Bicyclic amine derivatives as gabaa α5 receptor modulators

Abstract

The present invention provides compounds of formula (I) and / or salts thereof and / or stereoisomers thereof and / or enantiomers thereof and / or racemates thereof and / or diastereomers thereof and / or biologically active metabolites thereof and / or prodrugs thereof and / or solvates thereof and / or hydrates thereof and / or polymorphs thereof having affinity and selectivity for the gamma-aminobutyric acid A receptor subunit alpha 5 and act as GABAA α5 positive allosteric modulators, thereby useful in the treatment or prevention of diseases related to the GABAA α5 receptor, process for the preparation and intermediates of the preparation process thereof, pharmaceutical compositions comprising them alone or in combination with one or more other active ingredients and their use as medicaments.

Description

diazepam was used. After incubation samples were filtered over UniFilter® GF / B™ using Filtermate Harvester (Perkin Elmer) and washed with 5x1 mL binding buffer. The plate was dried at 40 °C for an hour and 40 pL Microscint (Perkin Elmer) scintillation cocktail was added to each well. The plate was read in Microbeta (Perkin Elmer). 5          The specific radioligand binding (SB) was defined as the difference between total binding (Tot) and the non-specific binding (NSB). Results are expressed as a percent inhibition of specific binding obtained in the presence of compound of interest. For IC50 and Kj determination a minimum of six drug concentrations in triplicate were used. IC50 values (i.e., concentration of compound giving 50% inhibition of specific binding) 10 were calculated from concentration-displacement curves by sigmoidal fitting using Origin 7.5 software. Kj values (i.e., inhibition constants) were calculated using the Cheng-Prusoff equation Kj = ICso / [1 +(L / Kd)], where [L] is the radioligand concentration and Kd the affinity of the labelled ligand for receptor. Kd was determined from the Saturation analyses. The compounds of the present invention were tested in the above described assay, 15 and all were found to have high affinity for the GABAa a5 receptor (Kj< 150 nM). Table 1 showing representative hGABAA a5 Kj test results, obtained by the above described binding assay: Ex. HGABAa a5 Kj (nM) Ex. hGABAA a5 Kj (nM) Ex. hGABAA a5 Kj (nM) 1 3.9 17 17.6 33 29.5 2 37.0 18 12.7 34 51.6 3 4.2 19 35.5 35 88.8 4 4.5 20 26.5 36 53.5 5 7.4 21 23.0 37 37.9 6 8.4 22 22.7 38 20.9 7 29.3 23 7.3 39 21.4 8 11.2 24 8.3 40 28.5 9 4.9 25 128 41 61.5 10 4.5 26 93.8 42 28.0 11 7.4 27 63.2 43 19.0 12 28.2 28 5.9 44 40.4 13 6.6 29 29.7 45 99.5 14 3.2 30 3.3 46 61.5 15 17.1 31 36.0 16 5.6 32 44.5 Biological example 2: Functional assay Human HEK293 cell lines expressing GABAa a5p3y2 receptors were used in functional assays using the QPatch automated patch clamp system. HEK293 cell lines stably expressing human recombinant GABAa a5p3y2 receptor subunits (Millipore, CYL3053) were cultured in DM EM supplemented with 10% FBS (Gibco), passed two times per week and plated on Petri dishes previously coated with poly-d-lysine. Automated whole-cell patch clamp recordings were made from cells 2-4 days after plating. Cells were detached using trypsin / EDTA (Sigma) treatment (2 minutes in 0.25% trypsin at 37 °C), then, after centrifugation (125 g, 3 min, 2x), resuspended in a serum-free based media (Gibco, CHO-S-SFM-II) containing 12.5 mM HEPES, 1* penicillin-streptomycin-amphotericin (SigmaMix) and soybean trypsin inhibitor (Sigma, 0.04 mg / ml). Cell suspension, as well as the extracellular solution (130 mM NaCI, 5 mM KCI, 5.1 mM HEPES, 4.9 mM HEPES-Na, 10 mM CaCI2, 2 mM MgCI2, 10 mM glucose and 0.1% DMSO, pH=7.35-7.4) and the intracellular solution (80 mM KCI, 50 mM KF, 36 mM KOH, 10 mM EGTA, 10 mM HEPES, 1.75 mM MgCI2, 0.5 mM CaCI2, 4 mM Na2ATP. 14 mM phosphocreatine, 50 ll / rnl creatine-phosphokinase, 0.3 mM GTP, pH=7.25-7.3) were added to the QPatch-HTX automated patch clamp system (Sophion) in single-cell mode at room temperature. Inward currents were evoked at a holding potential of -80 mV by 3-s-long applications of the control agonist GABA at 1 pM at 2-4-min intervals first in concentration-matched DMSO (0.1 or 0.3%) control solution for five times, then in the presence of the test compound for four times, finally in control solution again for three times (wash-out). At the end of the experiment 100 pM GABA was applied to saturate the GABA-response and to assess the efficacy of the control GABA application. Current signals were low-pass filtered at 100 Hz and recorded at a sampling rate of 1 kHz. The percentage modulation was calculated from the comparison of GABA-evoked peak current amplitudes in the presence and absence of the test compound. The compounds of the present invention were tested at 1 pM in the above described assay, and all were found to possess GABAa a5 positive allosteric modulator activity. Table 2 showing representative hGABAA a5 functional efficacy test results, obtained by the above described assay: Ex. hGABAAa5 efficacy (%) Ex. hGABAAa5 efficacy (%) Ex. hGABAAa5 efficacy (%) 1 155 16 146 32 155 2 100 19 129 33 71 7 125 20 111 34 62 8 133 21 134 37 53 9 106 22 68 40 86 10 131 24 88 42 99 11 114 25 73 43 85 13 129 29 102 44 96 14 126 30 59 45 97 15 115 31 115 46 76 Examples The present invention will be further illustrated by the following Intermediates and Examples without limiting the scope of the present invention to them. From the above description and from the Intermediates and Examples, the person skilled in the art may ascertain the essential features of the invention and without departing from its essence and scope, may make certain changes and modifications in order to adapt the invention to various applications and conditions. As a result, the invention is not limited to the following illustrative examples, but rather to the scope determined by the appended claims. In general, the compounds of formula (I) can be prepared according to the common general knowledge of the person 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 the person skilled in the art. Starting materials are commercially available and / or can be easily prepared by the person skilled in the art according to literature procedure. During the preparation of compounds combinatorial techniques can be used, for example, where intermediates are suitable for the use of these methods. Intermediate 1 5-r4-(chloromethvl)-5-methvl-1,2-oxazol-3-vH-2-methvlpvridine 1.00 g (4.89 mmol) of [5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methanol (WO 2018 / 104419 A1, Hoffmann-La Roche) was dissolved in 30 mL of phosphorus oxychloride. The reaction mixture was stirred for 2 hours at 115°C, then evaporated to dryness. Ethyl 5 acetate was added and washed with saturated sodium hydrogen carbonate solution and with water, dried over anhydrous sodium sulfate, and evaporated to obtain 0.95 g (87%) of the title compound. MS (ESI) m / z: 223.1 [M+H]+. Intermediate 2 10 5-r4-(chloromethvl)-5-methvl-1,2-oxazol-3-vH-2-(trifluoromethvl)pvridine In analogy of Intermediate 1, {5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yljmethanol (WO 2018 / 104419 A1, Hoffmann-La Roche) was converted into the title compound. MS (ESI) m / z: 277.1 [M+H]+. Intermediate 3 r4-methyl-1 -(6-methvlpyridin-3-vl)-1 H-1,2,3-triazol-5-yllmethanol Method A a: methyl (2E)-3-f(6-methvlpvridin-3-vl)amino1but-2-enoate To a mixture of 1.00 g (9.20 mmol) of commercially available 6-methylpyridine-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 was added. The reaction mixture was refluxed for 10 hours. After cooling, filtration of inorganics and concentration of the filtrate under reduced pressure afforded the residue which was used in the next step without further purification. MS (ESI) m / z: 207.1 [M+H]+. b: ethyl 4-methyl-1-(6-methylpyridin-3-yl)-1 / - / -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 methylbenzenesulfonehydrazide, 6.26 g (37.7 mmol) of potassium iodide in 70 mL of DMSO, 7.31 mL (75.5 mmol) of TBHP (70% solution in water) was added slowly. Then the mixture was stirred at 70°C for 24 hours. 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 MgSO4, filtered, and then concentrated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: DCM:MeOH, 0-10% gradient) afforded the desired product. Yield: 6.35 g (68 %), MS (ESI) m / z: 247.1 [M+H]+. c: f4-methvl-1-(6-methvlpyridin-3-vl)-1 H-1,2,3-triazol-5-yl1methanol 6.35 g (25.8 mmol) of ethyl 4-methyl-1-(6-methylpyridin-3-yl)-1 / - / -1,2,3-triazole-5-carboxylate was dissolved in 80 mL of anhydrous THF and cooled to 0 °C. 103 mL of DIBAL-H (1 M solution in toluene) was added dropwise under argon and the reaction mixture was stirred at room temperature for 1 hour. After cooling it was quenched with 71 mL of water and acidificated with 135 mL of 1M HCI. The combined organic layers were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo. The crude product was crystallised from isopropanol to obtain the title compound as a white solid. Yield: 3.42 g, (65%), MS (ESI) m / z: 205.1 [M+H]+. Method B a: 5-azido-2-methvlpyridine 5.0 g (46 mmol) of commercially available 6-methylpyridine-3-amine was diisolved in a mixture of 14 mL of cc. HCI and 14 mL of water and cooled to 0 °C. 3.19 g (46.2 mmol) of NaNO2 dissolved in 12 mL of water was added dropwise. The reaction mixture was stirred at 0 °C for 20 min then 10.6 mL (80 mmol) of trimethylsylil azide was added dropwise slowly and the reaction mixture was stirred at room temperature for 1.5 hour. After completion 70 mL of ethyl acetate was added and washed three times with 30 mL of saturated sodium carbonate solution and with water, dried over anhydrous sodium sulfate, and evaporated. The crude product was used in the next step without further purification. b: f4-methvl-1-(6-methvlpyridin-3-vl)-1 / - / -1,2,3-triazol-5-yl1methanol 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 coloumn chromatography (silica gel, eluent: cyclohexane:EtOAc 40-80 % gradient). Yield: 2.30 g (26 %), white solid. MS (ESI) m / z: 205.1 [M+H]+. Intermediate 4 (4-methyl-1 -r6-(trifluoromethvl)pyridin-3-vll-1 H-1,2,3-triazol-5-yl}methanol 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]+. Intermediate 5 {1 -r6-(difluoromethvl)pvridin-3-vH-4-methvl-1 H-1,2,3-triazol-5-yl}methanol 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]+. Intermediate 6 ri-(6-methoxvpvridin-3-vl)-4-methvl-1H-1,2,3-triazol-5-vl]methanol The compound was synthesized according to the procedure described for intermediate 3 using commercially available 6-methoxypyridin-3-amine in step a. MS (ESI) m / z: 221.1 [M+H]+. Example 1 6-{r5-methvl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vHmethoxv}-1,2,3,4-tetrahvdro-2,7-naphthyridine trifluoroacetic acid salt A:tert-butyl 6-{f5-methvl-3-(6-methvlpyridin-3-vl)-1,2-oxazol-4-vl1methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate 1.96 g (8.80 mmol) of 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-methylpyridine (Intermediate 1), and 2.20 mg (8.80 mmol) of commercially available tert-butyl 6-hydroxy-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate were dissolved in 120 mL of anhydrous acetonitrile. Then, 3.65 mg (26.40 mmol) of anhydrous potassium-carbonate was added to the solution, and the suspension was stirred under reflux for 12 h. The conversion was followed byTLC (EtOAc:cyclohexane=1:1 as eluent, silica plate). After the reaction completed, the mixture was filtered, and evaporated to give an oily crude product, which was purified by flash coloumn chromatography (silica gel, eluent: EtOAc:cyclohexane=1:1). Yield: 640 mg (16.6 %) white solid. MS (ESI) m / z: 437.3 [M+H]+. B:     6-{f5-methvl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vl1methoxy}-1,2,3,4-tetrahydro-2,7- naphthyridine trifluoroacetic acid salt 97.97 mg (0.22 mmol) of tert-butyl 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved in 10 mL of DCM. Then, 1489 mg (13.06 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 6 h. After the reaction completed, the mixture was evaporated to give the title compound. Yield: 90 mg (91%) yellow solid. MS (ESI) m / z: 337.1 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) 5 (ppm): 8.96-9.07 (br m, 2H), 8.81 (br d, J=2.0 Hz, 1H), 8.12 (dd, J=8.1, 2.3 Hz, 1H), 8.06 (s, 1H), 7.49 (d, J=8.1 Hz, 1H), 6.73 (s, 1H), 5.27 (s, 2H), 4.25 (br t, J=4.5 Hz, 2H), 3.31-3.39 (m, 2H), 2.95 (t, J=6.3 Hz, 2H), 2.57 (s, 3H), 2.56 (s, 3H). Example 2 6-((5-methvl-3-r6-(trifluoromethvl)pvridin-3-vll-1,2-oxazol-4-vl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetic acid salt F The title compound prepared according to the procedure described for Example 1 using 5-[4-(chloromethyl)-5-methyl-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Intermediate 2) in step a. MS (ESI) m / z: 391.2 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) 5 (ppm): 9.11 (d, J=1.9 Hz, 1H), 8.82-9.03 (br m, 2H), 8.48 (dd, J=8.1, 1.7 Hz, 1H), 8.11 (d, J=8.1, 1H), 8.04 (s, 1H), 6.73 (s, 1H), 5.33 (s, 2H), 4.24 (brt, 2H), 3.31-3.38 (br m, 2H), 2.94 (t, J=6.3 Hz, 2H), 2.61 (s, 3H). Example 3 2-methvl-6-{r5-methvl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vllmethoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine 450 mg (1.0 mmol) of 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetic acid salt (Example 1) was added to a solution of saturated NaHCOs and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. The obtained base was dissolved in 2 mL of water and 240 mg (4.0 mmol) of acetic acid, 122 mg (1.5 mmol) of formaldehyde solution (37% in water) and 131 mg (2.0 mmol) of zinc powder was added. The reaction mixture was stirred at 30°C for 48 hours. After the reaction was completed (monitored by TLC), the reaction mixture was neutralized with ammonia solution, and the resulting mixture was extracted with DCM. The combined organic layers were then dried over MgSO4, filtered, and then concentrated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=10:1) afforded the desired product. Yield: 59.3 mg (16.9 %), MS (ESI) m / z: 351.2 [M+H]+. Example 4 2-cvclobutvl-6-(r5-methvl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vllmethoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine To a solution of 200 mg (0.44 mmol) of 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetic acid salt (Example 1) in 4 mL of 2,2,2-triluoroethanol 112 mg (1.33 mmol) of NaHCOs was added and stirred for 30 min, then 32 mg (0.44 mmol) of cyclobutanone was added in one portion and the reaction mixture was warmed up to 45°C. The so obtained solution was stirred for 5 min, then 16.8 mg (0.44 mmol) of sodium borohydride was added. The reaction mixture was stirred at 45°C for 3 hours. After completion the solvent was evaporated, the residue was dissolved in DCM and washed with brine. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: EtOAc:MeOH=10:1) afforded the desired product. Yield: 28.1 mg (16.1 %), MS (ESI) m / z: 393.2 [M+H]+. Example 5 2-(cvclobutvlmethvl)-6-(r5-methvl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vllmethoxy}-1,2,3,4-tetrahvdro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 4 using commercially available cyclobutanecarbaldehyde. MS (ESI) m / z: 405.2 [M+H]+. Example 6 2-cvclopentvl-6-(r5-methvl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vHmethoxv}-1,2,3,4-tetrahydro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 4 using commercially available cyclopentanone. MS (ESI) m / z: 405.2 [M+H]+. Example 7 6-((5-methvl-3-r6-(trifluoromethvl)pvridin-3-vll-1,2-oxazol-4-vl}methoxv)-2-(oxan-4-yl)- 1,2,3,4-tetrahydro-2,7-naphthyridine F The title compound prepared according to the procedure described for Example 4 using 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetic acid salt (Example 2) and commercially available 5 tetrahydropyran-4-one. MS (ESI) m / z: 475.2 [M+H]+. Example 8 6-((5-methvl-3-r6-(trifluoromethvl)pvridin-3-vll-1,2-oxazol-4-vl}methoxy)-2-(oxolan-3-vl)-1,2,3,4-tetrahvdro-2,7-naphthyridine 10 The title compound prepared according to the procedure described for Example 4 using 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetic acid salt (Example 2) and commercially available 3-oxotetrahydrofuran. MS (ESI) m / z: 461.2 [M+H]+. 15 Example 9 6-(r5-methvl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vHmethoxv}-2-(oxolan-3-vl)-1,2,3,4-tetrahvdro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 4 using commercially available 3-oxotetrahydrofuran. MS (ESI) m / z: 407.2 [M+H]+. Example 10 10 6-{r5-methyl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vHmethoxv}-2-(oxetan-3-vl)-1,2,3,4-tetrahydro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 4 using commercially available 3-oxetanone. MS (ESI) m / z: 393.2 [M+H]+. Example 11 6-{r5-methyl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vHmethoxv}-2-(oxan-4-vl)-1,2,3,4-tetrahydro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 4 using commercially available 4-oxotetrahydropyran. MS (ESI) m / z: 421.2 [M+H]+. Example 12 2-(1-methanesulfonvlpropan-2-vl)-6-((5-methvl-3-r6-(trifluoromethvl)pyridin-3-vll-1,2-oxazol-4-vl}methoxv)-1,2,3,4-tetrahvdro-2,7-naphthvridine 183.6 mg (0.36 mmol) of 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetic acid salt (Example 2) was added to a solution of saturated Na2CO3 and extracted with DCM. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. The obtained base was added to a stirred solution of 49 mg (0.36 mmol) of methanesulfonylacetone in 1 mL of methanol and 1 mL of 2,2,2-triluoroethanol at room temperature. The mixture was stirred for 1 h. 84 mg (0.72 mmol) of triethylsilicon was added by syringe and followed by 57 mg (0.26 mmol) of indium(l 11) chloride (Lee et al., J. Org. Chern. 2008, 73, 22, 8829-8837). The reaction was allowed to stir at room temperature and was monitored by TLC. When the reaction was completed, the mixture was quenched by 1 mL of saturated K2CO3 solution. The mixture was extracted with EtOAc. The combined organic layer was washed with brine and finally was dried over Na2SO4. The crude product was purified by flash column chromatography (silica gel, eluent: cyclohexane:EtAOc=1:1). Yield: 21 mg (11 %), MS (ESI) m / z: 511.1 [M+H]+. Example 13 6-{r5-methyl-3-(6-methvlpvridin-3-vl)-1,2-oxazol-4-vHmethoxv}-2-(pvridin-2-vl)-1,2,3,4-tetrahydro-2,7-naphthyridine 283 mg (0.63 mmol) of 6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine trifluoroacetic acid salt (Example 1) was dissolved in 2 mL of 2-fluoropyridine the reaction mixture was stirred at 120°C for 3 h. The residue was purified by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=10:1). Yield: 50 mg (19.2 %). MS (ESI) m / z: 414.2 [M+H]+. Example 14 2-methvl-5-r5-methvl-4-((5H,6H,7H,8H-pvridor3,4-clpvridazin-3-vloxy}methvl)-1,2-oxazol-3-yllpyridine A: tert-butyl 2-methvl-5-f5-methvl-4-({5H,6H,7H,8H-pvridof3,4-clpvridazin-3-vloxv}methvl)-1,2-oxazol-3-vllpyridine-2-carboxvlate Under argon atmosphere a flask was charged with 660 mg (2.45 mmol) of commercially available tert-butyl 3-chloro-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxylate, 500 mg (2.45 mmol) of {5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methanol (WO 2018 / 104419 A1, Hoffmann-La Roche), 1595 mg (4.89 mmol) of CS2CO3, 98 mg (0.25 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 55 mg (0.24 mmol) of Pd(OAc)2 and 20 mL of anhydrous toluene. The mixture was stirred at 100°C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:1 as eluent, silica plate). The reaction mixture was filtered through a celite pad, washed with acetone, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash coloumn chromatography (silica gel, eluent: cyclohexane:EtAOc=1:1). Yield: 342 mg (32 %), white, amorphous solid. MS (ESI) m / z: 438.2 [M+H]+. B^J^methyLf^LSmethyPHlStLSliZtLSth^^ 3-yllpyridine 342 mg (0.78 mmol) of tert-butyl 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine-2-carboxylate was dissolved in 50 mL of DCM. Then, 1782 mg (15.63 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 24 h. After completion the mixture was evaporated, the residue was dissolved in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: EtOAc:MeOH=10:1) afforded the desired product. Yield: 132 mg (50 %), MS (ESI) m / z: 338.2 [M+H]+. Example 15 5-r5-methvl-4-((5H,6H,7H,8H-pvridor3,4-clpvridazin-3-vloxvknethvl)-1,2-oxazol-3-vH-2-(trifluoromethvl)pyridine F A: tert-butyl 5-f5-methvl-4-({5H,6H,7H,8H-pvridof3,4-clpvridazin-3-vloxv}methvl)-1,2-oxazol-3-vl1-2-(trifluoromethvl)pyridine-2-carboxvlate Under argon atmosphere a flask was charged with 668 mg (2.48 mmol) of commercially available tert-butyl 3-chloro-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxylate, 639 mg (2.48 mmol) of 5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methanol (WO 2018 / 104419 A1, Hoffmann-La Roche), 1614 mg (4.95 mmol) of CS2CO3, 99 mg (0.25 mmol) of rac-2-(di-fert-butylphosphino)-1,11-binaphthyl, 56 mg (0.25 mmol) of Pd(OAc)2 and 20 mL of anhydrous toluene. The mixture was stirred at 100°C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:1 as eluent, silica plate). The reaction mixture was filtered through a celite pad, washed with acetone, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash coloumn chromatography (silica gel, eluent: cyclohexane:EtAOc=1:1). Yield: 395 mg (32.5 %). MS (ESI) m / z: 492.2 [M+H]+. B: 5-r5-methvl-4-({5H,6H,7H,8H-pvridor3,4-clpvridazin-3-vloxv}methyl)-1,2-oxazol-3-vl1-2-(trifluoromethvl)pyridine 395 mg (0.80 mmol) of tert-butyl 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine-2-carboxylate was dissolved in 20 mL of DCM. Then, 916 mg (8.03 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 24 h. After completion the mixture was evaporated, the residue was dissolved in DCM and washed with saturated Na2COs solution and water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: EtOAc:MeOH=10:1) afforded the desired product. Yield: 175 mg (56 %), MS (ESI) m / z: 392.1 [M+H]+. Example 16 2-methvl-5-(5-methvl-4-K(7-methvl-5H,6H,7H,8H-pvridor3,4-clpyridazin-3-vl}oxv)methvll-1,2-oxazol-3-vl}pyridine To a solution of 74 mg (0.22 mmol) of 2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine (Example 14) in 5 mL of methanol 27 mg (0.33 mmol) of formaldehyde solution (37% in water) was added and the reaction mixture was warmed up to 50°C, then 93 mg (0.44 mmol) of sodium triacetoxyborohydride was added in one portion. The reaction mixture was stirred at 50°C for 5 hours. After completion the solvent was evaporated, the residue was dissolved in EtOAc and washed with saturated NaHCOs solution. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: EtOAc:MeOH=10:1) afforded the desired product. Yield: 40 mg (52 %), MS (ESI) m / z: 352.2 [M+H]+. Example 17 5-r5-methvl-4-((5H,6H,7H,8H-pvridor3,4-clpvridazin-3-vloxvknethvl)-1,2-oxazol-3-vH-2-(trifluoromethvl)pyridine F The title compound prepared according to the procedure described for Example 16 using 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Example 15). MS (ESI) m / z: 406.1 [M+H]+. Example 18 5-r5-methvl-4-((r7-(oxolan-3-vl)-5H,6H,7H,8H-pvridor3,4-clpvridazin-3-vHoxvknethvl)-1,2-oxazol-3-vll-2-(trifluoromethvl)pyridine heminapadisylate salt A: Synthesis of the free base To a solution of 130 mg (0.33 mmol) of 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Example 15) in 5 mL of 2,2,2-trifluoroethanol 29 mg (0.34 mmol) of 3-oxotetrahydrofuran and 13 mg (0.34 mmol) of sodium borohydride was added. The reaction mixture was stirred at 45°C for 12 hours. After completion the solvent was evaporated, the residue was dissolved in DCM and washed with water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=10:1) afforded the free base as an oil. Yield: 23 mg (15 %), MS (ESI) m / z: 462.2 [M+H]+ B: Synthesis of the heminapadisylate salt 23 mg (0.05 mmol) of 5-[5-methyl-4-({[7-(oxolan-3-yl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine was dissolved in 2 mL of ethanol and 18 mg (0.05 mmol) of 1,5-naphthalenedisulfonic acid tetrahydrate was added and stirred at 60°C for 10 minutes, then allowed to cool to rt. The precipitated product was collected by filtration, washed with cold ethanol and dried in vacuum to obtain the title compound as a white solid. Yield: 17 mg (56 %), MS (ESI) m / z: 462.2 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) 5 (ppm): 10.05-10.50 (br m, 1H), 9.12 (d, J=1.7 Hz, 1H), 8.49 (dd, J=8.1, 1.7 Hz, 1H), 8.10 (br d, J=8.2 Hz, 1H), 7.21 (br s, 1H), 4.40-4.85 (br m, 2H), 4.07-4.34 (br m, 2H), 3.91-4.06 (br m, 1H), 3.76-3.89 (m, 1H), 3.30-3.74 (br m, 5H), 3.00-3.18 (br m, 2H), 2.64 (s, 3H), 2.12-2.43 (br m, 2H); napadisylate (acid / base molar ratio 1:2) signals: 8.85 (dd, J=8.5, ~1 Hz, 2H), 7.91 (dd, J=7.0 Hz, 1.1 Hz, 2H), 7.38 (dd, J=8.5, 7.1 Hz, 2H). Example 19 3-(r3-((5-methvl-3-r6-(trifluoromethvl)pyridin-3-vll-1,2-oxazol-4-vl}methoxv)- 5H,6H,7H,8H-pvridor3,4-clpyridazin-7-vllmethvl}-1lambda6-thiolane-1,1-dione tart a rate salt F A: Synthesis of the free base In a microwave tube 100 mg (0.256 mmol) of 5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine (Example 15) was dissolved in 3 mL of acetonitrile, then 66 mg (0.51 mmol) of N,N-diisopropylethylamine and 54.6 mg (0.256 mmol) of 3-bromomethyltetrahydrothiophene 1,1-dioxide was added. The tube was placed in a microwave reactor and heated at 100°C with stirring for 3 hours. After the reaction completed, the mixture was evaporated and purified by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=10:1) to obtain 34 mg product as an oil. Yield: 38 mg (28.4 %), MS (ESI) m / z: 524.1 [M+H]+. B: Synthesis of the tartarate salt 11.2 mg (0.021 mmol) of 3-{[3-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl]methyl}-1lambda6-thiolane-1,1-dione was dissolved in 1 mL of ethanol and 3.2 mg (0.021 mmol) of L-(+)-tartaric acid was added and stirred at 60°C for 10 minutes, then allowed to cool to rt. The precipitated product was collected by filtration, washed with cold ethanol and dried in vacuum to obtain the title compound as a white solid. Yield: 12.5 mg (86.7 %), MS (ESI) m / z: 524.1 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) 5 (ppm): 11.40-13.60 (brm, 1H), 9.12 (d, J=1.7 Hz, 1H), 8.46 (dd, J=8.0 Hz, 1.8 Hz, 1H), 8.09 (d, J=8.0 Hz, 1H), 7.00 (s, 1H), 5.48 (s, 2H), 3.75 (s, 2H), 3.14-3.26 (m, 2H), 3.00-3.09 (m, 1H), 2.82 (t, J=5.4 Hz, 2H), 2.74-2.81 (m, 2H), 2.54-2.73 (m, 4H), 2.63 (s, 3H), 2.20-2.29 (m, 1H), 1.73-1.83 (m, 1H); tartarate (acid / base ratio 1:1) signal: 4.28 (s, 2H). Example 20 6-(r4-methyl-1 -(6-methylpyridin-3-vl)-1 H-1,2,3-triazol-5-vllmethoxy}-1,2,3,4-tetrahydro- 2,7-naphthyridine A: tert-butyl 6-{f4-methvl-1-(6-methvlpvridin-3-vl)-1H-1,2,3-triazol-5-vl1methoxy}-1,2,3,4-tetrahydro-2,7-naphthvridine-2-carboxylate Under argon atmosphere a flask was charged with 504 mg (1.88 mmol) of commercially available tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate, 383 mg (1.88 mmol) of [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3), 1220 mg (3.75 mmol) of CS2CO3, 74.7 mg (0.18 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 42 mg (0.18 mmol) of Pd(OAc)2 and 20 mL of anhydrous toluene. The mixture was stirred at 100°C for 12 h. The conversion was checked by TLC (cyclohexane: EtOAc=1:1 as eluent, silica plate). The reaction mixture was filtered through a celite pad, washed with acetone, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash coloumn chromatography (silica gel, eluent: cyclohexane:EtAOc 30-70% gradient). Yield: 287 mg (35 %). MS (ESI) m / z: 437.2 [M+H]+. B: 6-CT4-methvl-1-(6-methvlpvridin-3-vl)-1H-1,2,3-triazol-5-vl1methoxy}-1,2,3,4-tetrahvdro-2,7-naphthyridine 287 mg (0.65 mmol) of tert-butyl 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved in 12 mL of ethyl acetate. 12 mL of ethyl acetate saturated with hydrogen chloride was added dropwise to the solution. The reaction mixture was stirred for 30 minutes at room temperature. The white precipitate formed was filtered out, washed with small portion of ethyl acetate. The hydrochloride salt was added to a solution of saturated NaHCOs and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=10:1) afforded the desired product. Yield: 78 mg (35 %), MS (ESI) m / z: 337.2 [M+H]+. Example 21 2-methvl-6-(r4-methvl-1-(6-methvlpvridin-3-vl)-1H-1,2,3-triazol-5-vHmethoxv}-1,2,3,4-tetrahydro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 16 using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20). MS (ESI) m / z: 351.1 [M+H]+. Example 22 6-(r4-methyl-1 -(6-methylpyridin-3-vl)-1 H-1,2,3-triazol-5-vllmethoxy}-2-(propan-2-vl)- 1,2,3,4-tetrahvdro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 18, Step A using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1 H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available acetone. MS (ESI) m / z: 379.2 [M+H]+. 6-((1 -r6-(difluoromethvl)pyridin-3-vll-4-methvl-1 H-1,2,3-triazol-5-vl}methoxy)-1,2,3,4-tetrahvdro-2,7-naphthyridine A: tert-butyl 6-({1-f6-(difluoromethvl)pvridin-3-vl1-4-methyl-1H-1,2,3-triazol-5-vl}methoxv)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate Under argon atmosphere a flask was charged with 91.3 mg (0.34 mmol) of commercially available tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate, 81.6 mg (0.34 mmol) of {1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1 H-1,2,3-triazol-5-yl}methanol (Intermediate 5), 226 mg (0.69 mmol) of CS2CO3, 13.8 mg (0.034 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 7.8 mg (0.034 mmol) of Pd(OAc)2 and 10 mL of anhydrous toluene. The mixture was stirred at 100°C for 12 h. The conversion was checked by TLC (cyclohexane:EtOAc=1:2 as eluent, silica plate). The reaction mixture was filtered through a celite pad, washed with acetone, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash coloumn chromatography (silica gel, eluent: cyclohexane:EtAOc=1:2). Yield: 90 mg (56 %). MS (ESI) m / z: 473.2 [M+H]+. B:6-({1-f6-(difluoromethvl)pvridin-3-vl1-4-methyl-1 H-1,2,3-triazol-5-vl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine 90 mg (0.19 mmol) of tert-butyl 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved in 10 mL of DCM. Then, 652 mg (5.71 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 3 h. After completion the mixture was evaporated, the residue was dissolved in DCM and washed with saturated Na2CO3 solution and water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=10:1) afforded the desired product. Yield: 28.4 mg (40 %), MS (ESI) m / z: 373.2 [M+H]+. Example 24 6-((1 -r6-(difluoromethvl)pyridin-3-vll-4-methvl-1 H-1,2,3-triazol-5-vl}methoxv)-2-methyl- 1,2,3,4-tetrahvdro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 16 using 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 23). MS (ESI) m / z: 387.2 [M+H]+. Example 25 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine A: tert-butyl 6-({4-methyl-1-f6-(trifluoromethyl)pyridin-3-yl1-1 H-1,2,3-triazol-5-yllmethoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate Under argon atmosphere a flask was charged with 521 mg (1.94 mmol) of commercially available tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate, 500 mg (1.94 mmol) of 4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methanol (intermediate 4), 1260 mg (3.87 mmol) of CS2CO3, 77.2 mg (0.194 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 43.5 mg (0.194 mmol) of Pd(OAc)2 and 30 mL of anhydrous toluene. The mixture was stirred at 100°C for 12 h. The conversion was checked by TLC (DCM:MeOH=9:1 as eluent, silica plate). The reaction mixture was filtered through a celite pad, washed with acetone, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=9:1). Yield: 710 mg (74.8 %), amorphous solid. MS (ESI) m / z: 491.2 [M+H]+. B:6-({4-methvl-1-f6-(trifluoromethvl)pvridin-3-vl1-1 H-1,2,3-triazol-5-vl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine 710 mg (1.45 mmol) of tert-butyl 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved in 15 mL of DCM. Then, 3300 mg (29 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 24 h. After completion the mixture was evaporated, the residue was dissolved in DCM and washed with saturated Na2COs solution and water. The organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=9:1) afforded the desired product. Yield: 320 mg (56.6 %), MS (ESI) m / z: 391.2 [M+H]+. Example 26 6-((4-methvl-1-r6-(trifluoromethvl)pvridin-3-vll-1H-1,2,3-triazol-5-vl}methoxy)-2-(propan-2-vl)-1,2,3,4-tetrahvdro-2,7-naphthyridine To a solution of 160 mg (0.41 mmol) of 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 25) in 5 mL of 2,2,2-trifluoroethanol 23.8 mg (0.41 mmol) of acetone and 15.5 mg (0.41 mmol) of sodium borohydride was added. The reaction mixture was stirred at 45°C for 12 hours. After completion the solvent was evaporated, the residue was dissolved in DCM and washed with water. The organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=9:1) afforded the title compound. Yield: 61 mg (34 %), MS (ESI) m / z: 433.2 [M+H]+. 2-methyl-6-((4-methyl-1 -r6-(trifluoromethvl)pvridin-3-vH-1 H-1,2,3-triazol-5-vl}methoxy)- 1,2,3,4-tetrahvdro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 16 using 6 5 ({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4- tetrahydro-2,7-naphthyridine (Example 25, Step B). MS (ESI) m / z: 405.1 [M+H]+. Example 28 6-((1 -r6-(difluoromethvl)pyridin-3-vll-4-methvl-1 H-1,2,3-triazol-5-vl}methoxy)-2- 10 (propan-2-vl)-1,2,3,4-tetrahvdro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 18, Step A using 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1 H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 23) and commercially available acetone. MS (ESI) 15 m / z: 415.2 [M+H]+. Example 29 6-((4-methyl-1 -(6-methylpyridin-3-vl)-1 H-1,2,3-triazol-5-vllmethoxy}-2-(oxolan-3-vl)- 1,2,3,4-tetrahydro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 18, Step A using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1 H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available 3-oxotetrahydrofuran. MS (ESI) 5 m / z: 407.2 [M+H]+. Example 30 6-((1 -r6-(difluoromethvl)pyridin-3-vll-4-methvl-1 H-1,2,3-triazol-5-vl}methoxy)-2-(oxolan- 3-yl)-1,2,3,4-tetrahvdro-2,7-naphthyridine 10 The title compound prepared according to the procedure described for Example 18, Step A using 6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1 H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 23) and commercially available 3-oxotetrahydrofuran. MS (ESI) m / z: 443.2 [M+H]+. 15 Example 31 6-((4-methyl-1 -(6-methylpyridin-3-vl)-1 H-1,2,3-triazol-5-vllmethoxy}-2-(oxetan-3-vl)- 1,2,3,4-tetrahvdro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 18, Step A using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1 H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available 3-oxetanone. MS (ESI) m / z: 393.2 [M+H]+. Example 32 6-((4-methvl-1-r6-(trifluoromethvl)pvridin-3-vll-1H-1,2,3-triazol-5-vl}methoxy)-2-(oxolan-3-vl)-1,2,3,4-tetrahvdro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 26 using commercially available 3-oxotetrahydrofuran. MS (ESI) m / z: 461.2 [M+H]+. Example 33 6-{r4-methyl-1 -(6-methylpyridin-3-vl)-1 H-1,2,3-triazol-5-vllmethoxy}-2-(oxan-4-vl)- 1,2,3,4-tetrahydro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 18, Step A using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1 H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available 4-oxotetrahydropyran. MS (ESI) m / z: 421.2 [M+H]t Example 34 6-(f1 -(6-methoxvpyridin-3-vl)-4-methvl-1 H-1,2,3-triazol-5-vHmethoxv}-1,2,3,4-tetrahvdro-2,7-naphthyridine A: tert-butyl 6-{n-(6-methoxvpvridin-3-vl)-4-methyl-1 H-1,2,3-triazol-5-yl1methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate Under argon atmosphere a flask was charged with 300 mg (1.12 mmol) of commercially available tert-butyl 6-chloro-3,4-dihydro-2,7-naphthyridine-2(1H)-carboxylate, 246 mg (1.12 mmol) of [1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methanol (Intermediate 6), 727 mg (2.23 mmol) of CS2CO3, 44.5 mg (0.11 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 25 mg (0.11 mmol) of Pd(OAc)2 and 20 mL of anhydrous toluene. The mixture was stirred at 100°C for 12 h. The conversion was checked by TLC (cyclohexane: EtOAc=1:1 as eluent, silica plate). The reaction mixture was filtered through a celite pad, washed with acetone, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash coloumn chromatography (silica gel, eluent: cyclohexane:EtAOc=1:1). Yield: 200 mg (39.5 %). MS (ESI) m / z: 453.2 [M+H]+. B: 6-{n-(6-methoxvpvridin-3-vl)-4-methvl-1H-1,2,3-triazol-5-vl1methoxy}-1,2,3,4-tetrahvdro-2,7-naphthyridine 200 mg (0.44 mmol) of tert-butyl 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine-2-carboxylate was dissolved in in 7 mL of ethyl acetate. 7 mL of ethyl acetate saturated with hydrogen chloride was added dropwise to the solution. The reaction mixture was stirred for 30 minutes at room temperature. The white precipitate formed was filtered out, washed with small portion of ethyl acetate. The hydrochloride salt was added to a solution of saturated NaHCOs and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=10:1) afforded the desired product. Yield: 115 mg (74 %), MS (ESI) m / z: 353.2 [M+H]+. Example 35 6-((4-methvl-1-r6-(trifluoromethvl)pvridin-3-vll-1H-1,2,3-triazol-5-vl}methoxy)-2-(oxan-4-yl)-1,2,3,4-tetrahvdro-2,7-naphthyridine The title compound prepared according to the procedure described for Example 26 using commercially available 4-oxotetrahydropyran. MS (ESI) m / z: 475.3 [M+H]+. Example 36 3-(r6-((4-methvl-1-r6-(trifluoromethvl)pyridin-3-vll-1H-1,2,3-triazol-5-vlknethoxv)-1,2,3,4-tetrahvdro-2,7-naphthvridin-2-vllmethyl}-1lambda6-thiolane-1,1-dione heminapadisylate salt OH I O=S=O O=S=O I OH The free base of the title compound prepared according to the procedure described for Example 19, Step A using 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 25). The heminapadisylate salt prepared according to the procedure described for Example 18 in Step B. MS (ESI) m / z: 523.2 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) 5 (ppm): 9.45-9.70 (br m, 1H), 9.09 (d, J=2.4 Hz, 1H), 8.47 (dd, J=8.3 Hz, 2.2 Hz, 1H), 8.23 (d, J=8.3 Hz, 1H), 7.93-7.99 (br m, 1H), 6.72 (br s, 1H), 5.51 (s, 2H), 4.50-4.68 (m, 1H), 4.14-4.29 (br m, 1H), 3.60-3.76 (br m, 1H), 3.21-3.54 (br m, 5H), 3.00-3.12 (m, 3H), 2.84-3.00 (br m, 2H), 2.43 (s, 3H), 2.29-2.40 (br m, 1H), 1.77-1.91 (br m, 1H); napadisylate (acid / base molar ratio 1:2) signals: 8.85 (dd, J=8.5, ~1 Hz, 2H), 7.91 (dd, J=7.0 Hz, 1.1 Hz, 2H), 7.39 (dd, J=8.5, 7.1 Hz, 2H). Example 37 6-((4-methvl-1-r6-(trifluoromethvl)pvridin-3-vll-1H-1,2,3-triazol-5-vl}methoxv)-2- (pyridin-3-yl)-1,2,3,4-tetrahvdro-2,7-naphthyridine napadysilate salt F A: Synthesis of the free base In a microwave tube, under argon atmosphere 239 mg (0.612 mmol) of 6-({4-methyl-1-[6-(trifluoromethyl) pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 25), 117 mg (0.741 mmol) of 3-bromopyridine, 141 mg (1.26 mmol) of potassium tert-butoxide, 38 mg (0.061 mmol) of 2,2-bis(Diphenylphosphino)-1,1’-binaphthalene, 13.7 mg (0.061 mmol) of Pd(OAc)2 and 5 mL of anhydrous toluene. The tube was placed in a microwave reactor and heated at 120 °C with stirring for 1 hours. After the reaction completed, the mixture was evaporated and purified by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=10:1) to obtain 19 mg product as an oil. Yield: 19 mg (6.6 %), MS (ESI) m / z: 468.2 [M+H]+. B: Synthesis of the napadisylate salt 19 mg (0.041 mmol) of 6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(pyridin-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine was dissolved in 2 mL of methanol and 14.7 mg (0.041 mmol) of 1,5-naphthalenedisulfonic acid tetrahydrate was added and stirred at 60° C for 10 minutes, then allowed to cool to rt. The precipitated product was collected by filtration, washed with cold methanol, and dried in vacuum to obtain the title compound as a yellow solid. Yield: 11 mg (36 %), MS (ESI) m / z: 468.2 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) 5 (ppm): 9.09 (d, J=2.4 Hz, 1H), 8.46 (dd, J=8.4 Hz, 2.2 Hz, 1H), 8.43 (d, J=2.8 Hz, 1H), 8.21(d, J=8.4 Hz, 1H), 8.17 (d, J=5.3 Hz, 1H), 8.06 (dd, J=8.8 Hz, 2.7 Hz, 1H), 7.96 (s, 1H), 7.85 (dd, J=8.9 Hz, 5.4 Hz, 1H), 6.69 (s, 1H), 5.49 (s, 2H), 4.55 (s, 2H), 3.65 (t, J=6.0 Hz, 2H), 2.92 (t, J=6.0 Hz, 2H), 2.43 (s, 3H); napadisylate (acid / base molar ratio 1:1) signals: 8.86 (dd, J=8.5 Hz, ~1 Hz, 2H), 7.92 (dd, J=7.0 Hz, 1.1 Hz, 2H), 7.40 (dd, J=8.5 Hz, 7.1 Hz, 2H). Example 38 6-(r4-methyl-1 -(6-methvlpyridin-3-vl)-1 H-1,2,3-triazol-5-vllmethoxv}-2-K3S)-oxolan-3-vll-1,2,3,4-tetrahvdro-2,7-naphthyridine or enantiomer, tartarate salt Separation of the enantiomers of the racemic 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 29) by chiral HPLC (column: Lux i-Amylose-1 5pm 150x21,2mm) afforded the enantiopure title compound. MS (ESI) m / z: 407.2 [M+H]+. The tartarate salt prepared according to the procedure described for Example 19 in Step B. MS (ESI) m / z: 407.2 [M+H]+. Example 39 6-(f4-methyl-1 -(6-methvlpyridin-3-vl)-1 H-1,2,3-triazol-5-vllmethoxv}-2-K3R)-oxolan-3- yll-1,2,3,4-tetrahvdro-2,7-naphthyridine or enantiomer, tartarate salt Separation of the enantiomers of the racemic 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 29) by chiral HPLC (column: Lux i-Amylose-1 5pm 150x21,2mm) afforded the enantiopure title compound. MS (ESI) m / z: 407.2 [M+H]+. The tartarate salt prepared according to the procedure described for Example 19 in Step B. MS (ESI) m / z: 407.2 [M+H]+. Example 40 6-{M -(6-methoxvpyridin-3-vl)-4-methvl-1 H-1,2,3-triazol-5-vHmethoxy}-2-(oxan-4-vl)- 1,2,3,4-tetrahvdro-2,7-naphthyridine heminapadisylate salt OH I O=S=O o=s=o I OH The free base of the title compound prepared according to the procedure described for Example 18, Step A using 6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 34) and commercially available 4-oxotetrahydropyran. MS (ESI) m / z: 437.2 [M+H]+. The heminapadisylate salt prepared according to the procedure described for Example 18 in Step B. MS (ESI) m / z: 437.2 [M+H]+. 1H NMR (DMSO-d6, 800 MHz) 5 (ppm): 9.70-9.77 (br m, 1H), 8.41 (d, J=2.8 Hz, 1H), 8.01 (s, 1H), 7.97 (dd, J=8.8, 2.7 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H),6.74 (s, 1H), 5.35-5.41 (ABd, J=13.5 Hz, 2H), 4.52 (d, J=14.6, 1H), 4.31 (dd, J=15.0, 8.3 Hz, 1H), 3.98 (brd, J=11.1 Hz, 2H), 3.94 (s, 3H), 3.70-3.74 (m, 1H), 3.49-3.55 (m, 1H), 3.26-3.35 (m, 3H), 3.01-3.10 (m, 2H), 2.39 (s, 3H), 2.04 (br d, J=12.0 Hz, 1H), 1.99 (br d, J=12.2 Hz, 1H), 1.63-1.73 (m, 2H); napadisylate (acid / base molar ratio 1:2) signals: 8.85 (dd, J=8.4, 1.0 Hz, 2H), 7.91 (dd, J=7.0, 1.0 Hz, 2H), 7.38 (dd, J=8.4, 7.0 Hz, 2H). Example 41 6-(f4-methyl-1 -(6-methylpyridin-3-vl)-1 H-1,2,3-triazol-5-vllmethoxv}-2-(2-methvlpropyl)- 1,2,3,4-tetrahydro-2,7-naphthyridine heminapadisylate salt The free base of the title compound prepared according to the procedure described for Example 18, Step A using 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) and commercially available isobutyraldehyde. MS (ESI) m / z: 393.3 [M+H]+. The heminapadisylate salt prepared according to the procedure described for Example 18 in Step B. MS (ESI) m / z: 393.3 [M+H]+. 1H NMR (DMSO-d6, 400 MHz) 5 (ppm): 9.22-9.40 (br m, 1H), 8.67 (d, J=2.4 Hz, 1H), 7.99 (s, 1H), 7.98 (dd, J=8.3, 2.6 Hz, 1H), 7.52 (d, J=8.3 Hz, 1H), 6.72 (s, 1H), 5.39 (s, 2H), 4.56 (br d, J=14.43 Hz, 1H), 4.19 (dd, J=15.1, 7.7 Hz, 1H), 3.62-3.71 (m, 1H), 3.22-3.36 (m, 1H), 2.97-3.15 (m, 4H), 2.58 (s, 3H), 2.39 (s, 3H), 2.15 (sep, J=6.7, 1H), 0.98 (t, J=6.1 Hz, 6H); napadisylate (acid / base molar ratio 1:2) signals: 8.85 (dd, J=8.4, 1.2 Hz, 2H), 7.91 (dd, J=7.0, 1.2 Hz, 2H), 7.38 (dd, J=8.4, 7.0 Hz, 2H). Example 42 6-(r4-methyl-1 -(6-methylpyridin-3-vl)-1 H-1,2,3-triazol-5-vllmethoxy}-2-r3-(propan-2-yl)oxetan-3-yll-1,2,3,4-tetrahvdro-2,7-naphthyridine napadisylate salt A:     2-(3-(1 H-1,2,3-benzotriazol-1-yl)oxetan-3-yl1-6-CT4-methyl-1-(6-methylpyridin-3-yl)-1H- 1,2,3-triazol-5-yl1methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine To a solution of 1030 mg (3.06 mmol) of 6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine (Example 20) in 30 mL of DCM 243 mg (3.37 mmol) of 3-oxetanone and 383 mg (3.21 mmol) of 1 H-benzotriazole was added. The reaction mixture was stirred at rt for 12 hours. After completion the solvent was evaporated to dryness to obtain the title compound as a white solid. Yield: 1540 mg (98.7 %), MS (ESI) m / z: 510.2 [M+H]+. B:6-CT4-methvl-1-(6-methvlpvridin-3-vl)-1H-1,2,3-triazol-5-vl1methoxy}-2-f3-(propan-2-yl)oxetan-3-vl1-1,2,3,4-tetrahvdro-2,7-naphthyridine Under argon atmosphere a solution of 520 mg (1.02 mmol) of2-[3-(1H-1,2,3-benzotriazol-1-yl)oxetan-3-yl]-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine in 10 mL of THF was added to 593 mg (4.08 mmol) of isopropylmagnesium chloride lithium chloride complex solution in one portion. The reaction mixture was stirred at rt for 10 min. After the reaction completed, the mixture was quenched with water and extracted with EtOAc. The organic layer was separated, dried over MgSO4, filtered, and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: hexane:EtOAc: 2%Et3N, 30-60% gradient) afforded the title compound. Yield: 177 mg (40 %), MS (ESI) m / z: 435.2 [M+H]+. C:6-CT4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl1methoxy}-2-(3-(propan-2-yl)oxetan-3-yl1-1,2,3,4-tetrahydro-2,7-naphthyridine napadisylate salt The heminapadisylate salt prepared according to the procedure described for Example 36 in Step B. MS (ESI) m / z: 435.2 [M+H]+. 1H NMR (DMSO-d6, 500 MHz) 6 (ppm): 9.60-10.50 (br m, 1H), 8.71 (d, J=2.4 Hz, 1H), 8.04 (dd, J=8.3 Hz, 2.4 Hz, 1H), 7.99 (s, 1H), 7.57 (d, J=8.3 Hz, 1H), 6.75 (s, 1H), 5.41 (s, 2H), 4.69 (AB d, J=8.8 Hz, 2H), 4.66 (AB d, J=8.8 Hz, 2H), 4.354.61 (br m, 2H), 3.44-3.83 (br m, 2H), 3.04-3.17 (br m, 2H), 2.60 (s, 3H), 2.40 (s, 3H), 2.342.44 (m, 1H), 1.13 (d, J=6.7 Hz, 6H); napadisylate (acid / base molar ratio 1:1) signals: 8.85 (br d, J=8.6 Hz, 2H), 7.91 (d, J=7.0 Hz, 2H), 7.40 (dd, J=8.4 Hz, 7.3 Hz, 2H). Example 43 2-(3-ethvloxetan-3-vl)-6-(r4-methvl-1-(6-methvlpyridin-3-vl)-1H-1,2,3-triazol-5-vllmethoxv}-1,2,3,4-tetrahvdro-2,7-naphthyridine napadisylate salt The title compound prepared according to the procedure described for Example 42 using ethylmagnesium bromide solution in Step B. MS (ESI) m / z: 421.2 [M+H]+. 1H NMR (DMSO-d6, 500 MHz) 5 (ppm): 10.54-10.96 (br m, 1H), 8.70 (d, J=2.4 Hz, 1H), 8.02 (dd, J=8.3 Hz, 2.6 Hz, 1H), 7.95 (s, 1H), 7.56 (d, J=8.3 Hz, 1H), 6.75 (s, 1H), 5.41 (s, 2H), 4.80 (brd, 2H), 4.57 (d, J=8.1 Hz, 2H), 4.24-4.44 (br m, 2H), 3.26-3.52 (br m, 2H), 3.02-3.18 (br m, 2H), 2.60 (s, 3H), 2.40 (s, 3H), 1.78-1.96 (br m, 2H), 1.23 (t, J=7.3 Hz, 3H); napadisylate (acid / base molar ratio 1:1) signals: 8.85 (br d, J=8.5 Hz, 2H), 7.91 (dd, J=7.0 Hz, 0.9 Hz, 2H), 7.39 (dd, J=8.5 Hz, 7.1 Hz, 2H). Example 44 2-methvl-5-r4-methvl-5-((5H,6H,7H,8H-pvridor3,4-clpvridazin-3-vloxy}methvl)-1H-1,2,3-tri azol-1 -yllpyridine A: tert-butyl 2-methyl-5-r4-methyl-5-({5H,6H,7H,8H-pyridof3,4-clpyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yllpyridine-2-carboxylate In a microwave tube, under argon atmosphere 135 mg (0.50 mmol) of commercially available tert-butyl 3-chloro-5,8-dihydropyrido[3,4-c]pyridazine-7(6H)-carboxylate, 102 mg (0.50 mmol) of [4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methanol (Intermediate 3), 112 mg (1.00 mmol) of potassium tert-butoxide, 20 mg (0.05 mmol) of rac-2-(di-tert-butylphosphino)-1,11-binaphthyl, 11.2 mg (0.05 mmol) of Pd(OAc)2 and 10 mL of anhydrous toluene was added. The tube was placed in a microwave reactor and heated at 120°C with stirring for 3 hours. After the reaction completed, the mixture was filtered through a celite pad, washed with acetone, dried over anhydrous sodium sulfate, and evaporated. The residue was purified by flash coloumn chromatography (silica gel, eluent: cyclohexane: EtAOc=1:1). Yield: 57 mg (26 %). MS (ESI) m / z: 438.2 [M+H]+. B: 2-methvl-5-f4-methvl-5-({5H,6H,7H,8H-pvridof3,4-clpvridazin-3-vloxv}methvl)-1 H-1,2,3-triazol-1-vllpyridine 138 mg (0.31 mmol) of tert-butyl 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine-2-carboxylate was dissolved in 10 mL of DCM. Then, 360 mg (3.16 mmol) of trifluoroacetic acid was added to the solution, and the suspension was stirred at rt for 48 h. After completion the mixture was evaporated, the residue was dissolved in DCM and washed with saturated Na2COs solution and water. The organic layer was separated, dried over MgSO4, filtered and evaporated in vacuo. Purification of the residue by flash coloumn chromatography (silica gel, eluent: DCM:MeOH=10:1) afforded the desired product. Yield: 77 mg (72 %), MS (ESI) m / z: 338.1 [M+H]+. Example 45 5-r5-(fl7-(cvclobutvlmethvl)-5H,6H,7H,8H-pvridor3,4-clpvridazin-3-vlloxy}methvl)-4- methyl-1H-1,2,3-triazol-1-vll-2-methvlpyridine tartarate salt O OH OH O The free base of the title compound prepared according to the procedure described for Example 18, Step A using 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine (Example 44) and commercially available cyclobutanecarboxaldehyde. MS (ESI) m / z: 406.3 [M+H]+. The tartarate salt prepared according to the procedure described for Example 19 in Step B. MS (ESI) m / z: 406.3 [M+H]+. 1H NMR (DMSO-d6, 500 MHz) 5 (ppm): 8.67 (d, J=2.5 Hz, 1H), 7.97 (dd, J=8.3 Hz, 2.6 Hz, 1H), 7.49 (d, J=8.3 Hz, 1H), 6.96 (s, 1H), 5.53 (s, 2H), 3.68 (s, 2H), 2.80 (t, J=5.8 Hz, 2H), 2.64 (t, J=5.9 Hz, 2H), 2.55-2.62 (m, 1H), 2.57 (d, J=7.0 Hz, 2H), 2.56 (s, 3H), 2.41 (s, 3H), 2.00-2.08 (m, 2H), 1.75-1.93 (m, 2H), 1.64-1.73 (m, 2H); tartarate (acid / base ratio 1:1) signal: 4.28 (s, 2H). Example 46 5-(5-r((7-cvclobutvl-5H,6H,7H,8H-pvridor3,4-clpvridazin-3-vl}oxv)methvH-4-methvl-1H- 1,2,3-triazol-1-vl}-2-methvlpyridine tartarate salt O OH OH O The free base of the title compound prepared according to the procedure described for Example 18, Step A using 2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1 H-1,2,3-triazol-1-yl]pyridine (Example 44) and commercially available cyclobutanone. MS (ESI) m / z: 392.2 [M+H]+. The tartarate salt prepared according to the procedure described for Example 19 in Step B. MS (ESI) m / z: 392.2 [M+H]+. 1H NMR (DMSO-d6, 500 MHz) 5 (ppm): 8.67 (d, J=2.5 Hz, 1H), 7.98 (dd, J=8.3 Hz, 2.6 Hz, 1H), 7.50 (d, J=8.3 Hz, 1H), 6.97 (s, 1H), 5.53 (s, 2H), 3.58 (s, 2H), 2.95 (qui, J=7.6 Hz, 1H), 2.81 (brt, J=5.8 Hz, 2H), 2.57 (s, 3H), 2.52 (brt, J=5.8 Hz, 2H), 2.41 (s, 3H), 2.03-2.11 (m, 2H), 1.82-1.91 (m, 2H), 1.63-1.71 (m, 2H); tartarate (acid / base ratio 1:1) signal: 4.28 (s, 2H). Pharmaceutical preparation examples The following formulation examples illustrate representative pharmaceutical compositions of this invention. The present invention however is not limited to the following pharmaceutical compositions. A) Solid oral dosage forms I., Tablets Active ingredient(s) 0.01 - 90% Filler 1 - 99.9% Binder 0 - 20% Disintegrant 0 - 20% Lubricant 0-10% Other specific excipient(s) 0 - 50% Orodispersible films Active ingredient(s) 0.01 - 90% Film forming agent 1 - 99.9% Plasticizer 0 - 40% Other specific excipient(s) 0 - 50% B) Liquid oral dosage forms III., Oral suspensions Active ingredient(s) 0.01 - 50% Liquid vehicle 10-99.9% Wetting agent 0 - 50% Thickener 0 - 50% Buffering agent q.s. Osmotic agent 0 - 50% Preservatives q.s. IV., Syrups Active ingredient(s) Solvent Sugar component Flavouring agents C) Parenteral dosage forms V., Intravenous injections Active ingredient(s) Solvent Co-solvent Osmotic agent Buffering agent D) Other dosage forms VI., Suppositories Active ingredient(s) Suppository base Surface-active agents Lubricants Preservatives VII., Eye drops Active ingredient(s) Water Solvent Osmotic agent Viscosity enhancer Buffering agent Preservatives 0.01 - 50% 10-99.9% 1 - 20% 0-10% 0.01 - 50% 10-99.9% 0 - 99.9% 0 - 50% q.s. 0.01 - 50% 1 - 99.9% 0 - 20% 0 - 20% q.s. 0.01 - 50% 0 - 99.9% 0 - 99.9% 0 - 20% 0 - 20% q.s. q.s. VIII., Nasal drops or spray Active ingredient(s)                  0.01 - 50% Water                         0 - 99.9% Solvent                          0 - 99.9% Osmotic agent                   0 - 20% 5 Viscosity enhancer                0 - 20% Co-solvent                           q.s. Buffering agent                      q.s. Preservatives                        q.s. 10

Claims

1. A compound of formula (I)(I)whereinA is represented byMW*group, orgroup;R1 is an alkyl, an alkoxy, or a haloalkyl group;R2 is hydrogen; an alkyl group optionally substituted with -S(O)2-alkyl, cycloalkyl or heterocycle; a cycloalkyl group; a heterocycle group optionally substituted with an alkyl; or a heteroaryl group;Xis CH, orN;and / or salts thereof and / or stereoisomers thereof and / or enantiomers thereof and / or racemates thereof or diastereomers thereof and / or biologically active metabolites thereof or prodrugs thereof or solvates thereof or hydrates thereof and / or polymorphs thereof.

2. The compound according to claim 1,(l-a)whereinR1 is an alkyl, an alkoxy, or a haloalkyl group;R2 is hydrogen; an alkyl group optionally heterocycle; a cycloalkyl group; a heterocycle heteroaryl group;Xis CH, orN.substituted with -S(O)2-alkyl, cycloalkyl or group optionally substituted with an alkyl; or a3. The compound according to claim 1,(l-b)whereinR1 is an alkyl, an alkoxy, or a haloalkyl group;R2 is hydrogen; an alkyl group optionally heterocycle; a cycloalkyl group; a heterocycle heteroaryl group;Xis CH, orN.substituted with -S(O)2-alkyl, cycloalkyl or group optionally substituted with an alkyl; or a4. The compound according to any one of claims 1 to 3, whereinR1 is a Ci-ealkyl, a Ci.ealkoxy, or a halo-Ci-ealkyl group;R2 is hydrogen; a Ci.6alkyl group optionally substituted with -S(O)2-Ci-ealkyl, Cs-ycycloalkyl or a monovalent saturated or partly unsaturated monocyclic, bicyclic, fused, bridged or spiro ring system of 3 to 10 ring atoms comprising 1,2, 3 or 4 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon; a Cs-ycycloalkyl group; a monovalent saturated or partly unsaturated monocyclic, bicyclic, fused, bridged or spiro ring system of 3 to 10 ring atoms comprising 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon optionally substituted with a Ci-ealkyl; or a monovalent, heterocyclic aromatic, mono- or bicyclic ring system of 5 to 10 ring atoms,comprising 1,2 or 3 heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon;Xis CH orN.

5. The compound according to any one of claims 1 to 4, wherein R1 is a Ci.4alkyl, a Ci-4alkoxy, or a halo-Ci-4alkyl group.

6. The compound according to any one of claims 1 to 5, wherein R1 is a Ci.2alkyl, a Ci-2alkoxy, or a halo-Ci.2alkyl group.

7. The compound according to any one of claims 1 to 6, wherein R2 is hydrogen; a Ci-4alkyl group optionally substituted with -S(O)2-Ci-4alkyl, a C4-6cycloalkyl or a monovalent saturated monocyclic ring of 3 to 7 ring atoms comprising 1, or 2 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon; a C4-ecycloalkyl group; a monovalent saturated monocyclic ring of 3 to 7 ring atoms comprising 1, or 2 ring heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon optionally substituted with a Ci-4alkyl; or a monovalent, heterocyclic aromatic, monocyclic ring system of 5 to 6 ring atoms, comprising 1, or 2 heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon.

8. The compound according to any one of claims 1 to 7, wherein R2 is hydrogen; a Ci-4alkyl group optionally substituted with -S(O)2-Ci-2alkyl, C4-6cycloalkyl or a a monovalent saturated monocyclic ring of 3 to 7 ring atoms comprising one ring heteroatom selected from O and S, the remaining ring atoms being carbon; a C4-ecycloalkyl group; a monovalent saturated monocyclic ring of 3 to 7 ring atoms comprising one ring heteroatom selected from O and S, the remaining ring atoms being carbon optionally substituted with a Ci-4alkyl; or a monovalent, heterocyclic aromatic, monocyclic ring system of 6 ring atoms, comprising 1, or 2 heteroatoms independently selected from N, O and S, the remaining ring atoms being carbon.

9. The compound according to any one of claims 1 to 8, wherein R2 is hydrogen.

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

11. The compound according to any one of claims 1 to 9, wherein X is N.

12. The compound according to any one of claims 1 to 11 selected from the groupconsisting of6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine,2-methyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine,2-cyclobutyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine,2-(cyclobutylmethyl)-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine,2-cyclopentyl-6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxetan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,2-(1-methanesulfonylpropan-2-yl)-6-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[5-methyl-3-(6-methylpyridin-3-yl)-1,2-oxazol-4-yl]methoxy}-2-(pyridin-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,2-methyl-5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]pyridine,5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine,2-methyl-5-{5-methyl-4-[({7-methyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-1,2-oxazol-3-yl}pyridine,5-[5-methyl-4-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine,5-[5-methyl-4-({[7-(oxolan-3-yl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-1,2-oxazol-3-yl]-2-(trifluoromethyl)pyridine,3-{[3-({5-methyl-3-[6-(trifluoromethyl)pyridin-3-yl]-1,2-oxazol-4-yl}methoxy)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-7-yl]methyl}-1lambda6-thiolane-1,1-dione,6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine,2-methyl-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1 H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-methyl-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1 H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1 H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,2-methyl-6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-(propan-2-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({1-[6-(difluoromethyl)pyridin-3-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxetan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(oxolan-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine,6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,3-{[6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-1,2,3,4-tetrahydro-2,7-naphthyridin-2-yl]methyl}-1lambda6-thiolane-1,1-dione,6-({4-methyl-1-[6-(trifluoromethyl)pyridin-3-yl]-1H-1,2,3-triazol-5-yl}methoxy)-2-(pyridin-3-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[(3S)-oxolan-3-yl]-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[(3R)-oxolan-3-yl]-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[1-(6-methoxypyridin-3-yl)-4-methyl-1H-1,2,3-triazol-5-yl]methoxy}-2-(oxan-4-yl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-(2-methylpropyl)-1,2,3,4-tetrahydro-2,7-naphthyridine,6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-2-[3-(propan-2-yl)oxetan-3-yl]-1,2,3,4-tetrahydro-2,7-naphthyridine,2-(3-ethyloxetan-3-yl)-6-{[4-methyl-1-(6-methylpyridin-3-yl)-1H-1,2,3-triazol-5-yl]methoxy}-1,2,3,4-tetrahydro-2,7-naphthyridine,2-methyl-5-[4-methyl-5-({5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yloxy}methyl)-1H-1,2,3-triazol-1-yl]pyridine,5-[5-({[7-(cyclobutylmethyl)-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl]oxy}methyl)-4-methyl-1H-1,2,3-triazol-1 -yl]-2-methylpyridine, and5-{5-[({7-cyclobutyl-5H,6H,7H,8H-pyrido[3,4-c]pyridazin-3-yl}oxy)methyl]-4-methyl-1H-1,2,3-triazol-1-yl}-2-methylpyridineand / or salts thereof and / or stereoisomers thereof and / or enantiomers thereof and / or racemates thereof or diastereomers thereof and / or biologically active metabolites thereof or prodrugs thereof or solvates thereof or hydrates thereof and / or polymorphs thereof.

13. The compound according to any one of claims 1 to 12, for use as medicament.

14. The compound according to any one of claims 1 to 12, for use in the treatment orprevention of diseases related to the GABAa a5 receptor.

15. The compound according to claim 14, for use wherein the disease related to the GABAa a5 receptor is selected from the group consisting of a neurodevelopmental disorder, a neurodegenerative disorder, a neurocognitive disorder, schizophrenia, a mood disorder, a pain disorder, a substance-related and addictive disorder and other disease.

16. The compound according to claim 15, for use wherein the disease related to the GABAa a5 receptor 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), cognition deficiency disorders, memory deficits, age-associated memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorders, negative and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis.

17. The compound according to any one of claims 1 to 12 in combination with one or more other active ingredients, for use in the treatment or prevention of diseases related to the GABAa a5 receptor.

18. Use of a compound according to any one of claims 1 to 12, for the manufacture of a medicament for the treatment or prevention of diseases related to the GABAa a5 receptor.

19. The use according to claim 18, wherein the disease related to the GABAa a5 receptor is selected from the group consisting of a neurodevelopmental disorder, a neurodegenerative disorder, a neurocognitive disorder, schizophrenia, a mood disorder, a pain disorder, a substance-related and addictive disorder and other disease.

20. The use according to claim 19, wherein the disease related to the GABAa a5 receptor 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), cognition deficiency disorders, memory deficits, age-associated memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorders, negative and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis.

21. Use of a compound according to any one of claims 1 to 12 in combination with one or more other active ingredients, for the manufacture of a medicament for the treatment or prevention of diseases related to the GABAa a5 receptor.

22. A method of treating or preventing a disease related to the GABAa a5 receptor, comprising administering to a subject in need of such treatment or prevention an effective amount of at least one compound according to any one of claims 1 to 12.

23. The method according to claim 22, wherein the disease related to the GABAa a5 receptor is selected from the group consisting of a neurodevelopmental disorder, a neurodegenerative disorder, a neurocognitive disorder, schizophrenia, a mood disorder, a pain disorder, a substance-related and addictive disorder and other disease.

24. The method according to claim 23, wherein the disease related to the GABAa a5 receptor 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), cognition deficiency disorders, memory deficits, age-associated memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorders, negative and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis.

25. A method of treating or preventing a disease related to the GABAa a5 receptor comprising administering to a subject in need of such treatment or prevention an effective amount of at least one compound according to any one of claims 1 to 12 in combination with one or more other active ingredients.

26. A pharmaceutical composition comprising as active ingredient at least one compound according to any one of claims 1 to 12 and at least one physiologically or pharmaceutically acceptable excipient.

27. The pharmaceutical composition according to claim 26, wherein the composition further comprises one or more other active ingredients.

28. The pharmaceutical composition according to claim 26 or 27, for use in the treatment or prevention of a disease related to the GABAa a5 receptor.

29. The pharmaceutical composition according to claim 28, for use wherein the disease related to the GABAa a5 receptor is selected from the group consisting of a neurodevelopmental disorder, a neurodegenerative disorder, a neurocognitive disorder, schizophrenia, a mood disorder, a pain disorder, a substance-related and addictive disorder and other disease.

30. The pharmaceutical composition according to claim 29, for use wherein the disease related to the GABAa a5 receptor is selected from the group consisting of autism spectrum disorder (ASD), Angelman syndrome, Fragile X disorder, Prader-Willi syndrome, Rettsyndrome, Alzheimer's disease (AD), cognition deficiency disorders, memory deficits, age-associated memory impairment or cognitive decline, dementia, mild cognitive impairment (MCI), bipolar disorders, negative and / or cognitive symptoms associated with schizophrenia, epilepsy, post-traumatic stress disorder, amyotrophic lateral sclerosis.

31. A compound of formula (I”),whereinA is represented bygroup, orgroup;R1 is an alkyl, an alkoxy, or a haloalkyl group;R2 is an amino protecting group;Xis CH orN;with the proviso that the compound is nottert-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, ortert-butyl 6-({5-methyl-3-[6-(trifluoromethyl)pyridin-5 3-yl]-1,2-oxazol-4-yl}methoxy)-1,2,3,4-tetrahyd ro-2,7- naphthy rid i ne-2-carboxy late.