Bicyclic amine derivatives as GABAA α5 receptor modulators

Abstract

The present invention relates to a method for the treatment of GABA receptors having affinity and selectivity for the gamma-aminobutyric acid A receptor subunit alpha 5. A It acts as a positive allosteric modulator of α5, thereby inhibiting GABA A The present invention provides compounds of formula (I), and / or salts thereof, and / or stereoisomers thereof, and / or enantiomers thereof, and / or racemates thereof, and / or diastereomers thereof, and / or biologically active metabolites thereof, and / or prodrugs thereof, and / or solvates thereof, and / or hydrates thereof, and / or polymorphs thereof, useful in the treatment or prevention of diseases associated with the α5 receptor, processes for the preparation and intermediates in said processes for the preparation, pharmaceutical compositions comprising them alone or in combination with one or more other active ingredients, and their use as medicaments. TIFF2024536039000077.tif47170

Description

[Technical field]

[0001] FIELD OF THEINVENTION The present invention relates to the gamma-aminobutyric acid A receptor subunit alpha 5 (GABA A α5) and has affinity and selectivity for GABA A Positive allosteric modulator of α5 (GABA A α5 PAM), thereby inhibiting GABA A The present invention provides compounds of formula (I) useful in the treatment or prevention of diseases associated with the α5 receptor, processes for their preparation and intermediates in those processes for their preparation, pharmaceutical compositions containing them, and their use as medicaments. [Background technology]

[0002] 2. Background of the Invention Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. GABA-sensitive receptors are ligand-gated GABA receptors. A Receptors and G Protein-Coupled GABA B There are two main families of receptors.

[0003] Ligand-gated GABA A Receptors mediate the majority of inhibitory neurotransmission in the adult mammalian brain. They are composed of pentameric assemblies of multiple subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3) that form ligand-gated chloride channels (Olsen and Sieghart, Pharmacol Rev 2008, 60:243-260). The distribution of subunits varies developmentally and regionally in the brain. This high variability results in wide variation in inhibitory neuromechanisms, and in excitatory neuromechanisms in certain conditions, providing the potential for specific therapeutic interventions (Fritschy and Moehler, J Comp Neurol 1995, 359:154-194; Jacob, Front Mol Neurosci 2019, 12:Art 179). GABAA The physiological role and pharmacological profile of receptors strongly depend on the subunit composition. Studies in genetically modified mice have demonstrated that the composition of receptor subunits, particularly with respect to the α subtype, largely determines the pharmacology of compounds acting at benzodiazepine-sensitive allosteric modulating sites (BDZ sites) (Rudolph and Knoflach, Nat Rev Drug Discov 2011, 10:685-697). The widely distributed α1-containing receptors mediate sedative and amnesic effects, while α2- and α3-containing receptors are primarily responsible for anxiolytic, anticonvulsant and muscle relaxant effects (Sieghart and Sperk, Curr Top Med Chem 2002, 2:795-816; Whiting et al., Drug Discov Today 2003, 8:445-450). Receptors containing the α5 subunit (α5GABA A R) is preferentially expressed in the hippocampus, prefrontal cortex, amygdala, and nucleus accumbens (Olsen and Sieghart, Neuropharmacology 2009, 56:141-148; Sur et al., Brain Res 1999, 822:265-270; Martin et al., Biochem Soc Trans 2009, 37:1334-1337) and is thought to be involved in a variety of CNS disorders.

[0004] α5-containing receptors are mostly extrasynaptic and mediate tonic inhibition (Caraiscos et al., Proc Natl Acad Sci USA 2004, 101:3662-3667). In contrast to their inhibitory role in the mature nervous system, α5GABA A R can induce excitation in early hippocampal circuit development (Marchionni et al., J Physiol. 2007, 581:515-528). Their modulatory effects on the excitation of hippocampal and cortical principal neurons may support the role of α5GABA in neurodevelopment, cognition, learning and memory. AThis could explain the important effects of R and their potential therapeutic efficacy in a variety of disorders, including stroke, mild cognitive impairment, schizophrenia, depression, dementia-related conditions or diseases associated with impaired social cognition, or neurodevelopmental disorders, such as Down's syndrome or autism spectrum disorder (ASD) (Jacob, Front Mol Neurosci 2019, 12:Art 179; Mohamad and Tarmizi Che Has, J Mol Neurosci 2019, 67:343-351; Soh and Lynch, Curr Drug Targets 2015, 16:735-746).

[0005] Genetic and pharmacological reduction of α5-mediated tonic inhibition can improve learning and memory by enhancing neuroplasticity (Martin et al., J Neurosci 2010, 30:5269-5282) and network oscillatory activity (Towers et al., J Physiol 2004, 559:721-728; Glykis and Mody, Neurophysiol 2008, 95:2796-2807) (Moehler and Rudolph, F1000Res 2017 Feb 3;6.pii:F1000 Faculty Rev-101). However, α5GABA A Hippocampal and cortical hyperactivity resulting from reduced R function may also lead to characteristic behavioral changes in various CNS disorders, such as hyperactivity and impaired sensorimotor (Hauser et al., Mol Psychiatry 2005,10:201-207), impaired social behavior (Zurek et al., Ann Clin Transl Neurol 2016,3:392-398), and cognitive deficits in rodents (Engin et al., J Neurosci 2015,35:13698-13712; Martin et al., J Neurosci 2010,30:5269-5282; Prut et al., Genes Brain Behav 2010,9:478-488). In such pathologies, α5GABA receptors may be involved in the regulation of α5GABA receptor signaling. AFacilitating, rather than blocking, GABA R function may be a promising treatment for the positive, negative, and cognitive symptoms associated with such disorders. In support of this idea, GABA R activity in the ventral hippocampus has been shown to be increased in the ventral hippocampus. A Viral-induced overexpression of the receptor's α5 subunit normalized physiological and behavioral deficits in a rat model of schizophrenia (Donegan et al., Nature Communications 2019, 10:2819).

[0006] The University of Wisconsin-Milwaukee described certain 4H-benzo[f]imidazo[1,5-a][1,4]diazepine derivatives (WO2017 / 161370A1) as α5-preferring PAM compounds, e.g., SH-053-2'FR-CH3, MP-III-022 or GL-II-73 (Stamenic et al. Eur J Pharmacol 2016,791:433-433; Savic et al., Neuropsychopharmacology 2008,33:332-339; Prevot et al., ACS Chem. Neurosci. 2019,10:2088-2090), which showed cognitive-promoting, anxiolytic and antidepressant effects in mouse stress models and aged mice (Prevot et al., Mol Neuropsychiatry 2019,5:84-97). MP-III-022 and the 6,7-dihydro-2-benzothiophen-4(5H)-one α5 PAM compound 44 (Chambers et al., J Med Chem 2003,46:2227-2240) improved cognitive performance in young and aged rats, respectively (Poe,Michael M.,Theses and Dissertations.1301(2016) https: / / dc.uwm.edu / etd / 1301; Koh et al. Neuropharmacology 2013,64:145:152). Acute treatment with GL-II-73 reduced chemogenetically induced behavioral deficits in a mouse model of depression (Fee et al., Int J Neuropsychopharmacol 2021, 24:505-518), whereas chronic treatment with GL-II-73 reversed age-related neuronal atrophy and working memory impairment in adult mice (Sibille et al., Biol Psychiatry 2020, 87:Suppl1, p. S85). In addition, SH-053-2'FR-CH3 and MP-III-022 attenuated pathological changes in locomotor activity in rats in a developmental model of schizophrenia (Gill et al., Neuropsychopharmacology 2011, 36:1903-1911; Batinic et al. Int J Dev Neurosci 2017, 61:31-39).

[0007] AgeneBio Inc. is a GABA A We have described imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine derivatives (WO2015 / 095783A1) as α5 PAMs, and since their lead series has potent and selective compounds with good in vivo efficacy in rats with age-related dysfunction (https: / / grantome.com / grant / NIH / R44-AG063607-01), we have demonstrated that such compounds can suppress GABAergic signaling in the hippocampus under conditions of hippocampal hyperactivity in the preclinical evidence of biological studies of age-related cognitive dysfunction. A They found that it occupies the α5 receptor (Press release, AgeneBio, September 11, 2019; https: / / www.agenebio.com / agenebio-announces-additional-funding-to-advance-novel-gaba-a-therapeutic-program-to-address-alzheimers-and-other-cns-conditions / ).

[0008] The most preferred indication in the present invention is autism spectrum disorder (ASD). ASD is a complex heterogeneous neurodevelopmental disorder characterized by impaired social relationships, reduced communication, typical repetitive behaviors, and impairments in executive functions (Anagnostou et al., CMAJ 2014, 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 approved medications for the treatment of core symptoms of ASD. Current pharmacological treatments are limited to the atypical antipsychotics risperidone and aripiprazole, which are approved for the treatment of ASD-related aggression and irritability (Anagnostou et al., Curr Opin Neurol 2018, 31:119-125). Antidepressants are used off-label to reduce delusional / obsessive-compulsive symptoms in ASD, and these treatments are only moderately effective and tolerable (Carrasco et al., Pediatrics 2012, 129:e1301-e1310), therefore there is an unmet need for more selective pathophysiology-based treatments of the aforementioned conditions.

[0009] ASD is a condition where GABA A A chromosomal abnormality, i.e., a duplication of copy number variation in the q11.2-13 region on chromosome 15, has been reported in ASD patients. In humans, this region is involved in the regulation of GABAergic signaling. A It contains genes encoding the α5, β3, and γ3 subunits of the receptor (Coghlan et al., Neurosci Biobehav Rev 2012, 36:2044-2055). Exome studies of autistic individuals have shown that the α5 GABA A Gabra5, the gene for R and its anchoring protein radixin - / -and RDX, and identified missense mutations in α5GABA receptor agonists in ASD. A Further supporting the R deficit (Zurek et al., Ann Clin Transl Neurol 2016,3:392-398). There is growing evidence for an excitation / inhibition (E / I) imbalance resulting from impaired GABAergic function in ASD. Reduced expression of the GABA synthesis enzymes GAD65 and GAD67, as well as reduced expression of GABA R1, are thought to be key factors in determining whether GABA R1 is involved in ASD. A Reduced receptor density has been reported in postmortem ASD brains (Fatemi et al., Biol Psychiatry 2002 52:805-810; Oblak et al., Autism Res 2009, 2:205-219). In imaging studies using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS), GABA concentrations and GABA receptor agonists were significantly increased in the ASD brain. A Reduced receptor availability has been reported in patients with ASD (Mori et al., Brain Dev 2011, 34:648-654; Puts et al., Autism Res 2016, 10:608-619; Robertson et al., Curr Biol 2016, 26:80-85). Pilot PET studies have demonstrated increased α5GABA receptor availability across multiple brain regions. A R-selective tracer [ 11 C]Ro154513 reduced binding, suggesting α5GABA receptor agonism in ASD A A study suggested reduced levels of α5GABA R in ASD patients (Mendez et al., Neuropharmacology 2013, 68:195-201). Another study showed alterations in GABA-sensitive perceptual tasks in ASD patients (Horder et al., Sci Transl Med 2018, pii:eaam8434). Consistent with these observations, postmortem analysis showed that α5GABA AR expression was revealed in patients with ASD (Blatt et al., J Autism Dev Disord 2001,31:537-54; Fatemi et al. J Autism Dev Disord,2010,40:743-750). The impaired GABAergic function in ASD patients may be considered, so promoting cortical inhibition and restoring E / I balance by α5 PAM may be a viable therapeutic strategy in the treatment of the disease.

[0010] Increased neuronal excitability in the cortex can result in autism-like behavioral deficits in rodents (Yizhar et al., Nature 2011, 477:171-178). Supporting clinical findings, α5GABA A Genetic reduction of R. - / - In mice, Gabra5 showed reduced persistent currents and increased excitability of primary hippocampal neurons (Bonin et al., J Neurophysiol 2007, 98:2244-2254). In addition to impairments in executive functions, strong autistic-like behaviors and pathology were observed in Gabra5 mice. - / - This has been observed in mice (Zurek et al., Ann Clin Transl Neurol 2016, 3:392-398; Mesbah-Oskui et al., Neurotoxicol Teratol 2017, 61:115-122). Similarly, in a fragile X syndrome model (Fmr1 - / - ) mice with behavioral characteristics of ASD (Bakker and Oostra, Cytogenet Genome Res 2003, 100:111-123), A R downregulation and a defect in tonic inhibition (Curia et al., Cereb Cortex 2009, 19:1515-1520).

[0011] The prenatal valproate model has good construct and face validity, and is therefore a widely accepted disease model of ASD (Christensen et al., JAMA 2013,309:1696-1703; Roullet et al., Neurotox Teratol. 2013,36:45-56). In this method, time-mated female Wistar rats are administered a single dose of valproic acid on day 12.5 of gestation. After treatment with the investigational drug, offspring are behaviorally examined on day 59 of postnatal life in a social preference assay. The social preference test is a highly accepted assay for evaluating autistic behavior in rodents (Nadler et al., Genes Brain Behav 2007,3:303-314; Bambini-Junior et al., Brain Res 2011,1408:8-16). Briefly, in this assay, test animals are allowed to explore a conspecific, or a similar area, but without a target conspecific, separated by a dividing perforated wall. Autistic animals (such as prenatally valproate-exposed rats) spend little time engaged in social exploration during the test session. The reduction in social behavior in VPA-treated animals is consistent with the α5GABA A It is believed that the restoration of receptor-mediated inhibitory synaptic transmission may restore normal levels (Wang et al., Front Neurol 2018, 9:Article 1052). Thus, the present examples may be of great behavioral benefit in this preclinical disease model that reproduces the core symptoms of ASD. Thus, the compounds of the present invention, specifically GABA A It may be proposed that α5 PAM may have therapeutic potential for treating core symptoms of autism spectrum disorder in humans.

[0012] It has also been shown that positive modulators of GABA-A receptors, such as nonselective clonazepam at low doses, can ameliorate symptoms in preclinical models of ASD (Han et al., Nature 2012, 489:385-390; Okamoto et al., J Neuroimmunol 2018, 321:92-96), raising hopes that clinically used benzodiazepines could be used at extremely low doses for the treatment of the disease. In addition to this strategy, subunit-selective compounds, such as α2 / 3 modulators (AZD7325; https: / / www.clinicaltrials.gov / ct2 / show / NCT03678129) or positive allosteric modulators of α5, may provide alternative approaches for the treatment of ASD, possibly with 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).

[0013] Therefore, α5GABA, A GABA, a compound with high affinity and selectivity for R A α5 PAM is a neurodegenerative disorder characterized by a single symptom and / or multiple symptoms of the disease that are mediated by GABAergic receptor agonists. AIt may be used alone or in combination with one or more other active ingredients for the treatment or prevention of disorders of the central nervous system which may be associated with the alpha5 receptor. These include, but are not limited to, neurodevelopmental disorders such as autism spectrum disorder (ASD) (Mendez et al., Neuropharmacology 2013, 68:195-201), fragile X disorder (Curia et al., Cereb. Cortex 2009, 19:1515-1520), Prader-Willi syndrome (Bittel et al., J Med Genet 2003, 40:568-574), or Down syndrome (Braudeau et al., J Psychopharmacology 2011, 25:1030-1042; Martinez-Cue et al., J Neurosci 2013, 33:953-966), neurocognitive disorders (Collinson et al., J Neurosci 2002, 22:5572-5580), such as Alzheimer's disease (AD) (Kwakowsky et al., J Neurochem 2018,145:374-392;Solas et al.,Curr Pharm Des 2015;21:4960-4971;Wu et al., Nat Commun 2014, 4159), prodromal AD and mild cognitive impairment (Maubach, Curr Drug Targets CNS Neurol Disord 2003, 2:233-239), vascular cognitive impairment and vascular dementia (Gacsalyi et al., Eur J Pharmacol 2018, 834:118-125), frontotemporal lobar degeneration including frontotemporal dementia, progressive supranuclear palsy and corticobasal syndrome (Murley and Rowe, Brain 2018, 5:1263-1285), dementia with Lewy bodies (Khundakar et al., Acta Neuropathol Commun 2016, 4:66), age-related memory impairment and cognitive decline (Koh et al., Neuropharmacology 2013, 64:142-152), cognitive impairment associated with brain cancer, including but not limited to medulloblastoma (Sengupta et al., CNS Oncol 2014, 3:245-247), postoperative dementia (Cheng et al., J Neurosci 2006, 26:3713-3720), inflammation-induced dementia (Wang et al., Cell Rep 2012, 2:488-496), HIV-associated neurocognitive disorder (Green and Thayer, Neuropharmacology 2019, 149:161-168), cognitive impairment associated with diseases, including but not limited to migraine and tension-type headache (Russo et al., Am J Hum Genet 2005, 76:327-333), multiple sclerosis (Kammel et al., Neuroscience 2018,395:89-100), Parkinson's disease (Blaszczyk,Front Neurosci 2016,10:269-277), epilepsy (McGinnity et al.,Brain Commun 2021,3(1):fcaa190; Schipper et al.,Mol Neurobiol 2016,53:5252-5265), attention deficit hyperactivity disorder and adult attention deficit (Bollmann et al.,Transl Psychiatry 2015,8:e589;Edden et al., Arch Gen Psychiatry 2014,69:750-753), or including but not limited to post-traumatic stress disorder (Lu et al., Neuronal Plast 2017,5715-816), schizophrenia (Guidotti et al., Psychopharmacology 2005,180:191-205), positive symptoms, negative symptoms and / or cognitive symptoms associated with schizophrenia (Asai et al., Schizophrenia Res 2008,99:333-340; Donegan et al., Nature Communications 2019,10:Article number 2819; Gill et al., Neuropsychopharmacology 2011,36:1903-1911; Hauser et al., Mol Psychiatry 2005,10:201-207; Marques et al., Mol Psychiatry 2021,26:2616-2625; Redrobe et al., Psychopharmacology 2012,221:451-468), bipolar disorder (Otani et al., Neurosci Lett 2005,381:108-113), Huntington's disease (Du et al., Front Mol Neurosci. 2017,10:198), neurofibromatosis type I (Ribeiro et al., Cortex 2015,64:194-208), sleep disorders (Mesbah-Oskui et al., Neurotoxicol Teratol 2017,61:115-122), substance-related and addictive disorders, including, but not limited to, alcohol use disorder or gambling disorder (Mick et al., Addict Biol 2017,22:1601-1609; Stephens et al., Eur J Pharmacol 2005,526:240-250), fetal alcohol spectrum disorder (Toso et al., Am J Obstet Gynecol 2006,195:522-527), mood disorders (Bugay et al., Neuropsychopharmacology 2020,45:2289-2298; Carreno et al., Int J Neuropsychopharmacology 2017,20:504-509;Choudary et al., Proc Natl Acad Sci USA 2005,102:15653-15658; Fischell et al., Neuropsychopharmacology 2015;40:2499-2509), psychiatric disorders (Wearne et al., Neuropsychopharmacology 2016,111:107-118), substance-induced psychiatric disorders (Neugebauer et al., Behav Brain Res 2018,342:11-18), anxiety disorders (Behlke et al., Neuropsychopharmacology 2016,41:2492-2501; Botta et al., Nat Neuroscience 2015,18:1493-1500), fear-related disorders (Botta et al., Nat Neuroscience 2015,18:1493-1500; Crestani et al., Proc Natl Acad Sci USA 2002,99:8980-8985), stress disorders (Fischell et al., Neuropsychopharmacology 2015;40:2499-2509), Alzheimer's disease-related neuropsychiatric symptoms (Xu et al., Psychopharmacology 2018,235:1151-1161), stroke (Clarkson et al., Nature 2010,468:305-309; Lake et al., J Cereb Blood Flow Metab 2015,35:1601-1609), traumatic brain injury (Khodaei et al., Crit Care Med 2020,48:533-544), and neuropathic pain (Hernandez-Reyes et al., Pain 2019,160:1448-1458), as well as other CNS disorders including inflammatory pain (Bravo-Hernandez et al., Eur J Pharmacol. 2014,734:91-97; Munro et al., Neuropharmacology 2011,61:121-132). α5GABA; AModulating α5GABA may also be useful 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 Physiol 2008, 294:L1206-1216), and obesity (Xia et al., Mol Psychiatry 2021, doi:10.1038 / s41380-021-01053-w). A Compounds capable of modulating R are expected to be useful candidates for the treatment of, inter alia, neurodevelopmental disorders, neurocognitive disorders, mood disorders and schizophrenia.

[0014] GABA derivatives, including isoxazoles (e.g., WO2009 / 071477A1, WO2018 / 104419A1, WO2019 / 238633A1) and triazole derivatives (e.g., WO2012 / 062687A1, WO2014 / 001278A1, WO2014 / 001279A1, WO2014 / 001282A1, WO2020 / 016443A1). A Many structurally diverse compounds active against the α5 subunit of the receptor are known in the art (Guerrini et al., Expert Opin Ther Patents 2013, 23(7):843-866).

[0015] GABA A There has been a great deal of research into the α5 receptor and its modulators, but GABA A There remains a need for compounds that are useful in the treatment or prevention of diseases associated with the α5 receptor. Summary of the Invention

[0016] The present invention relates to a compound of formula (I) [ka] [In the formula, A is, [ka] Represented by; R 1 is an alkyl group, an alkoxy group, or a haloalkyl group; R 2 is hydrogen; an alkyl group optionally substituted with -S(O)2-alkyl, cycloalkyl or heterocycle; a cycloalkyl group; a heterocycle optionally substituted with alkyl; or a heteroaryl group; 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 solvates or its hydrates, and / or its polymorphs.

[0017] The present invention provides a compound of formula (I) as defined above for use as a medicine.

[0018] The present invention relates to GABA A There is provided a compound of formula (I) as defined above for use in the treatment or prevention of a disease associated with the α5 receptor.

[0019] The present invention relates to GABA A There is provided the use of a compound of formula (I) as defined above for the manufacture of a medicament for the treatment or prevention of a disease associated with the α5 receptor.

[0020] The present invention relates to GABA A Provided is a method for treating or preventing a disease associated with the α5 receptor, comprising 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.

[0021] The present invention relates to a compound of formula (I) as defined above, and GABA A Combination with one or more other active ingredients for the treatment or prevention of diseases associated with the alpha5 receptor is provided.

[0022] The present invention provides pharmaceutical compositions containing as an active ingredient a compound of formula (I) as defined above.

[0023] The present invention provides a medicament comprising a combination of a compound of formula (I) as defined above with one or more other active ingredients (combination pharmaceutical composition).

[0024] The present invention relates to a compound of formula (I) as defined above as an active ingredient, either alone or in combination with GABA. A Pharmaceutical compositions containing the compounds in combination with one or more other active ingredients for use in the treatment or prevention of diseases associated with the alpha5 receptor are provided.

[0025] The present invention provides processes for the preparation of compounds of formula (I) as defined above, as well as intermediates of the preparation processes.

[0026] The present invention also provides for the preparation of a pharmaceutical composition containing a compound of formula (I) as defined above, alone or in combination with one or more other active ingredients. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0027] The present invention relates to alpha5 subunit-containing gamma-aminobutyric acid A receptors (GABA A It has affinity and selectivity for GABA receptors (α5 receptors) and A The present invention provides compounds of formula (I) which act as positive allosteric modulators of the α5 receptor and are thereby useful in the treatment or prevention of diseases associated with the GABAA α5 receptor, processes for their preparation, pharmaceutical compositions comprising them alone or in combination with one or more other active ingredients, and their use as medicaments.

[0028] The present invention relates to a compound of formula (I) [ka] [In the formula, A is, [ka] Represented by; R 1 is an alkyl group, an alkoxy group, or a haloalkyl group; R 2 is hydrogen; an alkyl group optionally substituted with -S(O)2-alkyl, cycloalkyl or heterocycle; a cycloalkyl group; a heterocycle optionally substituted with alkyl; or a heteroaryl group; 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 solvates or its hydrates, and / or its polymorphs.

[0029] 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.

[0030] The nomenclature used is based on IUPAC systematic nomenclature unless otherwise indicated.

[0031] Any open valency appearing on a carbon, oxygen, sulfur or nitrogen atom in the structures herein indicates the presence of a hydrogen, unless otherwise indicated.

[0032] Definitions of common terms used in this specification, whether the terms appear individually or in combination with other groups, are set forth below.

[0033] "Optional" or "optionally" means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which the event or circumstance occurs as well as instances in which it does not occur.

[0034] The term "substituent" refers to an atom or group of atoms that replaces a hydrogen atom on a parent molecule.

[0035] The term "substituted" indicates that the defined group bears one or more substituents.

[0036] Any group may carry multiple substituents and when a variety of possible substituents are provided, the substituents are independently selected and do not have to be the same.

[0037] The term "unsubstituted" means that the defined group bears no substituents.

[0038] The term "optionally substituted" means that any atom of the defined group is unsubstituted or substituted with one or more substituents independently selected from the group of possible substituents. When a number of substituents is indicated, the term "one or more" means from one substituent to the maximum number of substituents possible, i.e., replacement of one hydrogen by a substituent up to replacement of all hydrogens. Possible substituents include, but are not limited to, C 1-4 Examples of the alkyl group include alkyl and oxo.

[0039] The term "alkyl", alone or in combination with other groups, refers to a straight or branched, single or multiply branched, hydrocarbon radical of 1 to 6 carbon atoms. Preferably, an alkyl group is of 1 to 4 carbon atoms. Examples include, but are not limited to, methyl, ethyl, propyl, i-propyl (isopropyl), n-butyl, 2-butyl (sec-butyl) or t-butyl (tert-butyl) groups. 1-2 An alkyl group is more preferred, and a methyl group is most preferred.

[0040] The term "alkoxy", alone or in combination with other groups, refers to an -O-alkyl group, where alkyl is as defined above. Preferably, the alkoxy group is an -O-alkyl group, where the alkyl group is from 1 to 4 carbon atoms. Examples include, but are not limited to, methoxy, ethoxy, i-propoxy, n-propoxy or t-butoxy. 1-2 An alkoxy group is more preferred, and a methoxy group is most preferred.

[0041] The terms "halogen," "halo," or "halide," alone or in combination with other groups, refer to fluoro, chloro, bromo, or iodo. Preferably, the halogen is fluorine.

[0042] The term "haloalkyl", alone or in combination with other groups, refers to an alkyl as defined above substituted with one or more of the same or different halogens on any carbon atom of said alkyl, as well as vicinal and / or geminal halo substitutions, e.g., perhaloalkyl groups. The term "perhaloalkyl" refers to an alkyl in which all hydrogen atoms are replaced by the same or different halogen atoms. Examples include, but are not limited to, trihalo, dihalo or monohaloalkyl groups, e.g., 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl or trifluoromethyl. Preferably, the haloalkyl group is halo-C 1-2 It is preferably an alkyl group, more preferably difluoromethyl or trifluoromethyl, most preferably trifluoromethyl.

[0043] 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 is cyclobutane or cyclopentane.

[0044] The term "heterocycle", alone or in combination with other groups, refers to a monovalent saturated or partially unsaturated monocyclic, bicyclic, fused, bridged, or spiro ring system of 3 to 10 ring atoms containing 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon. Examples of monocyclic heterocycles are aziridine, 2H-azirine, oxirane, thiirane, azetidine, oxetane, thietane, azetidin-2-one, pyrrolidine, pyrrolidinone, pyrroline, pyrazolidine, imidazoline, pyrazoline, tetrahydrofuran, dihydrofuran, dioxolane, tetrahydrothiophene, oxazolidine, dihydrooxazole, isoxazolidine, oxathiolane, sulfolane, thiazolidine, thiazoline ... Dindiones, succinimides, oxazolidones, hydantoins, piperidines, piperidinones, piperazines, tetrahydropyrans, tetrahydrothiopyrans, dihydropyrans, tetrahydropyridines, dioxanes, thianes, dithianes, 1,1-dioxo-thianes, morpholines, thiomorpholines, 1,1-dioxo-thiomorpholines, azepanes, diazepanes, homopiperazines, oxazepnayls, etc. Preferably, heterocycle, alone or in combination with other groups, refers to a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one or two ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon. More preferably, heterocycle, alone or in combination with other groups, refers to a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one ring heteroatom selected from O and S, the remaining ring atoms being carbon. Most preferably, heterocycle, alone or in combination with other groups, refers to a monovalent saturated monocyclic ring of 3 to 6 ring atoms containing one ring heteroatom selected from O and S, with the remaining ring atoms being carbon, e.g., oxetane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyran.

[0045] The term "heteroaryl", alone or in combination with other groups, refers to a monovalent heteroaromatic monocyclic or bicyclic ring system of 5 to 10 ring atoms containing 1, 2 or 3 heteroatoms independently selected from N, O and S, with the remaining ring atoms being carbon. Examples for heteroaryl are pyrrole, furan, thiophene, imidazole, oxazole, isoxazole, thiazole, isothiazole, triazole, tetrazole, oxadiazole, thiadiazole, tetrazole, pyridine, pyrazine, pyrazole, pyridazine, pyrimidine, triazine, azepine, diazepine, benzofuran, benzothiophene, indole, isoindole, isobenzofuran, benzimidazole, benzoxazole, benzoisoxazole, benzothiazole, benzoisothiazole, benzoxadiazole, benzothiadiazole, benzotriazole, purine, quinoline, isoquinoline, quinazoline, quinoxaline, carbazole, or acridine. Preferably, heteroaryl, alone or in combination with other groups, refers to a monovalent heteroaromatic monocyclic ring system of 5-6 ring atoms containing one or two heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon. More preferably, heteroaryl, alone or in combination with other groups, refers to a monovalent heteroaromatic monocyclic ring system of 6 ring atoms containing one or two heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon. Most preferably, heteroaryl, alone or in combination with other groups, refers to a monovalent heteroaromatic monocyclic ring system of 6 ring atoms containing one or two heteroatoms that are N, the remaining ring atoms being carbon, e.g., pyridine, pyridazine, pyrimidine, pyrazine.

[0046] The terms "compound of the invention", "compound of the invention", "compound of formula (I) as defined above" refer to a compound of formula (I), and / or a salt thereof, and / or a stereoisomer thereof, and / or an enantiomer thereof, and / or a racemate or a diastereomer thereof, and / or a biologically active metabolite thereof, or a prodrug thereof, or a solvate thereof, or a hydrate thereof, and / or a polymorph thereof.

[0047] The term "salts" refers to pharma- ceutically acceptable salts or non-pharmaceutically acceptable salts.

[0048] The term "pharmaceutical acceptable salt" refers to conventional acid or base addition salts that preserve the biological effectiveness and properties of the compound of formula (I) and can be formed with suitable non-toxic organic or inorganic acids or organic or inorganic bases.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, and various organic 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, pamoic acid, palmitic acid, benzenesulfonic acid, toluenesulfonic acid, toluenesulfonic acid, methanesulfonic acid, oxalic acid, tartaric acid, naphthalenedisulfonic acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid, etc. Sample base-addition salts are those derived from ammonium, potassium, sodium and, quaternary ammonium hydroxides, such as for example, tetramethylammonium hydroxide.

[0049] "Pharmaceutically unacceptable salts" may be preferable for the purification or isolation of the compounds of formula (I) and therefore are also within the scope of the invention.

[0050] The term "prodrug" refers to derivatives of compounds of formula (I) according to the invention that contain such groups which have no therapeutic effect themselves, but which, after chemical or metabolic degradation in vivo (biotransformation), become "biologically active metabolites" that are responsible for the therapeutic effect.

[0051] Optical isomers can be prepared by known methods, for example, by resolving racemic mixtures by forming diastereomeric salts or by forming covalent diastereomers using optically active acids or bases. Suitable acids include, for example, tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid, ditoluoyltartaric acid and camphorsulfonic acid. Diastereomeric 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. The optically active base or acid is then liberated from the separated diastereomeric salts. Various methods for separating optical isomers include chiral chromatography (e.g., chiral HPLC columns), which may optionally be used by derivatization in order to maximize the separation of the enantiomers. A suitable chiral HPLC column can be routinely selected as desired. Enzymatic separations performed by derivatization, if applicable, may also be used. Optically active compounds of formula (I) can also be prepared using optically active starting materials using chiral syntheses without racemization reaction conditions.

[0052] The absolute configuration of a chiral compound can be determined, for example, by optical rotation, VCD (Vibrational Circular Dichroism) and / or single crystal X-ray diffraction analysis, or by the determination of the diastereomeric pairs of compounds synthesized from the chiral compound. 1 It can be determined by 1 H NMR spectroscopic assay.

[0053] The compound of formula (I) may exist in various polymorphic forms.As known in the art, polymorphism is the ability of a compound to crystallize in two or more crystalline forms, i.e., polymorphic forms.The polymorphic forms of a particular compound can be defined by the same chemical formula or composition, and may differ in their chemical structure as the crystalline structures of two different chemical compounds.

[0054] The compound of formula (I) and its salts may also exist as solvates or hydrates, which are also within the scope of the present invention.The term "solvate" refers to the non-covalent stoichiometric or non-stoichiometric combination of a solvent and a solute.The term "hydrate" refers to the non-covalent stoichiometric or non-stoichiometric combination of water and a solute.

[0055] The present invention provides pharmaceutical compositions comprising as an active ingredient at least one compound of formula (I) as defined above.

[0056] The present invention provides a pharmaceutical composition comprising a combination of the compound of formula (I) defined above and one or more other active ingredients.The pharmaceutical composition may comprise at least one compound of the present invention together with one or more other active ingredients in a single dosage form or separately.The combination composition may be administered simultaneously, separately or sequentially.

[0057] The term "pharmaceutical composition" (or "composition") refers to a mixture or solution containing a therapeutically effective amount of active ingredients together with pharma- ceutically acceptable excipients to be administered to a subject in need thereof, e.g., a human.

[0058] The present invention also relates to the preparation of pharmaceutical compositions.

[0059] The pharmaceutical compositions of the present invention may be formulated into a variety of pharmaceutical formulations, including, but not limited to, solid oral dosage forms such as tablets (e.g., buccal, sublingual, effervescent, chewable, orally dispersible), capsules, pills, orally dispersible films, granules, powders, etc.; liquid formulations such as solutions, emulsions, suspensions, syrups, elixirs, drops, etc.; parenteral dosage forms such as intravenous injections, intramuscular injections, subcutaneous injections, etc.; eye drops, semi-solid ophthalmic preparations, semi-solid dermal preparations (ointments, creams, pastes, etc.), transdermal therapeutic systems, suppositories, rectal capsules, rectal solutions, emulsions and suspensions, etc.

[0060] The pharmaceutical compositions of the present invention may be administered in a variety of ways, such as, but not limited to, oral, rectal, mucosal, transdermal or intestinal administration; parenteral administration, including intramuscular, subcutaneous, intravenous, intramedullary injection, as well as intra-articular, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injection and eye drops.

[0061] Alternatively, the compound may be administered locally rather than systemically, for example, by direct injection of the compound into the kidney or heart, often in a modified release formulation. In addition, the drug may be administered in a targeted carrier system, for example, a tissue-specific antibody-encapsulated liposome.

[0062] The pharmaceutical compositions may be administered in various ways and in various pharmaceutical forms. The compounds of the present invention may be administered alone or in combination with pharma- ceutically acceptable excipients, in single or multiple doses.

[0063] For simple administration, it is preferred that the pharmaceutical composition consists of a dosage unit containing the amount of active ingredient to be administered once, or a small number of multiples, or halves, thirds, quarters, etc. Such a dosage unit is, for example, a tablet that may be slotted into a half or quarter to facilitate splitting the tablet into halves or quarters to measure the required amount of active ingredient.

[0064] Pharmaceutical compositions containing the active ingredient according to the present invention generally contain 0.001-500 mg of active ingredient per dosage unit. Of course, it is also possible that the amount of active ingredient in each formulation exceeds the above-mentioned limits either above or below.

[0065] The present invention also relates to pharmaceutical compositions for use in pediatric use such as, but not limited to, solutions, syrups, elixirs, suspensions, powders for the preparation of suspensions, dispersible or effervescent tablets, chewable tablets, orally disintegrating tablets or granules, tablets or coated tablets, effervescent powders or granules, capsules.

[0066] The pharmaceutical compositions of the present invention may be prepared by methods known per se, such as conventional mixing, dissolving, emulsifying, suspending, microencapsulating, lyophilizing, extrusion and spheronizing, layering, film-coating, granulating, encapsulating, pelleting or compressing.

[0067] The pharmaceutical composition of the present invention may be formulated in a conventional manner using one or more physiologically or pharmaceutical acceptable excipients that facilitate the incorporation of active ingredients into pharmaceutical forms that are pharmaceutical acceptable.The term "physiologically or pharmaceutical acceptable excipients" refers to any ingredient that is used in the formulation of pharmaceutical products that have no therapeutic activity and are non-toxic.Suitable formulations depend on the mode of administration selected.Any of the techniques and excipients well known in the art may be used.

[0068] The excipients applicable in the preparation may be selected from the following categories, for example but not limited to: tablet and capsule fillers, tablet and capsule binders, drug release modifiers, disintegrants, glidants, lubricants, sweeteners, flavorings, fragrances, coating materials, surfactants, stabilizers, preservatives or antioxidants, buffers, complexing agents, wetting agents or emulsifiers, salts for adjusting osmotic pressure, lyophilization excipients, microencapsulating agents, ointment materials, penetration enhancers, solubilizers, solvents, suppository materials, suspending agents.

[0069] The excipients and various methods of preparation described above are merely representative. Other materials and processing techniques known in the art may also be used.

[0070] The term "other active ingredients" includes, but is not limited to, 5-HT 1A Antagonists or agonists (e.g., Lecozotan, NLX 101, Sarizotan); 5-HT 1B and 5-HT 1Dagonists (such as rizatriptan, zolmitriptan, naratriptan and sumatriptan); 5-HT2 antagonists; 5-HT4 agonists (such as PRX-03140); 5-HT6 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, 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 (SFX 01, etc.); anti-amyloid antibodies, including anti-amyloid humanized monoclonal antibodies (e.g., bapineuzumab, ACCOOl, CAD 106, AZD3102, H12A11V1, etc.); anticholinergics (e.g., biperiden); anticonvulsants (e.g., acetazolamide, carbamazepine, eslicarbazepine acetate, ethosuximide, lacosamide, nitrazepam, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide, stiripentol, topiramate, valproate, etc.); anti-inflammatory compounds (e.g., (R)-flurbiprofen, nitroflurbiprofen, ND-1251, VP-025, HT-0712, and EHT-202, etc.) etc.);ApoE4 conformational modulators;atypical antipsychotics (such as aripiprazole, asenapine, brexpiprazole, briraloxazine, cariprazine, iloperidone, loxapine, lumateperone tosylate, lurasidone hydrochloride, molindone, olanzapine, paliperidone, quetiapine, risperidone, sulpiride and ziprasidone);barbiturates;beta-secretase inhibitors (such as verubecestat, and AZD3293) and gamma-secretase inhibitors (such as LY450139 and TAK 070) or modulators;blockers of Aβ oligomerization;Bradykinin B1 receptor antagonists (SSR240612, NVPSAA164, or WO2007 / 072092A2, WO2008 / 068540A1, WO2008 / 050167A1, WO2008 / 050168 A1); butyrophenones (such as haloperidol); calcium channel blockers (such as ziconotide and NMED160); CB-1 receptor antagonists or inverse agonists (such as drinabant, cannabidiol); CB-2 agonists (such as GW-842166X and SAB378) or CB modulators (cannabidivarin, T1 / C20, tetrahydrocannabinol conjugates, ZYN-002); cholinergic agents; phenothiazines (such as chlorpromazine, fluphenazine, mesoridazine, perphenazine, thioridazine, trifluoperazine, etc.) ;thioxanthenes (such as chlorprothixene and thiothixene);COMT inhibitors (such as entacapone);cyclopyrrolones;neuroleptics of the diphenylbutylpiperidine (such as pimozide) and indolone (such as molindron) classes;DNA-directed DNA polymerase inhibitors (such as suramin sodium);dopamine agonists and partial agonists (such as pramipexole, ropinirole);dopamine precursors (such as carbidopa, levodopa);dopamine transport inhibitors;enzyme modulators or supplements (such as CM-AT, CM-4612 and CM-182);fatty acid amide hydrolase inhibitors (such as JNJ 42165279);fatty acid or triglyceride supplements (such as triheptanoin);fenamate compounds (such as ASD-002);GABA; A blockers (such as S44819, NGD 97-1, α5IA, α5IA-II, MRK-016, vasumisanil, or any compound described in PCT / IB2019 / 058208); GABA A Receptor agonists (such as acamprosate); GABA A Signal transduction enhancers (AZD-7325, PF-06372865, L-838,417, TPA-023, brexanolone, zuranolone, alfaxalone, ganaxolone, gaboxadol, tiagabine, vigabatrin, bumetanide, etc.); GABA Breceptor agonists (such as arbaclofen or any of the compounds described in WO2018 / 167629A1 or WO2018 / 167630A1); gabapentinoids (such as pregabalin, gabapentin); glutamate modulators (such as AMO 04); glycine transport inhibitors; glycogen synthase kinase 3β inhibitors (such as tideglusib, AZD1080, SAR502250 and CEP16805); growth hormone secretagogues (such as ibutamoren, ibutamoren mesylate and capromorelin); HDAC inhibitors; heterocyclic dibenzazepines (such as clozapine); histamine H3 receptor antagonists and inverse agonists (S38093, ABT-834, ABT 829, GSK 189254, CEP16795 or any of the compounds described in WO2014 / 136075A1); HMG-CoA reductase inhibitors; imidazopyridines (such as zolpidem); immunomodulators (such as IMM-124E); KCNQ antagonists; lithium; LRRK2 inhibitors; LXR β agonists; lysine-specific demethylase 1 inhibitors (such as bafidemstat); M1 or M4 mAChR agonists or PAMs; MARK ligands; melatonin agonists; melatonin agonists and antagonists; methyl-CpG binding protein 2 (MECP2) gene replacement therapy (AVXS 201, etc.); mGluR2 antagonists or modulators; mGluR4 positive allosteric modulators (ADX-88178, Forex, etc.); mGluR5 antagonists (HTL-14242, AZD9272, mavoglurant, etc.); microbiome modulators (AB-2004, CP-101, SB-121, etc.); minor tranquilizers; MMP inhibitors; α7 nAChR agonists or positive allosteric modulators (such as ABT-126, AZD0328, EVP-6124, AVL-3288, PNU-120596, or any of the compounds described in WO2020 / 012422A1, WO2020 / 012423A1 or WO2020 / 012424A1) or antagonists (such as mecamylamine hydrochloride); neuropeptide receptor modulators (such as trophinetide, davunetide, NNZ-2591); neutrophil inhibitory factors;NK1 / NK3 receptor antagonists;NMDA receptor agonists or antagonists (e.g., memantine, neramexane, EVT101, AZD4282, BHV 5000);noradrenaline transport inhibitors;norepinephrine modulators;NOS inhibitors (e.g., SD6010 and 274150);NQO1 modulators (e.g., vatiquinone);NR2B antagonists (e.g., radiprodil);NSAIDs (e.g., ibuprofen);opioid analgesics (e.g., codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene);orexin antagonists Gonists 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 openers;PPAR gamma agonists (such as pioglitazone and rosiglitazone);prokineticin agonists and antagonists;pyrazolopyrimidines;pyrrolidone compounds modulating cholinergic / metabotropic glutamate receptors (such as fasoraceta) sigma-1 receptor agonists (such as bralcamesine); sodium channel blockers and antagonists (such as lamotrigine, VX409 and SPI860); sphingosine 1 phosphate receptor modulators (such as fingolimod, ozanimod, siponimod, ponesimod); SSRIs or SNRIs (fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine, sertraline; or desvenlafaxine , duloxetine, venlafaxine, etc.); sulfonamides (such as zonisamide); tau phosphorylation inhibitors; thrombolytic agents; triazolopyridines; benzodiazepines; tricyclic antidepressants; T-type calcium channel antagonists; tyrosine hydroxylase inhibitors (such as L1-79); vasopressin; V1a receptor antagonists (such as balovaptan, BTRX-323511, or any of the compounds described in WO2019 / 116324A1 or WO2019 / 116325A1); vitamin E;Refers to therapeutic agents including VR-1 antagonists (such as AMG517, 705498, 782443, PAC20030, VI 14380 and A425619) or other drugs that affect receptors or enzymes to increase the efficacy, safety, convenience or reduce unwanted side effects or toxicity of the compounds of the invention;

[0071] In one embodiment, the other active ingredient is 5-HT 1A antagonists or agonists (such as lecozotan, NLX 101, sarizotan); atypical antipsychotics (such as aripiprazole, asenapine, brexpiprazole, briraloxazine, cariprazine, iloperidone, loxapine, lumateperone tosylate, lurasidone hydrochloride, molindone, olanzapine, paliperidone, quetiapine, risperidone, sulpiride and ziprasidone); CB-1 receptor antagonists or inverse agonists (such as drinabant, cannabidiol); CB-2 agonists (such as GW-842166X and SAB378) or CB modulators (cannabidivarin, T1 / C20, tetrahydrocannabinol conjugates, ZYN-002); DNA-directed DNA polymerase inhibitors (such as sodium suramin); fatty acid amide hydrolase inhibitors (JNJ 42165279, etc.); fatty acid or triglyceride supplements (e.g., triheptanoin); GABA A Receptor agonists (such as acamprosate); GABA A Signal transduction enhancers (AZD-7325, PF-06372865, L-838,417, TPA-023, brexanolone, zuranolone, alfaxalone, ganaxolone, gaboxadol, tiagabine, vigabatrin, bumetanide, etc.); GABA Breceptor agonists (such as arbaclofen or any of the compounds described in WO2018 / 167629A1 or WO2018 / 167630A1); glutamate modulators (such as AMO 04); glycogen synthase kinase 3β inhibitors (such as tideglusib, AZD1080, SAR502250 and CEP16805); lysine-specific demethylase 1 inhibitors (such as bafidemstat); methyl-CpG binding protein 2 (MECP2) gene replacement therapy (such as AVXS 201); microbiome modulators (such as AB-2004, CP-101, SB-121); neuropeptide receptor modulators (such as trophinetide, davunetide, NNZ-2591); NMDA receptor agonists or antagonists (memantine, neramexane, EVT101, AZD4282, BHV 5000, etc.); NQO1 modulators (e.g., vatiquinone); oxytocin; cholinergic / metabotropic glutamate receptor modulating pyrrolidone compounds (e.g., fasoracetam, levetiracetam, brivaracetam, piracetam); sigma-1 receptor agonists (e.g., bralcamesine); sphingosine-1 phosphate receptor modulators (e.g., fingolimod, ozanimod, siponimod, ponesimod); SSRIs or SNRIs (e.g., fluoxetine, bromodiloacetate ... or desvenlafaxine, duloxetine, venlafaxine, etc.); tyrosine hydroxylase inhibitors (such as L1-79); vasopressin; or V1a receptor antagonists (such as balovaptan, BTRX-323511, or any of the compounds described in WO2019 / 116324A1 or WO2019 / 116325A1).

[0072] The term "modulator" refers to a molecule that interacts with a target receptor, where the interaction can be, for example, agonistic, antagonistic, or inverse agonistic.

[0073] The term "inhibitor" refers to a molecule that competes with, reduces or prevents the binding of a particular ligand to a particular receptor, or reduces or prevents the inhibition of the function of a particular protein.

[0074] The term "agonist" refers to a compound that has affinity for the binding site of a receptor and enhances the activity of a receptor-mediated response. A "full agonist" produces a complete response, whereas a "partial agonist" produces less than full activation even when the entire receptor population is occupied.

[0075] The term "inverse agonist" refers to a compound that produces an effect opposite to that of an agonist by binding to the same agonist binding site or reduces the effect of the agonist by binding at a different allosteric binding site.

[0076] The term "antagonist" refers to a compound that reduces or prevents the action of another compound or receptor site, or weakens the effect of an agonist. A "competitive antagonist" binds to the same site as an agonist but does not activate it, thus blocking the action of the agonist. A "noncompetitive antagonist" binds to an allosteric site on the receptor and prevents activation of the receptor. The binding of a "reversible antagonist" to the receptor is noncovalent (can be washed out), whereas the binding of an "irreversible antagonist" is covalent (cannot be washed out).

[0077] The term "allosteric modulator" refers to a compound that binds to a receptor at a site different from the agonist binding site, i.e., an allosteric site, where the affinity and / or activity of the receptor for an endogenous ligand or agonist is altered by inducing a conformational change in the receptor. A "positive allosteric modulator" or "PAM" increases the affinity and / or activity, whereas a "negative allosteric modulator" or "NAM" decreases the affinity and / or activity of the receptor. The compounds of formula (I) defined above are positive allosteric modulators.

[0078] The "inhibition constant" (K i The term K refers to the absolute binding affinity of a particular inhibitor to its receptor. It is measured using a competitive binding assay and follows the Cheng-Prusoff relationship: K i =IC 50 / [1+([L] / K D )] (where [L] is the concentration of radioactive ligand and K D is the affinity of the labeled ligand for the receptor binding sites) to determine the concentration at which a particular inhibitor would occupy half of the receptors in the absence of competing ligand (IC 50 ) is calculated from K i The value is pK i The values ​​can be logarithmically transformed (-logK i ), where higher values ​​indicate exponentially higher potency.

[0079] The term "submaximal effective concentration" refers to the concentration of a particular compound required to obtain 10% of the maximum specific effect.

[0080] The terms "condition," "defect," "deficiency," "disability," "disorder," "disease" or "disease state" are used interchangeably to refer to any disease, condition, symptom, syndrome, disorder or indication.

[0081] "GABA AThe term "α5 receptor-associated disease" refers to a disease in which one or more symptoms are related to GABA receptor-associated disorders. A It refers to the disease, condition or disorder of the central nervous system that can be related to α5 receptor.Such diseases include but are not limited to neurodevelopmental disorder, neurodegenerative disorder, neurocognitive disorder, schizophrenia, mood disorder, pain disorder, substance-related disorder and addictive disorder, or other diseases.

[0082] GABA A The diseases associated with α5 receptor may show comorbidity with each other.Comorbidity refers to a condition that exists simultaneously but independently with another condition in a patient, or a condition that causes, is caused by, or is otherwise related to another condition in the same patient.However, in psychiatric, psychological, or mental health diseases, comorbidity does not necessarily mean the presence of multiple diseases, but may instead reflect our current inability to provide a single diagnosis that is the primary cause of all symptoms.

[0083] The term "neurodevelopmental disorder" includes, but is not limited to, autism spectrum disorder (ASD), Angelman syndrome, fragile X disorder, Prader-Willi syndrome, Rett syndrome or Down syndrome.

[0084] The term "neurodegenerative disorder" includes, but is not limited to, Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), or amyotrophic lateral sclerosis (ALS).

[0085] The term "neurocognitive disorder" includes, but is not limited to, cognitive deficit disorders, memory deficits, age-related memory impairment or cognitive decline, dementia (or its different forms such as dementia in 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, post-operative dementia, or inflammation-induced dementia), Alzheimer's disease-related neuropsychiatric symptoms, mild cognitive impairment (MCI), vascular cognitive impairment (VCI), CNS conditions occurring after stroke, cognitive impairment associated with brain cancer (including, but not limited to, medulloblastoma), cognitive decline in Down's syndrome (DS), cognitive dysfunction in major depressive disorder (MDD), or HIV-associated neurocognitive disorder. The term "schizophrenia" includes, but is not limited to, different forms of schizophrenia, the positive symptoms, negative symptoms and / or cognitive symptoms associated with schizophrenia, schizotypal disorder and delusional disorder.

[0086] The term "pain disorder" includes, but is not limited to, nociceptive pain, neuropathic pain or inflammatory pain.

[0087] The term "mood disorder" includes, but is not limited to, depression-related disorders (such as major depressive disorder (MDD)), dysthymia, cyclothymic disorder, seasonal affective disorder / seasonal depression, depression after traumatic brain injury (TBI), postpartum depression, premenstrual dysphoric disorder, depressive symptoms associated with menopause, depression after substance abuse / withdrawal, bipolar disorder (bipolar disorder in remission, or bipolar depressive episode), substance (alcohol or drug)-induced or not otherwise specified mood disorder (MD-NOS).

[0088] The term "other diseases" includes, but is not limited to, 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 spectrum disorder, bronchoconstrictive diseases (such as asthma, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia) or obesity.

[0089] In one embodiment, GABA A Diseases associated with the α5 receptor include autism spectrum disorder (ASD); Angelman syndrome, fragile X disorder, Prader-Willi syndrome, Rett syndrome, Down syndrome, Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), cognitive impairment disorders, memory deficits, age-related memory impairment or cognitive decline, dementia or different forms thereof, such as Alzheimer's disease, Niemann-Pick disease, Parkinson's disease or Huntington's disease. Dementia in Alzheimer's disease, Dementia with Lewy Bodies (DLB), Frontotemporal Dementia, Vascular Dementia (VaD), Subcortical Dementia, Mixed Vascular and Subcortical Dementia, Multi-infarct Dementia, Post-operative Dementia, or Inflammatory Dementia, Neuropsychiatric Symptoms Associated with Alzheimer's Disease, Mild Cognitive Impairment (MCI), Vascular Cognitive Impairment (VCI), CNS conditions occurring after stroke, Cognitive impairment associated with brain cancer (including but not limited to medulloblastoma), Cognitive decline in Down's Syndrome (DS), cognitive dysfunction in major depressive disorder (MDD), HIV-associated neurocognitive disorders; different forms of schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, schizotypal and delusional disorders; nociceptive, neuropathic or inflammatory pain; depression-related disorders (such as major depressive disorder (MDD)), dysthymia, cyclothymic disorder, seasonal affective disorder / seasonal depression, depression after traumatic brain injury (TBI), postpartum depression, premenstrual dysphoric disorder, depression associated with menopause. symptoms, depression after substance abuse / withdrawal, bipolar disorder (bipolar disorder in remission, or a depressive episode of bipolar disorder), substance (alcohol or drug) induced, mood disorder not otherwise specified (MD-NOS); 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 spectrum disorder, bronchoconstrictive diseases (such as asthma, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia) or obesity.

[0090] In a preferred embodiment, GABA ADiseases associated with the α5 receptor refer to autism spectrum disorder (ASD), Angelman syndrome, fragile X disorder, Prader-Willi syndrome, Rett syndrome, Alzheimer's disease (AD), cognitive deficit disorder, memory deficit, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, negative and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, and amyotrophic lateral sclerosis.

[0091] The present invention relates to GABA A Provided is a method for treating or preventing a disease associated with the α5 receptor, comprising administering a therapeutically effective amount of a compound of formula (I) as defined above, alone or in the form of a pharmaceutical formulation together with at least one pharma- ceutically acceptable excipient, to a subject, preferably a mammal, more preferably a human being, in need of such treatment or prevention.

[0092] The present invention relates to GABA A Provided is a method for treating or preventing a disease associated with the α5 receptor, comprising administering a therapeutically effective amount of a compound of formula (I) as defined above in combination with one or more other active ingredients to a subject, preferably a mammal, more preferably a human being, in need of such treatment or prevention.

[0093] The present invention relates to a method for treating or preventing at least one symptom and / or symptoms of a neurodevelopmental disorder, a neurodegenerative disorder, a neurocognitive disorder, schizophrenia, a mood disorder, a pain disorder, a substance-related disorder, and an addictive disorder, or other disease, wherein at least one symptom and / or symptoms of the disease is / are increased by GABAergic stimulation in a subject, preferably a mammal, more preferably a human, suffering therefrom. AThe present invention provides a method that may be related to α5 receptor. The method of treatment comprises 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 the treatment or prevention. The method of treatment may comprise administering a pharmaceutical composition comprising 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 the treatment or prevention.

[0094] The present invention provides a method for the treatment or prevention of at least one of autism spectrum disorder (ASD), Angelman syndrome, Fragile X disorder, Prader-Willi syndrome, Rett syndrome, Alzheimer's disease (AD), cognitive deficit disorder, memory loss, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, negative symptoms and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, or one and / or more symptoms thereof in a subject suffering therefrom, preferably a mammal, more preferably a human being, which method comprises administering a therapeutically effective amount of a compound of formula (I) as defined above.

[0095] The present invention relates to GABA A There is provided a compound of formula (I) as defined above for use in the treatment or prevention of a disease associated with the α5 receptor.

[0096] The present invention relates to GABA A There is provided a compound of formula (I) as defined above in combination with one or more other active ingredients for use in the treatment or prevention of diseases associated with the α5 receptor.

[0097] The present invention provides compounds of formula (I) as defined above for use in the treatment or prevention of at least one of a neurodevelopmental disorder, a neurodegenerative disorder, a neurocognitive disorder, schizophrenia, a mood disorder, a pain disorder, a substance-related and addictive disorder, or other disease, or a symptom and / or symptoms thereof.

[0098] The present invention provides a compound of formula (I) as defined above for use in the treatment or prevention of at least one of autism spectrum disorder (ASD), Angelman syndrome, Fragile X disorder, Prader-Willi syndrome, Rett syndrome, Alzheimer's disease (AD), cognitive deficit disorder, memory loss, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, negative symptoms and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, or one and / or more symptoms thereof.

[0099] The present invention relates to GABA A There is provided the use of a compound of formula (I) as defined above for the manufacture of a medicament for the treatment or prevention of a disease associated with the α5 receptor.

[0100] The present invention relates to GABA A There is provided 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 a disease associated with the α5 receptor.

[0101] The present invention provides the use of a compound of formula (I) as defined above for the manufacture of a medicament for the treatment or prevention of at least one of a neurodevelopmental disorder, a neurodegenerative disorder, a neurocognitive disorder, schizophrenia, a mood disorder, a pain disorder, a substance-related disorder and an addictive disorder, or other disease, or a symptom and / or symptoms thereof.

[0102] The present invention provides the use of a compound of formula (I) as defined above for the manufacture of a medicament for the treatment or prevention of at least one of autism spectrum disorder (ASD), Angelman syndrome, Fragile X disorder, Prader-Willi syndrome, Rett syndrome, Alzheimer's disease (AD), cognitive deficit disorder, memory loss, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, negative symptoms and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis, or one and / or more symptoms thereof.

[0103] The present invention relates to GABA A It also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above for use in the treatment or prevention of diseases associated with the α5 receptor.

[0104] The present invention relates to GABA A It also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above, together with one or more other active ingredients, for use in the treatment or prevention of diseases associated with the α5 receptor.

[0105] The term "treatment" refers to the alleviation of a particular pathology, the elimination or reduction of one or more symptoms of a condition, the slowing or elimination of the progression of a disease state, and the prevention or delay of the recurrence of a condition in a patient or subject already suffering from or diagnosed with a disease. "Prophylaxis" (or the prevention or delay of the effects of a disease) is typically accomplished by administering a drug in the same or similar manner as would be given to a patient with an already occurring disease or condition.

[0106] The term "therapeutically effective amount" refers to an amount of active ingredient that results in the treatment, cure, prevention or amelioration of a disease or disease state or side effects, and reduces the progression of a disease or pathology, compared to a corresponding subject that does not receive such amount. This term also includes an effective amount that enhances normal physiological function. For use in therapy, the compound of formula (I) as defined above, and any salt thereof, and / or its salt, and / or its stereoisomer, and / or its enantiomer, and / or its racemate or its diastereomer, and / or its biologically active metabolite or its prodrug or its solvate or its hydrate, and / or its polymorph, may be administered in a therapeutically effective amount as raw chemical. In addition, the active ingredient is available as a pharmaceutical formulation.

[0107] The term "subject" refers to a vertebrate. In certain embodiments, the vertebrate is a mammal. Mammals include humans, non-human primates such as chimpanzees and other apes and monkey species, livestock such as cows, horses, sheep, goats and pigs, domestic animals such as rabbits, dogs and cats, and laboratory animals including rodents such as rats, mice and guinea pigs. In certain embodiments, the mammal is a human. The term subject does not denote a particular age or sex.

[0108] In one embodiment, the present invention provides a compound of formula (I') [ka] [In the formula, A is, [ka] Represented by; where any of rings A's moiety "a1" is bonded to moiety "a2" and any of rings A's moiety "b1" is bonded to moiety "b2"; R 1 , R 2 and X is as defined above for 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.

[0109] In one embodiment, the present invention provides a compound of formula (Ia) [ka] [In the formula, R 1 , R 2 and X is as defined above for 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.

[0110] In one embodiment, the present invention provides a compound of formula (Ib) [ka] [In the formula, R 1 , R 2 and X is as defined above for 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.

[0111] In one embodiment, the present invention provides a compound comprising R 1 But, C 1-6 Alkyl group, C 1-6 Alkoxy group, or halo-C 1-6The compound of formula (I) is

[0112] In one embodiment, the present invention provides a compound comprising R 2 But hydrogen; -S(O)2-C 1-6 Alkyl, C 3-7 Cycloalkyl, or a monovalent saturated or partially unsaturated monocyclic, bicyclic, fused, bridged or spiro ring system of 3 to 10 ring atoms containing 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, with the remaining ring atoms being carbon, optionally substituted C 1-6 Alkyl group; C 3-7 Cycloalkyl group; C 1-6 or a monovalent heteroaromatic monocyclic or bicyclic ring system of 5 to 10 ring atoms containing 1, 2 or 3 heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon, optionally substituted with alkyl;

[0113] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 1 But, C 1-6 Alkyl group, C 1-6 Alkoxy group, or halo-C 1-6 is an alkyl group; R 2 But hydrogen; -S(O)2-C 1-6 Alkyl, C 3-7 Cycloalkyl, or a monovalent saturated or partially unsaturated monocyclic, bicyclic, fused, bridged or spiro ring system of 3 to 10 ring atoms containing 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, with the remaining ring atoms being carbon, optionally substituted C 1-6 Alkyl group; C 3-7 Cycloalkyl group; C 1-6a monovalent saturated or partially unsaturated monocyclic, bicyclic, fused, bridged or spiro ring system of 3 to 10 ring atoms containing 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon, optionally substituted with alkyl; or a monovalent heteroaromatic monocyclic or bicyclic ring system of 5 to 10 ring atoms containing 1, 2 or 3 heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon. Concerning compounds of formula (I):

[0114] In one embodiment, the present invention provides a compound comprising R 1 But, C 1-4 Alkyl group, C 1-4 Alkoxy group, or halo-C 1-4 The compound of formula (I) is

[0115] In one embodiment, the present invention provides a compound comprising R 2 But hydrogen; -S(O)2-C 1-4 Alkyl, C 4-6 Cycloalkyl or an optionally substituted monovalent saturated monocyclic ring of 3 to 7 ring atoms containing 1 or 2 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon; 1-4 Alkyl group; C 4-6 Cycloalkyl group; C 1-4 or a monovalent heteroaromatic monocyclic ring system of 5 to 6 ring atoms containing 1 or 2 heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon, optionally substituted with alkyl;

[0116] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 1 But, C 1-4 Alkyl group, C 1-4 Alkoxy group, or halo-C 1-4 is an alkyl group; R 2 But hydrogen; -S(O)2-C 1-4 Alkyl, C 4-6 Cycloalkyl or an optionally substituted monovalent saturated monocyclic ring of 3 to 7 ring atoms containing 1 or 2 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon; 1-4 Alkyl group; C 4-6 Cycloalkyl group; C 1-4 a monovalent saturated monocyclic ring of 3 to 7 ring atoms, optionally substituted with alkyl, containing 1 or 2 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon; or a monovalent heteroaromatic monocyclic ring system of 5 to 6 ring atoms, containing 1 or 2 heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon; Concerning compounds of formula (I):

[0117] In one embodiment, the present invention provides a compound comprising R 1 But, C 1-2 Alkyl group, C 1-2 Alkoxy group, or halo-C 1-2 The compound of formula (I) is

[0118] In one embodiment, R 2 But hydrogen; -S(O)2-C 1-2 Alkyl, C 4-6 cycloalkyl, or a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one ring heteroatom selected from O and S, the remaining ring atoms being carbon, optionally substituted C 1-4 Alkyl group; C 4-6 Cycloalkyl group; C 1-4 a monovalent saturated monocyclic ring of 3 to 7 ring atoms, optionally substituted with alkyl, containing one ring heteroatom selected from O and S, the remaining ring atoms being carbon; or a monovalent heteroaromatic monocyclic ring system of 6 ring atoms, containing 1 or 2 heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon.

[0119] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: R 1 But, C 1-2 Alkyl group, C 1-2 Alkoxy group, or halo-C 1-2 is an alkyl group; R 2 But hydrogen; -S(O)2-C 1-2 Alkyl, C 4-6 cycloalkyl, or a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one ring heteroatom selected from O and S, the remaining ring atoms being carbon, optionally substituted C 1-4 Alkyl group; C 4-6 Cycloalkyl group; C 1-4 a monovalent saturated monocyclic ring of 3 to 7 ring atoms, optionally substituted with alkyl, containing one ring heteroatom selected from O and S, the remaining ring atoms being carbon; or a monovalent heteroaromatic monocyclic ring system of 6 ring atoms, containing one or two heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon. It relates to compounds of formula (I).

[0120] In one embodiment, the present invention is directed to compounds of formula (I) wherein X is CH.

[0121] In one embodiment, the present invention is directed to compounds of formula (I) wherein X is N.

[0122] In one embodiment, the present invention provides a compound comprising R 2 is hydrogen.

[0123] In one embodiment, the present invention provides a compound comprising R 1 is an alkyl group, an alkoxy group, or a haloalkyl group; R 2 is hydrogen; and X is CH or N.

[0124] In one embodiment, the present invention provides a compound comprising R 1 But, C 1-4 Alkyl group, C 1-4 Alkoxy group, or halo-C 1-4 R is an alkyl group; 2 is hydrogen; and X is CH or N.

[0125] In one embodiment, the present invention provides a compound comprising R 1 But, C 1-2 Alkyl group, or halo-C 1-2 R is an alkyl group; 2 is hydrogen; and X is CH or N.

[0126] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-methyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-cyclobutyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-(cyclobutylmethyl)-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-cyclopentyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxetan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-(1-methanesulfonylpropan-2-yl)-6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridin-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine, 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine, 2-methyl-5-{5-methyl-4-[({7-methyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-1,2-oxazol-3-yl}pyridine, 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine, 5-[5-methyl-4-({[7-(oxolan-3-yl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine, 3-{[3-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl]methyl}-1 lambda 6-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-naphthyridine, 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-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxetan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 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-naphthyridin-2-yl]methyl}-1 lambda 6-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-naphthyridine, 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-naphthyridine, 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-naphthyridine, 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3-(propan-2-yl)oxetan-3-yl]-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-(3-ethyloxetan-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-naphthyridine, 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine, 5-[5-({[7-(cyclobutylmethyl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-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]pyridazin-3-yl}oxy)methyl]-4-methyl-1H-1,2,3-triazol-1-yl}-2-methylpyridine Compounds of formula (I) as defined above selected from the group consisting of 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.

[0127] In describing the general synthesis, biological assays, intermediates and examples of compounds of formula (I), the following abbreviations have been used: TIFF2024536039000010.tif68170

[0128] Process for the preparation of compounds of formula (I) The compounds of formula (I) of the present invention can be synthesized according to the reaction schemes depicted in Schemes 1, 2, 3, 4 and 5.

[0129] X=CH and R 1 and R 2 Compounds of formula (Ia), wherein is as defined in any of the embodiments described above, can be prepared according to Schemes 1 and 2. [ka]

[0130] According to Scheme 1, a compound of formula (II) is reacted with a chlorinating agent, such as POCl3, to obtain an intermediate of formula (III). The hydroxy derivatives of formula (II) are known in the art (WO2018 / 104419A1) or can be synthesized by conventional methods. [ka]

[0131] According to Scheme 2, esterification between an alcohol of formula (IV) and an intermediate of formula (III) can be accomplished in a suitable solvent, such as acetonitrile, in the presence of a suitable base, such as K2CO3, to form a compound of formula (V). 2 Compounds of general formula (Ia) where R =H are obtained after removal of the protecting group of formula (V) using an acid, for example ethyl acetate saturated with hydrogen chloride or TFA in dichloromethane. 2 Compounds of general formula (Ia) where R =-S(O)2-alkyl, alkyl optionally substituted with cycloalkyl or heterocycle; cycloalkyl; heterocycle can be obtained by alkylation to give R 2 It was obtained from a compound of general formula (Ia) in which R 2 Compounds of general formula (Ia) where R = heteroaryl can be obtained by arylation to give 2 It was obtained from a compound of general formula (Ia) in which R 2Compounds of general formula (Ia), where R = alkyl optionally substituted heterocycle, can be obtained by condensation with benzotriazole and a carbonyl compound followed by a nucleophilic reaction using a Grignard reagent to give 2 The alcohols of formula (IV) can be obtained from compounds of general formula (Ia) where = H. The alcohols of formula (IV) can be purchased or prepared by conventional methods.

[0132] X=N and R 1 and R 2 Compounds of formula (Ia), wherein is as defined in any of the embodiments described above, can be prepared according to Scheme 3. [ka]

[0133] According to Scheme 3, esterification between chloro derivatives of formula (VI) and hydroxy derivatives of formula (II) can be carried out by a palladium-mediated process in the presence of a suitable base, for example, Cs2CO3, to give compounds of formula (VII). 2 Compounds of general formula (Ia) where R =H are obtained after removal of the protecting group of formula (VII) using an acid, for example ethyl acetate saturated with hydrogen chloride or TFA in dichloromethane. 2 Compounds of general formula (Ia) where R =-S(O)2-alkyl, alkyl optionally substituted with cycloalkyl or heterocycle; cycloalkyl; heterocycle can be obtained by alkylation to give R 2 It was obtained from a compound of general formula (Ia) in which R 2 Compounds of general formula (Ia) where R = heteroaryl can be obtained by arylation to give 2 It was obtained from a compound of general formula (Ia) in which R 2 Compounds of general formula (Ia), where R = alkyl optionally substituted heterocycle, can be obtained by condensation with benzotriazole and a carbonyl compound followed by a nucleophilic reaction using a Grignard reagent to give 2It is obtained from a compound of general formula (Ia) where = H. The chloro derivative of formula (VI) can be purchased or prepared by conventional methods.

[0134] X, R 1 and R 2 Compounds of formula (Ib), wherein is as defined in any of the embodiments described above, can be prepared according to Schemes 4 and 5. [ka]

[0135] In the first step, the compound of formula (1) is reacted with ethyl acetoacetate in a suitable solvent, such as DMSO, to obtain a compound of formula (2), which is coupled with N-tosylhydrazine in the presence of KI and TBHP to obtain a compound of formula (3) (Huang et al. Adv. Synth. Catal. 2018, 360: 3117-3123). Treatment of the compound of formula (3) with a reducing agent, such as DIBAL-H, in a suitable solvent, such as toluene, gives a compound of formula (VIII). Alternatively, the compound of formula (1) is converted to a diazonium salt, which is further reacted with trimethylsilyl azide to give a compound of formula (4). The compound of formula (4) is reacted with 2-butyn-1-ol to give a compound of formula (VIII). [ka]

[0136] According to Scheme 5, esterification between chloro derivatives of formula (VI) and hydroxy derivatives of formula (VIII) can be carried out by a palladium-mediated process in the presence of a suitable base, for example, Cs2CO3, to give compounds of formula (IX). 2 Compounds of general formula (Ib) where R =H are obtained after removal of the protecting group of formula (IX) using an acid, for example ethyl acetate saturated with hydrogen chloride or TFA in dichloromethane. 2Compounds of general formula (Ib) where R =-S(O)2-alkyl, alkyl optionally substituted with cycloalkyl or heterocycle; cycloalkyl; heterocycle can be obtained by alkylation to give R 2 It was obtained from a compound of general formula (Ib) in which R 2 Compounds of general formula (Ib) where R = heteroaryl can be obtained by arylation to give 2 It was obtained from a compound of general formula (Ib) in which R 2 Compounds of general formula (Ib), where R = alkyl optionally substituted heterocycle, can be obtained by condensation with benzotriazole and a carbonyl compound followed by a nucleophilic reaction using a Grignard reagent to give 2 The chloro derivatives of formula (VI) can be obtained from compounds of general formula (Ib) where = H. The chloro derivatives of formula (VI) can be purchased or prepared by conventional methods.

[0137] The reagents required for the above reactions and detailed process steps are provided in the intermediates and examples.

[0138] Therefore, the present invention provides Step (i) a coupling reaction selected from the group consisting of: (a-1) Reacting a compound of formula (IV) with a compound of formula (III) to obtain a compound of formula (V) (wherein X=CH and R 1 and R 2 is 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 is 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, R 1 and R 2 is 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 R1 is as defined above, and R 2 is hydrogen), and Step (iii) Optionally, reacting a compound of formula (I), 2 is hydrogen) to a compound of formula (I) 1 is as defined above, and R 2 is converted to -S(O)2-alkyl, cycloalkyl or heterocyclic optionally substituted alkyl group; cycloalkyl group; heterocyclic optionally substituted alkyl group; or heteroaryl group. The present invention relates to a process for the preparation of a compound of formula (I) as defined above, comprising:

[0139] In one embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 is as defined above, and R 2 is an amino protecting group (Peter GMWuts: Greene's Protective Groups in Organic Synthesis: 5th Edition, Chapter 7. Protection for the Amino Group, pages 895-1193), such as carbamate (methyl, 9-fluorenylmethyl, 2,2,2-trichloroethyl, tert-butyl, 2-(trimethylsilyl)ethyl, allyl, benzyl), trifluoroacetamide, benzylamine, allylamine, or tritylamine, preferably carbamate, most preferably tert-butyloxycarbonyl protecting group. [ka]

[0140] In a further embodiment, the present invention relates to a compound comprising: 1 and R 2is as defined above, with the proviso that the compound is not tert-butyl 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate or tert-butyl 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-5 3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate.

[0141] In another further embodiment, the present invention relates to a method for the preparation of a medicament ... 1 and R 2 The present invention provides a novel intermediate of formula (VII) synthesized in the process for preparing the compound of general formula (I), wherein

[0142] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: tert-Butyl 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine-2-carboxylate, and tert-Butyl 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine-2-carboxylate The present invention relates to an intermediate of formula (VII) selected from the group consisting of:

[0143] In yet another embodiment, the present invention provides a method for the preparation of a compound comprising the steps of: 1 and R 2 The present invention provides a novel intermediate of formula (IX) which is synthesized in the process for preparing a compound of general formula (I),

[0144] In one embodiment, the present invention provides a method for producing a pharmaceutical composition comprising: tert-butyl 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, tert-butyl 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, tert-butyl 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, tert-Butyl 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, and tert-Butyl 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine-2-carboxylate The present invention relates to an intermediate of formula (IX) selected from the group consisting of: EXAMPLES

[0145] The activity data for each of the compounds of formula (I) according to the invention are determined in vitro by the methods described below.

[0146] Biological Example 1: Binding Assays GABA used for receptor binding assays A The α5β3γ2 protein is human recombinant GABA AThe membranes were derived from HEK cells (Millipore CYL3073) expressing α5β3γ2 receptors. The cells were stored and cultured in-house according to the instructions provided by the supplier (Millipor). The cell pellet was homogenized at maximum speed for 15 seconds using an Ultra Turrax (Janke&Kunkel) in 10x modified Krebs-Henseleit buffer (membrane preparation buffer): 20 mM Tris, 120 mM NaCl, 100 mM KCl, 25 mM CaCl2 and 25 mM MgCl2 pH=7.4 at 4°C. The homogenate was centrifuged at 40,000g for 30 minutes at 4°C. The supernatant was discarded and the resulting pellet was washed in membrane preparation buffer. The pellet was resuspended in membrane preparation buffer and aliquots of 1.4 mL ampoules were stored at -70°C until use.

[0147] Receptor binding assays were performed in 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. Radioligand [ 3 H]Ro151788 (Perkin Elmer: NET757250UC) was prepared in binding buffer and added to each well in a volume of 50 μL to give a final concentration of 0.5 nM. Appropriate concentrations of test compounds were added in an additional 50 μL. The final assay volume was 300 μL. Incubation was performed for 60 min at 4° C. For non-specific binding, 10 μM unlabeled diazepam was used. After incubation, samples were filtered onto UniFilter® GF / B™ using a Filtermate Harvester (Perkin Elmer) and washed with 5×1 mL of binding buffer. Plates were dried for 1 h at 40° C. and 40 μL of Microscint (Perkin Elmer) scintillation cocktail was added to each well. Plates were read in a Microbeta (Perkin Elmer).

[0148] Specific radioligand binding (SB) was defined as the difference between total binding (Tot) and nonspecific binding (NSB). Results are expressed as the percentage inhibition of specific binding obtained in the presence of the compound of interest.

[0149] I C 50 and K. i A minimum of six drug concentrations were used in triplicate for determination of IC 50 The K values ​​(i.e., the concentration of compound that inhibits specific binding by 50%) were calculated from the concentration-displacement curves by sigmoidal fitting using Origin 7.5 software. i The value (i.e., the inhibition constant) is calculated using the Cheng-Prusoff equation, K i =IC 50 / [1+(L / K D )] (where [L] is the concentration of radioactive ligand and K D is the affinity of the labeled ligand for the receptor). D was determined from saturation analysis.

[0150] The compounds of the present invention were tested in the assays described above and all showed GABA A It was found to have high affinity for the α5 receptor (K i <150nM).

[0151] [Table 1]

[0152] Biological Example 2: Functional Assays GABA A A human HEK293 cell line expressing the α5β3γ2 receptor was used in functional assays using the QPatch automated patch clamp system.

[0153] Human Recombinant GABA AA HEK293 cell line stably expressing the α5β3γ2 receptor subunit (Millipore, CYL3053) was cultured in DMEM supplemented with 10% FBS (Gibco), passaged twice weekly, and plated onto Petri dishes precoated with poly- d -lysine.

[0154] Automated whole-cell patch clamp recordings were performed from cells 2-4 days after plating. Cells were detached using trypsin / EDTA (Sigma) treatment (2 min in 0.25% trypsin at 37°C) and then resuspended after centrifugation (125g, 3 min, twice) in serum-free based medium (Gibco, CHO-S-SFM-II) containing 12.5 mM HEPES, 1x penicillin-streptomycin-amphotericin (SigmaMix) and soybean trypsin inhibitor (Sigma, 0.04 mg / ml).

[0155] The cell suspension, as well as the extracellular solution (130 mM NaCl, 5 mM KCl, 5.1 mM HEPES, 4.9 mM HEPES-Na, 10 mM CaCl2, 2 mM MgCl2, 10 mM glucose and 0.1% DMSO, pH = 7.35-7.4) and the intracellular solution (80 mM KCl, 50 mM KF, 36 mM KOH, 10 mM EGTA, 10 mM HEPES, 1.75 mM MgCl2, 0.5 mM CaCl2, 4 mM Na2ATP, 14 mM creatine phosphate, 50 U / ml creatine-phosphokinase, 0.3 mM GTP, pH = 7.25-7.3) were added to a QPatch-HTX automated patch clamp system (Sophion) at room temperature in single-cell mode. Inward currents were elicited at a holding potential of -80 mV, first five times in concentration-matched DMSO (0.1 or 0.3%) control solution, followed by 3 s long applications of the control agonist GABA at 1 μM with 2-4 min intervals, then four times in the presence of test compound, and finally three times again in control solution (washout). At the end of the experiment, 100 μM GABA was applied to saturate the GABA response and to assess the effectiveness of the control GABA application. Current signals were low-pass filtered at 100 Hz and recorded at a sampling rate of 1 kHz.

[0156] The percentage of modulation was calculated from a comparison of the amplitude of the GABA-evoked peak current in the presence and absence of test compound.

[0157] The compounds of the invention were tested at 1 μM in the assay described above and all exhibited GABA A It was found to have positive allosteric modulator activity of α5.

[0158] [Table 2]

[0159] The present invention is further illustrated by the following intermediates and examples, without limiting the scope of the present invention to the following intermediates and examples. From the above description and the intermediates and examples, a person skilled in the art may ascertain the essential features of the present invention, and may make certain changes and modifications to adapt the present invention to various applications and conditions without departing from its essence and scope. As a result, the present invention is not limited to the following examples, but is limited in scope by the appended claims.

[0160] In general, the compounds of formula (I) can be prepared according to the ordinary general knowledge of those skilled in the art and / or the methods described in the working examples and / or intermediates. Solvents, temperatures, pressures and other reaction conditions can be easily selected by those skilled in the art. Starting materials are commercially available and / or can be easily prepared by those skilled in the art according to literature procedures. During the preparation of the compounds, combinatorial techniques can be used, for example, when intermediates are suitable for use in these methods.

[0161] Intermediate 1 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine [ka] 1.00 g (4.89 mmol) of [5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methanol (WO2018 / 104419A1, Hoffmann-La Roche) was dissolved in 30 mL of phosphorus oxychloride. The reaction mixture was stirred at 115° C. for 2 h and then evaporated to dryness. Ethyl acetate was added, washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate and evaporated to give 0.95 g (87%) of the title compound. MS (ESI) m / z: 223.1 [M+H] + .

[0162] Intermediate 2 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine [ka] Analogously to intermediate 1, {5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methanol (WO2018 / 104419A1, Hoffmann-La Roche) was converted to the title compound. MS (ESI) m / z: 277.1 [M+H] + .

[0163] Intermediate 3 [4-Methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol [ka] Method A a: Methyl (2E)-3-[(6-methylpyridin-3-yl)amino]but-2-enoate 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 were added. The reaction mixture was refluxed for 10 h. After cooling, filtration of the inorganics and concentration of the filtrate under reduced pressure gave a residue which was used in the next step without further purification. MS (ESI) m / z: 207.1 [M+H] + .

[0164] b: Ethyl 4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazole-5-carboxylate To a mixture of 8.31 g (37.7 mmol) of methyl (2E)-3-[(6-methylpyridin-3-yl)amino]but-2-enoate, 8.43 g (45.3 mmol) of methylbenzenesulfonhydrazide, 6.26 g (37.7 mmol) of potassium iodide in 70 mL of DMSO, 7.31 mL (75.5 mmol) of TBHP (70% solution in water) was slowly added. The mixture was then stirred at 70 °C for 24 h. After the reaction was complete (monitored by TLC), 140 g of sodium dithionite dissolved in 300 mL of water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The combined organic layers were then dried over MgSO4, filtered, and then concentrated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH, 0-10% gradient) afforded the desired product. Yield: 6.35g (68%), MS(ESI) m / z: 247.1[M+H] + .

[0165] c: [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol 6.35 g (25.8 mmol) of ethyl 4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazole-5-carboxylate was dissolved in 80 mL of anhydrous THF and cooled 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 h. After cooling, it was quenched with 71 mL of water and acidified with 135 mL of 1 M HCl. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated in vacuum. The crude product was crystallized from isopropanol to give the title compound as a white solid. Yield: 3.42 g, (65%), MS (ESI) m / z: 205.1 [M+H]+.

[0166] Method B a: 5-azido-2-methylpyridine 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 NaNO2 dissolved in 12 mL of water was added dropwise. The reaction mixture was stirred at 0° C. for 20 minutes, then 10.6 mL (80 mmol) of trimethylsylil azide was slowly added dropwise and the reaction mixture was stirred at room temperature for 1.5 hours. After completion, 70 mL of ethyl acetate was added, washed with 30 mL of saturated sodium carbonate solution and water three times, dried over anhydrous sodium sulfate and evaporated. The crude product was used in the next step without further purification.

[0167] b: [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol 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 gel, eluent: cyclohexane:EtOAc 40-80% gradient). Yield: 2.30 g (26%), white solid. MS (ESI) m / z: 205.1 [M+H]+.

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

[0169] Intermediate 5 {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol [ka] The compound was synthesized according to the procedure described for intermediate 3, using commercially available 6-(difluoromethyl)pyridin-3-amine in step a. MS (ESI) m / z: 241.1 [M+H]+.

[0170] Intermediate 6 [1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methanol [ka] The compound was synthesized according to the procedure described for intermediate 3, using commercially available 6-methoxypyridin-3-amine in step a. MS (ESI) m / z: 221.1 [M+H]+.

[0171] Example 1 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetate [ka] A: tert-butyl 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate 1.96 g (8.80 mmol) of 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (intermediate 1) and 2.20 mg (8.80 mmol) of commercially available tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate were dissolved in 120 mL of anhydrous acetonitrile. Then 3.65 mg (26.40 mmol) of anhydrous potassium carbonate were added to the solution and the suspension was stirred under reflux for 12 h. The conversion was followed by TLC (1:1 EtOAc:cyclohexane as eluent, silica plate). After the reaction was complete, the mixture was filtered and evaporated to give the oily crude product, which was purified by flash column chromatography (silica gel, eluent: 1:1 EtOAc:cyclohexane). Yield: 640 mg (16.6%) white solid. MS(ESI)m / z:437.3[M+H] + .

[0172] B: 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetate 97.97 mg (0.22 mmol) of tert-butyl 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved in 10 mL of DCM. Then, 1489 mg (13.06 mmol) of trifluoroacetic acid was added to the solution and the suspension was stirred at room temperature for 6 hours. After the reaction was completed, the mixture was evaporated to give the title compound. Yield: 90 mg (91%) yellow solid. MS (ESI) m / z: 337.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz) δ(ppm):8.96-9.07(br m, 2H), 8.81(br d, J=2.0Hz, 1H), 8.12(dd, J=8.1, 2.3Hz, 1H), 8.06(s, 1H), 7.49(d, J=8.1Hz, 1H), 6.73(s, 1H), 5.27(s, 2H), 4.25(br t, J=4.5Hz, 2H), 3.31-3.39(m, 2H), 2.95(t, J=6.3Hz, 2H), 2.57(s, 3H), 2.56(s, 3H).

[0173] Example 2 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetate [ka] The title compound was prepared according to the procedure described for Example 1, using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Intermediate 2) in step a. MS (ESI) m / z: 391.2 [M+H] + . 1 H NMR (DMSO-d6, 400MHz) δ(ppm):9.11(d, J=1.9Hz, 1H), 8.82-9.03(br m, 2H), 8.48(dd, J=8.1, 1.7Hz, 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=6.3Hz, 2H), 2.61(s, 3H).

[0174] Example 3 2-Methyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] 450 mg (1.0 mmol) of 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetate (Example 1) was added to a solution of saturated NaHCO3 and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuum. The obtained base was dissolved in 2 mL of water and 240 mg (4.0 mmol) of acetic acid, and 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 obtained mixture was extracted with DCM. The combined organic layers were then dried over MgSO4, filtered, and then concentrated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) afforded the desired product. Yield: 59.3 mg (16.9%), MS(ESI) m / z: 351.2 [M+H] + .

[0175] Example 4 2-Cyclobutyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] To a solution of 200 mg (0.44 mmol) of 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetate (Example 1) in 4 mL of 2,2,2-trifluoroethanol, 112 mg (1.33 mmol) of NaHCO3 was added and stirred for 30 minutes, then 32 mg (0.44 mmol) of cyclobutanone was added in one portion and the reaction mixture was warmed to 45° C. The solution so obtained was stirred for 5 minutes, then 16.8 mg (0.44 mmol) of sodium borohydride was added. The reaction mixture was stirred at 45° C. for 3 hours. After completion, the solvent was evaporated and the residue was dissolved in DCM and washed with brine. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: EtOAc:MeOH=10:1) afforded the desired product. Yield: 28.1 mg (16.1%), MS(ESI) m / z: 393.2 [M+H] + .

[0176] Example 5 2-(Cyclobutylmethyl)-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 4 using commercially available cyclobutanecarbaldehyde. MS (ESI) m / z: 405.2 [M+H] + .

[0177] Example 6 2-Cyclopentyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] 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] + .

[0178] Example 7 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 4 using 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetate (Example 2) and commercially available tetrahydropyran-4-one. MS (ESI) m / z: 475.2 [M+H] + .

[0179] Example 8 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 4 using 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetate (Example 2) and commercially available 3-oxotetrahydrofuran. MS (ESI) m / z: 461.2 [M+H] + .

[0180] Example 9 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 4 using commercially available 3-oxotetrahydrofuran. MS (ESI) m / z: 407.2 [M+H] + .

[0181] Example 10 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxetan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 4 using commercially available 3-oxetanone. MS (ESI) m / z: 393.2 [M+H] + .

[0182] Example 11 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 4 using commercially available 4-oxotetrahydropyran. MS (ESI) m / z: 421.2 [M+H] + .

[0183] Example 12 2-(1-Methanesulfonylpropan-2-yl)-6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] 183.6 mg (0.36 mmol) of 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetate (Example 2) was added to a solution of saturated Na2CO3 and extracted with DCM. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. The resulting base was added to a stirred solution of 49 mg (0.36 mmol) of methanesulfonylacetone in 1 mL of methanol and 1 mL of 2,2,2-triluoroethanol at room temperature. The mixture was stirred for 1 h. 84 mg (0.72 mmol) of triethylsilicon 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. Upon completion of the reaction, the mixture was quenched with 1 mL of saturated K2CO3 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] + .

[0184] Example 13 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridin-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] 283 mg (0.63 mmol) of 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine 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]+ .

[0185] Example 14 2-Methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine [ka] A: tert-butyl 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine-2-carboxylate Under an argon atmosphere, a flask was charged with 660 mg (2.45 mmol) of commercially available tert-butyl 3-chloro-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxylate, 500 mg (2.45 mmol) of {5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methanol (WO2018 / 104419A1, Hoffmann-La Roche), 1595 mg (4.89 mmol) of Cs2CO3, 98 mg (0.25 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 55 mg (0.24 mmol) of Pd(OAc)2, and 20 mL of anhydrous toluene. The mixture was stirred at 100 °C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:1 as eluent, silica plate). The reaction mixture was filtered through a celite pad, 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] + .

[0186] B: 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine 342 mg (0.78 mmol) of tert-butyl 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine-2-carboxylate was dissolved in 50 mL of DCM. Then, 1782 mg (15.63 mmol) of trifluoroacetic acid was added to the solution and the suspension was stirred at room temperature for 24 hours. After completion, the mixture was evaporated and the residue was dissolved in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: EtOAc:MeOH=10:1) gave the desired product. Yield: 132 mg (50%), MS (ESI) m / z: 338.2 [M+H] + .

[0187] Example 15 5-[5-Methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine [ka] A: tert-butyl 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine-2-carboxylate Under an argon atmosphere, a flask was charged with 668 mg (2.48 mmol) of commercially available tert-butyl 3-chloro-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxylate, 639 mg (2.48 mmol) of 5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methanol (WO2018 / 104419A1, Hoffmann-La Roche), 1614 mg (4.95 mmol) of Cs2CO3, 99 mg (0.25 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 56 mg (0.25 mmol) of Pd(OAc)2, and 20 mL of anhydrous toluene. The mixture was stirred at 100 °C for 12 h. The conversion was checked by TLC (cyclohexane: EtOAc = 1:1 as eluent, silica plate). The reaction mixture was filtered through a celite pad, 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] + .

[0188] B: 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine 395 mg (0.80 mmol) of tert-butyl 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine-2-carboxylate was dissolved in 20 mL of DCM. Then, 916 mg (8.03 mmol) of trifluoroacetic acid was added to the solution and the suspension was stirred at room temperature for 24 h. After completion, the mixture was evaporated and the residue was dissolved in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: EtOAc:MeOH=10:1) gave the desired product. Yield: 175 mg (56%), MS (ESI) m / z: 392.1 [M+H]+.

[0189] Example 16 2-Methyl-5-{5-methyl-4-[({7-methyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-1,2-oxazol-3-yl}pyridine [ka] To a solution of 74 mg (0.22 mmol) of 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine (Example 14) in 5 mL of methanol, 27 mg (0.33 mmol) of formaldehyde solution (37% in water) was added, the reaction mixture was warmed to 50° C., and then 93 mg (0.44 mmol) of sodium triacetoxyborohydride was added in one portion. The reaction mixture was stirred at 50° C. for 5 hours. After completion, the solvent was evaporated and the residue was dissolved in EtOAc and washed with saturated NaHCO3 solution. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: EtOAc:MeOH=10:1) afforded the desired product. Yield: 40 mg (52%), MS (ESI) m / z: 352.2 [M+H] + .

[0190] Example 17 5-[5-Methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine [ka] The title compound was prepared according to the procedure described for Example 16 using 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Example 15). MS (ESI) m / z: 406.1 [M+H] + .

[0191] Example 18 5-[5-Methyl-4-({[7-(oxolan-3-yl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine heminapadisylate [ka] A: Synthesis of the free base To a solution of 130 mg (0.33 mmol) of 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Example 15) in 5 mL of 2,2,2-trifluoroethanol, 29 mg (0.34 mmol) of 3-oxotetrahydrofuran and 13 mg (0.34 mmol) of sodium borohydride were added. The reaction mixture was stirred at 45° C. for 12 hours. After completion, the solvent was evaporated and the residue was dissolved in DCM and washed with water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) gave the free base as an oil. Yield: 23 mg (15%), MS (ESI) m / z: 462.2 [M+H] +

[0192] B: Synthesis of Hemina Padisylate 23 mg (0.05 mmol) of 5-[5-methyl-4-({[7-(oxolan-3-yl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine was dissolved in 2 mL of ethanol, 18 mg (0.05 mmol) of 1,5-naphthalenedisulfonic acid tetrahydrate was added, stirred at 60° C. for 10 min, and then cooled to room temperature. The precipitated product was collected by filtration, washed with cold ethanol, and dried in vacuum to give the title compound as a white solid. Yield: 17 mg (56%), MS (ESI) m / z: 462.2 [M+H] + . 1H NMR (DMSO-d6, 400MHz) δ(ppm):10.05-10.50(br m, 1H), 9.12(d, J=1.7Hz, 1H), 8.49(dd, J=8.1, 1.7Hz, 1H), 8.10(br d, J=8.2Hz, 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); napadisylate (acid / base molar ratio 1:2) signals: 8.85 (dd, J = 8.5, ca. 1 Hz, 2H), 7.91 (dd, J = 7.0 Hz, 1.1 Hz, 2H), 7.38 (dd, J = 8.5, 7.1 Hz, 2H).

[0193] Example 19 3-{[3-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl]methyl}-1 lambda 6-thiolane-1,1-dione tartrate [ka] A: Synthesis of the free base In a microwave tube, 100 mg (0.256 mmol) of 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Example 15) was dissolved in 3 mL of acetonitrile, and then 66 mg (0.51 mmol) of N,N-diisopropylethylamine and 54.6 mg (0.256 mmol) of 3-bromomethyltetrahydrothiophene 1,1-dioxide were added. The tube was placed in a microwave reactor and heated to 100° C. for 3 hours with stirring. After the reaction was complete, the mixture was evaporated and purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to give 34 mg of the product as an oil. Yield: 38 mg (28.4%), MS (ESI) m / z: 524.1 [M+H] + .

[0194] B: Synthesis of tartrate salts 11.2 mg (0.021 mmol) of 3-{[3-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl]methyl}-1 lambda 6-thiolane-1,1-dione was dissolved in 1 mL of ethanol, 3.2 mg (0.021 mmol) of L-(+)-tartaric acid was added, stirred at 60° C. for 10 min, and then cooled to room temperature. The precipitated product was collected by filtration, washed with cold ethanol, and dried in vacuum to give the title compound as a white solid. Yield: 12.5 mg (86.7%), MS (ESI) m / z: 524.1 [M+H] + . 1 H NMR (DMSO-d6, 400MHz) δ(ppm):11.40-13.60(br m, 1H), 9.12(d, J=1.7Hz, 1H), 8.46(dd, J=8.0Hz, 1.8Hz, 1H), 8.09(d, J=8.0H z, 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=5.4Hz, 2H), 2.74-2.81(m, 2H), 2.54-2.73(m, 4H), 2.63(s, 3 H), 2.20-2.29(m, 1H), 1.73-1.83(m, 1H); tartrate (acid / base ratio 1:1) signal: 4.28(s, 2H).

[0195] Example 20 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] A: tert-butyl 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate Under argon atmosphere, a flask was charged with 504 mg (1.88 mmol) of commercially available tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate, 383 mg (1.88 mmol) of [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (intermediate 3), 1220 mg (3.75 mmol) of Cs2CO3, 74.7 mg (0.18 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 42 mg (0.18 mmol) of Pd(OAc)2 and 20 mL of anhydrous toluene. The mixture was stirred at 100° C. for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:1 as eluent, silica plate). 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 30-70% gradient). Yield: 287 mg (35%). MS(ESI) m / z: 437.2 [M+H] + .

[0196] B: 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine 287 mg (0.65 mmol) of tert-butyl 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved 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 min. The white precipitate formed was filtered off and washed with a small amount of ethyl acetate. The hydrochloride salt was added to a solution of saturated NaHCO3 and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) gave the desired product. Yield: 78 mg (35%), MS (ESI) m / z: 337.2 [M+H]+.

[0197] Example 21 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-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 16 using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20). MS (ESI) m / z: 351.1 [M+H] + .

[0198] Example 22 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 18, Step A, using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available acetone. MS (ESI) m / z: 379.2 [M+H] + .

[0199] Example 23 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] A: tert-butyl 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate Under an argon atmosphere, a flask was charged with 91.3 mg (0.34 mmol) of commercially available tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-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 Cs2CO3, 13.8 mg (0.034 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 7.8 mg (0.034 mmol) of Pd(OAc)2, and 10 mL of anhydrous toluene. The mixture was stirred at 100° C. for 12 hours. The conversion was checked by TLC (cyclohexane:EtOAc=1:2 as eluent, silica plate). The reaction mixture was filtered through a celite pad, washed with acetone, dried over anhydrous sodium sulfate and evaporated. The residue was purified by flash column chromatography (silica gel, eluent: cyclohexane:EtAOc=1:2). Yield: 90 mg (56%). MS (ESI) m / z: 473.2 [M+H] + .

[0200] 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-naphthyridine 90 mg (0.19 mmol) of tert-butyl 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved in 10 mL of DCM. Then, 652 mg (5.71 mmol) of trifluoroacetic acid was added to the solution and the suspension was stirred at room temperature for 3 hours. After completion, the mixture was evaporated and the residue was dissolved in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) gave the desired product. Yield: 28.4 mg (40%), MS (ESI) m / z: 373.2 [M+H]+.

[0201] Example 24 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-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 16 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-naphthyridine (Example 23). MS (ESI) m / z: 387.2 [M+H] + .

[0202] Example 25 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] A: tert-butyl 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate Under an argon atmosphere, a flask was charged with 521 mg (1.94 mmol) of commercially available tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-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 Cs2CO3, 77.2 mg (0.194 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 43.5 mg (0.194 mmol) of Pd(OAc)2, and 30 mL of anhydrous toluene. The mixture was stirred at 100° C. for 12 hours. The conversion was checked by TLC (DCM:MeOH=9:1 as eluent, silica plate). The reaction mixture was filtered through a celite pad, 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] +.

[0203] 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-naphthyridine 710 mg (1.45 mmol) of tert-butyl 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved in 15 mL of DCM. Then, 3300 mg (29 mmol) of trifluoroacetic acid was added to the solution and the suspension was stirred at room temperature for 24 hours. After completion, the mixture was evaporated and the residue was dissolved in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH=9:1) gave the desired product. Yield: 320 mg (56.6%), MS (ESI) m / z: 391.2 [M+H] + .

[0204] Example 26 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] To a solution of 160 mg (0.41 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-naphthyridine (Example 25) in 5 mL of 2,2,2-trifluoroethanol, 23.8 mg (0.41 mmol) of acetone and 15.5 mg (0.41 mmol) of sodium borohydride were added. The reaction mixture was stirred at 45° C. for 12 hours. After completion, the solvent was evaporated and the residue was dissolved in DCM and washed with water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH=9:1) gave the title compound. Yield: 61 mg (34%), MS (ESI) m / z: 433.2 [M+H] + .

[0205] Example 27 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-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 16 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-naphthyridine (Example 25, Step B). MS (ESI) m / z: 405.1 [M+H] + .

[0206] Example 28 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 18, Step A, 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-naphthyridine (Example 23) and commercially available acetone. MS (ESI) m / z: 415.2 [M+H] + .

[0207] Example 29 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 18, Step A, using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available 3-oxotetrahydrofuran. MS (ESI) m / z: 407.2 [M+H] + .

[0208] Example 30 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-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 18, Step A, 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-naphthyridine (Example 23) and commercially available 3-oxotetrahydrofuran. MS (ESI) m / z: 443.2 [M+H] + .

[0209] Example 31 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxetan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 18, Step A, using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available 3-oxetanone. MS (ESI) m / z: 393.2 [M+H] + .

[0210] Example 32 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-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 26 using commercially available 3-oxotetrahydrofuran. MS (ESI) m / z: 461.2 [M+H] + .

[0211] Example 33 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 18, Step A, using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available 4-oxotetrahydropyran. MS (ESI) m / z: 421.2 [M+H] + .

[0212] Example 34 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] A: tert-butyl 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate Under argon atmosphere, a flask was charged with 300 mg (1.12 mmol) of commercially available tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate, 246 mg (1.12 mmol) of [1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methanol (intermediate 6), 727 mg (2.23 mmol) of Cs2CO3, 44.5 mg (0.11 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 25 mg (0.11 mmol) of Pd(OAc)2 and 20 mL of anhydrous toluene. The mixture was stirred at 100° C. for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:1 as eluent, silica plate). The reaction mixture was filtered through a celite pad, 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: 200 mg (39.5%). MS(ESI) m / z: 453.2 [M+H] + .

[0213] B: 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine 200 mg (0.44 mmol) of tert-butyl 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved 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 min. The white precipitate formed was filtered off and washed with a small amount of ethyl acetate. The hydrochloride salt was added to a solution of saturated NaHCO3 and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) gave the desired product. Yield: 115 mg (74%), MS (ESI) m / z: 353.2 [M+H]+.

[0214] Example 35 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-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 26 using commercially available 4-oxotetrahydropyran. MS (ESI) m / z: 475.3 [M+H] + .

[0215] Example 36 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-naphthyridin-2-yl]methyl}-1 lambda 6-thiolane-1,1-dione heminapadisylate [ka] The free base of the title compound was prepared according to the procedure described for Example 19, Step A, 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-naphthyridine (Example 25). The hemina padisylate salt was prepared according to the procedure described for Example 18, Step B. MS (ESI) m / z: 523.2 [M+H] + . 11H NMR (DMSO-d6, 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); Napadisylate (acid / base molar ratio 1:2) signals: 8.85 (dd, J = 8.5, about 1 Hz, 2H), 7.91 (dd, J = 7.0 Hz, 1.1 Hz, 2H), 7.39 (dd, J = 8.5, 7.1 Hz, 2H).

[0216] Example 37 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-naphthyridine napadysilate [Chemical formula] A: Synthesis of the free base In a microwave tube under argon atmosphere, 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-naphthyridine (Example 25), 117 mg (0.741 mmol) of 3-bromopyridine, 141 mg (1.26 mmol) of potassium tert-butoxide, 38 mg (0.061 mmol) of 2,2-bis(diphenylphosphino)-1,1'-binaphthalene, 13.7 mg (0.061 mmol) of Pd(OAc)2 and 5 mL of anhydrous toluene were added. The tube was placed in a microwave reactor and heated to 120° C. with stirring for 1 hour. After the reaction was completed, the mixture was evaporated and purified by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) to give 19 mg of the product as an oil. Yield: 19 mg (6.6%), MS(ESI) m / z: 468.2 [M+H] + .

[0217] B: Synthesis of napadisilate 19 mg (0.041 mmol) 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-naphthyridine was dissolved in 2 mL of methanol, 14.7 mg (0.041 mmol) of 1,5-naphthalenedisulfonic acid tetrahydrate was added, stirred at 60° C. for 10 minutes, and then cooled to room temperature. The precipitated product was collected by filtration, washed with cold methanol, and dried in vacuum to give the title compound as a yellow solid. Yield: 11 mg (36%), MS (ESI) m / z: 468.2 [M+H] + . 1H NMR (DMSO-d6, 400MHz) δ(ppm):9.09(d, J=2.4Hz, 1H), 8.46(dd, J=8.4Hz, 2.2Hz, 1H), 8.43(d, J=2.8Hz, 1H), 8.21(d, J=8.4Hz, 1H ), 8.17(d, J=5.3Hz, 1H), 8.06(dd, J=8.8Hz, 2.7Hz, 1H), 7.96(s, 1H), 7.85(dd, J=8.9Hz, 5.4Hz, 1H), 6.69( Napadisylate (acid / base Molar ratio 1:1) signal: 8.86 (dd, J=8.5Hz, approx. 1Hz, 2H), 7.92 (dd, J=7.0Hz, 1.1Hz, 2H), 7.40 (dd, J=8.5Hz, 7.1Hz, 2H).

[0218] Example 38 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-naphthyridine or enantiomer, tartrate [ka] Separation of the enantiomers of racemic 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 29) by chiral HPLC (column: Lux i-Amylose-1 5 μm 150×21.2 mm) gave the enantiopure title compound. MS (ESI) m / z: 407.2 [M+H] + The tartrate salt was prepared according to the procedure described for step B of Example 19. MS (ESI) m / z: 407.2 [M+H] + .

[0219] Example 39 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-naphthyridine or enantiomer, tartrate [ka] Separation of the enantiomers of racemic 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 29) by chiral HPLC (column: Lux i-Amylose-1 5 μm 150×21.2 mm) gave the enantiopure title compound. MS (ESI) m / z: 407.2 [M+H] + The tartrate salt was prepared according to the procedure described for step B of Example 19. MS (ESI) m / z: 407.2 [M+H] + .

[0220] Example 40 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine heminapadisylate [ka] The free base of the title compound was prepared according to the procedure described for Example 18, Step A, using 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 34) and commercially available 4-oxotetrahydropyran. MS (ESI) m / z: 437.2 [M+H] + Hemina padisylate was prepared according to the procedure described for step B of Example 18. MS (ESI) m / z: 437.2 [M+H] + . 1H NMR (DMSO-d6, 800MHz) δ(ppm):9.70-9.77(br m, 1H), 8.41(d, J=2.8Hz, 1H), 8.01(s, 1H), 7.97(dd, J=8.8, 2.7Hz, 1H), 7.06(d, J=8.8Hz, 1H), 6.74(s, 1H), 5.35-5.41(AB d, J=13.5Hz, 2H), 4.52(d, J=14.6, 1H), 4.31(dd, J=15.0, 8.3Hz, 1H), 3.98(br d. d, J=12.0Hz, 1H), 1.99(br d, J=12.2Hz, 1H), 1.63-1.73(m, 2H); Napadisylate (acid / base molar ratio 1:2) signal: 8.85 (dd, J=8.4, 1.0Hz, 2H), 7.91 (dd, J=7.0, 1.0Hz, 2H), 7.38 (dd, J=8.4, 7.0Hz, 2H).

[0221] Example 41 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-naphthyridine heminapadisylate [ka] The free base of the title compound was prepared according to the procedure described for Example 18, Step A, using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available isobutyraldehyde. MS (ESI) m / z: 393.3 [M+H] + Hemina padisylate was prepared according to the procedure described for step B of Example 18. MS (ESI) m / z: 393.3 [M+H] + . 1H NMR (DMSO-d6, 400MHz) δ(ppm):9.22-9.40(br m, 1H), 8.67(d, J=2.4Hz, 1H), 7.99(s, 1H), 7.98(dd, J=8.3, 2.6Hz, 1H), 7.52(d, J=8.3Hz, 1H), 6.72(s, 1H), 5.39(s, 2H), 4.56(br d, J=14.43Hz, 1H), 4.19(dd, J=15.1, 7.7Hz, 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=6.1Hz, 6H); Napadisylate (acid / base molar ratio 1:2) signal: 8.85 (dd, J=8.4, 1.2Hz, 2H), 7.91 (dd, J=7.0, 1.2Hz, 2H), 7.38 (dd, J=8.4, 7.0Hz, 2H).

[0222] Example 42 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3-(propan-2-yl)oxetan-3-yl]-1,2,3,4-tetrahydro-2,7-naphthyridine napadisilate [ka] 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-naphthyridine To a solution of 1030 mg (3.06 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-naphthyridine (Example 20) in 30 mL of DCM, 243 mg (3.37 mmol) of 3-oxetanone and 383 mg (3.21 mmol) of 1H-benzotriazole were added. The reaction mixture was stirred at room temperature for 12 hours. After completion, the solvent was evaporated to dryness to give the title compound as a white solid. Yield: 1540 mg (98.7%), MS (ESI) m / z: 510.2 [M+H] + .

[0223] B: 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3-(propan-2-yl)oxetan-3-yl]-1,2,3,4-tetrahydro-2,7-naphthyridine Under argon atmosphere, a solution 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-naphthyridine in 10 mL of THF was added in one portion to a solution of 593 mg (4.08 mmol) of isopropylmagnesium chloride lithium chloride complex. The reaction mixture was stirred at room temperature for 10 min. After the reaction was complete, the mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo. Purification of the residue by flash column chromatography (silica gel, eluent: hexane:EtOAc:2% Et3N, 30-60% gradient) afforded the title compound. Yield: 177 mg (40%), MS (ESI) m / z: 435.2 [M+H] + .

[0224] C: 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3-(propan-2-yl)oxetan-3-yl]-1,2,3,4-tetrahydro-2,7-naphthyridine napadisilate Hemina padisylate was prepared according to the procedure described for Example 36, Step B. MS (ESI) m / z: 435.2 [M+H] + . 1 H NMR (DMSO-d6, 500MHz) δ(ppm):9.60-10.50(br m, 1H), 8.71(d, J=2.4Hz, 1H), 8.04(dd, J=8.3Hz, 2.4Hz, 1H), 7.99(s, 1H), 7.57(d, J=8.3Hz, 1H), 6.75(s, 1H), 5.41(s, 2H), 4.69(AB d, J=8.8Hz, 2H), 4.66(AB d, J=8.8Hz, 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); napadisylate (acid / base molar ratio 1:1) signals: 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).

[0225] Example 43 2-(3-Ethyloxetan-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-naphthyridine napadisilate [ka] The title compound was prepared following the procedure described for Example 42 using ethylmagnesium bromide solution in step B. MS (ESI) m / z: 421.2 [M+H] + . 1 H NMR (DMSO-d6, 500MHz) δ(ppm):10.54-10.96(br m, 1H), 8.70(d, J=2.4Hz, 1H), 8.02(dd, J=8.3Hz, 2.6Hz, 1H), 7.95(s, 1H), 7.56(d, J=8.3Hz, 1H), 6.75(s, 1H), 5.41(s, 2H), 4.80(br d, 2H), 4.57(d, J=8.1Hz, 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=7.3Hz, 3H); Napadisylate (acid / base molar ratio 1:1) signal: 8.85(br d, J=8.5Hz, 2H), 7.91(dd, J=7.0Hz, 0.9Hz, 2H), 7.39(dd, J=8.5Hz, 7.1Hz, 2H).

[0226] Example 44 2-Methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine [ka] A: tert-butyl 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine-2-carboxylate In a microwave tube under argon atmosphere, 135 mg (0.50 mmol) of commercially available tert-butyl 3-chloro-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxylate, 102 mg (0.50 mmol) of [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3), 112 mg (1.00 mmol) of potassium tert-butoxide, 20 mg (0.05 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 11.2 mg (0.05 mmol) of Pd(OAc)2, and 10 mL of anhydrous toluene were added. The tube was placed in a microwave reactor and heated to 120° C. with stirring for 3 h. After the reaction was completed, the mixture was filtered through a celite pad, 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] + .

[0227] B: 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine 138 mg (0.31 mmol) of tert-butyl 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine-2-carboxylate was dissolved in 10 mL of DCM. Then, 360 mg (3.16 mmol) of trifluoroacetic acid was added to the solution and the suspension was stirred at room temperature for 48 hours. After completion, the mixture was evaporated and the residue was dissolved in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuum. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH=10:1) gave the desired product. Yield: 77 mg (72%), MS (ESI) m / z: 338.1 [M+H]+.

[0228] Example 45 5-[5-({[7-(cyclobutylmethyl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-4-methyl-1H-1,2,3-triazol-1-yl]-2-methylpyridine tartrate [ka] The free base of the title compound was prepared according to the procedure described for Example 18, Step A, using 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine (Example 44) and commercially available cyclobutanecarboxaldehyde. MS (ESI) m / z: 406.3 [M+H] + The tartrate salt was prepared according to the procedure described for step B of Example 19. MS (ESI) m / z: 406.3 [M+H] + . 1 H NMR (DMSO-d6, 500MHz) δ(ppm):8.67(d, J=2.5Hz, 1H), 7.97(dd, J=8.3Hz, 2.6Hz, 1H), 7.49(d, J=8.3Hz, 1H ), 6.96(s, 1H), 5.53(s, 2H), 3.68(s, 2H), 2.80(t, J=5.8Hz, 2H), 2.64(t, J=5.9Hz, 2H), 2.55-2.62(m, 1H), 2.57(d, J=7.0Hz, 2H), 2.56(s, 3H), 2.41(s, 3H), 2.00-2.0 8(m, 2H), 1.75-1.93(m, 2H), 1.64-1.73(m, 2H); tartrate (acid / base ratio 1:1) signal: 4.28(s, 2H).

[0229] Example 46 5-{5-[({7-cyclobutyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-4-methyl-1H-1,2,3-triazol-1-yl}-2-methylpyridine tartrate [ka] The free base of the title compound was prepared according to the procedure described for Example 18, Step A, using 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine (Example 44) and commercially available cyclobutanone. MS (ESI) m / z: 392.2 [M+H] +The tartrate salt was prepared according to the procedure described for step B of Example 19. MS (ESI) m / z: 392.2 [M+H] + . 1 H NMR (DMSO-d6, 500MHz) δ(ppm):8.67(d, J=2.5Hz, 1H), 7.98(dd, J=8.3Hz, 2.6Hz, 1H), 7.50(d, J=8.3Hz , 1H), 6.97(s, 1H), 5.53(s, 2H), 3.58(s, 2H), 2.95(qui, J=7.6Hz, 1H), 2.81(br t, J=5.8Hz, 2H), 2.57(s, 3H), 2.52(br t, J=5.8Hz, 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).

[0230] Examples of pharmaceutical preparations The following formulation examples illustrate representative pharmaceutical compositions of the present invention, but the present invention is not limited to the following pharmaceutical compositions.

[0231] A) Solid oral dosage forms I. Tablets Active ingredient 0.01~90% Bulking agent 1~99.9% Binder 0~20% Disintegrant 0~20% Lubricant 0~10% Other specific excipients 0-50% II. Oral dispersible films Active ingredient 0.01~90% Film forming agent 1~99.9% Plasticizer 0~40% Other specific excipients 0-50%

[0232] B) Liquid oral dosage forms III. Oral Suspensions Active ingredient 0.01~50% Liquid medium 10~99.9% Wetting agent 0~50% Thickener 0~50% Buffer agent (appropriate amount) Osmotic agents 0-50% Preservative (appropriate amount) IV. Syrup Active ingredient 0.01~50% Solvent 10~99.9% Sugar content 1~20% Flavoring agent 0~10%

[0233] C) Parenteral Dosage Forms V. Intravenous injections Active ingredient 0.01~50% Solvent 10~99.9% Co-solvent 0~99.9% Osmotic agents 0-50% Buffer agent (appropriate amount)

[0234] D) Other dosage forms VI. Suppositories Active ingredient 0.01~50% Suppository base 1~99.9% Surfactant 0~20% Lubricant 0~20% Preservative (appropriate amount)

[0235] VII. Eye drops Active ingredient 0.01~50% Water 0~99.9% Solvent 0~99.9% Osmotic agents 0-20% Viscosity enhancer 0~20% Buffer agent (appropriate amount) Preservative (appropriate amount)

[0236] VIII. Nose drops or sprays Active ingredient 0.01~50% Water 0~99.9% Solvent 0~99.9% Osmotic agents 0-20% Viscosity enhancer 0~20% Co-solvent Appropriate amount Buffer agent (appropriate amount) Preservative (appropriate amount)

Claims

1. Compounds of formula (I): 【Chemical 1】 [In the formula, A is, 【Chemistry 2】 is represented by; R １ is an alkyl group, an alkoxy group, or a haloalkyl group; R ２ is hydrogen; -S(O) ２ an alkyl group optionally substituted with alkyl, cycloalkyl or heterocycle; a cycloalkyl group; a heterocycle group optionally substituted with alkyl; or a heteroaryl group; X is CH or N; and / or its salts, and / or its stereoisomers, and / or its enantiomers, and / or its racemate or its diastereomers, its solvates or its hydrates, and / or its polymorphs.

2. R １ But C １－６ Alkyl group, C １－６ Alkoxy group, or halo-C １－６ is an alkyl group; R ２ is hydrogen; -S(O) ２ -C １－６ Alkyl, C ３－７ Cycloalkyl, or a monovalent saturated or partially unsaturated monocyclic, bicyclic, fused, bridged, or spiro ring system of 3 to 10 ring atoms containing 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon, optionally substituted C １－６ Alkyl group; C ３－７ Cycloalkyl group; C １－６ a monovalent saturated or partially unsaturated monocyclic, bicyclic, fused, bridged, or spiro ring system of 3 to 10 ring atoms containing 1, 2, 3, or 4 ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon, optionally substituted with alkyl; or a monovalent heteroaromatic monocyclic or bicyclic ring system of 5 to 10 ring atoms containing 1, 2, or 3 heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon; The compound of claim 1.

3. R １ But C １－４ Alkyl group, C １－４ Alkoxy group, or halo-C １－４ The compound of claim 1 which is an alkyl group.

4. R １ But C １－２ Alkyl group, C １－２ Alkoxy group, or halo-C １－２ The compound of claim 1 which is an alkyl group.

5. R ２ is hydrogen; -S(O) ２ -C １－４ Alkyl, C ４－６ cycloalkyl or a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing 1 or 2 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon, optionally substituted C １－４ Alkyl group; C ４－６ Cycloalkyl group; C １－４ 10. The compound of claim 1, which is a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one or two ring heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon, optionally substituted with alkyl; or a monovalent heteroaromatic monocyclic ring system of 5 to 6 ring atoms containing one or two heteroatoms independently selected from N, O, and S, with the remaining ring atoms being carbon.

6. R ２ is hydrogen; -S(O) ２ -C １－２ Alkyl, C ４－６ cycloalkyl, or a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one ring heteroatom selected from O and S, the remaining ring atoms being carbon, optionally substituted C １－４ Alkyl group; C ４－６ Cycloalkyl group; C １－４ 10. The compound of claim 1, which is a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one ring heteroatom selected from O and S, with the remaining ring atoms being carbon, optionally substituted with alkyl; or a monovalent heteroaromatic monocyclic ring system of 6 ring atoms containing one or two heteroatoms independently selected from N, O and S, with the remaining ring atoms being carbon.

7. R 1 is a C 1-4 alkyl group, a C 1-4 alkoxy group, or a halo-C 1-4 alkyl group; The compound of claim 1, wherein R 2 is hydrogen; —S(O) 2 —C 1-4 alkyl, C 4-6 cycloalkyl, or a C 1-4 alkyl group optionally substituted with a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one or two ring heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon; a C 4-6 cycloalkyl group; a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one or two ring heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon, optionally substituted with C 1-4 alkyl; or a monovalent heteroaromatic monocyclic ring system of 5 to 6 ring atoms containing one or two heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon.

8. R 1 is a C 1-2 alkyl group, a C 1-2 alkoxy group, or a halo-C 1-2 alkyl group; The compound of claim 1, wherein R 2 is hydrogen; —S(O) 2 —C 1-2 alkyl, C 4-6 cycloalkyl, or a C 1-4 alkyl group optionally substituted with a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one ring heteroatom selected from O and S, the remaining ring atoms being carbon; a C 4-6 cycloalkyl group; a monovalent saturated monocyclic ring of 3 to 7 ring atoms containing one ring heteroatom selected from O and S, the remaining ring atoms being carbon, optionally substituted with C 1-4 alkyl; or a monovalent heteroaromatic monocyclic ring system of 6 ring atoms containing one or two heteroatoms independently selected from N, O, and S, the remaining ring atoms being carbon.

9. R ２ The compound of claim 1 , wherein is hydrogen.

10. 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-methyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-cyclobutyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-(cyclobutylmethyl)-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-cyclopentyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxetan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-(1-methanesulfonylpropan-2-yl)-6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridin-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine, 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine, 2-methyl-5-{5-methyl-4-[({7-methyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-1,2-oxazol-3-yl}pyridine, 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine, 5-[5-methyl-4-({[7-(oxolan-3-yl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine, 3-{[3-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl]methyl}-1lambda 6-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-naphthyridine, 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-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxetan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 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-naphthyridin-2-yl]methyl}-1lambda 6-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-naphthyridine, 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-naphthyridine, 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-naphthyridine, 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 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-naphthyridine, 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3-(propan-2-yl)oxetan-3-yl]-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-(3-ethyloxetan-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-naphthyridine, 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine, 5-[5-({[7-(cyclobutylmethyl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-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]pyridazin-3-yl}oxy)methyl]-4-methyl-1H-1,2,3-triazol-1-yl}-2-methylpyridine The compound of claim 1 selected from the group consisting of: and / or its salts, and / or its stereoisomers, and / or its enantiomers, and / or its racemate or its diastereomers, its solvates or its hydrates, and / or its polymorphs.

11. GABA Ａ Use of a compound according to any one of claims 1 to 10 for the manufacture of a medicament for the treatment or prevention of a disease associated with the α5 receptor, comprising The use, wherein the disease associated with the GABA A α5 receptor is selected from the group consisting of neurodevelopmental disorders, neurodegenerative disorders, neurocognitive disorders, schizophrenia, mood disorders, pain disorders, substance-related and addictive disorders, and other diseases.

12. The GABA Ａ 12. The use according to claim 11, wherein the disease associated with α5 receptors is selected from the group consisting of autism spectrum disorder (ASD), Angelman syndrome, fragile X disorder, Prader-Willi syndrome, Rett syndrome, Alzheimer's disease (AD), cognitive deficit disorder, memory loss, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, negative symptoms and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, and amyotrophic lateral sclerosis.

13. A pharmaceutical composition comprising, as an active ingredient, at least one compound according to any one of claims 1 to 10, and at least one physiologically or pharmaceutically acceptable excipient.

14. GABA Ａ 14. The pharmaceutical composition according to claim 13 for the treatment or prevention of a disease associated with α5 receptors, The pharmaceutical composition, wherein the disease associated with the GABA A α5 receptor is selected from the group consisting of neurodevelopmental disorders, neurodegenerative disorders, neurocognitive disorders, schizophrenia, mood disorders, pain disorders, substance-related and addictive disorders, and other diseases.

15. The GABA Ａ 15. The pharmaceutical composition according to claim 14, for use wherein the disease associated with α5 receptors is selected from the group consisting of autism spectrum disorder (ASD), Angelman syndrome, fragile X disorder, Prader-Willi syndrome, Rett syndrome, Alzheimer's disease (AD), cognitive deficit disorder, memory loss, age-related memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorder, negative symptoms and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, and amyotrophic lateral sclerosis.

16. Compounds of formula (I″): 【Chemistry 3】 [In the formula, A is, 【Chemistry 4】 is represented by; R １ is an alkyl group, an alkoxy group, or a haloalkyl group; R ２ is an amino protecting group selected from the group consisting of a carbamate group, a benzyl group, an allyl group, and a trityl group; X is CH or N. (however, tert-butyl 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, or tert-Butyl 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-5,3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate (Excluding).

17. tert-butyl 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine-2-carboxylate. tert-Butyl 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine-2-carboxylate tert-butyl 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, tert-butyl 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, tert-butyl 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, tert-butyl 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, and tert-Butyl 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine-2-carboxylate 17. The compound of claim 16, selected from the group consisting of:

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