Inhibitors of TREK (TWIK-related K+ channel) channel function

Abstract

Compound of formula (I): JPEG2026521154000134.jpg4544 (wherein all symbols are defined herein) is disclosed. Also disclosed are pharmaceutical compositions comprising the compound, methods for preparing the compound, kits comprising the compound, and methods for using the compound to prevent and / or treat disorders associated with dysregulation of TREK-1, TREK-2, or both TREK-1 and TREK-2 in mammals.

Description

Technical Field

[0001] The present disclosure relates to disorders associated with K2P K + channels, specifically, compounds, compositions and methods for preventing and / or treating TREK (TWIK-related K+ channel) dysfunction for which inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide a therapeutic benefit.

Background Art

[0002] Potassium (K + ) channels are membrane proteins expressed in substantially all cells of an organism. K + channel subunits (about 80 genes) can be divided into three major structural classes, including shaker-type voltage-dependent (Kv), inwardly rectifying (Kir), and K + channels with two pore domains (K2P) (Kubo et al., Pharmacol Rev. 2005, 57, 509, Gutman, et al. Pharmacol Rev. 2005, 57, 473, Goldstein et al. Pharmacol Rev. 2005, 57, 527). The third family of K + channels was discovered 20 years ago (Leasge et al. EMBO J. 1996, 15, 1004). Fifteen human K2P K + channels have been identified to date and are classified into six structural subgroups, namely, TWIK, TREK (TWIK-related K + channels), TASK (TWIK-related acid-sensitive K + channels), TALK (TWIK-related ALkaline pH-activated K + channels), THIK (tandem pore domain halothane-inhibited K + channels), and TRESK (TWIK-related spinal cord K + channels) (Enyedi et al. Physiol. Rev. 2010, 90, 559). K2P K + channels contribute to background current or "leak" K +These channels are responsible for electrical currents. These channels are regulated by various physical and chemical stimuli, including membrane stretching, temperature, acidosis, lipids, and inhaled anesthetics. Furthermore, channel activity is strictly controlled by membrane receptor stimulation and second messenger phosphorylation pathways. This novel K + Some members of the channel family are highly expressed in the central and peripheral nervous systems and are suggested to play important physiological roles (TRENDs in Neurosci. 2001).

[0003] TREK-1 and TREK-2, belonging to the TREK subgroup, are thermally and mechanically gated K2s activated by lysophospholipids and PUFAs containing arachidonic acid. + These are channels. They are regulated by G protein-coupled receptors via PKA and PKC phosphorylation (Channels (Austin). 2011 Sep-Oct;5(5):402-9). The TREK-1 gene is widely expressed in the CNS, but its distribution in the periphery is limited. In the CNS, TREK-1 expression is most abundant in the striatum, caudate process and putamen, as well as in the spinal cord, fetal brain, amygdala and thalamus. Peripherally, TREK-1 expression is observed in the heart, stomach and small intestine. The TREK-2 gene has a very similar expression profile to TREK-1, and is particularly highly expressed in the caudal gland, putamen and fetal brain. However, in contrast to TREK-1, TREK-2 is also highly expressed in the cerebellum and corpus callosum, as well as in some peripheral tissues, particularly the kidney (Mol. Brain Res. 2001,86,101).

[0004] TREK-1-deficient mice exhibit increased efficacy of serotonin (5-HT) neurotransmission and a depression-resistant phenotype (Nature Neurosci. 2006, 9, 1134). Spadin, a naturally occurring peptide, blocks TREK-1, resulting in a rapid onset of antidepressant effects (Br.J.Pharmacol. 2014, 172, 771). Furthermore, antidepressants such as fluoxetine and paroxetine directly inhibit TREK channels (Nat.Neurosci. 2006, 9, 1134; Br.J.Pharmacol. 2005, 144, 821). Therefore, inhibition of TREK-1 by small molecules holds promise for the treatment of depression and other mood disorders (Front.Pharmacol. 2018, 9, 863).

[0005] Inhibition of TREK-1 protects mice from anesthesia-induced cognitive impairment, and coupled with its high density in the hippocampus, TREK-1 is a potential therapeutic target for other CNS disorders accompanied by volatile anesthetic-induced memory and cognitive impairment (Neurobiology of Learning and Memory, 2017, 145, 199). TREK-1 gene expression is increased in the hippocampus of schizophrenic patients compared to healthy controls (Neuropsychopharmacology 2010, 35, 239-57). Intrathecal injection of microRNA targeting TREK-1 improves neuropathic pain induced by chronic stenotic sciatic nerve injury (Neurochem Res. 2018, 43, 1143), suggesting that TREK-1 inhibition may be effective for cognitive impairment and neuropathic pain. TREK-1 knockdown significantly inhibits the proliferation of prostate cancer cells and induces G1 / S cell cycle arrest both in vitro and in vivo (Cancer Res. 2008, 68, 1197-203., Oncotarget. 2015, 6, 18460-8). TREK-1 is also overexpressed in human ovarian cancer tissue, and treatment with TREK-1 inhibitors (curcumin and L-methionine) suppresses the proliferation of ovarian cancer cells and increases late apoptosis (Clin. Transl. Oncol. 2013, 15, 910-8.). Therefore, TREK-1 inhibitors may be useful in the treatment of prostate and ovarian cancer. The TREK-1 gene is also expressed in the lungs, and TREK-1 knockdown leads to improvement in bleomycin-induced pulmonary fibrosis (Biomedicines. 2023, 11(5), 1279), indicating that TREK-1 inhibitors may be useful in the treatment of pulmonary fibrosis.

[0006] Neurotensin (NT) suppresses TREK-2 currents via NT receptor 1-mediated activation of the PLC / PKC pathway in astrocellular neurons of layer II of the entorhinal cortex, resulting in depolarization of membrane potential and enhanced neuronal excitability. Furthermore, enhanced NT-induced spatial learning is reduced in TREK-2 knockout mice, suggesting that TREK-2 inhibitors may be useful in treating cognitive disorders such as Alzheimer's disease (J. Neurosci. 2014, 34, 7027-42). TREK-2 is expressed in human bladder cancer cells and contributes to the regulation of resting membrane potential. TREK-2 KD reduces cell proliferation (Korean J. Physiol. Pharmacol. 2013, 17, 511-6). Therefore, TREK-2 inhibitors may also be effective in treating bladder cancer.

[0007] Selective inhibition of TREK-1 with small-sized inhibitors has potential therapeutic benefits for depression, schizophrenia, cognitive disorders including dementia, neuropathic pain, stroke, prostate cancer, ovarian cancer, and pulmonary fibrosis (Nat. Neurosci. 2006, 9, 1134, Neuropsychopharmacology 2010, 35, 239, Neurobiol. Learn Mem. 2017, 145, 199, Neurochem Res. 2018, 43, 1143, Neurosci Lett. 2018, 671, 93, Cancer Res. 2008, 68, 1197, Clin. Transl. Oncol. 2013, 15, 910, Biomedicines. 2023, 11(5), 1279).

[0008] Selective inhibition of TREK-2 with small molecule inhibitors has potential therapeutic benefits for cognitive impairments such as dementia, stroke, and bladder cancer (J.Neurosci.2014,34,7027,Biochem.Biophys.Res.Commun.2005,327,1163,Korean J.Physiol.Pharmacol.2013,17,511). TREK-2 expression levels are elevated in the cortex and hippocampus of an acute rat cerebral ischemia model (Biochem.Biophys.Res.Commun.2005,327,1163-9). Therefore, TREK-2 inhibitors may be useful in the treatment of stroke.

[0009] All of the aforementioned disorders can also be effectively treated with both TREK-1 and TREK-2 inhibitors, with varying degrees of TREK-1 and TREK-2 preference.

[0010] The following compounds are known to have structures similar to those of the compounds disclosed herein. [ka]

[0011] However, there is no description or suggestion that the compounds in this disclosure have significant inhibitory activity against TREK-1, TREK-2, or both TREK-1 and TREK-2. [Overview of the project] [Problems that the invention aims to solve]

[0012] Despite advances in K2P channel research and TREK-1 and TREK-2 pharmacological channel research, there is no potent and effective selective inhibitor of either TREK-1, TREK-2, or both TREK-1 and TREK-2, and K2P K +There is still a lack of effective compounds for treating TREK (TWIK-related K+ channel) dysfunction, particularly TREK-1, TREK-2, or both TREK-1 and TREK-2 inhibitors, which would provide therapeutic benefits for TREK-1, TREK-2, inflammatory, respiratory, renal, and cardiovascular disorders, cancer, or pulmonary fibrosis. [Means for solving the problem]

[0013] To achieve the above objectives, the inventors conducted intensive research to find a compound that has inhibitory effects on TREK-1, TREK-2, or both TREK-1 and TREK-2, and found that the compound of formula (I) has remarkable inhibitory activity on TREK-1, TREK-2, or both TREK-1 and TREK-2.

[0014] In one embodiment, the compound of formula (I), [ka] Or a pharmaceutically acceptable salt thereof is disclosed, In the formula, all symbols are defined as follows:

[0015] Also disclosed are pharmaceutical compositions containing the compound, methods for producing the compound, kits containing the compound, and methods for using the compound, compositions, and kits for the prevention and / or treatment of disorders such as neurological and / or psychiatric disorders associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2, in which inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide therapeutic benefits in mammals. [Brief explanation of the drawing]

[0016] [Figure 1]Figure 1 shows the effects of compounds 6, 14, 35, 59, and 73 in the forced swimming test of mice. The vertical axis represents immobility time, and the horizontal axis represents the groups administered with the vehicle, the test compound, or imipramine. Compared to the vehicle-treated group, *p<0.05 (Dunnett's test), #p<0.05, ##p<0.01, and ###p<0.001 (Student's t-test). [Figure 2] Figure 2 shows the effect of compound 59 in a mouse MK-801-induced novel object recognition test. The vertical axis represents the discrimination index, and the horizontal axis represents the groups administered with vehicle, compound 59, or clozapine, followed by induction of MK-801. Mice treated with vehicle without MK-801 induction were used as a control group. Compared to the vehicle-treated group, p<0.05 (Dunnett's test), compared to the vehicle-treated group, p<0.01 (Student's t-test), and compared to the control group, p<0.05 (Student's t-test). [Modes for carrying out the invention]

[0017] Inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2 are disclosed herein. In other words, this disclosure is, [1] Compound of formula (I), [ka] Or a pharmaceutically acceptable salt thereof is disclosed, During the ceremony, Ring A is, [ka] Alternatively, it may be an 8-10 membered bicyclic system substituted with 1-6 halogen atoms. R 1(1) hydrogen atoms, (2) C1-8 alkyl groups, (3) C1-8 haloalkyl groups, (4) C2-8 alkenyl groups, (5) C2-8 haloalkenyl groups, (6) C2-8 alkynyl groups, (7) C2-8 haloalkynyl groups, and (8) 4-6 member saturated monocyclic heterocycles, where one or two carbon atoms in each of groups (2)-(7) are independently (1)NR 8 (2) may be replaced by an oxygen atom or (3) an oxidized sulfur atom, R 1 Each of the groups (2) to (8) in this case has 1 to 6 R 1-1 It may also be replaced with R 1-1 (1) Deuterium atom, (2) Halogen atom, (3) Hydroxyl group, (4) C1-4 alkyl, (5) C1-4 haloalkyl, (6) C1-4 alkoxy, (7) C1-4 haloalkoxy, (8)-CO-NR 1-2 R 1-3 (9)-O-CO-R 1-4 (10)-SO2-R 1-5 , (11)-S(=O)(=NR 1-6 )-R 1-7 (12)-NR 1-8 R 1-9 , (13) selected from the group consisting of cyano and (14) 3- to 6-membered heterocycles, R 1-1 If there are 2 to 6 of them, multiple R 1-1 They may be the same or different from each other. R 1-2 , R 1-3 , R 1-4 , R 1-5 , R 1-6 , R 1-7 , R 1-8 and R 1-9 Each of these is independently selected from the group consisting of (1) a hydrogen atom, (2) C1-4 alkyl groups, and (3) C1-4 haloalkyl groups. R 2 (1) C1-4 alkyl or (2) C1-4 haloalkyl, R 3It is selected from the group consisting of (1) hydrogen atoms, (2) halogen atoms, (3) C1-4 alkyl and (4) C1-4 haloalkyl, R 3 If there are two or three, multiple R 3 They may be the same or different from each other. R 4 (1) halogen atoms, (2) C1-4 alkoxys, and (3) C1-4 haloalkoxys are selected from the group, R 5 It is selected from the group consisting of (1) hydrogen atoms, (2) halogen atoms, (3) C1-4 alkyl, (4) C1-4 haloalkyl, (5) C1-4 alkoxy and (6) C1-4 haloalkoxy, R 6 is (1) a hydrogen atom or (2) a halogen atom, R 6 If there are two, multiple R 6 They may be the same or different from each other. R 7 (1) A hydrogen atom or (2) A C1-4 alkyl group, R 8 (1) A hydrogen atom or (2) A C1-4 alkyl group, R 9 It is selected from the group consisting of (1) hydrogen atoms, (2) halogen atoms, (3) C1-4 alkyl and (4) C1-4 haloalkyl, R 10 is (1) a hydrogen atom or (2) a halogen atom, X 1 (1)CR 9 (2) N, X 2 (1)CR 10 (2) N, m is an integer between 1 and 3. The expression relates to a compound or a pharmaceutically acceptable salt thereof, where n is an integer of 1 or 2.

[0018] [2][1] A compound described in the formula (I-1): [ka] Compounds of (wherein all symbols are as defined in [1]), or a pharmaceutically acceptable salt thereof. The compound described in [2-1][1], with formula (I-1-1): [ka] Compounds of (wherein all symbols are as defined in [1]), or a pharmaceutically acceptable salt thereof. [3][1] A compound described in formula (I-2): [ka] Compounds of (wherein all symbols are as defined in [1]), or a pharmaceutically acceptable salt thereof. The compound described in [3-1][1], with formula (I-2-1): [ka] Compounds of (wherein all symbols are as defined in [1]), or a pharmaceutically acceptable salt thereof. [4][1] A compound described in formula (I-3): [ka] Compounds of (wherein all symbols are as defined in [1]), or a pharmaceutically acceptable salt thereof. The compound described in [4-1][1], with formula (I-3-1): [ka] Compounds of (wherein all symbols are as defined in [1]), or a pharmaceutically acceptable salt thereof. A compound described in [5][1], with formula (IA): [ka] Compounds of (wherein all symbols are as defined in [1]), or a pharmaceutically acceptable salt thereof. A compound described in [6][1], with formula (I-A1): [ka] (In the formula, ring A-1 may be substituted with 1 to 6 halogen atoms, which is an 8 to 10 membered bicyclic system.) The other symbols are as defined in [1]) of the compounds, or a pharmaceutically acceptable salt thereof. A compound described in any one of [7][1], [2], and [5], In the formula, ring A is, [ka] And, Other symbols are as defined in [1] for compounds, or a pharmaceutically acceptable salt thereof. A compound described in any one of [8][1]~[5] and [7], with formula (IB): [ka] Compounds of (wherein all symbols are as defined in [1]), or a pharmaceutically acceptable salt thereof. A compound described in any one of [9][1] to [8], In the formula, R 1 This is 1 to 6 R 1-1A A C1-4 alkyl group which may be substituted with R 1-1A It is selected from the group consisting of (1) deuterium atom, (2) hydroxyl group, (3) methyl, (4) methoxy, (5) cyano and (6) oxetane, R 1-1A If there are 2 to 6 of them, multiple R 1-1A They may be the same or different from each other. Other symbols are as defined in [1] for compounds, or a pharmaceutically acceptable salt thereof. A compound described in any one of

[10] [1] to [9], In the formula, R 1 This is 1 to 6 R 1-1B A C1-4 alkyl group which may be substituted with R 1-1B (1) a deuterium atom or (2) a hydroxyl group, R 1-1B If there are 2 to 6 of them, multiple R 1-1B They may be the same or different from each other. Other symbols are as defined in [1] for compounds, or a pharmaceutically acceptable salt thereof. The compounds described in

[11] [1], (1) 5-Chloro-2-methoxy-N-{1-methyl-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}benzamide, (2) 5-Chloro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxybenzamide, (3) 5-Chloro-N-{1-(2-hydroxy-2-methylpropyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxybenzamide, (4) 5-Chloro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxybenzamide, (5) 2-Fluoro-N-{1-(2-hydroxy-2-methylpropyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (6) 2-Fluoro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (7) 2-Fluoro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide, (8) 5-Chloro-2-methoxy-N-{1-(2-methoxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}benzamide, (9) 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (10) 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (11) N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}2-methoxy-5-(trifluoromethyl)benzamide, (12) 5-(difluoromethyl)-2-fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide, (13) 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethoxy)benzamide, (14) 5-(difluoromethoxy)-2-fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide, (15) 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethyl)benzamide, (16) 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethoxy)benzamide, (17) 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-6-methoxy-3-(trifluoromethyl)benzamide, (18) N-[3-(2-isopropylphenyl)-1-(2-methoxyethyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxy-5-(trifluoromethyl)benzamide, (19) 5-(difluoromethoxy)-2-fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide, (20)N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxy-5-(trifluoromethyl)benzamide, (21) 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethyl)benzamide, (22) 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-6-methoxy-3-(trifluoromethyl)benzamide, (23) 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide, (24) 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (25) 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide, (26) 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (27) 2-Fluoro-N-(1-(2-hydroxyethyl-2,2-d2)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide, (28) 2-Fluoro-N-(1-(2-hydroxyethyl-2,2-d2)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethoxy)benzamide, (29) 2-Fluoro-N-(1-(2-hydroxyethyl-2-d)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide or (30) 2-Fluoro-N-(1-(2-hydroxyethyl-1,1,2,2-d4)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof. A pharmaceutical composition comprising a compound described in any one of [1] to

[11] or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[13] The pharmaceutical composition according to

[12] , which is an inhibitor of TREK-1, TREK-2, or both TREK-1 and TREK-2.

[14] The pharmaceutical composition according to

[12] , which is a preventive and / or therapeutic agent for diseases associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2.

[15] The pharmaceutical composition according to

[14] , wherein the disorder associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2 is a neurological disorder and / or a psychiatric disorder. [15-1] The pharmaceutical composition according to

[14] , wherein the disease associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2 is a neurological disorder and / or psychiatric disorder, cognitive impairment, pain, cancer, or pulmonary fibrosis.

[16] The pharmaceutical composition according to

[15] or [15-1], wherein the neurological and / or psychiatric disorder is selected from the group consisting of depression, schizophrenia, anxiety disorder, bipolar disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, 22q11.2 deletion syndrome, neuropathic pain, or cerebral infarction. [16-1] The pharmaceutical composition according to

[16] , wherein schizophrenia is a cognitive disorder associated with schizophrenia. [16-2] The pharmaceutical composition according to

[16] , wherein the neurological and / or mental disorder is a cognitive disorder associated with depression or schizophrenia.

[17] A method for preventing and / or treating a disease associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2, comprising administering an effective amount of any one of the compounds described in [1] to

[11] or a pharmaceutically acceptable salt thereof to a mammal.

[18] A compound described in any one of [1] to

[11] or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of diseases associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2.

[19] Use of any one of the compounds described in [1] to

[11] or a pharmaceutically acceptable salt thereof for the manufacture of a prophylactic and / or therapeutic agent for a disease associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2. A compound described in any one of

[20] [1] to

[11] or a pharmaceutically acceptable salt thereof, (a) At least one drug known to reduce TREK-1 channel activity, (b) At least one drug known to reduce TREK-2 channel activity, (c) At least one agent known to prevent and / or treat a disease associated with TREK channel dysfunction, in which an inhibitor of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide therapeutic benefits in mammals. (d) Instructions for the prevention and / or treatment of diseases associated with TREK channel dysfunction in which inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide therapeutic benefits in mammals, and (e) Instructions for administering the compound in connection with cognitive behavioral therapy, and a kit comprising one or more of the above.

[0019] In this specification, TREK (TWIK related K) + Inhibitors of channel-subtypes 1 and 2 (TREK-1 and TREK-2), methods for producing the same, pharmaceutical compositions containing the same, and methods for using the same to prevent and / or treat neurological, psychiatric, inflammatory, respiratory, renal, and cardiovascular diseases associated with TREK channel dysfunction are disclosed.

[0020] definition Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by those skilled in the art. In case of any conflict, this specification, including its definitions, shall prevail. Preferred methods and materials are described below, but similar or equivalent methods and materials may be used in the practice or testing of this disclosure. All publications, patent applications, patents, and other references referenced herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative and not intended to limit the scope of this disclosure.

[0021] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” and “contain(s)” as used herein, and their variations thereof, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “an,” and “the” include plural references unless otherwise explicitly indicated in the context. This disclosure also intends other embodiments that “comprising,” “consisting of,” and “consisting essentially of” the embodiments or elements presented herein, whether expressly described or not.

[0022] The modifier "approximately" used in relation to quantity includes the stated value and has a meaning indicated by the context (for example, it includes, at least, the degree of error associated with the measurement of a particular quantity). The modifier "approximately" should also be considered to disclose a range defined by the absolute values ​​of two endpoints. For example, the expression "approximately 2 to approximately 4" also discloses the range "from 2 to 4". The term "approximately" can refer to ±10% of the stated number. For example, "approximately 10%" may indicate a range of 9% to 11%, and "approximately 1" may mean 0.9 to 1.1. Other meanings of "approximately" can become apparent from its context, for example, from rounding; for example, "approximately 1" may also mean 0.5 to 1.4.

[0023] The definitions of specific functional groups and chemical terms are explained in more detail below. In this disclosure, chemical elements are defined as follows: Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75 thIdentified according to the inner cover of the ed., specific functional groups are generally defined as described therein. Furthermore, general principles of organic chemistry, as well as specific functional moieties and reactivity, are described in *Organic Chemistry*, Thomas Sorrell, University Science Books, Sausalito, 1999, and *Smith and March March's Advanced Organic Chemistry*, 5 th Edition, John Wiley&Sons, Inc., New York, 2001, Larock, Comprehensive Organic Transformations, VCH Publishers, Inc., New York, 1989, Carruthers, Some Modern Methods of Organic Synthesis, 3 rd This information is contained in Edition, Cambridge University Press, Cambridge, 1987, and the entire contents of each of these publications are incorporated herein by reference.

[0024] As used herein, examples of "halogens" include fluorine, chlorine, bromine, and iodine atoms.

[0025] As used herein, examples of "C1-8 alkyl" include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, isobutyl, pentyl, 1,2-dimethylpropyl, 1-ethylpropyl, methylbutyl, hexyl, 1,3-dimethylbutyl, heptyl, and octyl groups. As used herein, examples of "C1-2 alkyl" include methyl and ethyl. As used herein, examples of "C1-3 alkyl" include methyl, ethyl, propyl, and isopropyl. As used herein, examples of "C1-4 alkyl" include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl, and isobutyl.

[0026] As used herein, examples of "C1-4 alkoxy" include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, and isobutoxy groups. As used herein, examples of "C1 haloalkyl" include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, and trichloromethyl. As used herein, examples of "C1-8 haloalkyl" include fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl, trichloromethyl, 2,2,2-trifluoroethyl, perfluoroethyl, perfluoropropyl, perfluoro(isopropyl), perfluorobutyl, perfluoro(sec-butyl), perfluoro(tert-butyl), perfluoro(isobutyl), perfluoropentyl, perfluorohexyl, perfluoroheptyl, and perfluorooctyl groups. Examples of "C1-4 haloalkyl" include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluoromethyl, trifluoromethyl, 1-fluoroethyl, 2-fluoroethyl, 2-chloroethyl, pentafluoroethyl, 1-fluoropropyl, 2-chloropropyl, 3-fluoropropyl, 3-chloropropyl, 4,4,4-trifluorobutyl, 1,1-difluoroethyl, 2-fluoro-2-propanyl, and 4-bromobutyl. Examples of "C1-4 haloalkoxys" include trifluoromethoxy, trichloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2,2,2-trichloroethoxy, 3-bromopropoxy, 3-chloropropoxy, and 2,3-dichloropropoxy.

[0027] Examples of "C2-8 alkenyls" include vinyl, propenyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl, as well as their isomers. Examples of "C2-8 haloalkenyls" include fluorovinyl, difluorovinyl, chlorovinyl, dichlorovinyl, perfluorovinyl, perchlorovinyl, 3,3,3-trifluoropropenyl, perfluoropropenyl, perfluorobutenyl, perfluoropentenyl, perfluorohexenyl, perfluoroheptenyl, and perfluorooctenyl, as well as their isomers.

[0028] Examples of "C2-8 alkynyls" include ethynyl, propynyl, butynyl, pentynyl, hexynyl, heptynyl, octinyl, and their isomers. Examples of "C2-8 haloalkynyls" include fluoroethynyl, chloroethynyl, 3,3,3-trifluoropropynyl, perfluoroethynyl, perfluoropropynyl, perfluorobutynyl, perfluoropentynyl, perfluorohexynyl, perfluoroheptynyl, perfluorooctinyl, and their isomers.

[0029] Examples of "4-6 member saturated monocyclic heterocycles" include oxetane, thietan, azetidine, diazetidine, pyrrolidine, pyrazolidine, imidazolidine, triazolidine, tetrazolidine, tetrahydrofuran, dioxolane, tetrahydrothiophene, oxathiolane, piperidine, piperazine, tetrahydropyran, dioxane, and dithiane.

[0030] Examples of "8-10 membered bicyclic systems" include pentalene, perhydropentalene, indene, perhydroindene, indan, azulene, perhydroazulene, naphthalene, dihydronaphthalene, tetrahydronaphthalene, perhydronaphthalene, thienopyrazole, thienoimidazole, pyrazolothiazole, indole, isoindole, indidine, benzofuran, isobenzofuran, benzothiophene, isobenzothiophene, indazole, purine, benzoxazole, benzothiazole, benzimidazole, imidazopyridine, benzofurazan, benzothiadiazole, benzotriazole, indoline, isoindoline, dihydrobenzofuran, perhydrobenzofuran, dihydroisobenzofuran, perhydroisobenzofuran, dihydrobenzothiophene, perhydrobenzothiophene, dihydroisobenzothiophene, perhydroisobenzothiophene, dihydroindazole, perhydroindazole, dihydrobenzoxazole, perhydrobenzoxazole, dihydrobe Nzothiazole, perhydrobenzothiazole, dihydrobenzimidazole, perhydrobenzimidazole, dioxaindan, benzodithiolane, dithianaphthalene, quinoline, isoquinoline, quinoridine, phthalazine, pteridine, naphthyridine, quinoxaline, quinazoline, cinnoline, chromene, dihydroquinoline, tetrahydroquinoline, perhydroquinoline, dihydroisoquinoline, tetrahydroisoquinoline, perhydroisoquinoline, dihydrophthalazine, tetrahydrophthalazine Examples include perhydrophthalazine, dihydronaphthyridine, tetrahydronaphthyridine, perhydronaphthyridine, dihydroquinoxaline, tetrahydroquinoxaline, perhydroquinoxaline, dihydroquinazoline, tetrahydroquinazoline, perhydroquinazoline, dihydrosinnoline, tetrahydrosinnoline, perhydrosinnoline, benzoxatian, dihydrobenzoxazine, dihydrobenzothiazine, pyrazinomorpholine, benzodioxane, chroman, and benzodithian.

[0031] Examples of 3-6 membered heterocycles include aziridine, azetidine, oxirane, oxetane, thiirane, thietan, pyrrole, imidazole, triazole, tetrazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, furan, pyran, thiophene, thiopyran, oxazole, isoxazole, thiazole, isothiazole, furazan, oxadiazole, oxazine, oxadiazine, thiadiazole, thiadin, thiadiazine, pyrroline, pyrrolidine, imida Zoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazoline, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydrofuran, tetrahydrofuran, dihydropyran, tetrahydropyran, dihi These include dorothiophene, tetrahydrothiophene, dihydrothiopyran, tetrahydrothiopyran, dihydroxazole, tetrahydroxazole (oxazolidine), dihydroisoxazole, tetrahydroisoxazole (isoxazolidine), dihydrothiazole, tetrahydrothiazole (thiazolidine), dihydroisothiazole, tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan ring, dihydroxadiazole, tetrahydroxadiazole (oxadiazolidine), dihydroxazine, tetrahydroxazine, dihydroxadiazine, tetrahydrothiadiazole (thiadiazolidine), dihydrothiadin, tetrahydrothiadiazine, dihydrothiadiazine, tetrahydrothiadiazine, morpholine ring, thiomorpholin, oxatian, dioxolane, dioxane, dithiolane, dithiane, etc.

[0032] In the case of the compounds described herein, the groups and substituents can be selected according to the acceptable valencies of the atoms and substituents, and as a result, the selection and substitution yield stable compounds that do not spontaneously undergo transformations such as rearrangement, cyclization, or elimination.

[0033] As used herein, the term “inhibitor” refers to a molecular entity (e.g., but not limited to, the compounds of this disclosure) that reduces or eliminates the activity of a target receptor protein. In this specification, the term "thallium flux assay" refers to a fluorescence-based assay used to monitor the activity of TREK channels. Thallium is a potassium homolog that readily flows through the pores of TREK channels. Thallium flux is measured using a commercially available thallium-sensitive fluorescent dye called Thallos. The detailed method is described below. In this specification, the term “patch clamp method” refers to a “representative” method for evaluating TREK channel pharmacology. A detailed description of the method will be provided later. In this specification, the term "MK-801-induced novel object recognition test" refers to experiments to evaluate in vivo efficacy in animal models of schizophrenic cognitive impairment. Detailed methods are described below. MK-801 is also known as dizosylpine. As used herein, the term “dysfunction” refers to any abnormal function that induces activation or inhibition of a channel in animals, particularly mammals, such as humans.

[0034] In this specification, when numerical ranges are indicated, each digit in between is explicitly intended with the same degree of clarity. For example, in the range 6–9, the digits 7 and 8 are intended in addition to 6 and 9, and in the range 6.0–7.0, the digits 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly intended.

[0035] compound In one embodiment, the compound of formula (I): [ka] Alternatively, a pharmaceutically acceptable salt thereof is disclosed, in which all symbols are defined as above.

[0036] In some embodiments, formula (I) is preferably formula (I-1): [ka] (All symbols in the formula are defined as previously defined.)

[0037] In some embodiments, formula (I) is preferably formula (I-1-1): [ka] (All symbols in the formula are defined as previously defined.)

[0038] In some embodiments, formula (I) is preferably formula (I-2): [ka] (All symbols in the formula are defined as previously defined.)

[0039] In some embodiments, formula (I) is preferably formula (I-2-1): [ka] (All symbols in the formula are defined as previously defined.)

[0040] In some embodiments, formula (I) is preferably formula (I-3): [ka] (All symbols in the formula are defined as previously defined.)

[0041] In some embodiments, formula (I) is preferably formula (I-3-1): [ka] (All symbols in the formula are defined as previously defined.)

[0042] In some embodiments, formula (I) is preferably formula (IA): [ka] (All symbols in the formula are defined as previously defined.)

[0043] In some embodiments, formula (I) is preferably formula (I-A1): [ka] (Ring A-1 is an 8-10 membered bicyclic system which may be substituted with 1-6 halogen atoms, and the other symbols are as defined above.)

[0044] In some embodiments, formula (I) is preferably formula (IB): [ka] (All symbols in the formula are defined as previously defined.)

[0045] Ring A is preferably (1) [ka] Or (2) an 8-10 membered bicyclic system which may be substituted with 1-3 halogen atoms, Other symbols are defined as previously mentioned.

[0046] A more preferred ring A is, (1) [ka] (2) dihydrobenzofuran, (3) imidazopyridine, or (4) quinoline. Each of the groups (2) to (4) may be substituted with a halogen atom. Other symbols are defined as previously mentioned.

[0047] The most preferred ring A is, [ka] Other symbols are defined as previously mentioned.

[0048] Ring A-1 is preferably an 8-10 membered bicyclic system which may be substituted with 1-3 halogen atoms. More preferably, ring A-1 is preferably an 8-10 membered bicyclic system which may be substituted with 1 halogen atom. The 8-10 membered bicyclic system of the A ring or A-1 ring is preferably (1) dihydrobenzofuran, (2) imidazopyridine, or (3) quinoline. The 4- to 6-membered saturated monocyclic heterocycle is preferably a pyrrolidine. The 3- to 6-membered heterocycle is preferably (1) oxetane, (2) thiazole, or (3) pyrrolidine. R 1 R is preferably (1) a hydrogen atom, (2) a C1-8 alkyl group, (3) a C1-8 haloalkyl group, or (8) a 4-6 member saturated monocyclic heterocycle. 1 is a C1-4 alkyl group. More preferably, R 1 It is ethyl. R 1 Preferably 1 to 4 R 1-1 It is replaced with R 1 This is 1 to 3 R 1-1 It is replaced with R. 1 is one or two R 1-1 It has been replaced with. R 1-1 Preferably, R is (1) a deuterium atom, (3) a hydroxyl group, (4) a C1-4 alkyl group, (6) a C1-4 alkoxy group, (13) a cyano group, or (14) a 3-6 membered heterocycle. More preferably, 1-1 is a deuterium atom, a hydroxyl group, methyl, methoxy, cyano, or oxetane. More preferably, R 1-1 R is a deuterium atom, a hydroxyl group, or a methoxy group. The most preferred R 1-1 It is a hydroxyl group. R 1-1The number is preferably 1 to 5. More preferably, R 1-1 The number is 1 or 2. Most preferably, R 1-1 The number is 1. R 1-1A is preferably (1) a deuterium atom or (2) a hydroxy group. More preferably, R 1-1A is (2) a hydroxy group. R 1-1A The number is preferably 1 to 5. More preferably, R 1-1A The number is 1 or 2. Most preferably, R 1-1A The number is 1. R 1-1B is preferably (2) a hydroxy group. R5] 1-1B The number is preferably 1 to 5. More preferably, R 1-1B The number is 1 or 2. Most preferably, R 1-1B The number is 1. R 1-2 is preferably (1) a hydrogen atom or (2) C1-4 alkyl. R 1-3 is preferably (1) a hydrogen atom or (2) C1-4 alkyl. R 1-4 is preferably C1-4 alkyl. <00°00667>R 1-5 is preferably C1-4 alkyl. R 1-6 is preferably a hydrogen atom. R 1-7 is preferably C1-4 alkyl. R 1-8 is preferably a hydrogen atom. R 1-9 is preferably a hydrogen atom. R 2 is preferably (1) isopropyl, (2) tert-butyl or (3) trifluoromethyl. More preferably, R 2 is (1) isopropyl or (2) trifluoromethyl. Most preferably, R 2 is trifluoromethyl. R3 is preferably (1) a hydrogen atom or (2) a methyl atom. More preferably R 3 It is a hydrogen atom. R 4 The is preferably (1) a fluorine atom, (2) a chlorine atom, (3) methoxy or (4) trifluoromethoxy. More preferably R 4 is (1) a fluorine atom or (2) methoxy. Most preferably, R 4 This is a fluorine atom. R 5 Preferably, R is (1) hydrogen atom, (2) fluorine atom, (3) chlorine atom, (4) methyl, (5) tert-butyl, (6) difluoromethyl, (7) trifluoromethyl, (8) difluoromethoxy, or (9) trifluoromethoxy. More preferably, 5 is (1) a chlorine atom, (2) difluoromethyl, (3) trifluoromethyl, (4) difluoromethoxy, or (5) trifluoromethoxy. Most preferably, R 5 It is trifluoromethyl. R 6 Preferably, R is (1) a hydrogen atom, (2) a fluorine atom. More preferably, 6 It is a hydrogen atom. R 7 Preferably, it is a hydrogen atom. R 8 The C1-C4 alkyl group is preferred. R 9 is preferably (1) a hydrogen atom or (2) a methyl atom. More preferably R 9 It is a hydrogen atom. R 10 Preferably, R is (1) a hydrogen atom, (2) a fluorine atom. More preferably, 10 It is a hydrogen atom. X 1 Preferably, it is CH. X 2 Preferably, it is CH. m is preferably an integer of 1 or 2. More preferably, m is an integer of 1. n is preferably an integer of 1 or 2. More preferably, n is an integer of 1.

[0049] In some embodiments, the compound is preferably, but not limited to, (1) 5-Chloro-2-methoxy-N-{1-methyl-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}benzamide, (2) 5-Chloro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxybenzamide, (3) 5-Chloro-N-{1-(2-hydroxy-2-methylpropyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxybenzamide, (4) 5-Chloro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxybenzamide, (5) 2-Fluoro-N-{1-(2-hydroxy-2-methylpropyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (6) 2-Fluoro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (7) 2-Fluoro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide, (8) 5-Chloro-2-methoxy-N-{1-(2-methoxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}benzamide, (9) 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (10) 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (11) N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}2-methoxy-5-(trifluoromethyl)benzamide, (12) 5-(difluoromethyl)-2-fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide, (13) 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethoxy)benzamide, (14) 5-(difluoromethoxy)-2-fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide, (15) 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethyl)benzamide, (16) 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethoxy)benzamide, (17) 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-6-methoxy-3-(trifluoromethyl)benzamide, (18) N-[3-(2-isopropylphenyl)-1-(2-methoxyethyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxy-5-(trifluoromethyl)benzamide, (19) 5-(difluoromethoxy)-2-fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide, (20)N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxy-5-(trifluoromethyl)benzamide, (21) 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethyl)benzamide, (22) 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-6-methoxy-3-(trifluoromethyl)benzamide, (23) 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide, (24) 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (25) 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide, (26) 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (27) 2-Fluoro-N-(1-(2-hydroxyethyl-2,2-d2)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide, (28) 2-Fluoro-N-(1-(2-hydroxyethyl-2,2-d2)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethoxy)benzamide, (29) 2-Fluoro-N-(1-(2-hydroxyethyl-2-d)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide or (30) 2-Fluoro-N-(1-(2-hydroxyethyl-1,1,2,2-d4)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.

[0050] The compound of formula (I) preferably has rings A and R 1 , R 2 , R 3 , R 7 , X 1 The compounds are those in which some or all of the preferred examples described above are combined for m. The compound of formula (I-1) preferably has rings A and R 1 , R 2 , R 3 The compounds are those in which some or all of the preferred examples described above are combined for m. The compound of formula (I-2) is preferably R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , X 2 , is a compound in which some or all of the preferred examples described above are combined for m and n. The compound of formula (I-3) is preferably R 1 , R2 , R 3 , R 4 , R 5 , R 6 , is a compound in which some or all of the preferred examples described above are combined for m and n. The compound of formula (IA) preferably has rings A and R 1 and R 2 This is a compound that combines some or all of the preferred examples described above. The compound of formula (I-A1) preferably has ring A-1, R 1 and R 2 This is a compound that combines some or all of the preferred examples described above. The compound of formula (IB) is preferably R 1 , R 2 , R 4 , R 5 and R 6 This is a compound that combines some or all of the preferred examples described above.

[0051] In some embodiments, the diseases associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2 are preferably neurological and / or psychiatric disorders, cancer, and / or pulmonary fibrosis.

[0052] More preferred conditions associated with impairment of TREK-1, TREK-2, or both TREK-1 and TREK-2 are depression, schizophrenia, anxiety disorders, bipolar disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, 22q11.2 deletion syndrome, neuropathic pain, and / or cerebral infarction.

[0053] More preferred disorders associated with impairments of TREK-1, TREK-2, or both TREK-1 and TREK-2 are depression, schizophrenia, anxiety disorders, and / or bipolar disorder.

[0054] The most preferred disorders associated with impairments in TREK-1, TREK-2, or both TREK-1 and TREK-2 are depression and / or schizophrenia.

[0055] In some embodiments, schizophrenia is preferably a cognitive impairment associated with schizophrenia (CIAS).

[0056] In some embodiments, the compound exhibits significant inhibitory activity against TREK-1, TREK-2, or both TREK-1 and TREK-2.

[0057] In some embodiments, the compound may selectively inhibit TREK-1. In some embodiments, the compound may selectively inhibit TREK-2. In some embodiments, the compound may inhibit both TREK-1 and TREK-2 to varying degrees. The compounds of this disclosure may inhibit TREK-1 and / or TREK-2 via a competitive antagonist mechanism or via an allosteric non-competitive mechanism.

[0058] The compounds disclosed herein enhance the TREK-1 and / or TREK-2 response in CHO-K1 cells transfected with TREK-1 or TREK-2, thereby improving IC50 response to TREK-1 or TREK-2. 50 ICs less than or equivalent to 50 This can inhibit the IC of TREK-2. That is, the compounds of the disclosure may be selective to TREK-1 compared to TREK-2, or may not be selective to TREK-2 compared to TREK-1. For example, in some embodiments, the compounds of the disclosure inhibit the TREK-1 response, while inhibiting the IC of TREK-2. 50 ICs that are approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or less than 1 / 500 50 This can be inhibited. In some embodiments, the compounds of the present disclosure inhibit the TREK-2 response, thereby inhibiting the IC of TREK-1. 50 ICs that are approximately 1 / 5, 1 / 10, 1 / 20, 1 / 30, 1 / 50, 1 / 100, 1 / 200, 1 / 300, 1 / 400, or less than 1 / 500 50 It can be inhibited by... In some embodiments, the compounds of the present disclosure are equivalent to IC50 The TREK-1 and TREK-2 responses can be inhibited by adjusting the value.

[0059] In this disclosure, isomers include all of these isomers unless otherwise specified. For example, each of alkyl, haloalkyl, alkenyl, haloalkenyl, alkynyl, haloalkynyl, alkoxy, and haloalkoxy includes both their linear and branched forms. Also included in the scope of this disclosure are double bond, ring or fused ring isomers (E-type, Z-type, cis-type, or trans-type), isomers due to the presence of a chiral carbon (R- or S-type, α- or β-configuration, enantiomers, diastereomers), optical isomers with optical rotation (D-type, L-type, d-type, or l-type), polar compounds obtained by chromatographic separation (highly polar, low polar), equilibrium compounds and rotational isomers, as well as mixtures of these in any mixing ratio and racemic mixtures. In this disclosure, isomers include all tautomers.

[0060] In this disclosure, unless otherwise specified, symbol: [ka] This indicates that the substituent is attached to the back side of the paper (in other words, the α configuration). symbol: [ka] This indicates that the substituent is attached to the front side of the paper (in other words, the β configuration). symbol: [ka] This represents the α-stereoconfiguration or β-stereoconfiguration, symbol: [ka] This symbol represents a mixture of α-configuration and β-configuration, insofar as it is substituted with a chiral carbon atom.

[0061] The compound may exist as stereoisomers containing a chiral or asymmetric center. The stereoisomers are "R" or "S" depending on the arrangement of substituents around the chiral carbon atom. The terms "R" and "S" as used herein refer to the configurations defined in Section E, Fundamental Stereochemistry, Pure Appl. Chem., 1976, 45:13-30 of the IUPAC 1974 Recommendations. This disclosure envisions various stereoisomers and mixtures thereof, which are particularly included within the scope of this disclosure. Stereoiomers include enantiomers and diastereomers, as well as mixtures of enantiomers or diastereomers. Individual stereoisomers of the compound can be prepared synthetically from commercially available starting materials containing a chiral or asymmetric center, or by the preparation of racemic mixtures and subsequent separation methods well known to those skilled in the art. These separation methods are exemplified by (1) binding of the enantiomer mixture to a chiral auxiliary, separation of the diastereomer mixture obtained by recrystallization or chromatography, and optionally liberation of an optically pure product from the auxiliary, as described in Furniss, Hannaford, Smith, and Tatchell, “Vogel’s Textbook of Practical Organic Chemistry”, 5th edition (1989), Longman Scientific & Technical, Essexcm20 2JE, England; (2) direct separation of the optical enantiomer mixture by chiral chromatography column; or (3) fractional recrystallization methods.

[0062] This compound may have tautomers and geometric isomers, and it should be understood that these also constitute embodiments of the present disclosure.

[0063] This disclosure also includes isotope-labeled compounds that are identical to those described in formula (I), except that one or more atoms are replaced by atoms having atomic masses or mass numbers different from those commonly found in nature. Suitable isotopes to be included in the compounds of this disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, and chlorine, and, for example, but not limited to, the following: 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 31 P, 32 P, 35 S, 18 F, and 36 It is Cl. Substitution with heavier isotopes can result in certain therapeutic benefits arising from greater metabolic stability, such as an increased in vivo half-life or a reduced required dose, and therefore may be preferable in some situations. This compound can incorporate positron-emitting isotopes for medical imaging and positron emission tomography (PET) studies to determine the receptor distribution. Suitable positron-emitting isotopes that can be incorporated into the compound of formula (I) are: 11 C, 13 N, 15 O, and 18 F is the isotope-labeled compound of formula (I). The isotope-labeled compound of formula (I) can generally be prepared by conventional techniques known to those skilled in the art, or by using a suitable isotope-labeled reagent instead of a non-isotope-labeled reagent, in a manner similar to that described in the attached examples.

[0064] Pharmaceutically acceptable salts The compounds of this disclosure may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to a salt or zwitterion of a compound that is soluble or dispersible in water or oil, suitable for the treatment of disorders without excessive toxicity, irritation, and allergic reactions, commensurate with a reasonable benefit / risk ratio, and effective for their intended use. Salts can be prepared during the final isolation and purification of the compound, or separately by reacting the amino group of the compound with a suitable acid. For example, the compound can be dissolved in a suitable solvent, such as methanol and water (but not limited to these), and treated with at least one equivalent of an acid, such as hydrochloric acid. The resulting salt can be precipitated, isolated by filtration, and dried under reduced pressure. Alternatively, the salt can be obtained by removing the solvent and excess acid under reduced pressure. Typical salts include acetate, adipine, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphor sulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate, oxalate, maleate, pivaphosphate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloride, bromide, sulfate, and phosphate. The amino group of this compound may also be quaternized with alkyl chlorides, bromides, and iodides, such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, and stearyl.

[0065] Basic addition salts can be prepared during the final isolation and purification of the disclosed compounds by the reaction of the carboxyl group with a suitable base, such as a hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or with an organic primary, secondary, or tertiary amine. For example, quaternary amine salts can be prepared derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, N,N-dibenzylphenethylamine, 1-ephenamine, and N,N'-dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, etc.

[0066] In the present invention, the compounds of the present invention include compounds represented by formula (I), or their salts, solvates, or cocrystals. The compound represented by formula (I) and its salts may exist in non-solvated or solvated forms with water or a pharmaceutically acceptable solvent such as ethanol. A preferred solvate is the hydrate. The compound represented by formula (I) and its salts can be converted to solvates by known methods.

[0067] The compound represented by formula (I) can form a cocrystal with a suitable cocrystal-forming agent. A pharmaceutically acceptable cocrystal formed with a pharmaceutically acceptable cocrystal-forming agent is preferred. A cocrystal is typically defined as a crystal composed of two or more different molecules due to intermolecular interactions other than ionic bonding. The cocrystal may also be a complex of a neutral molecule and a salt. Cocrystals can be prepared by recrystallization from a solvent using well-known methods, such as melt crystallization, or by physically grinding the components together. Suitable cocrystal-forming agents include those described in International Publication No. 2006 / 007448.

[0068] The compound represented by formula (I) can be administered as a prodrug. A prodrug of the compound represented by formula (I) refers to a compound that is converted in the body to the compound represented by formula (I) through a reaction with enzymes, gastric acid, etc. Prodrugs of the compound represented by formula (I) include, if the compound represented by formula (I) has an amino group, a compound in which that amino group is acylated, alkylated, or phosphorylated (for example, the compound represented by formula (I) in which the amino group is converted to eicosanoyl, alanyl, pentylaminocarbonyl, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methoxycarbonyl, tetrahydrofuranyl, pyrrolidylmethyl, pivaloyloxymethyl, acetoxymethyl, tert-butyl, etc.), and if the compound represented by formula (I) has a hydroxyl group, a compound in which that hydroxyl group is acylated, alkylated, phosphorylated, or converted to a borate (for example, the hydroxyl group is acetyl, palmitoyl, propanoyl, pivaloyl Examples include compounds represented by formula (I) that have been converted to succinyl, fuma, alanyl, dimethylaminomethylcarbonyl, etc., and, if the compound represented by formula (I) has a carboxyl group, compounds in which that carboxyl group has been esterified or amidized (for example, compounds represented by formula (I) in which the carboxyl group has been converted to methyl ester, ethyl ester, isopropyl ester, phenyl ester, carboxymethyl ester, dimethylaminomethyl ester, pivaloyloxymethyl ester, phthalidyl ester, 1-{(ethoxycarbonyl)oxy}ethyl ester, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl ester, 1-{[(cyclohexyloxy)carbonyl]oxy}ethyl ester, methylamide, etc.). Prodrugs of compounds represented by formula (I) may be those that are converted to compounds represented by formula (I) under physiological conditions, such as those disclosed in "Development of Pharmaceuticals," Vol. 7, "Molecular Design," pp. 163-198, 1990, Hirokawa Shoten Co., Ltd.

[0069] General synthesis The compound of formula (I) can be prepared by synthetic or metabolic processes. Preparation of the compound by metabolic processes includes processes that occur in the human or animal body (in vivo) or in vitro.

[0070] The abbreviations used in the following scheme description are as follows: DCM is dichloromethane, DIAD is diisopropyl azodicarboxylate, DIEA or DIPEA is N,N-diisopropylethylamine, SiO is ethyl acetate, LiAlH4 is lithium aluminum hydride, LiAlD4 is lithium aluminum deuteride, m-CPBA is m-chloroperoxybenzoic acid, MeCN is acetonitrile, NaBH4 is sodium borohydride, NaBD4 is sodium boron deuteride, NMI is N-methylimidazole, NMM is N-methylmorpholine, Pd / C is palladium-activated carbon, PPh3 is triphenylphosphine, TCFH is chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, TFA is trifluoroacetic acid, and THF is tetrahydrofuran.

[0071] The compound of formula (I) can be synthesized as shown in schemes I to XII. Scheme I [ka] Here, PG is selected from the group consisting of (1) benzyl, (2) 4-methoxybenzyl, and (3) 2,4-di-methoxybenzyl. As shown in Scheme I, compound A1 can be reacted with various bases commonly known in the art to obtain intermediate A3. For example, this reaction may be carried out in a solvent such as N-methylpyrrolidone, in the presence of a base (e.g., DIEA), while heating to about 150°C.

[0072] Scheme II [ka] Here, LG is selected from the group consisting of (1) halogen, (2) tosylate, (3) mesylate, and (4) triflate, and the other symbols are defined as above. As shown in Scheme II, intermediate A5 can be obtained by reacting compound A3 with intermediate A4 in the presence of a base commonly known in the art. For example, this reaction may be carried out in a solvent such as N-methylpyrrolidone, in the presence of a base (e.g., K2CO3), while heating to about 60°C.

[0073] Scheme III [ka] Here, R 11 and R 12 The group is selected from the group consisting of (1) a hydrogen atom, (2) a C1-2 alkyl group, and (3) a C1 haloalkyl group, and the other symbols are defined as described above. As shown in Scheme III, compound A3 can be reacted with various epoxides A6 in the presence of a base commonly known in the art to obtain intermediate A7. For example, this reaction may be carried out in a solvent such as N-methylpyrrolidone, in the presence of a base (e.g., K2CO3), while heating to about 60°C.

[0074] Scheme IV [ka] Here, R 13 (1) hydrogen atoms and (2) 1 to 6 R 1-1A Selected from the group consisting of C1-3 alkyl groups which may be substituted with each R 14 is (1) a hydrogen atom or (2) a deuterium atom, and has two R 14 These symbols may be the same or different from each other, and the other symbols are defined as described above. As shown in Scheme IV, intermediate A3 can be reacted with alcohol A8 in a solvent (e.g., THF) under standard conditions for the Mitsunobu reaction (e.g., PPh3 and DIAD) to obtain intermediate A9.

[0075] Scheme V [ka] All symbols are defined as described above.

[0076] Scheme V shows a general route to intermediate A11. Intermediate A11 can be obtained by coupling intermediate A5 with boronic acid A10 in a solvent (e.g., 1,4-dioxane / H2O) under standard conditions for the Suzuki-Miyaura coupling reaction (e.g., Pd(PPh3)4 and K3PO4). Scheme VI [ka] All symbols are defined as described above.

[0077] Scheme VI shows a general pathway to intermediate A12. Intermediate A12 can be obtained by deprotecting intermediate A11 under standard hydrogenation conditions (e.g., Pd / C, H2, SiO / MeOH) or acidic conditions (TFA).

[0078] Scheme VII [ka] Here, Z is either (1) a halogen atom or (2) a hydroxyl group, and the other symbols are defined as described above. Scheme VII shows a general route to the compound of formula (I). Intermediate A12 is reacted with compound A13 under standard amide coupling conditions (e.g., TCFH, NMI or NMM, MeCN) heated to about 30°C, or under standard acylation conditions (e.g., DIPEA, DCM) at 0°C, to R 7 As such, we can obtain formula (I) which has a hydrogen atom. 7 This can then be replaced with a C1-4 alkyl substituent by standard alkylation conditions commonly known in the art.

[0079] Scheme VIII [Chemical formula] Here, W is (1) an oxygen atom or (2) a nitrogen atom, and the other symbols are defined as above. Scheme VIII shows a general route to compound A15. R 1 Compound A14 of formula (I) in which R is ethylmethylsulfide can be reacted under standard oxidation conditions (e.g., m-CPBA) in a solvent such as DCM to obtain compound A15 (where W is an oxygen atom in the formula). Further, compound A15 (where W is a nitrogen atom in the formula) can be prepared under standard sulfoximine formation conditions generally known in the art. Compound A14 of formula (I) can be subjected to an oxidizing reagent (e.g., p-iodobenzenediacetate), ammonium carbonate, and a solvent (e.g., methanol) to obtain compound A15 (where W is a nitrogen atom in the formula).

[0080] Scheme IX [Chemical formula] <00�0892> All symbols are defined as above.

[0081] Scheme IX shows a general route to intermediate A17. R 4 and R 6 When at least one of them is a direct metallizing group or an electron-donating group, intermediate A16 can be reacted with standard formylation conditions (e.g., n-BuLi / DMF, POCl3 / DMF, hexamethylenetetramine / AcOH) to obtain intermediate A17.

[0082] Scheme X [Chemical formula] All symbols are defined as above. <I

[0083] Scheme X shows a general pathway to intermediate A18. Intermediate A18 can be obtained by reacting intermediate A17 under standard oxidation conditions (e.g., NaClO2 / NaH2PO4, H2CrO4, KMnO4, RuO4).

[0084] Scheme XI [ka]

[0085] Scheme XI shows the general pathway to compound A101. 1 Compound A101 can be obtained by reacting compound A100 of formula (I), in which the nitrogen of the tert-butylethyl carbamate and the methylene carbon adjacent to the nitrogen on the pyridadinone ring may be linked by a carbon chain, in a solvent such as HCl under standard acidic conditions (e.g., HCl).

[0086] Scheme XII [ka]

[0087] Scheme XII shows the general route to intermediate A203. Intermediate A202(R 1 Intermediate A11), which is ethoxycarbonylmethyl, can be reacted under standard reducing conditions (e.g., NaBH4, NaBD4, LiAlH4, LiAlD4) to obtain intermediate A203, where each R 15 is (1) a hydrogen atom or (2) a deuterium atom, and has two R 15 They may be the same or different from one another.

[0088] Compounds used as starting materials for each reaction, such as 3,4-dichloro-1H-pyridazine-6-one (A1) (CAS number: 17285-36-8), are either known or can be easily prepared by known methods.

[0089] The compound and its intermediates can be isolated and purified by methods well known to those skilled in the art of organic synthesis. Examples of conventional methods for isolating and purifying compounds can be found, for example, in "Vogel's Textbook of Practical Organic Chemistry," 5. th As described in edition (1989), by Furniss, Hannaford, Smith, and Tatchell, pub. Longman Scientific & Technical, Essexcm20 2JE, England, examples of chromatography on solid supports such as silica gel, alumina, or silica derivatized with alkylsilane groups; recrystallization at high or low temperatures with optional pretreatment with activated carbon; thin-layer chromatography; distillation at various pressures; sublimation under vacuum; and trituration.

[0090] The compounds of this disclosure may have at least one basic nitrogen, thereby allowing the compounds to be treated with an acid to form a desired salt. For example, a desired salt can be obtained by reacting the compound with an acid at room temperature or above, which is then precipitated and recovered by filtration after cooling. Examples of acids suitable for the reaction include, but are not limited to, tartaric acid, lactic acid, succinic acid, as well as mandelic acid, atrolactic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, naphthalenesulfonic acid, benzenesulfonic acid, carbonic acid, fumaric acid, maleic acid, gluconic acid, acetic acid, propionic acid, salicylic acid, hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, citric acid, hydroxybutyric acid, camphorsulfonic acid, malic acid, phenylacetic acid, aspartic acid, or glutamic acid.

[0091] The reaction conditions and reaction times for each individual step may vary depending on the specific reactants used and the substituents present in them. Specific procedures are presented in the Examples section. The reaction can be completed by conventional methods, for example, by removing the solvent from the residue, and further purified by methods commonly known in the art, such as, but not limited to, crystallization, distillation, extraction, trituration, and chromatography. Unless otherwise specified, starting materials and reagents are commercially available or can be prepared by those skilled in the art from commercially available substances using methods described in the chemical literature. If starting materials are not commercially available, they can be prepared by procedures selected from standard organic chemistry techniques, techniques similar to the synthesis of known structurally similar compounds, or techniques similar to the procedures described in the Scheme or Synthesis Examples section above.

[0092] Routine experiments, including the proper handling of reaction conditions, reagents, and the order of the synthetic pathway, the protection of any chemical functionalities incompatible with the reaction conditions, and the deprotection of the reaction sequence at appropriate points in time, are included within the scope of this disclosure. Appropriate protecting groups and methods for protecting and deprotecting different substituents using such appropriate protecting groups are well known to those skilled in the art, for example, in PGM Wuts and TW Greene, in Greene's book titled Protective Groups in Organic Synthesis (4 th This can be found in (ed.), John Wiley & Sons, NY (2006), which is incorporated herein by reference in its entirety. The synthesis of the compounds of this disclosure can be achieved by methods similar to those described in the synthesis schemes described above and in the specific examples.

[0093] If an optically active form of the compounds disclosed herein is required, it can be obtained by performing one of the procedures described herein using an optically active starting material (for example, prepared by asymmetric induction of a suitable reaction step), or by dividing a mixture of stereoisomers of the compound or intermediate using a standard procedure (such as chromatographic separation, recrystallization, or enzymatic resolution).

[0094] Similarly, if a pure geometric isomer of a compound is required, it can be obtained by using the pure geometric isomer as a starting material and performing one of the above procedures, or by separating a mixture of geometric isomers of the compound or intermediate using standard procedures such as chromatographic separation.

[0095] It should be understood that the described synthesis schemes and specific examples are illustrative and should not be construed as limiting the scope of this disclosure as defined in the attached claims. All substitutes, modifications, and equivalents of the synthesis methods and specific examples are included within the claims.

[0096] Pharmaceutical compositions and preparations The compounds of this disclosure can be incorporated into pharmaceutical compositions suitable for administration to a target (e.g., a patient, which may be human or non-human). The compounds of this disclosure may also be provided as formulations, such as spray-dried dispersions.

[0097] The pharmaceutical composition and formulation may contain a “therapeutically effective amount” or “preventively effective amount” of a drug. The “therapeutically effective amount” refers to an effective amount in the dosage and period necessary to achieve the desired therapeutic result. The therapeutically effective amount of the present composition can be determined by those skilled in the art and may vary depending on factors such as the disease state, age, sex and weight of the individual, and the ability of the composition to induce the desired response in the individual. The therapeutically effective amount is also an amount in which the therapeutically beneficial effect exceeds any toxic or harmful effects of the compound of the present invention (for example, the compound of formula (I)). The “preventively effective amount” refers to an effective amount in the dosage and period necessary to achieve the desired preventive result. Typically, since the preventive dosage is used for a subject before or at an early stage of the disease, the preventively effective amount is less than the therapeutically effective amount.

[0098] For example, the therapeutically effective amount of the compound of formula (I) can be about 0.01 mg to about 1000 mg per administration by oral administration to a patient once to several times per day, or about 0.01 mg to about 1000 mg per administration by parenteral administration to a patient, or continuous intravenous administration to a patient for 30 minutes to 24 hours per day. It can be administered to the patient once to several times per day.

[0099] Needless to say, as described above, the effective amount used varies depending on various conditions. Therefore, an effective amount lower than the above range may be sufficient, and an effective amount higher than the above range may be required.

[0100] Pharmaceutical compositions and formulations may contain pharmaceutically acceptable carriers. As used herein, the term “pharmaceutically acceptable carrier” means any kind of non-toxic, inert solid, semi-solid, or liquid filler, diluent, encapsulating material, or formulation aid. Some examples of substances that may function as pharmaceutically acceptable carriers include, but are not limited to, sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethylcellulose, ethylcellulose, and cellulose acetate; tragacanth powder; malt; gelatin; talc; excipients such as cocoa butter and suppository wax; and oils such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil, and soybean oil; and p Glycols such as propyl glycol; esters such as ethyl oleate and ethyl laurate (but not limited to these); agar; buffering agents such as magnesium hydroxide and aluminum hydroxide (but not limited to these); alginic acid; water free of pyrogens; isotonic saline solution; Ringer's solution; ethyl alcohol and phosphate buffer; and other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate (but not limited to these). In addition, colorants, release agents, coating agents, sweeteners, flavoring agents and fragrances, preservatives, and antioxidants may also be present in the composition at the discretion of the formulation.

[0101] Therefore, the compounds and their physiologically acceptable salts can be formulated, for example, for solid administration, eye drops, topical oily preparations, injection, inhalation (either orally or nasally), implantation, or for oral, buccal, parenteral, or rectal administration. The techniques and formulations can generally be found in "Remington's Pharmaceutical Sciences" (Meade Publishing Co., Easton, Pa.). Therapeutic compositions typically must be sterile and stable under manufacturing and storage conditions.

[0102] The route by which the compounds of this disclosure are administered and the form of the composition determine the type of carrier used. The composition may be in various forms suitable for systemic administration (e.g., oral, rectal, nasal, sublingual, buccal, implant, or parenteral) or topical administration (e.g., skin, lung, nose, ear, eye, liposome delivery system, or iontophoresis).

[0103] Carriers for systemic administration typically contain at least one of the following: diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, antioxidants, preservatives, flow enhancers, solvents, suspending agents, wetting agents, surfactants, or combinations thereof. All carriers can be freely selected in this composition.

[0104] Suitable diluents include sugars such as glucose, lactose, dextrose, and sucrose; diols such as propylene glycol; calcium carbonate; sodium carbonate; sugar alcohols such as glycerin; mannitol; and sorbitol. The amount of diluent in a whole-body or topical composition is typically about 50 to about 90%.

[0105] Suitable lubricants include silica, talc, stearic acid and its magnesium and calcium salts, calcium sulfate, and liquid lubricants such as polyethylene glycol, and vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil. The amount of lubricant in the whole-body or topical composition is typically about 5 to about 10%.

[0106] Suitable binders include polyvinylpyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder in the whole composition is typically about 5 to about 50%.

[0107] Suitable disintegrants include agar, alginic acid and its sodium salts, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clay, and ion exchange resins. The amount of disintegrant in the whole-body or topical composition is typically about 0.1 to about 10%.

[0108] Suitable colorants include FD&C dyes and other colorants. When used, the amount of colorant in the whole-body or topical composition is typically about 0.005 to about 0.1%. Suitable flavorings include menthol, peppermint, and fruit flavors. The amount of flavoring in the whole-body or topical composition is typically about 0.1 to about 1.0% at the time of use. Suitable sweeteners include aspartame and saccharin. The amount of sweetener in the whole-body or topical composition is typically about 0.001 to about 1%. Suitable antioxidants include butylated hydroxyanisole ("BHA"), butylated hydroxytoluene ("BHT"), and vitamin E. The amount of antioxidant in a systemic or topical composition is typically about 0.1 to about 5%. Suitable preservatives include benzalkonium chloride, methylparaben, and sodium benzoate. The amount of preservative in the whole-body or topical composition is typically about 0.01 to about 5%. A suitable flow promoter is silicon dioxide. The amount of the flow promoter in the whole-body or topical composition is typically about 1 to about 5%. Suitable solvents include water, isotonic saline, ethyl oleate, glycerin, hydroxylated castor oil, alcohols such as ethanol, and phosphate buffer. The amount of solvent in the whole-body or topical composition is typically about 0 to about 100%. Suitable suspending agents include AVICEL RC-591 (supplied by FMC Corporation, Philadelphia, Pennsylvania) and sodium alginate. The amount of suspending agent in the systemic or topical composition is typically about 1 to about 8%. Suitable surfactants include lecithin, polysorbate 80, and sodium lauryl sulfate, as well as TWEENS, provided by Atlas Powder Company in Wilmington, Delaware. Other suitable surfactants are disclosed in CTFA Cosmetic Ingredient Handbook, 1992, pp. 587-592, Remington's Pharmaceutical Sciences, 15th Ed. 1975, pp. 335-337, and McCutcheon's Volume 1, Emulsifiers & Detergents, 1994, North American Edition, pp. 236-239. The amount of surfactant in a whole-body or topical composition is typically about 0.1% to about 5%.

[0109] The amounts of components in a whole-body composition may vary depending on the type of whole-body composition being prepared, but generally, a whole-body composition contains 0.01% to 50% of the active compound (e.g., the compound of formula (I)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically contain 0.1% to 10% of the active substance and 90% to 99.9% of carriers such as diluents and solvents.

[0110] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms contain a safe and effective amount of the active substance, usually at least about 5%, more specifically about 25% to about 50%. Oral administration compositions contain about 50% to about 95% of the carrier, more specifically about 50% to about 75% of the carrier.

[0111] Tablets may be compressed tablets, powder tablets, enteric-coated tablets, sugar-coated tablets, film-coated tablets, or multi-compressed tablets. Tablets typically contain an active ingredient and a carrier containing components selected from diluents, lubricants, binders, disintegrants, colorants, flavorings, sweeteners, flow enhancers, and combinations thereof. Specific diluents include calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose. Specific binders include starch, gelatin, and sucrose. Specific disintegrants include alginic acid and croscarmellose. Specific lubricants include magnesium stearate, stearic acid, and talc. Specific colorants are FD&C dyes, which may be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavorings such as menthol, peppermint, fruit flavors, or combinations thereof.

[0112] Capsules (including implants, sustained-release formulations, and sustained-release formulations) typically comprise an active compound (e.g., a compound of formula (I)) and a carrier containing one or more previously disclosed diluents within a gelatin-containing capsule. Granules typically comprise the disclosed compound and, preferably, a flow enhancer, such as silicon dioxide, to improve flow properties. Implants may be of a biodegradable or non-biodegradable type.

[0113] The selection of components for the carrier for the oral composition depends on secondary concerns such as taste, cost, and storage stability, which are not important to the objectives of the present invention.

[0114] The solid composition can be coated by conventional methods, typically using pH or time-dependent coatings, resulting in the release of the disclosed compound into the gastrointestinal tract near the desired application site, or at various points in time and durations to delay the desired effect. The coating typically comprises one or more components selected from the group consisting of cellulose phthalate acetate, polyvinyl phthalate acetate, hydroxypropyl methylcellulose phthalate, ethylcellulose, EUDRAGIT® coating (available from Evonik Industries in Essen, Germany), waxes, and shellac.

[0115] Compositions for oral administration may be in liquid form. For example, preferred liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non-foaming granules, suspensions reconstituted from non-foaming granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, and syrups. Liquid oral administration compositions typically contain the disclosed compound and a carrier, i.e., a carrier selected from diluents, colorants, flavorings, sweeteners, preservatives, solvents, suspending agents, and surfactants. Oral liquid compositions preferably contain one or more components selected from colorants, flavorings, and sweeteners.

[0116] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal, and nasal dosage forms. Such compositions typically include one or more soluble filler substances, such as diluents including sucrose, sorbitol, and mannitol, and binders, such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose. Such compositions may further contain lubricants, colorants, flavoring agents, sweeteners, antioxidants, and flow enhancers.

[0117] The compounds of this disclosure can be administered topically. Topical compositions that can be applied topically to the skin may be in any form, including solids, solutions, oils, creams, ointments, gels, lotions, shampoos, leave-on and rinse-out hair conditioners, milks, cleansers, moisturizers, sprays, skin patches, and the like. A topical composition comprises the disclosed compounds (e.g., compounds of formula (I)) and a carrier. The carrier of the topical composition preferably helps the compound to penetrate the skin. The carrier may further comprise one or more optional components.

[0118] The amount of carrier used with the disclosed compound is sufficient to produce a composition in a quantity that is actually useful for administering the compound per unit dose. Techniques and compositions for producing useful dosage forms in the method of the present invention are described in the following references, namely, Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tables (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0119] The carrier may consist of a single component or a combination of two or more components. In a topical composition, the carrier includes a topical carrier. Suitable topical carriers include one or more components selected from phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohol, symmetrical alcohol, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, and combinations thereof. More specifically, carriers for skin application include propylene glycol, dimethyl isosorbide, and water, and even more specifically, phosphate-buffered saline, isotonic water, deionized water, monofunctional alcohol, and symmetrical alcohol.

[0120] The carrier of the topical composition may further contain one or more components selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0121] Suitable emollients include stearyl alcohol, glyceryl monolicinoleate, glyceryl monostearate, propane-1,2-diol, butane-1,3-diol, mink oil, cetyl alcohol, isopropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol, isopropyl laurate, hexyl laurate, decyl oleate, octadecane-2-ol, isocetyl alcohol, cetyl palmitate, and di-n-b Examples include palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof, as well as isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and isostearic acid. Specific emollients for the skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient in a skin-based topical composition is typically about 5% to about 95%.

[0122] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant in the topical composition is typically about 0% to about 95%.

[0123] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethyl sulfoxide, dimethylformamide, tetrahydrofuran, and combinations thereof. Specific examples of solvents include ethyl alcohol and homotopic alcohols. The amount of solvent in the topical composition is typically about 0% to about 95%.

[0124] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. A specific example of a humectant is glycerin. The amount of humectant in the topical composition is typically between 0% and 95%.

[0125] The amount of thickener in a topical composition is typically between approximately 0% and 95%.

[0126] Suitable powders include β-cyclodextrin, hydroxypropyl cyclodextrin, chalk, talc, fuller's earth, kaolin, starch, gum, colloidal silicon dioxide, sodium polyacrylate, tetraalkylammonium smectite, trialkylarylammonium smectite, chemically modified magnesium aluminum silicate, organically modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethylcellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder in the topical composition is typically 0% to 95%.

[0127] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, and particularly about 0.001% to about 0.1%.

[0128] Suitable pH-adjusting additives include HCl or NaOH in amounts sufficient to adjust the pH of the topical pharmaceutical composition.

[0129] In some embodiments, the following components are mixed together in a conventional manner and compressed into tablets to obtain 10,000 tablets, each containing 5 mg of the active ingredient. 5-Chloro-N-{1-(2-hydroxy-2-methylpropyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxybenzamide (50g), Carboxymethylcellulose calcium (disintegrant) (20g), Magnesium stearate (lubricant) (10g) Microcrystalline cellulose (920g).

[0130] Spray-dried dispersion formulation The compounds of this disclosure may be formulated as spray-dried dispersions (SDDs). An SDD is a single-phase amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution in which the compound is molecularly "dissolved" in a solid matrix. SDDs are obtained by dissolving the drug and polymer in an organic solvent and then spray-drying the solution. The use of spray-drying for pharmaceutical applications can result in amorphous dispersions with increased solubility for drugs of Class II (high permeability, low solubility) and Class IV (low permeability, low solubility) in the Biologics Classification System (BCS). Formulation and process conditions are selected to ensure that the solvent evaporates rapidly from the droplets, thereby not providing sufficient time for phase separation or crystallization. SDDs have demonstrated long-term stability and manufacturability. For example, SDDs have demonstrated a shelf life of more than two years. The advantages of SDD include, but are not limited to, improved oral bioavailability of poorly water-soluble compounds, delivery using conventional solid dosage forms (e.g., tablets and capsules), reproducible, controllable, and scalable manufacturing processes, and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.

[0131] In one embodiment, the present disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I).

[0132] How to use The compounds, pharmaceutical compositions, and formulations disclosed herein are K2PK inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2, which would provide therapeutic benefits. + Channels, especially TREK (TWIK related K + It may be used in the treatment of diseases such as neurological disorders, psychiatric disorders, inflammatory diseases, respiratory diseases, renal diseases, cardiovascular diseases, cancer, or pulmonary fibrosis, which are associated with channel dysfunction.

[0133] Treatment of disability The compounds, pharmaceutical compositions, and formulations of this disclosure may be used in methods for the prevention and / or treatment of diseases such as neurological and / or psychiatric disorders associated with TREK channel dysfunction, in which inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide therapeutic benefits. Methods for prevention and / or treatment may include administering to a subject in need of such prevention and / or treatment a therapeutically effective amount of the compound of formula (I), or a pharmaceutical composition containing a therapeutically effective amount of the compound of formula (I).

[0134] In some embodiments, the present disclosure provides a method for enhancing cognition and / or treating, preventing, improving, controlling or reducing the risk of psychiatric symptoms such as schizophrenia and depression in a mammal, comprising the step of administering to the mammal a therapeutically effective amount of a compound of formula (I), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I).

[0135] The compounds and compositions disclosed herein may be useful in treating, preventing, improving, controlling, or reducing the risk of various diseases associated with selective TREK channel inhibition. Accordingly, a method is provided for treating or preventing a disease of interest, comprising the step of administering to a subject an amount effective to treat the disease of interest.

[0136] Also provided is a method for preventing and / or treating one or more diseases related to target TREK channel activity, comprising the step of administering a therapeutically effective amount of a compound of formula (I), or a pharmaceutical composition containing a therapeutically effective amount of a compound of formula (I), to the target.

[0137] In some embodiments, the Disclosure provides a method for preventing and / or treating a disease associated with TREK channel dysfunction in which an inhibitor of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide therapeutic benefits in a mammal, the method comprising administering to a mammal an effective amount of at least one compound of the Disclosure or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one compound of the Disclosure or a pharmaceutically acceptable salt thereof.

[0138] In some embodiments, the compounds and compositions of the present disclosure have utility in the prevention and / or treatment of various neurological disorders, psychiatric disorders and cognitive impairments, cancer or pulmonary fibrosis associated with TREK-1 and / or TREK-2 inhibition, where inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide therapeutic benefits, including, among others, one or more of the following conditions or diseases: depression, schizophrenia, psychotic disorder NOS, short-term psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic destructiveness, delayed-onset psychosis, myxedema psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, substance-induced psychotic disorder, neuropathic pain, prostate cancer, ovarian cancer and pulmonary fibrosis.

[0139] In some embodiments, psychotic disorders or mental disorders are disorders associated with conditions selected from depression, major depressive disorder, postpartum depression, treatment-resistant depression, affective disorders, bipolar disorder, electrolyte disorders, Alzheimer's disease, neuropathy, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder, anxiety disorders, and 22q11.2 deletion disorders.

[0140] In some embodiments, the neurological disease is selected from brain tumors, Lewy body dementia, vascular dementia, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis (ALS), and anti-NMDA receptor encephalitis.

[0141] In some embodiments, the psychotic disorder or mental disorder is selected from schizophrenia, brief psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder. In some embodiments, schizophrenia is selected from catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disintegrative schizophrenia, and undifferentiated schizophrenia. In some embodiments, the disorder is selected from schizoid personality disorder, schizotyped personality disorder, and paranoid personality disorder. In some embodiments, the psychotic disorder is due to a general medical condition or is substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine).

[0142] In some embodiments, preferred neurological disorders include schizophrenia, short-term psychotic disorder, schizophrenia-like disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder.

[0143] Here, "schizophrenia" includes the negative symptoms of schizophrenia and cognitive impairments associated with schizophrenia (CIAS).

[0144] In some embodiments, the Disclosure provides a method for preventing and / or treating cognitive impairment, comprising administering an effective amount of a compound or composition of the Disclosure to a patient in need thereof. In some embodiments, cognitive impairment includes dementia (associated with Alzheimer's disease, ischemia, polyinfarct dementia, trauma, vascular disease or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jakob disease, perinatal hypoxia, other common medical conditions or substance abuse), delirium, amnesia, substance-induced persistent delirium, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinsonian-ALS dementia complex, Alzheimer's disease, age-related cognitive decline, and mild cognitive impairment.

[0145] The revised text of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington, D.C.) provides diagnostic tools for cognitive disorders, including dementia, delirium, amnesia, and age-related cognitive decline. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013, American Psychiatric Association, Washington, D.C.) provides diagnostic tools for neurocognitive disorders (NCDs), which include delirium, subsequent severe NCDs, mild NCDs, and syndromes of their etiological subtypes. Severe or mild NCD subtypes include NCD due to Alzheimer's disease, vascular NCD, Lewy body NCD, NCD due to Parkinson's disease, frontotemporal NCD, NCD due to traumatic brain injury, NCD due to HIV infection, substance / drug-induced NCD, NCD due to Huntington's disease, NCD due to prion disease, NCD due to another medical condition, NCD due to multiple etiologies, and NCD of unknown origin. The NCD categories in DSM-5 encompass a group of impairments where the primary clinical deficit is in cognitive function and is acquired rather than developmental. As used herein, the term “cognitive impairment” includes the prevention and / or treatment of cognitive and neurocognitive impairments as described in DSM-IV-TR or DSM-5. Those skilled in the art will understand that alternative nomenclature, classifications and classification systems exist for mental disorders, and that these systems evolve with medical and scientific advances. Accordingly, the term “cognitive impairment” is intended to include impairments similar to those described in other diagnostic sources.

[0146] In some embodiments, the Disclosure provides a method for preventing and / or treating schizophrenia or psychosis, comprising administering an effective amount of a compound or composition of the Disclosure to a patient in need thereof. Specific schizophrenic or psychotic conditions include paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia or anaplastic schizophrenia, and substance-induced psychotic disorders. DSM-IV-TR provides a diagnostic tool that includes paranoid schizophrenia, disorganized schizophrenia, catatonic schizophrenia, anaplastic schizophrenia or residual schizophrenia, and substance-induced psychotic disorders. DSM-5 excludes subtypes of schizophrenia and instead includes a dimensional approach to assess the severity of core symptoms of schizophrenia to capture heterogeneity in the type and severity of symptoms expressed across individuals with psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes the prevention and / or treatment of mental disorders as described in DSM-IV-TR or DSM-5. Those skilled in the art will understand that alternative nomenclature, classification, and classification systems exist for mental disorders, and that these systems evolve with medical and scientific advances. Therefore, the term “schizophrenia or psychosis” is intended to encompass disorders similar to those described in other diagnostic sources.

[0147] In some embodiments, the Disclosure provides a method for preventing and / or treating pain, comprising administering an effective amount of a compound or composition of the Disclosure to a patient in need of pain prevention and / or treatment. Specific embodiments of pain include bone pain and arthralgia (osteoarthritis), repetitive movement pain, dental pain, cancer pain, myofascial pain (muscle injury, fibromyalgia), perioperative pain (general surgery, gynecology), chronic pain, and neuropathic pain.

[0148] In some embodiments, the present disclosure provides a method for preventing and / or treating an inflammatory disease, comprising administering an effective amount of a compound or composition of the present disclosure to a patient in need thereof. In some embodiments, inflammatory diseases include intestinal allergies, inflammatory bowel disease, allergic asthma, allergic dermatitis, and allergic rhinitis.

[0149] In some embodiments, the present disclosure provides a method for preventing and / or treating a respiratory disease, comprising administering an effective amount of a compound or composition of the present disclosure to a patient in need thereof. In some embodiments, respiratory diseases include asthma, chronic obstructive pulmonary disease, pulmonary fibrosis, pneumonia, and lung cancer.

[0150] In some embodiments, the present disclosure provides a method for preventing and / or treating kidney disease, comprising administering an effective amount of a compound or composition of the present disclosure to a patient in need thereof. In some embodiments, kidney disease includes nephritis syndrome and renal failure.

[0151] In some embodiments, the present disclosure provides a method for preventing and / or treating a cardiovascular disease, comprising administering an effective amount of a compound or composition of the present disclosure to a patient in need thereof. In some embodiments, cardiovascular diseases include coronary artery disease, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmias, congenital heart disease, valvular heart disease, cardiac inflammation, aortic aneurysm, peripheral artery disease, thromboembolic disease, and venous thrombosis.

[0152] In some embodiments, the present disclosure provides a method for preventing and / or treating cancer, comprising administering an effective amount of a compound or composition of the present disclosure to a patient in need of prevention and / or treatment of cancer. In some embodiments, cancers include cranial nerves (e.g., pediatric brain tumors (e.g., neuroblastoma, medulloblastoma, astrocytoma (e.g., juvenile pilocytic astrocytoma), ependymoma, craniopharyngioma, germ cell tumors, optic glioma, choroid plexus papilloma and pontine glioma), adult brain tumors (e.g., adult astrocytoma, adult malignant astrocytoma, adult glioblastoma, adult ependymoma, adult malignant ependymoma, adult malignant oligodendroglioma, adult medulloblastoma, adult meningioma and adult malignant meningioma), gliomas (e.g., astrocytoma, oligodendroglioma, ependymoma and brainstem glioma), Cancers associated with pituitary adenoma, acoustic Schwann cell tumor, retinoblastoma, and uveal melanoma; airway cancers (e.g., pharyngeal cancer (e.g., nasopharyngeal, oropharyngeal, and hypopharyngeal cancers), laryngeal cancer, paranasal sinus cancer, lung cancer (e.g., small cell lung cancer and non-small cell lung cancer), thymoma, and mesothelioma); gastrointestinal cancers (e.g., esophageal cancer, stomach cancer, duodenal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, and anal cancer)); oral cancers (e.g., gingival cancer, tongue cancer, and salivary gland cancer); urinary tract cancers (e.g., penile cancer, renal pelvis, and ureteral cancer) (e.g., renal cell carcinoma, testicular tumors, prostate cancer, prostate cancer and bladder cancer), cancers affecting women (e.g., vulvar cancer, uterine cancer (e.g., cervical cancer and endometrial cancer), uterine sarcoma, trophoblastic diseases (e.g., hydatidiform teratomas, choriocarcinoma, placental trophoblastic tumors and persistent trophoblastic disease), vaginal cancer, breast cancer, mammary sarcoma, ovarian cancer and ovarian germ cell tumors), skin cancers (e.g., melanoma (also known as malignant melanoma) (e.g., lentigo malignant melanoma, superficial spreading melanoma, nodular melanoma, acral lentigo melanoma and erosive melanoma) Melanoma), mycosis fungoides, squamous cell carcinoma, basal cell carcinoma, signs of skin cancer and intraepidermal carcinoma (e.g., actinic keratosis, Bowen's disease and Paget's disease), lymphomatoid papulosis, cutaneous CD30-positive anaplastic large cell lymphoma, Sézary syndrome and cutaneous B-cell lymphoma), bone and muscle cancers (e.g., osteosarcoma, soft tissue sarcoma, rhabdomyosarcoma, synovial sarcoma and liposarcoma), thyroid cancer, carcinoid, liver cancer (also known as hepatoblastoma), hepatoblastoma, bile duct cancer, gallbladder cancer, pancreatic cancer, pancreatic endocrine tumors (e.g., insulinoma,Gastrinoma and VIPoma), unknown primary hereditary tumors, familial carcinomas (e.g., hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, hereditary breast and ovarian cancer syndrome, Lie-Fraumeni syndrome, hereditary melanoma, Wilms' tumor, hereditary papillary renal cell carcinoma, von Hippel-Lindau syndrome, and multiple endocrine neoplasms), leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia) Examples include diseases such as chronic myeloproliferative disorders, adult T-cell leukemia / lymphoma, chronic lymphocytic leukemia, and small lymphocytic lymphoma, multiple myeloma, primary macroglobulinemia, and malignant lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma (intermediate and high-grade lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, follicular lymphoma, mantle cell lymphoma, MALT (mucosa-associated lymphoid tissue) lymphoma, and NK (natural killer) cell lymphoma)). In some embodiments, the cancer is preferably lung cancer, prostate cancer, and ovarian cancer.

[0153] The compound and composition may be further useful in methods for preventing, treating, controlling, improving, or reducing the risk of the diseases, disorders, and conditions described herein. The compound and composition may be further useful in combination with other agents in methods for preventing, treating, controlling, improving, or reducing the risk of the aforementioned diseases, disorders, and conditions.

[0154] In the prevention and / or treatment of conditions requiring inhibition of TREK channels (TREK-1, TREK-2, or both TREK-1 and TREK-2), appropriate dose levels may range from approximately 0.01 to 1000 mg per day, which can be administered to patients as a single or multiple dose. For oral administration, the composition may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient for symptomatic dose adjustments to the patient being treated. The compound can be administered in regimens of one to four times daily. This administration regimen can be adjusted to produce an optimal therapeutic response. However, it should be understood that specific dose levels and frequencies for any particular patient may vary and depend on various factors, including the activity of the specific compound used, its metabolic stability and duration of action, age, weight, overall health, sex, diet, mode and timing of administration, excretion rate, drug combinations, severity of the particular condition, and the host being treated.

[0155] In some embodiments, the diseases for which inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide therapeutic benefits may be selected from psychosis, schizophrenia, behavioral disorders, disruptive behavioral disorders, bipolar disorder, psychotic episodes of anxiety disorders, anxiety associated with psychosis, psychotic mood disorders such as severe major depressive disorder, mood disorders associated with psychotic disorders, acute mania, depression associated with bipolar disorder, mood disorders associated with schizophrenia, behavioral symptoms of intellectual disability, autism spectrum disorder, motor disorders, Tourette syndrome, akinetic-rigid syndrome, motor disorders associated with Parkinson's disease, tardive dyskinesia, drug-induced and neurodegenerative dyskinesia, attention deficit hyperactivity disorder, cognitive impairment, dementia, and memory impairment.

[0156] In some embodiments, the disease for which inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2 provide therapeutic benefits is Alzheimer's disease.

[0157] Simultaneous treatment This disclosure further relates to the administration of selective TREK channel inhibitors to improve treatment outcomes in connection with cognitive therapy or behavioral therapy. Specifically, in some embodiments, this disclosure relates to concurrent therapies comprising the step of administering effective amounts and doses of at least one disclosed compound or a pharmaceutically acceptable salt thereof to a mammal.

[0158] In some embodiments, the administration improves treatment outcomes in the context of cognitive therapy or behavioral therapy. Administration in relation to cognitive therapy or behavioral therapy may be continuous or intermittent. Administration does not need to be simultaneous with treatment, but may occur before, during, and / or after treatment.

[0159] It is understood that the disclosed concurrent therapies may be used in connection with the disclosed compounds, compositions, kits, and their use.

[0160] Combination therapy In the methods of use described herein, additional therapeutic agents may be administered simultaneously with or sequentially to the compounds and compositions of the Disclosure. Sequential administration includes administration before or after the compounds and compositions of the Disclosure. In some embodiments, one or more additional therapeutic agents may be administered in the same composition as the compounds of the Disclosure. In other embodiments, there may be a time interval between the administration of the additional therapeutic agent and the administration of the compounds of the Disclosure. In some embodiments, administering the additional therapeutic agent together with the disclosed compounds may allow for lower doses and / or administration at lower intervals of the other therapeutic agents. When used in combination with one or more other active ingredients, the compounds of the present invention and the other active ingredients can be used in lower doses than when each is used alone. Accordingly, the pharmaceutical compositions of the present invention include those containing one or more other active ingredients in addition to the compound of formula (I). The above combinations include not only combinations of the compound of the present invention with one other active compound, but also combinations with two or more other active compounds.

[0161] The compounds disclosed herein can be used alone or in combination with one or more other drugs in the treatment, prevention, control, improvement or reduction of risk of the aforementioned diseases, disorders and conditions for which the compounds or other drugs are useful, and the drug combination is safer or more effective than either drug alone. The other drugs can be administered concurrently or sequentially with the disclosed compounds, in the routes and amounts commonly used for such administration. When the disclosed compounds are used concurrently with one or more other drugs, a pharmaceutical composition in unit dosage forms containing such drugs and the disclosed compounds can be used. However, combination therapy can also be administered on overlapping schedules. It is also conceivable that a combination of one or more active ingredients and the disclosed compounds may be more effective than any of the monotherapy agents. Therefore, when used in combination with one or more other active ingredients, the compounds disclosed herein and the other active ingredients can be used at lower doses than when each is used alone.

[0162] The pharmaceutical compositions and methods of the present invention may further comprise other therapeutic compounds described herein that are typically applied to the prevention and / or treatment of the aforementioned pathological conditions.

[0163] The above combinations include not only combinations of the disclosed compound with one other active compound, but also combinations with two or more other active compounds. Similarly, the disclosed compound can be used in combination with other drugs used to prevent, treat, control, improve, or reduce the risk of diseases or conditions for which the disclosed compound is useful. Such other drugs can be administered simultaneously or sequentially with the compound of the present invention, in the routes and amounts commonly used for that purpose. When the compound of the present invention is used simultaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the disclosed compound is preferred. Therefore, the pharmaceutical composition may also contain one or more other active ingredients in addition to the compound of the present invention.

[0164] The weight ratio of the disclosed compound to the second active ingredient can be varied and depends on the effective dose of each ingredient. Generally, the effective dose of each is used. For example, when combining the compound of the present invention with another agent, the weight ratio of the disclosed compound to the other agent is generally in the range of about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of the compound of the present invention with other active ingredients are also generally within the aforementioned range, but in any case, the effective dose of each active ingredient should be used.

[0165] In such combinations, the disclosed compound and other active agents can be administered separately or in combination. Furthermore, the administration of one element may occur before, simultaneously with, or after the administration of other agents.

[0166] Accordingly, the compounds of this disclosure may be used alone or in combination with other agents known to be beneficial for the target indication, or with other agents that affect receptors or enzymes that increase the efficacy, safety, or convenience of the compounds of this disclosure, or reduce undesirable side effects or toxicity. The subject compounds and other agents may be administered simultaneously in either combination therapy or in any of the specified combinations.

[0167] In one embodiment, the compound can be used in combination with anti-Alzheimer's agents, β-secretase inhibitors, cholinergic agents, γ-secretase inhibitors, HMG-CoA reductase inhibitors, M1 allosteric agonists, M1 positive allosteric modulators, ibuprofen-containing NSAIDs, vitamin E, and anti-amyloid antibodies. In another embodiment, the subject compound can be used with sedatives, hypnotics, anxiolytics, (typical and atypical) antipsychotics, anxiolytics, cyclopyrrolone, imidazopyridine, pyrazolopyrimidine, minor tranquilizers, melatonin agonists and antagonists, melatonin agonists, benzodiazepines, barbiturates, 5HT-2 antagonists, etc., such as azinazolam, arobarbital, aronimide, alprazolam, amisulpride, amitriptyline, amobarbital, Amoxapine, aripiprazole, bentazepam, benzothamine, brotizolam, bupropion, buspirone, butabarbital, butyral, caprin, carbochloral, chloralbetaine, chloralhydrate, clomipramine, clonazepam, cloperidone, chlorazepate, chlordiazepoxide, chloretate, chlorpromazine, clozapine, siprazepam, desipramine, dextramol, diazepam, dichlorophenazone, divalproex Diphenhydramine, doxepin, estazolam, etochlorbinol, etomidate, phenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutetimide, harazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloquan, melatonin, mehobarbital, meprobamate, methacaron, midaflural, Midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraaldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, proptyline, quazepam, ketiapine, leclazepam, risperidone, lorethamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, thiothixen,Tracazolate, tranylcipromain, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoroperazine, trimethodine, trimipramine, urdazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and their salts, as well as combinations thereof, can be used in combination with these, or the subject compound can be administered in conjunction with the use of physical methods such as phototherapy or electrical stimulation.

[0168] In some embodiments, the compound can be used in combination with anticholinergics such as levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), biperiden (as its hydrochloride or lactate), and trihexyphenidyl (benzhexitol) hydrochloride, COMT inhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists, and dopamine receptor agonists such as allentemol, bromocriptine, phenoldopamine, rislide, naxagolide, pergolide, and pramipexole. It will be understood that the dopamine agonist may be in the form of pharmaceutically acceptable salts, such as allentemol hydrobromide, bromocriptine mesylate, phenoldopamine mesylate, naxagolide hydrochloride, and pergolide mesylate. Lithrid and pramipexole are generally used in their unsalted forms.

[0169] In some embodiments, the compound can be used in combination with compounds from phenothiazines, thioxanthenes, heterocyclic dibenzazepines, butyrophenones, diphenylbutylpiperidines, and indolone-class neuroleptics. Preferred examples of phenothiazines include chlorpromazine, mesolidazine, thioridazine, acetophenazine, fluphenazine, perphenazine, and trifluoroperazine. Preferred examples of thioxanthenes include chlorprothixene and thiothixene. An example of a dibenzazepine is clozapine. An example of a butyrophenone is haloperidol. An example of a diphenylbutylpiperidine is pimozide. An example of an indolone is morindron. Other neuroleptics include roxapine, sulpiride, and risperidone. It will be understood that when nerve blockers are used in combination with the subject compound, they may be in the form of pharmaceutically acceptable salts, such as chlorpromazine hydrochloride, mesolidazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, fluphenazine enatate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothicene hydrochloride, haloperidol decanoate, roxapine succinate, and morindone hydrochloride. Perphenazine, chlorprothicene, clozapine, haloperidol, pimozide, and risperidone are generally used in non-salt forms. Therefore, the subject compound can be used in combination with acetophenazine, allentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixen, clozapine, diazepam, phenoldopamine, fluphenazine, haloperidol, levodopa, levodopa in combination with benserazide, levodopa in combination with carbidopa, rislid, roxapine, mesolidazine, morindron, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, trifluoperazine, or ziprasidone.

[0170] In some embodiments, the compound can be used in combination with antidepressants or anxiolytics such as norepinephrine reuptake inhibitors (including tertiary and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible monoamine oxidase inhibitors (RIMAs), serotonin and norepinephrine reuptake inhibitors (SNRIs), corticotropin-releasing factor (CRF) antagonists, α-adrenergic receptor antagonists, neurokinin-1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1A agonists or antagonists, particularly 5-HT1A partial agonists, and corticotropin-releasing factor (CRF) antagonists. Specific examples of drugs include amitriptyline, clomipramine, doxepin, imipramine and trimipramine amoxapine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazide, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and piroxazine; alprazolam, chlordiazepoxide, clonazepam, clorazepate, diazepam, harazepam, lorazepam, oxazepam and prazepam; buspirone, fresinoxane, gepirone and ipsapirone, and their pharmaceutically acceptable salts.

[0171] In some embodiments, the compound can be administered co-administered with orthosteric muscarinic agonists, muscarinic enhancers, or cholinesterase inhibitors. In some embodiments, the compound can be administered co-administered with GlyT1 inhibitors such as risperidone, clozapine, haloperidol, fluoxetine, prazepam, xameline, lithium, phenobarbitol, and their salts, as well as combinations thereof, without limitation.

[0172] In one embodiment, the other drug for the prevention and / or treatment of schizophrenia is at least one drug selected from typical antipsychotics, atypical antipsychotics, and the like.

[0173] Examples of typical antipsychotics include chlorpromazine, fluphenazine, haloperidol, and sulpiride. Examples of atypical antipsychotics include serotonin-dopamine antagonists, multi-acting receptor-targeted antipsychotics, and dopamine partial agonists. Examples of serotonin-dopamine antagonists include risperidone, perospirone, ziprasidone, and blonanserin. Examples of multi-acting receptor-targeted antipsychotics include olanzapine, ketiapine, clozapine, and lurasidone. Examples of dopamine partial agonists include aripiprazole and caliprazine.

[0174] In one embodiment, other drugs for the prevention and / or treatment of depression are at least one drug selected from benzodiazepine anxiolytics, thienodiazepine anxiolytics, non-benzodiazepine anxiolytics, neurokinin-1 (NK1) antagonists, tricyclic antidepressants, tetracyclic antidepressants, monoamine oxidase (MAO) inhibitors, triazolopyridine antidepressants, serotonin and norepinephrine reuptake inhibitors (SNRIs), selective serotonin reuptake inhibitors (SSRIs), serotonin reuptake inhibitors, noradrenaline and specific serotonergic antidepressants (NaSSAs), noradrenaline and dopamine disenzymes (NDDIs), selective serotonin reuptake promoters (SSREs), and the like.

[0175] Examples of benzodiazepine anxiolytics include alprazolam, oxazepam, cloxazolam, chlorazepate dipotassium, chlordiazepoxide, diazepam, tofisosum, triazolam, prazepam, fludiazepam, flutazolam, flutoprazepam, bromazepam, mexazolam, medazepam, ethylloflazepa, and chlorazepam. Examples of thienodiazepine anti-anxiety medications include etizolam and clotiazepam. Examples of non-benzodiazepine anxiolytics include tandospirone citrate and hydroxyzine hydrochloride.

[0176] Examples of neurokinin-1 (NK1) antagonists include aprepitant and fossaprepitant meglumine. Examples of tricyclic antidepressants include amitriptyline hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, doslepin hydrochloride, nortriptyline hydrochloride, lofepramine hydrochloride, trimipramine maleate, and amoxapine. Examples of tetracyclic antidepressants include maprotiline hydrochloride, mianserin hydrochloride, and setiptiline maleate. Examples of monoamine oxidase (MAO) inhibitors include safrazine hydrochloride. Examples of triazolopyridine antidepressants include trazodone hydrochloride. Examples of serotonin and norepinephrine reuptake inhibitors (SNRIs) include milnacipran hydrochloride, venlafaxine hydrochloride, and duloxetine hydrochloride. Examples of selective serotonin reuptake inhibitors (SSRIs) include fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, and escitalopram oxalate. Examples of serotonin reuptake inhibitors include trazodone hydrochloride. Examples of noradrenaline and specific serotonergic antidepressants (NaSSAs) include mirtazapine. Examples of norepinephrine and dopamine withdrawal inhibitors (NDDIs) include agomelatine. Examples of selective serotonin reuptake promoters (SSREs) include thianeptine.

[0177] In one embodiment, other drugs for the prevention and / or treatment of atrial fibrillation are at least one drug selected from beta-blockers, digoxin, and the like. In one embodiment, other drugs for the prevention and / or treatment of pain are at least one drug selected from acetaminophen, nonsteroidal anti-inflammatory drugs, opioids, antidepressants, antiepileptic drugs, N-methyl-D-aspartate antagonists, muscle relaxants, antiarrhythmic drugs, steroids, bisphosphonates, and the like. Examples of antiarrhythmic drugs include lidocaine and mexiletine.

[0178] Nonsteroidal anti-inflammatory drugs include, for example, aspirin preparations including sasapirin, sodium salicylate, aspirin, aspirin-dialuminate, diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, clinol, fenbufen, nabumetone, proglummetacin, indomethacin farnesil, acemetacin, proglummetacin maleate, amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofen calcium, and thia. Examples include profen, oxaprozin, pranoprofen, loxoprofen sodium, aluminoprofen, zaltoprofen, mefenamic acid, aluminum mefenamate, tolfenamic acid, phloxataphenin, ketophenylbutazone, oxyfenbutazone, piroxicam, tenoxicam, ampiroxicam, napagel ointment, epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emorphazon, sulpyrine, migrenin, saridon, Sedes G, Amipiro N, Sorbon, pyrine-based cold treatments, acetaminophen, phenacetin, dimethothiazine mesylate, meloxicam, celecoxib, rofecoxib, valdecoxib, simetride-containing preparations, and nonpyrine-based cold treatments.

[0179] Examples of opioids include codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, and propoxyfen.

[0180] Examples of antidepressants include tricyclic antidepressants (e.g., imipramine hydrochloride, clomipramine hydrochloride, doslepin hydrochloride, nortriptyline hydrochloride, lofepramine hydrochloride, trimipramine maleate, amoxapine), tetracyclic antidepressants (e.g., maprotiline hydrochloride, mianserin hydrochloride, setiptiline maleate), monoamine oxidase (MAO) inhibitors (safrazine hydrochloride), serotonin and norepinephrine reuptake inhibitors (SNRIs) (e.g., milnacipran hydrochloride, venlafaxine hydrochloride), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluvoxamine maleate, paroxetine hydrochloride), and serotonin reuptake inhibitors (e.g., trazodone hydrochloride).

[0181] Examples of antiepileptic drugs include phenobarbital, pridomin, phenytoin, ethosuximide, zonisamide, nitrazepam, clonazepam, carbamazepine, sodium valproate, acetazolamide, sulzyme, gabapentin, and pregabalin. Examples of N-methyl-D-aspartate antagonists include ketamine hydrochloride, amantadine hydrochloride, memantine hydrochloride, dextromethorphan, and methadone. Examples of muscle relaxants include succinylcholine, succinylcholine, vecuronium bromide, pancuronium bromide, and dantrolene sodium.

[0182] Examples of steroids used as topical agents include clobetasol propionate, diflorasone diacetate, fluocinonide, mometasone furoate, betamethasone dipropionate, betamethasone propionate butyrate, betamethasone valerate, difluprednate, budesonide, difluprednate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, and dexamethasone acetate. Examples include sone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone propionate butyrate, deprodone propionate, prednisolone acetate valerate, fluocinolone acetonide, beclomethasone propionate, triamcinolone acetonide, flumethasone pivalate, alclomethasone dipropionate, clobetazone butyrate, prednisolone, beclomethasone propionate, and fludroxycortide.

[0183] Examples of bisphosphonates include etidronate, pamidronate, alendronate, risedronate, zoledroneate, and minodronate.

[0184] Mode of administration Methods of prevention and / or treatment may include any number of forms of administration of the disclosed composition. Examples of forms of administration include tablets, pills, sugar-coated tablets, hard and soft gel capsules, granules, pellets, aqueous solutions, lipid solutions, oily solutions or other solutions, emulsions, such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. In the preparation of pharmaceutical compositions for oral administration, the drug may be mixed with commonly known and used adjuvants and excipients, such as gum arabic, talcum, starch, sugars (e.g., mannitose, methylcellulose, lactose, etc.), gelatin, surfactants, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, crosslinking agents, dispersants, emulsifiers, lubricants, preservatives, flavoring agents (e.g., ether oil), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol), or bioavailability enhancers (e.g., Gelucire®). In the pharmaceutical composition, the drug may also be dispersed in fine particles, such as nanoparticle compositions.

[0185] For parenteral administration, the drug may be dissolved or suspended in a physiologically acceptable diluent, such as water, a buffer solution, or an oil, with or without a solubilizer, surfactant, dispersant, or emulsifier. Examples of oils that may be used include, but are not limited to, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil, and sesame oil. More generally, for parenteral administration, the drug may be in the form of an aqueous solution, lipid solution, oily solution, or other type of solution or suspension, or it may even be administered in the form of liposomes or nanosuspensions.

[0186] As used herein, the term “parenteral” refers to modes of administration including intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous, and intra-articular injections and infusions. Because this compound has low toxicity, it can be safely used as a pharmaceutical product.

[0187] kit In one embodiment, the present disclosure relates to at least one disclosed compound or a pharmaceutically acceptable salt thereof, (a) At least one drug known to reduce TREK1 activity, (b) At least one drug known to reduce TREK2 activity, (c) At least one agent known to prevent and / or treat a disorder associated with TREK dysfunction in which TREK1, TREK2, or both TREK1 / TREK2 inhibitors provide therapeutic benefits in mammals. (d) Instructions for the prevention and / or treatment of disorders related to TREK dysfunction in which TREK1, TREK2, or both TREK1 / TREK2 inhibitors provide therapeutic benefits in mammals, or (e) Instructions for administering the compound in connection with cognitive therapy or behavioral therapy, one or more of the above, are provided as part of a kit.

[0188] In some embodiments, at least one disclosed compound and at least one drug are formulated together. In some embodiments, at least one disclosed compound and at least one drug are packaged together. The kit may also include compounds and / or products that are packaged together with other components, formulated together, and / or delivered together. For example, a drug manufacturer, drug reseller, physician, pharmacy, or pharmacist may provide a kit comprising the disclosed compound and / or product and other components for delivery to a patient. The kit described herein can be used in connection with the disclosed uses.

[0189] This kit may include information, instructions, or both, that the use of the kit provides for the prevention and / or treatment of medical conditions in mammals (especially humans). Such information and instructions may be in the form of language, photographs, or both. In addition, or otherwise, this kit may include information, instructions, or both, regarding the compound, composition, or both, and a method of applying the compound or composition, preferably with the benefit of preventing and / or treating medical conditions in mammals (e.g., humans).

[0190] The compounds and processes of the present invention will be better understood by referring to the following examples, which are intended to be illustrative and not limit the scope of the invention. [Examples]

[0191] This disclosure will be described below in detail by examples and biological examples that do not limit this disclosure. The compounds described in this disclosure and the examples will be named according to IUPAC nomenclature. IUPAC nomenclature can be performed, for example, using ACD / Name (registered trademark, version 2019.2.0, available from Advanced Chemistry Development Inc.), ACD / Name Batch (registered trademark, version 12.02.45356, available from Advanced Chemistry Development Inc.), or ChemDraw Professional (registered trademark, version 17.1.0.105 or 18.0.0.231, available from PerkinElmer Inc.). In each of the following examples, the name of the target compound of the example may be written after the example number and referred to as the "title compound".

[0192] All NMR spectra were recorded using a 400 MHz AMX Bruker NMR spectrometer or a Bruker AVANCE III 400 MHz NMR or 600 MHz spectrometer. 1The H chemical shift is reported as the δ value (ppm) at low magnetic fields, using a deuterated solvent as an internal standard. The data is reported as follows: chemical shift, multiplicity (s=singlet, bs=broad singlet, d=doublet, t=triplet, q=quadruplet, dd=doublet of doublet, m=multiplet, ABq=ABquadruplet), coupling constant, and integral. The LCMS analysis conditions were as follows, and unless otherwise specified, the MS data for the examples were measured by reversed-phase LCMS (1).

[0193] Inverted phase LCMS (1): Reverse-phase LC-MS analysis was performed using a SHIMADZU LC20-MS2010 with an ESI source. The MS parameters were as follows: Mobile phase: 1.5 mL / 4 L TFA aqueous solution (solvent A) and 0.75 mL / 4 L TFA acetonitrile solution (solvent B), with an elution gradient of 5% to 95% (solvent B) over 0.7 minutes, followed by elution at a flow rate of 1.5 ml / min at 95% for 0.4 minutes and then at 5% for 0.4 minutes; Column: Agilent Pursit 5 C18 20*2.0 mm; Wavelength: UV 220 nm, 254 nm, 215 nm; Column temperature: 50 °C; MS ionization: ESI.

[0194] Inverted phase LCMS (2) Reverse-phase LC-MS analysis was performed using a SHIMADZU LC20-MS2020 with an ESI source. The MS parameters were as follows: Mobile phase: 0.8 mL / 4 L of aqueous NH3H2O ​​solution (solvent A) and acetonitrile solution (solvent B), with an elution gradient of 10% to 80% (solvent B) over 6.5 minutes, held at 95% for 0.5 minutes at a flow rate of 0.8 ml / min; Column: Xbridge Shield RP-18, 5 μm, 2.1*50 mm; Wavelength: UV 220 nm, 254 nm, 215 nm; Column temperature: 50 °C; MS ionization: ESI.

[0195] Inverted phase LCMS (3) Reverse-phase LC-MS analysis was performed using a SHIMADZU LC20-MS2020 with an ESI source. The MS parameters were as follows: Mobile phase: 0.8 mL / 4 L of aqueous NH3H2O ​​solution (solvent A) and acetonitrile solution (solvent B), with an elution gradient of 50% to 100% (solvent B) over 2.5 minutes, followed by elution at a flow rate of 0.8 ml / min at 95% for 0.5 minutes and then at 50% for 0.5 minutes; Column: Xbridge Shield RP-18, 5 μm, 2.1*50 mm; Wavelength: UV 220 nm, 254 nm, 215 nm; Column temperature: 50 °C; MS ionization: ESI.

[0196] Inverted phase LCMS (4) Reverse-phase LC-MS analysis was performed using an Agilent 1200 system consisting of a binary pump with degasser, a high-performance autosampler, a column compartment with thermostat, a C18 column, a diode array detector (DAD), and an Agilent 6150 MSD, with the following parameters. The gradient conditions involved using a 0.1% TFA aqueous solution as the aqueous phase and adding acetonitrile from 5% to 95% over 1.4 minutes. The sample was separated at 0.5 mL / min using a Waters Acquity UPLC BEH C18 column (1.7 μm, 1.0 × 50 mm), maintaining the column and solvent temperatures at 55°C. The DAD was set to scan from 190 to 300 nm, and the signals used were at 220 nm and 254 nm (both with a bandwidth of 4 nm). The MS detector consisted of an electrospray ionization source, and low-resolution mass spectra were acquired by scanning from 140 AMU to 700 AMU with a step size of 0.2 AMU, 0.13 cycles / second, and a peak width of 0.008 mins. The dry gas flow rate was set to 13 liters / min at 300°C, and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set to 3000 V, and the fragmenter voltage was set to 100 V. Data acquisition was performed using Agilent Chemstation and Analytical Studio Reviewer software.

[0197] Inverted phase LCMS (5) Reverse-phase LC-MS analysis was performed using a SHIMADZU LCMS-2020 equipped with an ESI source. The MS parameters were as follows: Mobile phase: 0.1% TFA aqueous solution (solvent A) and 0.1% TFA acetonitrile solution (solvent B), elution and retention at 5% (solvent B) for 0.1 minutes, gradient from 5% to 95% (solvent B) over 1.1 minutes, retention at 95% for 0.4 minutes at a flow rate of 1.0 ml / min, Column: YMC Triart C18 Φ2.0 mm*L30 mm, Wavelength: UV 220 nm, 254 nm, Column temperature: 30°C, Detector: MS, ELSD, MS ionization: ESI.

[0198] Preparative HPLC (FA): Example: Mobile phase: 0.225% FA in water (solvent A) and acetonitrile (solvent B), elution gradient 55%~85% (solvent B) for 7.8 minutes, then held at 100% for 2 minutes, flow rate 25 ml / min, column: Welch Xtimate C18 150*25mm*5μm

[0199] Preparative HPLC (TFA): Example: Mobile phase: 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B), using an appropriate elution gradient depending on the compound, flow rate 40 ml / min, column: YMC TriartC18 75*30 mm*5 μm

[0200] Preparative HPLC (NH3H2O): Example: Mobile phase: 0.05% NH3H2O ​​and 10 mM NH4HCO3 in water (solvent A) and acetonitrile (solvent B), elution gradient 37%~67% (solvent B) for 9.5 minutes, then held at 100% for 2 minutes, flow rate 25 ml / min, column: Phenomenex Gemini 150*25mm*10μm.

[0201] The abbreviations used in the following examples are as follows: AcCl is acetyl chloride, AcOH is acetic acid, Ac2O is acetic anhydride, AlMe3 is trimethylaluminum, BnNH2 is benzylamine, CMBP is cyanomethylenetributylphosphoran, DCM is dichloromethane, DIAD is diisopropyldiazene-1,2-dicarboxylate, DIEA or DIPEA is N,N-diisopropylethylamine, DMF is N,N-dimethylformamide, DMSO is dimethyl sulfoxide, siRNA or EA is ethyl acetate, FA is formic acid, Hex is hexane, m-CPBA is m-chloroperbenzoic acid, MeCN is acetonitrile, MTBE is methyl tert-butyl ether or tert-butyl methyl ether, NaBH4 is sodium borohydride, NaBD4 is sodium boronite, NMI is N-methylimidazole, NMM is N-methylmorpholine, NMP is N-methylpyrrolidone, Pd A-taPhos is bis[di-tert-butyl(4-dimethylaminophenyl)phosphine]palladium(0), PE is petroleum ether, PhMe is toluene, Py is pyridine, TCFH is chloro-N,N,N',N'-tetramethylformamidinium hexafluorophosphate, TEA is triethylamine, and TFA is trifluoroacetic acid.

[0202] Scheme 1 [ka] 4-(benzylamino)-3-chloro-1H-pyridazin-6-one (A19): Compound 3,4-dichloro-1H-pyridazin-6-one (A1) (CAS No.: 17285-36-8, 25.0 g, 152 mmol, 1.00 equivalent) was dissolved in NMP (150 mL) to which BnNH2 (17.9 g, 167 mmol, 18.1 mL, 1.10 equivalent) and DIPEA (29.4 g, 227 mmol, 39.3 mL, 1.50 equivalent) were added. The mixture was stirred at 150 °C for 3 hours. LC-MS showed that compound A1 was completely consumed. The reaction mixture was poured into 1 M HCl (1.00 L). The resulting mixture was stirred at room temperature for 30 minutes. The precipitate was filtered and washed with H2O to obtain the crude product. The crude product was triturated with Â1 / Hex(2 / 1, 400 mL) to obtain compound A19 (30.6 g, 130 mmol, crude yield: 85.7%). MS(ESI)m / z=236.0[M+H] + . 1 H NMR:(400MHz,DMSO-d6)δ=12.23(s,1H),7.50-7.09(m,6H),5.40(s,1H),4.37(d,J=6.0Hz,2H).

[0203] Scheme 2 [ka] To a solution prepared by dissolving compound A19 (1.35 g, 5.73 mmol, 1.00 equivalent) and K2CO3 (1.58 g, 11.5 mmol, 2.00 equivalent) in ethyl 2-[(benzylamino)-3-chloro-6-oxopyridazin-1-yl]acetate (A21):NMP (10 mL), ethyl chloroethyl (A20) (CAS number: 105-39-5, 1.05 g, 8.59 mmol, 0.92 mL, 1.50 equivalent) was added. The mixture was stirred at 60°C for 4 hours. LC-MS showed that compound A19 was completely consumed. The reaction mixture was filtered through Celite® and then washed with ethyl ethyl acetate (100 mL). H2O (100 mL) was added to the filtrate, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phase was washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure. The resulting residue was tritulated with Hex / siRNA (4 / 1, 30 mL), filtered, and dried. Compound A21 (1.39 g, 4.32 mmol, 75.4% yield in two steps) was obtained. MS(ESI)m / z=322.1[M+H] + . 1 H NMR:(400MHz,DMSO-d6)δ=7.57(br t,J=6.0Hz,1H),7.39-7.30(m,4H),7.31-7.22(m,1H),5.54(s,1H),4.65( s,2H),4.40(d,J=6.0Hz,2H),4.10(q,J=7.2Hz,2H),1.17(t,J=7.2Hz,3H).

[0204] Scheme 3 [ka] 2-[4-(benzylamino)-6-oxo-3-[2-(trifluoromethyl)phenyl]pyridazin-1-yl]ethyl acetate (A23):1,4-dioxane (180 mL) and H2O (20 mL) were used to suspend compound A21 (11.1 g, 34.5 mmol, 1.00 equivalent), 2-trifluoromethylphenylboronic acid (A22) (CAS No.: 1423-27-4, 9.83 g, 51.7 mmol, 1.50 equivalent), and K3PO4 (11.0 g, 51.7 mmol, 1.50 equivalent). Pd A-taPhos (1.22 g, 1.72 mmol, 0.05 equivalent) was added to the degassed suspension. The reaction mixture was stirred at 100°C for 2 hours. Saturated aqueous NH4Cl (300 mL) was added to the reaction mixture. The mixture was extracted with  (200 mL x 2). The combined organic layer was washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography. The crude product was triturated with  / Hex (2 / 1, 200 mL) to obtain compound A23 (10.8 g, 25.0 mmol, yield 72.4%). MS(ESI) m / z = 432.1 [M+H] + . 1 H NMR:(400MHz,CDCl3)δ7.84(d,J=7.6Hz,1H),7.73-7.60(m,2H),7.50(d,J=7.6Hz,1H),7.37-7.27(m,3H),7.19 (d,J=6.8Hz,2H),5.86(s,1H),4.94-4.69(m,2H),4.34-4.16(m,4H),4.15-4.00(m,1H),1.27(t,J=7.2Hz,3H).

[0205] Scheme 4 [ka] 5-(benzylamino)-2-(2-hydroxyethyl)-6-[2-(trifluoromethyl)phenyl]pyridazin-3-one (A24): Compound A23 (60 g, 139 mmol, 1.00 equivalent) was dissolved in THF (700 mL). NaBH4 (30.46 g, 805.1 mmol, 5.79 equivalents) was added at 0°C. The reaction mixture was stirred at 50°C for 12 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was quenched with 0.5 mol / L aqueous HCl (500 mL). The resulting mixture was extracted with ELISA (500 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure to obtain compound A24 (63.1 g, crude). MS(ESI)m / z=390.1[M+H] + . 1 H NMR:(400MHz,CDCl3)δ=7.92-7.81(m,1H),7.76-7.60(m,2H),7.48(d,J=7.6Hz,1H),7.37- 7.28(m,3H),7.19(d,J=7.2Hz,2H),5.91(s,1H),4.41-4.25(m,4H),3.96(t,J=4.8Hz,2H).

[0206] Scheme 5 [ka] Compound A24 (63 g, 162 mmol, 1.00 equivalent) was dissolved in 2-(4-(benzylamino)-6-oxo-3-(2-(trifluoromethyl)phenyl)pyridazin-1(6H)-yl)ethyl acetate (A25):DCM (600 mL). To this solution, acetyl chloride (19.1 g, 243 mmol, 17.3 mL, 1.50 equivalent) and pyridine (25.6 g, 323 mmol, 26.1 mL, 2.00 equivalent) were added at 25°C. The reaction mixture was stirred at 25°C for 16 hours. LC-MS showed that the starting materials were completely consumed. The reaction mixture was quenched with saturated NaHCO3 aqueous solution (2.00 L). The mixture was extracted with ethyl acetate (1.00 L x 3). The combined organic phase was washed with 0.5 mol / L HCl aqueous solution (2.00 L) and dried over Na2SO4. The filtrate was evaporated under reduced pressure and triturated with siRNA / MTBE (1 / 10, 500 mL) to obtain compound A25 (41.4 g, 96.0 mmol, 69% yield in two steps). m / z = 432.2 [M + H] + . 1 H NMR:(400MHz,CDCl3)δ=7.85(d,J=7.6Hz,1H),7.74-7.59(m,2H),7.46(d,J=7.2Hz,1H),7.38-7.27(m,3H),7.19(br d,J=7.2Hz,2H),5.86(s,1H),4.50-4.28(m,4H),4.26(m,2H),2.00(s,3H).

[0207] Scheme 6 [ka] Compound A25 (10 g, 23.2 mmol, 1.00 equivalent, 4 batches) was dissolved in ethyl acetate (A26): ethyl acetate (80 mL) and MeOH (20 mL). Pd / C (20.00 g, 10% purity, 1.00 equivalent) was added to the solution. The mixture was stirred at 60°C for 16 hours under an H2 atmosphere. LC-MS showed that the starting material was completely consumed. The reaction mixture was filtered through Celite® and then washed with ethyl acetate (200 mL x 2). The filtrate was evaporated under reduced pressure to obtain compound A26 (26.9 g, 78.8 mmol, 85% yield). MS(ESI) m / z = 342.1 [M + H] + . 1 H NMR:(400MHz,CDCl3)δ=7.85(d,J=7.6Hz,1H),7.76-7.60(m,2H),7.45(d,J=7.2Hz,1H),6.04(s,1H),4.51-4.22(m,4H),4.06(br s,2H),2.01(s,3H).

[0208] Scheme 7 [ka] 2-[4-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-6-oxo-3-[2-(trifluoromethyl)phenyl]pyridazin-1-yl]ethyl acetate (A28):NMP (220 mL) was used to dissolve compound A26 (20 g, 58.60 mmol, 1.00 equivalent), 2-fluoro-5-(trifluoromethyl)benzoic acid (A27) (CAS No.: 115029-23-7, 30.5 g, 147 mmol, 2.50 equivalent), and DIPEA (26.5 g, 205 mmol, 35.7 mL, 3.50 equivalent). TCFH (41.1 g, 147 mmol, 2.50 equivalent) was added at 0°C. The reaction mixture was stirred at 25°C for 12 hours. LC-MS showed that the starting materials were completely consumed. The reaction mixture was quenched with saturated NH4Cl aqueous solution (2.00 L), and the mixture was extracted with RINKAN (500 mL x 3). The combined organic layer was washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure to obtain compound A28 (34.25 g, crude). MS(ESI)m / z = 532.3 [M + H] + .

[0209] Scheme 8 [ka] 2-Fluoro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide (compound (Cpd) 59):MeOH (400 mL) was used to dissolve compound A28 (34.2 g, crude) in a solution. To this solution, aqueous NaOH solution (5 M, 15.5 mL, 77.5 mmol, 1.20 equivalents) was added to prepare a mixture at 0°C. The mixture was stirred at 0°C for 20 minutes. LC-MS showed that the starting material had been completely consumed. H2O (2.00 L) was added to the reaction mixture (pH approximately 9.0). The mixture was extracted with ethyl acetate (500 mL x 4). The combined organic layers were washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure to obtain the crude product. By recrystallizing the crude residue from EtOH (300 mL) / H2O (300 mL), compound 59 (18.8 g, 38.4 mmol, 65.5% yield in two steps) was obtained as a pale yellow solid.

[0210] Scheme 9 [ka] 6-Chloro-5-((2,4-dimethoxybenzyl)amino)pyridazine-3(2H)-one (A30): To a solution of A1 (1.0 g, 6.1 mmol) dissolved in NMP (20 mL), DIEA (1.6 mL, 9.1 mmol) and 2,4-dimethoxybenzylamine (A29) (1.0 mL, 6.7 mmol) were added. The reaction was heated to 130 °C. After 1 hour, the reaction was cooled to room temperature and extracted with DCM / water (2 ×). The combined organic layers were then washed with water (3 times). The organic layers were dried with (Na2SO4), filtered, and concentrated. The residue was purified by normal-phase column chromatography (gradient: 0-100% siRNA / hexane) to obtain the desired compound A30 (1.56 g, yield 87%). ES-MS[M+H] + :296.0.

[0211] Scheme 10 [ka] Compound A30 (600 mg, 2.03 mmol) was dissolved in a solution of 5-amino-6-(2-isopropylphenyl)pyridazine-3(2H)-one (A32):1,4-dioxane and water (15 mL; 2:1). To this solution, 2-isopropylphenylboronic acid (A31) (366 mg, 2.23 mmol), [1,1'-bis(diphenylphosphino)ferrocene](dppf)dichloropalladium(II) (149 mg, 0.20 mmol), and potassium carbonate (711 mg, 5.1 mmol) were added. The sealed vial was evacuated, purged with nitrogen (3 times), and the reaction mixture was heated to 130°C. After 16 hours, the heat source was removed, and DCM (10 mL) was added to the reaction mixture. The mixture was filtered through hydrophobic frit, and the organic layer was concentrated under reduced pressure. TFA was added to the residue. After 15 minutes at room temperature, a saturated solution of sodium bicarbonate was slowly added to neutralize the reaction. The mixture was extracted using DCM (3 × 50 mL), and the organic layers were combined and concentrated. The residue was purified by normal-phase column chromatography (gradient: 0-7% DCM / MeOH) to obtain the desired compound A32 (183 mg, yield 39%). ES-MS[M+H] + :230.2.

[0212] Scheme 11 [ka] 5-amino-6-(2-isopropylphenyl)-2-(2-(methylthio)ethyl)pyridazine-3(2H)-one (A34): Compound A32 (110 mg, 0.48 mmol) was dissolved in DMF (4 mL). To this solution, 2-chloromethyl sulfide (A33) (0.09 mL, 0.86 mmol) and cesium carbonate (236 mg, 0.72 mmol) were added. The mixture was heated to 80°C. After 3 hours, the solvent was removed. The residue was dissolved in DMSO and purified by reverse-phase chromatography (gradient: 17-80% MeCN in H2O containing 0.05% NH4OH) to obtain the desired compound A34 (84 mg, yield 58%). ES-MS[M+H] + :304.1.

[0213] Scheme 12 [ka] N-(3-(2-isopropylphenyl)-1-(2-(methylthio)ethyl)-6-oxo-1,6-dihydropyridazin-4-yl)-2-methoxy-5-(trifluoromethyl)benzamide (A36): Compound A34 (28 mg, 0.09 mmol) was dissolved in MeCN (1 mL). To this solution, 2-methoxy-5-(trifluoromethyl)benzoyl chloride (A35) (31 mg, 0.13 mmol) and triethylamine (0.06 mL, 0.46 mmol) were added. After 1 hour at room temperature, the solvent was concentrated, and the residue was dissolved in DMSO (1 mL). The mixture was purified by reverse-phase chromatography (gradient: 50-88% MeCN in H2O containing 0.1% TFA) to obtain the desired compound A36 (46 mg, 99% yield). ES-MS[M+H] + :506.0.

[0214] Scheme 13 [ka] N-{3-(2-isopropylphenyl)-1-[2-(methylsulfonyl)ethyl]-6-oxo-1,6-dihydro-4-pyridazinyl}-2-methoxy-5-(trifluoromethyl)benzamide (compound 41): Compound A36 (24 mg, 0.05 mmol) was dissolved in DCM (0.5 mL), and m-CPBA (16 mg, 0.09 mmol) was added to the solution. After 1 hour at room temperature, the solvent was evaporated, and the resulting residue was purified by reverse-phase chromatography (gradient: 35-65% MeCN in H2O containing 0.05% NH4OH) to obtain compound 41 (9 mg, yield 37%).

[0215] Scheme 14 [ka] N-{3-(2-isopropylphenyl)-1-[2-(S-methylsulfonimidoyl)ethyl]-6-oxo-1,6-dihydro-4-pyridazinyl}-2-methoxy-5-(trifluoromethyl)benzamide (compound 42): Compound A36 (24 mg, 0.05 mmol) was dissolved in MeOH (0.5 mL), to which p-iodobenzene diacetate (PIDA) (31 mg, 0.10 mmol) and ammonium carbonate (7 mg, 0.07 mmol) were added. After 1 hour at room temperature, the solvent was removed, and the reaction product was purified by reverse-phase chromatography (gradient: 30-75% MeCN in H2O containing 0.05% NH4OH) to obtain compound 42 (1.5 mg).

[0216] Scheme 15 [ka] To a solution prepared by dissolving compound A19 (1.36 g, 5.77 mmol, 1.00 equivalent) and K2CO3 (1.04 g, 7.50 mmol, 1.30 equivalents) in 5-(benzylamino)-6-chloro-2-methylpyridazin-3-one (A38):NMP (10 mL), iodomethane (A37) (CAS number: 74-88-4, 1.23 g, 8.66 mmol, 0.54 mL, 1.50 equivalents) was added. The mixture was stirred at 60°C for 4 hours. LC-MS showed that compound A19 was completely consumed. The reaction mixture was quenched with 0.1 mol / L aqueous HCl (150 mL). The resulting mixture was extracted with siRNA (30 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure. The obtained residue was tritulated with Hex / Â(1 / 1, 50 mL), filtered, and dried. Compound A38 (605 mg, 4.32 mmol, two-step yield 42%) was obtained. MS(ESI) m / z = 249.9[M] +

[0217] Scheme 16 [ka] 5-(benzylamino)-6-(2-isopropylphenyl)-2-methylpyridazin-3-one (A39):1,4-dioxane (10 mL) and H2O (1 mL) were used to suspend compound A38 (430 mg, 1.72 mmol, 1.00 equivalent), compound A31 (CAS number: 89787-12-2, 527 mg, 3.21 mmol, 1.87 equivalents), and K3PO4 (731 mg, 3.44 mmol, 2.00 equivalents) in a degassed suspension. Pd A-taPhos (152 mg, 0.21 mmol, 0.12 equivalents) was added to the suspension. The reaction mixture was stirred at 110°C for 3 hours. LCMS showed that the starting materials were completely consumed. Saturated aqueous NH4Cl solution (100 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (60 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography to obtain compound A39 (499 mg, 1.50 mmol, yield 86.9%). MS(ESI)m / z=334.0[M+H] + .

[0218] Scheme 17 [ka] 5-amino-6-(2-isopropylphenyl)-2-methylpyridazin-3-one (A40):MeOH (14 mL) was used to dissolve compound A39 (490 mg, 1.47 mmol, 1.00 equivalent). Pd(OH)2 (420 mg, 20% purity, 0.40 equivalent) was added to this solution. The mixture was stirred at 50°C for 16 hours under an H2 atmosphere. LC-MS showed that the starting material was completely consumed. The reaction mixture was filtered through Celite® and then washed with siRNA (100 mL x 2). The filtrate was evaporated under reduced pressure to obtain compound A40 (3.72 g, 1.53 mmol, quantitative). MS(ESI)m / z = 244.0[M+H] + .

[0219] Scheme 18 [ka] To a solution prepared by dissolving compound A19 (2.6 g, 9.9 mmol, 1.00 equivalent) and K2CO3 (3.4 g, 25 mmol, 2.50 equivalents) in 5-(benzylamino)-6-chloro-2-(2-hydroxy-2-methylpropyl)pyridazin-3-one (A42):NMP (20 mL), isobutylene oxide (A41) (CAS number: 558-30-5, 1.4 g, 20 mmol, 2.00 equivalent) was added. The mixture was stirred at 60°C for 4 hours. LC-MS showed that compound A19 was completely consumed. The reaction mixture was quenched with saturated NH4Cl aqueous solution (150 mL). The resulting mixture was extracted with ELISA (30 mL x 3). The combined organic layers were washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain compound A42 (3.16 mg, 10.3 mmol, 100% yield). MS(ESI)m / z=308.7[M+H] +

[0220] Scheme 19 [ka] 5-(benzylamino)-2-(2-hydroxy-2-methylpropyl)-6-(2-isopropylphenyl)pyridazin-3-one (A43):1,4-dioxane (15 mL) and H2O (2 mL) were used to suspend compound A42 (1.26 g, 4.09 mmol, 1.00 equivalent), compound A31 (CAS number: 89787-12-2, 2.02 g, 12.3 mmol, 3.00 equivalent), and K3PO4 (2.61 g, 12.3 mmol, 3.00 equivalent) in a degassed suspension. Pd A-taPhos (580 mg, 0.82 mmol, 0.20 equivalent) was added to the suspension. The reaction mixture was stirred at 95°C for 16 hours. LCMS showed that the starting materials were completely consumed. NH4Cl aqueous solution (100 mL) was added to the reaction mixture. The mixture was extracted with dimethyl phosphate (60 mL x 3). The combined organic layers were washed with brine and dried over Na₂SO₄. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography to obtain compound A43 (1.44 g, 3.68 mmol, yield 89.9%). MS(ESI) m / z = 392.2 [M + H] + .

[0221] Scheme 20 [ka] 5-amino-2-(2-hydroxy-2-methylpropyl)-6-(2-isopropylphenyl)pyridazin-3-one (A44): Compound A43 (1.44 g, 3.68 mmol, 1.00 equivalent) was dissolved in MeOH (20 mL), to which Pd(OH)2 (3.0 g, 20% purity, 1.16 equivalents) was added. The mixture was stirred at room temperature under an H2 atmosphere for 4 hours. LC-MS showed that the starting material was completely consumed. The reaction mixture was filtered through Celite® and then washed with siRNA (100 mL x 2). The filtrate was evaporated under reduced pressure to obtain compound A44 (1.03 g, 3.42 mmol, 92.9% yield). MS(ESI)m / z=302.1[M+H] + .

[0222] Scheme 21 [ka] 2-Fluoro-6-methoxy-3-(trifluoromethyl)benzaldehyde (AB199-4): A solution of 2-fluoro-4-methoxy-1-(trifluoromethyl)benzene (AB199-3) (CAS number: 1214344-33-8, 1.5 g, 7.73 mmol) was dissolved in THF (15 mL), to which lithium diisopropylamine (LDA) (4.64 mL, 9.27 mmol) was added under nitrogen at -70°C. The reaction mixture was stirred at -70°C for 1 hour, and then DMF (1.4 mL, 18.2 mmol) was added to the reaction mixture. After the addition, the reaction mixture was stirred at -70°C for 1 hour. TLC (PE / siRNA=3 / 1) showed the observation of new spots (Rf=0.3). The reaction mixture was poured into saturated NH4Cl aqueous solution (10 mL) and extracted with siRNA (20 mL x 4). The combined organic layers were washed with brine (20 mL x 2), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain compound AB199-4 (1.78 g, 8.01 mmol, quantitative yield).

[0223] Scheme 22 [ka] 2-Fluoro-6-methoxy-3-(trifluoromethyl)benzoic acid (AB199): Compound AB199-4 (2.86 g, 12.9 mmol) was dissolved in tert-butanol (15 mL) and THF (15 mL), to which 2-Me-2-butene (27.3 mL, 258 mmol) was added. Then, a solution of NaClO2 (11.64 g, 128.8 mmol) and NaH2PO4 (12.97 g, 93.99 mmol) dissolved in water (30 mL) was added at 0°C. The mixture was stirred at 20°C for 3 hours. TLC (PE / siRNA=3 / 1) showed the observation of new spots (Rf=0). The reaction mixture was concentrated, then poured into water (20 mL), acidified with 6N HCl aqueous solution to pH=1, and extracted with siRNA (40 mL × 4). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to obtain a yellow oily substance. The residue was purified by normal-phase column chromatography (gradient: 0-50% PE / Âi) to obtain compound AB199 (1.94 g, 8.15 mmol, yield 63%). H NMR(400MHz,CHLOROFORM-d)δ=7.66(t,1H),6.84(d,1H),3.70(s,3H).

[0224] Scheme 22-1 [ka] 1-(tert-butyl)-4-fluorobenzene (AB184-2): 1-fluoro-4-(trifluoromethyl)benzene (AB184-1) (CAS number: 402-44-8, 0.080 mL, 0.61 mmol) was dissolved in dichloroethane (3 mL), and AlMe3 (1.52 mL, 3.05 mmol) was added at 25 °C. The mixture was stirred at 50 °C for 16 hours. The reaction mixture was poured into 1 N HCl (4 mL) and extracted with DCM (10 mL × 4). The combined organic layers were washed with saturated NaCl aqueous solution (10 mL × 2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product was purified by flash column (PE) to obtain AB184-2 (30 mg, 0.20 mmol, yield 32%) as a white oil.

[0225] Scheme 23 [ka] 5-Chloro-2-methoxy-N-{1-methyl-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}benzamide (Compound 1): Compound 1 was prepared by a method similar to Scheme 7, and the reaction was carried out using 5-amino-2-methyl-6-(2-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (A45) and 5-chloro-2-methoxybenzoic acid (A46) (CAS number: 3438-16-2). Here, Compound A45 was prepared by a method similar to Scheme 16 → Scheme 17, and the reaction was carried out using the corresponding boronic acid compound instead of Compound A31.

[0226] Scheme 24 [ka] 5-Chloro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxybenzamide (compound 6): Compound 6 was prepared by a method similar to that of Scheme 7.

[0227] Scheme 25 [ka] 5-Chloro-N-{1-(2-hydroxy-2-methylpropyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxybenzamide (compound 14): Compound 14 was prepared by a method similar to Scheme 7. Here, 5-amino-2-(2-hydroxy-2-methylpropyl)-6-(2-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (A47) was prepared by a method similar to Scheme 19 → Scheme 20, where the reaction was carried out using the corresponding boronic acid compound instead of compound A31.

[0228] Scheme 26 [ka] 5-Chloro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxybenzamide (compound 35): Compound 35 was prepared by a method similar to Scheme 7 → Scheme 8.

[0229] Scheme 27 [ka] 2-Fluoro-N-{1-(2-hydroxy-2-methylpropyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide (compound 47): Compound 47 was prepared by a method similar to that of Scheme 7, and the reaction therein was carried out using compound A47 and compound A27 (CAS number: 115029-23-7).

[0230] Scheme 28 [ka] 2-Fluoro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide (compound 60): Compound 60 was prepared by a method similar to Scheme 7 → Scheme 8, and the reaction here was carried out using compound A26 and 2-fluoro-5-(trifluoromethoxy)benzoic acid (A48) (CAS number: 115029-23-7).

[0231] Scheme 29 [ka] 5-Chloro-2-methoxy-N-{1-(2-methoxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}benzamide (compound 63): Compound 63 was prepared by a method similar to Scheme 7. Here, 5-amino-2-(2-methoxyethyl)-6-(2-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (A49) was prepared by a method similar to Scheme 2 → Scheme 3 → Scheme 6, and the reaction here was carried out using the corresponding alkylating reagent instead of compound A20.

[0232] Scheme 30 [ka] 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide (compound 66): Compound 66 was prepared by a method similar to Scheme 7. Here, (S)-5-amino-2-(2-hydroxypropyl)-6-(2-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (A50) was prepared by a method similar to Scheme 2 → Scheme 3 → Scheme 6, where the reaction was carried out using the corresponding alkylating reagent instead of compound A20.

[0233] Scheme 31 [ka] 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide (compound 67): Compound 67 was prepared by a method similar to Scheme 7. Here, (R)-5-amino-2-(2-hydroxypropyl)-6-(2-(trifluoromethyl)phenyl)pyridazin-3(2H)-one (A51) was prepared by a method similar to Scheme 2 → Scheme 3 → Scheme 6, where the reaction was carried out using the corresponding alkylating reagent instead of compound A20.

[0234] Scheme 32 [ka] N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxy-5-(trifluoromethyl)benzamide (compound 68): Compound 68 was prepared by a method similar to Scheme 7 → Scheme 8, and the reaction here was carried out using compound A26 and 2-methoxy-5-(trifluoromethyl)benzoic acid (A52) (CAS number: 4864-01-1).

[0235] Scheme 33 [ka] 5-(difluoromethyl)-2-fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide (compound 70): Compound 70 was prepared by a method similar to that of Scheme 7, and the reaction therein was carried out using compound A40 and 5-(difluoromethyl)-2-fluorobenzoic acid (A53) (CAS number: 1429421-95-3).

[0236] Scheme 34 [ka] 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethoxy)benzamide (compound 72): Compound 72 was prepared by a method similar to that of Scheme 7, and the reaction therein was carried out using A40 and compound A48 (CAS number: 115029-23-7).

[0237] Scheme 35 [ka] 5-(difluoromethoxy)-2-fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide (compound 74): Compound 74 was prepared by a method similar to that of Scheme 7, and the reaction therein was carried out using compound A40 and 5-(difluoromethoxy)-2-fluorobenzoic acid (A54) (CAS number: 1214383-11-5).

[0238] Scheme 36 [ka] 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethyl)benzamide (compound 78): Compound 78 was prepared by a method similar to that of Scheme 7.

[0239] Scheme 37 [ka] Compound 82 was prepared by a method similar to that of Scheme 7.

[0240] Scheme 38 [ka] 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-6-methoxy-3-(trifluoromethyl)benzamide (compound 83): Compound 83 was prepared by a method similar to that of Scheme 7.

[0241] Scheme 39 [ka] N-[3-(2-isopropylphenyl)-1-(2-methoxyethyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxy-5-(trifluoromethyl)benzamide (compound 85): Compound 85 was prepared by a method similar to Scheme 7. Here, 5-amino-6-(2-isopropylphenyl)-2-(2-methoxyethyl)pyridazin-3(2H)-one (A55) was prepared by a method similar to Scheme 18 → Scheme 19 → Scheme 20, where the reaction was carried out using the corresponding alkylating reagent instead of compound A41.

[0242] Scheme 40 [ka] 5-(difluoromethoxy)-2-fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide (compound 86): Compound 86 was prepared by a method similar to that of Scheme 7.

[0243] Scheme 41 [ka] N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxy-5-(trifluoromethyl)benzamide (compound 87): Compound 87 was prepared by a method similar to that of Scheme 7.

[0244] Scheme 42 [ka] 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethyl)benzamide (compound 89): Compound 89 was prepared by a method similar to that of Scheme 7.

[0245] Scheme 43 [ka] 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-6-methoxy-3-(trifluoromethyl)benzamide (compound 90): Compound 90 was prepared by a method similar to that of Scheme 7.

[0246] Scheme 44 [ka] 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide (compound 93): Compound 93 was prepared by a method similar to Scheme 7. Here, (R)-5-amino-2-(2-hydroxypropyl)-6-(2-isopropylphenyl)pyridazin-3(2H)-one (A56) was prepared by a method similar to Scheme 18 → Scheme 19 → Scheme 20, and the reaction was carried out using the corresponding alkylating reagent instead of compound A41.

[0247] Scheme 45 [ka] 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide (compound 94): Compound 94 was prepared by a method similar to that of Scheme 7.

[0248] Scheme 46 [ka] 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide (compound 95): Compound 95 was prepared by a method similar to Scheme 7. Here, (S)-5-amino-2-(2-hydroxypropyl)-6-(2-isopropylphenyl)pyridazin-3(2H)-one (A57) was prepared by a method similar to Scheme 18 → Scheme 19 → Scheme 20, and the reaction was carried out using the corresponding alkylating reagent instead of compound A41.

[0249] Scheme 47 [ka] 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide (compound 96): Compound 96 was prepared by a method similar to that of Scheme 7.

[0250] Scheme 48 [ka] N-[1-(2-aminoethyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-5-chloro-2-methoxybenzamide (compound 23): A102 was synthesized by amide formation using compounds A32 and A46 in a manner similar to Scheme 7. To a solution of compound A102 (28 mg, 0.070 mmol, 1.00 equivalent) and K2CO3 (29.1 mg, 0.211 mmol, 3.00 equivalent) dissolved in NMP (2 mL), tert-butyl N-(2-bromoethyl)carbamate (A103) (CAS number: 39684-80-5, 31.5 mg, 0.140 mmol, 2.00 equivalent) was added. The mixture was stirred at 60°C for 1 hour. LCMS showed that compound A102 was completely consumed. H2O (10 mL) was added to the reaction mixture, and the mixture was extracted with RINKAN (20 mL × 2). The organic phase was washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure. To the RINKAN (2 mL) solution of the obtained residue, 4 M HCl (2 mL) in RINKAN was added. The mixture was stirred at room temperature for 1 hour, and then evaporated under reduced pressure. The residue was purified by reversed-phase column chromatography (gradient: 50-88% MeCN in H2O containing 0.225% FA) to obtain the desired compound 23 (19.6 mg, yield 63%).

[0251] Scheme 49 [ka] 2-Fluoro-N-(1-(2-hydroxyethyl-2-d)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide (compound 99):DCM (8 mL) was dissolved in compound 59 (95 mg, 0.194 mmol, 1.00 equivalent), to which des-martin periodinane (CAS number: 87413-09-0, 165 mg, 0.388 mmol, 2.00 equivalent) was added. The mixture was stirred overnight at room temperature. LC-MS showed that compound 59 was completely consumed. Saturated aqueous NaHCO3 (10 mL) was added to the reaction mixture, and the mixture was extracted with siRNA (20 mL x 2). The combined organic layers were washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure. To the obtained residue in a THF (10 mL) solution, NaBD4 (CAS number: 15681-89-7, 40.6 mg, 0.971 mmol, 5.00 equivalents) was added. The mixture was stirred at room temperature. After 20 minutes, saturated NaHCO3 aqueous solution (10 mL) was added to the reaction mixture. The mixture was extracted with ethyl acetate (20 mL x 2). The combined organic layers were washed with brine and dried over Na2SO4. The filtrate was evaporated under reduced pressure. The residue was purified by reversed-phase column chromatography (gradient: 5-95% MeCN in H2O containing 0.1% TFA) to obtain the desired compound 99 (30 mg, 31% yield in 2 steps).

[0252] Scheme 50 [ka] 5-(benzylamino)-6-chloro-2-(2-hydroxyethyl-1,1,2,2-d4)pyridazine-3(2H)-one (compound A205): Compound A19 (3.9 g, 16.5 mmol, 1.00 equivalent) and 1,1,2,2-tetraduterioethane-1,2-diol (A204) (CAS number: 2219-51-4, 2.2 g, 33.0 mmol, 2.00 equivalent) were suspended in toluene (50 mL). Cyanomethylenetributylphosphorane (CMBP, CAS number: 157141-27-0, 5.0 g, 21.0 mmol, 1.20 equivalent) was added to the suspension. The mixture was stirred at 60°C for 4 hours. LC-MS showed that compound A19 was completely consumed. The reaction mixture was evaporated under reduced pressure. The residue was purified by normal-phase column chromatography (gradient: 10-100% hexane / siRNA, followed by 5% MeOH / siRNA) to obtain compound A205 (1.30 g, 4.60 mmol, yield 28%). MS(ESI) m / z = 284.2 [M+H] + .

[0253] Scheme 51 [ka] 2-Fluoro-N-(1-(2-hydroxyethyl-2,2-d2)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide (compound 97): Compound 97 was prepared using A206 instead of A26 in a manner similar to Scheme 7 → Scheme 8. Here, 2-(4-amino-6-oxo-3-(2-(trifluoromethyl)phenyl)pyridazin-1(6H)-yl)ethyl-1,1-d2 acetate (A206) ​​was prepared in a manner similar to Scheme 4 → Scheme 5 → Scheme 6, where the reaction was carried out using NaBD4 instead of NaBH4.

[0254] Scheme 52 [ka] 2-Fluoro-N-(1-(2-hydroxyethyl-2,2-d2)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethoxy)benzamide (compound 98): Compound 98 was prepared using A206 instead of A26 in a manner similar to Scheme 28.

[0255] Scheme 53 [ka] 2-Fluoro-N-(1-(2-hydroxyethyl-1,1,2,2-d4)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide (compound 100): Compound 100 was prepared using A207 instead of A26 in a manner similar to Scheme 7 → Scheme 8. Here, 5-amino-2-(2-hydroxyethyl-1,1,2,2-d4)-6-[2-(trifluoromethyl)phenyl]pyridazin-3(2H)-one (A207) was prepared using a manner similar to Scheme 3 → Scheme 6, where the reaction was carried out using A205 instead of A21.

[0256] Table 1 shows the synthesis of compounds not described in Schemes 1-53. [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] [Table 1-10] [Table 1-11] [Table 1-12]

[0257] Table 2 shows the above LCMS and 1 The data measured under 1H NMR conditions is shown. Unless otherwise specified, LCMS analysis is performed using the reversed-phase LCMS(1) method. 1 1H NMR was obtained by the method described above. The compounds shown in Table 2 were prepared in the same manner using appropriate starting materials, and our TREK-1 thallium (Tl + The compounds were evaluated by flux assay. Unless otherwise specified, the data were measured by Method 1 of the TREK-1 thallium flux assay described below. Each compound in this disclosure was found to have significant inhibitory activity against TREK-1, TREK-2, or both TREK-1 and TREK-2.

[0258] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 2-6] [Table 2-7] [Table 2-8] [Table 2-9] [Table 2-10] [Table 2-11] [Table 2-12] [Table 2-13] [Table 2-14] [Table 2-15] [Table 2-16] [Table 2-17] [Table 2-18]

[0259] Example 1: In vitro activity of TREK-1 and TREK-2 inhibitors The measurement conditions for TREK-1 and TREK-2 inhibitor activity are as follows: Thallium flux assay using TREK-1 Method 1; CHO-K1 cells stably expressing hTREK-1 were cultured in T225 flasks. The cells were loaded with FluxOR dye and seeded into 384-well plates on the experimental day. The test compound or control compound (tert-butyl(3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4-chlorophenyl)carbamate) or 0.3% DMSO (vehicle control) was directly added to the cell plates, incubated for 10 minutes, and then treated with thallium-stimulating buffer to initiate thallium flux. To measure the efficacy and potency of the test compound, the change in fluorescence intensity (ΔRatio) and inhibition percentage were calculated using the following formula: ΔRatio = (Fluorescence intensity 25 seconds after thallium addition) / (Average fluorescence intensity before thallium addition) Inhibition % = {1 - (ΔRatio of test compound - ΔRatio of 10 μM control compound) / (ΔRatio of 0.3% DMSO - ΔRatio of 10 μM control compound)} × 100 The inhibition percentage against compound concentration was plotted on XLfit, and IC 50 I calculated it.

[0260] Method 2; CHO-K1 cells stably expressing human TREK-1 (hTREK-1) were cultured in T225 flasks. The cells were loaded with FluxOR dye and seeded into 384-well plates on the experimental day. The test compound or control compound (tert-butyl(3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4-chlorophenyl)carbamate) or 0.3% DMSO (vehicle control), prepared on a separate plate, was added to the cell plate and incubated for 10 minutes. Then, cells containing the test compound or control compound (tert-butyl(3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4-chlorophenyl)carbamate) or 0.3% DMSO (vehicle control) were treated with thallium-stimulating buffer to initiate thallium flux. To measure the efficacy and potency of the test compound, the change in fluorescence intensity (ΔRatio) and inhibition % were calculated using the following formula: ΔRatio = (Fluorescence intensity 25 seconds after thallium addition) / (Average fluorescence intensity before thallium addition) Inhibition % = {1 - (ΔRatio of test compound - ΔRatio of 10 μM control compound) / (ΔRatio of 0.3% DMSO - ΔRatio of 10 μM control compound)} × 100 The inhibition percentage against compound concentration was plotted on XLfit, and IC 50 I calculated it. Each compound disclosed herein was found to possess significant TREK-1 inhibitory activity.

[0261] Thallium flux assay using TREK-2 HEK293 cells stably expressing human TREK-2 (hTREK-2) were seeded in 384-well plates, cultured overnight, and Thallos dye was added the following day. The test compound or control compound (tert-butyl(3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4-chlorophenyl)carbamate) or 0.3% DMSO (vehicle control), prepared on separate plates, was added to the cell plates, incubated for 10 minutes, and then the cells were treated with thallium-stimulating buffer to initiate thallium flux. To measure the efficacy and potency of the test compound, the change in fluorescence intensity (ΔRatio) and inhibition percentage were calculated using the following formula: ΔRatio = (Fluorescence intensity 25 seconds after thallium addition) / (Average fluorescence intensity before thallium addition) Inhibition % = {1 - (ΔRatio of test compound - ΔRatio of 10 μM control compound) / (ΔRatio of 0.3% DMSO - ΔRatio of 10 μM control compound)} × 100

[0262] Patch Clamp Method hTREK-1 and mTREK-1 Patch Clamp Assay CHO-K1 cells stably expressing hTREK-1 or CHO-K1 cells transiently expressing mouse TREK-1 (mTREK-1) were plated onto coverslips and voltage-clamped in a patch-clamp configuration. Cells were voltage-clamped at a holding potential of -80mV and stepped down to 0mV over 500 milliseconds. The voltage was then increased from -120mV to +80mV over a duration of 500 milliseconds. This step-ramp protocol was repeated every 10 seconds. The bath solution contained: 135mM NaCl, 5mM KCl, 2mM CaCl2, 1mM MgCl2, 5mM D-glucose, 10mM HEPES, and 10mM sucrose (adjusted to pH 7.4 with NaOH, 300 mosmol / kg H2O). The pipette solution contained: 135 mM KCl, 2 mM MgCl2, 1 mM EGTA, 10 mM HEPES, and 2 mM Na2ATP (adjusted to pH 7.35 with KOH, 285 mosmol / kg H2O). The test compound was dissolved in the bath solution. The effect of the test compound on the current was calculated at 0 mV using the following formula: Inhibition % = (1 - current after / current before) × 100 The inhibition percentage versus compound concentration was plotted in GraphPad Prism, and IC 50 I calculated it. Each compound disclosed herein was found to possess significant TREK-1 inhibitory activity.

[0263] hTREK-2 Patch Clamp Assay Human TREK-2 stably expressing HEK293 cells were seeded on coverslips and voltage-clamped with the full cell composition using a patch-clamp method. The cells were voltage-clamped at a holding potential of -80mV and stepped down to 0mV over 500 milliseconds. The voltage was then increased from -120mV to +80mV over a duration of 500 milliseconds. This step-ramp protocol was repeated every 10 seconds. The bath solution contained: 135mM NaCl, 5mM KCl, 2mM CaCl2, 1mM MgCl2, 5mM D-glucose, 10mM HEPES, and 10mM sucrose (adjusted to pH 7.4 with NaOH, 300mosmol / kg H2O). The pipette solution contained: 135 mM KCl, 2 mM MgCl2, 1 mM EGTA, 10 mM HEPES, and 2 mM Na2ATP (adjusted to pH 7.35 with KOH, 285 mosmol / kg H2O). The test compound was dissolved in the bath solution. The experiment was completed by adding the control compound (tert-butyl(3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4-chlorophenyl)carbamate) so that the maximum inhibition could be determined. The effect of the test compound on the current can be calculated at 0 mV using the following formula. Inhibition % = {1 - (current in the presence of a control compound with a post-current of -10 μM) / (current in the presence of a control compound with a pre-current of -10 μM)} × 100.

[0264] In some embodiments, the compounds of the present disclosure inhibited the TREK-1 channel response in the form of a decrease in thallium fluorescence in a thallium flux assay, or in the form of a decrease in current measured at 0 mV in a patch-clamp electrophysiological assay. The compounds of this disclosure may inhibit TREK-1 and / or TREK-2 via an inhibitory mechanism or via an allosteric regulatory mechanism. The compounds shown in Table 2 were prepared in the same manner using appropriate starting materials, and the inventors' TREK-1 thallium (Tl + The results were evaluated by a flux assay. Unless otherwise specified, the data were measured using Method 1 of the TREK-1 thallium flux assay described above.

[0265] Example 2. In vivo pharmacological study Compulsory swimming test Drug: The test compound was prepared in a 10% Tween 80 / 90% sterile water vehicle. After vigorously vortexing, the prepared compound was placed in an ultrasonic water bath for 1 hour. The test compound was prepared to a concentration suitable for oral administration (PO) at a dose of 10 mL / kg body weight. Animals: Six-week-old adult male BALB / cCrSlc mice (Japanese SLC) were used. They were housed in an animal care facility certified by the Japan Health Science Foundation, under a 12-hour light / dark cycle (lights on: 7am, lights off: 7pm), with free access to food and water. The animals were allowed to acclimate to the facility for at least six days prior to the experiment, and behavioral tests were conducted during the light period. All experiments were approved by the Animal Management and Use Committee of Ono Pharmaceutical Co., Ltd. Apparatus: For the forced swimming test, a transparent plastic cylinder (10 cm in diameter x 25 cm in height) filled with 10 cm of water heated to 24 ± 2°C was used. Procedure: Plastic animal cages (29cm x 44cm x 20cm, 8 animals each) were moved from the animal facility to a soundproof room on the morning of the test. After a 5-hour acclimatization period, the vehicle solution or test compound was administered orally 1 hour before the forced swimming procedure. Imipramine (60 mg / kg, orally) was administered as a positive control. Behavioral analysis: The total immobility time inside the cylinder was recorded for 6 minutes using a video camera and used as an indicator of antidepressant-like behavior. Data Analysis: Statistical analysis was performed using EXSUS ver 8.1 (CAC Croit Corporation). The total immobility time of the vehicle solution group and the compound group was analyzed. The vehicle treatment group and the compound treatment group were analyzed by one-way ANOVA, followed by Dunnett's test. The vehicle treatment group and the imipramine treatment group were analyzed by Student's t-test. A p-value of ≤0.05 was considered statistically significant. Results: Compounds 6, 14, 35, 59, and 73 at 10 mg / kg significantly reduced immobility time. The data are shown in Figure 1. Conclusion: Systemic administration of compounds 6, 14, 35, 59, and 73 induced a reduction in immobility time in the forced swimming test, a preclinical rodent model of depressive-like behavior.

[0266] MK-801-induced novel object recognition test: Drug: The test compound was prepared in a 20% Kolliphor HS 15 / propylene glycol (7:3) / 80% sterile water vehicle. After vigorously vortexing, the prepared compound was placed in an ultrasonic water bath for 1 hour. The compound was prepared to a concentration suitable for oral administration (po) at a dose of 10 mL / kg body weight. MK-801 bicarbonate maleate was obtained from Sigma-Aldrich, dissolved in sterile physiological saline, and administered intraperitoneally at a dose of 1 mL / kg body weight (0.2 mg / kg). Animals: Six-week-old adult male C57BL / 6J mice (Charles River Japan) were used. They were housed in an animal care facility certified by the Japan Health Science Foundation, under a 12-hour light / dark cycle (lights on: 7am, lights off: 7pm), with free access to food and water. The animals were allowed to acclimate to the housing facility for a minimum of six days prior to the experiment, and behavioral tests were conducted during the light period. All experiments were approved by the Animal Management and Use Committee of Ono Pharmaceutical Co., Ltd. Apparatus: An opaque plastic chamber (35cm x 40cm x 18cm) was used for a novel object recognition test. The test subjects could be placed at both ends of the chamber. A video camera was mounted above the apparatus to record the actions. Procedure: At least one day prior to the habituation behavior test, the animals were acclimatized for 10 minutes in an empty test chamber, i.e., in the absence of any objects. One hour after administering the training vehicle, the animals were administered either the compound (po) or clozapine (1 mg / kg, orally). Thirty minutes after administering saline or MK-801, the animals were placed in a test chamber containing two identical objects (LEGO® blocks) for a 10-minute session. The animals were then returned to their home cages. Ninety minutes after the recognition training session ended, the animals were reintroduced into a test chamber where one of two identical objects had been replaced with a new object (a glass vial). Behavioral analysis: Observers, unaware of the treatment conditions and the location of the new objects, scored the interaction between the animals and the two objects offline using video recordings. The duration the animals explored each object was determined as the total time the animals were facing the object with their noses at a distance of 2 cm or less and exhibiting some recognizable whisker movement. From this data, the discrimination index was calculated as follows. Discrimination index = 100 × (Time to search for new objects - Time to search for known objects) / (Time to search for new objects + Time to search for known objects) Data Analysis: Statistical analysis can be performed using EXSUS ver 8.1 (CAC Croit Corporation). The vehicle treatment group and the compound treatment group were analyzed by one-way ANOVA, followed by Dunnett's test. The vehicle and vehicle-MK-801, and the vehicle-MK-801 and clozapine groups can be analyzed by Student's t-test. A p-value of ≤0.05 is considered statistically significant. Results: Compound 59 at 3 mg / kg significantly reduced the discrimination index. The data are shown in Figure 2. Conclusion: Systemic administration of compound 59 resulted in improvement in the MK-801-induced novel object recognition test, a preclinical rodent model of cognitive impairment behavior.

[0267] Novel Restricted Feeding Trial Drug: The test compound was prepared in a 20% Kolliphor HS 15 / propylene glycol (7:3) / 80% sterile water vehicle. After vigorously vortexing, the prepared compound was placed in an ultrasonic water bath for 1 hour. The compound was prepared to a concentration suitable for oral administration (po) at a dose of 10 mL / kg body weight. Animals: Six-week-old adult male Slc:ICR mice (Slc Japan Co., Ltd.) were housed in an animal breeding facility certified by the Japan Health Science Promotion Foundation with a 12-hour light-dark cycle (lights on: 7:00 AM, lights off: 7:00 PM) and were acclimatized for at least six days prior to the experiment. The animals had free access to water and were fasted for only 24 hours prior to the experiment. All experiments were approved by the Animal Management and Use Committee of Ono Pharmaceutical Co., Ltd. Apparatus: For the novel suppression feeding test, an opaque plastic open field (60 cm in diameter) was used under 200 lux. A video camera was mounted above the apparatus to record the behavior. Procedure: Animals were transferred to the test facility and allowed to acclimate for 5 hours before the test. One hour after administration of the vehicle, the compound (po), or the positive control scopolamine (0.03 mg / kg, ip), the animals were placed in an open field with food pellets. Behavioral analysis: The latency to the onset of feeding behavior was recorded and used as an indicator of early-onset antidepressant-like behavior. The test was stopped immediately after the first feeding episode, with a cutoff time of 5 minutes. Data Analysis: Statistical analysis can be performed using EXSUS ver 8.1 (CAC Croit Corporation). The vehicle treatment group and the compound treatment group were analyzed by one-way ANOVA, followed by Dunnett's test. The vehicle and scopolamine treatment groups were analyzed by Student's t-test. A p-value ≤ 0.05 is considered statistically significant. Results and Conclusions: Systemic administration of the compounds disclosed herein resulted in improved latency in a novel inhibitory feeding study, a preclinical rodent model of depressive-like behavior.

[0268] The above-mentioned detailed description and accompanying examples are illustrative and should not be construed as limitations on the scope of this disclosure, and the scope of this disclosure is understood to be defined solely by the accompanying claims and their equivalents.

Claims

1. Compound of formula (I), 【Chemistry 1】 or a pharmaceutically acceptable salt thereof During the ceremony, Ring A is, 【Chemistry 2】 Alternatively, it may be an 8-10 membered bicyclic system substituted with 1-6 halogen atoms. R １ (1) hydrogen atom, (2) C1-8 alkyl, (3) C1-8 haloalkyl, (4) C2-8 alkenyl, (5) C2-8 haloalkenyl, (6) C2-8 alkynyl, (7) C2-8 haloalkynyl, and (8) 4-6 member saturated monocyclic heterocycle, where one or two carbon atoms in each of groups (2) to (7) are independently (1) NR ８ (2) may be replaced by an oxygen atom or (3) an oxidized sulfur atom, R １ Each of the groups (2) to (8) in the above has 1 to 6 R １－１ It may also be replaced with R １－１ is selected from the group consisting of (1) a deuterium atom, (2) a halogen atom, (3) a hydroxy group, (4) C1-4 alkyl, (5) C1-4 haloalkyl, (6) C1-4 alkoxy, (7) C1-4 haloalkoxy, (8) -CO-NR １－２ R １－３ , (9) -O-CO-R １－４ , (10) -SO ２ -R １－５ , (11) -S(=O)(=NR １－６ )-R １－７ , (12) -NR １－８ R １－９ , (13) cyano and (14) a 3- to 6-membered heterocyclic ring R １－１ If there are 2 to 6 of them, multiple R １－１ They may be the same or different from each other. R １－２ , R １－３ , R １－４ , R １－５ , R １－６ , R １－７ , R １－８ and R １－９ Each of these is independently selected from the group consisting of (1) a hydrogen atom, (2) C1-4 alkyl groups, and (3) C1-4 haloalkyl groups. R ２ (1) C1-4 alkyl or (2) C1-4 haloalkyl, R ３ (1) hydrogen atoms, (2) halogen atoms, (3) C1-4 alkyl groups, and (4) C1-4 haloalkyl groups are selected from the group consisting of these elements. R ３ If there are two or three, multiple R ３ They may be the same or different from each other. R ４ (1) halogen atoms, (2) C1-4 alkoxys, and (3) C1-4 haloalkoxys are selected from the group consisting of these elements. R ５ (1) hydrogen atoms, (2) halogen atoms, (3) C1-4 alkyl groups, (4) C1-4 haloalkyl groups, (5) C1-4 alkoxy groups, and (6) C1-4 haloalkoxy groups are selected from the group consisting of these elements. R ６ (1) is a hydrogen atom or (2) is a halogen atom, R ６ If there are two of them, multiple R ６ They may be the same or different from each other. R ７ (1) a hydrogen atom or (2) a C1-4 alkyl group, R ８ (1) a hydrogen atom or (2) a C1-4 alkyl group, R ９ (1) hydrogen atoms, (2) halogen atoms, (3) C1-4 alkyl groups, and (4) C1-4 haloalkyl groups are selected from the group consisting of these elements. R １０ (1) is a hydrogen atom or (2) is a halogen atom, X １ (1) CR ９ (2) N, X ２ (1) CR １０ (2) N, m is an integer between 1 and 3. A compound or a pharmaceutically acceptable salt thereof, where n is an integer of 1 or 2.

2. The compound according to claim 1, wherein formula (I-A): 【Transformation 3】 Compounds of (all symbols in the formula are as defined in claim 1), or a pharmaceutically acceptable salt thereof.

3. A compound according to claim 1 or claim 2, In the formula, ring A is 【Chemistry 4】 And, Other symbols are compounds as defined in claim 1. or a pharmaceutically acceptable salt thereof.

4. A compound according to any one of claims 1 to 3, wherein formula (I-B): 【Transformation 5】 Compounds of (all symbols in the formula are as defined in claim 1), or a pharmaceutically acceptable salt thereof.

5. A compound according to any one of claims 1 to 4, In the formula, R １ This includes 1 to 6 R １－１Ａ A C1-4 alkyl group which may be substituted with R １－１Ａ It is selected from the group consisting of (1) deuterium atom, (2) hydroxyl group, (3) methyl, (4) methoxy, (5) cyano and (6) oxetane, R １－１Ａ If there are 2 to 6 of them, multiple R １－１Ａ They may be the same or different from each other. Other symbols are compounds as defined in claim 1. or a pharmaceutically acceptable salt thereof.

6. The compound according to claim 1, (1) 5-chloro-2-methoxy-N-{1-methyl-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}benzamide, (2) 5-Chloro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxybenzamide, (3) 5-Chloro-N-{1-(2-hydroxy-2-methylpropyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxybenzamide, (4) 5-Chloro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxybenzamide, (5) 2-Fluoro-N-{1-(2-hydroxy-2-methylpropyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (6) 2-Fluoro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (7) 2-Fluoro-N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide, (8) 5-chloro-2-methoxy-N-{1-(2-methoxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}benzamide, (9) 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (10) 2-fluoro-N-{1-[(2R)-2-hydroxypropyl]-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (11) N-{1-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-1,6-dihydro-4-pyridazinyl}-2-methoxy-5-(trifluoromethyl)benzamide, (12) 5-(difluoromethyl)-2-fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide, (13) 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethoxy)benzamide, (14) 5-(difluoromethoxy)-2-fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide, (15) 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethyl)benzamide, (16) 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethoxy)benzamide, (17) 2-Fluoro-N-[3-(2-isopropylphenyl)-1-methyl-6-oxo-1,6-dihydro-4-pyridazinyl]-6-methoxy-3-(trifluoromethyl)benzamide, (18) N-[3-(2-isopropylphenyl)-1-(2-methoxyethyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxy-5-(trifluoromethyl)benzamide, (19) 5-(difluoromethoxy)-2-fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]benzamide, (20) N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-2-methoxy-5-(trifluoromethyl)benzamide, (21) 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-5-(trifluoromethyl)benzamide, (22) 2-Fluoro-N-[1-(2-hydroxy-2-methylpropyl)-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl]-6-methoxy-3-(trifluoromethyl)benzamide, (23) 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide, (24) 2-Fluoro-N-{1-[(2R)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (25) 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethoxy)benzamide, (26) 2-Fluoro-N-{1-[(2S)-2-hydroxypropyl]-3-(2-isopropylphenyl)-6-oxo-1,6-dihydro-4-pyridazinyl}-5-(trifluoromethyl)benzamide, (27) 2-Fluoro-N-(1-(2-hydroxyethyl-2,2-d ２ )-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide, (28) 2-Fluoro-N-(1-(2-hydroxyethyl-2,2-d ２ )-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethoxy)benzamide, (29) 2-Fluoro-N-(1-(2-hydroxyethyl-2-d)-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide or (30) 2-Fluoro-N-(1-(2-hydroxyethyl-1,1,2,2-d ４ )-6-oxo-3-(2-(trifluoromethyl)phenyl)-1,6-dihydropyridazin-4-yl)-5-(trifluoromethyl)benzamide, or a pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

8. The pharmaceutical composition according to claim 7, wherein the inhibitor is TREK-1, TREK-2, or both TREK-1 and TREK-2.

9. The pharmaceutical composition according to claim 7, which is a preventive and / or therapeutic agent for diseases related to dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2.

10. The pharmaceutical composition according to claim 9, wherein the disease associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2 is a neurological and / or psychiatric disorder.

11. The pharmaceutical composition according to claim 10, wherein the neurological and / or mental disorder is selected from the group consisting of depression, schizophrenia, anxiety disorder, bipolar disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, 22q11.2 deletion syndrome, neuropathic pain, or cerebral infarction.

12. A method for preventing and / or treating a disease associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2, comprising administering an effective amount of any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof to a mammal.

13. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of diseases associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2.

14. Use of a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof for the manufacture of a preventive and / or therapeutic agent for diseases associated with dysfunction of TREK-1, TREK-2, or both TREK-1 and TREK-2.

15. A compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof, (a) At least one drug known to reduce TREK-1 channel activity, (b) At least one drug known to reduce TREK-2 channel activity, (c) At least one agent known to prevent and / or treat a disease associated with TREK channel dysfunction, in which an inhibitor of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide a therapeutic benefit in mammals. (d) Instructions for the prevention and / or treatment of diseases associated with TREK channel dysfunction in which inhibitors of TREK-1, TREK-2, or both TREK-1 and TREK-2 would provide therapeutic benefits in mammals, and (e) A kit comprising one or more instructions for administering the compound in connection with cognitive behavioral therapy.

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