance-related and addiction disorders or other diseases or symptoms thereof and A method for a subject (preferably a mammal, more preferably a human) of at least one of the syndromes, wherein the symptoms of the disease and / or one of the syndromes may be related to the GABA Aα5 receptor. This method of treatment involves administering a therapeutically effective amount of a compound of formula (I) as defined above to a subject (preferably a mammal, more preferably a human) in need of such treatment or prevention. Methods of treatment may include administering to a subject (preferably a mammal, more preferably a human) in need of such treatment a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) as defined above.

[0096] The invention provides a method for treating or preventing autism spectrum disorder (ASD), Angelman syndrome, fragile X disease, Prader-Willi syndrome, Rett syndrome, Alzheimer's disease (AD), and cognitive deficiency. Illness, memory deficiency, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, negative and / or cognitive symptoms associated with schizophrenia, epilepsy A method for a subject (preferably a mammal, more preferably a human) of at least one of the following syndromes, post-traumatic stress disorder, amyotrophic lateral sclerosis, or symptoms and / or syndromes thereof, comprising administering a therapeutically effective amount of the above Compounds of formula (I) as defined.

[0097] The present invention provides compounds of formula (I) as defined above for use in the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0098] The present invention provides a combination of a compound of formula (I) as defined above with one or more other active ingredients for the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0099] The present invention provides for the treatment or prevention of neurodevelopmental disorders, neurodegenerative diseases, neurocognitive disorders, psychosis disorders, affective disorders, pain disorders, substance-related and addiction disorders or other diseases or symptoms thereof and / or A compound of formula (I) as defined above for at least one of the syndromes.

[0100] The present invention provides methods for treating or preventing autism spectrum disorder (ASD), Angelman syndrome, fragile X disease, Prader-Willi syndrome, Rett syndrome, Alzheimer's disease (AD), and cognitive deficiency. Illness, memory deficiency, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, negative and / or cognitive symptoms associated with schizophrenia, epilepsy A compound of formula (I) as defined above for at least one of amyotrophic lateral sclerosis, post-traumatic stress disorder, amyotrophic lateral sclerosis or symptoms and / or syndromes thereof.

[0101] The present invention provides the use of a compound of formula (I) as defined above in the manufacture of a medicament for the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0102] The present invention provides the use of a compound of formula (I) as defined above in combination with one or more other active ingredients for the manufacture of a medicament for the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0103] The present invention provides compounds of formula (I) as defined above for use in the treatment or prevention of neurodevelopmental disorders, neurodegenerative diseases, neurocognitive disorders, schizophrenia, affective disorders, pain disorders, and substance-related disorders. and the use of pharmaceuticals for at least one of addiction disorders or other diseases or their symptoms and / or syndromes.

[0104] The present invention provides compounds of formula (I) as defined above for use in the treatment or prevention of autism spectrum disorder (ASD), Angelman syndrome, fragile X disease, Prader-Willi syndrome, Rett syndrome, Alzheimer's disease, Alzheimer's disease (AD), cognitive deficit disorder, memory deficiency, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, schizophrenia-related disorder The use of pharmaceuticals for at least one of negative and / or cognitive symptoms, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, or symptoms and / or syndromes thereof.

[0105] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above for the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0106] The present invention also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above and one or more other active ingredients for the treatment or prevention of diseases associated with GABA Aα5 receptors.

[0107] The term "treatment" refers to the alleviation of a specific pathological condition, the elimination or alleviation of one or more symptoms of such condition, the slowing or elimination of the progression of a disease state, and the pathological condition in patients or subjects who have or are diagnosed with such disease prevention or delay of recurrence. "Prophylaxis" (or prevention or delay of the effects of a disease) is generally accomplished by administering a drug in the same or similar manner as would be administered to a patient with an already developed disease or condition.

[0108] The term "therapeutically effective amount" refers to an amount of an active ingredient that results in treatment, cure, prevention or amelioration of a disease or disease state or side effects, and reduces the progression of the disease or pathological condition, as compared to a corresponding subject who does not receive such amount. The term also includes an amount effective to enhance normal physiological function. The compound of formula (I) as defined above and any salt thereof and / or its salts and / or its stereoisomers and / or its enantiomers and / or its racemates or its non-enantiomers for treatment The construct and / or its biologically active metabolite or its prodrug or its solvate or its hydrate and / or its polymorph can be administered as the original chemical in a therapeutically effective amount. In addition, the active ingredients are available as pharmaceutical compositions.

[0109] The term "subject" refers to a vertebrate animal. In some embodiments, the vertebrate is a mammal. Mammals include humans, non-human primates (such as chimpanzees and other apes and monkeys), farm animals (such as cattle, horses, sheep, goats, and pigs), domestic animals (such as rabbits, dogs, and cats) , laboratory animals (including rodents, such as rats, mice and guinea pigs). In some embodiments, the mammal is a human. The term subject does not denote a specific age or gender.

[0110] In a specific example, the present invention relates to compounds of formula (I’) in A is expressed as base or base; Among them, for the compound of formula (I) and / or its salt and / or its stereoisomer and / or its enantiomer and / or its racemate or its diastereomer and / or its biologically active metabolism substance or its prodrug or its solvate or its hydrate and / or its polymorph, the position "a1" of any ring A is attached to the position "a2", and the position "b1" of any ring A therein "Attachment site "b2"; R1, R2 and X are as defined above.

[0111] In a specific example, the present invention relates to compounds of formula (I-a) Among them, for the compound of formula (I) and / or its salt and / or its stereoisomer and / or its enantiomer and / or its racemate or its diastereomer and / or its biologically active metabolism substance or its prodrug or its solvate or its hydrate and / or its polymorph, R1, R2 and X are as defined above. [] []

[0112] In a specific example, the present invention relates to compounds of formula (I-b) Among them, for the compound of formula (I) and / or its salt and / or its stereoisomer and / or its enantiomer and / or its racemate or its diastereomer and / or its biologically active metabolism substance or its prodrug or its solvate or its hydrate and / or its polymorph, R1, R2 and X are as defined above.

[0113] In a specific example, the present invention relates to compounds of formula (I), wherein R 1 is C 1-6 alkyl, C 1-6 alkoxy or halo-C 1-6 alkyl.

[0114] In a specific example, the present invention relates to compounds of formula (I), wherein R 2 is hydrogen; C 1-6 alkyl, optionally via -S(O) 2-C 1-6 alkyl, C 3-7 cycloalkyl or monovalent saturated or partially unsaturated ring atoms having 3 to 10 ring atoms containing 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon Substituted with a monocyclic, bicyclic, fused, bridged or spiro ring system; C 3-7 cycloalkyl; 3 having 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S A monovalent saturated or partially unsaturated monocyclic, bicyclic, fused, bridged or spirocyclic ring system with up to 10 ring atoms and the remaining ring atoms being carbon, optionally substituted with C 1-6 alkyl; or having A monovalent heterocyclic aromatic monocyclic or bicyclic ring system containing 1, 2 or 3 heteroatoms independently selected from N, O and S, with 5 to 10 ring atoms and the remaining ring atoms being carbon.

[0115] In a specific example, the present invention relates to compounds of formula (I), wherein R 1 is C 1-6 alkyl, C 1-6 alkoxy or halo-C 1-6 alkyl; R 2 is hydrogen; C 1-6 alkyl, which is optionally passed through -S(O) 2-C 1-6 alkyl, C 3-7 cycloalkyl or has 1, 2, 3 or 4 3 to 10 ring atoms of ring heteroatoms independently selected from N, O and S and the remaining ring atoms are monovalent saturated or partially unsaturated monocyclic, bicyclic, fused, bridged or spirocyclic system substitutions of carbon; C 3-7 cycloalkyl; having 3 to 10 ring atoms containing 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are monovalent saturated or partially unsaturated carbons. Saturated monocyclic, bicyclic, fused, bridged or spiro ring system, which is optionally substituted by C 1-6 alkyl; or has 1, 2 or 3 independently selected from N, O and S A monovalent heterocyclic aromatic monocyclic or bicyclic system with 5 to 10 ring atoms of heteroatoms and the remaining ring atoms being carbon.

[0116] In a specific example, the present invention relates to compounds of formula (I), wherein R 1 is C 1-4 alkyl, C 1-4 alkoxy or halo-C 1-4 alkyl.

[0117] In a specific example, the present invention relates to compounds of formula (I), wherein R 2 is hydrogen; C 1-4 alkyl, optionally via -S(O) 2-C 1-4 alkyl, C 4-6 cycloalkyl or monovalent saturated monocyclic ring substitution with 3 to 7 ring atoms containing 1 or 2 ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon; C 4- 6 cycloalkyl; having 3 to 7 ring atoms containing 1 or 2 ring heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon monovalent saturated monocyclic rings, which are optionally processed C 1-4 alkyl substitution; or monovalent heterocyclic aromatic monocyclic ring system with 5 to 6 ring atoms containing 1 or 2 heteroatoms independently selected from N, O and S, and the remaining ring atoms are carbon .

[0118] In a specific example, the present invention relates to compounds of formula (I), wherein R 1 is C 1-4 alkyl, C 1-4 alkoxy or halo-C 1-4 alkyl; R 2 is hydrogen; C 1-4 alkyl, which is optionally passed through -S(O) 2-C 1-4 alkyl, C 4-6 cycloalkyl or having 1 or 2 independently selected from 3 to 7 ring atoms of the ring heteroatoms of N, O and S and the remaining ring atoms are monovalent saturated monocyclic substitutions of carbon; C 4-6 cycloalkyl; having 1 or 2 independently selected from N, A monovalent saturated monocyclic ring with 3 to 7 ring atoms of the ring heteroatoms of O and S and the remaining ring atoms being carbon, which is optionally substituted with a C 1-4 alkyl group; or has 1 or 2 independently A monovalent heterocyclic aromatic monocyclic ring system with 5 to 6 ring atoms selected from N, O and S heteroatoms and the remaining ring atoms being carbon. [] []

[0119] In a specific example, the present invention relates to compounds of formula (I), wherein R 1 is C 1-2 alkyl, C 1-2 alkoxy or halo-C 1-2 alkyl.

[0120] In a specific example, the present invention relates to compounds of formula (I), wherein R 2 is hydrogen; C 1-4 alkyl, optionally via -S(O) 2-C 1-2 alkyl, C 4-6 cycloalkyl or having 3 to 7 ring atoms containing a ring heteroatom selected from O and S, and the remaining ring atoms are monovalent saturated monocyclic substitutions of carbon; C 4-6 cycloalkyl; having A monovalent saturated monocyclic ring with 3 to 7 ring atoms selected from the ring heteroatoms of O and S and the remaining ring atoms being carbon, which is optionally substituted by C 1-4 alkyl; or has a structure containing 1 or 2 A monovalent heterocyclic aromatic monocyclic ring system with 6 ring atoms independently selected from N, O and S heteroatoms and the remaining ring atoms being carbon.

[0121] In a specific example, the present invention relates to compounds of formula (I), wherein R 1 is C 1-2 alkyl, C 1-2 alkoxy or halo-C 1-2 alkyl; R 2 is hydrogen; C 1-4 alkyl, which is optionally passed through -S(O) 2-C 1-2 alkyl, C 4-6 cycloalkyl or has a ring selected from O and S Monovalent saturated monocyclic substitution of 3 to 7 ring atoms of heteroatoms and the remaining ring atoms being carbon; C 4-6 cycloalkyl; 3 to 7 ring atoms containing one ring heteroatom selected from O and S And the remaining ring atoms are monovalent saturated or monocyclic carbon rings, which are optionally substituted by C 1-4 alkyl groups; or have 6 heteroatoms including 1 or 2 independently selected from N, O and S. A monovalent heterocyclic aromatic monocyclic ring system with one ring atom and the remaining ring atoms being carbon. [] []

[0122] In a specific example, the present invention relates to compounds of formula (I), wherein X is CH.

[0123] In a specific example, the present invention relates to compounds of formula (I), wherein X is N.

[0124] In a specific example, the present invention relates to compounds of formula (I), wherein R 2 is hydrogen.

[0125] In a specific example, the present invention relates to compounds of formula (I), wherein R 1 is alkyl, alkoxy or haloalkyl; R 2 is hydrogen; and X is CH or N.

[0126] In a specific example, the present invention relates to compounds of formula (I), wherein R 1 is C 1-4 alkyl, C 1-4 alkoxy or halo-C 1-4 alkyl; R 2 is hydrogen; and X is CH or N.

[0127] In a specific example, the present invention relates to compounds of formula (I-a), wherein R 1 is C 1-2 alkyl or halo-C 1-2 alkyl; R 2 is hydrogen; and X is CH or N.

[0128] In a specific example, the present invention relates to compounds of formula (I) as defined above, which are selected from the group consisting of the following: 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- dyridine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7- dyridine, 2-Methyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- dyridine, 2-cyclobutyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- dyridine, 2-(cyclobutylmethyl)-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- dyridine, 2-Cyclopentyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- dyridine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy)-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy)-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-2-(oxetan-3-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 2-(1-methanesulfonylpropan-2-yl)-6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-2-(pyridin-2-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 2-Methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]pyridine, 5-[5-Methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine, 2-Methyl-5-{5-methyl-4-[({7-methyl-5H,6H,7H,8H-pyrido[3,4-c]ta -3-yl}oxy)methyl]-1,2- Azol-3-yl}pyridine, 5-[5-Methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine, 5-[5-methyl-4-({[7-(oxolan-3-yl)-5H,6H,7H,8H-pyrido[3,4-c]ta -3-yl]oxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine, 3-{[3-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy)-5H,6H,7H,8H-pyrido[3,4-c]pyra -7-yl]methyl}-1λ6-thiolane-1,1-dione, 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4 -Tetrahydro-2,7- dyridine, 2-Methyl-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1, 2,3,4-Tetrahydro-2,7- dyridine, 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(propan-2- base)-1,2,3,4-tetrahydro-2,7- dyridine, 6-({1-[6-(Difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-methyl Base-1,2,3,4-tetrahydro-2,7- dyridine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2 ,3,4-tetrahydro-2,7- dyridine, 6-({1-[6-(Difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2 ,3,4-tetrahydro-2,7- dyridine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-( Prop-2-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 2-Methyl-6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy )-1,2,3,4-tetrahydro-2,7- dyridine, 6-({1-[6-(Difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-( Prop-2-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxolane Alk-3-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-({1-[6-(Difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-( Oxolan-3-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxetane -3-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-( Oxolan-3-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxane Alk-4-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3, 4-Tetrahydro-2,7- dyridine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-( Oxan-4-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 3-{[6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy) -1,2,3,4-Tetrahydro-2,7- Din-2-yl]methyl}-1λ6-thiolane-1,1-dione, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-( Pyridin-3-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[(3S)- Oxolan-3-yl]-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[(3R)- Oxolan-3-yl]-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxaheterocycle Hexan-4-yl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(2-methyl Propyl)-1,2,3,4-tetrahydro-2,7- dyridine, 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3-(propyl -2-yl)oxetan-3-yl]-1,2,3,4-tetrahydro-2,7- dyridine, 2-(3-ethyloxetan-3-yl)-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazole -5-yl]methoxy}-1,2,3,4-tetrahydro-2,7- dyridine, 2-Methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine, 5-[5-({[7-(cyclobutylmethyl)-5H,6H,7H,8H-pyrido[3,4-c]ta -3-yl]oxy}methyl)-4-methyl-1H-1,2,3-triazol-1-yl]-2-methylpyridine, and 5-{5-[({7-cyclobutyl-5H,6H,7H,8H-pyrido[3,4-c]ta -3-yl}oxy)methyl]-4-methyl-1H-1,2,3-triazol-1-yl}-2-methylpyridine and / or its salts and / or its stereoisomers and / or its enantiomers and / or its racemates or its diastereomers and / or its biologically active metabolites or its prodrugs or its solvents compound or its hydrates and / or its polymorphs. [] []

[0129] In describing the general synthesis, bioassays, intermediates and examples of compounds of formula (I), the following abbreviations have been used: Cs 2CO 3 = cesium carbonate DCM=dichloromethane Na 2SO 4 = sodium sulfate Pd(OAc) 2=Palladium(II) acetate DIBAL-H=diisobutylaluminum hydride DMSO = dimethyl sulfoxide POCl 3=phosphorus oxychloride TBHP=tertiary butyl hydroperoxide EtOAc=ethyl acetate K 2CO 3 = potassium carbonate TFA = trifluoroacetic acid THF=tetrahydrofuran MeOH=methanol MgSO 4 = magnesium sulfate Na 2CO 3 = sodium carbonate TLC=thin layer chromatography brine = a highly concentrated solution of salt (usually sodium chloride) NaHCO 3 = sodium bicarbonate rt=room temperature,25℃ [for preparation formula] [(I)] [Method of compound] []

[0130] The compound of formula (I) of the present invention can be based on [reaction diagram] [1] [,] [2] [,] [3] [,] [4] [as well as] The reaction sequence was synthesized as described in [5].

[0131] Compounds of formula (I-a) (wherein X=CH, R 1 and R 2 are as defined in any one of the above specific examples) can be according to [reaction diagram] [1] [and] [2] Preparation. []

[0132] according to [reaction diagram] [1], The reaction of a compound of formula (II) and a chlorinating agent (such as POCl 3) provides an intermediate of formula (III). The hydroxyl derivative of formula (II) is known in the technical field to which the invention belongs (WO 2018 / 104419 A1) or can be synthesized by traditional methods. []

[0133] according to [reaction diagram] [2], The etherification reaction between the alcohol of formula (IV) and the intermediate of formula (III) can be completed in the presence of a suitable base (such as K 2CO 3) and in a suitable solvent (such as acetonitrile) To form a compound of formula (V). After removal of the protecting group of formula (V) using an acid, such as ethyl acetate saturated with hydrogen chloride or TFA in dichloromethane, compounds of general formula (I-a) (where R 2 =H) are obtained. Compounds of general formula (I-a) (where R 2 = optionally via -S(O) 2-alkyl, Cycloalkyl or heterocyclic substituted alkyl; cycloalkyl; heterocycle). Compounds of general formula (I-a) (where R 2 =heteroaryl) are obtained from those compounds of general formula (I-a) (where R 2 =H) by arylation. General formula (I-a) is obtained from compounds of general formula (I-a) (where R 2 = H) by condensation with benzotriazole and carbonyl compounds, followed by nucleophilic reaction using Grignard reagent. Compounds (where R 2 = optionally alkyl-substituted heterocycle). Alcohols of formula (IV) can be purchased or can be prepared by conventional methods.

[0134] Compounds of formula (I-a) (wherein X=N, R 1 and R 2 are as defined in any one of the above specific examples) can be according to [reaction diagram] [3] Preparation. []

[0135] according to [reaction diagram] [3], the etherification reaction between the chlorine derivative of formula (VI) and the hydroxyl derivative of formula (II) can be carried out by a palladium-mediated method in the presence of a suitable base (such as, Cs 2CO 3) Proceed to provide compounds of formula (VII). After removal of the protecting group of formula (VII) using an acid, such as ethyl acetate saturated with hydrogen chloride or TFA in dichloromethane, compounds of general formula (I-a) (where R 2 =H) are obtained. Compounds of general formula (I-a) (where R 2 = optionally via -S(O) 2-alkyl, Cycloalkyl or heterocyclic substituted alkyl; cycloalkyl; heterocycle). Compounds of general formula (I-a) (where R 2 =heteroaryl) are obtained from those compounds of general formula (I-a) (where R 2 =H) by arylation. Compounds of general formula (I-a) (where R 2 = H) are obtained from compounds of general formula (I-a) (where R 2 = H) by condensation with benzotriazole and carbonyl compounds, followed by nucleophilic reactions using Grenard reagents. R 2 =heterocycle optionally substituted with alkyl). Chlorine derivatives of formula (VI) can be purchased or can be prepared by traditional methods.

[0136] Compounds of formula (I-b) (wherein X=N, R 1 and R 2 are as defined in any one of the above specific examples) can be according to [reaction diagram] [4] [and] [5] Preparation. []

[0137] In the first step, the compound of formula (1) is reacted with ethyl acetyl acetate in a suitable solvent (such as DMSO) to obtain the compound of formula (2), which is reacted with N-toluene in the presence of KI and TBHP Sulfonyl hydrazine coupling to obtain the compound of formula (3) (Huang et al. Adv. Synth. Catal. 2018, 360:3117-3123). Compounds of formula (3) are treated with a reducing agent (such as DIBAL-H) ​​in a suitable solvent (such as toluene) to provide compounds of formula (VIII). Alternatively, the compound of formula (1) is converted into a diazonium salt, which is further reacted with trimethylsilyl azide to obtain the compound of formula (4). The compound of formula (4) is reacted with 2-butyn-1-ol to obtain the compound of formula (VIII). []

[0138] according to [reaction diagram] [5], The etherification reaction between the chlorine derivative of formula (VI) and the hydroxyl derivative of formula (VIII) can be carried out by a palladium-mediated method in the presence of a suitable base (such as, Cs 2CO 3) Proceed to provide compounds of formula (IX). After removal of the protecting group of formula (IX) using an acid, such as ethyl acetate saturated with hydrogen chloride or TFA in dichloromethane, compounds of general formula (I-b) (where R 2 =H) are obtained. Compounds of general formula (I-b) (where R 2 = optionally via -S(O) 2-alkyl, Cycloalkyl or heterocyclic substituted alkyl; cycloalkyl; heterocycle). Compounds of general formula (I-b) (where R 2 =heteroaryl) are obtained from those compounds of general formula (I-b) (where R 2 =H) by arylation. Compounds of general formula (I-b) (where R 2 = H) are obtained from compounds of general formula (I-b) (where R 2 = H) by condensation with benzotriazole and carbonyl compounds, followed by nucleophilic reaction using a Grenzier reagent. R 2 =heterocycle optionally substituted with alkyl). Alcohols of formula (VI) can be purchased or can be prepared by conventional methods.

[0139] The reagents and detailed procedural steps required for the above reactions are set forth in the Intermediates and Examples.

[0140] Accordingly, the present invention relates to a process for the preparation of a compound of formula (I) as defined above, comprising The coupling reaction of step (i) is selected from the group consisting of the following: [] [](a-1) react the compound of formula (IV) with the compound of formula (III) to obtain the compound of formula (V), wherein X=CH and R 1 and R 2 are as defined above; (a-2) reacting a compound of formula (VI) with a compound of formula (II) to obtain a compound of formula (VII), wherein X=N and R 1 and R 2 are as defined above; and (b) reacting a compound of formula (VI) with a compound of formula (VIII) to obtain a compound of formula (IX), wherein X, R1 and R2 are as defined above Step (ii) deprotection of a compound of formula (V), (VII) or (IX) to obtain a compound of formula (I), wherein A, X and R 1 are as defined above and R 2 is hydrogen, and Step (iii) optionally converts a compound of formula (I), wherein R is hydrogen, into a compound of formula (I), wherein A, X and R are as defined above and R is optionally - S(O) 2-alkyl, cycloalkyl or heterocyclic substituted alkyl; cycloalkyl; optionally alkyl substituted heterocyclyl; or heteroaryl).

[0141] In one aspect, the invention provides novel intermediates of formula (I'') synthesized in a method for preparing compounds of general formula (I), wherein A, X and R are as defined above and R 2 is an amino protecting group (Peter G. M. Wuts: Greene's Protective Groups in Organic Synthesis: Fifth Edition, Chapter 7. Protection for the Amino Group, pages 895-1193), such as carbamate (methyl, 9- Benzylmethyl, 2,2,2-trichloroethyl, tertiary butyl, 2-(trimethylsilyl)ethyl, allyl, benzyl), trifluoroacetamide, benzyl Amine, allylamine or tritylamine, preferably carbamate, preferably tertiary butoxycarbonyl protecting group.

[0142] In another aspect, the invention provides novel intermediates of formula (V) synthesized in a process for the preparation of compounds of general formula (I) (wherein ), provided that the compound is not 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid or 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid.

[0143] In another aspect, the invention provides novel intermediates of formula (VII) synthesized in a process for preparing compounds of general formula (I), wherein X is N and R 1 and R 2 are as defined above .

[0144] In a specific example, the present invention relates to the intermediate of formula (VII), which is selected from the group consisting of the following: 2-Methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]pyridine-2-carboxylic acid tertiary butyl ester, and 5-[5-Methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine-2-carboxylic acid tertiary butyl ester.

[0145] In yet another aspect, the invention provides novel intermediates of formula (IX) synthesized in a method for preparing compounds of general formula (I), wherein X, R1 and R2 are as defined above.

[0146] In a specific example, the present invention relates to the intermediate of formula (IX), which is selected from the group consisting of the following: 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4 -Tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2 ,3,4-tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid, 6-({1-[6-(Difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2 ,3,4-tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid, 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3, 4-Tetrahydro-2,7- tertiary butyl ester of 2-carboxylic acid, and 2-Methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine-2-carboxylic acid tertiary butyl ester.

[0147] The activity data of various compounds of formula (I) of the present invention are determined in vitro by the following method. [creature example] [1] [:binding assay] []

[0148] The GABA Aα5β3γ2 protein used in the receptor binding assay was derived from membranes produced by HEK cells (Millipore CYL3073) expressing human recombinant GABA Aα5β3γ2 receptor. Cells were stored and cultured in house according to the instructions provided by the supplier (Millipore). Cell pellets were incubated at 4°C in 10x modified Krebs-Henseleit buffer (membrane preparation buffer): 20 mM Tris, 120 mM NaCl, 100 mM KCl, 25 mM CaCl 2 and 25 mM MgCl 2pH=7.4, using Ultra Turrax (Janke & Kunkel) at maximum speed for 15 seconds to homogenize. Centrifuge the homogenate at 40,000 g for 30 min at 4°C. The supernatant was discarded and the resulting pellet was washed in membrane preparation buffer. Resuspend the pellet in membrane preparation buffer and store aliquots of 1.4 mL ampoules at -70 °C until use.

[0149] Receptor binding assays were performed in a 96-well format in deep well plates. For each 96-well plate, one ampoule of membrane homogenate was thawed and diluted in binding buffer (50 mM Tris pH=7.4, 100 mM KCl) and 200 μL was dispensed into each well. The radioligand [3H]Ro151788 (Perkin Elmer: NET757250UC) was prepared in binding buffer and a volume of 50 μL was added to each well to give a final concentration of 0.5 nM. Add the appropriate concentration of test compound(s) to an additional 50 µL. The final assay volume is 300 µL. Incubate at 4°C for 60 minutes. For nonspecific binding, 10 µM unlabeled diazepam was used. After incubation, samples were filtered on UniFilter® GF / B TM using Filtermate Harvester (Perkin Elmer) and washed with 5x1 mL binding buffer. Allow the plate to dry for 1 hour at 40°C and add 40 µL of Microscint (Perkin Elmer) scintillation cocktail to each well. Discs were read in Microbeta (Perkin Elmer).

[0150] Specific radioligand binding (SB) is defined as the difference between total binding (Tot) and non-specific binding (NSB). Results are expressed as percent inhibition of specific binding obtained in the presence of the compound of interest.

[0151] For IC50 and K1 determinations, at least six drug concentrations were used, performed in triplicate. The IC 50 value (i.e., the concentration of compound that produces 50% inhibition of specific binding) was calculated from the concentration-displacement curve with S-shaped fitting using Origin 7.5 software. The K i value (i.e., the inhibition constant) is calculated using the Zheng-Prusafor equation K i = IC 50 / [1+(L / K D)], where [L] is the radioligand concentration and K D is the labeled The affinity of the ligand for the receptor. K D is determined by saturation analysis.

[0152] Compounds of the invention were tested in the assay described above and all compounds were found to have high affinity for the GABA Aα5 receptor (K i <150 nM). [creature example] [2] [:Functional Measurement] []

[0153] The human HEK293 cell line expressing the GABA Aα5β3γ2 receptor was used for functional assays using the QPatch automated patch clamp system.

[0154] HEK293 cell lines stably expressing human recombinant GABA Aα5β3γ2 receptor subunit (Millipore, CYL3053) were cultured in DMEM supplemented with 10% FBS (Gibco), passed twice weekly, and plated on previously coated poly- d-lysine on the Petri dish.

[0155] Automated whole-cell patch-clamp recordings were obtained from cells 2 to 4 days after plating. Cells were detached by trypsin / EDTA (Sigma) treatment (2 min in 0.25% trypsin at 37°C), followed by centrifugation (125 g, 3 min, 2 times) and resuspended in 12.5 mM HEPES. , 1× penicillin-streptomycin-amphotericin (SigmaMix) and soybean trypsin inhibitor (Sigma, 0.04 mg / ml) in serum-free medium (Gibco, CHO-S-SFM-II).

[0156] In single-cell mode at room temperature, add cell suspension and extracellular solution (130 mM NaCl, 5 mM KCl, 5.1 mM HEPES, 4.9 mM HEPES-Na, 10 mM CaCl, 2 mM MgCl, 10 mM glucose, and 0.1% DMSO, pH=7.35 to 7.4) and intracellular solution (80 mM KCl, 50 mM KF, 36 mM KOH, 10 mM EGTA, 10 mM HEPES, 1.75 mM MgCl 2, 0.5 mM CaCl 2, 4 mM Na 2ATP, 14 mM creatine phosphate, 50 U / ml creatine-phosphokinase, 0.3 mM GTP, pH=7.25 to 7.3). Inward currents were induced at a holding potential of -80 mV by first adding 1 μM of the control agonist GABA at 2 to 4 min intervals in a concentration-matched DMSO (0.1 or 0.3%) control solution. Five 3 s long applications were performed, followed by four applications in the presence of the test compound and finally three more applications in the control solution (washout). At the end of the experiment, 100 μM GABA was applied to saturate the GABA response, and the efficacy of control GABA applications was assessed. The current signal was low-pass filtered at 100 Hz and recorded at a sampling rate of 1 kHz.

[0157] Percent modulation was calculated by comparing the amplitude of GABA-evoked peak currents in the presence and absence of the test compound.

[0158] Compounds of the invention were tested at 1 μM in the above assay and all compounds were found to possess GABA Aα5 positive allosteric modulator activity. [Example] []

[0159] The present invention will be further illustrated by the following intermediates and examples, but the scope of the present invention is not limited to them. From the above description, as well as intermediates and examples, those skilled in the technical field to which the invention belongs can determine the necessary features of the invention, and without departing from its essence and scope, can make certain changes and modifications to make the invention Inventions adapt to a variety of applications and conditions. As a result, the present invention is not limited to the following illustrative examples, but rather to the extent determined by the scope of the appended claims.

[0160] Generally speaking, the compounds of formula (I) can be prepared according to the common sense of those skilled in the technical field to which the invention belongs and / or the methods and / or intermediates described with respect to the working examples. Solvents, temperatures, pressures and other reaction conditions can be easily selected by those skilled in the art to which the invention belongs. Starting materials are commercially available and / or can be readily prepared by a person skilled in the art to which the invention pertains according to documented procedures. During the preparation of compounds, combinatorial techniques can be used where, for example, intermediates are suitable for such methods. [] [Intermediate] [1] [5-[4-(] [Chloromethyl] [)-5-] [Methyl] [-1,2-] [azole] [-3-] [base] []-2-] [Methylpyridine] [] []

[0161] 1.00 g (4.89 mmol) of [5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methanol (WO 2018 / 104419 A1, Hoffmann-La Roche) was dissolved in 30 mL of phosphorus oxychloride. The reaction mixture was stirred at 115°C for 2 hours and then evaporated to dryness. Ethyl acetate was added and washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and evaporated to obtain 0.95 g (87%) of the title compound. MS (ESI) m / z: 223.1 [M+H] +. [Intermediate] [2] [5-[4-(] [Chloromethyl] [)-5-] [Methyl] [-1,2-] [azole] [-3-] [base] []-2-(] [Trifluoromethyl] [)] [Pyridine] [] []

[0162] Similar to intermediate 1, {5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methanol (WO 2018 / 104419 A1, Hoffmann-La Roche) was converted to the title compound. MS (ESI) m / z: 277.1 [M+H] +. [] [Intermediate] [3] [[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1 , H , -1,2,3- ] [Triazole] [-5-] [base] []] [Methanol] [] [] Method A a: (2E)-3-[(6-methylpyridin-3-yl)amino]but-2-enoic acid methyl ester

[0163] To a mixture of 1.00 g (9.20 mmol) of commercially available 6-methylpyridin-3-amine and 1.40 mL (1.11 mmol) of ethyl acetoacetate in 30 mL of ethanol, 1.67 g (13.9 mmol) of Anhydrous magnesium sulfate and 0.10 mL (1.85 mmol) of acetic acid. The reaction mixture was refluxed for 10 hours. After cooling, filtration of the inorganics and concentration of the filtrate under reduced pressure provided a residue, which was used in the next step without further purification. MS (ESI) m / z: 207.1 [M+H] +. b: 4-Methyl-1-(6-methylpyridin-3-yl)-1 H-1,2,3-triazole-5-carboxylic acid ethyl ester

[0164] In 8.31 g (37.7 mmol) of (2E)-3-[(6-methylpyridin-3-yl)amino]but-2-enoic acid methyl ester, 8.43 g (45.3 mmol) of toluenesulfonate To a mixture of hydrazine and 6.26 g (37.7 mmol) of potassium iodide in 70 mL of DMSO, slowly add 7.31 mL (75.5 mmol) of TBHP (70% solution in water). Next, the mixture was stirred at 70°C for 24 hours. After the reaction was completed (monitored by TLC), 140 g of sodium disulfite dissolved in 300 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. Next, the combined organic layers were dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica, eluent: DCM:MeOH, 0 to 10% gradient) to provide the desired product. Yield: 6.35 g (68 %), MS (ESI) m / z: 247.1 [M+H] + . c: [4-Methyl-1-(6-methylpyridin-3-yl)-1 H-1,2,3-triazol-5-yl]methanol

[0165] Dissolve 6.35 g (25.8 mmol) of 4-methyl-1-(6-methylpyridin-3-yl)-1 H-1,2,3-triazole-5-carboxylic acid ethyl ester in 80 mL of ethanol. water in THF, and cool to 0°C. 103 mL of DIBAL-H (1 M solution in toluene) was added dropwise under argon, and the reaction mixture was stirred at room temperature for 1 hour. After cooling, quench with 71 mL of water and acidify with 135 mL of 1 M HCl. The combined organic layers were washed with brine, dried over NaSO, filtered and evaporated in vacuo. The crude product was crystallized from isopropanol to obtain the title compound as a white solid. Yield: 3.42 g, (65%), MS (ESI) m / z: 205.1 [M+H]+. Method B a: 5-azido-2-methylpyridine

[0166] 5.0 g (46 mmol) of commercially available 6-methylpyridin-3-amine was dissolved in a mixture of 14 mL of concentrated HCl and 14 mL of water and cooled to 0 °C. 3.19 g (46.2 mmol) of NaNO 2 dissolved in 12 mL of water was added dropwise. The reaction mixture was stirred at 0°C for 20 min, then 10.6 mL (80 mmol) of trimethylsilyl azide was slowly added dropwise and the reaction mixture was stirred at room temperature for 1.5 h. After completion, 70 mL of ethyl acetate was added, washed three times with 30 mL of saturated sodium carbonate solution and water, dried over anhydrous sodium sulfate and evaporated. The crude product was used in the next step without further purification. b: [4-Methyl-1-(6-methylpyridin-3-yl)-1 H-1,2,3-triazol-5-yl]methanol

[0167] 5.81 g (43.3 mmol) of 5-azido-2-methylpyridine was dissolved in 3.24 mL (43.3 mmol) of 2-butyn-1-ol, and the reaction mixture was stirred at 100°C for 10 h. The residue was purified by flash column chromatography (silica, eluent:cyclohexane:EtOAc 40 to 80% gradient). Yield: 2.30 g (26%), white solid. MS (ESI) m / z: 205.1 [M+H]+. [Intermediate] [4] [{4-] [Methyl] [-1-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1 , H , -1,2,3- ] [Triazole] [-5-] [base] [}] [Methanol] [] []

[0168] The compound was synthesized according to the procedure described for intermediate 3 using commercially available 6-(trifluoromethyl)pyridin-3-amine from step a. MS (ESI) m / z: 259.1 [M+H]+. [] [Intermediate] [5] [{1-[6-(] [Difluoromethyl] [)] [Pyridine] [-3-] [base] []-4-] [Methyl] [-1 , H , -1,2,3- ] [Triazole] [-5-] [base] [}] [Methanol] [] []

[0169] The compound was synthesized according to the procedure described for intermediate 3 using commercially available 6-(difluoromethyl)pyridin-3-amine from step a. MS (ESI) m / z: 241.1 [M+H]+. [] [Intermediate] [6] [[1-(6-] [methoxypyridine] [-3-] [base] [)-4-] [Methyl] [-1 , H , -1,2,3- ] [Triazole] [-5-] [base] []] [Methanol] [] []

[0170] The compound was synthesized according to the procedure described for intermediate 3 using commercially available 6-methoxypyridin-3-amine from step a. MS (ESI) m / z: 221.1 [M+H]+. [Example] [1] [6-{[5-] [Methyl] [-3-(6-] [Methylpyridine] [-3-] [base] [)-1,2-] [ , ] [azole] [-4-] [base] []] [Methoxy] [}-1,2,3,4-] [tetrahydrogen] [-2,7-] [ ] [Pyridine trifluoroacetate] [] [] A: 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid

[0171] 1.96 g (8.80 mmol) of 5-[4-(chloromethyl)-5-methyl-1,2- Azol-3-yl]-2-methylpyridine (Intermediate 1) and 2.20 mg (8.80 mmol) of commercially available 6-hydroxy-3,4-dihydro-2,7- Dissolve tertiary butyl ester of 2(1H)-carboxylate in 120 mL of anhydrous acetonitrile. Next, 3.65 mg (26.40 mmol) of anhydrous potassium carbonate was added to the solution, and the suspension was stirred under reflux for 12 h. After conversion, TLC was performed (EtOAc: cyclohexane = 1:1 as eluent, silicon disk). After the reaction was completed, the mixture was filtered and evaporated to obtain an oily crude product, which was purified by flash column chromatography (silica gel, eluent: EtOAc: cyclohexane = 1:1). Yield: 640 mg (16.6%) white solid. MS (ESI) m / z: 437.3 [M+H] +. B: 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- Trifluoroacetate

[0172] 97.97 mg (0.22 mmol) of 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- Tertiary butyl 2-carboxylate was dissolved in 10 mL of DCM. Next, 1489 mg (13.06 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 6 h. After the reaction was complete, the mixture was evaporated to give the title compound. Yield: 90 mg (91%) yellow solid. MS (ESI) m / z: 337.1 [M+H] +. 1H NMR (DMSO-d 6, 400 MHz) δ (ppm): 8.96-9.07 (br m, 2H), 8.81 (br d, J=2.0 Hz, 1H), 8.12 (dd, J=8.1, 2.3 Hz, 1H), 8.06 (s, 1H), 7.49 (d, J=8.1 Hz, 1H), 6.73 (s, 1H), 5.27 (s, 2H), 4.25 (br t, J=4.5 Hz, 2H), 3.31 -3.39 (m, 2H), 2.95 (t, J=6.3 Hz, 2H), 2.57 (s, 3H), 2.56 (s, 3H). [Example] [2] [6-({5-] [Methyl] [-3-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1,2-] [ ] [azole] [-4-] [base] [}] [Methoxy] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , trifluoroacetate] [] []

[0173] Use 5-[4-(chloromethyl)-5-methyl-1,2- from step a Azol-3-yl]-2-(trifluoromethyl)pyridine (Intermediate 2) The title compound was prepared according to the procedure described for Example 1. MS (ESI) m / z: 391.2 [M+H] +. 1H NMR (DMSO-d 6, 400 MHz) δ (ppm): 9.11 (d, J=1.9 Hz, 1H), 8.82-9.03 (br m, 2H), 8.48 (dd, J=8.1, 1.7 Hz, 1H ), 8.11 (d, J=8.1, 1H), 8.04 (s, 1H), 6.73 (s, 1H), 5.33 (s, 2H), 4.24 (br t, 2H), 3.31-3.38 (br m, 2H ), 2.94 (t, J=6.3 Hz, 2H), 2.61 (s, 3H). [Example] [3] [2-] [Methyl] [-6-{[5-] [Methyl] [-3-(6-] [Methylpyridine] [-3-] [base] [)-1,2-] [ ] [azole] [-4-] [base] []] [Methoxy] [}-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0174] Add 450 mg (1.0 mmol) of 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- Trifluoroacetate (Example 1) and extracted with EtOAc. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The obtained base was dissolved in 2 mL of water, and 240 mg (4.0 mmol) of acetic acid, 122 mg (1.5 mmol) of formaldehyde solution (37% in water), and 131 mg (2.0 mmol) of zinc powder were added. The reaction mixture was stirred at 30°C for 48 hours. After the reaction was completed (monitored by TLC), the reaction mixture was neutralized with ammonia solution, and the resulting mixture was extracted with DCM. The combined organic layers were then dried over MgSO4, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to provide the desired product. Yield: 59.3 mg (16.9 %), MS (ESI) m / z: 351.2 [M+H] + . [Example] [4] [2-] [cyclobutyl] [-6-{[5-] [Methyl] [-3-(6-] [Methylpyridine] [-3-] [base] [)-1,2-] [ ] [azole] [-4-] [base] []] [Methoxy] [}-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0175] 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- Trifluoroacetate (Example 1) was added to 4 mL of 2,2,2-trifluoroethanol solution of 112 mg (1.33 mmol) of NaHCO 3 and stirred for 30 minutes, then a portion of 32 mg (0.44 mmol) of cyclobutanone and the reaction mixture was warmed to 45°C. The solution so obtained was stirred for 5 min, followed by the addition of 16.8 mg (0.44 mmol) of sodium borohydride. The reaction mixture was stirred at 45°C for 3 hours. Upon completion the solvent was evaporated, the residue was taken up in DCM and washed with brine. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: EtOAc:MeOH=10:1) to provide the desired product. Yield: 28.1 mg (16.1 %), MS (ESI) m / z: 393.2 [M+H] +. [Example] [5] [2-(] [cyclobutylmethyl] [)-6-{[5-] [Methyl] [-3-(6-] [Methylpyridine] [-3-] [base] [)-1,2-] [ ] [azole] [-4-] [base] []] [Methoxy] [}-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0176] The title compound was prepared according to the procedure described for Example 4 using commercially available cyclobutanecarboxaldehyde. MS (ESI) m / z: 405.2 [M+H] +. [Example] [6] [2-] [Cyclopentyl] [-6-{[5-] [Methyl] [-3-(6-] [Methylpyridine] [-3-] [base] [)-1,2-] [ ] [azole] [-4-] [base] []] [Methoxy] [}-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0177] The title compound was prepared according to the procedure described for Example 4 using commercially available cyclopentanone. MS (ESI) m / z: 405.2 [M+H] +. [Example] [7] [6-({5-] [Methyl] [-3-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1,2-] [ ] [azole] [-4-] [base] [}] [Methoxy] [)-2-(] [Oxane] [-4-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0178] Use 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7- The title compound was prepared according to the procedure described for Example 4 using trifluoroacetate (Example 2) and commercially available tetrahydropyran-4-one. MS (ESI) m / z: 475.2 [M+H] +. [Example] [8] [6-({5-] [Methyl] [-3-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1,2-] [ ] [azole] [-4-] [base] [}] [Methoxy] [)-2-(] [Oxolane] [-3-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0179] Use 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy) 1,2,3,4-tetrahydro-2,7- The title compound was prepared according to the procedure described for Example 4 using pyridine trifluoroacetate (Example 2) and commercially available 3-side oxytetrahydrofuran. MS (ESI) m / z: 461.2 [M+H] +. [Example] [9] [6-{[5-] [Methyl] [-3-(6-] [Methylpyridine] [-3-] [base] [)-1,2-] [ ] [azole] [-4-] [base] []] [Methoxy] [}-2-(] [Oxolane] [-3-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0180] The title compound was prepared according to the procedure described for Example 4 using commercially available 3-side oxytetrahydrofuran. MS (ESI) m / z: 407.2 [M+H] +. [Example]

[10] [6-{[5-] [Methyl] [-3-(6-] [Methylpyridine] [-3-] [base] [)-1,2-] [ ] [azole] [-4-] [base] []] [Methoxy] [}-2-(] [Oxetane] [-3-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0181] The title compound was prepared according to the procedure described for Example 4 using commercially available 3-propiolactone. MS (ESI) m / z: 393.2 [M+H] +. [Example]

[11] [6-{[5-] [Methyl] [-3-(6-] [Methylpyridine] [-3-] [base] [)-1,2-] [ ] [azole] [-4-] [base] []] [Methoxy] [}-2-(] [Oxane] [-4-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0182] The title compound was prepared according to the procedure described for Example 4 using commercially available 4-pendant oxytetrahydropyran. MS (ESI) m / z: 421.2 [M+H] +. [Example]

[12] [2-(1-] [methanesulfonylpropyl] [-2-] [base] [)-6-({5-] [Methyl] [-3-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1,2-] [ ] [azole] [-4-] [base] [}] [Methoxy] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0183] To the saturated Na2CO3 solution, add 183.6 mg (0.36 mmol) of 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7- Trifluoroacetate (Example 2) and extracted with DCM. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The base obtained was added to a stirred solution of 49 mg (0.36 mmol) of methanesulfonate acetone in 1 mL of methanol and 1 mL of 2,2,2-trifluoroethanol at room temperature. The mixture was stirred for 1 h. 84 mg (0.72 mmol) of triethylsilica was added via syringe, followed by 57 mg (0.26 mmol) of indium (III) chloride (Lee et al., J. Org. Chem. 2008, 73, 22, 8829 -8837). The reaction was stirred at room temperature and monitored by TLC. When the reaction is complete, quench the mixture with 1 mL of saturated KCO solution. The mixture was extracted with EtOAc. The combined organic layers were washed with brine and finally dried over Na2SO4. The crude product was purified by flash column chromatography (silica gel, eluent:cyclohexane:EtAOc=1:1). Yield: 21 mg (11 %), MS (ESI) m / z: 511.1 [M+H] +. [Example]

[13] [6-{[5-] [Methyl] [-3-(6-] [Methylpyridine] [-3-] [base] [)-1,2-] [ , ] [azole] [-4-] [base] []] [Methoxy] [}-2-(] [Pyridine] [-2-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ ] [pyridine] [] []

[0184] 283 mg (0.63 mmol) of 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2- Azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7- Trifluoroacetate (Example 1) was dissolved in 2 mL of 2-fluoropyridine, and the reaction mixture was stirred at 120°C for 3 h. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1). Yield: 50 mg (19.2 %). MS (ESI) m / z: 414.2 [M+H] +. [] [Example]

[14] [2-] [Methyl] [-5-[5-] [Methyl] [-4-({5H,6H,7H,8H-] [pyrido] [[3,4-c]] [ta] [ , ] [-3-] [baseoxy] [}] [Methyl] [)-1,2-] [ , ] [azole] [-3-] [base] []] [Pyridine] [] [] A: 2-Methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]pyridine-2-carboxylic acid tertiary butyl ester

[0185] Under an argon atmosphere, 660 mg (2.45 mmol) of commercially available 3-chloro-5,8-dihydropyrido[3,4-c]pyridino[3,4-c]pyridine was added. -7(6H)-tert-butylcarboxylate, 500 mg (2.45 mmol) of {5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methanol (WO 2018 / 104419 A1, Hoffmann-La Roche), 1595 mg (4.89 mmol) of Cs 2CO 3, 98 mg (0.25 mmol) of rac-2-(di-tertiary butylphosphine) Pd)-1,11-binaphthyl, 55 mg (0.24 mmol) of Pd(OAc) 2 and 20 mL of anhydrous toluene were charged into the flask. The mixture was stirred at 100 °C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:1 as eluent, silicon disk). The reaction mixture was filtered through a pad of celite, washed with acetone, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluent:cyclohexane:EtAOc=1:1). Yield: 342 mg (32 %), white, amorphous solid. MS (ESI) m / z: 438.2 [M+H] +. B: 2-Methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]pyridine

[0186] 342 mg (0.78 mmol) of 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridino] -3-yloxy}methyl)-1,2- Azol-3-yl]pyridine-2-carboxylic acid tertiary butyl ester was dissolved in 50 mL of DCM. Next, 1782 mg (15.63 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 24 h. Upon completion the mixture was evaporated, the residue was taken up in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: EtOAc:MeOH=10:1) to provide the desired product. Yield: 132 mg (50 %), MS (ESI) m / z: 338.2 [M+H] +. [Example]

[15] [5-[5-] [Methyl] [-4-({5H,6H,7H,8H-] [pyrido] [[3,4-c]] [ta] [ , ] [-3-] [baseoxy] [}] [Methyl] [)-1,2-] [ , ] [azole] [-3-] [base] []-2-(] [Trifluoromethyl] [)] [Pyridine] [] [] A: 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine-2-carboxylic acid tertiary butyl ester

[0187] Under an argon atmosphere, 668 mg (2.48 mmol) of commercially available 3-chloro-5,8-dihydropyrido[3,4-c]pyridino -7(6H)-tert-butylcarboxylate, 639 mg (2.48 mmol) of 5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methanol (WO 2018 / 104419 A1, Hoffmann-La Roche), 1614 mg (4.95 mmol) of Cs 2CO 3, 99 mg (0.25 mmol) of rac-2-(di-tertiary butylphosphine) Pd)-1,11-binaphthyl, 56 mg (0.25 mmol) of Pd(OAc) 2 and 20 mL of anhydrous toluene were charged into the flask. The mixture was stirred at 100 °C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:1 as eluent, silicon disk). The reaction mixture was filtered through a pad of celite, washed with acetone, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluent:cyclohexane:EtAOc=1:1). Yield: 395 mg (32.5 %). MS (ESI) m / z: 492.2 [M+H] +. B: 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine

[0188] 395 mg (0.80 mmol) of 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]da -3-yloxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine-2-carboxylic acid tertiary butyl ester was dissolved in 20 mL of DCM. Next, 916 mg (8.03 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 24 h. Upon completion the mixture was evaporated, the residue was taken up in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: EtOAc:MeOH=10:1) to provide the desired product. Yield: 175 mg (56 %), MS (ESI) m / z: 392.1 [M+H]+. [Example]

[16] [2-] [Methyl] [-5-{5-] [Methyl] [-4-[({7-] [methyl] [-5H,6H,7H,8H-] [pyrido] [[3,4-c]] [ta] [ , ] [-3-] [base] [}] [Oxygen] [)] [Methyl] []-1,2-] [ , ] [azole] [-3-] [base] [}] [Pyridine] [] []

[0189] In 74 mg (0.22 mmol) of 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]da -3-yloxy}methyl)-1,2- Azol-3-yl]pyridine (Example 14) was added to 5 mL of methanol solution with 27 mg (0.33 mmol) of formaldehyde solution (37% in water), and the reaction mixture was heated to 50°C, and then a 93 mg (0.44 mmol) of sodium triacetyloxyborohydride. The reaction mixture was stirred at 50°C for 5 hours. After completion the solvent was evaporated, the residue was dissolved in EtOAc and washed with saturated NaHCO solution. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: EtOAc:MeOH =10:1) to provide the desired product. Yield: 40 mg (52 %), MS (ESI) m / z: 352.2 [M+H] + . [Example]

[17] [5-[5-] [Methyl] [-4-({5H,6H,7H,8H-] [pyrido] [[3,4-c]] [ta] [ , ] [-3-] [baseoxy] [}] [Methyl] [)-1,2-] [ , ] [azole] [-3-] [base] []-2-(] [Trifluoromethyl] [)] [Pyridine] [] []

[0190] Use 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine (Example 15) The title compound was prepared according to the procedure described for Example 16. MS (ESI) m / z: 406.1 [M+H] +. [Example]

[18] [5-[5-] [Methyl] [-4-({[7-(] [Oxolane] [-3-] [base] [)-5H,6H,7H,8H-] [pyrido] [[3,4-c]] [Ta, , ] [-3-] [base] []] [Oxygen] [}] [Methyl] [)-1,2-] [ , ] [azole] [-3-] [base] []-2-(] [Trifluoromethyl] [)] [Pyridine henaphthalene disulfonate] [] [] A: Synthesis of free base

[0191] In 130 mg (0.33 mmol) of 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]da -3-yloxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine (Example 15) was added to a solution of 5 mL of 2,2,2-trifluoroethanol with 29 mg (0.34 mmol) of 3-side oxytetrahydrofuran and 13 mg (0.34 mmol) of sodium borohydride. The reaction mixture was stirred at 45°C for 12 hours. Upon completion the solvent was evaporated, the residue was taken up in DCM and washed with water. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to provide the free base as an oil. Yield: 23 mg (15 %), MS (ESI) m / z: 462.2 [M+H] + B: Synthesis of hemidadisulfonate

[0192] 23 mg (0.05 mmol) of 5-[5-methyl-4-({[7-(oxolan-3-yl)-5H,6H,7H,8H-pyrido[3,4- c]da -3-yl]oxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine was dissolved in 2 mL of ethanol, and 18 mg (0.05 mmol) of 1,5-naphthalenedisulfonic acid tetrahydrate was added and stirred at 60°C 10 minutes, then allow to cool to room temperature. The precipitated product was collected by filtration, washed with cold ethanol and dried under vacuum to obtain the title compound as a white solid. Yield: 17 mg (56 %), MS (ESI) m / z: 462.2 [M+H] + . 1H NMR (DMSO-d 6, 400 MHz) δ (ppm): 10.05-10.50 (br m, 1H), 9.12 (d, J=1.7 Hz, 1H), 8.49 (dd, J=8.1, 1.7 Hz, 1H ), 8.10 (br d, J=8.2 Hz, 1H), 7.21 (br s, 1H), 4.40-4.85 (br m, 2H), 4.07-4.34 (br m, 2H), 3.91-4.06 (br m, 1H), 3.76-3.89 (m, 1H), 3.30-3.74 (br m, 5H), 3.00-3.18 (br m, 2H), 2.64 (s, 3H), 2.12-2.43 (br m, 2H); naphthalene Diformate (acid / base molar ratio 1:2) signal: 8.85 (dd, J=8.5, ~1 Hz, 2H), 7.91 (dd, J=7.0 Hz, 1.1 Hz, 2H), 7.38 (dd , J=8.5, 7.1 Hz, 2H). [Example]

[19] [3-{[3-({5-] [Methyl] [-3-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1,2-] [ , ] [azole] [-4-] [base] [}] [Methoxy] [)-5H,6H,7H,8H-] [pyrido] [[3,4-c]] [Ta, , ] [-7-] [base] []] [Methyl] [}-1λ6-] [Thiolane] [-1,1-] [Diketartrate] [] [] A: Synthesis of free base

[0193] In a microwave tube, place 100 mg (0.256 mmol) of 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]d -3-yloxy}methyl)-1,2- Azol-3-yl]-2-(trifluoromethyl)pyridine (Example 15) was dissolved in 3 mL of acetonitrile, then 66 mg (0.51 mmol) of N,N-diisopropylethylamine and 54.6 mg were added mg (0.256 mmol) of 3-bromomethyltetrahydrothiophene 1,1-dioxide. Place the tube in a microwave reactor and heat at 100°C for 3 hours with stirring. After the reaction was completed, the mixture was evaporated and purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to obtain 34 mg of the product as an oil. Yield: 38 mg (28.4 %), MS (ESI) m / z: 524.1 [M+H] + . B: Synthesis of tartrate

[0194] 11.2 mg (0.021 mmol) of 3-{[3-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2- Azol-4-yl}methoxy)-5H,6H,7H,8H-pyrido[3,4-c]pyra -7-yl]methyl}-1λ6-thiolane-1,1-dione was dissolved in 1 mL of ethanol, and 3.2 mg (0.021 mmol) of L-(+)-tartaric acid was added and the solution was added at 60 °C for 10 minutes, then allowed to cool to room temperature. The precipitated product was collected by filtration, washed with cold ethanol and dried under vacuum to obtain the title compound as a white solid. Yield: 12.5 mg (86.7 %), MS (ESI) m / z: 524.1 [M+H] + . 1H NMR (DMSO-d 6, 400 MHz) δ (ppm): 11.40-13.60 (br m, 1H), 9.12 (d, J=1.7 Hz, 1H), 8.46 (dd, J=8.0 Hz, 1.8 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.00 (s, 1H), 5.48 (s, 2H), 3.75 (s, 2H), 3.14-3.26 (m, 2H), 3.00-3.09 (m , 1H), 2.82 (t, J=5.4 Hz, 2H), 2.74-2.81 (m, 2H), 2.54-2.73 (m, 4H), 2.63 (s, 3H), 2.20-2.29 (m, 1H), 1.73-1.83 (m, 1H); Tartrate (acid / base ratio 1:1) signal: 4.28 (s, 2H). [Example]

[20] [6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] [] A: 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3 ,4-Tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid

[0195] Under an argon atmosphere, 504 mg (1.88 mmol) of commercially available 6-chloro-3,4-dihydro-2,7- Tributyl 2(1H)-carboxylate, 383 mg (1.88 mmol) of [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazole -5-yl]methanol (Intermediate 3), 1220 mg (3.75 mmol) of Cs 2CO 3 , 74.7 mg (0.18 mmol) of rac-2-(di-tertiary butylphosphino)-1,11-bis Naphthalene, 42 mg (0.18 mmol) of Pd(OAc) 2 and 20 mL of anhydrous toluene were charged into the flask. The mixture was stirred at 100 °C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:1 as eluent, silicon disk). The reaction mixture was filtered through a pad of celite, washed with acetone, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluent:cyclohexane:EtAOc=30 to 70% gradient). Yield: 287 mg (35%). MS (ESI) m / z: 437.2 [M+H] +. B: 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3 ,4-Tetrahydro-2,7- aridine

[0196] 287 mg (0.65 mmol) of 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy} -1,2,3,4-Tetrahydro-2,7- Dissolve tertiary butyl ester of 2-carboxylic acid in 12 mL of ethyl acetate. 12 mL of ethyl acetate saturated with hydrogen chloride was added dropwise to the solution. The reaction mixture was stirred at room temperature for 30 minutes. The white precipitate that formed was filtered off and washed with a small portion of ethyl acetate. The hydrochloride salt was added to the saturated NaHCO solution and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to provide the desired product. Yield: 78 mg (35 %), MS (ESI) m / z: 337.2 [M+H]+. [Example] [twenty one] [2-] [Methyl] [-6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0197] Using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3, 4-Tetrahydro-2,7- (Example 20), the title compound was prepared according to the procedure described for Example 16. MS (ESI) m / z: 351.1 [M+H] +. [Example] [twenty two] [6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-2-(] [C] [-2-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0198] Using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3, 4-Tetrahydro-2,7- The title compound was prepared according to the procedure described for Example 18, Step A, using pyridine (Example 20) and commercial acetone. MS (ESI) m / z: 379.2 [M+H] +. [] [Example] [twenty three] [6-({1-[6-(] [Difluoromethyl] [)] [Pyridine] [-3-] [base] []-4-] [Methyl] [-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] [] A: 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1 ,2,3,4-tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid

[0199] Under an argon atmosphere, 91.3 mg (0.34 mmol) of commercially available 6-chloro-3,4-dihydro-2,7- Tributyl 2(1H)-carboxylate, 81.6 mg (0.34 mmol) of {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2, 3-Triazol-5-yl}methanol (Intermediate 5), 226 mg (0.69 mmol) of Cs 2CO 3, 13.8 mg (0.034 mmol) of rac-2-(di-tertiary butylphosphino)-1 , 11-binaphthyl, 7.8 mg (0.034 mmol) of Pd(OAc) 2 and 10 mL of anhydrous toluene were charged into the flask. The mixture was stirred at 100 °C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:2 as eluent, silicon disk). The reaction mixture was filtered through a pad of celite, washed with acetone, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluent: cyclohexane: EtOAc=1:2). Yield: 90 mg (56 %). MS (ESI) m / z: 473.2 [M+H] +. B: 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1 ,2,3,4-tetrahydro-2,7- aridine

[0200] 90 mg (0.19 mmol) of 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl} Methoxy)-1,2,3,4-tetrahydro-2,7- Tertiary butyl 2-carboxylate was dissolved in 10 mL of DCM. Next, 652 mg (5.71 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 3 h. Upon completion the mixture was evaporated, the residue was taken up in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to provide the desired product. Yield: 28.4 mg (40 %), MS (ESI) m / z: 373.2 [M+H]+. [] [Example] [twenty four] [6-({1-[6-(] [Difluoromethyl] [)] [Pyridine] [-3-] [base] []-4-] [Methyl] [-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-2-] [Methyl] [-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0201] Using 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1, 2,3,4-Tetrahydro-2,7- (Example 23), the title compound was prepared according to the procedure described for Example 16. MS (ESI) m / z: 387.2 [M+H] +. [] [Example]

[25] [6-({4-] [Methyl] [-1-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] [] A: 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1 ,2,3,4-tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid

[0202] Under an argon atmosphere, 521 mg (1.94 mmol) of commercially available 6-chloro-3,4-dihydro-2,7- Tributyl 2(1H)-carboxylate, 500 mg (1.94 mmol) of 4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3 -Triazol-5-yl}methanol (Intermediate 4), 1260 mg (3.87 mmol) of Cs 2CO 3, 77.2 mg (0.194 mmol) of rac-2-(di-tertiary butylphosphino)-1, 11-binaphthyl, 43.5 mg (0.194 mmol) of Pd(OAc) 2 and 30 mL of anhydrous toluene were charged into the flask. The mixture was stirred at 100 °C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=9:1 as eluent, silicon disk). The reaction mixture was filtered through a pad of celite, washed with acetone, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=9:1). Yield: 710 mg (74.8 %), amorphous solid. MS (ESI) m / z: 491.2 [M+H] +. B: 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1 ,2,3,4-tetrahydro-2,7- aridine

[0203] 710 mg (1.45 mmol) of 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl} Methoxy)-1,2,3,4-tetrahydro-2,7- Tertiary butyl 2-carboxylate was dissolved in 15 mL of DCM. Next, 3300 mg (29 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 24 h. Upon completion the mixture was evaporated, the residue was taken up in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=9:1) to provide the desired product. Yield: 320 mg (56.6 %), MS (ESI) m / z: 391.2 [M+H] +. [] [Example]

[26] [6-({4-] [Methyl] [-1-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-2-(] [C] [-2-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0204] 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl} at 160 mg (0.41 mmol) Methoxy)-1,2,3,4-tetrahydro-2,7- 23.8 mg (0.41 mmol) of acetone and 15.5 mg (0.41 mmol) of sodium borohydride were added to 5 mL of 2,2,2-trifluoroethanol solution (Example 25). The reaction mixture was stirred at 45°C for 12 hours. Upon completion the solvent was evaporated, the residue was taken up in DCM and washed with water. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=9:1) to provide the title compound. Yield: 61 mg (34 %), MS (ESI) m / z: 433.2 [M+H] + . [Example]

[27] [2-] [Methyl] [-6-({4-] [Methyl] [-1-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0205] Using 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1, 2,3,4-Tetrahydro-2,7- The title compound was prepared according to the procedure described for Example 16 (Example 25, Step B). MS (ESI) m / z: 405.1 [M+H] +. [] [Example]

[28] [6-({1-[6-(] [Difluoromethyl] [)] [Pyridine] [-3-] [base] []-4-] [Methyl] [-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-2-(] [C] [-2-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0206] Using 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1, 2,3,4-Tetrahydro-2,7- The title compound was prepared according to the procedure described for Example 18, Step A, using ethanol (Example 23) and commercial acetone. MS (ESI) m / z: 415.2 [M+H] +. [Example]

[29] [6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-2-(] [Oxolanes] [-3-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0207] Using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3, 4-Tetrahydro-2,7- The title compound was prepared according to the procedure described for Example 18, Step A, using pyridine (Example 20) and commercially available 3-side oxytetrahydrofuran. MS (ESI) m / z: 407.2 [M+H] +. [] [Example]

[30] [6-({1-[6-(] [Difluoromethyl] [)] [Pyridine] [-3-] [base] []-4-] [Methyl] [-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-2-(] [Oxolane] [-3-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0208] Using 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1, 2,3,4-Tetrahydro-2,7- The title compound was prepared according to the procedure described for Example 18, Step A, using pyridine (Example 23) and commercially available 3-side oxytetrahydrofuran. MS (ESI) m / z: 443.2 [M+H] +. [Example]

[31] [6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-2-(] [oxetine] [-3-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0209] Using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3, 4-Tetrahydro-2,7- The title compound was prepared according to the procedure described for Example 18, Step A, using 3-propiolactone (Example 20) and commercially available 3-propiolactone. MS (ESI) m / z: 393.2 [M+H] +. [Example]

[32] [6-({4-] [Methyl] [-1-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-2-(] [Oxolane] [-3-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0210] The title compound was prepared according to the procedure described for Example 26 using commercially available 3-side oxytetrahydrofuran. MS (ESI) m / z: 461.2 [M+H] +. [Example]

[33] [6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-2-(] [Oxane] [-4-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0211] Using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3, 4-Tetrahydro-2,7- The title compound was prepared according to the procedure described for Example 18, Step A, using pyridine (Example 20) and commercially available 4-pendant oxytetrahydropyran. MS (ESI) m / z: 421.2 [M+H] +. [Example]

[34] [6-{[1-(6-] [methoxypyridine] [-3-] [base] [)-4-] [Methyl] [-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] [] A: 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2, 3,4-Tetrahydro-2,7- Tertiary butyl ester of 2-carboxylic acid

[0212] Under an argon atmosphere, 300 mg (1.12 mmol) of commercially available 6-chloro-3,4-dihydro-2,7- Tributyl 2(1H)-carboxylate, 246 mg (1.12 mmol) of [1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-tris Azol-5-yl]methanol (Intermediate 6), 727 mg (2.23 mmol) of Cs 2CO 3 , 44.5 mg (0.11 mmol) of rac-2-(di-tertiary butylphosphino)-1,11- Binaphthyl, 25 mg (0.11 mmol) of Pd(OAc) 2 and 20 mL of anhydrous toluene were charged into the flask. The mixture was stirred at 100 °C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:1 as eluent, silicon disk). The reaction mixture was filtered through a pad of celite, washed with acetone, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluent:cyclohexane:MeOH=1:1). Yield: 200 mg (39.5 %). MS (ESI) m / z: 453.2 [M+H] +. B: 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2, 3,4-Tetrahydro-2,7- aridine

[0213] 200 mg (0.44 mmol) of 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-Tetrahydro-2,7- Dissolve tertiary butyl ester of 2-carboxylic acid in 7 mL of ethyl acetate. 7 mL of ethyl acetate saturated with hydrogen chloride was added dropwise to the solution. The reaction mixture was stirred at room temperature for 30 minutes. The white precipitate that formed was filtered off and washed with a small portion of ethyl acetate. The hydrochloride salt was added to the saturated NaHCO solution and extracted with EtOAc. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to provide the desired product. Yield: 115 mg (74 %), MS (ESI) m / z: 353.2 [M+H]+. [Example]

[35] [6-({4-] [Methyl] [-1-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-2-(] [Oxane] [-4-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [] []

[0214] The title compound was prepared according to the procedure described for Example 26 using commercially available 4-side oxytetrahydropyran. MS (ESI) m / z: 475.3 [M+H] +. [Example]

[36] [3-{[6-({4-] [Methyl] [-1-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridine] [-2-] [base] []] [Methyl] [}-1λ6-] [Thiolane] [-1,1-] [Diketone henaphthalene disulfonate] [] []

[0215] Using 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1, 2,3,4-Tetrahydro-2,7- The free base of the title compound was prepared according to the procedure described for Example 19, Step A. The henaphthalene disulfonate salt was prepared according to the procedure described for Example 18, Step B. MS (ESI) m / z: 523.2 [M+H] +. 1H NMR (DMSO-d 6, 400 MHz) δ (ppm): 9.45-9.70 (br m, 1H), 9.09 (d, J=2.4 Hz, 1H), 8.47 (dd, J=8.3 Hz, 2.2 Hz, 1H), 8.23 ​​(d, J=8.3 Hz, 1H), 7.93-7.99 (br m, 1H), 6.72 (br s, 1H), 5.51 (s, 2H), 4.50-4.68 (m, 1H), 4.14 -4.29 (br m, 1H), 3.60-3.76 (br m, 1H), 3.21-3.54 (br m, 5H), 3.00-3.12 (m, 3H), 2.84-3.00 (br m, 2H), 2.43 ( s, 3H), 2.29-2.40 (br m, 1H), 1.77-1.91 (br m, 1H); Naphthalenedicarboxylate (acid / base molar ratio 1:2) signal: 8.85 (dd, J=8.5 , ~1 Hz, 2H), 7.91 (dd, J=7.0 Hz, 1.1 Hz, 2H), 7.39 (dd, J=8.5, 7.1 Hz, 2H). [] [Example]

[37] [6-({4-] [Methyl] [-1-[6-(] [Trifluoromethyl] [)] [Pyridine] [-3-] [base] []-1H-1,2,3-] [Triazole] [-5-] [base] [}] [Methoxy] [)-2-(] [Pyridine] [-3-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ ] [pyridine naphthalene disulfonate] [] [] A: Synthesis of free base

[0216] In a microwave tube, under an argon atmosphere, add 239 mg (0.612 mmol) of 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1, 2,3-triazol)-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7- (Example 25), 117 mg (0.741 mmol) of 3-bromopyridine, 141 mg (1.26 mmol) of tertiary potassium butoxide, 38 mg (0.061 mmol) of 2,2-bis(diphenylphosphine) )-1,1'-binaphthyl, 13.7 mg (0.061 mmol) of Pd(OAc) 2, and 5 mL of anhydrous toluene. Place the tube in a microwave reactor and heat at 120°C for 1 hour with stirring. After the reaction was completed, the mixture was evaporated and purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to obtain 19 mg of the product as an oil. Yield: 19 mg (6.6 %), MS (ESI) m / z: 468.2 [M+H] + . B: Synthesis of naphthalene disulfonate

[0217] 19 mg (0.041mmol) of 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl} Methoxy)-2-(pyridin-3-yl)-1,2,3,4-tetrahydro-2,7- Dissolve pyridine in 2 mL of methanol, add 14.7 mg (0.041 mmol) of 1,5-naphthalenedisulfonic acid tetrahydrate, and stir at 60°C for 10 minutes, then cool to rt. The precipitated product was collected by filtration, washed with cold methanol, and dried under vacuum to obtain the title compound as a yellow solid. Yield: 11 mg (36 %), MS (ESI) m / z: 468.2 [M+H] +. 1H NMR (DMSO-d 6, 400 MHz) δ (ppm): 9.09 (d, J=2.4 Hz, 1H), 8.46 (dd, J=8.4 Hz, 2.2 Hz, 1H), 8.43 (d, J=2.8 Hz, 1H), 8.21(d, J=8.4 Hz, 1H), 8.17 (d, J=5.3 Hz, 1H), 8.06 (dd, J=8.8 Hz, 2.7 Hz, 1H), 7.96 (s, 1H) , 7.85 (dd, J=8.9 Hz, 5.4 Hz, 1H), 6.69 (s, 1H), 5.49 (s, 2H), 4.55 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 2.43 (s, 3H); Naphthalene dicarboxylate (acid / base molar ratio 1:1) signal: 8.86 (dd, J=8.5 Hz, ~1 Hz, 2H ), 7.92 (dd, J=7.0 Hz, 1.1 Hz, 2H), 7.40 (dd, J=8.5 Hz, 7.1 Hz, 2H). [Example]

[38] [6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-2-[(3S)-] [Oxolane] [-3-] [base] []-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , enantiomer or enantiomer, tartrate] [] []

[0218] Racemic 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxa Cyclopentan-3-yl)-1,2,3,4-tetrahydro-2,7- Separation of the pyridine (Example 29) by chiral HPLC (column: Lux i-Amylose-1 5 µm 150×21,2 mm) afforded the mirror image pure title compound. MS (ESI) m / z: 407.2 [M+H] +. The tartrate salt was prepared according to the procedure described for Example 19, Step B. MS (ESI) m / z: 407.2 [M+H] +. [Example]

[39] [6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-2-[(3R)-] [Oxolane] [-3-] [base] []-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , enantiomer or enantiomer, tartrate] [] []

[0219] Racemic 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxa Cyclopentan-3-yl)-1,2,3,4-tetrahydro-2,7- Separation of the pyridine (Example 29) by chiral HPLC (column: Lux i-amylose-1 5 µm 150×21,2 mm) afforded the mirror image pure title compound. MS (ESI) m / z: 407.2 [M+H] +. The tartrate salt was prepared according to the procedure described for Example 19, Step B. MS (ESI) m / z: 407.2 [M+H] +. [Example]

[40] [6-{[1-(6-] [methoxypyridine] [-3-] [base] [)-4-] [Methyl] [-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-2-(] [Oxane] [-4-] [base] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , hemidylene henaphthalene disulfonate] [] []

[0220] Use 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3 ,4-Tetrahydro-2,7- The free base of the title compound was prepared according to the procedure described for Example 18, Step A, using pyridine (Example 34) and commercially available 4-pendant oxytetrahydropyran. MS (ESI) m / z:437.2 [M+H] +. The henaphthalene disulfonate salt was prepared according to the procedure described in Step B for Example 18. MS (ESI) m / z: 437.2 [M+H] +. 1H NMR (DMSO-d 6, 800 MHz) δ (ppm): 9.70-9.77 (br m, 1H), 8.41 (d, J=2.8 Hz, 1H), 8.01 (s, 1H), 7.97 (dd, J =8.8, 2.7 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 6.74 (s, 1H), 5.35-5.41 (AB d, J=13.5 Hz, 2H), 4.52 (d, J=14.6 , 1H), 4.31 (dd, J=15.0, 8.3 Hz, 1H), 3.98 (br d, J=11.1 Hz, 2H), 3.94 (s, 3H), 3.70-3.74 (m, 1H), 3.49-3.55 (m, 1H), 3.26-3.35 (m, 3H), 3.01-3.10 (m, 2H), 2.39 (s, 3H), 2.04 (br d, J=12.0 Hz, 1H), 1.99 (br d, J =12.2 Hz, 1H), 1.63-1.73 (m, 2H); Naphthalenedicarboxylate (acid / base molar ratio 1:2) signal: 8.85 (dd, J=8.4, 1.0 Hz, 2H), 7.91 ( dd, J=7.0, 1.0 Hz, 2H), 7.38 (dd, J=8.4, 7.0 Hz, 2H). [Example]

[41] [6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-2-(2-] [Methylpropyl] [)-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , hemidylene henaphthalene disulfonate] [] []

[0221] Using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3, 4-Tetrahydro-2,7- The free base of the title compound was prepared according to the procedure described for Example 18, Step A, using pyridine (Example 20) and commercially available isobutyraldehyde. MS (ESI) m / z: 393.3 [M+H]+. The henaphthalene disulfonate salt was prepared according to the procedure described in Step B for Example 18. MS (ESI) m / z: 393.3 [M+H] +. 1H NMR (DMSO-d 6, 400 MHz) δ (ppm): 9.22-9.40 (br m, 1H), 8.67 (d, J=2.4 Hz, 1H), 7.99 (s, 1H), 7.98 (dd, J =8.3, 2.6 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 6.72 (s, 1H), 5.39 (s, 2H), 4.56 (br d, J=14.43 Hz, 1H), 4.19 ( dd, J=15.1, 7.7 Hz, 1H), 3.62-3.71 (m, 1H), 3.22-3.36 (m, 1H), 2.97-3.15 (m, 4H), 2.58 (s, 3H), 2.39 (s, 3H), 2.15 (sep, J=6.7, 1H), 0.98 (t, J=6.1 Hz, 6H); Naphthalenedicarboxylate (acid / base molar ratio 1:2) signal: 8.85 (dd, J= 8.4, 1.2 Hz, 2H), 7.91 (dd, J=7.0, 1.2 Hz, 2H), 7.38 (dd, J=8.4, 7.0 Hz, 2H). [Example]

[42] [6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-2-[3-(] [C] [-2-] [base] [)] [Oxetane] [-3-] [base] []-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridinium naphthalene disulfonate] [] [] A: 2‐[3‐(1H‐1,2,3‐benzotriazol‐1‐yl)oxetan‐3‐yl]‐6‐{[4‐methyl‐1‐(6‐ Methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7- aridine [] []

[0222] 6-{[4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy} at 1030 mg (3.06 mmol) -1,2,3,4-Tetrahydro-2,7- 243 mg (3.37 mmol) of 3-propiolactone and 383 mg (3.21 mmol) of 1H-benzotriazole were added to a solution of 30 mL of DCM (Example 20). The reaction mixture was stirred at rt for 12 hours. Upon completion, the solvent was evaporated to dryness to obtain the title compound as a white solid. Yield: 1540 mg (98.7 %), MS (ESI) m / z: 510.2 [M+H] +. B: 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3- (Prop-2-yl)oxetan-3-yl]-1,2,3,4-tetrahydro-2,7- aridine

[0223] Under an argon atmosphere, add one portion of 520 mg (1.02 mmol) of 2-[3-(1H-1,2,3- Benzotriazol-1-yl)oxetan-3-yl]-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3- Triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7- Dissolve in 10 mL of THF. The reaction mixture was stirred at rt for 10 min. After the reaction was completed, the mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica, eluent:hexane:EtOAc:2% Et 3N, 30 to 60% gradient) to obtain the title compound. Yield: 177 mg (40 %), MS (ESI) m / z: 435.2 [M+H] +. C: 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3- (Prop-2-yl)oxetan-3-yl]-1,2,3,4-tetrahydro-2,7- pyridinium naphthalene disulfonate

[0224] The henaphthalene disulfonate salt was prepared according to the procedure described for Example 36, Step B. MS (ESI) m / z: 435.2 [M+H] +. 1H NMR (DMSO-d 6, 500 MHz) δ (ppm): 9.60-10.50 (br m, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.04 (dd, J=8.3 Hz, 2.4 Hz, 1H), 7.99 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 6.75 (s, 1H), 5.41 (s, 2H), 4.69 (AB d, J=8.8 Hz, 2H), 4.66 (AB d, J=8.8 Hz, 2H), 4.35-4.61 (br m, 2H), 3.44-3.83 (br m, 2H), 3.04-3.17 (br m, 2H), 2.60 (s, 3H), 2.40 (s, 3H), 2.34-2.44 (m, 1H), 1.13 (d, J=6.7 Hz, 6H); Naphthalenedicarboxylate (acid / base molar ratio 1:1) signal: 8.85 (br d, J=8.6 Hz, 2H), 7.91 (d, J=7.0 Hz, 2H), 7.40 (dd, J=8.4 Hz, 7.3 Hz, 2H). [Example]

[43] [2-(3-] [Ethyloxetane] [-3-] [base] [)-6-{[4-] [Methyl] [-1-(6-] [Methylpyridine] [-3-] [base] [)-1H-1,2,3-] [Triazole] [-5-] [base] []] [Methoxy] [}-1,2,3,4-] [tetrahydrogen] [-2,7-] [ , pyridinium naphthalene disulfonate] [] []

[0225] The title compound was prepared according to the procedure described for Example 42, Step B, using ethylmagnesium bromide solution. MS (ESI) m / z: 421.2 [M+H] +. 1H NMR (DMSO-d 6, 500 MHz) δ (ppm): 10.54-10.96 (br m, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.02 (dd, J=8.3 Hz, 2.6 Hz, 1H), 7.95 (s, 1H), 7.56 (d, J=8.3 Hz, 1H), 6.75 (s, 1H), 5.41 (s, 2H), 4.80 (br d, 2H), 4.57 (d, J= 8.1 Hz, 2H), 4.24-4.44 (br m, 2H), 3.26-3.52 (br m, 2H), 3.02-3.18 (br m, 2H), 2.60 (s, 3H), 2.40 (s, 3H), 1.78-1.96 (br m, 2H), 1.23 (t, J=7.3 Hz, 3H); Naphthalenedicarboxylate (acid / base molar ratio 1:1) signal: 8.85 (br d, J=8.5 Hz, 2H), 7.91 (dd, J=7.0 Hz, 0.9 Hz, 2H), 7.39 (dd, J=8.5 Hz, 7.1 Hz, 2H). [Example]

[44] [2-] [Methyl] [-5-[4-] [Methyl] [-5-({5H,6H,7H,8H-] [pyrido] [[3,4-c]] [Ta, ] [-3-] [baseoxy] [}] [Methyl] [)-1H-1,2,3-] [Triazole] [-1-] [base] []] [Pyridine] [] [] A: 2-Methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine-2-carboxylic acid tertiary butyl ester

[0226] In a microwave tube, under an argon atmosphere, add 135 mg (0.50 mmol) of commercially available 3-chloro-5,8-dihydropyrido[3,4-c]da -7(6H)-Carboxylic acid tertiary butyl ester, 102 mg (0.50 mmol) [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazole -5-yl]methanol (Intermediate 3), 112 mg (1.00 mmol) tertiary potassium butoxide, 20 mg (0.05 mmol) rac-2-(di-tertiary butylphosphino)-1,11 -Binaphthyl, 11.2 mg (0.05 mmol) of Pd(OAc) 2 and 10 mL of anhydrous toluene. The tube was placed in a microwave reactor and heated at 120°C for 3 hours with stirring. After the reaction was completed, the mixture was filtered through a pad of celite, washed with acetone, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash column chromatography (silica gel, eluent:cyclohexane:EtAOc=1:1). Yield: 57 mg (26 %). MS (ESI) m / z: 438.2 [M+H] +. B: 2-Methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]ta -3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine

[0227] 138 mg (0.31 mmol) of 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridino] -3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine-2-carboxylic acid tertiary butyl ester was dissolved in 10 mL of DCM. Next, 360 mg (3.16 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 48 h. Upon completion the mixture was evaporated, the residue was taken up in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO, filtered and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to provide the desired product. Yield: 77 mg (72 %), MS (ESI) m / z: 338.1 [M+H]+. [Example]

[45] [5-[5-({[7-(] [cyclobutylmethyl] [)-5H,6H,7H,8H-] [pyrido] [[3,4-c]] [Ta, , ] [-3-] [base] []] [Oxygen] [}] [Methyl] [)-4-] [Methyl] [-1H-1,2,3-] [Triazole] [-1-] [base] []-2-] [methylpyridine tartrate] [] []

[0228] Use 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3, 4-c]pyrido -3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine (Example 44) and commercially available cyclobutanecarboxaldehyde, as described for Example 18, Step A The free base of the title compound was prepared according to the procedure described. MS (ESI) m / z: 406.3 [M+H] +. The tartrate salt was prepared according to the procedure described for Example 19, Step B. MS (ESI) m / z: 406.3 [M+H] +. 1H NMR (DMSO-d 6, 500 MHz) δ (ppm): 8.67 (d, J=2.5 Hz, 1H), 7.97 (dd, J=8.3 Hz, 2.6 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 6.96 (s, 1H), 5.53 (s, 2H), 3.68 (s, 2H), 2.80 (t, J=5.8 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.55-2.62 (m, 1H), 2.57 (d, J=7.0 Hz, 2H), 2.56 (s, 3H), 2.41 (s, 3H), 2.00-2.08 (m, 2H), 1.75-1.93 (m, 2H), 1.64-1.73 (m, 2H); tartrate (acid / alkali ratio 1:1) signal: 4.28 (s, 2H). [Example]

[46] [5-{5-[({7-] [cyclobutyl] [-5H,6H,7H,8H-] [pyrido] [[3,4-c]] [Ta, , ] [-3-] [base] [}] [Oxygen] [)] [Methyl] []-4-] [Methyl] [-1H-1,2,3-] [Triazole] [-1-] [base] [}-2-] [methylpyridine tartrate] [] []

[0229] Use 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3, 4-c]pyrido -3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine (Example 44) and commercially available cyclobutanone as described for Example 18, Step A The free base of the title compound was prepared using the following procedure. MS (ESI) m / z: 392.2 [M+H] +. The tartrate salt was prepared according to the procedure described for Example 19, Step B. MS (ESI) m / z: 392.2 [M+H] +. 1H NMR (DMSO-d 6, 500 MHz) δ (ppm): 8.67 (d, J=2.5 Hz, 1H), 7.98 (dd, J=8.3 Hz, 2.6 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 6.97 (s, 1H), 5.53 (s, 2H), 3.58 (s, 2H), 2.95 (qui, J=7.6 Hz, 1H), 2.81 (br t, J=5.8 Hz, 2H) , 2.57 (s, 3H), 2.52 (br t, J=5.8 Hz, 2H), 2.41 (s, 3H), 2.03-2.11 (m, 2H), 1.82-1.91 (m, 2H), 1.63-1.71 ( m, 2H); tartrate (acid / base ratio 1:1) signal: 4.28 (s, 2H). [Pharmaceutical preparation examples] []

[0230] The following formulation examples illustrate representative pharmaceutical compositions of the invention. However, the present invention is not limited to the following pharmaceutical compositions. A) Solid oral dosage form I., tablets Active ingredient(s) 0.01 to 90% Filler 1 to 99.9% Binder 0 to 20% Disintegrant 0 to 20% Lubricant 0 to 10% (Various) other specified excipients 0 to 50% II., Orodispersible Film (Multiple) active ingredients 0.01 to 90% Film former 1 to 99.9% Plasticizer 0 to 40% (Various) other specified excipients 0 to 50% B) Liquid oral dosage form III., oral suspension Active ingredients (various) 0.01 to 50% Liquid vehicle 10 to 99.9% Wetting agent 0 to 50% Thickener 0 to 50% Buffer appropriate amount Penetrant 0 to 50% Preservatives appropriate amount IV., Syrup Active ingredients (various) 0.01 to 50% Solvent 10 to 99.9% Sugar component 1 to 20% Flavoring 0 to 10% C) Parenteral dosage forms V., intravenous injection Active ingredients (various) 0.01 to 50% Solvent 10 to 99.9% Co-solvent 0 to 99.9% Penetrant 0 to 50% Buffer appropriate amount D) Other dosage forms VI., Suppositories Active ingredients (various) 0.01 to 50% Suppository base 1 to 99.9% Surfactant 0 to 20% Lubricant 0 to 20% Preservatives appropriate amount VII., eye drops Active ingredients (various) 0.01 to 50% Water 0 to 99.9% Solvent 0 to 99.9% Penetrant 0 to 20% Tackifier 0 to 20% Buffer appropriate amount Preservatives appropriate amount VIII., Nasal spray or spray Active ingredients (various) 0.01 to 50% Water 0 to 99.9% Solvent 0 to 99.9% Penetrant 0 to 20% Tackifier 0 to 20% Co-solvent appropriate amount Buffer appropriate amount Preservatives appropriate amount

Claims

1. A compound of formula (I), wherein A is represented as a radical or a group; R1 is a C1-6 alkyl, C1-6 alkoxy, or halo-C1-6 alkyl; R2 is hydrogen; C1-6 alkyl, which is substituted as needed with -S(O)2-C1-6 alkyl, C3-7 cycloalkyl, or a monocyclic, bicyclic, fused, bridged, or spirocyclic system having 1, 2, 3, or 4 independent cyclic heteroatoms selected from N, O, and S, and the remaining cyclic atoms being carbon, consisting of 3 to 10 monovalent saturated or partially unsaturated ring atoms; C3-7 cycloalkyl; a monocyclic, bicyclic, fused, bridged, or spirocyclic system having 1, 2, 3, or 4 independent cyclic heteroatoms selected from N, O, and S, and the remaining cyclic atoms being carbon, consisting of 3 to 10 monovalent saturated or partially unsaturated ring atoms, which is substituted as needed with C1-6 alkyl; or a monocyclic or bicyclic system of a monovalent heterocyclic aromatic compound having 5 to 10 ring atoms, consisting of 1, 2, or 3 independent heteroatoms selected from N, O, and S, and the remaining cyclic atoms being carbon; X is CH or N; And / or its salts and / or its stereoisomers and / or its hydrates.

2. The compound of claim 1, wherein R1 is a C1-6 alkyl, C1-6 alkoxy, or halo-C1-6 alkyl; R2 is hydrogen; C1-6 alkyl, which is substituted as needed with -S(O)2-C1-6 alkyl, C3-7 cycloalkyl, or a monocyclic, bicyclic, fused, bridged, or spirocyclic system having 1, 2, 3, or 4 independent cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, having 3 to 10 ring atoms in a monocyclic saturated or partially unsaturated state; C3-7 cycloalkyl; a monocyclic, bicyclic, fused, bridged, or spirocyclic system having 1, 2, 3, or 4 independent cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, having 3 to 10 ring atoms in a monocyclic saturated or partially unsaturated state, which is substituted as needed with C1-6 alkyl; or a monocyclic or bicyclic system of a monovalent heterocyclic aromatic compound having 5 to 10 ring atoms containing 1, 2, or 3 independent heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; X is CH or N.

3. The compound of claim 1, wherein R1 is a C1-6 alkyl, C1-6 alkoxy, or halo-C1-6 alkyl; R2 is hydrogen; C1-6 alkyl, which is substituted as needed with -S(O)2-C1-6 alkyl, C3-7 cycloalkyl, or a monocyclic, bicyclic, fused, bridged, or spirocyclic system having 1, 2, 3, or 4 independent cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, having 3 to 10 ring atoms in a monocyclic saturated or partially unsaturated state; C3-7 cycloalkyl; a monocyclic, bicyclic, fused, bridged, or spirocyclic system having 1, 2, 3, or 4 independent cyclic heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon, having 3 to 10 ring atoms in a monocyclic saturated or partially unsaturated state, which is substituted as needed with C1-6 alkyl; or a monocyclic or bicyclic system of a monovalent heterocyclic aromatic compound having 5 to 10 ring atoms containing 1, 2, or 3 independent heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon; X is CH or N.

4. A compound of any one of claims 1 to 3, wherein R1 is a C1-4 alkyl, C1-4 alkoxy, or halo-C1-4 alkyl.

5. A compound of any one of claims 1 to 3, wherein R1 is a C1-2 alkyl, C1-2 alkoxy, or halo-C1-2 alkyl.

6. A compound of any one of claims 1 to 3, wherein R2 is hydrogen; C1-4 alkyl, which is optionally substituted with -S(O)2-C1-4 alkyl, C4-6 cycloalkyl, or a monocyclic saturated ring having 3 to 7 ring atoms, comprising one or two independent cyclic heteroatoms selected from N, O, and S and the remaining ring atoms being carbon; C4-6 cycloalkyl; a monocyclic saturated ring having 3 to 7 ring atoms, comprising one or two independent cyclic heteroatoms selected from N, O, and S and the remaining ring atoms being carbon, which is optionally substituted with C1-4 alkyl; or a monocyclic heterocyclic aromatic monocyclic system having 5 to 6 ring atoms, comprising one or two independent heteroatoms selected from N, O, and S and the remaining ring atoms being carbon.

7. A compound of any one of claims 1 to 3, wherein R2 is hydrogen; C1-4 alkyl, which is optionally substituted by -S(O)2-C1-2 alkyl, C4-6 cycloalkyl or a monocyclic saturated ring having 3 to 7 ring atoms containing one heteroatom selected from O and S and the remaining ring atoms being carbon; C4-6 cycloalkyl; a monocyclic saturated ring having 3 to 7 ring atoms containing one heteroatom selected from O and S and the remaining ring atoms being carbon, which is optionally substituted by C1-4 alkyl; or a monocyclic heterocyclic aromatic monocyclic system having 6 ring atoms containing one or two heteroatoms independently selected from N, O and S and the remaining ring atoms being carbon.

8. A compound of any one of claims 1 to 3, wherein R2 is hydrogen.

9. A compound of any one of claims 1 to 3, wherein X is CH.

10. A compound of any one of claims 1 to 3, wherein X is N.

11. The compound of claim 1 is selected from the group consisting of: 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-idine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-azol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-idine, 2-methyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-idine, 2-Cyclobutyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-idine, 2-(cyclobutylmethyl)-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-idine, 2-Cyclopentyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-idine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-azol-4-yl}methoxy)-2-(oxecyclohexane-4-yl)-1,2,3,4-tetrahydro-2,7-idine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-azol-4-yl}methoxy)-2-(oxecyclopentane-3-yl)-1,2,3,4-tetrahydro-2,7-idine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-2-(oxecyclopentane-3-yl)-1,2,3,4-tetrahydro-2,7-idine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-2-(oxecyclobut-3-yl)-1,2,3,4-tetrahydro-2,7-idine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-2-(oxecyclohexane-4-yl)-1,2,3,4-tetrahydro-2,7-idine, 2-(1-methanesulfonylpropyl-2-yl)-6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-azol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-idine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-2-(pyridin-2-yl)-1,2,3,4-tetrahydro-2,7-idine, 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]tad-3-yloxy}methyl)-1,2-Azol-3-yl]pyridine, 5-[5-methyl-4-({5H,6H,7H,8H-pyridano[3,4-c]tad-3-yloxy}methyl)-1,2-azol-3-yl]-2-(trifluoromethyl)pyridine, 2-methyl-5-{5-methyl-4-[({7-methyl-5H,6H,7H,8H-pyridano[3,4-c]tad-3-yl}oxy)methyl]-1,2-azol-3-yl}pyridine, 5-[5-methyl-4-({5H,6H,7H,8H-pyridano[3,4-c]tad-3-yloxy}methyl)-1,2-azol-3-yl]-2-(trifluoromethyl)pyridine, 5-[5-methyl-4-({[7-(oxocyclopentan-3-yl)-5H,6H,7H,8H-pyrido[3,4-c]ta-3-yl]oxy}methyl)-1,2-azol-3-yl]-2-(trifluoromethyl)pyridine, 3-{[3-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-azol-4-yl}methoxy)-5H,6H,7H,8H-pyrido[3,4-c]ta-7-yl]methyl}-1λ6-thiocyclopentan-1,1-dione, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-idine, 2-Methyl-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-idine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(propyl-2-yl)-1,2,3,4-tetrahydro-2,7-idine, 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-methyl-1,2,3,4-tetrahydro-2,7-idine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-idine, 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-idine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(propyl-2-yl)-1,2,3,4-tetrahydro-2,7-idine, 2-Methyl-6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-Piridine, 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-(propyl-2-yl)-1,2,3,4-tetrahydro-2,7-iridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxepane-3-yl)-1,2,3,4-tetrahydro-2,7-iridine, 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-(oxepane-3-yl)-1,2,3,4-tetrahydro-2,7-iridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxecyclobut-3-yl)-1,2,3,4-tetrahydro-2,7-idine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(oxecyclopentan-3-yl)-1,2,3,4-tetrahydro-2,7-idine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxecyclohexane-4-yl)-1,2,3,4-tetrahydro-2,7-idine, 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-idine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(oxacyclohexane-4-yl)-1,2,3,4-tetrahydro-2,7-idine, 3-{[6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-pyridin-2-yl]methyl}-1λ6-thiacyclopentane-1,1-dione, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(pyridin-3-yl)-1,2,3,4-tetrahydro-2,7-pyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[(3S)-oxacyclopentan-3-yl]-1,2,3,4-tetrahydro-2,7-pyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[(3R)-oxacyclopentan-3-yl]-1,2,3,4-tetrahydro-2,7-pyridine,7-Piridine, 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxecyclohexane-4-yl)-1,2,3,4-tetrahydro-2,7-iridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(2-methylpropyl)-1,2,3,4-tetrahydro-2,7-iridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3-(propyl-2-yl)oxecyclobut-3-yl]-1,2,3,4-tetrahydro-2,7-iridine, 2-(3-ethyloxetanebut-3-yl)-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-idine, 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyridino[3,4-c]pyridyl-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine, 5-[5-({[7-(cyclobutylmethyl)-5H,6H,7H,8H-pyrido[3,4-c]tad-3-yl]oxy}methyl)-4-methyl-1H-1,2,3-triazol-1-yl]-2-methylpyridine, and 5-{5-[({7-cyclobutyl-5H,6H,7H,8H-pyrido[3,4-c]tad-3-yl}oxy)methyl]-4-methyl-1H-1,2,3-triazol-1-yl}-2-methylpyridine and / or its salts and / or its stereoisomers and / or its hydrates.

12. Use of any one of claims 1 to 11 in the manufacture of a medicament for the treatment or prevention of diseases associated with the GABAA α5 receptor.

13. As claimed in claim 12, wherein the disease related to the GABAA α5 receptor is selected from the group consisting of neurodevelopmental disorders, neurodegenerative diseases, neurocognitive disorders, schizophrenia, affective disorders, pain disorders, substance-related and addictive disorders, or other diseases, wherein the other diseases are selected from the group consisting of attention deficit hyperactivity disorder and adult attention deficit, other stress-related conditions, stroke, neurofibromatosis type I, multiple sclerosis, acute meningitis, alcohol use disorder, fetal alcohol group disorder, bronchoconstriction disorder, and obesity.

14. As used in claim 13, wherein the disease associated with the GABAA α5 receptor is selected from the group consisting of autism spectrum disorder (ASD), Ingman syndrome, Fragile X disease, Predwell syndrome, Rett syndrome, Alzheimer's disease (AD), cognitive impairment, memory loss, age-related memory deficits or cognitive decline, bipolar disorder, negative and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, and amyotrophic lateral sclerosis.

15. Use of a compound of any one of claims 1 to 11 in combination with one or more other active ingredients in the manufacture of a medicament for the treatment or prevention of diseases associated with GABAA α5 receptor.

16. A pharmaceutical composition comprising at least one compound as an active ingredient, such as any one of claims 1 to 11, and at least one physiologically or pharmaceutically acceptable excipient.

17. The pharmaceutical composition of claim 16, wherein the composition further comprises one or more other active ingredients.

18. Use of a pharmaceutical composition as claimed in claim 16 or 17 in the manufacture of a medicament for the treatment or prevention of diseases associated with the GABAA α5 receptor.

19. As claimed in claim 18, wherein the disease related to the GABAA α5 receptor is selected from the group consisting of neurodevelopmental disorders, neurodegenerative diseases, neurocognitive disorders, schizophrenia, affective disorders, pain disorders, substance-related and addictive disorders, or other diseases, wherein the other diseases are selected from the group consisting of attention deficit hyperactivity disorder and adult attention deficit, other stress-related conditions, stroke, neurofibromatosis type I, multiple sclerosis, acute meningitis, alcohol use disorder, fetal alcohol group disorder, bronchoconstriction disorder, and obesity.

20. As used in claim 19, wherein the disease associated with the GABAA α5 receptor is selected from the group consisting of autism spectrum disorder (ASD), Ingman syndrome, Fragile X disease, Predwell syndrome, Rett syndrome, Alzheimer's disease (AD), cognitive impairment, memory loss, age-related memory deficits or cognitive decline, bipolar disorder, negative and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, and amyotrophic lateral sclerosis.

21. A compound of formula (I''), wherein A is represented by a radical or a group; R1 is a C1-6 alkyl, C1-6 alkoxy, or halo-C1-6 alkyl; R2 is an amino protecting group selected from the group consisting of aminocarbamate, benzyl, allyl, and triphenylmethyl; X is CH or N; provided that the compound is not 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-azol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-pyridine-2-carboxylic acid tributyl ester, or 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-azol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-pyridine-2-carboxylic acid tributyl ester.