Naphthyridine and pyrido[3,4-c]pyridazine derivatives as GABA A alpha 5 receptor modulators

Abstract

The present invention provides a method for the treatment of GABAergic steroids having affinity and selectivity for the gamma-aminobutyric acid A receptor subunit alpha 5. A Acts as a positive allosteric regulator of α5, thereby increasing the GABA A Provided are compounds of formula (I), and / or salts thereof, and / or biologically active metabolites thereof, and / or prodrugs thereof, and / or solvates thereof, and / or hydrates thereof, and / or polymorphs thereof, processes for their preparation and intermediates in the preparation processes, pharmaceutical compositions containing them alone or in combination with one or more other active ingredients, and their use as medicaments, which are useful in the treatment or prevention of diseases associated with the α5 receptor. [Formula 1] TIFF2023520647000122.tif46170

Description

[Technical Field]

[0001] 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 α5 positive allosteric modulator (GABA A α5PAM), thereby inhibiting GABA A Provided are compounds of formula (I), processes for their preparation and intermediates in the preparation processes, pharmaceutical compositions containing them, and their use as medicaments, which are useful in the treatment or prevention of diseases associated with the α5 receptor. [Background technology]

[0002] Gamma-aminobutyric acid (GABA) is the major inhibitory neurotransmitter in the central nervous system. GABA-sensitive receptors are ligand-gated GABA receptors. A Receptor and G Protein-Coupled GABA B They are divided into two main families of receptors.

[0003] Ligand-gated GABA A The Cl receptor mediates most inhibitory neurotransmission in the adult mammalian brain. This receptor is a ligand-gated Cl receptor. - GABA channels are composed of a pentameric assembly of multiple subunits (α1-6, β1-3, γ1-3, δ, ε, π, θ, ρ1-3) (Olsen and Sieghart, Pharmacol Rev 2008, 60:243-260). The distribution of subunits differs developmentally and regionally in the brain. This high variability results in wide variations in inhibitory and, under certain conditions, excitatory neuronal mechanisms, providing the potential for specific therapeutic intervention (Fritschy and Mohler, J Comp Neurol 1995, 359:154-194; Jacob, Front Mol Neurosci 2019, 12:Art 179). AThe physiological role and pharmacological profile of receptors are strongly dependent on the subunit composition. Studies in genetically modified mice have demonstrated that the composition of receptor subunits, particularly the α subtype, significantly determines the pharmacology of compounds acting at the benzodiazepine-sensitive allosteric modulatory site (BDZ site) (Rudolph and Knoflach, Nat Rev Drug Discov 2011, 10:685-697). The widely distributed α1-containing receptors mediate sedative and amnesic effects, whereas 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). α5 subunit-containing receptors (α5GABA receptors) are also involved in the pharmacology of benzodiazepine-sensitive allosteric modulatory sites (BDZ sites) (Rudolph and Knoflach, Nat Rev Drug Discov 2011, 10:685-697). The α5 subunit-containing receptors (α5GABA receptors) mediate sedative and amnesic effects, whereas 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). 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 primarily 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 receptors A α5GABA R can induce excitation in early hippocampal circuit development (Marchionni et al., J Physiol. 2007, 581:515-528). Their modulatory effects on the excitability of hippocampal and cortical principal neurons may support the role of α5GABA R in neurodevelopment, cognition, learning, and memory. AThis can explain the important effects of R and their potential therapeutic utility in a variety of disorders, including stroke, mild cognitive impairment, schizophrenia, depression, dementia-related conditions or diseases associated with impairments in social cognition, or neurodevelopmental disorders such as Down 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 reductions in α5-mediated tonic inhibition can improve learning and memory through enhanced 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) (Mohler and Rudolph, F1000Res 2017 Feb 3;6.pii:F1000 Faculty Rev-101). However, α5GABA A The hippocampal and cortical hyperactivity resulting from reduced α5GABA function can also lead to increased locomotor activity and impaired sensorimotor gating (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), behavioral changes that are characteristic of various CNS disorders. AFacilitation, rather than blockade, of R may be a promising treatment for the positive, negative, and cognitive symptoms associated with such diseases.

[0006] The University of Wisconsin-Milwaukee has described certain 4H-benzo[f]imidazo[1,5-a][1,4]diazepine derivatives (WO2017 / 161370A1), such as SH-053-2'FR-CH3, MP-III-022, or GL-II-73, as preferred PAM compounds of α5, which exhibit cognitive-enhancing, anxiolytic, and antidepressant effects in stressed and aged mice (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) (Prevot et al. Mol Neuropsychiatry 2019, 5:84-97). MP-III-022 and the α5PAM compound 44, 6,7-dihydro-2-benzothiophen-4(5H)-one (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). Additionally, SH-053-2'FR-CH3 and MP-III-022 reversed pathological alterations 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 AWe have described imidazo[1,5-a][1,2,4]-triazolo[1,5-d][1,4]benzodiazepine derivatives as α5PAMs (WO2015 / 095783A1), because their lead series has potent and selective compounds with good in vivo efficacy in aging-impaired rats ( https: / / grantome.com / grant / NIH / R44-AG063607-01 ), and preclinical evidence from biological studies of age-related cognitive impairment suggests that such compounds may increase hippocampal GABA levels in states of hippocampal hyperactivity. A It was found to occupy 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 for this invention is autism spectrum disorder (ASD). ASD is a complex, heterogeneous neurodevelopmental disorder characterized by impaired social relationships, reduced communication, typical repetitive behaviors, and impaired executive function (Anagnostou et al., CMAJ 2014, 186:509-519; Diagnostic and Statistical Manual of Mental Disorders, 5th ed., Arlington, VA: American Psychiatric Association; 2013-299.00 Diagnostic Criteria for Autism Spectrum Disorder). There are no medications approved for the treatment of core symptoms of ASD. Current pharmacological treatments are limited to the atypical antipsychotics risperidone and aripiprazole, approved for the treatment of ASD-related irritability. Antidepressants are used off-label to reduce delusional / compulsive symptoms in ASD; the efficacy and tolerability of these treatments are modest (Carrasco et al., Pediatrics 2012, 129:e1301-e1310), and therefore, there is an unmet need for more selective, pathophysiology-based treatments for these conditions.

[0009] ASD is caused by GABA A In addition to the R subunit, genomic alterations may be involved. Chromosomal abnormalities, namely copy number variations in the q11.2-13 region of chromosome 15, have been reported in ASD patients. In humans, this region is involved in the regulation of GABAergic signaling. AIt 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 demonstrated a role for α5 GABA receptors in ASD. A Further supporting R deficiency, α5GABA A Gabraα5, the gene for R and its anchoring protein radixin - / - and RDX (Zurek et al., Ann Clin Transl Neurol 2016,3:392-398). There is increasing evidence of an excitatory / inhibitory (E / I) imbalance resulting from impaired GABAergic function in ASD. Reduced expression of the GABA-synthesizing enzymes GAD65 and GAD67, as well as increased expression of GABA receptors, may contribute to the development of GABAergic dysfunction. 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). Imaging studies using positron emission tomography (PET) and magnetic resonance spectroscopy (MRS) have shown that GABA levels and GABA receptor agonists are significantly reduced in ASD patients. 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 a role for α5GABA receptor availability in ASD. A α5GABA across multiple brain regions suggesting reduced levels of R A R-selective tracer [ 11 C]Ro154513 (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 reduced binding of α5GABA. AThese results revealed a reduction in the expression of R (Blatt et al., J Autism Dev Disord 2001, 31:537-54; Fatemi et al., J Autism Dev Disord 2010, 40:743-750). Impaired GABAergic function in ASD patients may be considered, and therefore promoting cortical inhibition and restoring E / I balance by α5PAM may be a feasible therapeutic strategy for the treatment of the disease.

[0010] Increased neuronal excitability in the cortex can lead to autism-like behavioral deficits in rodents (Yizhar et al., Nature 2011, 477:171-178). In support of clinical findings, α5GABA A Genetic reduction of R. Gabra5 - / - Gabra5 showed reduced tonic currents and increased excitability of primary hippocampal neurons in mice (Bonin et al., J Neurophysiol 2007, 98:2244-2254). In addition to impairments in executive function, autism-like behaviors and pathology were observed in healthy individuals. - / - 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, which are associated with behavioral features of ASD (Bakker and Oostra, Cytogenet Genome Res 2003, 100:111-123). A showed a downregulation of R and a defect in tonic inhibition (Curia et al., Cereb Cortex 2009, 19:1515-1520).

[0011] The prenatal valproate model has excellent construct and face validity, and therefore it is 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, mated female Wistar rats are administered a single dose of valproic acid on the 12.5th day of pregnancy. After treatment with the investigational drug, offspring are behaviorally examined in a social preference test on the 59th day of birth. The social preference test is a well-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 explore a conspecific or similar arena separated by a partition wall with a hole, but without a conspecific target. Autistic animals (such as prenatally valproate-exposed rats) spend less time in social exploration during the test session. The reduction in social behavior in VPA-treated animals is consistent with the α5 GABAergic pathway. A It is believed that the restoration of inhibitory synaptic transmission mediated by GABA receptors can restore normal levels (Wang et al., Front Neurol 2018, 9:Article 1052). Therefore, examples of the present invention may have significant behavioral benefits in this preclinical disease model that recapitulates the core symptoms of ASD. Therefore, the compounds of the present invention, specifically GABA receptor-mediated inhibitory synaptic transmission, may be useful in treating ASD. A It can be suggested that α5PAM may have therapeutic potential for the core symptoms of autism spectrum disorder in humans.

[0012] Positive modulators of GABA-A receptors, such as low-dose nonselective clonazepam, have also demonstrated symptomatic relief 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 this disorder. In addition to this strategy, subunit-selective compounds, such as α5 positive allosteric modulators, may offer an alternative approach for the treatment of ASD, possibly with an improved therapeutic window. Thus, RG7816 (RO7017773), an α5-selective PAM compound, is in clinical development for the treatment of ASD ( https: / / www.clinicaltrials.gov / ct2 / show / NCT04299464 ).

[0013] Therefore, α5GABA A GABA, a compound with affinity and selectivity for R A α5PAM is a GABA-dependent protein that is involved in the pathogenesis of GABAergic disorders. 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 that may be associated with the α5 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), and multiple sclerosis (Kammel et al., Neuroscience 2018,395:89-100), Parkinson's disease (Blaszczyk, Front Neurosci 2016,10:269-277), epilepsy (Schipper et al., Mol Neurobiol 2016,53:5252-5265), attention deficit hyperactivity disorder and attention deficit in adults (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 2017,2017:571-5816), 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; Gill et al., Neuropsychopharmacology 2011,36:1903-1911; Hauser et al., Mol Psychiatry 2005,10:201-207; 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), type I neurofibromatosis (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 (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., Neuropharmacology 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), neuropathic pain (Hernandez-Reyes et al., Pain 2019,160:1448-1458) and inflammatory pain (Bravo-Hernandez et al., Eur J Pharmacol. 2014,734:91-97; Munro et al., Neuropharmacology 2011,61:121-132). A Modulating α5GABA R may also be beneficial in treating diseases and conditions including, but not limited to, bronchoconstrictive disorders, 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). ACompounds capable of modulating R are expected to be useful candidates for the treatment of neurodevelopmental disorders, neurocognitive disorders, mood disorders and schizophrenia, among others.

[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 different 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 Despite numerous studies and modulators of the α5 receptor, GABA A There remains an unmet need to provide compounds that may be 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] is represented by R 1 is C 1-4 Alkyl or halo-C 1-4 is an alkyl group, R 2 is C 1-4 Alkyl groups, halo-C 1-4 Alkyl group, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl group, C1-4 Alkoxy group, C 3-7 Cycloalkyl groups, C 6-10 Aryl group, optionally substituted C 3-10 Heterocyclic groups, C 5-10 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are independently H, C 1-4 Alkyl group, C 3-7 Cycloalkyl group or C 3-10 a heterocyclic group; X is CH or N and / or its salts, and / or its stereoisomers, and / or its enantiomers, and / or its racemates, and / or its diastereomers, and / or its biologically active metabolites, and / or its prodrugs, and / or its solvates, and / or its hydrates, and / or its polymorphs.

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

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

[0019] The present invention is directed to the 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 is directed to the 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, e.g., a human, in need of such treatment or prevention.

[0021] The present invention is directed to the AThere is provided a combination of a compound of formula (I) as defined above with one or more other active ingredients for the treatment or prevention of diseases associated with the α5 receptor.

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

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

[0024] The present invention is directed to the A There is provided a pharmaceutical composition containing as an active ingredient a compound of formula (I) as defined above, alone or in combination with one or more other active ingredients, for use in the treatment or prevention of diseases associated with the α5 receptor.

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

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

[0027] The present invention provides compounds of formula (I) which have affinity and selectivity for gamma-aminobutyric acid A receptors containing the alpha5 subunit (GABAα5 receptors) and act as positive allosteric modulators of the GABAα5 receptor, thereby being useful in the treatment or prevention of diseases associated with the GABAα5 receptor, processes for their preparation, pharmaceutical compositions containing them alone or in combination with one or more other active ingredients, and their use as medicines.

[0028] The present invention relates to a compound of formula (I) [ka] (In the formula, A is, [ka] is represented by R 1 is C 1-4 Alkyl or halo-C 1-4 is an alkyl group, R 2 is C 1-4 Alkyl groups, halo-C 1-4 Alkyl group, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-7 Cycloalkyl groups, C 6-10 Aryl group, optionally substituted C 3-10 Heterocyclic groups, C 5-10 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are independently H, C 1-4 Alkyl group, C 3-7 Cycloalkyl group or C 3-10 a heterocyclic group; X is CH or N and / or its salts, and / or its stereoisomers, and / or its enantiomers, and / or its racemate, and / or its diastereomers, and / or its biologically active metabolites, and / or its prodrugs, and / or its solvates, and / 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 general terms used herein are provided whether or not they are terms in question, individually or in combination with other groups described below.

[0033] "Optionally" or "optionally" means that the subsequently described event or circumstance may, but need not, occur, and that the description includes cases where the event or circumstance occurs and cases where 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" means that the specified group bears one or more substituents.

[0036] Where any group may bear multiple substituents and a variety of possible substituents is provided, the substituents are independently selected and do not have to be the same.

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

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

[0039] "C 1-4 The term "alkyl," alone or in combination with other groups, refers to a straight or branched, single- or multiply-branched hydrocarbon radical, consisting 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). C 1-2 Alkyl groups are preferred, with methyl groups being most preferred.

[0040] "C 1-4 The term "alkoxy", alone or in combination with other groups, means -OC 1-4 Alkyl groups (where C 1-4 Alkyl is as defined above. Examples include, but are not limited to, methoxy, ethoxy, i-propoxy, n-propoxy, or t-butoxy.

[0041] "C 1-4 Alkyl-S(O)2-C 1-4 The term "alkyl," alone or in combination with other groups, means the radical -S(O)-C 1-4 Alkyl-substituted C 1-4 Alkyl groups (wherein any C 1-4 Alkyl is as defined above. Methylsulfonylmethane or ethylsulfonylmethane groups are preferred.

[0042] The terms "halogen," "halo," or "halide," alone or in combination with other groups, refer to fluoro, chloro, bromo, or iodo, preferably fluoro.

[0043] "Haro-C 1-4 The term "alkyl," alone or in combination with other groups, refers to any of the C 1-4C as defined above, where any carbon atom on the alkyl is substituted with one or more identical or different halogens. 1-4 The term "perhaloalkyl" refers to a C alkyl group, including vicinal and / or geminal halo substitutions such as perhaloalkyl groups. The term "perhaloalkyl" refers to a C alkyl group, in which all hydrogen atoms have been replaced by the same or different halogen atoms. 1-4 Examples include, but are not limited to, trihalo, dihalo, or monohalo-C 1-4 Alkyl groups include, for example, 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, difluoromethyl, or trifluoromethyl. 1-4 The alkyl group is a halo-methyl group, more preferably difluoromethyl or trifluoromethyl, most preferably trifluoromethyl.

[0044] "C 3-7 The term "cycloalkyl group" refers to a monovalent, monocyclic, saturated carbocyclic group containing 3 to 7 carbon ring atoms. Examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, and cycloheptane. 3-4 Cycloalkyl groups are preferred.

[0045] "C 6-10 The term "aryl group" refers to a monovalent monocyclic or bicyclic aromatic carbocyclic group containing 6 to 10 carbon ring atoms. Bicyclic aryl groups contain at least one aromatic carbocyclic group. Examples include phenyl, dihydro-indene, indene, naphthyl, diaryl, tetralin, anthryl, azulenyl, indanyl, and the like. Phenyl is preferred.

[0046] "C 3-10The term "heterocyclic group," 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, dihydro-oxazole, isoxazolidine, oxathiolane, sulfolane, thiazolidine, thiazolinone ... zolidinedione, succinimide, oxazolidone, hydantoin, piperidine, piperidinone, piperazine, tetrahydropyran, tetrahydrothiopyran, dihydropyran, tetrahydropyridine, dioxane, thiane, dithiane, 1,1-dioxo-thiane, morpholine, thiomorpholine, 1,1-dioxo-thiomorpholine, azepane, diazepane, homopiperazine, oxazepnayl, etc. C containing one or two ring heteroatoms independently selected from N, O, and S. 4-6 Heterocyclic groups are preferred.

[0047] "C 5-10The term "heteroaryl group," 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 of 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, benzisoxazole, benzothiazole, benzisothiazole, benzoxadiazole, benzothiadiazole, benzotriazole, purine, quinoline, isoquinoline, quinazoline, quinoxaline, carbazole, or acridine. C containing 1 or 2 ring heteroatoms independently selected from N, O and S 5-6 Heteroaryl groups are preferred.

[0048] The terms "compound of this 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 thereof, and / or a diastereomer thereof, and / or a biologically active metabolite thereof, and / or a prodrug thereof, and / or a solvate thereof, and / or a hydrate thereof, and / or a polymorph thereof.

[0049] The term "salts" refers to pharmaceutically acceptable salts and / or pharmaceutically unacceptable salts.

[0050] The term "pharmaceutically acceptable salt" refers to conventional acid or base addition salts that retain the biological effectiveness and properties of the compounds of Formula (I), which may be formed with suitable non-toxic organic or inorganic acids or bases. Examples of acid addition salts include, but are not limited to, salts derived from inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, sulfamic acid, phosphoric acid, nitric acid, and perchloric acid, as well as salts derived from various organic acids 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, methanesulfonic acid, oxalic acid, tartaric acid, succinic acid, citric acid, malic acid, lactic acid, glutamic acid, fumaric acid, and the like. Examples of base addition salts include salts derived from ammonium, potassium, sodium, and quaternary ammonium hydroxides, such as tetramethylammonium hydroxide. These salts often exhibit more favorable solubility than the compounds used for their preparation and are therefore more suitable for use in the preparation of various pharmaceutical formulations.

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

[0052] The term "prodrug" refers to derivatives of the compounds of formula (I) according to the present invention that contain groups that do not themselves have a therapeutic effect but that, after chemical or metabolic degradation in vivo (biotransformation), become "biologically active metabolites" that are responsible for the therapeutic effect. Such degradable groups related to the compounds of formula (I) of the present invention, particularly groups suitable for prodrugs, are known in the art and may also be applied to the compounds of the present invention (Rautio et al., Nature Reviews-Drug Discovery 2008,7:255-270).

[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 into 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 compounds.

[0054] The compound of formula (I) and its salts can also exist as solvates or hydrates, which are also within the scope of the present invention.The term "solvate" refers to a non-covalent stoichiometric or non-stoichiometric combination of a solvent and a solute.The term "hydrate" refers to a 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 the compound of formula (I) defined above in combination with one or more other active ingredients.The pharmaceutical composition can 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 combined composition can 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 pharmaceutically acceptable excipients to be administered to a subject, e.g., a human in need thereof.

[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, orodispersible), capsules, pills, orodispersible films, granules, powders, etc.; liquid preparations 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 skin preparations (ointments, creams, pastes, etc.), transdermal therapeutic systems, other forms of medicine such as 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, including, but not limited to, oral, rectal, mucosal, transdermal or intestinal administration; intramuscular, subcutaneous, intravenous, intramedullary injection, as well as parenteral administration, including intraarticular, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injection and eye drops.

[0061] Alternatively, compounds may be administered locally rather than systemically, often in modified release formulations, for example, by direct injection of the compound into the kidney or heart.In addition, drugs may be administered in targeted carrier systems, for example, tissue-specific antibodies encapsulated in liposomes.Liposomes selectively transport active agents to the target organs that absorb them.

[0062] Pharmaceutical compositions can be administered in various ways and in various pharmaceutical forms.The compound of the present invention can be administered alone or in combination with pharmaceutically acceptable excipients in single or multiple doses.The dosage required to achieve appropriate therapeutic effect can vary widely, and must always be adapted to the individual needs of the degree of disease, the condition and weight of the patient being treated and the sensitivity to active ingredient, the method of dosage regimen and the number of daily treatments.

[0063] For ease of administration, the pharmaceutical composition is preferably comprised of a dosage unit containing a single or a small multiple, or a half, third, or quarter, of the amount of active ingredient to be administered. Such dosage units, for example, tablets, may be provided with half or quarter grooves to facilitate dividing the tablet into halves or quarters to measure out the required amount of active ingredient.

[0064] Pharmaceutical compositions containing the active ingredient according to the present invention generally contain about 0.01 to 500 mg of the active ingredient per dosage unit. Of course, the amount of the active ingredient in each formulation may exceed or fall below the above limits.

[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 can be formulated in a conventional manner using one or more physiologically or pharmaceutically acceptable excipients that facilitate the incorporation of active ingredients into pharmaceutically acceptable pharmaceutical forms.The term "physiologically or pharmaceutically acceptable excipients" refers to any component that is used in formulating non-toxic pharmaceutical products that do not have therapeutic activity.Appropriate formulations depend on the mode of administration selected.Any technique and excipient known in the art can be used.

[0068] The excipients applied 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, taste masking agents, flavoring agents, 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] Another embodiment of the present invention relates to the use of certain binders, such as, but not limited to, hydrophilic polymers, hot melt extrusion excipients, surfactants, buffers, complexing agents, emulsifiers, lyophilization excipients, disintegrants, microencapsulating agents, penetration enhancers, solubilizers, co-solvents, suspending agents, which can improve the solubility, dissolution, penetration, absorption or bioavailability of the active ingredient.

[0070] The excipients and various methods of preparation described above are merely representative. Other materials and process techniques known in the art can also be used.

[0071] 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); and androgen receptor modulators (SFX 01, etc.); anti-amyloid antibodies, e.g., anti-amyloid humanized monoclonal antibodies (bapineuzumab, ACCOl, CAD 106, AZD3102, H12A11V1, etc.); anticholinergic drugs (biperiden, etc.); anticonvulsants (acetazolamide, carbamazepine, eslicarbazepine acetate, ethosuximide, lacosamide, nitrazepam, oxcarbazepine, perampanel, phenobarbital, phenytoin, primidone, rufinamide, stiripentol, topiramate, valproate, etc.); anti-inflammatory compounds ((R)-flurbiprofen, nitroflurbiprofen, ND-1251, VP-025, HT-0712, and EH T-202, etc.); ApoE4 conformational modifiers; atypical antipsychotics (such as aripiprazole, asenapine, brexpiprazole, briraloxazine, cariprazine, iloperidone, loxapine, lumateperone tosylate, lurasidone hydrochloride, molindone, olanzapine, paliperidone, quetiapine, risperidone, sulpiride, and ziprasidone, etc.); 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 (such as SSR240612, NVPSAA164, or any of the compounds described in WO2007 / 072092A2, WO2008 / 068540A1, WO2008 / 050167A1, WO2008 / 050168A1); 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 agonists; phenothiazines thioxanthenes (such as chlorpromazine, fluphenazine, mesoridazine, perphenazine, thioridazine, and trifluoperazine); thioxanthenes (such as chlorprothixene and thiothixene); COMT inhibitors (such as entacapone); cyclopyrrolones; the neuroleptic classes of diphenylbutylpiperidines (such as pimozide) and indolones (such as molindron); DNA-dependent DNA polymerase inhibitors (such as suramin sodium); dopamine agonists and partial agonists (such as pramipexole and ropinirole); dopamine precursors (such as carbidopa and levodopa); dopamine transport inhibitors; enzyme modulators or substitutes (such as CM-AT, CM-4612, and CM-182); fatty acid amide hydrolase inhibitors (such as JNJ 42165279); fatty acid or triglyceride substitutes (such as triheptanoin); fenamic acid 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 (e.g., 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 and gabapentin); glutamate modulators (such as AMO 04); glycine transport inhibitors; glycogen synthase kinase 3 beta 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 vafidemstat); 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, Foliglarax, 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 (such as memantine, neramexane, EVT101, AZD4282, and BHV 5000); noradrenaline transport inhibitors; norepinephrine modulators; NOS inhibitors (such as SD6010 and 274150); NQO1 modulators (such as vaquiquinone); NR2B antagonists (such as radiprodil); NSAIDs (such as ibuprofen); opioid analgesics (such as codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, pentazocine, and propoxyphene); and orexin antagonists and agonists; oxytocin; p25 / CDK5 inhibitors; PDE10 inhibitors; PDE4 inhibitors (such as HT0712); PDE9 inhibitors (such as BI40936); PI3KB inhibitors (such as BBP-472); potassium channel openers; PPAR gamma agonists (such as pioglitazone and rosiglitazone); prokineticin agonists and antagonists; pyrazolopyrimidines; pyrrolidone compounds that modulate cholinergic / metabotropic glutamate receptors (fasoracetam, levetiracetam, 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, and ponesimod); SSRIs or SNRIs (such as fluoxetine, citalopram, escitalopram, fluvoxamine, paroxetine, and sertraline; or desvenlafaxine and 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;This 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;

[0072] In one embodiment, the other active ingredient is 5-HT 1A Antagonists or agonists (e.g., lecozotan, NLX 101, sarizotan); atypical antipsychotics (e.g., 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 (e.g., drinabant, cannabidiol); CB-2 agonists (e.g., GW-842166X and SAB378) or CB modulators (e.g., cannabidivarin, T1 / C20, tetrahydrocannabinol conjugates, ZYN-002); DNA-dependent DNA polymerase inhibitors (e.g., suramin sodium); fatty acid amide hydrolase inhibitors (e.g., JNJ 42165279, etc.); fatty acid or triglyceride substitutes (e.g., triheptanoin); GABA A Receptor agonists (e.g., 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 3 beta inhibitors (such as tideglusib, AZD1080, SAR502250, and CEP16805); lysine-specific demethylase 1 inhibitors (such as vafidemstat); 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., vaquiquinone); oxytocin; pyrrolidone compounds that modulate cholinergic / metabotropic glutamate receptors (e.g., fasoracetam, levetiracetam, brivaracetam, piracetam); sigma-1 receptor agonists (e.g., buralcamesine); sphingosine-1 phosphate receptor modulators (e.g., fingolimod, ozanimod, siponimod, ponesimod); SSRIs or SNRIs (e.g., fluoxetine, citalopram) 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).

[0073] 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.

[0074] 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.

[0075] The term "agonist" refers to a compound that has affinity for the receptor binding site and enhances the activity of the receptor-mediated response. A "full agonist" produces a full response, whereas a "partial agonist" produces less than full activation even when the entire receptor population is occupied.

[0076] 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 an agonist by binding at a different allosteric binding site.

[0077] The term "antagonist" refers to a compound that reduces or prevents the action of another compound or receptor site, or counteracts 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 "non-competitive antagonist" binds to an allosteric site on the receptor and prevents receptor activation. A "reversible antagonist" binds to the receptor non-covalently (can be washed out), while an "irreversible antagonist" binds covalently (cannot be washed out).

[0078] 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, and alters the affinity and / or activity of the receptor for an endogenous ligand or agonist due to a conformational change in the receptor. A "positive allosteric modulator" or "PAM" increases affinity and / or activity, whereas a "negative allosteric modulator" or "NAM" decreases receptor affinity and / or activity. The compounds of formula (I) defined above are positive allosteric modulators.

[0079] "Inhibition coefficient" (K iThe term K refers to the absolute binding affinity of a particular inhibitor to its receptor. This 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 radioligand concentration and K D is the affinity of the labeled ligand for the receptor binding site) to determine the concentration at which a particular inhibitor occupies half of the receptors in the absence of competing ligand (IC 50 ) is calculated from K i The value is pK i Value (-logK i ), where larger values ​​indicate exponentially higher potency.

[0080] The term "submaximal effective concentration" refers to the concentration of a particular compound required to obtain 10% of the maximum of a particular effect.

[0081] The terms "condition," "defect," "deficiency," "impairment," "disorder," "disease" or "disease state" are used interchangeably and refer to any disease, condition, symptom, syndrome, disorder or manifestation.

[0082] "GABA A The term "α5 receptor-associated disease" refers to a disease in which one of the symptoms and / or syndromes is GABAergic. A It refers to diseases, conditions or disorders of the central nervous system that may be related to α5 receptors. These diseases include, but are not limited to, neurodevelopmental disorders, neurodegenerative disorders, neurocognitive disorders, schizophrenia, mood disorders, pain disorders, substance-related and addictive disorders, or other diseases.

[0083] GABA AThe diseases associated with α5 receptor may show comorbidity with each other.Comorbidity refers to the pathology that exists simultaneously but is unrelated to another condition in a patient, or the pathology that causes, is caused by, or is related to another condition in the same patient.However, in psychiatry, the comorbidity of psychological or mental health diseases does not necessarily mean the existence of multiple diseases, but may instead reflect our current inability to provide a single diagnosis that accounts for all symptoms.

[0084] 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.

[0085] 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).

[0086] The term "neurocognitive disorder" includes, but is not limited to, cognitive deficit disorder, memory deficit, age-related memory impairment or cognitive decline, dementia (or its different forms such as 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 impairment 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 and delusional disorders.

[0087] The term "pain disorder" includes, but is not limited to, nociceptive, neuropathic or inflammatory pain.

[0088] 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 a depressive episode of bipolar disorder), bipolar disorder, substance (alcohol or drug)-induced, or mood disorder not otherwise specified (MD-NOS).

[0089] The term "other disorders" includes, but is not limited to, attention deficit hyperactivity disorder and adult attention deficit, other stress-related conditions, stroke, neurofibromatosis type 1, multiple sclerosis, acute meningitis, alcohol use disorder, fetal alcohol spectrum disorder, or bronchoconstrictive disorders (such as asthma, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia).

[0090] In one embodiment, GABA ADiseases 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, amyotrophic lateral sclerosis (ALS), cognitive impairment, memory deficits, age-related memory impairment or cognitive decline, dementia in Alzheimer's disease, Niemann-Pick disease, Parkinson's disease, or Huntington's disease, dementia with Lewy bodies, and dementia with Lewy bodies. Dementia or its different forms, such as dementia (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 impairment in Down's syndrome (DS); cognitive impairment in major depressive disorder (MDD), HIV-associated neurocognitive disorders; different forms of schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, schizophrenic and delusional disorders; nociceptive, neuropathic or inflammatory pain; depression-related disorders (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, substance use disorders) Refers to bipolar disorder, substance (alcohol or drug)-induced mood disorder not otherwise specified (MD-NOS); attention deficit hyperactivity disorder and adult attention deficit disorder, other stress-related conditions, stroke, neurofibromatosis type 1, multiple sclerosis, acute meningitis, alcohol use disorder, fetal alcohol spectrum disorder, or bronchoconstrictive diseases (such as asthma, chronic obstructive pulmonary disease, and bronchopulmonary dysplasia).

[0091] In a preferred embodiment, GABA ADiseases associated with the α5 receptor include 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 dysfunction 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.

[0092] The present invention is directed to the A Provided is a method for treating or preventing a disease associated with the α5 receptor, comprising the step of administering a therapeutically effective amount of a compound of formula (I) as defined above, alone or together with at least one pharmaceutically acceptable excipient, in the form of a pharmaceutical formulation to a subject, preferably a mammal, more preferably a human, in need of such treatment or prevention.

[0093] The present invention is directed to the A Provided is a method for treating or preventing a disease associated with the α5 receptor, which comprises 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, in need of such treatment or prevention.

[0094] The present invention relates to a method for treating or preventing 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 at least one of its symptoms and / or syndromes, wherein one of the symptoms and / or syndromes of the disease is induced by GABAergic stimulation in a subject, preferably a mammal, more preferably a human, suffering therefrom. AThe present invention provides a method for treating a disease that may be related to α5 receptors. 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 such treatment or prevention. The method of treatment may comprise administering a therapeutically effective amount of a pharmaceutical composition comprising a compound of formula (I) as defined above to a subject, preferably a mammal, more preferably a human, in need of such treatment.

[0095] The present invention provides a method of treating or preventing 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 dysfunction 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 at least one of the symptoms and / or syndromes thereof, in a subject, preferably a mammal, more preferably a human being, suffering therefrom, which method comprises administering a therapeutically effective amount of a compound of formula (I) as defined above.

[0096] The present invention is directed to the A There is provided a compound of formula (I) as defined above for use in the treatment or prevention of diseases associated with the α5 receptor.

[0097] The present invention is directed to the 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 alpha5 receptor.

[0098] The present invention provides compounds of formula (I) as defined above for use in the treatment or prevention of at least one neurodevelopmental disorder, neurodegenerative disorder, neurocognitive disorder, schizophrenia, mood disorder, pain disorder, substance-related and addictive disorder, or other disease, or symptom and / or syndrome thereof.

[0099] 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 deficit, age-related memory dysfunction 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 symptoms and / or syndromes thereof.

[0100] The present invention is directed to the 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.

[0101] The present invention is directed to the 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 diseases associated with the α5 receptor.

[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 neurodevelopmental disorder, neurodegenerative disorder, neurocognitive disorder, schizophrenia, mood disorder, pain disorder, substance-related and addictive disorder, or other disease, or symptom and / or syndrome thereof.

[0103] 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 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 dysfunction 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 at least one symptom and / or syndrome thereof.

[0104] The present invention is directed to the 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.

[0105] The present invention is directed to the A It also relates to a pharmaceutical composition comprising a compound of formula (I) as defined above and one or more other active ingredients for use in the treatment or prevention of diseases associated with the α5 receptor.

[0106] The term "treatment" refers to the alleviation of a particular condition, 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 the condition in a patient or subject already suffering from or diagnosed with a disease. "Prevention" (or prophylaxis 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 the disease or an already occurring condition.

[0107] The term "therapeutically effective amount" refers to an amount of an active ingredient that results in the treatment, cure, prevention, or amelioration of a disease or disease state or side effects, or reduces the progression of a disease or pathological condition, compared to a corresponding subject not receiving such amount. This term also includes an amount effective to enhance normal physiological function. For use in therapy, the compound of formula (I) defined above, and any 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, may be administered in a therapeutically effective amount as raw chemicals. In addition, the active ingredient is available as a pharmaceutical formulation. The precise therapeutically effective amount of the compound of formula (I) defined above depends on many factors, including, but not limited to, the age and weight of the subject (patient), the specific type and severity of the disease requiring treatment, the nature of the pharmaceutical product, and the route of administration.

[0108] 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 ape and monkey species, livestock such as cows, horses, sheep, goats, and pigs, domestic animals such as rabbits, dogs, and cats, and laboratory animals such as rodents, including rats, mice, and guinea pigs. In certain embodiments, the mammal is a human. The term subject does not denote a particular age or sex.

[0109] In one embodiment, the present invention provides a compound of formula (I') [ka] (In the formula, A is, [ka] is represented by where any ring A moiety "a1" is bonded to moiety "a2" and any ring A moiety "b1" is bonded to moiety "b2"; R 1 , R 2 and X is as defined above for a compound of formula (I), and / or a salt thereof, and / or a stereoisomer thereof, and / or an enantiomer thereof, and / or a racemate thereof, and / or a diastereomer thereof, and / or a biologically active metabolite thereof, and / or a prodrug thereof, and / or a solvate thereof, and / or a hydrate thereof, and / or a polymorph thereof). Regarding.

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

[0111] In one embodiment, the present invention provides a compound of formula (Ib) [ka] (In the formula, R 1 , R 2 and X are as defined above for 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).

[0112] In one embodiment, the present invention provides a compound of formula (Ic) [ka] (In the formula, R 1 , R 2 and X are as defined above for 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).

[0113] In one embodiment, the present invention relates to compounds of formula (I) wherein X is CH.

[0114] In one embodiment, the present invention relates to compounds of formula (I) wherein X is N.

[0115] In one embodiment, the present invention provides a compound comprising R 1 But C 1-4 The present invention relates to compounds of formula (I) wherein the group is an alkyl group.

[0116] In one embodiment, the present invention provides a compound comprising R 1 But, Halo-C 1-4 The present invention relates to compounds of formula (I) wherein the group is an alkyl group.

[0117] In one embodiment, the present invention provides a compound comprising R 2 But C 1-4 The present invention relates to compounds of formula (I) wherein the group is an alkyl group.

[0118] In one embodiment, the present invention provides a compound comprising R 2 But, Halo-C 1-4 The present invention relates to compounds of formula (I) wherein the group is an alkyl group.

[0119] In one embodiment, the present invention provides a compound comprising R 2 But C 1-4 Alkyl-S(O)2-C 1-4 The present invention relates to compounds of formula (I) wherein the group is an alkyl group.

[0120] In one embodiment, the present invention provides a compound comprising R 2 But C 1-4 is an alkoxy group.

[0121] In one embodiment, the present invention provides a compound comprising R 2 But C 3-7 The compound of formula (I) is a cycloalkyl group.

[0122] In one embodiment, the present invention provides a compound comprising R 2 But C 6-10 The present invention relates to compounds of formula (I) in which the aryl group is

[0123] In one embodiment, the present invention provides a compound comprising R 2 optionally substituted C 3-10 The compound of formula (I) is a heterocyclic group.

[0124] In one embodiment, the present invention provides a compound comprising R 2 But C 5-10 The compound of formula (I) is a heteroaryl group.

[0125] In one embodiment, the present invention provides a compound comprising R 2 But NR 3 R 4 group (in the formula, R 3 and R 4 are independently H, C 1-4 Alkyl group, C 3-7 Cycloalkyl group or C 3-10 is a heterocyclic group).

[0126] In one embodiment, the present invention provides a compound comprising R 1 But C 1-2 is an alkyl group or a halo-methyl group, and R 2 But C 1-4 Alkyl groups, halo-methyl groups, C 1-2 Alkyl-S(O)2CH3 group, C 1-4 Alkoxy group, C 3-5 Cycloalkyl groups, phenyl groups, optionally substituted C 4-6 Heterocyclic groups, C 5-6 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are independently H, C 1-2 Alkyl group, C 3-5 Cycloalkyl group or C 4-7 is a heterocyclic group).

[0127] In one embodiment, the present invention provides a compound comprising R 1 is a methyl group, a difluoromethyl group, or a trifluoromethyl group, and R 2 But C1-4 Alkyl groups, halo-methyl groups, C 1-2 Alkyl-S(O)2CH3 group, C 1-4 Alkoxy group, C 3-5 Cycloalkyl groups, phenyl groups, optionally substituted C 4-6 Heterocyclic groups, C 5-6 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are independently H, C 1-2 Alkyl group, C 3-5 Cycloalkyl group or C 4-6 is a heterocyclic group).

[0128] In one embodiment, the present invention provides a compound comprising R 1 is a methyl group, a difluoromethyl group, or a trifluoromethyl group, and R 2 However, methyl group, fluoromethyl group, trifluoromethyl group, methylsulfonylmethane group, tert-butoxy group, C 3-4 Optionally substituted C containing 1 or 2 ring heteroatoms independently selected from cycloalkyl, phenyl, N, O and S 4-6 Heterocyclic groups, C containing 1 or 2 ring heteroatoms independently selected from N, O and S 5-6 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are each independently H, a methyl group, or C 3-4 Cycloalkyl group or C 5-6 is a heterocyclic group).

[0129] In one embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. 1-[6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]ethanone, 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, tert-butyl 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, 1-[6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]ethanone, 2-methanesulfonyl-1-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 2-cyclopropanecarbonyl-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-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridine-3-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-1lambda 6-thiane-1,1-dione, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxane-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-cyclobutanecarbonyl-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-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxolane-3-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyrrolidine-1-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, N,N-dimethyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxamide, 1-methyl-4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one, 4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-1-(propan-2-yl)pyrrolidin-2-one, 2-(4-methyl-1,2-oxazole-5-carbonyl)-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-(3-methyl-1,2-oxazole-5-carbonyl)-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-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxane-3-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 1-methyl-5-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)piperidin-2-one, (5R)-1-methyl-5-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one, (5S)-1-methyl-5-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one, 1-ethyl-4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one, 1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)ethan-1-one, 3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-N-(oxan-4-yl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazine-7-carboxamide, 4-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazine-7-carbonyl)morpholine, 2-methyl-5-[5-methyl-4-({[7-(oxane-4-carbonyl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-1,2-oxazol-3-yl]pyridine, 5-{4-[({7-cyclopropanecarbonyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-5-methyl-1,2-oxazol-3-yl}-2-methylpyridine, 1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)propan-1-one, 2-fluoro-1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)ethan-1-one, 2-methyl-1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)propan-1-one, 5-{4-[({7-cyclobutanecarbonyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-5-methyl-1,2-oxazol-3-yl}-2-methylpyridine, N-cyclopropyl-3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazine-7-carboxamide, 1-[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]ethan-1-one, 2-methanesulfonyl-1-[6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]ethan-1-one, 2,2,2-trifluoro-1-[6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]ethan-1-one, 1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 2-fluoro-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 2-methyl-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 2,2-dimethyl-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 3-methyl-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)butan-1-one, 2-benzoyl-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 2-cyclopropanecarbonyl-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-cyclobutanecarbonyl-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-(oxane-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 1-[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]ethan-1-one, 1-[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]propan-1-one, 2-fluoro-1-[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]ethan-1-one, 2-methyl-1-[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]propan-1-one, 2-cyclopropanecarbonyl-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, 1-[3-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone, 1-[3-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone, 1-[3-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone, 1-[6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]ethanone, 1-[6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]propan-1-one, 2-fluoro-1-[6-({4-methyl-1-[6-(difluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]ethan-1-one, 2-cyclopropanecarbonyl-6-({4-methyl-1-[6-(difluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-methyl-1-[6-({4-methyl-1-[6-(difluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propan-1-one, 1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 2,2-dimethyl-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 2-methyl-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 3-methyl-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)butan-1-one, 2-cyclopropanecarbonyl-6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-cyclobutanecarbonyl-6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-benzoyl-6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-fluoro-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxane-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, and 1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone The present invention relates to compounds of formula (I) as defined above selected from the group consisting of:

[0130] The following abbreviations have been used in describing the general synthesis, biological assays, intermediates and examples of compounds of formula (I): AcCN = acetonitrile Cs2CO3 = Cesium carbonate DCM = dichloromethane DIBAL-H = diisobutylaluminum hydride DIPEA = N-ethyl-N-(propan-2-yl)propan-2-amine DMF = N,N-dimethylformamide DMSO = dimethyl sulfoxide K2CO3 = Potassium Carbonate LiAlH4 = lithium aluminum hydride LiHMDS = lithium bis(trimethylsilyl)amide POCl3 = phosphorus oxychloride TBAF = tetrabutylammonium fluoride TBHP = tert-butyl hydroperoxide TfO = trifluoromethanesulfonic anhydride THF = tetrahydrofuran TLC = thin layer chromatography Brine = a highly concentrated solution of salt (usually sodium chloride)

[0131] Processes for the preparation of compounds of formula (I) The present invention also relates to a process for the preparation of a compound of formula (I) as defined above, which comprises: (i) reacting an amine derivative of formula (II) or a bicyclic amine derivative of formula (VI) with a compound represented by the formula (III) R 2 COCl (wherein, R 2 is C 1-4 Alkyl groups, halo-C 1-4 Alkyl group, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-7 Cycloalkyl groups, C 6-10 Aryl group, optionally substituted C 3-10 Heterocyclic groups, C 5-10 a heteroaryl group), or HNR of formula (IV) 3 R 4 (In the formula, R 3 and R 4 are independently H, C 1-4 Alkyl group, C 3-7 Cycloalkyl group or C 3-10 a heterocyclic group) to form an intermediate of formula (V) or (VII) 2 is as defined for formula (I) [ka] (ii) reacting the intermediate of formula (V) or (VII) with a compound of formula (VIII), (IX), (X), or (XI) according to step (a1), (a2), (b), or (c) to obtain a compound of formula (I): (a1) Reacting a compound of formula (V) with a compound of formula (IX) to give a compound of formula (Ia) (wherein X=CH, R 1 and R2 is as defined above), or [ka] (a2) Reacting a compound of formula (VII) with a compound of formula (VIII) to give a compound of formula (Ia) (wherein X=N, R 1 and R 2 is as defined above), or [ka] (b) reacting a compound of formula (VII) with a compound of formula (X) to form a compound of formula (Ib) (wherein X, R 1 and R 2 is as defined above), [ka] (c) reacting a compound of formula (VII) with a compound of formula (XI) to give a compound of formula (Ic) (wherein X, R 1 and R 2 is as defined above). [ka]

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

[0133] According to Scheme 1, a commercially available bicyclic amine derivative of formula (II) can be reacted with an R-type amine of formula (III) in a suitable base such as EtN. 2 Acylation with COCl provides an amide derivative of formula (V); or R 2 =NR 3 R4 amine derivatives of formula (II) can be converted to HNR 3 R 4 (In the formula, R 3 and R 4 is as defined above) to form a compound of formula (V). Acyl chlorides of formula (III) and amines of formula (IV) are commercially available or can be prepared by conventional methods, where R 2 The definition of is the same as that described above for formula (I).

[0134] In one aspect, the present invention provides a novel intermediate of formula (V) synthesized in the process for preparing compounds of general formula (I), wherein X is CH or N, and R 2 is C 1-4 Alkyl groups, halo-C 1-4 Alkyl group, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-7 Cycloalkyl groups, C 6-10 Aryl group, optionally substituted C 3-10 Heterocyclic groups, C 5-10 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are independently H, C 1-4 Alkyl group, C 3-7 Cycloalkyl group or C 3-10 heterocyclic group); preferably, R 2 But C 1-4 Alkyl groups, halo-methyl groups, C 1-2 Alkyl-S(O)2CH3 group, C 1-4 Alkoxy group, C 3-5 Cycloalkyl groups, phenyl groups, optionally substituted C 4-6 Heterocyclic groups, C 5-6 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3and R 4 are independently H, C 1-2 Alkyl group, C 3-5 Cycloalkyl group or C 4-7 heterocyclic group); more preferably, R 2 However, methyl group, fluoromethyl group, trifluoromethyl group, methylsulfonylmethane group, C 3-4 Optionally substituted C containing 1 or 2 ring heteroatoms independently selected from cycloalkyl, phenyl, N, O and S 4-6 Heterocyclic groups, C containing 1 or 2 ring heteroatoms independently selected from N, O and S 5-6 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are each independently H, a methyl group, or C 3-4 Cycloalkyl group or C 5-6 The compounds 2,5,6,8-tetrahydro-3-oxo-pyrido[3,4-c]pyridazine-7(3H)-carboxylic acid ethyl ester, 2,5,6,8-tetrahydro-3-oxo-pyrido[3,4-c]pyridazine-7(3H)-carboxylic acid methyl ester, 2,5,6,8-tetrahydro-3-oxo-pyrido[3,4-c]pyridazine-7(3H)-carboxylic acid 1,1-dimethylethyl ester and 3,4,6,7-tetrahydro-6-oxo-2,7-naphthyridine-2(1H)-carboxylic acid 1,1-dimethylethyl ester are known in the art (CN102924452A, WO2006 / 065215A1).

[0135] In one embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. 1-(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone, 1-(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-(methylsulfonyl)ethanone, cyclopropyl(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyridin-3-yl)methanone, (1,1-dioxidetetrahydro-2H-thiopyran-4-yl)(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyridin-4-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone, cyclobutyl(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydrofuran-3-yl)methanone, 4-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpyrrolidin-2-one, 4-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-(propan-2-yl)pyrrolidin-2-one, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(4-methyl-1,2-oxazol-5-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(3-methyl-1,2-oxazol-5-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-3-yl)methanone, 5-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpiperidin-2-one, (5R)-5-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpyrrolidin-2-one, (5S)-5-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpyrrolidin-2-one, 1-ethyl-4-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]pyrrolidin-2-one, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyrrolidin-1-yl)methanone, and 6-Hydroxy-N,N-dimethyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide The present invention relates to an intermediate of formula (V) selected from the group consisting of:

[0136] [ka]

[0137] According to Scheme 2, a compound of formula (VIII) is reacted with a chlorinating agent such as POCl to provide an intermediate of formula (IX). Both the hydroxy derivative of formula (VIII) and the intermediate of formula (IX) are known in the art (WO2018 / 104419A1; WO2019 / 238633A1) or can be synthesized by conventional methods.

[0138] [ka]

[0139] According to Scheme 3, esterification between an alcohol of formula (V) and an intermediate of formula (IX) can be achieved in a suitable solvent such as acetonitrile in the presence of a suitable base such as KCO to form a compound of formula (Ia).

[0140] Compounds of formula (Ia) (wherein X=N, R 1 and R 2 where is as defined in any of the embodiments described above) can be prepared according to Schemes 4 and 5.

[0141] [ka]

[0142] According to Scheme 4, the commercially available bicyclic amine derivative of formula (VI) can be reacted with the R 2 Acylation with COCl provides amide derivatives of formula (VII); or R 2 =NR 3 R 4 amine derivatives of formula (VI) can be converted to HNR 3 R 4 (In the formula, R 3 and R 4 is as defined above) to form a compound of formula (VII). Acyl chlorides of formula (III) and amines of formula (IV) are commercially available or can be prepared by conventional methods, where R 2 The definition of is the same as that described above for formula (I).

[0143] In one aspect, the present invention provides a novel intermediate of formula (VII) synthesized in the process for preparing compounds of general formula (I), wherein X is CH or N, and R 2 is C 1-4 Alkyl groups, halo-C 1-4 Alkyl group, C 1-4 Alkyl-S(O)2-C 1-4 Alkyl group, C 1-4 Alkoxy group, C 3-7 Cycloalkyl groups, C 6-10 Aryl group, optionally substituted C 3-10 Heterocyclic groups, C 5-10 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are independently H, C 1-4 Alkyl group, C 3-7Cycloalkyl or C 3-10 heterocyclic group); preferably, R 2 But C 1-4 Alkyl groups, halo-methyl groups, C 1-2 Alkyl-S(O)2CH3 group, C 1-4 Alkoxy group, C 3-5 Cycloalkyl groups, phenyl groups, optionally substituted C 4-6 Heterocyclic groups, C 5-6 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are independently H, C 1-2 Alkyl group, C 3-5 Cycloalkyl group or C 4-7 heterocyclic group); more preferably, R 2 However, methyl group, fluoromethyl group, trifluoromethyl group, methylsulfonylmethane group, C 3-4 Optionally substituted C containing 1 or 2 ring heteroatoms independently selected from cycloalkyl, phenyl, N, O and S 4-6 Heterocyclic groups, C containing 1 or 2 ring heteroatoms independently selected from N, O and S 5-6 Heteroaryl group, or NR 3 R 4 group (in the formula, R 3 and R 4 are each independently H, a methyl group, or C 3-4 Cycloalkyl group or C 5-6 heterocyclic group), provided that: X is CH and R 2 is a 3-pyridyl group or a [6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidin-5-yl] group; and R 2is a tert-butoxy group). The compounds (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)[6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidin-5-yl]-methanone; (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-3-pyridinyl-methanone; 3-chloro-5,8-dihydro-pyrido[3,4-c]pyrimidin-5-yl Ridazine-7(6H)-carboxylic acid 1,1-dimethylethyl ester; and 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylic acid 1,1-dimethylethyl ester are known in the art (WO2019 / 104285A1, US2016 / 102088A1, US2017 / 057966A1, WO2012 / 129344A1).

[0144] In one embodiment, the present invention provides a method for producing a medicament for the treatment of a pulmonary arthritis. 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone, 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-fluoroethanone, 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-methylpropan-1-one, 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2,2-dimethylpropan-1-one, 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-3-methylbutan-1-one, (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(phenyl)methanone, 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)propan-1-one, (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclopropyl)methanone, (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclobutyl)methanone, (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)ethanone, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(morpholin-4-yl)methanone, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(cyclopropyl)methanone, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)propan-1-one, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2-fluoroethanone, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2-methylpropan-1-one, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(cyclobutyl)methanone, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2-(methylsulfonyl)ethanone, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2,2,2-trifluoroethanone, 3-chloro-N-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxamide, and 3-Chloro-N-cyclopropyl-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxamide The present invention relates to an intermediate of formula (VII) selected from the group consisting of:

[0145] [ka]

[0146] According to Scheme 5, etherification between amide derivatives of formula (VII) and hydroxy derivatives of formula (VIII) can be carried out by a palladium-mediated process in the presence of a suitable base such as CsCO to provide compounds of formula (Ia).

[0147] A compound of formula (Ib) 1 and R 2 where is as defined in any of the embodiments described above) can be prepared according to Schemes 6 and 7.

[0148] [ka]

[0149] In the first step, a compound of formula (1) is reacted with ethyl acetoacetate in a suitable solvent such as DMSO to give a compound of formula (2), which is then coupled with N-tosylhydrazide in the presence of KI and TBHP to give a compound of formula (3) (Huang et al. Adv. Synth. Catal. 2018, 360:3117-3123). Treatment of a compound of formula (4) with a reducing agent such as DIBAL-H in a suitable solvent such as toluene gives a compound of formula (X). Alternatively, a compound of formula (1) is converted into 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 (X).

[0150] In one aspect, the present invention provides novel intermediates of formula (X) (wherein R 1 is C 1-4 Alkyl or halo-C 1-4 is an alkyl group, preferably C 1-2is an alkyl group or a halo-methyl group), more preferably the intermediate of formula (X) is [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol, {4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methanol, or {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol is.

[0151] [ka]

[0152] According to Scheme 7, etherification between amide derivatives of formula (VII) and hydroxy derivatives of formula (X) can be carried out by a palladium-mediated process in the presence of a suitable base such as CsCO to provide compounds of formula (Ib).

[0153] A compound of formula (Ic) 1 and R 2 wherein is as defined in any of the embodiments described above) can be prepared according to Schemes 8 and 9. [ka]

[0154] In the first step, a compound of formula (5) is reacted with ethyl acetate in the presence of a suitable base, such as LiHMDS, to give a compound of formula (6), which is then reacted with triphenylphosphine oxide and TfO in the presence of a base, such as triethylamine, in a suitable solvent, such as 1,2-dichloroethane, to give a compound of formula (7). The compound of formula (7) is reacted with trimethylsilylmethyl azide in the presence of a base, such as DIPEA, in a suitable solvent, such as DMF, to give a compound of formula (8). Treatment of the compound of formula (8) with a reducing agent, such as LiAlH, in a suitable solvent, such as THF, gives a compound of formula (9), which is treated with TBAF in a suitable solvent, such as THF, to give a compound of formula (XI).

[0155] In one aspect, the present invention provides a novel intermediate of formula (XI) (wherein R 1 is C 1-4 Alkyl or halo-C 1-4 is an alkyl group, preferably C 1-2 The intermediate of formula (XI) is [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol, and is most preferably an alkyl group or a halo-methyl group, and most preferably a methyl group, a difluoromethyl group, or a trifluoromethyl group. In one embodiment, the intermediate of formula (XI) is [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol. [ka]

[0156] According to Scheme 9, etherification between amide derivatives of formula (VII) and hydroxy derivatives of formula (XI) can be carried out by a palladium-mediated process in the presence of a suitable base such as CsCO to provide compounds of formula (Ic).

[0157] The reagents required for the above reactions and detailed process steps are given in the examples.

[0158] The activity data for each of the compounds of formula (I) of the present invention are determined in vitro by the methods described below.

[0159] Biological Example 1: Binding Assays GABA receptor binding assays used A α5β3γ2 protein is human recombinant GABA A The membranes were derived from HEK cells (Millipore CYL3073) expressing α5β3γ2 receptors. Cells were stored and cultured internally according to the instructions provided by the supplier (Millipore). The cell pellet was homogenized 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, using an Ultra Turrax (Janke & Kunkel) at maximum speed for 15 seconds at 4°C. The homogenate was centrifuged at 40,000 g for 30 minutes at 4°C. The supernatant was discarded, and the resulting pellet was washed with membrane preparation buffer. The pellet was resuspended in membrane preparation buffer, and aliquots in 1.4 mL ampoules were stored at -70°C until use.

[0160] Receptor binding assays were performed in a 96-well format in deep well plates. For each 96-well plate, one ampoule of membrane homogenate was thawed and diluted in binding buffer (50 mM Tris pH=7.4, 100 mM KCl), and 200 μL was dispensed into each well. 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. An additional 50 μL of test compound at the appropriate concentration was added. The final assay volume was 300 μL. Incubation was carried out at 4°C for 60 minutes. 10 μM unlabeled diazepam was used for nonspecific binding. 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 at 40°C for 1 hour, and 40 μL of Microscint (Perkin Elmer) scintillation cocktail was added to each well. Plates were read in a Microbeta (Perkin Elmer).

[0161] Specific radioligand binding (SB) was defined as the difference between total binding (Tot) and nonspecific binding (NSB). Results are expressed as percent inhibition of specific binding obtained in the presence of the compound of interest.

[0162] I C 50 and K. i A minimum of six drug concentrations were used in triplicate to determine IC 50 K values ​​(i.e., the concentration of compound giving 50% inhibition of specific binding) were calculated from the concentration-displacement curves by sigmoidal fitting using Origin 7.5 software. i The value (i.e., the inhibition constant) was calculated using the Cheng-Prusoff equation K i =IC 50 / [1+(L / K D )] (where [L] is the radioligand concentration and K D is the affinity of the labeled ligand for the receptor). D was determined from saturation analysis.

[0163] Compounds of the invention were tested in the assays described above and all exhibited GABAergic activity. AIt was found to have high affinity (Ki<100 nM) for the α5 receptor.

[0164] [Table 1]

[0165] 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.

[0166] Human Recombinant GABA A HEK293 cell line (Millipore, CYL3053) stably expressing the α5β3γ2 receptor subunit was cultured in DMEM medium supplemented with 10% FBS (Gibco), passaged twice a week, and plated onto Petri dishes precoated with poly- d -lysine.

[0167] Automated whole-cell patch-clamp recordings were performed on 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 in serum-free basal medium (Gibco, CHO-S-SFM-II) containing 12.5 mM HEPES, 1× penicillin-streptomycin-amphotericin (SigmaMix), and soybean trypsin inhibitor (Sigma, 0.04 mg / ml) after centrifugation (125 g, 3 min, 2×).

[0168] 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 CaCl, 2 mM MgCl, 10 mM glucose, and 0.1% DMSO, pH = 7.35–7.4) and intracellular solution (80 mM KCl, 50 mM KF, 36 mM KOH, 10 mM EGTA, 10 mM HEPES, 1.75 mM MgCl, 0.5 mM CaCl, 4 mM NaATP, 14 mM phosphocreatine, 50 U / ml creatine phosphokinase, and 0.3 mM GTP, pH = 7.25–7.3) were added to a QPatch-HTX automated patch clamp system (Sophion) in single-cell mode at room temperature. Inward currents were elicited at a holding potential of -80 mV by 3-second long applications of 1 μM of the control agonist GABA at 2-4 min intervals: first five times in a concentration-matched DMSO (0.1 or 0.3%) control solution, 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 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.

[0169] Percentage modulation was calculated from comparison of the amplitude of the GABA-evoked peak current in the presence and absence of test compound.

[0170] Compounds of the invention were tested at 1 μM in the assay described above and all exhibited GABAergic activity. A It was found to have positive allosteric modulator activity of α5.

[0171] [Table 2] [Example]

[0172] 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 intermediates and examples, those skilled in the art can ascertain the essential features of the present invention, and can 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 illustrative examples, but rather is limited in scope by the appended claims.

[0173] In general, compounds of formula (I) can be prepared according to the common general knowledge of those skilled in the art and / or the methods described for 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 such as compounds of formulas (II), (III), (IV), (VI), (1), and (5) 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.

[0174] 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) was dissolved in 30 mL of phosphorus oxychloride. The reaction mixture was stirred at 115° C. for 2 hours and then evaporated to dryness. Ethyl acetate was added, 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] + .

[0175] 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] + .

[0176] Intermediate 3 [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol [ka]

[0177] 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 hours. After cooling, the inorganics were filtered off and the filtrate was concentrated under reduced pressure to give a residue that was used in the next step without further purification. MS (ESI) m / z: 207.1 [M+H] + .

[0178] 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, and 6.26 g (37.7 mmol) of potassium iodide in 70 mL of DMSO, 7.31 mL (75.5 mmol) of TBHP (70% aqueous solution) was slowly added. The mixture was then stirred at 70 °C for 24 h. After the reaction was completed (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 MgSO, filtered, and concentrated in vacuo. 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] + .

[0179] 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 toluene solution) was added dropwise under argon, and the reaction mixture was stirred at room temperature for 1 hour. 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 vacuo. 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] + .

[0180] 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 NaNO dissolved in 12 mL of water was added dropwise. The reaction mixture was stirred at 0 °C for 20 minutes, and then 10.6 mL (80 mmol) of trimethylsilyl azide was slowly added dropwise, and the reaction mixture was stirred at room temperature for 1.5 hours. Upon completion, 70 mL of ethyl acetate was added, washed three times with 30 mL of saturated sodium carbonate solution and water, dried over anhydrous sodium sulfate, and evaporated. The crude product was used in the next step without further purification.

[0181] 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] + .

[0182] 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] + .

[0183] 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] +。

[0184] Intermediate 6 [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol [ka]

[0185] a: Ethyl 3-(6-methylpyridin-3-yl)-3-oxopropanoate 25 g (170 mmol) of commercially available methyl-6-methylnicotinate was dissolved in 97 mL (992 mmol) of ethyl acetate and cooled to -50°C under an argon atmosphere. 165 mL of lithium bis(trimethylsilyl)amide (1 M in THF) was added dropwise to the solution. The cooling bath was removed and the mixture was allowed to warm to room temperature. The conversion was checked by TLC (eluent: cyclohexane: EtOAc = 1:1, silica plate). The reaction mixture was washed with saturated sodium carbonate solution and water, dried over anhydrous sodium sulfate, and evaporated. The resulting residue was purified by flash column chromatography (silica gel, eluent: cyclohexane: EtOAc 50% gradient). Yield: 22.71 g (66%). MS (ESI) m / z: 208.1 [M+H] + .

[0186] b: Ethyl 3-(6-methylpyridin-3-yl)prop-2-ynoate Under an argon atmosphere, 25 g (90 mmol) of triphenylphosphine oxide was dissolved in 100 mL of 1,2-dichloroethane and cooled in an ice-water bath. 15.5 mL (92 mmol) of trifluoromethanesulfonic anhydride was added dropwise. After stirring for 15 min, a solution of 7.94 g (38.3 mmol) of ethyl 3-(6-methylpyridin-3-yl)-3-oxopropanoate in 70 mL of 1,2-dichloroethane was added, followed by the dropwise addition of 25 mL (180 mmol) of triethylamine. After the addition was complete, the reaction mixture was refluxed for 1 h. The conversion was checked by TLC (eluent: cyclohexane: EtOAc = 1:1, silica plate). The reaction mixture was washed with water, dried over anhydrous sodium sulfate, and evaporated. The resulting residue was purified by flash column chromatography (silica gel, eluent: cyclohexane: EtOAc 50% gradient). Yield: 2.90g (40%). MS(ESI)m / z:190.1[M+H] + .

[0187] c: ethyl 1-trimethylsilanylmethyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazole-5-carboxylate To a suspension of 584 mg (3.07 mmol) of copper(I) iodide in 35 mL of DMF, 2.61 mL (15.3 mmol) of DIPEA and 2.90 g (15 mmol) of ethyl 3-(6-methylpyridin-3-yl)prop-2-ynoate were added, followed by 11.6 g (90 mmol) of trimethylsilylmethyl azide at room temperature. The reaction mixture was stirred at 120 °C for 3 hours. The mixture was poured into water and extracted with ethyl acetate. The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and evaporated. The resulting residue was purified by flash column chromatography (reverse-phase silica gel, eluent: AcCN:HO 50% gradient). Yield: 1.53 g (31%). MS (ESI) m / z: 319.2 [M+H] + .

[0188] d: [1-trimethylsilanylmethyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol Under an argon atmosphere, 1.53 g (4.80 mmol) of ethyl 1-trimethylsilanylmethyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazole-5-carboxylate was dissolved in 30 mL of anhydrous THF and cooled to 0 °C. 179 mg (5.28 mmol) of LiAlH was added in portions. After the addition was complete, the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was poured into an ice-cold solution of saturated sodium carbonate solution, ethyl acetate was added, and the mixture was filtered over Celite. The organic layer was separated, dried over NaSO, filtered, and evaporated in vacuo. The crude product was used in the next step without further purification. Yield: 1.25 g (94%), MS (ESI) m / z: 277.2 [M+H] + .

[0189] e: [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol To a solution of 1.25 g (4.52 mmol) of [1-trimethylsilanylmethyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol in 20 mL of THF, 1.42 g (5.06 mmol) of tetrabutylammonium fluoride hydrate was added dropwise at room temperature and stirred for 1 h. The THF was evaporated, and the residue was dissolved in ethyl acetate and washed with water. The organic layer was separated, dried over Na2SO4, filtered, and evaporated in vacuo. Purification of the residue by flash column chromatography (silica gel, eluent: DCM:MeOH, 0-10% gradient) afforded the desired product. Yield: 0.48 g (52%), MS (ESI) m / z: 205.1 [M+H] + .

[0190] Intermediate 7 1-(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone [ka] 370 mg (2.46 mmol) of commercially available 5,6,7,8-tetrahydro-2,7-naphthyridin-3-ol was dissolved in 30 mL of anhydrous dichloromethane. 1.37 mL (9.85 mmol) of anhydrous triethylamine was added to the solution in one portion, and the reaction mixture was cooled in an ice-water bath. A solution of 0.19 mL (2.46 mmol) of acetyl chloride in 5 mL of anhydrous dichloromethane was added dropwise to the stirring reaction mixture. The cooling bath was removed, and the mixture was allowed to warm to room temperature. The conversion was checked by TLC (eluent: DCM:MeOH = 95:5, silica plate). The reaction mixture was evaporated and purified by flash column chromatography (silica gel, eluent: DCM:MeOH, 0-5% gradient) to give the desired product. Yield: 0.20 g (42%), MS (ESI) m / z: 193.1 [M+H] + .

[0191] [Table 3-1]

[0192] [Table 3-2]

[0193] [Table 3-3]

[0194] Intermediate 28 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone [ka] 500 mg (2.44 mmol) of 6-chloro-1,2,3,4-tetrahydro-2,7-naphthyridine hydrochloride was dissolved in 30 mL of anhydrous dichloromethane. 542 mg (0.75 mL, 5.36 mmol) of anhydrous triethylamine was added to this solution in one portion, and the reaction mixture was cooled in an ice-water bath. A solution of 191 mg (0.174 mL, 2.44 mmol) of acetyl chloride in 5 mL of anhydrous dichloromethane was added dropwise to the stirring reaction mixture over 10 minutes. The cooling bath was removed, and the mixture was allowed to warm to room temperature. The conversion was checked by TLC (eluent: DCM:MeOH = 95:5, silica plate). The reaction mixture was washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and evaporated. Yield: 420 mg (82%), a white solid identified as the title compound. MS (ESI) m / z: 211.1 [M+H] + .

[0195] [Table 4]

[0196] Intermediate 38 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)ethanone [ka] 530 mg (2.57 mmol) of 3-chloro-5,6,7,8-tetrahydropyrido[3,4-c]pyridazine hydrochloride was dissolved in 20 mL of anhydrous dichloromethane. 520 mg (0.716 mL, 5.14 mmol) of anhydrous triethylamine was added to this solution in one portion, and the reaction mixture was cooled in an ice-water bath. A solution of 264 mg (2.59 mmol) of acetyl chloride in 5 mL of anhydrous dichloromethane was added dropwise to the stirring reaction mixture over 10 min. The cooling bath was removed, and the mixture was allowed to warm to room temperature. The conversion was checked by TLC (eluent: DCM:MeOH = 9:1, silica plate). The reaction mixture was washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and evaporated. The crude product was purified by flash column chromatography (silica gel, eluent: DCM:MeOH, 0-10% gradient) to give the desired product. Yield: 340 mg (62.5%), MS (ESI) m / z: 212.1 [M+H] + .

[0197] [Table 5]

[0198] Intermediate 48 3-chloro-N-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxamide [ka] To a solution of 125 mg (1.24 mmol) of 4-aminotetrahydropyran in 15 mL of anhydrous dichloromethane, 528 mg (0.712 mL, 3.02 mmol) of DIPEA was added in one portion. The reaction mixture was cooled in an ice-water bath, and then 148 mg (0.50 mmol) of bis(trichloromethyl)carbonate was added in one portion. The resulting solution was stirred for 30 min, and then 230 mg (1.07 mmol) of 3-chloro-5,6,7,8-tetrahydropyrido[3,4-c]pyridazine hydrochloride was added in portions over a period of 5 min. The cooling bath was removed, and the mixture was allowed to warm to room temperature and stirred for 8 h. The reaction mixture was washed with saturated sodium bicarbonate solution and water, dried over anhydrous sodium sulfate, and evaporated. The resulting residue was purified by flash column chromatography (silica gel, eluent: DCM:MeOH, 0-10% gradient). Yield: 154 mg (38%), a white amorphous solid identified as the title compound. MS (ESI) m / z: 297.1 [M+H] + .

[0199] Intermediate 49 3-Chloro-N-cyclopropyl-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxamide [ka] The compound was prepared according to the procedure described for intermediate 48 using commercially available cyclopropylamine. Yield: 143 mg (51%), MS (ESI) m / z: 253.1 [M+H] + .

[0200] Example 1 1-[6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]ethanone [ka] 232 mg (1.04 mmol) of 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and 200 mg (1.04 mmol) of 1-(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone (Intermediate 7) were dissolved in 20 mL of anhydrous acetonitrile. 431 mg (3.12 mmol) of anhydrous potassium carbonate was then added to the solution, and the suspension was stirred under reflux for 2 hours. The conversion was followed by TLC (eluent: DCM:MeOH = 10:1, silica plate). After the reaction was complete, the mixture was filtered and evaporated to give 410 mg of an oily crude product, which was purified by flash column chromatography (silica gel, eluent: DCM:MeOH, 0-10% gradient). Yield: 100 mg (25.4%), white solid. MS(ESI)m / z:379.2[M+H] + .

[0201] Example 2 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 [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-methylpyridine (Intermediate 1) and tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (Intermediate 8). MS (ESI) m / z: 437.3 [M+H] + .

[0202] Example 3 tert-Butyl 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate [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) and tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate (Intermediate 8). MS (ESI) m / z: 491.2 [M+H] + .

[0203] Example 4 1-[6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]ethanone [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) and 1-(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone (Intermediate 7). MS (ESI) m / z: 433.1 [M+H] + .

[0204] Example 5 2-Methanesulfonyl-1-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one [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-methylpyridine (Intermediate 1) and 1-(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-(methylsulfonyl)ethanone (Intermediate 9). MS (ESI) m / z: 457.1 [M+H] + .

[0205] Example 6 2-Cyclopropanecarbonyl-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 1 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and cyclopropyl(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)methanone (Intermediate 10). MS (ESI) m / z: 405.2 [M+H] + .

[0206] Example 7 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridine-3-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine [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-methylpyridine (Intermediate 1) and (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyridin-3-yl)methanone (Intermediate 11). MS (ESI) m / z: 442.2 [M+H] + .

[0207] Example 8 4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-1lambda 6-thiane-1,1-dione [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-methylpyridine (Intermediate 1) and (1,1-dioxidetetrahydro-2H-thiopyran-4-yl)(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)methanone (Intermediate 12). MS (ESI) m / z: 497.2 [M+H] + .

[0208] Example 9 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine [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-methylpyridine (Intermediate 1) and (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyridin-4-yl)methanone (Intermediate 13). MS (ESI) m / z: 442.2 [M+H] + .

[0209] Example 10 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxane-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine [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-methylpyridine (Intermediate 1) and (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (Intermediate 14). MS (ESI) m / z: 449.3 [M+H] + .

[0210] Example 11 2-Cyclobutanecarbonyl-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 1 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and cyclobutyl(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)methanone (Intermediate 15). MS (ESI) m / z: 419.2 [M+H] + .

[0211] Example 12 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxolane-3-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine [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-methylpyridine (Intermediate 1) and (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydrofuran-3-yl)methanone (Intermediate 16). MS (ESI) m / z: 435.2 [M+H] + .

[0212] Example 13 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyrrolidine-1-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine [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-methylpyridine (Intermediate 1) and (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyrrolidin-1-yl)methanone (Intermediate 26). MS (ESI) m / z: 434.3 [M+H] + .

[0213] Example 14 N,N-Dimethyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxamide [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-methylpyridine (Intermediate 1) and 6-hydroxy-N,N-dimethyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide (Intermediate 27). MS (ESI) m / z: 408.1 [M+H] + .

[0214] Example 15 1-methyl-4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one [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-methylpyridine (Intermediate 1) and 4-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpyrrolidin-2-one (Intermediate 17). MS (ESI) m / z: 462.3 [M+H] + .

[0215] Example 16 4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-1-(propan-2-yl)pyrrolidin-2-one [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-methylpyridine (Intermediate 1) and 4-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-(propan-2-yl)pyrrolidin-2-one (Intermediate 18). MS (ESI) m / z: 490.2 [M+H] + .

[0216] Example 17 2-(4-methyl-1,2-oxazole-5-carbonyl)-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 1 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(4-methyl-1,2-oxazol-5-yl)methanone (Intermediate 19). MS (ESI) m / z: 446.2 [M+H] + .

[0217] Example 18 2-(3-methyl-1,2-oxazole-5-carbonyl)-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 1 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(3-methyl-1,2-oxazol-5-yl)methanone (Intermediate 20). MS (ESI) m / z: 446.2 [M+H] + .

[0218] Example 19 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxane-3-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine [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-methylpyridine (Intermediate 1) and (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-3-yl)methanone (Intermediate 21). MS (ESI) m / z: 449.2 [M+H] + .

[0219] Example 20 1-Methyl-5-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)piperidin-2-one [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-methylpyridine (Intermediate 1) and 5-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpiperidin-2-one (Intermediate 22). MS (ESI) m / z: 476.3 [M+H] + .

[0220] Example 21 (5R)-1-Methyl-5-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one [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-methylpyridine (Intermediate 1) and (5R)-5-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpyrrolidin-2-one (Intermediate 23). MS (ESI) m / z: 462.2 [M+H] + .

[0221] Example 22 (5S)-1-Methyl-5-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one [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-methylpyridine (Intermediate 1) and (5S)-5-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpyrrolidin-2-one (Intermediate 24). MS (ESI) m / z: 462.2 [M+H] + .

[0222] Example 23 1-Ethyl-4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one [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-methylpyridine (Intermediate 1) and 1-ethyl-4-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]pyrrolidin-2-one (Intermediate 25). MS (ESI) m / z: 476.2 [M+H] + .

[0223] Example 24 1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)ethan-1-one [ka] Under an argon atmosphere, a flask was charged with 196 mg (0.926 mmol) of 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)ethanone (Intermediate 38), 189 mg (0.926 mmol) of 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1), 603 mg (1.85 mmol) of CsCO, 37 mg (0.093 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 21 mg (0.094 mmol) of Pd(OAc), and 10 mL of anhydrous toluene. The mixture was stirred at 100 °C for 12 h. The conversion was checked by TLC (cyclohexane: EtOAc = 1:1, silica plate as eluent). The reaction mixture was filtered through a pad of Celite, washed with acetone, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash column chromatography (silica gel, eluent: cyclohexane:EtAOc=1:1). Yield: 71 mg (20%), white amorphous solid. MS (ESI) m / z: 380.3 [M+H] + .

[0224] Example 25 3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-N-(oxan-4-yl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazine-7-carboxamide [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and 3-chloro-N-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxamide (Intermediate 48). MS (ESI) m / z: 465.3 [M+H] + .

[0225] Example 26 4-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazine-7-carbonyl)morpholine [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(morpholin-4-yl)methanone (Intermediate 39). MS (ESI) m / z: 451.2 [M+H] + .

[0226] Example 27 2-Methyl-5-[5-methyl-4-({[7-(oxane-4-carbonyl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-1,2-oxazol-3-yl]pyridine [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (Intermediate 40). MS (ESI) m / z: 450.2 [M+H] + .

[0227] Example 28 5-{4-[({7-cyclopropanecarbonyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-5-methyl-1,2-oxazol-3-yl}-2-methylpyridine [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(cyclopropyl)methanone (Intermediate 41). MS (ESI) m / z: 406.2 [M+H] + .

[0228] Example 29 1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)propan-1-one (Intermediate 42). MS (ESI) m / z: 394.2 [M+H] + .

[0229] Example 30 2-Fluoro-1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2-fluoroethanone (Intermediate 43). MS (ESI) m / z: 398.2 [M+H] + .

[0230] Example 31 2-Methyl-1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2-methylpropan-1-one (Intermediate 44). MS (ESI) m / z: 408.2 [M+H] + .

[0231] Example 32 5-{4-[({7-cyclobutanecarbonyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-5-methyl-1,2-oxazol-3-yl}-2-methylpyridine [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(cyclobutyl)methanone (Intermediate 45). MS (ESI) m / z: 420.1 [M+H] + .

[0232] Example 33 N-Cyclopropyl-3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazine-7-carboxamide [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1) and 3-chloro-N-cyclopropyl-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxamide (Intermediate 49). MS (ESI) m / z: 421.2 [M+H] + .

[0233] Example 34 1-[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]ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Intermediate 2) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)ethanone (Intermediate 38). MS (ESI) m / z: 434.2 [M+H] + .

[0234] Example 35 2-Methanesulfonyl-1-[6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Intermediate 2) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2-(methylsulfonyl)ethanone (Intermediate 46). MS (ESI) m / z: 511.1 [M+H] + .

[0235] Example 36 2,2,2-trifluoro-1-[6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Intermediate 2) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2,2,2-trifluoroethanone (Intermediate 47). MS (ESI) m / z: 487.2 [M+H] + .

[0236] Example 37 1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone (Intermediate 28). MS (ESI) m / z: 379.2 [M+H] + .

[0237] Example 38 2-Fluoro-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-fluoroethanone (Intermediate 29). MS (ESI) m / z: 397.1 [M+H] + .

[0238] Example 39 2-Methyl-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-methylpropan-1-one (Intermediate 30). MS (ESI) m / z: 407.2 [M+H] + .

[0239] Example 40 2,2-Dimethyl-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2,2-dimethylpropan-1-one (Intermediate 31). MS (ESI) m / z: 421.2 [M+H] + .

[0240] Example 41 3-methyl-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)butan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-3-methylbutan-1-one (Intermediate 32). MS (ESI) m / z: 421.2 [M+H] + .

[0241] Example 42 2-Benzoyl-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 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(phenyl)methanone (Intermediate 33). MS (ESI) m / z: 441.2 [M+H] + .

[0242] Example 43 1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)propan-1-one (Intermediate 34). MS (ESI) m / z: 393.2 [M+H] + .

[0243] Example 44 2-Cyclopropanecarbonyl-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 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclopropyl)methanone (Intermediate 35). MS (ESI) m / z: 405.2 [M+H] + .

[0244] Example 45 2-Cyclobutanecarbonyl-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 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclobutyl)methanone (Intermediate 36). MS (ESI) m / z: 419.2 [M+H] + .

[0245] Example 46 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxane-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (Intermediate 37). MS (ESI) m / z: 449.2 [M+H] + .

[0246] Example 47 1-[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]ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [{4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methanol (Intermediate 4) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone (Intermediate 28). MS (ESI) m / z: 433.2 [M+H] + .

[0247] Example 48 1-[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]propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [{4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methanol (Intermediate 4) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)propan-1-one (Intermediate 34). MS (ESI) m / z: 447.2 [M+H] + .

[0248] Example 49 2-Fluoro-1-[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]ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [{4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methanol (Intermediate 4) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-fluoroethanone (Intermediate 29). MS (ESI) m / z: 451.1 [M+H] + .

[0249] Example 50 2-Methyl-1-[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]propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [{4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methanol (Intermediate 4) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-methylpropan-1-one (Intermediate 30). MS (ESI) m / z: 461.2 [M+H] + .

[0250] Example 51 2-Cyclopropanecarbonyl-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 24 using [{4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methanol (Intermediate 4) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclopropyl)methanone (Intermediate 35). MS (ESI) m / z: 459.2 [M+H] + .

[0251] Example 52 1-[3-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone [ka] The title compound was prepared according to the procedure described for Example 24 using [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)ethanone (Intermediate 38). MS (ESI) m / z: 380.2 [M+H] + .

[0252] Example 53 1-[3-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone [ka] The title compound was prepared according to the procedure described for Example 24 using [{4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methanol (Intermediate 4) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)ethanone (Intermediate 38). MS (ESI) m / z: 434.2 [M+H] + .

[0253] Example 54 1-[3-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone [ka] The title compound was prepared according to the procedure described for Example 24 using {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol (Intermediate 5) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)ethanone (Intermediate 38). MS (ESI) m / z: 416.2 [M+H] + .

[0254] Example 55 1-[6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]ethanone [ka] The title compound was prepared according to the procedure described for Example 24 using {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol (Intermediate 5) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone (Intermediate 28). MS (ESI) m / z: 415.2 [M+H] + .

[0255] Example 56 1-[6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol (Intermediate 5) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)propan-1-one (Intermediate 34). MS (ESI) m / z: 429.2 [M+H] + .

[0256] Example 57 2-Fluoro-1-[6-({4-methyl-1-[6-(difluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol (Intermediate 5) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-fluoroethanone (Intermediate 29). MS (ESI) m / z: 433.2 [M+H] + .

[0257] Example 58 2-Cyclopropanecarbonyl-6-({4-methyl-1-[6-(difluoromethyl)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 24 using {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol (Intermediate 5) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclopropyl)methanone (Intermediate 35). MS (ESI) m / z: 441.2 [M+H] + .

[0258] Example 59 2-Methyl-1-[6-({4-methyl-1-[6-(difluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol (Intermediate 5) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-methylpropan-1-one (Intermediate 30). MS (ESI) m / z: 443.2 [M+H] + .

[0259] Example 60 1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)ethanone (Intermediate 28). MS (ESI) m / z: 379.2 [M+H] + .

[0260] Example 61 2,2-Dimethyl-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2,2-dimethylpropan-1-one (Intermediate 31). MS (ESI) m / z: 421.2 [M+H] + .

[0261] Example 62 1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)propan-1-one (Intermediate 34). MS (ESI) m / z: 393.2 [M+H] + .

[0262] Example 63 2-Methyl-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-methylpropan-1-one (Intermediate 30). MS (ESI) m / z: 407.2 [M+H] + .

[0263] Example 64 3-Methyl-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)butan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-3-methylbutan-1-one (Intermediate 32). MS (ESI) m / z: 421.2 [M+H] + .

[0264] Example 65 2-Cyclopropanecarbonyl-6-{[1-methyl-4-(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 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclopropyl)methanone (Intermediate 35). MS (ESI) m / z: 405.2 [M+H] + .

[0265] Example 66 2-Cyclobutanecarbonyl-6-{[1-methyl-4-(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 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclobutyl)methanone (Intermediate 36). MS (ESI) m / z: 419.2 [M+H] + .

[0266] Example 67 2-Benzoyl-6-{[1-methyl-4-(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 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(phenyl)methanone (Intermediate 33). MS (ESI) m / z: 441.2 [M+H] + .

[0267] Example 68 2-Fluoro-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one [ka] The title compound was prepared according to the procedure described for Example 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-fluoroethanone (Intermediate 29). MS (ESI) m / z: 397.2 [M+H] + .

[0268] Example 69 6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxane-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine [ka] The title compound was prepared according to the procedure described for Example 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone (Intermediate 37). MS (ESI) m / z: 397.2 [M+H] + .

[0269] Example 70 1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone [ka] The title compound was prepared according to the procedure described for Example 24 using [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6) and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)ethanone (Intermediate 38). MS (ESI) m / z: 408.2 [M+H] + .

[0270] Examples of pharmaceutical preparations The following formulation examples show representative pharmaceutical compositions of the present invention, but the present invention is not limited to the following pharmaceutical compositions.

[0271] 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%

[0272] II. Oral dispersible films Active ingredient 0.01~90% Film-forming agent 1~99.9% Plasticizer 0~40% Other specific excipients 0-50%

[0273] B) Liquid oral dosage form III. Oral suspension Active ingredient 0.01~50% Liquid medium 10~99.9% Wetting agent 0~50% Thickener 0~50% Buffer agent (appropriate amount) Osmotic drugs 0-50% Preservative (appropriate amount)

[0274] IV. Syrup Active ingredient 0.01~50% Solvent 10~99.9% Sugar component 1~20% Flavoring agent 0~10%

[0275] C) Parenteral dosage forms V. Intravenous injections Active ingredient 0.01~50% Solvent 10~99.9% Co-solvent 0~99.9% Osmotic drugs 0-50% Buffer agent (appropriate amount)

[0276] 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)

[0277] 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)

[0278] VIII. Nasal 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) 【Chemistry 1】 (In the formula, A is, 【Chemistry 2】 is represented by R １ is C １－４ Alkyl group or halo-C １－４ is an alkyl group, R ２ is C １－４ Alkyl group, halo-C １－４ Alkyl group, C １－４ Alkyl-S(O) ２ -C １－４ Alkyl group, C １－４ Alkoxy group, C ３－７ Cycloalkyl group, C ６－１０ aryl group, optionally substituted C ３－１０ Heterocyclic group, C ５－１０ heteroaryl group, or NR ３ R ４ group (in the formula, R ３ and R ４ are each independently H, C １－４ Alkyl group, C ３－７ Cycloalkyl group or C ３－１０ a heterocyclic group; X is CH or N. and / or its salts, and / or its stereoisomers, and / or its enantiomers, and / or its racemates, and / or its diastereomers, and / or its solvates, and / or its hydrates, and / or its polymorphs. 【Request Item 2】 【Chemistry 3】 (In the formula, R １ is C １－４ Alkyl group or halo-C １－４ is an alkyl group, R ２ is C １－４ Alkyl group, halo-C １－４ Alkyl group, C １－４ Alkyl-S(O) ２ -C １－４ Alkyl group, C １－４ Alkoxy group, C ３－７ Cycloalkyl group, C ６－１０ aryl group, optionally substituted C ３－１０ Heterocyclic group, C ５－１０ heteroaryl group, or NR ３ R ４ group (in the formula, R ３ and R ４ are each independently H, C １－４ Alkyl group, C ３－７ Cycloalkyl group or C ３－１０ a heterocyclic group; X is CH or N.

2. The compound of claim 1, wherein: 【Request Item 3】 【Chemistry 4】 (In the formula, R １ is C １－４ Alkyl group or halo-C １－４ is an alkyl group, R ２ is C １－４ Alkyl group, halo-C １－４ Alkyl group, C １－４ Alkyl-S(O) ２ -C １－４ Alkyl group, C １－４ Alkoxy group, C ３－７ Cycloalkyl group, C ６－１０ aryl group, optionally substituted C ３－１０ Heterocyclic group, C ５－１０ heteroaryl group, or NR ３ R ４ group (in the formula, R ３ and R ４ are each independently H, C １－４ Alkyl group, C ３－７ Cycloalkyl group or C ３－１０ a heterocyclic group; X is CH or N.

2. The compound of claim 1, wherein: [Request Item 4] [Chemistry 5] (In the formula, R １ is C １－４ Alkyl group or halo-C １－４ is an alkyl group, R ２ is C １－４ Alkyl group, halo-C １－４ Alkyl group, C １－４ Alkyl-S(O) ２ -C １－４ Alkyl group, C １－４ Alkoxy group, C ３－７ Cycloalkyl group, C ６－１０ aryl group, optionally substituted C ３－１０ Heterocyclic group, C ５－１０ heteroaryl group, or NR ３ R ４ group (in the formula, R ３ and R ４ are each independently H, C １－４ Alkyl group, C ３－７ Cycloalkyl group or C ３－１０ a heterocyclic group; X is CH or N.

2. The compound of claim 1, wherein:

5. R １ But C １－２ The compound of any one of claims 1 to 4, which is an alkyl group or a halo-methyl group.

6. R １ The compound according to any one of claims 1 to 5, wherein is a methyl group, a difluoromethyl group, or a trifluoromethyl group.

7. R ２ But C １－４ Alkyl group, halo-methyl group, C １－２ Alkyl-S(O) ２ CH ３ Group, C １－４ Alkoxy group, C ３－５ cycloalkyl group, phenyl group, optionally substituted C ４－６ Heterocyclic group, C ５－６ heteroaryl group, or NR ３ R ４ group (in the formula, R ３ and R ４ are each independently H, C １－２ Alkyl group, C ３－５ Cycloalkyl group or C ４－７ The compound according to any one of claims 1 to 6, wherein R is a heterocyclic group.

8. R ２ is a methyl group, a fluoromethyl group, a trifluoromethyl group, a methylsulfonylmethane group, a tert-butoxy group, C ３－４ Optionally substituted C containing 1 or 2 ring heteroatoms independently selected from cycloalkyl, phenyl, N, O and S; ４－６ Heterocyclic groups, C containing 1 or 2 ring heteroatoms independently selected from N, O and S ５－６ heteroaryl group, or NR ３ R ４ group (in the formula, R ３ and R ４ are each independently H, a methyl group, or C ３－４ Cycloalkyl group or C ４－６ The compound according to any one of claims 1 to 7, wherein R is a heterocyclic group.

9. The compound of any one of claims 1 to 8, wherein X is CH.

10. The compound of any one of claims 1 to 8, wherein X is N.

11. 1-[6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]ethanone, 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, tert-butyl 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate, 1-[6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]ethanone, 2-methanesulfonyl-1-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 2-cyclopropanecarbonyl-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-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridine-3-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-1 lambda 6-thiane-1,1-dione, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridine-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxane-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-cyclobutanecarbonyl-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-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxolane-3-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyrrolidine-1-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, N,N-dimethyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxamide, 1-methyl-4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one, 4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)-1-(propan-2-yl)pyrrolidin-2-one, 2-(4-methyl-1,2-oxazole-5-carbonyl)-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-(3-methyl-1,2-oxazole-5-carbonyl)-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-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxane-3-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 1-methyl-5-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)piperidin-2-one, (5R)-1-methyl-5-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one, (5S)-1-methyl-5-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one, 1-ethyl-4-(6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carbonyl)pyrrolidin-2-one, 1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)ethan-1-one, 3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-N-(oxan-4-yl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazine-7-carboxamide, 4-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazine-7-carbonyl)morpholine, 2-methyl-5-[5-methyl-4-({[7-(oxane-4-carbonyl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-1,2-oxazol-3-yl]pyridine, 5-{4-[({7-cyclopropanecarbonyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-5-methyl-1,2-oxazol-3-yl}-2-methylpyridine, 1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)propan-1-one, 2-fluoro-1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)ethan-1-one, 2-methyl-1-(3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl)propan-1-one, 5-{4-[({7-cyclobutanecarbonyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-5-methyl-1,2-oxazol-3-yl}-2-methylpyridine, N-cyclopropyl-3-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-5H,6H,7H,8H-pyrido[3,4-c]pyridazine-7-carboxamide, 1-[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]ethan-1-one, 2-methanesulfonyl-1-[6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]ethan-1-one, 2,2,2-trifluoro-1-[6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]ethan-1-one, 1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 2-fluoro-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 2-methyl-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 2,2-dimethyl-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 3-methyl-1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)butan-1-one, 2-benzoyl-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 1-(6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 2-cyclopropanecarbonyl-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-cyclobutanecarbonyl-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-(oxane-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 1-[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]ethan-1-one, 1-[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]propan-1-one, 2-fluoro-1-[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]ethan-1-one, 2-methyl-1-[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]propan-1-one, 2-cyclopropanecarbonyl-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, 1-[3-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone, 1-[3-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone, 1-[3-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone, 1-[6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]ethanone, 1-[6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-3,4-dihydro-2,7-naphthyridin-2(1H)-yl]propan-1-one, 2-fluoro-1-[6-({4-methyl-1-[6-(difluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]ethan-1-one, 2-cyclopropanecarbonyl-6-({4-methyl-1-[6-(difluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-methyl-1-[6-({4-methyl-1-[6-(difluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]propan-1-one, 1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 2,2-dimethyl-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 2-methyl-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)propan-1-one, 3-methyl-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)butan-1-one, 2-cyclopropanecarbonyl-6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-cyclobutanecarbonyl-6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-benzoyl-6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine, 2-fluoro-1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl)ethan-1-one, 6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxane-4-carbonyl)-1,2,3,4-tetrahydro-2,7-naphthyridine, 1-(6-{[1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl]ethanone, and Pharmaceutically acceptable salts thereof The compound according to any one of claims 1 to 10, selected from the group consisting of:

12. A combination of a compound according to any one of claims 1 to 11 with one or more other active ingredients.

13. GABA Ａ Use of a compound according to any one of claims 1 to 11 or a combination according to claim 12 for the manufacture of a medicament for the treatment or prevention of diseases associated with the α5 receptor.

14. The GABA Ａ 14. The use of claim 13, wherein the disease associated with alpha 5 receptors is selected from the group consisting of neurodevelopmental disorders, neurodegenerative disorders, neurocognitive disorders, schizophrenia, mood disorders, pain disorders, substance-related disorders, addictive disorders, attention deficit hyperactivity disorder, attention deficit in adults, stress-related conditions, stroke, neurofibromatosis type 1, multiple sclerosis, acute meningitis, alcohol use disorders, fetal alcohol spectrum disorders, and bronchoconstrictive disorders.

15. The GABA Ａ 15. The use according to claim 14, wherein the disease associated with alpha 5 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 deficit, age-related memory dysfunction 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.

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

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

18. 17. The pharmaceutical composition of claim 16, used in combination with one or more other active ingredients.

19. GABA Ａ The pharmaceutical composition according to any one of claims 16 to 18, for the treatment or prevention of a disease associated with the α5 receptor.

20. The GABA Ａ 20. The pharmaceutical composition of claim 19, wherein the disease associated with the alpha5 receptor is selected from the group consisting of neurodevelopmental disorders, neurodegenerative disorders, neurocognitive disorders, schizophrenia, mood disorders, pain disorders, substance-related disorders, addictive disorders, attention deficit hyperactivity disorder, attention deficit in adults, stress-related conditions, stroke, neurofibromatosis type I, multiple sclerosis, acute meningitis, alcohol use disorders, fetal alcohol spectrum disorders, and bronchoconstrictive disorders.

21. The GABA Ａ 21. The pharmaceutical composition of claim 20, 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 deficit, age-related memory dysfunction 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.

22. Compound of formula (V) 【Transformation 6】 (In the formula, R ２ is C １－４ Alkyl group, halo-C １－４ Alkyl group, C １－４ Alkyl-S(O) ２ -C １－４ Alkyl group, C １－４ Alkoxy group, C ３－７ Cycloalkyl group, C ６－１０ aryl group, optionally substituted C ３－１０ Heterocyclic group, C ５－１０ heteroaryl group, or NR ３ R ４ group (in the formula, R ３ and R ４ are each independently H, C １－４ Alkyl group, C ３－７ Cycloalkyl group or C ３－１０ a heterocyclic group; X is CH or N; however, X is N and R ２ is a methoxy group or an ethoxy group; R ２ is a tert-butoxy group; and (Except when X is CH and R 2 is a methyl group).

23. Compound of formula (VII) 【Transformation 7】 (In the formula, R ２ is C １－４ Alkyl group, halo-C １－４ Alkyl group, C １－４ Alkyl-S(O) ２ -C １－４ Alkyl group, C １－４ Alkoxy group, C ３－７ Cycloalkyl group, C ６－１０ aryl group, optionally substituted C ３－１０ Heterocyclic group, C ５－１０ heteroaryl group, or NR ３ R ４ group (in the formula, R ３ and R ４ are each independently H, C １－４ Alkyl group, C ３－７ Cycloalkyl group or C ３－１０ a heterocyclic group; X is CH or N; however, X is CH and R ２ is a 3-pyridyl group or a [6-methyl-4-[(1-methylcyclopropyl)amino]furo[2,3-d]pyrimidin-5-yl] group; and R ２ is a tert-butoxy group, and (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methanone, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(1-methyl-1H-pyrrol-2-yl)methanone, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(5-methyl-3-isothiazolyl)methanone, and 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2,2,2-trifluoroethanone (Except).

24. A compound of formula (X) or a compound of formula (XI) １ is C １－４ Alkyl group or halo-C １－４ alkyl group). 【Transformation 8】 25. A compound selected from the following: 1-(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-(methylsulfonyl)ethanone, cyclopropyl(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyridin-3-yl)methanone, (1,1-dioxidetetrahydro-2H-thiopyran-4-yl)(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyridin-4-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone, cyclobutyl(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydrofuran-3-yl)methanone, 4-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpyrrolidin-2-one, 4-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-(propan-2-yl)pyrrolidin-2-one, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(4-methyl-1,2-oxazol-5-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(3-methyl-1,2-oxazol-5-yl)methanone, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-3-yl)methanone, 5-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpiperidin-2-one, (5R)-5-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpyrrolidin-2-one, (5S)-5-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]-1-methylpyrrolidin-2-one, 1-ethyl-4-[(6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)carbonyl]pyrrolidin-2-one, (6-hydroxy-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(pyrrolidin-1-yl)methanone, 6-Hydroxy-N,N-dimethyl-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxamide 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-fluoroethanone, 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2-methylpropan-1-one, 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-2,2-dimethylpropan-1-one, 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)-3-methylbutan-1-one, (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(phenyl)methanone, 1-(6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)propan-1-one, (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclopropyl)methanone, (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(cyclobutyl)methanone, (6-chloro-3,4-dihydro-2,7-naphthyridin-2(1H)-yl)(tetrahydro-2H-pyran-4-yl)methanone, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)ethanone, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(morpholin-4-yl)methanone, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(tetrahydro-2H-pyran-4-yl)methanone, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(cyclopropyl)methanone, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)propan-1-one, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2-fluoroethanone, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2-methylpropan-1-one, (3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)(cyclobutyl)methanone, 1-(3-chloro-5,8-dihydropyrido[3,4-c]pyridazin-7(6H)-yl)-2-(methylsulfonyl)ethanone, 3-chloro-N-(tetrahydro-2H-pyran-4-yl)-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxamide, 3-chloro-N-cyclopropyl-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxamide [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol, {4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methanol, {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methanol, and [1-methyl-4-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol.

26. A compound of formula (V) or (VII) as an intermediate in the preparation of a compound according to any one of claims 1 to 11: 【Chemistry 9】 (In the formula, R 2 is a C 1-4 alkyl group, a halo-C 1-4 alkyl group, a C 1-4 alkyl-S(O) 2 -C 1-4 alkyl group, a C 1-4 alkoxy group, a C 3-7 cycloalkyl group, a C 6-10 aryl group, an optionally substituted C 3-10 heterocyclic group, a C 5-10 heteroaryl group, or an NR 3 R 4 group, wherein R 3 and R 4 are each independently H, a C 1-4 alkyl group, a C 3-7 cycloalkyl group or a C 3-10 heterocyclic group; X is CH or N), Compounds of formula (X) or (XI): 【Chemistry 10】 wherein R 1 is a C 1-4 alkyl group or a halo-C 1-4 alkyl group; or The compound of claim 25 Use of.

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