Difluoromethylpyridine-2-yltriazole

Abstract

To provide: compounds useful in treating central nervous system diseases and other diseases; pharmaceutical compositions; and processes for the manufacture of the same.SOLUTION: The present invention relates to: difluoromethyl-pyridin-2-yl triazoles of general formula (I), which are modulators of GABAA receptors containing the α5 subunit; pharmaceutical compositions containing the compounds; and processes for the manufacture of the compounds.SELECTED DRAWING: None

Description

[Technical Field]

[0001] This invention provides GABA containing an α5 subunit. A This invention relates to difluoromethylpyridine-2-yltriazole of general formula (I), a receptor modulator. The compound is useful for treating central nervous system and other diseases. Furthermore, the invention relates to a method for preparing pharmaceutical compositions and a method for producing the compound according to the present invention. [Background technology]

[0002] GABA A The α5 subunit has been suggested to be a therapeutic target in the treatment of various central nervous system diseases and disorders. GABA as a therapeutic target. A The relationship between the α5 subunit and various neurological disorders, circadian rhythm disorders, and pain states has been established. GABA containing the α5 subunit A Compounds that can modulate receptors are particularly expected to be useful candidates for the treatment of cognitive impairment, Alzheimer's disease, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive dysfunction associated with schizophrenia, and cognitive deficits associated with Down syndrome, autism, neurofibromatosis type 1, or after stroke.

[0003] International Publication No. 2012 / 062687 (corresponding to European Patent Application Publication No. 2638029) discloses triazole derivatives for the treatment of neurological disorders. International Publication No. 2020 / 016443 discloses difluoromethyl-phenyltriazole as a GABA receptor modulator for the treatment of neurological disorders. The compound contains a difluoromethyl group bonded to a phenyl group linked to a triazole ring. The present invention describes difluoromethyl-pyridin-2-yltriazoles. Said compounds contain a difluoromethyl group bonded to a 2-pyridine group linked to a triazole ring. The combination of the 2-pyridine group with the bonded difluoromethyl group is surprisingly a considerably more potent modulator of GABA containing the α5 subunit than similar compounds described in International Publication No. 2020 / 016443 A receptor compounds. The modulatory potency of the compounds can be measured as the Ki value of the compound in Assay A described below. In this case, the combination of the pyridine group in place of the phenyl group used in the phenyltriazoles of International Publication No. 2020 / 016443 and the difluoromethyl group at the 4-position unexpectedly increases the potency of the claimed compounds generally by at least about 10-fold or more. Potency is associated with GABA A 5R binding constant Ki, and the increase in potency leads to a reduction in the effective dose of each compound in the treatment of diseases. SUMMARY OF THE INVENTION

[0004] Object of the present invention Surprisingly, pyridin-2-yl-triazoles of general formula (I) [Chemical Formula] (I) (wherein Xa and Xb are different from each other and represent C or N, R1 is substituted phenyl, or a 5-membered or 6-membered heterocyclyl ring containing 1, 2 or 3 heteroatoms) exhibit improved properties with respect to GABA A 5R binding properties, leading to reduced dosage of the compound and minimized side effects in disease treatment, and are excellent negative modulators of GABA A 5R (i.e., GABA AIt was found to be a negative regulator of the α5 subunit. Furthermore, the compound of the present invention has excellent CNS penetration with a low efflux rate from brain compartments, which is necessary for drugs that have the desired effect in the CNS and high metabolic stability.

[0005] Therefore, one aspect of the present invention is GABA A This refers to a compound or salt thereof, represented by formula (I), which is a negative regulator of 5R. Another aspect of the present invention is high GABA A GABA with 5R binding properties A This refers to a compound according to formula (I), or a pharmaceutically acceptable salt thereof, that is a negative regulator of 5R. Another aspect of the present invention is high GABA A GABA possesses excellent CNS penetration characteristics, including 5R binding properties, a low efflux rate from brain compartments, and high metabolic stability. A This refers to a compound according to formula (I), or a pharmaceutically acceptable salt thereof, that is a negative regulator of 5R.

[0006] Further aspects of the present invention relate to a pharmaceutical composition comprising at least one compound according to formula (I) or a pharmaceutically acceptable salt thereof, together with one or more inert carriers and / or diluents. A further aspect of the present invention relates to a method for producing the compound of the present invention.

[0007] In particular, the present invention relates to acute neurological disorders, chronic neurological disorders, cognitive impairment, Alzheimer's disease, memory loss, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, bipolar disorder, autism, Down syndrome, neurofibromatosis type 1, postoperative cognitive decline, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis, dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug dependence, motor disorders, Parkinson's disease, restless limb syndrome, cognitive deficit disorder, polyinfarct dementia, and Disorders such as depression, major depressive disorder, neuropsychiatric states, psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke, attention deficit, eating disorders, loss of appetite, anorexia nervosa, cachexia, weight loss, muscle atrophy, pain states, chronic pain, nociceptive pain, postoperative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, eye pain, inflammatory pain, fracture pain, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, post-traumatic brain injury recovery, post-stroke pain, post-ischemic pain, fibromyalgia, chronic headache, migraine, tension headache, diabetic neuropathic pain, phantom limb pain, visceral pain and skin pain, etc., GABA A The present invention relates to a compound according to formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound according to formula (I) or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of diseases or conditions that may be affected by negative regulation of 5R. Other results or conclusions of the present invention will be directly apparent to those skilled in the art from the above and below descriptions. [Modes for carrying out the invention]

[0008] The present invention relates to compounds of general formula (I). [ka] (I) Or relating to the salt. (In the formula, Xa and Xb are distinct from each other and represent either C or N. R1 is a substituted phenyl or a 5-membered or 6-membered substituted heterocyclyl ring containing one, two, or three heteroatoms.

[0009] In particular, either Xa or Xb is C. R1 is preferably Phenyl substituted with carbamoyl, Unsubstituted 2-pyridone, or 2-pyridone substituted with a halogen such as fluorine, or 2-pyridone substituted with methyl or ethyl at the nitrogen atom. 2,3 or 4-pyridyls substituted with cyano-(NC-) or thiomethylate-, amino-, methyl-amino-, methylsulfonyl-, or halogens, Unsubstituted pyrimidinyl-, or C 1-6 -Alkyl-, amino-, -hydroxymethyl- substituted pyrimidinyl-, or pyrazinyl- or pyridazinyl, C 1-6 Pyrrolyl- substituted with alkyl- or NC-CH2-CH2-, and C 1-6 -alkyl-, C 3-5 -Cycloalkyl-, NC-CH2-CH2-, amino-, methyl-amino-, or halogen-substituted pyrazolyl-, C 1-6 imidazoly-, imidazoly-, substituted with alkyl-, carbamoyl-, NC-CH2-CH2-, amino-, or methylamino-, Unsubstituted triazolyl- or methyl-, etc. 1-3 -Alkyl----- Triazolyl-, Methyl-substituted oxazolyl- and NC-CH2-CH2-substituted thiophenyl- It is selected from the group consisting of the following.

[0010] Unless otherwise specified, groups, residues, and substituents, particularly R1, are defined as described above and as follows. When residues, substituents, or groups appear multiple times in a compound, they may have the same or different meanings. Some preferred meanings for groups and substituents in the compounds according to the present invention are given below. In a further embodiment of the present invention, R1 is Phenyls substituted with carbamoyl, for example

[0011] [ka] and Unsubstituted 2-pyridone, or 2-pyridone substituted with a halogen such as fluorine, or 2-pyridone substituted with methyl or ethyl at the nitrogen, for example

[0012] [ka] It is selected from the group consisting of the following. In a further embodiment of the present invention, R1 is NC- or -thiomethylate-, amino-, methyl-amino- or -methylsulfonyl or halogen-substituted 2,3 or 4-pyridyl, for example

[0013] [ka] That is the case.

[0014] In further embodiments of the present invention, R1 is selected from the group consisting of the compounds of claim 1 or salts thereof, and R1 is Unsubstituted pyrimidinyl-, or C 1-6 Pyrimidinyl-, pyrazinyl-, or pyradazinyl- substituted with alkyl-, amino-, or hydroxymethyl-, for example

[0015] [ka] That is the case.

[0016] In a further embodiment of the present invention, R1 is C 1-6 Pyrrolyl- substituted with alkyl- or NC-CH2-CH2-, and C 1-6 -alkyl-, C 3-5-Cycloalkyl-, NC-CH2-CH2-, -amino, -methyl-amino, or -halogen-substituted pyrazolyl-, for example.

[0017] [ka] [ka] That is the case.

[0018] In a further embodiment of the present invention, R1 is C 1-6 -alkyl-, carbamoyl, NC-CH2-CH2-, amino- or -methylamino- substituted imidazoly-, for example. [ka] That is the case.

[0019] In a further embodiment of the present invention, R1 is Unsubstituted triazolyl- or C 1-3 Triazolyl- substituted with alkyl, for example [ka] That is the case.

[0020] Furthermore, in a further embodiment of the present invention, R1 is Oxazolyl- substituted with methyl or thiophenyl- substituted with NC-CH2-CH2-, for example.

[0021] [ka] That is the case.

[0022] Even more preferable are the following compounds listed in Table 1. [Table 1] TIFF0007933973000013.tif218147 TIFF0007933973000014.tif223149 TIFF0007933973000015.tif223149 TIFF0007933973000016.tif223149 TIFF0007933973000017.tif223149 TIFF0007933973000018.tif218144 TIFF0007933973000019.tif223147 TIFF0007933973000020.tif218144 TIFF0007933973000021.tif223149 TIFF0007933973000022.tif223149 TIFF0007933973000023.tif223149 TIFF0007933973000024.tif218147 TIFF0007933973000025.tif229149 TIFF0007933973000026.tif223149 TIFF0007933973000027.tif223147 TIFF0007933973000028.tif223150 TIFF0007933973000029.tif223148 TIFF0007933973000030.tif151144 Some terms used earlier and below to describe the compounds according to the present invention are defined in more detail here.

[0023] Terms not specifically defined herein should be given the meanings that those skilled in the art can provide in light of the disclosure and context. However, when used herein, unless otherwise specified, the following terms shall have the meanings indicated and the following provisions shall be observed.

[0024] In the groups, radicals, or parts defined below, the number of carbon atoms is often specified before the group, for example, C 1-6 -Alkyl refers to an alkyl group or radical having 1 to 6 carbon atoms. Generally, for groups such as HO-, H2N-, (O)S-, (O)2S-, NC-(cyano), HOOC-, F3C-, or similar, a person skilled in the art can determine the group bond site to the molecule from the free valence of the group itself. In combined groups containing two or more subordinate groups, the last listed subordinate group is the group bond site, for example, the substituent "aryl-C 1-3 -alkyl- is C 1-3 This refers to an aryl group bonded to an alkyl group, where the latter part is bonded to the core or group to which the substituent is attached.

[0025] In general, the binding site of a given residue to another group is variable; that is, any possible atom within the residue that has a substitutable hydrogen can be the linkage site to the group to which it is bound, unless otherwise indicated. When the compounds of the present invention are described in terms of chemical names and formulas, the formula shall prevail in the event of any inconsistency. Unless otherwise indicated, throughout this specification and the appended claims, a given chemical formula or chemical name encompasses tautomers and all stereo, optical and geometric isomers (e.g., enantiomers, diastereomers, E / Z isomers, etc.) and racemates thereof, as well as mixtures of distinct enantiomers in various proportions, mixtures of diastereomers, or mixtures of any of the above forms, wherein such isomers and enantiomers also exist as salts containing pharmaceutically acceptable salts thereof, and as solvates of them, such as hydrates, including solvates of the free compounds or solvates of salts of the compounds.

[0026] The phrases “medically acceptable” or “physiologically acceptable” are used herein to refer to compounds, substances, compositions, and / or dosage forms that, within the bounds of appropriate medical judgment, are suitable for use in contact with human and animal tissues without excessive toxicity, irritation, allergic response, or other problems or complications, and that are balanced by a reasonable benefit-risk ratio. As used herein, “pharmaceutically acceptable salt” means a derivative of a disclosed compound in which the parent compound has been modified by the preparation of an acid or base salt thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines, alkali or organic salts of acidic residues such as carboxylic acids, and the like. For example, such salts include salts derived from benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, fumaric acid, gentisic acid, hydrobromic acid, hydrochloric acid, maleic acid, malic acid, malonic acid, mandelic acid, methanesulfonic acid, 4-methylbenzenesulfonic acid, phosphoric acid, salicylic acid, succinic acid, sulfuric acid, and tartaric acid.

[0027] Further pharmaceutically acceptable salts may be formed from cations derived from ammonia, L-arginine, calcium, 2,2'-iminobisethanol, L-lysine, magnesium, N-methyl-D-glucamine, potassium, sodium, and tris(hydroxymethyl)-aminomethane. The pharmaceutically acceptable salts of the present invention can be synthesized from parent compounds containing basic or acidic moieties by conventional chemical methods. Generally, such salts can be prepared by reacting the free acidic or basic forms of these compounds with a sufficient amount of a suitable base or acid in water, or an organic diluent such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile, or a mixture thereof. Salts of acids other than those mentioned above (e.g., trifluoroacetates) that are useful for purifying or isolating the compounds of the present invention also constitute part of the present invention.

[0028] As used herein, the term "substituted" means that any one or more hydrogen atoms in a given atom are substituted by a group selected from those shown, provided that the substitution does not exceed the number of valence electrons that the given atom can occupy, and the substitution results in a stable compound. As used herein, the term “partially unsaturated” means that the specified group or part contains one, two, or more double bonds, preferably one or two. Preferably, as used herein, the term “partially unsaturated” does not include fully unsaturated groups or parts. The term "halogen" generally refers to fluorine (F), chlorine (Cl), bromine (Br), and iodine (I).

[0029] n is an integer between 2 and n, and the term "C" can be used either alone or in combination with another base. 1-n "-alkyl" refers to an acyclic, saturated, branched, or linear hydrocarbon group having 1 to n carbon atoms. For example, the term C 1-5 -Alkyl is the group H3C-, H3C-CH2-, H3C-CH2-CH2-, H3C-CH(CH3)-, H3C-CH2-CH2-CH2-, H3C-CH2-CH(CH3)-, H3C-CH(CH3)-CH2-, H3C-C(CH3)2-, H3C-CH2-CH2-CH2-CH2-, H3C- CH2-CH2-CH(CH3)-, H3C-CH2-CH(CH3)-CH2-, H3C-CH(CH3)-CH2-CH2-, H3C-CH2-C(CH3)2-, H3C-C(CH3)2-CH2-, H3C-CH(CH3)-CH(CH3)- and H3C-CH2-CH(CH2CH3)-.

[0030] n is an integer between 4 and n, and the term "C" can be used either alone or in combination with another base. 3-n "Cycloalkyl" refers to a cyclic, saturated, unbranched hydrocarbon group having 3 to n carbon atoms. For example, the term C 3-7 -Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cyclohepcyl.

[0031] Many of the terms given earlier may be used repeatedly in the definition of formulas or bases, and in each case, independently of each other, have one of the meanings given earlier.

[0032] The compounds according to the present invention are obtained, in principle, using known synthesis methods. Preferably, the compounds are obtained by the following methods according to the present invention, which are described in more detail below. The basic chemical synthesis routes used for the compounds disclosed herein are: Route 1: [ka] [ka]

[0033] Route 2: [ka] [ka] That is the case.

[0034] Abbreviation [Table 2] Analytical HPLC method Method A

[0035] [Table 3] Method B

[0036] [Table 4] Method C

[0037] [Table 5] Method D

[0038] Table 6 Method E

[0039] Table 7 Method F

[0040] Table 8 Method G

[0041] Table 9 Method H

[0042] Table 10 Method I

[0043] Table 11 Method J

[0044] Table 12 Method K Table 13 Method L

[0045] Table 14 Method M

[0046] [Table 15] Method N

[0047] [Table 16]

[0048] Preparation of Starting Compounds I-XVIII (Example I) :[3-(5-difluoromethylpyridine-2-yl)-5-methyl-3H-[1,2,3]triazol-4-yl]methanol

[0049] [ka] A solution of 2-azido-5-difluoromethylpyridine (25.7 g, 151 mmol) in 50 mL of buta-2-an-1-ol was stirred at 120°C for 5 days. Excess alcohol was evaporated as much as possible under vacuum. Using DCM / acetone (10:1) as an eluent, column chromatography on silica gel yielded 9.00 g of 3-(5-difluoromethylpyridine-2-yl)-5-methyl-3H-[1,2,3]triazol-4-yl]methanol as a white solid. 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.32 - 2.43 (m, 3 H) 4.86 (s, 2 H) 7.26 (t, J=56Hz 1 H) 8.11 (d, J=8.59 Hz, 1 H) 8.31 (s, 1 H) 8.84 (d, J=0.76 Hz, 1H)

[0050] (Example II) :2-Bromo-5-(difluoromethyl)pyridine [ka] To a solution of 6-bromopyridine-3-carbaldehyde (186 g, 1.00 mol) in 1.86 L of dichloromethane at 0°C, diethylaminosulfur trifluoride (185 ml, 1.40 mol) is added dropwise. The mixture is stirred at rt for 18 hours. The reaction mixture is poured over ice and saturated NaHCO3. The aqueous phase is extracted three times by DCM. The combined organic layer is dried over Na2SO4, filtered, and concentrated. The residue is purified by column chromatography (silica gel, hexane / EE(4 / 1)) to obtain 170 g of product.

[0051] C6H4BrF2N (M=208.0g / mol) ESI-MS: 208[M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ = 8.65 (d, J = 1.3 Hz, 1H), 7.91-8.08 (m, 1H), 7.76-7.92 ppm (m, 1H), 7.17 (t, J = 56 Hz, 1H)

[0052] (Example III) :5-(difluoromethyl)-2-[2-(trimethylsilyl)ethynyl]pyridine [ka] To a solution of Example II (120 g, 0.58 mol), bis(triphenylphosphine)palladium(II) chloride (20.2 g, 0.03 mol), copper(I) iodide (5.49 g, 0.03 mol), and triethylamine (250 mL, 1.73 mol) in 600 mL of tetrahydrofuran at 0°C, ethynyl-trimethyl-silane (160 mL, 1.15 mol) was added dropwise. The resulting mixture was stirred at RT for 18 hours. The mixture was filtered through Celite. The cake was washed with RINKAN. The filtrate was washed with water, dried over Na2SO4, filtered, and concentrated. 117 g of the product was obtained by purification by column chromatography (silica gel, hexane / EE(19 / 1)).

[0053] C 11 H 13 F2NSi (M=225.3g / mol) ESI-MS: 226[M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ = 8.76 (d, J = 0.8 Hz, 1H), 8.01 (dt, J = 8.1, 0.9 Hz, 1H), 7.69 (d, J = 8.1 Hz, 1H), 7.16 (t, J = 56 Hz, 1H) 0.23-0.30 ppm (m, 9H)

[0054] (Example IV) :5-difluoromethyl-2-ethynylpyridine [ka] To a solution of Example III (100.0 g, 0.42 mol) in 800 mL of tetrahydrofuran, water (15.0 mL, 834 mmol) was added. The resulting solution was cooled to 0°C, and then a solution of 1.0 M tetrabutylammonium fluoride in THF (143 mL, 0.50 mol) was added dropwise. After 1 hour, TLC indicated that the reaction was complete. Water was added, and the aqueous layer was extracted three times with diethyl ether. The combined organic layers were dried, filtered, and carefully concentrated. The residue was purified by column chromatography (silica gel, hexane / DCM (1 / 1~0 / 1)) to obtain the product.

[0055] C8H5F2N (M=153.1g / mol) ESI-MS: 154[M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ = 8.77 (d, J = 0.8 Hz, 1H), 8.03 (br d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.1 Hz, 1H), 7.17 (t, J = 56 Hz, 1H) 4.50 ppm (s, 1H)

[0056] (Example V) :5-Difluoromethyl-2-(1-trimethylsilanylmethyl-1H-[1,2,3]triazol-4-yl)pyridine

[0057] [ka] To a solution of Example IV (50.0 g, 0.30 mol) in 1.5 L of DMF, copper(I) iodide (10.9 g, 0.06 mol) and N,N-diisopropylethylamine (50.360 mL, 0.29 mol) were added, followed by the addition of trimethylsilylmethyl azide (50.6 mL, 0.34 mol) in droplets. The resulting mixture was stirred at rt for 24 hours. The reaction was rapidly cooled by the addition of water / brine, then ethyl acetate was added, and the mixture was filtered through Celite. The filtrate was extracted three times with ethyl acetate, dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (silica gel, hexane / EE(3 / 1)), followed by solid tritulation with pentane and drying, yielded 68.0 g of the product.

[0058] C 12 H 16 F2N4Si (M=282.4g / mol) ESI-MS: 283[M+H] + R t (HPLC): 3.52 minutes (Method M) 1 H NMR (DMSO-d6, 400 MHz): δ = 8.78 (s, 1H), 8.52 (s, 1H), 8.13-8.20 (m, 1H), 8.05-8.12 (m, 1H), 7.17 (t, J = 56 Hz, 1H) 4.10 (s, 2H), 0.11 ppm (s, 9H)

[0059] (Example VI) :5-Difluoromethyl-2-(1-methyl-1H-[1,2,3]triazol-4-yl)pyridine [ka] To the solution of Example V (93.0 g, 0.33 mol) in 1.86 L of tetrahydrofuran, water (11.9 ml, 0.66 mol) is added. The resulting solution is cooled to 0°C, and tetrabutylammonium fluoride (395.2 ml, 0.40 mol) is added dropwise. The reaction mixture is stirred at 0°C for 1.5 hours. Water is added, and the THF is evaporated. The formed precipitate is filtered, washed with water, and dried to obtain 51.0 g of product.

[0060] C9H8F2N4 (M=210.1g / mol) ESI-MS: 211[M+H] + 1 H NMR (DMSO-d6, 400 MHz): δ = 8.80 (d, J = 1.0 Hz, 1H), 8.65 (s, 1H), 8.14-8.19 (m, 1H), 8.03-8.13 (m, 1H), 7.17 (t, J = 56 Hz, 1H), 4.13 ppm (s, 3H)

[0061] (Example VII) :5-(5-difluoromethylpyridine-2-yl)-3-methyl-3H-[1,2,3]triazole-4-carbaldehyde [ka] To a solution of Example VI (40.0 g, 0.19 mol) in 1.2 L of tetrahydrofuran at -65°C, a 2.5 M solution of N-butyllithium (114.2 mL, 0.29 mol) in hexane was added dropwise. The resulting mixture was stirred at this temperature for 1.5 hours. Then, N,N-dimethylformamide (147.4 mL, 1.90 mol) was added dropwise, and the reaction mixture was stirred at 0°C for 30 minutes. The reaction was rapidly cooled by slowly adding an aqueous solution of NH4Cl. The aqueous layer was extracted three times with ethyl acetate. The combined organic layer was dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (silica gel, DCM / EE (7 / 3~5 / 5)) followed by tritulation with pentane yielded 19.9 g of the product.

[0062] C9H8F2N4 (M=238.2g / mol) ESI-MS: 239[M+H] + R t (HPLC): 2.68 minutes (Method M) 1 H NMR (DMSO-d6, 400 MHz): δ = 10.68 (s, 1H), 8.92 (d, J = 0.8 Hz, 1H), 8.34 (d, J = 8.3 Hz, 1H), 8.22 (dd, J = 8.1, 1.0 Hz, 1H), 7.23 (t, J = 56 Hz, 1H), 4.29 ppm (s, 3H)

[0063] (Example VIII) :5-(5-difluoromethylpyridine-2-yl)-3-methyl-3H-[1,2,3]triazole-4-carbaldehyde

[0064] [ka] Example VII (19.9 g, 0.08 mol) was dissolved in 199 mL of methanol and 99.5 mL of tetrahydrofuran. The resulting solution was cooled to 0°C. Sodium borohydride (6.32 g, 0.17 mol) was then added little by little, and the reaction mixture was stirred at this temperature for 2 hours. The reaction was rapidly cooled by adding water. The MeOH was evaporated, and the resulting precipitate was collected by filtration, washed with water, and dried. The solid was triturated with pentane to obtain 19.4 g of the product.

[0065] C9H8F2N4 (M=240.2g / mol) ESI-MS: 241[M+H] + R t (HPLC): 3.52 minutes (Method N) 1 H NMR (DMSO-d6, 400 MHz): δ = 8.83 (s, 1H), 8.22 (d, J = 8.1 Hz, 1H), 8.11 (br d, J = 8.1 Hz, 1H), 7.18 (t, J = 56 Hz, 1H), 5.53 (s, 1H), 5.09 (d, J = 3.8 Hz, 2H), 4.11 ppm (s, 3H)

[0066] (Example IX.1) :3-[3-(5-difluoromethylpyridine-2-yl)-5-methyl-3H-[1,2,3]triazol-4-ylmethoxy]-6-iodopyridazine

[0067] [ka] To a solution of Example I (4.00 g, 16.6 mmol) in 50 mL of THF, sodium hydride (1.10 g, 25.0 mmol) and 3,6-diiodopyridazine (5.50 g, 17.0 mmol) were added. The reaction mixture was stirred overnight at 80°C. The reaction mixture was evaporated. The residue was rapidly cooled with water, and the product was extracted by DCM. The organic phase was combined, and the organic phase was dried over MgSO4 and evaporated. The crude product was purified by column chromatography (silica gel, CH / EE(6 / 4)) to obtain 6.30 g of the product.

[0068] C 14 H 11 F 2I N6O (M=444.2g / mol) ESI-MS: 445[M+H] + R t (HPLC): 0.57 min (Method A) 1 H NMR (DMSO-d6, 400 MHz): δ = 8.53-8.80 (m, 1H), 8.33 (dt, J = 8.5, 1.1 Hz, 1H), 7.96 (d, J = 9.1 Hz, 1H), 7.22 (t, J = 52 Hz, 1H), 6.95 (d, J = 9.1 Hz, 1H), 5.95 (s, 2H), 2.36-2.45 ppm (m, 3H)

[0069] The compounds in Examples IX.2 to IX.4, as mentioned in the following table, are prepared according to the basic procedure of Example IX.1 described earlier. [Table 17] The reaction conditions mentioned in the table below were used in Examples IX.2 to IX.4.

[0070] [Table 18]

[0071] (Example X.1) :1-(6-chloropyridazine-3-yl)-1H-pyrazole-4-carbonitrile [ka] To a solution of 4-cyanopyrazole (312 mg, 3.40 mmol) in 5 mL of DMF, 3,6-dichloropyridazine (500 mg, 3.40 mmol) and potassium carbonate (1.40 g, 10.1 mmol) were added, and the reaction mixture was stirred overnight in RT. The mixture was rapidly cooled in ice water, and the precipitate was filtered. The residue was washed with water, and the isolated solid was dried in a vacuum drying cabinet to obtain 524 mg of the product. C8H4ClN5 (M=205.6g / mol) ESI-MS:206[M+H] + R t (HPLC): 0.80 min (Method C)

[0072] The following compounds are prepared according to the basic procedure of Example X.1 described above. [Table 19]

[0073] (Example XI) :3-Chloro-6-(5-methyl-1H-1,2,4-triazol-1-yl)pyridazine [ka] Dissolve 6-chloropyridazin-3-yl)-hydrazine (16.4 g, 113 mmol) and N-[1-dimethylaminometh-(E)-ylidene]acetamide (15.5 g, 136 mmol) in 164 mL of acetic acid. Place the mixture in a preheated oil bath at 80°C. Stir the reaction at this temperature for 30 minutes (TLC monitoring), and evaporate the acetic acid under vacuum. Dissolve the residue in ethyl acetate, and slowly neutralize the organic layer with NaHCO3 (concentrated aqueous solution). Dry the organic layer over Na2SO4 and evaporate the solvent. Purify the product on silica gel using ethyl acetate / hexane (3:1) as an eluent. 10.2 g of 3-chloro-6-(5-methyl-[1,2,4]triazol-1-yl)-pyridazine is obtained as a creamy solid.

[0074] (Example XII) :Methyl 1-(6-chloropyridazine-3-yl)-1H-imidazole-4-carboxylate [ka] To a solution of sodium hydride (1.74 g, 43.6 mmol) in 50 mL of DMF, methyl 1H-imidazole-4-carboxylate (5.00 g, 39.6 mmol) is added at 0°C. The reaction mixture is stirred for 30 minutes. To the reaction mixture, a solution of 3,6-dichloropyridazine (5.90 g, 39.6 mmol) in 30 mL of DMF at 0°C is added, and the mixture is stirred for 20 hours until it reaches RT. The reaction mixture is rapidly cooled with water under ice cooling, the precipitate is filtered, washed, and dried to obtain 3.90 g of product.

[0075] C9H7ClN4O2 (M=238.6g / mol) ESI-MS: 239[M+H] + 1H NMR (400 MHz, DMSO-d6) δ = 8.74 (d, J = 1.3 Hz, 1H), 8.72 (d, J = 1.0 Hz, 1H), 8.43 (d, J = 9.3 Hz, 1H), 8.25 (d, J = 9.3 Hz, 1H), 3.82 (s, 3H)

[0076] (Example XIII) :1-(6-chloropyridazine-3-yl)-1H-imidazole-4-carboxylic acid [ka] To a solution of 1,4-dioxane (3.80 g, 15.8 mmol) from Example XII, 16.0 mL of NaOH (16.0 mmol) was added, and the mixture was stirred at RT for 18 hours. The reaction mixture was rapidly cooled with ice and 1 M HCl (16.0 mL, 16.0 mmol). The precipitate was filtered, washed, and dried to obtain 3.30 g of the product.

[0077] C8H5ClN4O2 (M=224.6g / mol) ESI-MS: 225[M+H] + R t (HPLC): 0.58 min (Method C)

[0078] (Example XIV) :1-(6-chloropyridazine-3-yl)-1H-imidazole-4-carboxamide [ka] To the solution of Example VI (1.00 g, 4.50 mmol) in 10 mL of DMF, DIPEA (2.30 mL, 13.4 mmol) and TBTU (1.40 g, 4.50 mmol) were added and the mixture was stirred at RT for 10 minutes. Ammonium bicarbonate (1.10 g, 13.4 mmol) was added and the reaction mixture was stirred at RT for 1 hour. The mixture was rapidly cooled with ice, the precipitate was filtered, washed, and dried to obtain 0.80 g of the product.

[0079] C8H6ClN5O (M=223.6g / mol) ESI-MS: 224[M+H] + R t (HPLC): 0.54 min (Method C)

[0080] (Example XV) :1-[6-(4-cyano-1H-imidazol-1-yl)pyridazine-3-yl]-1H-imidazole-4-carbonitride [ka] To a solution of 1H-imidazole-4-carbonitride (9.30 g, 99.9 mmol) in 100 mL of DMF, add Example III (20.5 g, 99.9 mmol) and potassium carbonate (41.4 g, 299 mmol), and stir the reaction mixture at 50°C for 18 hours. Add 1H-imidazole-4-carbonitride (5.00 g, 53.7 mmol), and stir the mixture at 50°C for 3 days.

[0081] The mixture was rapidly cooled with water, the precipitate was filtered, and after drying, 25.8 g of the product was obtained. C 12 H6N8 (M=262.2g / mol) ESI-MS:263[M+H] + R t (HPLC): 0.74 min (Method C)

[0082] (Example XVI.1) :3-Chloro-6-(4-Chloro-1H-pyrazol-1-yl)pyridazine [ka] To a solution of 4-chloro-1H-pyrazole (688 mg, 7.00 mmol) in 5 mL of DMF, 3,6-dichloropyridazine (500 mg, 3.36 mmol) and cesium carbonate (2.40 g, 7.38 mmol) were added, and the reaction mixture was stirred overnight in RT. The mixture was rapidly cooled with water, and the precipitate was filtered to obtain 686 mg of the product. C8H6N8 (M=215.0g / mol) ESI-MS: 216[M+H] + R t (HPLC): 0.51 min (Method A) The following compounds are prepared according to the basic procedure described above (Example XVI.1).

[0083] [Table 20-1] [Table 20-2]

[0084] (Example XVII) :6-(pyrazine-2-yl)-2,3-dihydropyridazine-3-one [ka] Acetylpyrazine (3.00 g, 24.6 mmol) is added to an aqueous solution of 2-oxoacetic acid hydrate (2.26 g, 25.0 mmol) in K2CO3 (6.79 g, 49.0 mmol in 30 mL of water). The mixture is stirred at RT for 6 hours. Then acetic acid (12.9 mL, 221 mmol) and hydrazine hydrate (1.42 mL, 29.0 mmol) are added, and the reaction mixture is refluxed for 2 hours. The solution is cooled at RT and basicized to pH 7 with K2CO3. The precipitate is filtered and dried in an oven at 40°C to obtain 1.29 g of product.

[0085] C8H6N4O (M=174.1g / mol) ESI-MS: 175[M+H] + R t (HPLC): 0.23 min (Method A)

[0086] (Example XVIII) :3-Chloro-6-(pyrazine-2-yl)pyridazine [ka] The solution of Example XVII (1.50 g, 6.03 mmol) in POCl3 (5.00 mL, 53.6 mmol) was stirred at 100°C for 1 hour. The reaction mixture was evaporated, and the residue was diluted with DCM under cooling. 10 mL of saturated NaHCO3 solution was added, and this solution was added dropwise to the cold saturated NaHCO3 solution under stirring until the solution became neutral. After 30 minutes, the solution was filtered through Celite and extracted with DCM. The organic layer was collected and dried, and the solvent was evaporated. The product was purified by column chromatography (silica gel, CH / EE(1 / 1)) to obtain 570 mg of the product.

[0087] C8H6ClN4 (M=192.6g / mol) ESI-MS: 193[M+H] + R t (HPLC): 0.33 min (Method A)

[0088] Preparation of the final compound (Example 1) :5-[6-({1-[5-(difluoromethyl)pyridine-2-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]-1-methyl-1,2-dihydropyridine-2-one

[0089] [ka] To 1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,2-dihydropyridine-2-one (159 mg, 0.70 mmol), 1.5 mL of methanol, 3 mL of 1,4-dioxane, 2 M sodium carbonate aqueous solution (0.60 mL, 1.10 mmol), and a solution in Pd-PEPPSI (9.50 mg, 0.01 mmol) from Example IX.1 (250 mg, 0.60 mmol) were added under argon, and the reaction mixture was stirred at 100°C for 3 hours. The mixture was purified by preparative HPLC to obtain 96.1 mg of the product.

[0090] C 20H 17 F2N7O2 (M=425.4g / mol) ESI-MS: 426[M+H] + R t (HPLC): 0.58 min (Method D) 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.41 - 2.46 (m, 3 H) 3.48 - 3.57 (m, 3 H) 5.96 - 6.08 (m, 2 H) 6.47 - 6.58 (m, 1 H) 7.21 (t, J = 56 Hz 1 H) 7.23 (s, 1 H) 7.95 - 8.06 (m, 1 H) 8.13 - 8.22 (m, 2 H) 8.29 - 8.38 (m, 1 H) 8.51 (d, J=2.66 Hz, 1 H) 8.65 - 8.71 (m, 1 H) The following compounds are prepared according to the basic procedure of Example 1 described above.

[0091] [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] [Table 21-5] [Table 21-6] [Table 21-7] [Table 21-8] [Table 21-9]

Table 21-10

Table 21-11

[0092] For the Example compounds, the reaction conditions in Table 2 were used.

Table 22

[0093] (Example 36)

Chemical Formula

[0094] C 18 H 15 F₂N₉O₂ (M=427.4 g / mol) ESI-MS: 428[M+H] + R t (HPLC): 0.77 min (Method C) The following compounds are prepared according to the general procedure of Example 6 described earlier.

[0095]

Table 23-1

Table 23-2

[0096] For Example Compounds 37 to 41, the reaction conditions in the following table were used.

Table 24

[0097] (Example 42) :1-[6-({1-[5-(difluoromethyl)pyridin-2-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazin-3-yl]-1H-imidazole-4-carbonitrile

[0098]

Chemical Formula

[0099] C 18 H 13 F₂N₉O (M=409.3g / mol) ESI-MS: 410[M+H] + R t (HPLC): 0.50 min (Method A) 1H NMR (400 MHz, DMSO-d6) δ ppm 2.34 - 2.48 (m, 3 H) 5.97 - 6.14 (m, 2 H) 7.22 (t, J = 56 Hz, 1H) 7.50 - 7.64 (m, 1 H) 8.16 - 8.19 (m, 1 H) 8.19 - 8.21 (m, 1 H) 8.31 - 8.43 (m, 1 H) 8.67 (d, J=1.14 Hz, 1 H) 8.73 (d, J=1.27 Hz, 1 H) 8.90 - 8.95 (m, 1 H) Compounds 43-47 in the following table are prepared according to the basic procedure of Example 42 described above.

[0100] [Table 25-1] [Table 25-2] For example compounds 43-47, the reaction conditions shown in the table below were used.

[0101] [Table 26]

[0102] (Example 48) :3-({4-[5-(difluoromethyl)pyridine-2-yl]-1-methyl-1H-1,2,3-triazol-5-yl}methoxy)-6-(5-methyl-1H-1,2,4-triazol-1-yl)pyridazine

[0103] [ka] To a solution of Example VIII (200 mg, 0.83 mmol) and Example XI (163 mg, 0.83 mmol) in 10 mL of dioxane is added sodium tert-pentoxide (101 mg, 0.92 mmol). The reaction mixture is stirred at 90°C overnight, then at RT over the weekend. The reaction mixture is diluted with water, and the precipitate is filtered. The crude solid is recrystallized from MeOH to give 212 mg of the product.

[0104] C 17 H 15 F2N9O (M=399.4g / mol) ESI-MS: 400[M+H] + R t (HPLC): 0.46 min (Method A) The following Compounds 49 and 50 are prepared according to the general procedure of Example 48 described earlier.

[0105] Table 27 For Example Compounds 49 to 50, the reaction conditions in the following table were used.

[0106] Table 28

[0107] (Example 51) : 3-(4-chloro-1H-pyrazol-1-yl)-6-({4-[5-(difluoromethyl)pyridin-2-yl]-1-methyl-1H-1,2,3-triazol-5-yl}methoxy)pyridazine

[0108] Chemical Formula Sodium hydride (21.8 mg, 0.50 mmol) was added to the solutions of Example VIII (100 mg, 0.42 mmol) and Example XVI.1 (89.5 mg, 0.42 mmol) in 2 mL of DCM. The reaction mixture was stirred overnight in RT. The reaction mixture was directly purified by preparative HPLC to obtain 41.6 mg of product.

[0109] C 17 H 13 ClF2N8O (M=418.8g / mol) ESI-MS: 397[M+H] + R t (HPLC): 0.86 min (Method F) The following compounds are prepared according to the basic procedure described above (Example 51).

[0110] [Table 29]

[0111] For example compounds 52-53, the reaction conditions shown in the table below were used. [Table 30]

[0112] (Example 54) :3-({1-[5-(difluoromethyl)pyridine-2-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-6-(4-fluoro-1H-pyrazol-1-yl)pyridazine

[0113] [ka] To a solution of 4-fluoro-1H-pyrazole (6.00 mg, 0.10 mmol) in 1 mL of dioxane, Example IX.1 (30.0 mg, 0.10 mmol), copper(I) iodide (5.10 mg, 0.03 mmol), potassium phosphate (57.3 mg, 0.30 mmol), and (1R,2R)-N,N'-dimethyl-1,2-cyclohexanediamine (8.50 μL, 0.05 mmol) were added under argon. Then 100 μL of 25% ammonia was added, and the mixture was stirred for a further 15 minutes. The reaction mixture was filtered through an alox cartridge and an SPE-thiol cartridge, and then purified by preparative HPLC to obtain 20.2 mg of the product.

[0114] C 17 H 13 F3N8O (M=402.3g / mol) ESI-MS: 403[M+H] + R t (HPLC): 0.84 min (Method F) The following compound 55 is prepared according to the basic procedure of Example 54 described above.

[0115] [Table 31]

[0116] For example compound 55, the following reaction conditions were used. [Table 32]

[0117] (Example 56) :3-({1-[5-(difluoromethyl)pyridine-2-yl]-4-methyl-1H-1,2,3-triazol-5-yl}methoxy)-6-(pyrazine-2-yl)pyridazine

[0118] [ka] To a solution of 2-tributylstannylpyrazine (83.0 mg, 0.23 mmol) in 2 mL of dioxane, Example IX.2 (53.0 mg, 0.15 mmol), cesium fluoride (46.0 mg, 0.30 mmol), and xphos (26.0 mg, 0.03 mmol) were added under argon. The reaction mixture was purified by preparative HPLC to obtain 17.0 mg of the product.

[0119] C 18 H 14 F2N8O (M=396.3g / mol) ESI-MS: 397[M+H] + R t (HPLC): 0.92 min (Method G) 1 H NMR (400 MHz, DMSO-d6) δ ppm 2.47 (s, 3 H) 6.11 (s, 2 H) 7.22 (t, J = 56 Hz, 1H) 7.35 (d, J=9.25 Hz, 1 H) 8.20 (d, J=8.49 Hz, 1 H) 8.32 - 8.37 (m, 1 H) 8.39 (d, J=9.25 Hz, 1 H) 8.67 (d, J=1.14 Hz, 1 H) 8.74 - 8.84 (m, 2 H) 9.55 - 9.66 (m, 1 H)

[0120] (Biological examples) Assay A: Human GABA A α5β3γ 2s To HEK cells expressing the receptor 3 H-flumazenil ( 3 In vitro inhibition of H-Ro 15-1788) binding The benzodiazepine modulator unit is an antagonist. 3 It can be selectively labeled with H-flumazenil. For various combinations of subunits 3 The affinity of H-flumazenil is α1β2γ2, α2β2γ2, α3β2γ2, and α5β2γ 2sThe reported concentrations for each receptor are 1.0 nM, 1.1 nM, 1.5 nM, and 0.4 nM, respectively, and for the α4β2γ2 and α6β2γ2 receptors, they are 107 nM and 90 nM, respectively (see Sieghart; Pharmacol. Rev. 1995 47 181-234). α5β3γ mutation 2s GABA A The pharmacological properties of the receptor are similar to those of the wild-type receptor with respect to 3H-flumazenyl binding.

[0121] Cell culture and membrane preparation Recombinant Human GABA A α5β3γ 2s HEK-293 cell lines (plasmid H46 / E9 / B10) exhibiting stable receptor expression should be stored in a T175 polystyrene flask or roller bottle (1700 cm³). 2 Seeds were seeded in Fisher Scientific CCI-431191 and cultured in Dulbecco's Modified Eagle Medium (DMEM) containing GlutaMAX™, supplemented with 10% fetal bovine serum and one or both of the following antibiotics: hygromycin B (50 pg / ml, γ2 subunit) or G418 (0.5 mg / ml, Ω5 subunit) (37°C, 5% CO2). Once the culture reaches confluence, remove the DMEM and wash the cells once in Dulbecco's phosphate-buffered saline (DPBS) (10 ml for a T175 flask, 50 ml for a roller bottle). After adding DPBS to the culture for approximately 5 minutes (10 ml for a T175 flask, 100 ml for a roller bottle), gently shake or tap the flask to easily detach the cells from the surface. Transfer the cell suspension to a Falcon tube and centrifuge at 23,500 × g for 10 minutes at 2°C. Using an Ultra-Turrax homogenizer, wash the pellet once in 15 ml of Tris-citrate buffer (50 mM, pH 7.1) and centrifuge at 27,000 × g for 10 minutes at 2°C. Resuspend the washed pellet in 15 ml of Tris-citrate buffer and freeze at -80°C until the day of the binding experiment.

[0122] Assay On the day of the experiment, thaw the cell membrane preparation and centrifuge at 27,000 × g for 10 minutes at 2°C. Resuspend the pellet in Tris-citrate buffer at a rate of 15–50 pg of protein per assay using an Ultra-Turrax homogenizer, and then use it for the binding assay. A fixed amount of 500 μl of cell suspension is mixed with 25 μl of test compound solution and 3 Add the compound to 25 μl of H-flumazenil (1 nM, final concentration), mix, and incubate at 2°C for 40 minutes. Nonspecific binding is determined using clonazepam (1 μM, final concentration). All dilution of test compounds and incubation of assays shall be performed in glass vials / 96-vial plates. 3 Prepare a solution of H-flumazenil to 22 times the desired final concentration. Dissolve the compound in 100% DMSO (10 mM storage solution), dilute with 48% ethanol-water, and test in triplicate in 1:3 or 1:10 dilutions. When screening multiple compounds, test only one concentration of each compound in a single well. Although a reference compound is not always present, compare all and nonspecific bindings in each experiment performed with the data obtained during assay validation.

[0123] The bond, The process is terminated by either 1) rapid filtration using a Brandel Cell Recovery System with a Whatman GF / C glass fiber filter, followed by five washes with 1 ml of ice-cold buffer, or 2) rapid filtration using a Tomtec Cell Recovery System with a UniFilter GF / C glass fiber filter plate, followed by a wash with approximately 5 ml of ice-cold buffer. 1) Separate large filters are equipped with Tri-Garb® counting devices (PerkinElmer Life and Analytical Sciences), or 2) The 96-well filter plate is equipped with a Topcount™ counting device (PerkinElmer Life and Analytical Sciences). The amount of radioactivity on the filter is determined using conventional liquid scintillation counting. Specific binding is all binding minus nonspecific binding.

[0124] calculation I C 50 ( 3 Before calculating the concentration (μM) of the test compound that inhibits the specific binding of H-flumazenil by 50%, a 25-75% inhibition of specific binding must be achieved. IC for test compounds 50 The value is expressed as: B = 100 - (100 * C) n / (I C 50 n +C n )) It is determined based on, In the formula, B is the percentage of binding for all specific bindings, C is the concentration of the test compound, and n is the Hill coefficient. For screening purposes, n is set to 1. IC 50 The values ​​are calculated from the concentration response curve using a nonlinear regression method with the curve fitting program GraphPad Prism. The Ki value for the test compound is given by the formula developed by Cheng and Prusoff: K=IC 50 / (1+L / K d ) Using IC 50 It can be calculated from the value, During the ceremony, 3 K about H-flumazenyl d The concentration is 0.36 nM, and L is the concentration in the inhibition assay. 3 This is the measured concentration of H-flumazenil.

[0125] result The efficacy observed in Assay A, for example, compounds 1, 13, 10, and 28 of International Publication No. 2020 / 016433, and also in example compounds 42, 56, 5, and 55 of the present invention, is shown in the table below.

[0126] [Table 33] TIFF0007933973000107.tif67136

[0127] [Table 34] TIFF0007933973000109.tif239149

[0128] Assay B: α5β2γ2GABA A In vitro evaluation of receptor regulation The regulatory effect of the compound of formula (I) will be determined by electrophysiological recording in oocytes using the two-electrode potential fixation (TEVC) technique. Human GABA will be administered to oocytes in a 3:1:3 ratio. A cRNAs of receptor subunits α5, β2, and γ2 were injected, and a submaximal EC called GABA control was performed. 5-20 The regulatory effect is evaluated by co-applying GABA concentration (0.5 μM). As a standard, the compound is tested for each oocyte at five concentrations (3.16, 0.316, 0.0316, 0.00316, and 0.000316 μM), starting from the minimum concentration. The peak current amplitude, after subtracting background, is normalized for each GABA control current and converted to a percentage change, and the + / - SEM is plotted as the compound concentration increases. The plotted data points are fitted to the empirical Hill equation using nonlinear regression. Maximum effect (bottom) and potency (LogEC) are calculated. 50 The 95% confidence interval for ) is derived from this fitting routine.

[0129] [Table 35] TIFF0007933973000111.tif104155

[0130] These data demonstrate that the compounds of the present invention exhibit strong negative modulation of target binding and GABA receptor function. The data particularly show that the compounds exhibit strong negative modulation of GABA receptor function compared to compounds known in International Publication No. 2020 / 016433. A It exhibits improved properties regarding 5R binding, which also indicates that the effective dose of the compound can be reduced in disease treatment (Ballard, TM, et al. (2009). RO4938581, a novel cognitive enhancer acting at GABA). A See also α5 subunit-containing receptors. Psychopharmacology (2009) 202: 207-223; J. Pharmacol. Exp. Ther. (2006) 316: 1335-1345).

[0131] Evaluation of efflux in 30 human MDR1 gene-transfected Madin-Darby canine kidney (MDCK) cells to assess brain penetration (Drug Metabolism and Disposition February 2008, 36 (2) 268-275; DOI: https: / / doi.org / 10.1124 / dmd.107.017434) The apparent permeability coefficient (PE) of compounds across a monolayer of MDCK-MDR1 cells is measured in both apical-basal (AB) and basal-apical (BA) transport directions (pH 7.4, 37°C). AB permeability (PEAB) represents drug absorption from blood to the brain, while BA permeability (PEBA) represents drug efflux from the brain back into the bloodstream via both passive permeability and active transport mechanisms, primarily mediated by overexpressed human MDR1 P-gp, via efflux and uptake transporters expressed in MDCK-MDR1 cells. Compounds are assigned a permeability / absorption class by comparing their AB permeability to that of a reference compound with known in vitro permeability and oral absorption in humans. Identical or similar permeability in both transport directions indicates passive permeability, while unidirectional permeability indicates further active transport mechanisms. A PEBA greater than PEAB indicates the involvement of active efflux mediated by MDR1 P-gp. Active transport saturates in a concentration-dependent manner.

[0132] MDCK-MDR1 cells (1-2 x 10⁵ cells / 1 cm² area) are seeded into a filter insert (Costar transwell polycarbonate or PET filter, 0.4 μm pore size) and cultured for 7 days (DMEM). Subsequently, MDR1 expression is enhanced by culturing the cells in complete medium with 5 mM sodium butyrate for 2 days. The compound is dissolved in a suitable solvent (DMSO, etc., 1-20 mM stock solution). To prepare the transport solution (0.1-300 μM compound, final DMSO <= 0.5%), the stock solution is diluted with HTP-4 buffer (128.13 mM NaCl, 5.36 mM KCl, 1 mM MgSO4, 1.8 mM CaCl2, 4.17 mM NaHCO3, 1.19 mM Na2HPO4x7H2O, 0.41 mM NaH2PO4xH2O, 15 mM HEPES, 20 mM glucose, 0.25% BSA, pH 7.4). To measure AB or BA permeation (3 filter repeats), the transport solution (TL) is applied to the apical or bottom-side donor side. The receiver side contains the same buffer as the donor side. For concentration measurement by HPLC-MS / MS or scintillation counting, samples are collected from the donor side at the start and end of the experiment, and from the receiver side at various intervals of up to 2 hours. The volume of the collected receptor is replaced with a new receptor solution.

[0133] [Table 36] These data demonstrate that the compounds of the present invention possess excellent brain penetration properties, along with a low efflux rate from brain compartments.

[0134] Evaluation of metabolic stability in human liver microsomes (human MSTs) The metabolic stability of the compounds according to the present invention can be studied as follows. The metabolic degradation of the test compound is analyzed at 37°C using pooled human liver microsomes. Each time point contains a final incubation volume of 100 μL, consisting of TRIS buffer pH 7.6 (0.1 M), MgCl2 (5 mM), microsomal protein (1 mg / mL), and the test compound at a final concentration of 1 μM. After a short pre-incubation period at 37°C, the reaction is initiated by adding beta-nicotinamide adenine dinucleotide phosphate, reduced form (NADPH, 1 mM), and terminated by transferring a fixed volume to the solvent at various time points. After centrifugation (10000 g, 5 min), a fixed volume of the supernatant is analyzed by LC-MS / MS for the amount of the parent compound. The half-life (t1 / 2) is determined by the slope of the semi-logarithmic plot of the concentration-time profile.

[0135] [Table 37]

[0136] GABA containing α5 subunit A Considering its ability to modulate receptor activity and its favorable pharmacokinetic properties, the compound of general formula (I) according to the present invention, or a physiologically acceptable salt thereof, is a GABA containing an α5 subunit. AIt is suitable for the treatment and / or prophylactic treatment of all diseases or conditions that may be affected by receptor modulation. Therefore, the compounds according to the present invention, including physiologically acceptable salts thereof, are suitable for diseases, particularly acute neurological disorders, chronic neurological disorders, cognitive impairments, Alzheimer's disease, memory loss, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairments associated with schizophrenia, bipolar disorder, autism, Down syndrome, neurofibromatosis type 1, postoperative cognitive decline, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis, dementia caused by AIDS, psychotic disorders, substance-induced psychotic disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug dependence, movement disorders, Parkinson's disease, restless limb syndrome, cognitive deficit disorders, It is particularly suitable for the prevention or treatment of multiple infarct dementia, mood disorders, depression, major depressive disorder, neuropsychiatric states, psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke, attention deficit, eating disorders, loss of appetite, anorexia nervosa, cachexia, weight loss, muscle atrophy, pain states, chronic pain, nociceptive pain, postoperative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, eye pain, pain due to inflammation, pain due to fracture, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, recovery from traumatic brain injury, post-stroke pain, post-ischemic pain, fibromyalgia, chronic headache, migraine, tension headache, diabetic neuropathic pain, phantom limb pain, visceral pain, and skin pain. Compounds according to the present invention, including physiologically acceptable salts thereof, are particularly more suitable for the treatment of cognitive impairment, postoperative cognitive decline, Alzheimer's disease, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, cognitive deficits associated with Down syndrome, cognitive deficits associated with autism, cognitive deficits associated with neurofibromatosis type 1, or cognitive deficits after stroke.

[0137] In a further embodiment of the present invention, the present invention relates to a method for the treatment or prevention of the diseases and conditions mentioned above, the method comprising the administration to a human being an effective amount of a compound of general formula (I), or a pharmaceutically acceptable salt thereof. The typical daily dose range for the compound of general formula (I) is 0.1 to 1000 mg, preferably 1 to 500 mg, administered orally, and administered 1 to 4 times per day in each case. Each medication unit may conveniently contain 0.1 to 500 mg, preferably 1 to 100 mg.

[0138] The actual pharmaceutically effective dose or therapeutic dosage depends on factors known to those skilled in the art, such as the patient's age and weight, the route of administration, and the severity of the disease. In any case, the combination is administered in a dosage and manner that allows the pharmaceutically effective dose to be delivered based on the patient's individual condition. Suitable preparations for administering a compound of formula I containing a pharmaceutically acceptable salt are obvious to those skilled in the art and include, for example, tablets, pills, capsules, suppositories, lozenges, troches, liquids, syrups, elixirs, pouches, injections, inhalants, powders, etc. The content of the pharmaceutically active compound should be in the range of 0.1 to 95% by mass, preferably 5.0 to 90% by mass, of the overall composition. Suitable tablets can be obtained, for example, by mixing one or more compounds according to Formula I with known excipients, such as inert diluents, carriers, disintegrants, adjuvants, surfactants, binders, and / or lubricants. The tablets may consist of multiple layers.

[0139] For this purpose, the compound of formula I prepared according to the present invention may optionally be formulated with other active substances and with one or more inert conventional carriers and / or diluents, and with fatty substances such as corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, citric acid, tartaric acid, water, polyvinylpyrrolidone, water / ethanol, water / glycerol, water / sorbitol, water / polyethylene glycol, propylene glycol, cetyl stearyl alcohol, carboxymethylcellulose, or hard fat, or a suitable mixture thereof.

[0140] The compounds according to the present invention may be used in combination with other active substances, particularly for the treatment and / or prevention of the diseases and conditions mentioned above. A list of examples includes donepezil, memantine, acetazolamide, carbamazepine, eslicarbazepine acetate, ethosuximide, gabapentin, lacosamide, lamotrigine, levetiracetam, brivalacetam, nitrazepam, oxcarbazepine, perampanel, piracetam, phenobarbital, phenytoin, pregabalin, primidone, rufinamide, sodium valproate, stiripentol, thiagabin, and topi. These include Lamat, Vigabatrin, Zonisamide, Levodopa, Carbidopa, Haloperidol, Roxapine, Thioridazine, Morindone, Thiotixen, Fluphenazine, Mesolidazine, Trifluoperazine, Perphenazine, Chlorpromazine, Aripiprazole, Asenapine Maleate, Clozapine, Iloperidone, Lurasidone, Olanzapine, Paliperidone, Quetiapine, Risperidone, Ziprasidone, and Zolpidem.

[0141] For the combination partners mentioned earlier, the dosage is usefully between 1 / 5 of the minimum dose usually recommended and 1 / 2 of the maximum dose usually recommended. Therefore, in another embodiment, the present invention relates to the use of a compound according to the present invention or a pharmaceutically acceptable salt thereof, combined with at least one of the previously described active substances as a combination partner, for preparing a pharmaceutical composition suitable for the treatment or prevention of the previously described diseases or conditions.

[0142] The compound according to the present invention may be used in combination with another active substance simultaneously or with a time difference, but particularly within a short time interval. When administered simultaneously, both active substances are administered to the patient; however, when used with a time difference, the two active substances are administered to the patient within a period of 12 hours or less, but particularly within 6 hours or less.

[0143] As a result, in another embodiment, the present invention relates to a pharmaceutical composition comprising, optionally, one or more inert carriers and / or diluents, a compound according to the present invention or a pharmaceutically acceptable salt thereof, and at least one of the previously described active substances as a combination partner. The compounds according to the present invention may be present together in one formulation, for example, a tablet or a capsule, or they may be present separately in two identical or different formulations, for example, as a so-called kit of parts. Another aspect of the present invention may be as follows: [1] A compound having formula (I) or a salt thereof. [ka] (I) (In the formula, Xa and Xb are distinct from each other and represent either C or N. R1 is a substituted phenyl or a 5-membered or 6-membered substituted heterocyclyl ring containing one, two, or three heteroatoms. [2] The compound described in [1] above or a salt thereof, wherein either Xa or Xb is C. [3] R1 is Phenyl substituted with carbamoyl [ka] and Unsubstituted 2-pyridone, or 2-pyridone substituted with a halogen such as fluorine, or 2-pyridone substituted with methyl or ethyl at the nitrogen atom. [ka] A compound or salt thereof selected from the group consisting of the above [1]. [4] R1 is NC- or -thiomethylate-, amino-, methyl-amino- or -methylsulfonyl or halogen-substituted 3-pyridyl [ka] The compound or salt thereof described in [1] above. [5] R1 is Substituted or unsubstituted pyrimidinyl-(C 1-6 (substituted with -alkyl-, -amino, -hydroxymethyl) or pyrazinyl-, [ka] The compound or salt thereof described in [1] above. [6] R1 is C 1-6 -alkyl- or NC-CH 2 -CH 2 Pyrrolyl- substituted with -, and C 1-6 -alkyl-, C 3-5 -Cycloalkyl-, NC-CH 2 -CH 2 -, -amino, -methyl-amino, or -halogen-substituted pyrazolyl

change

change

change

change

change

[10] R1 is Phenyl substituted with carbamoyl, Unsubstituted 2-pyridone, or 2-pyridone substituted with a halogen such as fluorine, or 2-pyridone substituted with methyl or ethyl at the nitrogen atom. NC- or thiomethylate-, amino-, methyl-amino-, methylsulfonyl- or halogen-substituted 3-pyridyl Unsubstituted pyrimidinyl-, or C 1-6 -Alkyl-, amino-, -hydroxymethyl- substituted pyrimidinyl- or pyrazinyl-, C 1-6 -alkyl- or NC-CH 2 -CH 2 Pyrrolyl- substituted with -, and C 1-6 -alkyl-, C 3-5 -Cycloalkyl-, NC-CH 2 -CH 2 -, amino-, methyl-amino-, or --halogen-substituted pyrazolyl-, C 1-6 -alkyl-, carbamoyl-, NC-CH 2 -CH 2 -, imidazoly- substituted with amino- or -methylamino-, Unsubstituted triazolyl- or methyl-, etc. 1-3 -Alkyl----- Triazolyl-, Methyl-substituted oxazolyl- and NC-CH 2 -CH 2 - Substituted with thiophenyl- A compound or salt thereof selected from the group consisting of the above [1]. 〔11〕 Table 1-1 Table 1-2 Table 1-3 Table 1-4 Table 1-5 Table 1-6 Table 1-7 Table 1-8 Table 1-9 A compound or a salt thereof selected from the group of compounds comprising the above [1].

[12] A salt of any one of the compounds described in [1] to

[11] above, for use as a medicine.

[13] A pharmaceutical product prepared with any one of the compounds described in [1] to

[11] above or a salt thereof.

[14] The compound or salt thereof described in [1] above, wherein formula (I) is one of the formulas of compounds 22 to 56 and 39.

[15] A method for preparing the compound described in [1], comprising the following chemical reaction pathway. (a)

change

change

[16] A method for preparing the compound described in [1], comprising the following chemical reaction pathway.

change

change

[17] A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, and at least one compound described in any one of items [1] to

[11] above, or a pharmaceutically acceptable salt thereof.

[18] Acute neurological disorders, chronic neurological disorders, cognitive impairment, Alzheimer's disease, memory loss, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, bipolar disorder, autism, Down syndrome, neurofibromatosis type 1, postoperative cognitive decline, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis, AIDS-induced dementia, psychotic disorders, substance-induced psychotic disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug dependence, movement disorders, Parkinson's disease, restless limb syndrome, cognitive deficit disorder, multiple infarct dementia, mood disorders, depression, major depressive disorder The pharmaceutical composition described in

[17] above for the treatment or prevention of disorders, neuropsychiatric states, psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke, attention deficit, eating disorders, loss of appetite, anorexia nervosa, cachexia, weight loss, muscle atrophy, pain states, chronic pain, nociceptive pain, postoperative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, eye pain, pain due to inflammation, pain due to fracture, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, recovery after traumatic brain injury, post-stroke pain, post-ischemic pain, fibromyalgia, chronic headache, migraine, tension headache, diabetic neuropathic pain, phantom limb pain, visceral pain, and skin pain.

[19] The pharmaceutical composition according to

[18] , comprising 0.1 to 1000 mg, preferably 1 to 500 mg, of the compound or a pharmaceutically acceptable salt thereof described in any one of [1] to

[11] above, in a therapeutically effective amount.

[20] A compound according to any one of items [1] to

[11] above, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to item

[17] above, for use in the prevention or treatment of cognitive impairment, postoperative cognitive decline, Alzheimer's disease, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, cognitive deficits associated with Down syndrome, cognitive deficits associated with autism, cognitive deficits associated with neurofibromatosis type 1, or cognitive deficits after stroke.

Claims

1. A compound having formula (I) or a salt thereof. 【Chemistry 1】 (I) (In the formula, Xa and Xb are distinct from each other and represent either C or N. R1 is, C 1-6 -Alkyl- or NC-CH 2 -CH 2 Pyrrolyl- substituted with -, 【change】 、 C 1-6 -Alkyl-, C 3-5 -Cycloalkyl-,NC-CH 2 -CH 2 -, amino-, methyl-amino-, or halogen-substituted pyrazolyl-, or 【change】 The arrows in the chemical formula indicate the bond position to the pyridazine ring in formula (I).

2. R1 is C 1-6 -alkyl- or NC-CH 2 -CH 2 -pyrrolyl which is substituted, the compound according to claim 1 or a salt thereof.

3. R1 is, The compound or salt thereof according to claim 1 (the arrows in the chemical formula indicate the bond position to the pyridazine ring in formula (I)).

4. R1 is C 1-6 -Alkyl-, C 3-5 -Cycloalkyl-,NC-CH 2 -CH 2 The compound or salt thereof according to claim 1, wherein the compound is a pyrazolyl- substituted with -, amino-, methyl-amino-, or halogen-.

5. R1 is, The compound or salt thereof according to claim 1 (the arrows in the chemical formula indicate the bond position to the pyridazine ring in formula (I)). 【Request Item 6】 【Table 1-1】 Table 1-2 Table 1-3 A compound or salt thereof according to claim 1, selected from the group of compounds comprising the above.

7. A pharmaceutical composition comprising a salt of the compound described in any one of claims 1 to 6.

8. A pharmaceutical composition comprising a compound or a salt thereof as described in any one of claims 1 to 6.

9. A pharmaceutical composition comprising one or more pharmaceutically acceptable carriers, and at least one compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

10. Acute neurological disorders, chronic neurological disorders, cognitive impairment, Alzheimer's disease, memory loss, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, bipolar disorder, autism, Down syndrome, neurofibromatosis type 1, postoperative cognitive decline, sleep disorders, circadian rhythm disorders, amyotrophic lateral sclerosis, AIDS-induced dementia, psychotic disorders, substance-induced psychotic disorders, anxiety disorders, generalized anxiety disorder, panic disorder, delusional disorder, obsessive-compulsive disorder, acute stress disorder, drug dependence, movement disorders, Parkinson's disease, restless limb syndrome, cognitive deficit disorder, multiple infarct dementia, mood disorders, depression, major depressive disorder, neuropsychiatric conditions A pharmaceutical composition according to any one of claims 7 to 9, for use in the treatment or prevention of psychosis, attention deficit hyperactivity disorder, neuropathic pain, stroke, attention deficit, eating disorder, loss of appetite, nervous anorexia, cachexia, weight loss, muscle atrophy, pain state, chronic pain, nociceptive pain, postoperative pain, osteoarthritis pain, rheumatoid arthritis pain, musculoskeletal pain, burn pain, eye pain, pain due to inflammation, pain due to fracture, hyperalgesia, neuropathic pain, herpes-related pain, HIV-related neuropathic pain, traumatic nerve injury, recovery after traumatic brain injury, post-stroke pain, post-ischemic pain, fibromyalgia, chronic headache, migraine, tension headache, diabetic neuropathic pain, phantom limb pain, visceral pain, and skin pain.

11. The pharmaceutical composition according to claim 10, comprising 0.1 to 1000 mg of a compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 6 in a therapeutically effective amount.

12. The pharmaceutical composition according to claim 10 for use in the prevention or treatment of cognitive impairment, postoperative cognitive decline, Alzheimer's disease, schizophrenia, positive, negative and / or cognitive symptoms associated with schizophrenia, cognitive impairment associated with schizophrenia, cognitive deficits associated with Down syndrome, cognitive deficits associated with autism, cognitive deficits associated with neurofibromatosis type 1, or cognitive deficits after stroke.

Images