Inhibitors of TREK (TWIK related k+ channels) channel function

Abstract

Disclosed is a compound of formula (I): Also disclosed are pharmaceutical compositions comprising the compound, methods of making the compound, kits comprising the compound and method of 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 a mammal.

Description

[DESCRIPTION][Title of Invention]INHIBITORS OF TREK (TWIK RELATED K+CHANNELS) CHANNEL FUNCTION [Technical Field]

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

[0002] Potassium (K+) channels are membrane proteins that are expressed in virtually every cell of the organism. K+channel subunits (~80 genes) can be divided into three main structural classes comprising shaker type voltage-gated (Kv), inward rectifier (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). The 15 human K2P K+channels have been identified so far and classified into 6 structural subgroups: 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+channel) (Enyedi et al. Physiol. Rev. 2010, 90, 559). K2P K+channels are responsible for background or Teak’ K+currents. These channels are regulated by various physical and chemical stimuli, including membrane stretch, temperature, acidosis, lipids and inhalational anaesthetics. Furthermore,channel activity is tightly controlled by membrane receptor stimulation and second messenger phosphorylation pathways. Several members of this novel family of K+channels are highly expressed in the central and peripheral nervous systems in which they are proposed to play an important physiological role (TRENDS in Neurosci. 2001).

[0003] TREK-1, and TREK-2, which belong to TREK subgroup, are thermo- and mechanogated K+channel that is activated by lysophospholipids and PUFAs including arachidonic acid. They are regulated by G-protein-coupled receptors through PKA and PKC phosphorylation (Channels (Austin). 2011 Sep-Oct;5(5):402-9). TREK-1 gene is widely expressed in the Central Nervous System (CNS) with limited distribution in the periphery. In the CNS, TREK-1 expression is highest in the striatal tissues, the caudate and the putamen, as well as in spinal cord, foetal brain, amygdala and thalamus. In the periphery, TREK-1 expression is observed in heart, stomach and small intestine. TREK -2 gene has quite a similar expression profile compared to TREK-1 with high expression in particularly caudate, putamen and foetal brain. However, in contrast to TREK-1, TREK-2 is also highly expressed in cerebellum and corpus callosum as well as in several peripheral tissues, particularly kidney (Mol. Brain Res. 2001, 86, 101).

[0004] TREK-1 deficient mice display an 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 and results in a rapid onset of antidepressant efficacy (Br. J. Pharmacol. 2014, 172, 771). Moreover, antidepressants such as fluoxetine and paroxetine directly inhibit TREK channels (Nat. Neurosci. 2006, 9, 1134; Br. J. Pharmacol. 2005, 144, 821). Thus, inhibition of TREK-1 with a small molecule holds promise for the treatment of depression, as well as other mood disorders (Front. Pharmacol. 2018, 9,

[0005] Inhibition of TREK- 1 protects mice from cognitive impairment induced by anesthesia and, coupled with a high density in the hippocampus, TREK-1 is a potential therapeutic target against memory impairment induced by volatile anesthetics and in other CNS disorders with cognitive deficits (Neurobiology of Learning and Memory, 2017, 145, 199). TREK-1 gene expression is increased in hippocampus of patients with schizophrenia compared to healthy control (Neuropsychopharmacology 2010, 35, 239-57.). Intrathecal injection of microRNA targeting to TREK-1 ameliorates neuropathic pain induced by chronic constriction sciatic nerve injury (Neurochem Res. 2018, 43, 1143), suggesting that inhibition of TREK-1 may be efficacious in cognitive disorders and neuropathic pain. Knockdown of TREK-1 significantly inhibits prostatic cancer cell proliferation in vitro and in vivo, and induces a Gl / S cell cycle arrest (Cancer Res. 2008, 68, 1197-203., Oncotarget. 2015, 6, 18460-8.). TREK-1 is also overexpressed in human ovarian cancer tissues, and the treatment of TREK-1 inhibitors (curcumin and L-methionine) suppress ovarian cancer cell proliferation and increase late apoptosis (Clin. Transl. Oncol. 2013, 15, 910-8.). Thus, TREK-1 inhibitors can be useful for the treatment of prostatic and ovarian cancer. TREK-1 gene is also expressed in lung and TREK-1 knockdown leads to amelioration of bleomycin-induced lung fibrosis (Biomedicines. 2023, 11(5), 1279.), indicating that TREK-1 inhibitors can be useful for the treatment of lung fibrosis.

[0006] Neurotensin (NT) suppresses TREK-2 current through NT receptor 1 -mediated activation of PLC / PKC pathway in entorhinal cortex layer II stellate neurons, leading to depolarization of membrane potential and enhancement of neuronal excitability. Furthermore, NT -induced enhancement of spatial learning is diminished in TREK -2 KO mice, suggesting that TREK-2inhibitors may be useful for the treatment of cognitive impairment, such as Alzheimer's disease (J. Neurosci. 2014, 34, 7027-42.). TREK-2 is expressed in human bladder carcinoma cell in which TREK-2 contributes to the regulation of resting membrane potential. TREK-2 KD decreases the cell proliferation (Korean J. Physiol. Pharmacol. 2013, 17, 511-6.). Thus, TREK-2 inhibitors also may be efficacious in the treatment of bladder carcinoma.

[0007] Selective inhibition of TREK-1, by a small molecule inhibitor, has potential therapeutic benefit for: depression, schizophrenia, cognitive disorders including dementia, neuropathic pain, stroke, prostatic cancer, ovarian cancer and lung 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, by a small molecule inhibitor, has potential therapeutic benefit for: cognitive disorders including dementia, stroke and bladder carcinoma (J. Neurosci. 2014, 34, 7027, Biochem. Biophys. Res. Commun. 2005, 327, 1163, Korean J. Physiol. Pharmacol. 2013, 17, 511). The expression level of TREK -2 is increased in cortex and hippocampus of acute rat cerebral ischemia model (Biochem. Biophys. Res. Commun. 2005, 327, 1163-9.) Thus, TREK-2 inhibitors may be useful for the treatment of stroke.

[0009] All of the above mentioned disorders may also be effectively treated by a both TREK-1 and TREK-2 inhibitor with varying degrees of TREK-1 and TREK-2 preference.

[0010] The following compound is known to have a structure similar to the compounds in thisdisclosure.[Chem. 1](CAS No.:385798-10-7)

[0011] However, there is no statement or suggestion that the compounds in this disclosure have a prominent TREK-1, TREK-2 or both TREK-1 and TREK-2 inhibitory activity.[Summary of Invention][Technical Problem]

[0012] Despite advances in K2P K+channel research and TREK-l / TREK-2 pharmacology channel research, there is still a scarcity of compounds that are potent, efficacious, and selective inhibitors of the either TREK-1, TREK-2 or both TREK-1 and TREK-2, and also effective in the treatment of neurological, psychiatric, inflammatory, respiratory, renal and cardiovascular disorders, cancer or lung fibrosis associated with K2P K+channels, specifically TREK (TWIK Related K+channels) dysfunction for which inhibitors of TREK-1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit.[Solution to Problem]

[0013] In order to achieve the foregoing objects, the present inventors conducted intensive studies to find compounds having a TREK-1, TREK-2 or both TREK-1 and TREK-2 inhibitoryeffect, and found that a compound of formula (I) or formula (I- A) has a prominent TREK-1, TREK-2 or both TREK-1 and TREK-2 inhibitory activity.In the present specification, the definition of all symbols formula (I) applies to formula (I-A).

[0014] In one aspect, disclosed are a compound of formula (I),[Chem. 2]or a pharmaceutically acceptable salt thereof.In one aspect, disclosed are a compound of formula (I-A),[Chem. 3]or a pharmaceutically acceptable salt thereof.

[0015] Also disclosed are pharmaceutical compositions comprising the compound, methods of making the compound, kits comprising the compound, and methods of using the compound, compositions and kits for prevention and / or treatment of disorders, such as neurological and / or psychiatric disorders, associated with TREK-1, TREK-2 or both TREK-1 and TREK-2dysfunction for which inhibitors of TREK- 1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit in a mammal.[Brief Description of Drawings]

[0016] [Fig- 1]Fig. 1; Shows that the effect of Compound 1 in the mouse forced swim test. The vertical axis shows the immobility time, and the horizontal axis shows the group to which vehicle, Compound 1 or imipramine was administered. *p<0.05 compared to vehicle-treated group (Dunnetf s test), ###p<0.001 compared to vehicle-treated group (Student t-test). [Fig- 2]Fig. 2; Shows that the effect of Compound 1 in the mouse MK-801 -induced novel object recognition test. The vertical axis shows the discrimination index, and the horizontal axis shows the group to which vehicle, Compound 1 or clozapine followed by MK-801 induction, was administered. Mice treated with vehicle without MK-801 induction were tested as a control group. *p<0.05 compared to vehicle-treated group (Dunnetf s test), ##p<0.01 compared to vehicle-treated group (Student t-test), $p<0.05 compared to control group (Student t-test). [Description of Embodiments]

[0017] Disclosed herein are inhibitors of TREK-1, TREK-2 or both TREK-1 and TREK-2.That is, the disclosure relates to;[1] A compound of formula (I- A):[Chem. 4]or a pharmaceutically acceptable salt thereof; whereinR.1is (1) a hydrogen atom or (2) Cl-8 alkyl;2 1R is selected from the group consisting of (1) a halogen atom, (2) Cl-4 alkoxy and (3) Cl-4 haloalkoxy;R3is (1) Cl-4 alkyl or (2) Cl-4 haloalkyl;R4is (1) Cl-4 alkyl or (2) Cl-4 haloalkyl.[1-1] A compound of formula (I):[Chem. 5]or a pharmaceutically acceptable salt thereof; whereinR.1is (1) a hydrogen atom or (2) Cl-8 alkyl;2R is (1) a fluorine atom or (2) methoxy.[2] A pharmaceutical composition comprising a compound according to [1], or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.[3] The pharmaceutical composition according to [2], which is a TREK-1, TREK-2 or bothTREK-1 and TREK-2 inhibitor.Disclosed herein are inhibitors of the TREK (TWIK Related K+channels) - subtypes 1 and 2 (TREK-1 and TREK-2), methods of making the same, pharmaceutical compositions comprising the same, and methods of preventing and / or treating neurological, psychiatric, inflammatory, respiratory, renal and cardiovascular disorders associated with TREK channel dysfunction using the same.

[0018] DefinitionsUnless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In case of conflict, the present document, including definitions, will control. Preferred methods and materials are described below, although methods and materials similar or equivalent to those described herein can be used in practice or testing of the present disclosure. All publications, patent applications, patents and other references mentioned herein are incorporated by reference in their entirety. The materials, methods, and examples disclosed herein are illustrative only and not intended to be limiting.

[0019] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, 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 the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of’ and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0020] The modifier “about” used in connection with a quantity is inclusive of the stated value and has the meaning dictated by the context (for example, it includes at least the degree of error associated with the measurement of the particular quantity). The modifier “about” should also be considered as disclosing the range defined by the absolute values of the two endpoints. For example, the expression “from about 2 to about 4” also discloses the range “from 2 to 4.” The term “about” may refer to plus or minus 10% of the indicated number. For example, “about 10%” may indicate a range of 9% to 11%, and “about 1” may mean from 0.9-1.1. Other meanings of “about” may be apparent from the context, such as rounding off, so, for example “about 1” may also mean from 0.5 to 1.4.

[0021] Definitions of specific functional groups and chemical terms are described in more detail below. For purposes of this disclosure, the chemical elements are identified in accordance with the Periodic Table of the Elements, CAS version, Handbook of Chemistry and Physics, 75thEd., inside cover, and specific functional groups are generally defined as described therein. Additionally, general principles of organic chemistry, as well as specific functional moi eties and reactivity, are described in Organic Chemistry, Thomas Sorrell, University Science Books, Sausalito, 1999; Smith and March March's Advanced Organic Chemistry, 5thEdition, John Wiley & Sons, Inc., New York, 2001; Larock, Comprehensive Organic Transformations, VCH rd Publishers, Inc., New York, 1989; Carruthers, Some Modern Methods of Organic Synthesis, 3 Edition, Cambridge University Press, Cambridge, 1987; the entire contents of each of which are incorporated herein by reference.Examples of the “Cl -8 alkyl” as used herein 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.Examples of the “Cl -4 alkyl” as used herein include methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-butyl and isobutyl.Examples of the “Cl -4 alkoxy” as used herein include methoxy, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy and isobutoxy groups.Examples of the “Cl -4 haloalkyl” include fluoromethyl, chloromethyl, bromomethyl, iodomethyl, difluorom ethyl, 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 and the like.Examples of the “Cl -4 haloalkoxy” include trifluoromethoxy, tri chloromethoxy, chloromethoxy, bromomethoxy, fluoromethoxy, iodomethoxy, difluoromethoxy, dibromomethoxy, 2-chloroethoxy, 2,2,2-trifluoroethoxy, 2, 2, 2-tri chloroethoxy, 3 -bromopropoxy, 3 -chloropropoxy, 2,3 -dichloropropoxy and the like.For compounds described herein, groups and substituents thereof may be selected in accordance with permitted valence of the atoms and the substituents, such that the selections and substitutions result in a stable compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, and the like.

[0022] The term “inhibitor” as used herein refers to a molecular entity (e.g., but not limited to, a disclosed compound) that decreases or disappears the activity of the target receptor protein.The term “thallium flux assay” herein refers to a fluorescence-based assay used to monitor the activity of TREK channels. Thallium is a congener of potassium that readily fluxes through the pore of TREK channels. Thallium flux is measured using a commercially available, thallium-sensitive fluorescent dye called Thallos. The detail method is described below.The term “patch clamp technique” herein refers to the “gold standard” technique forevaluating TREK channel pharmacology. The detail method is described below.The term “forced swim test” herein refers to the experiment to evaluate in vivo efficacy in the depression-like model.The term “MK-801 -induced novel object recognition test” herein refers to the experiment to evaluate in vivo efficacy in the schizophrenic cognitive impairment animal model. The detail method is described below. MK-801 is also known as dizocilpine.The term “dysfunction” as used herein refers to any abnormal functions that induce activation or inhibition of the channel in an animal, in particular a mammal, for example a human.

[0023] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6-9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 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 contemplated.

[0024] CompoundsIn one aspect, disclosed is a compound of formula (I):[Chem. 6]or a pharmaceutically acceptable salt thereof.In one aspect, disclosed is a compound of formula (I-A):[Chem. 7]or a pharmaceutically acceptable salt thereof.R1is preferably a hydrogen atom or Cl-4 alkyl. More preferable R1is a hydrogen atom, methyl or ethyl. Most preferable1is a hydrogen atom.R is preferably a fluorine atom.2 1 2 1R is preferably a halogen atom or Cl-4 alkoxy. More preferable R is a fluorine atom or methoxy.3 3R is preferably Cl-4 haloalkyl. More preferable R is trifluorom ethyl.R^ is preferably Cl-4 haloalkyl. More preferable R^ is trifluoromethyl.The compound of the formula (I-A) is preferably such a compound that some or all the1 2 1 3 4 above-mentioned preferred examples for R , R , R and R are combined.The compound of the formula (I) is preferably such a compound that some or all the1 2 above-mentioned preferred examples for R and R are combined.In some embodiments, a disorder associated with TREK-1, TREK-2 or bothTREK-1 and TREK-2 dysfunction is preferably neurological and / or psychiatric disorder, cancer and / or lung fibrosis.

[0025] More preferable disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK-2 dysfunction is depression, schizophrenia, anxiety disorders, bipolar disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, 22ql l.2deletion syndrome, neuropathic pain and / or cerebral infarction.

[0026] Furthermore preferable disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK-2 dysfunction is depression, schizophrenia, anxiety disorders, and / or bipolar disorder.

[0027] Most preferable disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK- 2 dysfunction is depression and / or schizophrenia.

[0028] In some embodiments, schizophrenia is preferably cognitive impairment associated with schizophrenia (CIAS).

[0029] In some embodiments, the compounds have a prominent TREK-1, TREK-2 or both TREK-1 and TREK-2 inhibitory activity.

[0030] In some embodiments, the compounds may inhibit TREK-1 selectively. In some embodiments, the compounds may inhibit TREK -2 selectively. In some embodiments, the compounds may inhibit both TREK-1 and TREK-2 to varying degrees. The disclosed compounds may inhibit TREK-1 and / or TREK-2 via a competitive antagonist mechanism or through an allosteric, non-competitive mechanism.

[0031] The disclosed compounds may inhibit TREK-1 and / or TREK-2 response in TREK-1 or TREK-2 -transfected CHO-K1 cells with an IC50 less than, or equivalent to the IC50 for TREK-1 or TREK-2. That is, a disclosed compound can have selectivity for the TREK-1 vis-a-vis TREK- 2, a disclosed compound can have selectivity for the TREK -2 vis-a-vis TREK-1, or noselectivity. For example, in some embodiments, a disclosed compound can inhibit TREK-1 response with an IC50 of about 5-fold less, about 10-fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400- fold less, or greater than about 500-fold less than that for TREK-2. In some embodiments, a disclosed compound can inhibit TREK-2 response with an IC50 of about 5-fold less, about 10- fold less, about 20-fold less, about 30-fold less, about 50-fold less, about 100-fold less, about 200-fold less, about 300-fold less, about 400-fold less, or greater than about 500-fold less than that for TREK-1. In some embodiments, a disclosed compound can inhibit TREK-1 and TREK-2 responses with comparable IC50 values.

[0032] In the present disclosure, the isomer includes all of these isomers, unless otherwise specified. For example, each of an alkyl, a haloalkyl, an alkenyl, a haloalkenyl, an alkynyl, a haloalkynyl, an alkoxy and a haloalkoxy includes both of a linear form and a branched form thereof. In addition, an isomer in a double bond, a ring or a condensed ring (an E-, Z-, cis- or trans-form), an isomer due to the presence of an asymmetric carbon or the like (an R- or S-form, an a- or P-configuration, an enantiomer, a diastereomer), an optical isomer having an optical rotation (a D-, L-, d- or 1-form), a polar body obtained by chromatographic separation (a highly polar body, a poorly polar body), an equilibrium compound and a rotational isomer, and a mixture and a racemic mixture thereof at an arbitrary mixing ratio are also included within the scope of the present disclosure. In the present disclosure, the isomer includes all of tautomeric isomers.

[0033] The compound may exist as a stereoisomer wherein asymmetric or chiral centers are present. The stereoisomer is “7?” or “S” depending on the configuration of substituents aroundthe chiral carbon atom. The terms “7?” and “5” used herein are configurations as defined in IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, in Pure Appl. Chem., 1976, 45: 13-30. The disclosure contemplates various stereoisomers and mixtures thereof and these are specifically included within the scope of this disclosure. Stereoisomers include enantiomers and diastereomers, and mixtures of enantiomers or diastereomers. Individual stereoisomers of the compounds may be prepared synthetically from commercially available starting materials, which contain asymmetric or chiral centers or by preparation of racemic mixtures followed by methods of resolution well-known to those of ordinary skill in the art. These methods of resolution are exemplified by (1) attachment of a mixture of enantiomers to a chiral auxiliary, separation of the resulting mixture of diastereomers by recrystallization or chromatography and optional liberation of the 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, Essex CM20 2JE, England, or(2) direct separation of the mixture of optical enantiomers on chiral chromatographic columns, or(3) fractional recrystallization methods.

[0034] It should be understood that the compound may possess tautomeric forms, as well as geometric isomers, and that these also constitute embodiments of the disclosure.

[0035] The present disclosure also includes an isotopically-labeled compound, which is identical to those recited in formula (I) or formula (LA), but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes suitable for inclusion in the compounds of the disclosure are hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur,fluorine, and chlorine, such as, but not limited to2H,3H,18F, and36C1, respectively. Substitution with heavier isotopes can afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life or reduced dosage requirements and, hence, may be preferred in some circumstances. The compound may incorporate positron-emitting isotopes for medical imaging and positron-emitting tomography (PET) studies for determining the distribution of receptors. Suitable positronemitting isotopes that can be incorporated in compounds of formula (I) or formula (I- A) are ^C, 13 15 18N, O, and F. Isotopically-labeled compounds of formula (I) or formula (I-A) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically- labeled reagent in place of non-isotopically-labeled reagent.

[0036] Pharmaceutically Acceptable SaltsThe disclosed compounds may exist as pharmaceutically acceptable salts. The term “pharmaceutically acceptable salt” refers to salts or zwitterions of the compounds which are water or oil-soluble or dispersible, suitable for treatment of disorders without undue toxicity, irritation, and allergic response, commensurate with a reasonable benefit / risk ratio and effective for their intended use. The salts may be prepared during the final isolation and purification of the compounds or separately by reacting an amino group of the compounds with a suitable acid. For example, a compound may be dissolved in a suitable solvent, such as but not limited to methanol and water and treated with at least one equivalent of an acid, like hydrochloric acid. The resulting salt may precipitate out and be isolated by filtration and dried under reduced pressure. Alternatively, the solvent and excess acid may be removed under reduced pressure to provide a salt. Representative salts include acetate, adipate, alginate, citrate, aspartate, benzoate,benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerophosphate, hemisulfate, heptanoate, hexanoate, formate, isethionate, fumarate, lactate, maleate, methanesulfonate, naphthylenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3 -phenylpropionate, picrate, oxalate, maleate, pivalate, propionate, succinate, tartrate, trichloroacetate, trifluoroacetate, glutamate, para-toluenesulfonate, undecanoate, hydrochloric, hydrobromic, sulfuric, phosphoric and the like. The amino groups of the compounds may also be quaternized with alkyl chlorides, bromides and iodides such as methyl, ethyl, propyl, isopropyl, butyl, lauryl, myristyl, stearyl and the like.

[0037] Basic addition salts may be prepared during the final isolation and purification of the disclosed compounds by reaction of a phosphate and / or amide group with a suitable base such as the hydroxide, carbonate, or bicarbonate of a metal cation such as lithium, sodium, potassium, calcium, magnesium, or aluminum, or an organic primary, secondary, or tertiary amine. Quaternary amine salts can be prepared, such as those derived from methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, tributylamine, pyridine, A,A-dimethylaniline, A-methylpiperidine, A-methylmorpholine, dicyclohexylamine, procaine, dibenzylamine, A,A-dibenzylphenethylamine, 1 -ephenamine and A,A- dibenzylethylenediamine, ethylenediamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.

[0038] In the present disclosure, all the mentions of the compound of the present disclosure include a compound represented by formula (I) or formula (I- A), or a salt, a solvate, or a cocrystal thereof.The compound represented by formula (I) or formula (I-A) and a salt thereof may bepresent in a not-solvation form, or in a solvation form with pharmaceutically acceptable solvent such as water or ethanol. Preferable solvates include hydrate. The compound represented by formula (I) or formula (I- A) and a salt thereof can be converted into a solvate by a well-known method.

[0039] The compound represented by formula (I) or formula (I-A) can form a cocrystal with an appropriate cocrystal former. As the cocrystal, pharmaceutically acceptable cocrystal that is formed with a pharmaceutically acceptable cocrystal former is preferable. The cocrystal is typically defined as a crystal that is formed of two or more different molecules by intermolecular interaction that is different from ionic bond. Furthermore, the cocrystal may be a composite of a neutral molecule and a salt. The cocrystal can be prepared by recrystallization from a solvent by a well-known method, for example, melting crystallization, or physically pulverizing the components together. Appropriate cocrystal formers include ones described in W02006 / 007448. Pharmaceutical Compositions and FormulationsThe disclosed compounds may be incorporated into pharmaceutical compositions suitable for administration to a subject (such as a patient, which may be a human or non -human). The disclosed compounds may also be provided as formulations, such as spray-dried dispersion formulations.

[0040] The pharmaceutical compositions and formulations may include a “therapeutically effective amount” or a “prophylactically effective amount” of the agent. A “therapeutically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired therapeutic result. A therapeutically effective amount of the composition may be determined by a person skilled in the art and may vary according to factors such as the diseasestate, age, sex, and weight of the individual, and the ability of the composition to elicit a desired response in the individual. A therapeutically effective amount is also one in which any toxic or detrimental effects of a compound of the disclosure (e.g., a compound of formula (I) or formula (I-A)) are outweighed by the therapeutically beneficial effects. A “prophylactically effective amount” refers to an amount effective, at dosages and for periods of time necessary, to achieve the desired prophylactic result. Typically, since a prophylactic dose is used in subjects prior to or at an earlier stage of disease, the prophylactically effective amount will be less than the therapeutically effective amount.

[0041] For example, a therapeutically effective amount of a compound of formula (I) or formula (I-A), may be about 0.01 mg to about 1000 mg at a time by oral administration to a patient for once to several times per day, or about 0.01 mg to about 1000 mg at a time by parenteral administration to a patient, or continuous administration to a patient for 30 minutes to 24 hours per day intravenously. It may be administrated to patients once to several times per day.

[0042] Needless to say, as mentioned above, the effective amount to be used vary dependent upon various conditions. Therefore, effective amount lower than the ranges specified above may be sufficient in some cases, and effective amount higher than the ranges specified above are needed in some cases.

[0043] The pharmaceutical compositions and formulations may include pharmaceutically acceptable carriers. The term “pharmaceutically acceptable carrier,” as used herein, means a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Some examples of materials which can serve as pharmaceuticallyacceptable carriers are sugars such as, but not limited to, lactose, glucose and sucrose; starches such as, but not limited to, corn starch and potato starch; cellulose and its derivatives such as, but not limited to, sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as, but not limited to, cocoa butter and suppository waxes; oils such as, but not limited to, peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, corn oil and soybean oil; glycols; such as propylene glycol; esters such as, but not limited to, ethyl oleate and ethyl laurate; agar; buffering agents such as, but not limited to, magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as, but not limited to, sodium lauryl sulfate and magnesium stearate, as well as coloring agents, releasing agents, coating agents, sweetening, flavoring and perfuming agents, preservatives and antioxidants can also be present in the composition, according to the judgment of the formulator.

[0044] Thus, the compounds and their physiologically acceptable salts may be formulated for administration by, for example, solid dosing, eye drop, in a topical oil-based formulation, injection, inhalation (either through the mouth or the nose), implants, or oral, buccal, parenteral, or rectal administration. Techniques and formulations may generally be found in “Remington's Pharmaceutical Sciences,” (Meade Publishing Co., Easton, Pa.). Therapeutic compositions must typically be sterile and stable under the conditions of manufacture and storage.

[0045] The route by which the disclosed compounds are administered and the form of the composition will dictate the type of carrier to be used. The composition may be in a variety of forms, suitable, for example, for systemic administration (e.g., oral, rectal, nasal, sublingual,buccal, implants, or parenteral) or topical administration (e.g., dermal, pulmonary, nasal, aural, ocular, liposome delivery systems, or iontophoresis).

[0046] Carriers for systemic administration typically include at least one of diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, combinations thereof, and others. All carriers are optional in the compositions.

[0047] 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(s) in a systemic or topical composition is typically about 50 to about 90%.

[0048] Suitable lubricants include silica, talc, stearic acid and its magnesium salts 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 oil of theobroma. The amount of lubricant(s) in a systemic or topical composition is typically about 5 to about 10%.

[0049] Suitable binders include polyvinyl pyrrolidone; magnesium aluminum silicate; starches such as corn starch and potato starch; gelatin; tragacanth; and cellulose and its derivatives, such as sodium carboxymethylcellulose, ethyl cellulose, methylcellulose, microcrystalline cellulose, and sodium carboxymethylcellulose. The amount of binder(s) in a systemic composition is typically about 5 to about 50%.

[0050] Suitable disintegrants include agar, alginic acid and the sodium salt thereof, effervescent mixtures, croscarmellose, crospovidone, sodium carboxymethyl starch, sodium starch glycolate, clays, and ion exchange resins. The amount of disintegrant(s) in a systemic or topical composition is typically about 0.1 to about 10%.

[0051] Suitable colorants include a colorant such as an FD&C dye. When used, the amount of colorant in a systemic or topical composition is typically about 0.005 to about 0.1%.Suitable flavors include menthol, peppermint, and fruit flavors. The amount of flavor(s), when used, in a systemic or topical composition is typically about 0.1 to about 1.0%.Suitable sweeteners include aspartame and saccharin. The amount of sweetener(s) in a systemic 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(s) in a systemic or topical composition is typically about 0.1 to about 5%.Suitable preservatives include benzalkonium chloride, methyl paraben and sodium benzoate. The amount of preservative(s) in a systemic or topical composition is typically about 0.01 to about 5%.Suitable glidants include silicon dioxide. The amount of glidant(s) in a systemic or topical composition is typically about 1 to about 5%.Suitable solvents include water, isotonic saline, ethyl oleate, glycerine, hydroxylated castor oils, alcohols such as ethanol, and phosphate buffer solutions. The amount of solvent(s) in a systemic or topical composition is typically from about 0 to about 100%.Suitable suspending agents include AVICEL RC-591 (from FMC Corporation of Philadelphia, PA) and sodium alginate. The amount of suspending agent(s) in a systemic ortopical composition is typically about 1 to about 8%.Suitable surfactants include lecithin, Polysorbate 80, and sodium lauryl sulfate, and the TWEENS from Atlas Powder Company of Wilmington, Delaware. Suitable surfactants include those disclosed in the C.T.F.A. 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(s) in the systemic or topical composition is typically about 0.1% to about 5%.

[0052] Although the amounts of components in the systemic compositions may vary depending on the type of systemic composition prepared, in general, systemic compositions include 0.01% to 50% of an active compound (e.g., a compound of formula (I) or formula (I-A)) and 50% to 99.99% of one or more carriers. Compositions for parenteral administration typically include 0.1% to 10% of actives and 90% to 99.9% of a carrier including a diluent and a solvent.

[0053] Compositions for oral administration can have various dosage forms. For example, solid forms include tablets, capsules, granules, and bulk powders. These oral dosage forms include a safe and effective amount, usually at least about 5%, and more particularly from about 25% to about 50% of actives. The oral dosage compositions include about 50% to about 95% of carriers, and more particularly, from about 50% to about 75%.

[0054] Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed. Tablets typically include an active component, and a carrier comprising ingredients selected from diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, glidants, 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 the FD&C dyes, which can be added for appearance. Chewable tablets preferably contain sweeteners such as aspartame and saccharin, or flavors such as menthol, peppermint, fruit flavors, or a combination thereof.

[0055] Capsules (including implants, time release and sustained release formulations) typically include an active compound (e.g., a compound of formula (I) or formula (I-A)), and a carrier including one or more diluents disclosed above in a capsule comprising gelatin. Granules typically comprise a disclosed compound, and preferably glidants such as silicon dioxide to improve flow characteristics. Implants can be of the biodegradable or the non-biodegradable type.

[0056] The selection of ingredients in the carrier for oral compositions depends on secondary considerations like taste, cost, and shelf stability, which are not critical for the purposes of this disclosure.

[0057] Solid compositions may be coated by conventional methods, typically with pH or timedependent coatings, such that a disclosed compound is released in the gastrointestinal tract in the vicinity of the desired application, or at various points and times to extend the desired action. The coatings typically include one or more components selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, EUDRAGIT (Registered Trademark) coatings (available from Evonik Industries of Essen, Germany), waxes and shellac.

[0058] Compositions for oral administration can have liquid forms. For example, suitable liquid forms include aqueous solutions, emulsions, suspensions, solutions reconstituted from non- effervescent granules, suspensions reconstituted from non-effervescent granules, effervescent preparations reconstituted from effervescent granules, elixirs, tinctures, syrups, and the like. Liquid orally administered compositions typically include a disclosed compound and a carrier, namely, a carrier selected from diluents, colorants, flavors, sweeteners, preservatives, solvents, suspending agents, and surfactants. Peroral liquid compositions preferably include one or more ingredients selected from colorants, flavors, and sweeteners.

[0059] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically include one or more of soluble filler substances such as diluents including sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose, and hydroxypropyl methylcellulose. Such compositions may further include lubricants, colorants, flavors, sweeteners, antioxidants, and glidants.

[0060] The disclosed compounds can be topically administered. Topical compositions that can be applied locally 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. Topical compositions include: a disclosed compound (e.g., a compound of formula (I) or formula (I- A)), and a carrier. The carrier of the topical composition preferably aids penetration of the compounds into the skin. The carrier may further include one or more optional components.

[0061] The amount of the carrier employed in conjunction with a disclosed compound is sufficient to provide a practical quantity of composition for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods of this disclosure are described in the following references: Modern Pharmaceutics, Chapters 9 and 10, Banker & Rhodes, eds. (1979); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1981); and Ansel, Introduction to Pharmaceutical Dosage Forms, 2nd Ed., (1976).

[0062] A carrier may include a single ingredient or a combination of two or more ingredients. In the topical compositions, the carrier includes a topical carrier. Suitable topical carriers include one or more ingredients selected from phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, symmetrical alcohols, aloe vera gel, allantoin, glycerin, vitamin A and E oils, mineral oil, propylene glycol, PPG-2 myristyl propionate, dimethyl isosorbide, castor oil, combinations thereof, and the like. More particularly, carriers for skin applications include propylene glycol, dimethyl isosorbide, and water, and even more particularly, phosphate buffered saline, isotonic water, deionized water, monofunctional alcohols, and symmetrical alcohols.

[0063] The carrier of a topical composition may further include one or more ingredients selected from emollients, propellants, solvents, humectants, thickeners, powders, fragrances, pigments, and preservatives, all of which are optional.

[0064] Suitable emollients include stearyl alcohol, glyceryl monoricinoleate, 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, octadecan-2-ol, isocetyl alcohol, cetyl palmitate, di-n-butyl sebacate, isopropyl myristate, isopropyl palmitate, isopropyl stearate, butyl stearate, polyethylene glycol, triethylene glycol, lanolin, sesame oil, coconut oil, arachis oil, castor oil, acetylated lanolin alcohols, petroleum, mineral oil, butyl myristate, isostearic acid, palmitic acid, isopropyl linoleate, lauryl lactate, myristyl lactate, decyl oleate, myristyl myristate, and combinations thereof. Specific emollients for skin include stearyl alcohol and polydimethylsiloxane. The amount of emollient(s) in a skin-based topical composition is typically about 5% to about 95%.

[0065] Suitable propellants include propane, butane, isobutane, dimethyl ether, carbon dioxide, nitrous oxide, and combinations thereof. The amount of propellant(s) in a topical composition is typically about 0% to about 95%.

[0066] Suitable solvents include water, ethyl alcohol, methylene chloride, isopropanol, castor oil, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether, dimethylsulfoxide, dimethyl formamide, tetrahydrofuran, and combinations thereof. Specific solvents include ethyl alcohol and homotopic alcohols. The amount of solvent(s) in a topical composition is typically about 0% to about 95%.

[0067] Suitable humectants include glycerin, sorbitol, sodium 2-pyrrolidone-5-carboxylate, soluble collagen, dibutyl phthalate, gelatin, and combinations thereof. Specific humectants include glycerin. The amount of humectant(s) in a topical composition is typically 0% to 95%.

[0068] The amount of thickener(s) in a topical composition is typically about 0% to about 95%.

[0069] Suitable powders include beta-cyclodextrins, hydroxypropyl cyclodextrins, chalk, talc, fullers earth, kaolin, starch, gums, colloidal silicon dioxide, sodium polyacrylate, tetra alkyl ammonium smectites, trialkyl aryl ammonium smectites, chemically-modified magnesium aluminum silicate, organically-modified montmorillonite clay, hydrated aluminum silicate, fumed silica, carboxyvinyl polymer, sodium carboxymethyl cellulose, ethylene glycol monostearate, and combinations thereof. The amount of powder(s) in a topical composition is typically 0% to 95%.

[0070] The amount of fragrance in a topical composition is typically about 0% to about 0.5%, particularly, about 0.001% to about 0.1%.

[0071] Suitable pH adjusting additives include HC1 or NaOH in amounts sufficient to adjust the pH of a topical pharmaceutical composition.

[0072] In some embodiments, the following components are mixed with each other in a usual method and punched out to obtain 10,000 tablets each containing 5 mg of the active ingredient.2-[4-{[2-methoxy-5-(trifluoromethyl)benzoyl]amino}-6-oxo-3-[2- (trifluoromethyl)phenyl]-l(6H)-pyridazinyl]ethyl dihydrogen phosphate (50 g); carboxymethylcellulose calcium (disintegrating agent) (20 g); magnesium stearate (lubricant) (10 g); microcrystalline cellulose (920 g).

[0073] Spray-Dried Dispersion FormulationsThe disclosed compounds may be formulated as a spray-dried dispersion (SDD). A SDD is a single-phase, amorphous molecular dispersion of a drug in a polymer matrix. It is a solid solution with the compound molecularly “dissolved” in a solid matrix. SDDs are obtained by dissolving drug and a 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 of Biopharmaceutics Classification System (BCS) class II (high permeability, low solubility) and class IV (low permeability, low solubility) drugs. Formulation and process conditions are selected so that the solvent quickly evaporates from the droplets, thus allowing insufficient time for phase separation or crystallization. SDDs have demonstrated longterm stability and manufacturability. For example, shelf lives of more than 2 years have been demonstrated with SDDs. Advantages of SDDs include, but are not limited to, enhanced oral bioavailability of poorly water-soluble compounds, delivery using traditional solid dosage forms (e.g., tablets and capsules), a reproducible, controllable and scalable manufacturing process and broad applicability to structurally diverse insoluble compounds with a wide range of physical properties.

[0074] This in one embodiment, the disclosure may provide a spray-dried dispersion formulation comprising a compound of formula (I) or formula (I-A).

[0075] Methods of UseThe disclosed compounds, pharmaceutical compositions and formulations may be used in methods for treatment of disorders, such as neurological, psychiatric, inflammatory, respiratory, renal and cardiovascular disorders, cancer or lung fibrosis associated with K2P K+channels, specifically TREK (TWIK Related K+channels) dysfunction for which inhibitors of TREK- 1,TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit.

[0076] Treating disordersThe disclosed compounds, pharmaceutical compositions and formulations may be used in methods for prevention and / or treatment of disorders, 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 offer therapeutic benefit. The methods of prevention and / or treatment may comprise administering to a subject in need of such prevention and / or treatment a therapeutically effective amount of a compound of formula (I) or formula (I-A), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or formula (I-A).

[0077] In some embodiments, the disclosure provides to a method for enhancing cognition and / or treating, preventing, ameliorating, 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 formula (I-A), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or formula (I-A).

[0078] The compounds and compositions disclosed herein may be useful for treating, preventing, ameliorating, controlling or reducing the risk of a variety of disorders associated with selective TREK channel inhibition. Thus, provided is a method of treating or preventing a disorder in a subject comprising the step of administering to the subject at least one disclosed compound or at least one disclosed pharmaceutical composition, in an amount effective to treatthe disorder in the subject.

[0079] Also provided is a method for the prevention and / or treatment of one or more disorders associated with TREK channel activity in a subject comprising the step of administering to the subject a therapeutically effective amount of a compound of formula (I) or formula (I- A), or a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula (I) or formula (I-A).

[0080] In some embodiments, the disclosure provides a method for the prevention and / or treatment of a disorder associated with TREK channel dysfunction in which inhibitors of TREK- 1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit in a mammal, comprising the step of administering to the mammal an effective amount of at least one disclosed compound or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising at least one disclosed compound or pharmaceutically acceptable salt thereof.

[0081] In some embodiments, the disclosed compounds and compositions have utility in preventing and / or treating a variety of neurological, psychiatric and cognitive disorders , cancer or lung fibrosis associated with the TREK-1 and / or 2 inhibition in which inhibitors of TREK-1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit, including one or more of the following conditions or diseases: depression, schizophrenia, psychotic disorder NOS, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic break, tardive psychosis, myxedematous psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychoticfeatures, substance-induced psychotic disorder, neuropathic pain, prostatic cancer, ovarian cancer and lung fibrosis.

[0082] In some embodiments, the psychotic disorder or psychiatric disorder is a psychosis associated with an illness selected from depression, major depressive disorder, postpartum depression, treatment-resistant depression, affective disorder, bipolar disorder, electrolyte disorder, Alzheimer's disease, neurological disorder, hypoglycemia, AIDS, lupus, and post- traumatic stress disorder, anxiety disorder and 22ql 1.2 deletion disorder.

[0083] In some embodiments, the neurological disorder is selected from brain tumor, dementia with Lewy bodies, cerebrovascular dementia, multiple sclerosis, sarcoidosis, Lyme disease, syphilis, Alzheimer's disease, Parkinson's disease, Amyotrophic lateral sclerosis (ALS) and anti- NMDA receptor encephalitis.

[0084] In some embodiments, the psychotic or psychiatric disorder is selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder. In some embodiments, the schizophrenia is selected from catastrophic schizophrenia, catatonic schizophrenia, paranoid schizophrenia, residual schizophrenia, disorganized schizophrenia, and undifferentiated schizophrenia. In some embodiments, the disorder is selected from schizoid personality disorder, schizotypal personality disorder, and paranoid personality disorder. In some embodiments, the psychotic disorder is due to a general medical condition and is substance-induced or drug-induced (phencyclidine, ketamine and other dissociative anesthetics, amphetamine and other psychostimulants, and cocaine).

[0085] In some embodiments, schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, and shared psychotic disorder are preferred for the neurological disorder.

[0086] The term “schizophrenia” used herein includes negative symptoms of schizophrenia and cognitive impairment associated with schizophrenia (CIAS).

[0087] In some embodiments, the present disclosure provides a method for preventing and / or treating a cognitive disorder, comprising administering to a patient in need thereof an effective amount of a compound or a composition of the present disclosure. In some embodiments, cognitive disorders include dementia (associated with Alzheimer's disease, ischemia, multiinfarct dementia, trauma, vascular problems or stroke, HIV disease, Parkinson's disease, Huntington's disease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia, other general medical conditions or substance abuse), delirium, amnestic disorder, substance-induced persisting delirium, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinsonian-ALS demential complex, dementia of the Alzheimer's type, age-related cognitive decline, and mild cognitive impairment.

[0088] The text revision of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) (2000, American Psychiatric Association, Washington DC) provides a diagnostic tool that includes cognitive disorders including dementia, delirium, amnestic disorders and age-related cognitive decline. The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) (2013, American Psychiatric Association, Washington DC) providesa diagnostic tool for neurocognitive disorders (NCDs) that include delirium, followed by the syndromes of major NCD, mild NCD, and their etiological subtypes. The major or mild NCD subtypes include NCD due to Alzheimer's disease, vascular NCD, NCD with Lewy bodies, NCD due to Parkinson's disease, frontotemporal NCD, NCD due to traumatic brain injury, NCD due to HIV infection, substance / medication-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 unspecified NCD. The NCD category in DSM-5 encompasses the group of disorders in which the primary clinical deficit is in cognitive function, and that are acquired rather than developmental. As used herein, the term “cognitive disorders” includes prevention and / or treatment of those cognitive disorders and neurocognitive disorders as described in DSM-IV-TR or DSM-5. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “cognitive disorders” is intended to include like disorders that are described in other diagnostic sources.

[0089] In some embodiments, the present disclosure provides a method for preventing and / or treating schizophrenia or psychosis, comprising administering to a patient in need thereof an effective amount of a compound or composition of the present disclosure. Particular schizophrenia or psychosis pathologies are paranoid, disorganized, catatonic or undifferentiated schizophrenia and substance-induced psychotic disorder. DSM-IV-TR provides a diagnostic tool that includes paranoid, disorganized, catatonic, undifferentiated or residual schizophrenia, and substance-induced psychotic disorder. DSM-5 eliminated the subtypes of schizophrenia, and instead includes a dimensional approach to rating severity for the core symptoms of schizophrenia, to capture the heterogeneity in symptom type and severity expressed acrossindividuals with psychotic disorders. As used herein, the term “schizophrenia or psychosis” includes prevention and / or treatment of those mental disorders as described in DSM-IV-TR or DSM-5. The skilled artisan will recognize that there are alternative nomenclatures, nosologies and classification systems for mental disorders, and that these systems evolve with medical and scientific progress. Thus the term “schizophrenia or psychosis” is intended to include like disorders that are described in other diagnostic sources.

[0090] In some embodiments, the present disclosure provides a method for preventing and / or treating pain, comprising administering to a patient in need thereof an effective amount of a compound or composition of the present disclosure. Particular pain embodiments are bone and joint pain (osteoarthritis), repetitive motion pain, dental pain, cancer pain, myofascial pain (muscular injury, fibromyalgia), perioperative pain (general surgery, gynecological), chronic pain and neuropathic pain.

[0091] In some embodiments, the present disclosure provides a method for preventing and / or treating inflammatory disorder, comprising administering to a patient in need thereof an effective amount of a compound or a composition of the present disclosure. In some embodiments, inflammatory disorders include intestinal allergies, inflammatory bowel disease, allergic asthma, allergic dermatitis and allergic rhinitis.

[0092] In some embodiments, the present disclosure provides a method for preventing and / or treating respiratory disorder, comprising administering to a patient in need thereof an effective amount of a compound or a composition of the present disclosure. In some embodiments, respiratory disorders include asthma, chronic obstructive pulmonary disease, pulmonary fibrosis,pneumonia, and lung cancer.

[0093] In some embodiments, the present disclosure provides a method for preventing and / or treating renal disorder, comprising administering to a patient in need thereof an effective amount of a compound or a composition of the present disclosure. In some embodiments, renal disorders include nephritic syndrome and kidney failure.

[0094] In some embodiments, the present disclosure provides a method for preventing and / or treating cardiovascular disorder, comprising administering to a patient in need thereof an effective amount of a compound or a composition of the present disclosure. In some embodiments, cardiovascular disorders include coronary artery diseases, heart failure, hypertensive heart disease, rheumatic heart disease, cardiomyopathy, arrhythmia, congenital heart disease, valvular heart disease, carditis, aortic aneurysms, peripheral artery disease, thromboembolic disease, and venous thrombosis.

[0095] In some embodiments, the present disclosure provides a method for preventing and / or treating cancer, comprising administering to a patient in need thereof an effective amount of a compound or a composition of the present disclosure. In some embodiments, cancers include cancer associated with cerebral nerve (for example, pediatric brain tumors (for example, neuroblastoma, medulloblastoma, astrocytoma (for example, juvenile pilocytic astrocytoma), ependymoma, craniopharyngioma, germ cell tumors, optic nerve glioma, choroid plexus papilloma and pontine glioma), adult brain tumors (for example, adult astrocytoma, adult malignant astrocytoma, adult glioblastoma, adult ependymoma, adult malignant ependymoma, adult malignant oligodendroglioma, adult medulloblastoma, adult meningioma and adultmalignant meningioma), glioma (for example, astrocytoma, oligodendroglioma, ependymoma and brain stem glioma), pituitary adenoma, acoustic schwannoma, retinoblastoma and uveal malignant melanoma), respiratory tract cancer (for example, pharyngeal cancer (for example, nasopharyngeal cancer, oropharyngeal cancer and hypopharyngeal cancer), laryngeal cancer, nasal sinus cancer, lung cancer (for example, small cell cancer and non-small-cell cancer), thymoma and mesothelioma), gastrointestinal cancer (for example, esophageal cancer, gastric cancer, duodenal cancer and large bowel cancer (for example, colon cancer, rectal cancer and anal cancer)), oral cancer (for example, gingival cancer, tongue cancer and salivary gland cancer), urinary system cancer (for example, penile cancer, renal pelvis ureter cancer, renal cell cancer, testicular tumor, prostate cancer, prostatic cancer and bladder cancer), cancers that affect women (for example, vulvar cancer, uterine cancer (for example, cervical cancer and endometrial cancer), uterine sarcoma, trophoblastic disease (for example, hydatidiform mole, choriocarcinoma, placental-site trophoblastic tumor and persistent trophoblastic disease), vaginal cancer, breast cancer, breast sarcoma, ovarian cancer and ovarian germ cell tumor), skin cancer (for example, melanoma (also known as malignant melanoma) (for example, malignant lentiginous melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma and erosive melanoma), mycosis fungoides, squamous cell carcinoma, basal cell carcinoma, premonitory signs of skin cancer • intraepidermal carcinoma (for example, actinic keratosis, Bowen's disease and Paget's disease), lymphomatoid papulosis, cutaneous CD30 positive anaplastic large cell lymphoma, Sezary syndrome and cutaneous B-cell lymphoma), bone and muscle cancer (for example, osteosarcoma, soft tissue sarcoma, rhabdomyosarcoma, synovial sarcoma and liposarcoma), thyroid cancer, carcinoid, liver cancer (also known as hepatoma), hepatoblastoma, bile duct cancer, gallbladder cancer, pancreatic cancer, pancreatic endocrine tumors (for example, insulinoma, gastrinoma and VIPoma), carcinoma of unknownprimary, hereditary tumors • familial tumors (for example, hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, hereditary breast and ovarian cancer syndrome, Li- Fraumeni syndrome, hereditary melanoma, Wilms' tumor, hereditary papillary renal cell carcinoma, von Hippel-Lindau syndrome and multiple endocrine neoplasia), leukemia (for example, acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia, chronic myeloproliferative disorder, adult T-cell leukemialymphoma, chronic lymphocytic leukemia and small lymphocytic lymphoma), multiple myeloma, primary macroglobulinemia, malignant lymphoma (for example, Hodgkin's lymphoma, non-Hodgkin's lymphoma (intermediate- and high-grade lymphomas, Burkitt's lymphoma, lymphoblastic lymphoma, follicular lymphoma, mantle-cell lymphoma, MALT (Mucosa-Associated Lymphoid Tissue) lymphoma and NK (natural killer) cell lymphoma)). In some embodiments, cancer is preferably lung, prostatic and ovarian cancer.

[0096] The compounds and compositions may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the diseases, disorders and conditions noted herein. The compounds and compositions may be further useful in a method for the prevention, treatment, control, amelioration, or reduction of risk of the aforementioned diseases, disorders and conditions, in combination with other agents.

[0097] In the prevention and / or treatment of conditions which require inhibition of a TREK channel (TREK-1, TREK-2 or both TREK-1 and TREK-2), an appropriate dosage level may be about 0.01 to 1000 mg per day, which can be administered to a patient in single or multiple doses. For oral administration, the compositions may be provided in the form of tablets containing 1.0 to 1000 milligrams of the active ingredient for the symptomatic adjustment of thedosage to the patient to be treated. The compounds can be administered on a regimen of 1 to 4 times per day. This dosage regimen can be adjusted to provide the optimal therapeutic response. It will be understood, however, that the specific dose level and frequency of dosage for any particular patient can be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

[0098] In some embodiments, the disorder in which inhibitors of TREK-1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit can be selected from psychosis, depression, schizophrenia, conduct disorder, disruptive behavior disorder, bipolar disorder, psychotic episodes of anxiety, 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 manifestations of mental retardation, autistic disorder, movement disorders, Tourette's syndrome, akinetic-rigid syndrome, movement disorders associated with Parkinson's disease, tardive dyskinesia, drug induced and neurodegeneration based dyskinesias, attention deficit hyperactivity disorder, cognitive disorders, dementias, and memory disorders.

[0099] In some embodiments, the disorder in which inhibitors of TREK-1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit is Alzheimer's disease.

[0100] Co-therapeutic methodsThe present disclosure is further directed to administration of a selective TREK channel inhibitor for improving treatment outcomes in the context of cognitive or behavioral therapy. That is, in some embodiments, the disclosure relates to a co-therapeutic method comprising a step of administering to a mammal an effective amount and dosage of at least one disclosed compound, or a pharmaceutically acceptable salt thereof.

[0101] In some embodiments, administration improves treatment outcomes in the context of cognitive or behavioral therapy. Administration in connection with cognitive or behavioral therapy can be continuous or intermittent. Administration need not be simultaneous with therapy and can be before, during, and / or after therapy.

[0102] It is understood that the disclosed co-therapeutic methods can be used in connection with the disclosed compounds, compositions, kits, and uses.

[0103] Combination TherapiesIn the methods of use described herein, additional therapeutic agent(s) may be administered simultaneously or sequentially with the disclosed compounds and compositions. Sequential administration includes administration before or after the disclosed compounds and compositions. In some embodiments, the additional therapeutic agent or agents may be administered in the same composition as the disclosed compounds. In other embodiments, there may be an interval of time between administration of the additional therapeutic agent and the disclosed compounds. In some embodiments, administration of an additional therapeutic agent with a disclosed compound may allow lower doses of the other therapeutic agents and / or administration at less frequent intervals. When used in combination with one or more otheractive ingredients, the compounds of the present disclosure and the other active ingredients may be used in lower doses than when each is used singly. Accordingly, the pharmaceutical compositions of the present disclosure include those that contain one or more other active ingredients, in addition to a compound of formula (I) or a compound of formula (I-A). The above combinations include combinations of a compound of the present disclosure not only with one other active compound, but also with two or more other active compounds.

[0104] The disclosed compounds can be used as single agents or in combination with one or more other drugs in the treatment, prevention, control, amelioration or reduction of risk of the aforementioned diseases, disorders and conditions for which the compound or the other drugs have utility, where the combination of drugs together are safer or more effective than either drug alone. The other drug(s) can be administered by a route and in an amount commonly used therefor, contemporaneously or sequentially with a disclosed compound. When a disclosed compound is used contemporaneously with one or more other drugs, a pharmaceutical composition in unit dosage form containing such drugs and the disclosed compound may be used. However, the combination therapy can also be administered on overlapping schedules. It is also envisioned that the combination of one or more active ingredients and a disclosed compound can be more efficacious than either as a single agent. Thus, when used in combination with one or more other active ingredients, the disclosed compounds and the other active ingredients can be used in lower doses than when each is used singly.

[0105] The pharmaceutical compositions and methods of the present disclosure can further comprise other therapeutically active compounds as noted herein which are usually applied in the prevention and / or treatment of the above mentioned pathological conditions.

[0106] The above combinations include combinations of a disclosed compound not only with one other active compound, but also with two or more other active compounds. Likewise, disclosed compounds can be used in combination with other drugs that are used in the prevention, treatment, control, amelioration, or reduction of risk of the diseases or conditions for which disclosed compounds are useful. Such other drugs can be administered, by a route and in an amount commonly used therefor, contemporaneously or sequentially with a compound of the present disclosure. When a compound of the present disclosure is used contemporaneously with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to a disclosed compound is preferred. Accordingly, the pharmaceutical compositions include those that also contain one or more other active ingredients, in addition to a compound of the present disclosure.

[0107] The weight ratio of a disclosed compound to the second active ingredient can be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the present disclosure is combined with another agent, the weight ratio of a disclosed compound to the other agent will generally range from about 1000: 1 to about 1 : 1000, preferably about 200: 1 to about 1 :200. Combinations of a compound of the present disclosure and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.

[0108] In such combinations a disclosed compound and other active agents can be administered separately or in conjunction. In addition, the administration of one element can be prior to,concurrent to, or subsequent to the administration of other agent(s).

[0109] Accordingly, the disclosed compounds can be used alone or in combination with other agents which are known to be beneficial in the subject indications or other drugs that affect receptors or enzymes that either increase the efficacy, safety, convenience, or reduce unwanted side effects or toxicity of the disclosed compounds. The subject compound and the other agent can be coadministered, either in concomitant therapy or in a fixed combination.

[0110] In some embodiments, the compound can be employed in combination with antiAlzheimer's agents, beta-secretase inhibitors, cholinergic agents, gamma-secretase inhibitors, HMG-CoA reductase inhibitors, Mi allosteric agonists, Mi positive allosteric modulators, NSAIDs including ibuprofen, vitamin E, and anti-amyloid antibodies. In another embodiment, the subject compound can be employed in combination with sedatives, hypnotics, anxiolytics, antipsychotics (typical and atypical), antianxiety agents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minor tranquilizers, melatonin agonists and antagonists, melatonergic agents, benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as: adinazolam, allobarbital, alonimid, alprazolam, amisulpride, amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam, benzoctamine, brotizolam, bupropion, buspirone, butabarbital, butalbital, capuride, carbocloral, chloral betaine, chloral hydrate, clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide, clorethate, chlorpromazine, clozapine, cyprazepam, desipramine, dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine, doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam, flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine, fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine, imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone,melatonin, mephobarbital, meprobamate, methaqualone, midaflur, midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline, olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine, phenelzine, phenobarbital, prazepam, promethazine, propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone, roletamide, secobarbital, sertraline, suproclone, temazepam, thioridazine, thiothixene, tracazolate, tranylcypromine, trazodone, triazolam, trepipam, tricetamide, triclofos, trifluoperazine, trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, ziprasidone, zolazepam, zolpidem, and salts thereof, and combinations thereof, and the like, or the subject compound can be administered in conjunction with the use of physical methods such as with light therapy or electrical stimulation.[OH l]In some embodiments, the compound can be employed in combination with levodopa (with or without a selective extracerebral decarboxylase inhibitor such as carbidopa or benserazide), anticholinergics such as biperiden (optionally as its hydrochloride or lactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMT inhibitors such as entacapone, MAO-B inhibitors, antioxidants, A2a adenosine receptor antagonists, cholinergic agonists, NMDA receptor antagonists, serotonin receptor antagonists and dopamine receptor agonists such as alentemol, bromocriptine, fenoldopam, lisuride, naxagolide, pergolide and pramipexole. It will be appreciated that the dopamine agonist can be in the form of a pharmaceutically acceptable salt, for example, alentemol hydrobromide, bromocriptine mesylate, fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate. Lisuride and pramipexol are commonly used in a non-salt form.

[0112] In some embodiments, the compound can be employed in combination with a compound from the phenothiazine, thioxanthene, heterocyclic dibenzazepine, butyrophenone,diphenylbutylpiperidine and indoIone classes of neuroleptic agent. Suitable examples of phenothiazines include chlorpromazine, mesoridazine, thioridazine, acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitable 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 indoIone is molindolone. Other neuroleptic agents include loxapine, sulpiride and risperidone. It will be appreciated that the neuroleptic agents when used in combination with the subject compound can be in the form of a pharmaceutically acceptable salt, for example, chlorpromazine hydrochloride, mesoridazine besylate, thioridazine hydrochloride, acetophenazine maleate, fluphenazine hydrochloride, flurphenazine enathate, fluphenazine decanoate, trifluoperazine hydrochloride, thiothixene hydrochloride, haloperidol decanoate, loxapine succinate and molindone hydrochloride. Perphenazine, chlorprothixene, clozapine, haloperidol, pimozide and risperidone are commonly used in a non-salt form. Thus, the subject compound can be employed in combination with acetophenazine, alentemol, aripiprazole, amisulpride, benzhexol, bromocriptine, biperiden, chlorpromazine, chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine, haloperidol, levodopa, levodopa with benserazide, levodopa with carbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide, olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine, risperidone, sulpiride, tetrabenazine, trihexyphenidyl, thioridazine, thiothixene, trifluoperazine or ziprasidone.

[0113] In some embodiments, the compound can be employed in combination with an antidepressant or anti -anxiety agent, including norepinephrine reuptake inhibitors (including tertiary amine tricyclics and secondary amine tricyclics), selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOIs), reversible inhibitors of monoamine oxidase (RIMAs),serotonin and noradrenaline reuptake inhibitors (SNRIs), corticotropin releasing factor (CRF) antagonists, a-adrenoreceptor antagonists, neurokinin- 1 receptor antagonists, atypical antidepressants, benzodiazepines, 5-HT1 A agonists or antagonists, especially 5-HT1 A partial agonists, and corticotropin releasing factor (CRF) antagonists. Specific agents include: amitriptyline, clomipramine, doxepin, imipramine and trimipramine; amoxapine, desipramine, maprotiline, nortriptyline and protriptyline; fluoxetine, fluvoxamine, paroxetine and sertraline; isocarboxazid, phenelzine, tranylcypromine and selegiline; moclobemide: venlafaxine; duloxetine; aprepitant; bupropion, lithium, nefazodone, trazodone and viloxazine; alprazolam, chlordiazepoxide, clonazepam, chlorazepate, diazepam, halazepam, lorazepam, oxazepam and prazepam; buspirone, flesinoxan, gepirone and ipsapirone, and pharmaceutically acceptable salts thereof.

[0114] In some embodiments, the compounds can be coadministered with orthosteric muscarinic agonists, muscarinic potentiators, or cholinesterase inhibitors. In some embodiments, the compounds can be coadministered with GlyTl inhibitors and the like such as, but not limited to: risperidone, clozapine, haloperidol, fluoxetine, prazepam, xanomeline, lithium, phenobarbital, and salts thereof and combinations thereof.

[0115] In some embodiments, the other drugs for the prevention and / or treatment of schizophrenia is at least one drug selected from typical antipsychotics, atypical antipsychotics, and the like.

[0116] The typical antipsychotics may include, for example, chlorpromazine, fluphenazine, haloperidol, sulpiride and the like.The atypical antipsychotics may include, for example, serotonin-dopamine antagonist, multi-acting receptor targeted antipsychotics, dopamine partial agonist and the like.The serotonin-dopamine antagonist may include, for example, risperidone, perospirone, ziprasidone, blonanserin and the like.The multi-acting receptor targeted antipsychotics may include, for example, olanzapine, quetiapine, clozapine, lurasidone and the like.The dopamine partial agonist may include, for example, aripiprazole, cariprazine and the like.

[0117] In some embodiments, the other drugs for the prevention and / or treatment of depression is at least one drug selected from benzodiazepine antianxiety drug, thienodiazepine antianxiety drug, non-benzodiazepine antianxiety drug, neurokinin-1 (NK1) antagonist, tricyclic antidepressant, tetracyclic antidepressant, monoamine oxidase (MAO) inhibitor, triazolopyridine antidepressant, serotonin and noradrenaline reuptake inhibitor (SNRI), selective serotonin reuptake inhibitor (SSRI), serotonin reuptake inhibitor, noradrenergic and specific serotonergic antidepressant (NaSSA), noradrenaline and dopamine disinhibition drug (NDDI), selective serotonin reuptake enhancer (SSRE), and the like.

[0118] The benzodiazepine antianxiety drug may include, for example, alprazolam, oxazepam, oxazolam, cloxazolam, clorazepate dipotassium, chlordiazepoxide, diazepam, tofisopam, triazolam, prazepam, fludiazepam, flutazolam, flutoprazepam, bromazepam, mexazolam, medazepam, ethyl loflazepate, lorazepam and the like.The thienodiazepine antianxiety drug may include, for example, etizolam, clotiazepam and the like.The non-benzodiazepine antianxiety drug may include, for example, citric acid tandospirone, hydroxyzine hydrochloride and the like.

[0119] The neurokinin-1 (NK1) antagonist may include, for example, aprepitant, fosaprepitant meglumine and the like.The tricyclic antidepressant may include, for example, amitriptyline hydrochloride, imipramine hydrochloride, clomipramine hydrochloride, dosulepin hydrochloride, nortriptyline hydrochloride, lofepramine hydrochloride, trimipramine maleate, amoxapine and the like.The tetracyclic antidepressant may include, for example, maprotiline hydrochloride, mianserin hydrochloride, setiptiline maleate and the like.The monoamine oxidase (MAO) inhibitor may include, for example, safrazine hydrochloride and the like.The triazolopyridine antidepressant may include, for example, Trazodone Hydrochloride and the like.The serotonin and noradrenaline reuptake inhibitor (SNRI) may include, for example, milnacipran hydrochloride, venlafaxine hydrochloride, duloxetine hydrochloride and the like.The selective serotonin reuptake inhibitor (SSRI) may include, for example, fluvoxamine maleate, paroxetine hydrochloride, fluoxetine hydrochloride, citalopram hydrochloride, sertraline hydrochloride, escitalopram oxalate and the like.The serotonin reuptake inhibitor may include, for example, trazodone hydrochloride and the like.The noradrenergic and specific serotonergic antidepressant (NaSSA) may include, for example, mirtazapine and the like.The noradrenaline and dopamine disinhibition drug (NDDI) may include, for example,agomelatine and the like.The selective serotonin reuptake enhancer (SSRE) may include, for example, tianeptine and the like.

[0120] In some embodiments, the other drugs for the prevention and / or treatment of pain is at least one drug selected from acetaminophen, a nonsteroid anti-inflammatory drug, an opioid, an antidepressant, an antiepileptic agent, an / ' / -methyl -D-aspartate antagonist, a muscle relaxant, an anti arrhythmic agent, a steroid, a bisphosphonate and the like.The anti arrhythmic agent may include, for example, lidocaine, mexiletine and the like.

[0121] The nonsteroid anti-inflammatory drug may include, for example, sasapyrine, sodium salicylate, aspirin, aspirin formulations such as those containing aspirin-dialuminate, diflunisal, indomethacin, suprofen, ufenamate, dimethylisopropylazulene, bufexamac, felbinac, diclofenac, tolmetin sodium, Clinoril, fenbufen, nabumetone, proglumetacin, indomethacin famesil, acemetacin, proglumetacin maleate, amfenac sodium, mofezolac, etodolac, ibuprofen, ibuprofen piconol, naproxen, flurbiprofen, flurbiprofen axetil, ketoprofen, fenoprofen calcium, tiaprofen, oxaprozin, pranoprofen, loxoprofen sodium, alminoprofen, zaltoprofen, mefenamic acid, aluminium mefenamate, tolfenamic acid, floctafenine, ketophenylbutazone, oxyphenbutazone, piroxicam, tenoxicam, ampiroxicam, Napageln ointment, epirizole, tiaramide hydrochloride, tinoridine hydrochloride, emorfazone, sulpyrine, Migrenin, Saridon, Sedes G, Amipylo-N, Sorbon, pilin cold remedies, acetaminophen, phenacetin, dimetotiazine mesilate, meloxicam, celecoxib, rofecoxib, valdecoxib, simetride-containing formulations and non-pilin cold remedies and the like.

[0122] The opioid may include, for example, codeine, fentanyl, hydromorphone, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene and the like.

[0123] The antidepressant may include, for example, tricyclic antidepressants (e.g., imipramine hydrochloride, clomipramine hydrochloride, dosulepin 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 noradrenaline reuptake inhibitors (SNRIs) (e.g., milnacipran hydrochloride, venlafaxine hydrochloride), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluvoxamine maleate, paroxetine hydrochloride, ), serotonin reuptake inhibitors (e.g., trazodone hydrochloride) and the like.

[0124] The antiepileptic agent may include, for example, phenobarbital, Puridomin, phenytoin, ethosuximide, zonisamide, nitrazepam, clonazepam, carbamazepine, sodium valproate, acetazolamide, sulthiame, gabapentin, pregabalin and the like.The Mm ethyl -D-aspartate antagonist may include, for example, ketamine hydrochloride, amantadine hydrochloride, memantine hydrochloride, dextromethorphan, methadone and the like.The muscle relaxant may include, for example, succinylcholine, suxamethonium, vecuronium bromide, pancuronium bromide, dantrolene sodium and the like.

[0125] The steroid may include, for example, as topical agents, clobetasol propionate, diflorasone diacetate, fluocinonide, mometasone furoate, betamethasone dipropionate, betamethasone butyrate propionate, betamethasone valerate, difluprednate, budesonide,diflucortolone valerate, amcinonide, halcinonide, dexamethasone, dexamethasone propionate, dexamethasone valerate, dexamethasone acetate, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone butyrate propionate, deprodone propionate, prednisolone valerate acetate, fluocinolone acetonide, beclometasone propionate, triamcinolone acetonide, flumetasone pivalate, alclometasone dipropionate, clobetasone butyrate, prednisolone, beclometasone propionate, fludroxycortide and the like.

[0126] The bisphosphonate may include, for example, etidronate, pamidronate, alendronate, risedronate, zoledronate, minodronate and the like.

[0127] Modes of AdministrationMethods of prevention and / or treatment may include any number of modes of administering a disclosed composition. Modes of administration may include tablets, pills, sugar- coated tablet, hard and soft gel capsules, granules, pellets, aqueous, lipid, oily or other solutions, emulsions such as oil-in-water emulsions, liposomes, aqueous or oily suspensions, syrups, elixirs, solid emulsions, solid dispersions or dispersible powders. For the preparation of pharmaceutical compositions for oral administration, the agent may be admixed with commonly known and used adjuvants and excipients such as for example, gum arabic, talcum, starch, sugars (such as, e.g., mannitose, methyl cellulose, lactose), gelatin, surface-active agents, magnesium stearate, aqueous or non-aqueous solvents, paraffin derivatives, cross-linking agents, dispersants, emulsifiers, lubricants, conserving agents, flavoring agents (e.g., ethereal oils), solubility enhancers (e.g., benzyl benzoate or benzyl alcohol) or bioavailability enhancers (e.g. Gelucire.TM.). In the pharmaceutical composition, the agent may also be dispersed in a microparticle, e.g. a nanoparticulate composition.

[0128] For parenteral administration, the agent can be dissolved or suspended in a physiologically acceptable diluent, such as, e.g., water, buffer, oils with or without solubilizers, surface-active agents, dispersants or emulsifiers. As oils for example and without limitation, olive oil, peanut oil, cottonseed oil, soybean oil, castor oil and sesame oil may be used. More generally spoken, for parenteral administration, the agent can be in the form of an aqueous, lipid, oily or other kind of solution or suspension or even administered in the form of liposomes or nano-suspensions.

[0129] The term “parenteral administration” as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrastemal, subcutaneous and intraarticular injection and infusion.The present compound has low toxicity and thus can be safely used as a medicament.

[0130] KitsIn one aspect, the disclosure provides kits comprising at least one disclosed compound or a pharmaceutically acceptable salt thereof, and one or more of:(a) at least one agent known to decrease a TREK-1 activity;(b) at least one agent known to decrease a TREK-2 activity;(c) at least one agent known to prevent and / or treat a disorder associated with TREK dysfunction in which inhibitors of TREK- 1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit in a mammal;(d) instructions for preventing and / or treating a disorder associated with TREK dysfunction in which inhibitors of TREK- 1, TREK-2 or both TREK-1 and TREK-2 would offertherapeutic benefit in a mammal; or(e) instructions for administering the compound in connection with cognitive or behavioral therapy.

[0131] In some embodiments, the at least one disclosed compound and the at least one agent are co-formulated. In some embodiments, the at least one disclosed compound and the at least one agent are co-packaged. The kits can also comprise compounds and / or products co-packaged, coformulated, and / or co-delivered with other components. For example, a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and / or product and another component for delivery to a patient.That the disclosed kits can be employed in connection with disclosed methods of use.

[0132] The kits may include information, instructions, or both that use of the kit will provide prevention and / or treatment for medical conditions in mammals (particularly humans). The information and instructions may be in the form of words, pictures, or both, and the like. In addition or in the alternative, the kit may include the compound, a composition, or both; and information, instructions, or both, regarding methods of application of compound, or of composition, preferably with the benefit of preventing and / or treating medical conditions in mammals (e.g., humans).

[0133] The compounds and processes of the disclosure will be better understood by reference to the following examples, which are intended as an illustration of and not a limitation upon the scope of the disclosure.In one aspect, the present disclosure provides the following embodiments.(1)A compound of formula (I-A):[Chem. 8]or a pharmaceutically acceptable salt thereof; whereinR.1is (1) a hydrogen atom or (2) Cl-8 alkyl;2 1R is selected from the group consisting of (1) a halogen atom, (2) Cl-4 alkoxy and (3) Cl-4 haloalkoxy;R3is (1) Cl-4 alkyl or (2) Cl-4 haloalkyl;R4is (1) Cl-4 alkyl or (2) Cl-4 haloalkyl.(2)The compound according to [1], which is a compound of formula (I):[Chem. 9]or a pharmaceutically acceptable salt thereof; wherein2R is (1) a fluorine atom or (2) methoxy;and R.1is as defined in [1],(3) A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 2-[4-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-6-oxo-3-[2-(trifluoromethyl)phenyl]pyridazin-1 -yl]ethyl dihydrogen phosphate.(4) A compound of the following structure:[Chem. 10](5) A pharmaceutically acceptable salt of the compound of the following structure:[Chem. 11](6) A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 2-[4-{[2-methoxy-5-(trifluoromethyl)benzoyl]amino}-6-oxo-3-[2-(trifluoromethyl)phenyl]-l(6H)- pyridazinyl] ethyl dihydrogen phosphate.(7)] A compound of the following structure:[Chem. 12](8) A pharmaceutically acceptable salt of the compound of the following structure:[Chem. 13](9) A pharmaceutical composition comprising the compound or the pharmaceutical acceptable salt according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.(10) The pharmaceutical composition according to [9], which is a TREK-1, TREK-2 or both TREK-1 and TREK-2 inhibitor.(11) The pharmaceutical composition according to [9], which is a preventive and / or therapeutic agent for a disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK-2 dysfunction.(12) The pharmaceutical composition according to

[0011] , wherein the disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK-2 dysfunction is a neurological disorder, psychiatric disorder, cognitive disorder, pain, cancer and / or lung fibrosis.(13) The pharmaceutical composition according to

[0012] , wherein the neurological and / or psychiatric disorder is selected from the group consisting of depression, schizophrenia, anxietydisorders, bipolar disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, 22ql l.2 deletion syndrome, neuropathic pain and cerebral infarction.(13-1) The pharmaceutical composition according to

[0013] , wherein schizophrenia is cognitive impairment associated with schizophrenia.(13-2) The pharmaceutical composition according to

[0012] , wherein the neurological and / or psychiatric disorder is depression or cognitive impairment associated with schizophrenia.(14) A method for preventing and / or treating a disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK -2 dysfunction, comprising administering an effective amount of the compound according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof to a mammal.(15) The compound according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof for use in prevention and / or treatment of a disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK -2 dysfunction.(16) Use of the compound according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof for manufacturing a preventive and / or therapeutic agent for a disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK-2 dysfunction.(17) A kit comprising the compound according to any one of [1] to [8], or a pharmaceutically acceptable salt thereof, and one or more of:(a) at least one agent known to decrease a TREK-1 channel activity;(b) at least one agent known to decrease a TREK-2 channel activity;(c) at least one agent known to prevent and / or treat a disorder associated with TREK channel dysfunction in which inhibitors of TREK- 1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit in a mammal;(d) instructions for preventing and / or treating a disorder associated with TREK channel dysfunction in which inhibitors of TREK- 1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit in a mammal; and(e) instructions for administering the compound in connection with cognitive behavioral therapy. [Examples]

[0134] Synthesis ExamplesThe present disclosure is hereinafter specifically described by way of Examples and Biological Examples which do not limit the present disclosure. The present compounds and compounds described in Examples are denominated according to the IUPAC nomenclature. Naming according to the IUPAC nomenclature can be done using, for example, 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 objective compound of the Example is described subsequently to the number of the Example, and the compound is sometimes referred to as the “title compound”.

[0135] All NMR spectra were recorded on a 400 MHz AMX Bruker NMR spectrometer or a Bruker AVANCE III 400MHz NMR or 600MHz spectrometer.1H chemical shifts are reported in 6 values in ppm downfield with the deuterated solvent as the internal standard. Data are reported as follows: chemical shift, multiplicity (s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet, ABq = AB quartet), coupling constant, integration.

[0136] LCMS analysis conditions are as below. The MS data in Examples were measured by Reversed-phase LCMS method (1) unless otherwise specified.

[0137] Reversed-phase LCMS (1):Reversed-phase LCMS analysis was obtained on a SHIMADZU LC20-MS2010 with ESI source. MS parameters were as follows: Mobile Phase: 1.5 mL / 4 L TFA in water (solvent A) and 0.75 mL / 4 L TFA in acetonitrile (solvent B), using the elution gradient 5%-95% (solvent B) over 0.7 minutes, then holding at 95% for 0.4 minutes, at 5% for 0.4 min, at a flow rate of 1.5 ml / min; Column: Agilent Pursit 5 C18 20*2.0 mm; Wavelength: UV 220nm, 254nm, 215nm; Column temperature: 50 °C; MS ionization: ESI.

[0138] Reversed-phase LCMS (2):Reversed-phase LCMS analysis was obtained on a SHIMADZU LC20-MS2020 with ESI source. MS parameters were as follows: Mobile Phase: 0.8 mL / 4 L NH3H2O in water (solvent A) and acetonitrile (solvent B), using the elution gradient 10%-80% (solvent B) over 6.5 minutes and holding at 95% for 0.5 minutes at a flow rate of 0.8 ml / min; Column: Xbridge Shield RP-18, 5 pm, 2.1*50 mm; Wavelength: UV 220nm, 254nm, 215nm; Column temperature: 50°C; MS ionization: ESI.

[0139] Reversed-phase LCMS (3):Reversed-phase LCMS analysis was obtained on a SHIMADZU LC20-MS2020 with ESI source. MS parameters were as follows: Mobile Phase: 0.8 mL / 4 L NH3H2O in water (solvent A) and acetonitrile (solvent B), using the elution gradient 50%-100% (solvent B) over 2.5minutes then holding at 95% for 0.5 minutes, at 50% for 0.5 min, at a flow rate of 0.8 ml / min; Column: Xbridge Shield RP-18, 5 gm, 2.1*50 mm; Wavelength: UV 220nm, 254nm, 215nm; Column temperature: 50°C; MS ionization: ESI.

[0140] Reversed-phase LCMS (4):Reversed-phase LCMS analysis was performed using an Agilent 1200 system comprised of a binary pump with degasser, high-performance autosampler, thermostatted column compartment, C18 column, diode-array detector (DAD) and an Agilent 6150 MSD with the following parameters. The gradient conditions were 5% to 95% acetonitrile with the aqueous phase 0.1% TFA in water over 1.4 minutes. Samples were separated on a Waters Acquity UPLC BEH C18 column (1.7 pm, 1.0 x 50 mm) at 0.5 mL / min, with column and solvent temperatures maintained at 55 °C. The DAD was set to scan from 190 to 300 nm, and the signals used were 220 nm and 254 nm (both with a band width of 4nm). The MS detector was configured with an electrospray ionization source, and the low-resolution mass spectra were acquired by scanning from 140 to 700 AMU with a step size of 0.2 AMU at 0.13 cycles / second, and peak width of 0.008 minutes. The drying gas flow was set to 13 liters per minute at 300 °C and the nebulizer pressure was set to 30 psi. The capillary needle voltage was set at 3000 V, and the fragmentor voltage was set at 100V. Data acquisition was performed with Agilent Chemstation and Analytical Studio Reviewer software.

[0141] Reversed-phase LCMS (5):Reversed-phase LCMS analysis was obtained on a SHIMADZU LCMS-2020 with ESI source. MS parameters were as follows: Mobile Phase: 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B), using the elution holding at 5% (solvent B) for 0.1 minutes,gradient 5%-95% (solvent B) over 1.1 minutes and holding at 95% for 0.4 minutes at a flow rate of 1.0 ml / min; Column: YMC Triart C18 2.0 mm* L30mm; Wavelength: UV 220nm, 254nm; Column temperature: 30°C; detector MS, ELSD; MS ionization: ESI.

[0142] Prep-HPLC (FA):An example: Mobile Phase: 0.225% FA in water (solvent A) and acetonitrile (solvent B), using the elution gradient 55%-85% (solvent B) over 7.8 minutes then holding at 100% for 2 minutes, at a flow rate of 25 ml / min; Column: Welch Xtimate C18 150*25mm*5pm

[0143] Prep-HPLC (TFA):An example: Mobile Phase: 0.1% TFA in water (solvent A) and 0.1% TFA in acetonitrile (solvent B), using an appropriate elution gradient according to a compound, at a flow rate of 40 ml / min; Column: YMC TriartC18 75*30mm*5pm

[0144] Prep-HPLC (NH3H2O):An example: Mobile Phase: 0.05% NH3H2O and 10 mM NH4HCO3 in water (solvent A) and acetonitrile (solvent B), using the elution gradient 37%-67% (solvent B) over 9.5 minutes then holding at 100% for 2 minutes, at a flow rate of 25 ml / min; Column: Phenomenex Gemini 150*25mm*10pm.

[0145] Abbreviations which have been used in the descriptions of following examples are: AcCl is acetyl chloride; Bn is benzyl group; DCM is dichloromethane; DIPEA is N,N- diisopropylethylamine; DMSO is dimethyl sulfoxide; Et is ethyl; EtOAc is ethyl acetate; FA is formic acid; Hex is Hexane; m-CPBA is m-chloroperoxybenzoic acid; MeOH is methanol;MeCN is acetonitrile; MTBE is methyl tert-butyl ether or tert-butyl methyl ether; NaBH4 is sodium borohydride; NMP is A-methylpyrrolidone; Pd A-taPhos is bis[di-tert-butyl(4- dimethylaminophenyl)phosphine]palladium(0); Py is pyridine; TCFH is chloro-N,N,N’,N’- tetramethylformamidinium hexafluorophosphate; TFA is trifluoroacetic acid, THF is tetrahydrofuran.

[0146] Scheme 1[Chem. 14]4-(benzylamino)-3-chloro-lH-pyridazin-6-one (A19): To a solution of 3,4-dichloro-lH- pyridazin-6-one (Al) (CAS No.: 17285-36-8, 25.0 g, 152 mmol, 1.00 eq) in NMP (150 mL) was added BnNH2 (17.9 g, 167 mmol, 18.1 mL, 1.10 eq) and DIPEA (29.4 g, 227 mmol, 39.3 mL, 1.50 eq). The mixture was stirred at 150°C for 3 hrs. LCMS showed the Compound Al was consumed completely. The reaction mixture was poured into IM HC1 (1.00 L). The resulting mixture was stirred at room temperature for 30 min. The resulting precipitate was filtered and washed with H2O to afford a crude product. The crude product was triturated with EtO Ac / Hex (2 / 1, 400 mL) to afford Compound A19 (30.6 g, 130 mmol, crude yield: 85.7%).ESI-MS m / z = 236.0 [M+H]+.1H NMR: (400 MHz, DMSO-d6) 6 = 12.23 (s, 1H), 7.50 - 7.09 (m, 6H), 5.40 (s, 1H), 4.37 (d, J = 6.0 Hz, 2H).

[0147] Scheme 2[Chem. 15]ethyl 2-[4-(benzylamino)-3-chloro-6-oxo-pyridazin-l-yl] acetate (All): To a solution ofCompound A19 (1.35 g, 5.73 mmol, 1.00 eq) and K2CO3 (1.58g, 11.5 mmol, 2.00 eq) in NMP (10 mL) was added ethyl chloroacetate (A20) (CAS No.: 105-39-5, 1.05 g, 8.59 mmol, 0.92 mL, 1.50 eq). The mixture was stirred at 60°C for 4 hrs. LCMS showed the Compound A19 was consumed completely. The reaction mixture was filtered through Celite (Registered Trademark), and then washed with EtOAc (100 mL). To the filtrate was added H2O (100 mL), and the mixture was extracted with EtOAc (50 mL x 3). The organic phase was washed with brine and dried over Na2SO . The filtrate was evaporated under reduced pressure. The resulting residue was triturated with HexZEtOAc (4 / 1, 30 mL), filtered and dried. Compound All (1.39 g, 4.32 mmol, 75.4% yield in 2 steps) was obtained.ESI-MS m / z = 322.1 [M+H]+.1H NMR:(400 MHz, DMSO-d6) 6 = 7.57 (br t, J= 6.0 Hz, 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 = 6.0 Hz, 2H), 4.10 (q, J = 7.2 Hz, 2H), 1.17 (t, J = 7.2 Hz, 3H).

[0148] Scheme 3[Chem. 16]2-[4-(benzylamino)-6-oxo-3-[2-(trifluoromethyl) phenyl] pyridazin-l-yl] ethyl acetate(A23): To a degassed suspension of Compound All (11.1 g, 34.5 mmol, 1.00 eq), 2- trifluoromethylphenylboronic acid (A22) (CAS No.: 1423-27-4, 9.83 g, 51.7 mmol, 1.50 eq) andK3PO4 (11.0 g, 51.7 mmol, 1.50 eq) in 1,4-dioxane (180 mL) and H2O (20 mL) was added PdA-taPhos (1.22 g, 1.72 mmol, 0.05 eq). The reaction mixture was stirred at 100°C for 2 hrs. To the reaction mixture was added saturated NHqCl-aq (300 mL). The mixture was extracted with EtOAc (200 mL x 2). The combined organic phase was washed with brine and dried over Na2SC>4. The filtrate was evaporated under reduced pressure and purified by silica gel column chromatography. The crude product was triturated with EtOAc / Hex (2 / 1, 200 mL) to afford Compound A23 (10.8 g, 25.0 mmol, 72.4% yield).ESI-MS m / z = 432.1 [M+H]+.1H NMR: (400 MHz, CDCI3) 6 7.84 (d, J= 7.6 Hz, 1H), 7.73 - 7.60 (m, 2H), 7.50 (d, J= 7.6 Hz, 1H), 7.37 - 7.27 (m, 3H), 7.19 (d, J= 6.8 Hz, 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 = 7.2 Hz, 3H).

[0149] Scheme 4[Chem. 17]5-(benzylamino)-2-(2-hydroxyethyl)-6-[2-(trifluoromethyl) phenyl] pyridazin-3-one (A24):To a solution of Compound A23 (60 g, 139 mmol, 1.00 eq) in THF (700 mL) was added NaBHq (30.46 g, 805.1 mmol, 5.79 eq) at 0°C. The reaction mixture was stirred at 50°C for 12 hrs.LCMS showed the starting material was consumed completely. The reaction mixture was quenched with 0.5 mol / L HCl-aq (500 mL). The resulting mixture was extracted with EtOAc (500 mL x 3). The combined organic phase was washed with brine and dried over Na2SOq. The filtrate was evaporated under reduced pressure to give Compound A24 (63.1 g, crude).ESI-MS m / z = 390.1 [M+H]+.1H NMR: (400 MHz, CDCI3) 6 = 7.92 - 7.81 (m, 1H), 7.76 - 7.60 (m, 2H), 7.48 (d, J= 7.6 Hz, 1H), 7.37 - 7.28 (m, 3H), 7.19 (d, J= 7.2 Hz, 2H), 5.91 (s, 1H), 4.41 - 4.25 (m, 4H), 3.96 (t, J =4.8 Hz, 2H).

[0150] Scheme 5[Chem. 18]2-(4-(benzylamino)-6-oxo-3-(2-(trifluoromethyl)phenyl)pyridazin-l(6H)-yl)ethyl acetate(A25): To a solution of Compound A24 (63 g, 162 mmol, 1.00 eq) in DCM (600 mL) was addedacetyl chloride (19.1 g, 243 mmol, 17.3 mL, 1.50 eq) and pyridine (25.6 g, 323 mmol, 26.1 mL, 2.00 eq) at 25°C. The reaction mixture was stirred at 25°C for 16 hrs. LCMS showed the starting material was consumed completely. The reaction mixture was quenched with saturated NaHCC>3-aq (2.00 L). The mixture was extracted with EtOAc (1.00 L x 3). The combined organic phase was washed with 0.5 mol / L HCl-aq (2.00 L) and dried over Na2SOq. The filtrate was evaporated under reduced pressure and triturated with EtOAc / MTBE (1 / 10, 500 mL) to give Compound A25 (41.4 g, 96.0 mmol, 69% yield in 2 steps).ESI-MS m / z = 432.2 [M+H]+.1H NMR: (400 MHz, CDCI3) 6 = 7.85 (d, J= 7.6 Hz, 1H), 7.74 - 7.59 (m, 2H), 7.46 (d, J= 7.2 Hz, 1H), 7.38 - 7.27 (m, 3H), 7.19 (br d, J= 7.2 Hz, 2H), 5.86 (s, 1H), 4.50 - 4.28 (m, 4H), 4.26 (m, 2H), 2.00 (s, 3H).

[0151] Scheme 6[Chem. 19]2-[4-amino-6-oxo-3-[2-(trifluoromethyl)phenyl]pyridazin-l-yl]ethyl acetate (A26): To a solution of Compound A25 (10 g, 23.2 mmol, 1.00 eq, 4 batches) in EtOAc (80 mL) and MeOH(20 mL) was added Pd / C (20.0 g, 10% purity, 1.00 eq). The mixture was stirred at 60°C for 16 hrs under H2 atmosphere. LCMS showed the starting material was consumed completely. The reaction mixture was filtered through Celite (Registered Trademark), then washed with EtOAc (200 mL x 2). The filtrate was evaporated under reduced pressure to afford Compound A26 (26.9g, 78.8 mmol, 85% yield).ESI-MS tn / z = 342.1 [M+H]1H NMR: (400 MHz, CDCI3) 6 = 7.85 (d, J= 7.6 Hz, 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).

[0152] Scheme 7[Chem. 20]2-[4-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-6-oxo-3-[2-(trifluoromethyl)phenyl]pyridazin-l-yl]ethyl acetate (A28): To a solution of Compound A26(20 g, 58.60 mmol, 1.00 eq), 2-fluoro-5-(trifluoromethyl)benzoic acid (A27) (CAS No. : 115029-23-7, 30.5 g, 147 mmol, 2.50 eq) and DIPEA (26.5 g, 205 mmol, 35.7 mL, 3.50 eq) in NMP (220 mL) was added TCFH (41.1 g, 147 mmol, 2.50 eq) at 0°C. The reaction mixture was stirred at25°C for 12 hrs. LCMS showed the starting material was consumed completely. To the reaction mixture was quenched with saturated NHqCl-aq (2.00 L) and the mixture was extracted with EtOAc (500 mL x 3). The combined organic phase was washed with brine and dried overNa2SC>4. The filtrate was evaporated under reduced pressure to afford Compound A28 (34.25 g, crude).ESI-MS m / z = 532.3 [M+H]+.

[0153] Scheme 8[Chem. 21]2-fluoro-N-{l-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-l,6-dihydro-4- pyridazinyl}-5-(trifluoromethyl)benzamide (Compound 1): To a solution of Compound A28(34.2 g, crude) in MeOH (400 mL) was added NaOH-aq (5 M, 15.5 mL, 77.5 mmol, 1.20 eq) into the mixture at 0°C. The mixture was stirred at 0°C for 20 min. LCMS showed the starting material was consumed completely. H2O (2.00 L) was added to the reaction mixture (pH ~ 9.0). The mixture was extracted with EtOAc (500 mL x 4). The combined organic phase was washed with brine and dried over Na2SC>4. The filtrate was evaporated under reduced pressure to afford a crude product. The crude residue was recrystallized from EtOH (300 mL) / H2O (300 mL) to afford Compound 1 (18.8 g, 38.4 mmol, 65.5% yield in 2 steps) as a light yellow solid.ESI-MS m / z = 490.2 [M+H]+, LCMS Retention Time = 1.085 min.1H NMR: (400 MHz, DMSO-d6) 6 = 9.66 (s, 1H), 7.87-7.99 (m, 3H), 7.62-7.80 (m, 4H), 7.52 (t, 1H), 4.83 (t, 1H), 4.12 (t, 2H), 3.66-3.70 (m, 2H).

[0154] Scheme 9[Chem. 22]dibenzyl 2-[4-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-6-oxo-3-[2-(trifluoromethyl)phenyl]pyridazin-l-yl]ethyl phosphate (A30): To a suspention of Compound 1 (398 mg, 0.813 mmol, 1.00 eq) in DCM (3 mL) was added IH-tetrazole (74 mg, 1.06 mmol, 1.30 eq, CAS No.: 288-94-8) and dibenzyl diethylphosphorami dite (Compound A29, 387 mg, 1.22 mmol, 1.50 eq, CAS No.: 67746-43-4) into the mixture at 0°C. The mixture was stirred at0°C for 5 min. MeCN (0.5 mL) was added to the mixture and the resulting solution was stirred at 25°C for 1.5 hrs. m-CPBA (300 mg, 1.22 mmol, 1.50 eq) was added to the mixture. The reaction mixture was stirred at 25°C for 10 min. To the reaction mixture was added saturated NaHCOs-aq(10 mL). The mixture was extracted with DCM (20 mL x 2). The combined organic phase was washed with brine and dried over Na2SOq. The filtrate was evaporated under reduced pressure.The residue was purified by normal phase column chromatography (gradient: 10-100%Hexane / EtOAc, then 5-20% MeOH / EtOAc) to afford Compound A30 (609 mg, crude).

[0155] Scheme 10[Chem. 23]2-[4-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-6-oxo-3-[2-(trifluoromethyl)phenyl]pyridazin-l-yl]ethyl dihydrogen phosphate (Compound 2): To a solution of Compound A30 (609 mg, 0.813 mmol, 1.00 eq, impure) in EtOAc (8 mL) and MeOH(8 mL) was added Pd(OH)2 (600 mg, 20% purity, 1.05 eq). The mixture was stirred at 25°C for 4 hrs under H2 atmosphere. LCMS showed the starting material was consumed completely. The reaction mixture was filtered through Celite (Registered Trademark), then washed with EtOAc(20 mL x 2). The filtrate was evaporated under reduced pressure. The residue was purified by reverse phase column chromatography (gradient: 30-80% MeCN / 0.1% FA / H2O) to affordCompound 2 (97 mg, 0.17 mmol, 21% yield in 2 steps).ESI-MS m / z = 570.2 [M+H] , LCMS Retention Time = 1.041 min.1H NMR: (400 MHz, DMSO-d6) 8 = 9.66 (s, 1H), 7.88-7.99 (m, 3H), 7.66-7.81 (m, 4H), 7.52(m, 1H), 4.28 (br s, 2H), 3.90-4.17 (m, 2H).

[0156] Scheme 11[Chem. 24]N-{l-(2-hydroxyethyl)-6-oxo-3-[2-(trifluoromethyl)phenyl]-l,6-dihydro-4-pyridazinyl}-2- methoxy-5-(trifluoromethyl)benzamide (Compound 3): The Compound 3 was prepared in an analogous manner to Scheme 7 Scheme 8, where the reaction was carried out usingCompound A26 and 2-methoxy-5-(trifluoromethyl)benzoic acid (A31) (CAS No.: 4864-01-1).ESI-MS m / z = 502.2 [M+H] , HPLC Retention Time = 1.099 min.1H NMR: (400 MHz, DMSO-d6) 6 = 9.43 (s, 1H), 8.20 (d, 1H), 8.05 (d, 1H), 7.86-7.97 (m, 4H),7.79 (d, 1H), 7.32 (d, 1H), 4.79-4.84 (m, 1H), 4.11 (m, 2H), 3.67 (m, 2H), 3.33 (s, 3H).

[0157] Scheme 12[Chem. 25]dibenzyl 2-[4-[[2-methoxy-5-(trifluoromethyl)benzoyl]amino]-6-oxo-3-[2- (trifluoromethyl)phenyl]pyridazin-l-yl]ethyl phosphate (A32): To a suspention of Compound3 (70 mg, 0.139 mmol, 1.00 eq) in DCM (3 mL) was added IH-tetrazole (13 mg, 0.181 mmol, 1.30 eq) and dibenzyl diethylphosphoramidite (Compound A29, 53 mg, 0.167 mmol, 1.20 eq) into the mixture at 0°C. The mixture was stirred at 0°C for 5 min. MeCN (0.5 mL) was added to the mixture and the resulting solution was stirred at 25°C for 1.5 hrs. m-CPBA (41 mg, 0.167 mmol, 1.20 eq) was added to the mixture. The reaction mixture was stirred at 25°C for 10 min.To the reaction mixture was added saturated NaHCO3-aq (10 mL). The mixture was extracted with DCM (20 mL x 2). The combined organic phase was washed with brine and dried overNa2SC>4. The filtrate was evaporated under reduced pressure. The residue was purified by normal phase column chromatography (gradient: 10-100% Hexane / EtOAc, then 5-20%MeOH / EtOAc) to afford Compound A32 (25.3 mg, 0.033 mmol, 24% yield).1H NMR: (400 MHz, DMSO d-6) 8 =9.40 (s, 1H), 8.20 (br s, 1H), 7.98-8.06 (m, 1H), 7.88-7.91(m, 1H), 7.86 - 7.88 (m, 3H), 7.66 (m, 1H), 7.27-7.38 (m, 11H), 4.95 (d, 4H), 4.32 (br s, 4H),3.36 (s, 3H)

[0158] Scheme 13[Chem. 26]2- [4- [[2-methoxy-5-(trifluoromethyl)benzoyl] am ino ]-6-oxo-3- [2-(trifluoromethyl)phenyl]pyridazin-l-yl]ethyl dihydrogen phosphate (Compound 4): To a solution of Compound A32 (25 mg, 0.032 mmol, 1.00 eq) in EtOAc (1 mL) was added Pd(OH)2 (30 mg, 20% purity, 1.30 eq). The mixture was stirred at 25°C for 4 hrs under H2 atmosphere.LCMS showed the starting material was consumed completely. The reaction mixture was filtered through Celite (Registered Trademark), then washed with EtOAc (20 mL x 2). The filtrate was evaporated under reduced pressure to afford Compound 4 (6.1mg, 0.010 mmol, 32% yield).ESI-MS m / z = 582.2 [M+H]+. LCMS Retention Time = 1.028 min.1H NMR: (400 MHz, DMSO d-6) 6 = 9.41 (s, 1H), 8.18 (s, 1H), 8.04 (br d, 1H), 7.80-7.98 (m, 5H), 7.23-7.36 (m, 1H), 4.16-4.28 (m, 2H), 3.91-4.10 (m, 2H), 3.36 (s, 3H).LCMS analysis was carried out by method of Reverse-phase LCMS (5) unless otherwise specifiedNMR was taken by the method described above.[Biological Examples]

[0159] Example 1: In vitro TREK-1 and TREK-2 Inhibitor ActivityMeasurement conditions of TREK- 1 and TREK -2 Inhibitor Activity are as below.TREK-1 Thallium flux assayMethod 1;CH0-K1 cells stably expressing hTREK-1 were cultured in T225 flask. The cells were loaded with FluxOR dye and plated in 384 well plate at the experiment day. Test compounds or control compound (tert-butyl (3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4- chlorophenyl)carbamate) or 0.3% DMSO (vehicle control) were added directly to the cell plates and incubated for 10 min, and then treated with thallium stimulus buffer to initiate thallium flux. To measure the efficacy and potency of test compounds, the change in fluorescence intensity (ARatio) and % inhibition were calculated using the following equations:ARatio = (fluorescence intensity at 25 seconds after thallium addition) / (average of fluorescent intensity before thallium addition)% inhibition = { 1 - (ARatio of test compound - ARatio of 10 pM control compound) / (ARatio of 0.3% DMSO - ARatio of 10 pM control compound) }x 100% inhibition vs compound concentration were plotted in XLfit and calculated IC50-Results: The compounds shown in Table 1 were evaluated in our TREK-1 Thallium (T1+) flux assay. The data were measured by Method 1 of TREK-1 Thallium flux assay unless otherwise specified as described below. It was found that Compound 1 and 3 which are possibly produced in the metabolism process of animals and humans from Compound 2 and 4, respectively, have a prominent TREK-1 inhibitory activity.

[0160] [Table 1]

[0161] Method 2;CHO-K1 cells stably expressing human TREK-1 (hTREK-1) are cultured in T225 flask. The cells are loaded with FluxOR dye and plated in 384 well plate at the experiment day. Test compounds or control compound (tert-butyl (3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4- chlorophenyl)carbamate) or 0.3% DMSO (vehicle control) which are prepared on separate plates are added to the cell plates and incubated for 10 min, and then the cells with test compounds or control compound (tert-butyl (3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4- chlorophenyl)carbamate) or 0.3% DMSO (vehicle control) are treated with thallium stimulus buffer to initiate thallium flux. To measure the efficacy and potency of test compounds, the change in fluorescence intensity (ARatio) and % inhibition are calculated using the following equations:ARatio = (fluorescence intensity at 25 seconds after thallium addition) / (average of fluorescent intensity before thallium addition)% inhibition = { 1 - (ARatio of test compound - ARatio of 10 pM control compound) / (ARatio of 0.3% DMSO - ARatio of 10 pM control compound) }x 100% inhibition vs compound concentration were plotted in XLfit and calculated IC50-

[0162] TREK-2 Thallium flux assayHEK293 cells stably expressing human TREK -2 (hTREK-2) are plated in 384-well plates, cultured overnight, loaded with Thallos dye the following day. Test compounds or control compound (tert-butyl (3-((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4- chlorophenyl)carbamate) or 0.3% DMSO (vehicle control) which are prepared on separate plates are added to the cell plates and incubated for 10 min, and then the cells are treated with thallium stimulus buffer to initiate thallium flux. To measure the efficacy and potency of test compounds, the change in fluorescence intensity (ARatio) and % inhibition are calculated using the following equations:ARatio = (fluorescence intensity at 25 seconds after thallium addition) / (average of fluorescent intensity before thallium addition)% inhibition = { 1 - (ARatio of test compound - ARatio of 10 pM control compound) / (ARatio of 0.3% DMSO - ARatio of 10 pM control compound) }x 100

[0163] Patch clamp technique hTREK-1 and mTREK-1 patch clamp assayCHO-K1 cells stably expressing hTREK-1 were plated on glass coverslips, and voltage clamped in the whole-cell configuration of the patch clamp technique. Cells were voltage clamped at a holding potential of -80 mV and then stepped to 0 mV for 500 msec. The voltage was subsequently ramped from -120mV to +80 mV over a 500 msec duration. This step-ramp protocol was repeated every 10 sec. The bathing solution contained the following: 135 mM NaCl, 5 mM KC1, 2 mM CaCh, 1 mM MgCh, 5 mM D-Glucose, 10 mM HEPES, 10 mM sucrose (adjusted to pH 7.4 with NaOH, 300 mosmol / kg H2O). The pipette solution contained the following: 135 mM KC1, 2 mM MgCh, 1 mM EGTA, 10 mM HEPES, 2 mM Na2ATP (adjusted to pH 7.35 with KOH, 285 mosmol / kg H2O). Test compounds were dissolved into thebathing solution. The effects of test compound on the currents were calculated at 0 mV using the following equations:% inhibition = (1-post current / pre current) x 100% inhibition vs compound concentrations were plotted in GraphPad Prism and calculated IC50. mTREK-1 patch clamp assay is conducted by a similar procedure to hTREK-1 patch clamp assay above using CHO-K1 cells transiently expressing mouse TREK-1 (mTREK- 1).Results: It was found that Compound 1 has a prominent hTREK-1 inhibitory activity.

[0164] hTREK-2 patch clamp assayHEK293 cells stably expressing human TREK -2 are plated on glass coverslips, and voltage clamped in the whole-cell configuration of the patch clamp technique. Cells are voltage clamped at a holding potential of -80 mV and the stepped to 0 mV for 500 msec. The voltage is subsequently ramped from -120mV to +80 mV over a 500 msec duration. This step-ramp protocol is repeated every 10 sec. The bathing solution contained the following: 135 mM NaCl, 5 mM KC1, 2 mM CaC12, 1 mM MgC12, 5 mM D-Glucose, 10 mM HEPES, 10 mM sucrose (adjusted to pH 7.4 with NaOH, 300 mosmol / kg H2O). The pipette solution contained the following: 135 mM KC1, 2 mM MgC12, 1 mM EGTA, 10 mM HEPES, 2 mM Na2ATP (adjusted to pH 7.35 with KOH, 285 mosmol / kg H2O). Test compounds are dissolved into the bathing solution. Experiments are terminated with the addition of the control compound (tert-butyl (3- ((4-(benzyloxy)-2-methylphenyl)carbamoyl)-4-chlorophenyl)carbamate) so that maximal inhibition can be determined. The effects of test compound on the currents can be calculated at 0 mV using the following equations:% inhibition = { 1 - (post current - current in the presence of 10 pM control compound) / (precurrent - current in the presence of 10 pM control compound)} x 100

[0165] Example 2. In vivo pharmacology testForced swim testDrugs: Test compound was formulated in 10% Tween 80 / 90% sterile water vehicle. Following vigorous vortexing, the formulated compound was placed in an ultrasonic water bath for 1 hour. Test compound was formulated at a concentration that allowed for an oral (p.o.) administration of 10 mL dosing solution / kg body weight.Animals: Adult male BALB / cCrSlc mice (Japan SLC) at six-week-old were used. They were housed in an animal care facility certified by the Japan Health Sciences Foundation under a 12- hour light / dark cycle (lights on: 7 a.m.; lights off: 7 p.m.) and had free access to food and water. Animals were acclimated to the housing facility for at least six days before being tested and the behavioral testing was performed during the light phase. All experiments were approved by the Institutional Animals Care and Use Committee of Ono Pharmaceutical Co., Ltd.Apparatus: For the forced swim test, a clear plastic cylinder (10 cm diameter x 25 cm height) containing 10 cm water in depth warmed 24 ± 2°C was used.Procedure: Plastic animal cages (29 cm x 44 cm x 20 cm, 8 animals for each) were moved from the animal facility to the soundproof room in the morning of the test. After acclimation for 5 hours, the vehicle solution or test compound was administered orally an hour before the forced swim procedure. Imipramine (60 mg / kg, p.o.) was administered as a positive control.Behavioral analysis: The total immobility time in the above cylinder was recorded for six minutes using a video camera, and used as an index of antidepressant-like behaviors.Data Analysis: Statistical analyses were performed using EXSUS ver 8.1 (CAC Croit Corporation). The total immobility time of the vehicle solution and compound groups wereanalyzed. The vehicle and compound-treated groups were analyzed by one-way ANOVA followed by Dunnetf s test. The vehicle and imipramine-treated group were analyzed by Student t-test. A p-value = 0.05 is considered to represent a significant difference.Results: Compound 1 at 3 mg / kg significantly reduced the immobility time. Data are illustrated in Figure 1.Conclusions: Systemic administration of Compound 1 caused reduction of immobility time in the forced swim test, a preclinical rodent model of depression-like behavior.

[0166] MK-801-induced novel object recognition testDrugs: Test compound was formulated in 20% Kolliphor HS 15 / propylene glycol (7:3) / 80% sterile water vehicle. Following vigorous vortexing, the formulated compound was placed in an ultrasonic water bath for 1 hour. The compound was formulated at a concentration that allowed for an oral (p.o.) administration of 10 mL dosing solution / kg body weight. MK-801 hydrogen maleate was obtained from Sigma-Aldrich, dissolved in sterile saline, and dosed intraperitoneally in a volume of 1 mL / kg body weight (0.2 mg / kg).Animals: Adult male C57BL / 6J mice (Charles River Japan) at six-week-old were used. They were housed in an animal care facility certified by the Japan Health Sciences Foundation under a 12-hour light / dark cycle (lights on: 7 a.m.; lights off: 7 p.m.) and had free access to food and water. Animals were acclimated to the housing facility for a minimum of six days before being tested and the behavioral testing was performed during the light phase. All experiments were approved by the Institutional Animals Care and Use Committee of Ono Pharmaceutical Co., Ltd. Apparatus: For the novel object recognition test an opaque Plastic chamber (35 cm x 40 cm x 18 cm) was used. At opposite ends of the chamber test objects could be placed. A video camera was mounted above the apparatus for recording the behavior.Procedure: Habituation. At least one day prior to behavioral testing, animals were habituated to the empty testing chamber, i.e. in the absence of any objects, for ten minutes.Training. One hour after administration of vehicle, the compound (p.o.) or clozapine (1 mg / kg, p.o.), and 30 minutes after administration of saline or MK-801, animals were placed into the testing chamber that contained two identical objects (LEGO (registered Trademark) blocks) for a session duration of 10 minutes. Afterwards, animals were returned to their home cage.Recognition. Ninety minutes after the end of the training session, animals were reintroduced to the test chamber where one of the two identical objects have been replaced by a novel object (glass vial) for a total of 10 minutes.Behavioral analysis: An observer blinds to treatment condition and novel object location used the video recordings to score the interaction of the animal with the two objects offline. The duration an animal explored each object was determined as the total time an animal is facing the object with its nose being 2 cm away from the object and some discernible whisker movement being present. From these data, a Discrimination Index is calculated as follows:Discrimination Index = 100 x (time exploring Novel object - time exploring Familiar object) / time exploring Novel object + time exploring Familiar object).Data Analysis: Statistical analyses can be performed using EXSUS ver 8.1 (CAC Croit Corporation). The vehicle and compound-treated groups were analyzed by one-way ANOVA followed by Dunnetf s test. The vehicle and vehicle-MK-801, and vehicle-MK-801 and clozapine groups can be analyzed by Student t-test. A p-value = 0.05 is considered to represent a significant difference.Results: Compound 1 at 3 mg / kg significantly increased Discrimination Index. Data are illustrated in Figure 2.Conclusions: Systemic administration of Compound 1 caused amelioration in the MK-801-induced novel object recognition test, a preclinical rodent model of cognitive disrupted behavior.

[0167] Novel suppressed feeding testDrugs: Test compound was formulated in 20% Kolliphor HS 15 / propylene glycol (7:3) / 80% sterile water vehicle. Following vigorous vortexing, the formulated compound was placed in an ultrasonic water bath for 1 hour. The compound was formulated at a concentration that allowed for an oral (p.o.) administration of 10 mL dosing solution / kg body weight.Animals: Adult male SlcTCR mice (Japan SLC Inc.) at six-week-old were housed in an animal care facility certified by the Japan Health Sciences Foundation under a 12-hour light / dark cycle (lights on: 7 a.m.; lights off: 7 p.m.), acclimated at least for six days before the test. The animals had free access to water, and were fasted only for 24 hours before the test. All experiments were approved by the Institutional Animals Care and Use Committee of Ono Pharmaceutical Co., Ltd.Apparatus: For the novel suppressed feeding test, an opaque Plastic open field (60 cm in diameter) under 200 Lux was used. A video camera was mounted above the apparatus for recording the behavior.Procedure: Animals were moved to the testing facility and acclimated for 5 hours prior to the test. One hour after administration of vehicle, the compound (p.o.) or scopolamine (0.03 mg / kg, i.p.) as a positive control, animals were placed into the open field, in which a food pellet is placed in the center.Behavioral analysis: The latency to initiate a feeding behavior was recorded, and used as an index of early onset antidepressant-like behaviors. The test was stopped immediately after the first feeding episode and the cut-off time was 5 minutes.Data Analysis: Statistical analyses can be performed using EXSUS ver 8.1 (CAC Croit Corporation). The vehicle and compound-treated groups were analyzed by one-way ANOVAfollowed by Dunnetf s test. The vehicle and scopolamine-treated group were analyzed by Student t-test. A p-value = 0.05 is considered to represent a significant difference.Results & Conclusions: Systemic administration of Compound 1 caused amelioration of latency time in the novel suppressed feeding test, a preclinical rodent model of depression-like behavior.

[0168] Example 3. Pharmacokinetic Study in RatsThe pharmacokinetics of Compound 2, a phosphate prodrug of Compound 1, was evaluated in rats.[Preparation of Drug Solution for Administration]

[0169] A drug solution for oral administration was prepared by weighing of Compound 2 and dissolving it in a vehicle at 0.3 mg / mL .[Collection of Plasma Sample]

[0170] The drug solution was orally administered at 10 mL / kg (3 mg / kg) through an oral probe into the stomach of male Crl:CD(SD) rats (THE JACKSON LABORATORY JAPAN, INC) that had been fasted since the day before administration. 0.3 mL of blood was collected from the jugular vein using a heparinized syringe at 15, 30 minutes, 1, 2, 4, 7, and 24 hours after administration. After blood collection, the blood was centrifuged at 16,200 g for 3 minutes at 4°C in a tabletop centrifuge, and the obtained plasma was stored at -20°C until measurement of the plasma concentration.[Preparation of Analytical Sample and Analysis]

[0171] The plasma was thawed, stirred, and centrifuged at 16200 g for 3 minutes at 4°C. 10 pL of thesupernatant was mixed with 40 pL of acetonitrile and 160 pL of a mixture of acetonitrile / ethanol (7 / 3) containing an internal standard. Furthermore the mixture and 50% acetonitrile were mixed in equal amounts and analyzed by LC / MS / MS. The LC / MS / MS analysis was performed under the following conditions. The resulting supernatant was filtered and the filtrate was analyzed by LC / MS / MS. The analysis was performed by LC / MS / MS under the following conditions.[HPLC Condition]

[0172] Measurement Apparatus: Nexera X2 system (manufactured by Shimadzu Corporation.) Analytical column: Shim-pack XR-ODS II 2.0 mm ID x 75 mm Analytical column temperature: 40°C Flow rate: 0.5 mL / minMobile phase: A: 0.2% formic acid / 5 mmol / L ammonium acetate B: acetonitrileTime program

[0173] [Table 2][MS / MS Conditions]

[0174] Measurement Apparatus: QTRAP6500 (manufactured by AB Sciex Pte. Ltd.)• Compound 2Scan type: MRMPolarity: positiveDetection: m / z (QI): 570.174, m / z (Q3): 472.132DP (Declustering Potential): 95EP (Entrance Potential): 12CE (Collision Energy): 23CXP (Collision Cell Exit Potential): 17• Compound 1Scan type: MRMPolarity: positiveDetection: m / z (QI): 490.301, m / z (Q3): 263.213DP (Declustering Potential): 105EP (Entrance Potential): 12CE (Collision Energy): 38CXP (Collision Cell Exit Potential): 19[Results]

[0175] The results of the kinetic study in rats are shown below.Table 3 and Table 4 show the plasma concentration of Compound 1 and Compound 2, respectively, after single oral administration of Compound 2 to fasted Crl:CD(SD) rats. And Table 5 shows pharmacokinetic parameters of Compound 1. Compound 2 was below the lower limit of quantification at all time points. For Compound 1, the Cmax was 169 ng / mL, the Tmax was 1.5 h, the AUCinf was 757 ng • h / mL.

[0176] It was found that Compound 1 was produced in the metabolism process of rats fromCompound 2. Compound 3 is expected to be produced in the metabolism process of rats fromCompound 4 in the same manner as Compound 1.

[0177] [Table 3]Plasma concentration of Compound 1 after single oral administration of Compound 2 to fasted Crl:CD(SD) ratsBLQ: Lower than 0.48 ng / mL

[0178] [Table 4]Plasma concentration of Compound 2 after single oral administration of Compound 2 to fasted Crl:CD(SD) ratsBLQ: Lower than 16 ng / mL

[0179] [Table 5]Pharmacokinetic parameters of Compound 1 after single oral administration of Compound 2 to fasted Crl:CD(SD) rats

[0180] It is understood that the foregoing detailed description and accompanying examples are merely illustrative and are not to be taken as limitations upon the scope of the disclosure, which is defined solely by the appended claims and their equivalents.

Claims

[CLAIMS]

1. A compound of formula (I-A):[Chem. 1]or a pharmaceutically acceptable salt thereof; whereinR1is (1) a hydrogen atom or (2) Cl-8 alkyl;2 1R is selected from the group consisting of (1) a halogen atom, (2) Cl-4 alkoxy and (3) Cl-4 haloalkoxy;R3is (1) Cl-4 alkyl or (2) Cl-4 haloalkyl;R4is (1) Cl-4 alkyl or (2) Cl-4 haloalkyl.

2. The compound according to claim 1, which is a compound of formula (I):[Chem. 2]or a pharmaceutically acceptable salt thereof;wherein2R is (1) a fluorine atom or (2) methoxy; and R.1is as defined in claim 1.

3. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 2-[4-[[2-fluoro-5-(trifluoromethyl)benzoyl]amino]-6-oxo-3-[2-(trifluoromethyl)phenyl]pyridazin- 1 -yl]ethyl dihydrogen phosphate.

4. A compound of the following structure:[Chem. 4]

5. A pharmaceutically acceptable salt of a compound of the following structure:[Chem. 5]

6. A compound or a pharmaceutically acceptable salt thereof, wherein the compound is 2-[4-{[2-methoxy-5-(trifluoromethyl)benzoyl]amino}-6-oxo-3-[2-(trifluoromethyl)phenyl]-l(6H)- pyridazinyl] ethyl dihydrogen phosphate.

7. A compound of the following structure:[Chem. 6]

8. A pharmaceutically acceptable salt of a compound of the following structure:[Chem. 7]

9. A pharmaceutical composition comprising the compound according to any one of claims1 to 8, or the pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, which is a TREK-1, TREK-2 or both TREK-1 and TREK -2 inhibitor.

11. The pharmaceutical composition according to claim 9, which is a preventive and / or therapeutic agent for a disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK-2 dysfunction.

12. The pharmaceutical composition according to claim 11, wherein the disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK-2 dysfunction is a neurological disorder, psychiatric disorder, cognitive disorder, pain, cancer and / or lung fibrosis.

13. The pharmaceutical composition according to claim 12, wherein the neurological and / or psychiatric disorder is selected from the group consisting of depression, schizophrenia, anxiety disorders, bipolar disorder, Alzheimer's disease, Parkinson's disease, Huntington's disease, Amyotrophic lateral sclerosis, 22ql l.2 deletion syndrome, neuropathic pain and cerebral infarction.

14. A method for preventing and / or treating a disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK -2 dysfunction, comprising administering an effective amount of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof to a mammal.

15. The compound according to any one of claims 1 to 8, or a pharmaceutically acceptablesalt thereof for use in prevention and / or treatment of a disorder associated with TREK-1, TREK- 2 or both TREK-1 and TREK-2 dysfunction.

16. Use of the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof for manufacturing a preventive and / or therapeutic agent for a disorder associated with TREK-1, TREK-2 or both TREK-1 and TREK-2 dysfunction.

17. A kit comprising the compound according to any one of claims 1 to 8, or a pharmaceutically acceptable salt thereof, and one or more of:(a) at least one agent known to decrease a TREK-1 channel activity;(b) at least one agent known to decrease a TREK-2 channel activity;(c) at least one agent known to prevent and / or treat a disorder associated with TREK channel dysfunction in which inhibitors of TREK- 1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit in a mammal;(d) instructions for preventing and / or treating a disorder associated with TREK channel dysfunction in which inhibitors of TREK- 1, TREK-2 or both TREK-1 and TREK-2 would offer therapeutic benefit in a mammal; and(e) instructions for administering the compound in connection with cognitive behavioral therapy.

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