Heterocyclic compounds

Abstract

The present invention provides a therapeutic agent for ADHD that has efficacy comparable to that of central stimulants and has a low risk of drug dependence and abuse equivalent to existing non-central stimulants, more specifically, a compound represented by general formula [I]: Formula [I] JPEG2024525719000065.jpg4787 [wherein each symbol is as defined in the specification.]

Description

[Technical Field]

[0001] This invention relates to heterocyclic compounds, and more specifically, to heterocyclic compounds having reuptake inhibitory effects on serotonin, norepinephrine, and / or dopamine. [Background technology]

[0002] Attention-Deficit Hyperactivity Disorder (ADHD) is a developmental disorder characterized by inattention, hyperactivity, and impulsivity as core symptoms. The prevalence is estimated to be 5% in children and 2.5% in adults (Non-Patent Literature 1), and it has been reported that more than 65% of patients diagnosed with ADHD in childhood continue to experience ADHD symptoms into adulthood (Non-Patent Literature 2). ADHD is not limited to its core symptoms; it has been reported that it can cause various secondary and comorbid disorders as individuals grow older (Non-Patent Literature 3). In general, individuals with ADHD have a high prevalence of mood disorders, anxiety disorders, externalization disorders, or substance use disorders, and they often experience difficulties in daily life in terms of independence, education, employment, and economic status (Non-Patent Literature 4). To overcome such disorders, it is considered necessary to confirm the diagnosis early and begin treatment. The pathogenesis of ADHD is thought to involve monoamine nervous systems, such as dopamine neurons. Drug treatment for ADHD mainly involves central nervous system stimulants (amphetamine, methamphetamine, methylphenidate and their derivatives, etc.) and non-central nervous system stimulants (atomoxetine, guanfacine, clonidine, etc.) that act on the monoamine nervous system. Central nervous system stimulants offer superior efficacy (rapid onset and effect), but carry a risk of drug dependence and abuse, and have a short duration of effect. Non-central nervous system stimulants have a lower risk of drug dependence and abuse, but take time to stabilize their effects. Among non-central nervous system stimulants, atomoxetine (a norepinephrine reuptake inhibitor) is used as a first-line drug, or as a second-line drug when central nervous system stimulants are ineffective or their side effects are unacceptable. Bupropion (a norepinephrine / dopamine reuptake inhibitor), an antidepressant, is also sometimes used (Non-Patent Literature 5). Furthermore, the involvement of the serotonergic system has been reported in impulsivity, one of the core symptoms of ADHD (Non-Patent Literature 6), and there are also reports that impulsivity-like symptoms in ADHD model animals can be suppressed by serotonin reuptake inhibitors (Non-Patent Literature 7). Patent documents 1 and 2 disclose heterocyclic compounds as therapeutic agents for diseases affecting the central nervous system. [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] WO2012 / 036253 [Patent Document 2] WO2013 / 137479 [Non-patent literature]

[0004] [Non-Patent Document 1] Lancet, 395, 450-462, 2020 [Non-Patent Document 2] Psycho Med.,36(2),159-65, 2006 [Non-Patent Document 3] Clinical Psychopharmacology, 17(09), 1229-1236, 2014 [Non-Patent Document 4] Clinical Psychopharmacology, 15(11), 1811-1820, 2012 [Non-Patent Document 5] Neuropsychiatr Dis Treat. 2014 Aug 1;10:1439-49 [Non-Patent Document 6] Neurochemistry International 82 (2015) 52-68 [Non-Patent Document 7] Pharmacol Biochem Behav., 105, 89-97, 2013 [Summary of the Invention] [Problem to be Solved by the Invention]

[0005] An object of the present invention is to provide a therapeutic agent for ADHD that has efficacy comparable to central stimulants and has a low risk of drug dependence and abuse equivalent to existing non-central stimulants. Another object of the present invention is to provide a drug that exhibits sustained effects with less drug interaction, at a lower dosage and at a lower blood drug concentration, due to its excellent pharmacokinetic properties (high metabolic stability, long duration of effective blood concentration maintenance, low protein binding rate, low CYP inhibition rate) and sustained pharmacological action. [Means for Solving the Problem]

[0006] As a result of intensive studies to solve the above problems, the present inventors succeeded in synthesizing a heterocyclic compound represented by the following general formula, which has a structure in which a hydroxyethoxy group is bonded to an aryl moiety, and which can be used for producing a desired drug. The present invention has been completed based on such findings.

[0007] That is, the present invention includes the following embodiments. [1-1] Formula [I]: JPEG0007918251000001.jpg5088[In the formula, R 11 , R 12 and R 13 are the same or different, each independently being hydrogen or C 1-6 alkyl, or R 11 and R 12 form a 3- to 8-membered cycloalkane together with the adjacent carbon atom; R 22 , R 23 , R 25 and R 26These are identical or different, each independently of hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 It is alkoxy, or R 22 and R 23 It forms a 9-10 membered bicyclic system with the adjacent benzene ring, further containing an oxygen atom as a ring constituent element; R 31 and R 32 [These are either the same or different, and each is independently hydrogen or halogen.] A compound represented by or a salt thereof. [1-2] The compound or salt thereof described in [1-1], wherein formula [I] is selected from formula [Ia], formula [Ib], formula [Ic], or formula [Id]. JPEG0007918251000002.jpg84146 [The symbols in the formula are the same as above] [1-3] In formula [I], R 11 , R 12 and R 13 These are either the same or different, independently of each other, hydrogen or methyl, or R 11 and R 12 It forms cyclobutyl with adjacent carbon atoms; R 22 , R 23 , R 25 and R 26 These are, either identical or distinct, each independently, hydrogen, fluorine, chlorine, methyl, or methoxy, or R 22 and R 23 It forms a benzofuran with the adjacent benzene ring; R 31 and R 32 These are, either identical or distinct, hydrogen or fluorine, each independently; The compound or salt thereof described in [1-1] or [1-2]. [1-4] In formula [I], R 22 , R 23 , R 25 and R 26 A compound or salt thereof described in any of [1-1] to [1-3], wherein two or more of the atoms are hydrogen. [1-5] A compound or salt thereof selected from the group consisting of the following compounds, as described in any of [1-1] to [1-4]. JPEG0007918251000003.jpg124150[2] A pharmaceutical composition comprising, as an active ingredient, any compound described in [1-1] to [1-5] or a salt thereof, and a pharmaceutically acceptable carrier. [3-1] An agent for the treatment, prevention and / or diagnosis of disorders related to serotonin, norepinephrine and / or dopamine nerve dysfunction, comprising any of the compounds described in [1-1] to [1-5] or a salt thereof as an active ingredient. [3-2] Disorders include attention-deficit / hyperactivity disorder (ADHD), Tourette's syndrome, autism spectrum disorder, Asperger's syndrome, depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder, anxiety associated with various diseases, generalized anxiety disorder, phobias, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, acute stress disorder, hypochondriasis, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorders, obesity, chemical addiction, pain, fibromyalgia, apathy, Alzheimer's disease, memory impairment, Parkinson's disease, restless legs syndrome, internal A therapeutic, prophylactic and / or diagnostic agent for disorders selected from the group consisting of secretory disorders, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorders, negative symptoms of schizophrenia, affective disorders of schizophrenia, cognitive impairment of schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulsivity dysregulation, trichotillomania, kleptomania, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome, and headache [3-1]. [3-3] The therapeutic, preventive and / or diagnostic agent described in [3-2], wherein depression is selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymia; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; mild depression; recurrent short-term depressive disorder; treatment-resistant depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactolation syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes mellitus, viral infections, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; middle-aged depression; geriatric depression; childhood and adolescent depression; and drug-induced depression such as interferon. [3-4] Anxiety associated with various diseases, selected from the group consisting of head injury, brain infection, inner ear disorder, heart failure, arrhythmia, hyperadrenofunction, hyperthyroidism, asthma, and chronic obstructive pulmonary disease, as described in [3-2] for the treatment, prevention, and / or diagnosis. [3-5] A therapeutic, prophylactic and / or diagnostic agent as described in [3-2], wherein the pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia and diabetic neuropathy. [4-1] A pharmaceutical composition for the treatment, prevention and / or diagnosis of disorders related to serotonin, norepinephrine and / or dopamine nerve dysfunction, comprising any compound described in [1-1] to [1-5] or a salt thereof as an active ingredient. [4-2] Disorders include attention-deficit / hyperactivity disorder (ADHD), Tourette's syndrome, autism spectrum disorder, Asperger's syndrome, depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder, anxiety associated with various diseases, generalized anxiety disorder, phobias, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, acute stress disorder, hypochondriasis, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorders, obesity, chemical addiction, pain, fibromyalgia, apathy, Alzheimer's disease, memory impairment, Parkinson's disease, restless legs syndrome, endocrine disorders. A pharmaceutical composition for the treatment, prevention and / or diagnosis of a disorder selected from the group consisting of [4-1]: a disorder, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorder, negative symptoms of schizophrenia, affective disorder of schizophrenia, cognitive impairment of schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulse control disorder, trichotillomania, kleptomania, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome, and headache. [4-3] The therapeutic, preventive and / or diagnostic pharmaceutical composition according to [4-2], wherein depression is selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymia; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; mild depression; recurrent short-term depressive disorder; treatment-resistant depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactolation syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes mellitus, viral infections, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; middle-aged depression; geriatric depression; childhood and adolescent depression; and drug-induced depression such as interferon. [4-4] The therapeutic, preventive and / or diagnostic pharmaceutical composition according to [4-2], wherein the anxiety associated with various diseases is selected from the group consisting of head injury, brain infection, inner ear disorder, heart failure, arrhythmia, adrenal insufficiency, hyperthyroidism, asthma and chronic obstructive pulmonary disease. [4-5] A therapeutic, preventive and / or diagnostic pharmaceutical composition according to [4-2], wherein the pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia and diabetic neuropathy. [5-1] A method for treating, preventing and / or diagnosing disorders related to serotonin, norepinephrine and / or dopamine nerve dysfunction, comprising administering an effective amount of any of the compounds or salts thereof described in [1-1] to [1-5] to a subject. [5-2] Disorders include attention-deficit / hyperactivity disorder (ADHD), Tourette's syndrome, autism spectrum disorder, Asperger's syndrome, depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder, anxiety associated with various diseases, generalized anxiety disorder, phobias, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, acute stress disorder, hypochondriasis, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorders, obesity, chemical addiction, pain, fibromyalgia, apathy, Alzheimer's disease, memory impairment, Parkinson's disease, restless legs syndrome, internal A method for the treatment, prevention and / or diagnosis of a disorder selected from the group consisting of secretory disorders, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorders, negative symptoms of schizophrenia, affective disorders of schizophrenia, cognitive impairment of schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulse control disorder, trichotillomania, kleptomania, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome and headache [5-1]. [5-3] Depression is a type of depression selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymia; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; mild depression; recurrent short-term depressive disorder; treatment-resistant depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactolation syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes mellitus, viral infections, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; middle-aged depression; geriatric depression; childhood and adolescent depression; and drug-induced depression such as interferon-induced depression, as described in [5-2]. [5-4] Anxiety associated with various diseases, selected from the group consisting of head injury, brain infection, inner ear disorder, heart failure, arrhythmia, hyperadrenofunction, hyperthyroidism, asthma, and chronic obstructive pulmonary disease, as described in [5-2]. Treatment, prevention and / or diagnostic methods. [5-5] The treatment, prevention and / or diagnostic method described in [5-2], wherein the pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia and diabetic neuropathy. [6-1] A compound or salt thereof described in any of [1-1] to [1-5] for use in the treatment, prevention and / or diagnosis of disorders associated with serotonin, norepinephrine and / or dopaminergic nerve dysfunction. [6-2] Disorders include attention-deficit hyperactivity disorder (ADHD), Tourette's syndrome, autism spectrum disorder, Asperger's syndrome, depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder, anxiety associated with various diseases, generalized anxiety disorder, phobias, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, acute stress disorder, hypochondriasis, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorders, obesity, chemical addiction, pain, fibromyalgia, and apathy. A disorder selected from the group consisting of Alzheimer's disease, memory impairment, Parkinson's disease, restless legs syndrome, endocrine disorders, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorders, negative symptoms of schizophrenia, affective disorders of schizophrenia, cognitive impairment of schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulse control disorder, trichotillomania, kleptomania, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome, and headache [6-1], the compound or salt thereof. [6-3] Depression is a type of depression selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymia; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; mild depression; recurrent short-term depressive disorder; treatment-resistant depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactolemia syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes mellitus, viral infections, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; middle-aged depression; geriatric depression; childhood and adolescent depression; and drug-induced depression such as interferon. [6-2] The compound or salt thereof. [6-4] The anxiety associated with various diseases is selected from the group consisting of head injury, brain infection, inner ear disorder, heart failure, arrhythmia, adrenal insufficiency, hyperthyroidism, asthma, and chronic obstructive pulmonary disease. [6-2] The compound or salt thereof. [6-5] The pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia, and diabetic neuropathy. [6-2] The compound or salt thereof. [7-1] Use of any of the compounds described in [1-1] to [1-5] or salts thereof in the manufacture of a pharmaceutical product for use in the treatment, prevention and / or diagnosis of disorders associated with serotonin, norepinephrine and / or dopaminergic nerve dysfunction. [7-2] Disorders include attention-deficit / hyperactivity disorder (ADHD), Tourette's syndrome, autism spectrum disorder, Asperger's syndrome, depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder, anxiety associated with various diseases, generalized anxiety disorder, phobias, obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, acute stress disorder, hypochondriasis, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorders, obesity, chemical addiction, pain, fibromyalgia, apathy, Alzheimer's disease, memory impairment, Parkinson's disease, and restless legs syndrome. Use as described in [7-1] for disorders selected from the group consisting of leg syndrome, endocrine disorders, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorders, negative symptoms of schizophrenia, affective disorders of schizophrenia, cognitive impairment of schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulsivity dysregulation, trichotillomania, kleptomania, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome, and headache. [7-3] Depression is a depression selected from the group consisting of major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymia; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; mild depression; recurrent short-term depressive disorder; treatment-resistant depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactolation syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes mellitus, viral infections, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc.; middle-aged depression; geriatric depression; childhood and adolescent depression; and drug-induced depression such as interferon. [7-2] Use as described above. [7-4] Anxiety associated with various diseases is selected from the group consisting of head injury, brain infection, inner ear disorder, heart failure, arrhythmia, adrenal insufficiency, hyperthyroidism, asthma, and chronic obstructive pulmonary disease. [7-2] Use as described above. [7-5] The use described in [7-2], wherein the pain is selected from the group consisting of chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia, and diabetic neuropathy. [8] Use of any of the compounds or salts thereof described in [1-1] to [1-5] as serotonin reuptake inhibitors, norepinephrine reuptake inhibitors and / or dopamine reuptake inhibitors. [Effects of the Invention]

[0008] Drugs that inhibit the reuptake of serotonin, norepinephrine, and / or dopamine at appropriate levels and proportions are expected to be therapeutic agents that combine the best properties of both stimulants and non-stimulants. In in vitro studies, this compound potently and optimally inhibits the reuptake of the three monoamines mentioned above. Furthermore, in rat in vivo microdialysis studies, this compound, administered orally at low doses, sustainably increases extracellular monoamine concentrations in the prefrontal cortex and striatum. In addition, in evaluations of its effects on improving hyperactivity-like and impulsivity-like symptoms in spontaneously hypertensive rats prone to stroke (SHRSP), this compound shows efficacy at low doses when administered orally. [Modes for carrying out the invention]

[0009] The terms and phrases used in this specification are described in detail below.

[0010] In this specification, "halogen" refers to fluorine, chlorine, bromine, or iodine. Preferably, it is fluorine, chlorine, or bromine, and more preferably fluorine or chlorine.

[0011] In this specification, "C 1-6 "Alkyl" refers to a group with 1 to 6 carbon atoms (C 1-6 ) are linear or branched alkyl groups, and specific examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, etc. Also, "C 1-6 "Alkyl" refers to a C molecule in which 1 to 7 hydrogen atoms are replaced by deuterium atoms. 1-6 Alkyl compounds are also included.

[0012] In this specification, "C 1-6 "Alkoxy" refers to a group of atoms with 1 to 6 carbon atoms (C 1-6 ) are linear or branched alkoxys, and specific examples include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, 3-methylpentoxy, etc.

[0013] In this specification, "3- to 8-membered cycloalkane" means a cycloalkane with 3 to 8 carbon atoms (C 3-8 These are cycloalkanes, and specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0014] In this specification, "a 9-10 membered bicyclic system containing an oxygen atom as a ring constituent element along with a benzene ring" refers to a fused ring consisting of a saturated or unsaturated 5-6 membered heterocycle containing one oxygen atom as a ring constituent element and a benzene ring. Specific examples include benzofuran, dihydrobenzofuran, benzopyran, and dihydrobenzopyran.

[0015] In this specification, "protecting group" is not particularly limited as long as it functions as a protecting group, but examples include alkyl groups (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, acetylmethyl); alkyl (alkenyl)carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E)-2-methyl-2-butenoyl); arylcarbonyl groups (e.g., benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, 4-toluyl, 4-anissoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)ben Zoyl, 4-phenylbenzoyl); tetrahydro(thio)pyranyl(furanyl) groups (e.g., tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl); silyl groups (e.g., trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyldiisopropylsilyl, methylditert-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl, triphenylsilyl, ditert-butylisobutylsilyl); alkoxymethyl groups (e.g., methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl);Examples include aralkyl groups (e.g., benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl); and carbamate groups (e.g., tert-butylcarbamate, allylcarbamate, benzylcarbamate).

[0016] In this specification, "silyl protecting group" is not particularly limited as long as it functions as a silicon-containing protecting group, but examples include trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, methyldiisopropylsilyl, methylditert-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl, triphenylsilyl, ditert-butylisobutylsilyl, and the like.

[0017] In this specification, "protecting agent" is not particularly limited as long as it can introduce a protecting group to the functional group of the desired purpose, but examples include alkylating agents (e.g., dimethyl sulfate, diazomethane, methyl bromide, methyl iodide, Meerwein reagent, methyl trifluoromethanesulfonate, ethyl bromide, isobutylene, 2-hydroxyethyl bromide); alkyl (alkenyl) carbonylating agents (e.g., acetic anhydride, acetyl chloride, ketene, propionyl chloride, butyryl chloride, pivaloyl chloride, chloroacetyl chloride, trifluoro) Acetate anhydride); arylcarbonylating agents (e.g., benzoyl chloride, benzoic acid anhydride, benzoyl cyanide, α-naphthoyl chloride); tetrahydro(thio)pyranyl(furanyl)ating agents (3,4-dihydro-2H-pyran, 2,3-dihydrofuran, 2-chlorotetrahydrofuran); silylating agents (e.g., trimethylsilyl chloride, triethylsilyl chloride, isopropyldimethylsilyl chloride, tert-butyldimethylsilyl chloride, methyldiisopropylsilyl chloride, methylditert-butylsilyl chloride) Triisopropylsilyl chloride, diphenylmethylsilyl chloride, diphenylbutylsilyl chloride, diphenylisopropylsilyl chloride, phenyldiisopropylsilyl chloride, triphenylsilyl chloride, ditert-butylisobutylsilyl triflate are used, and imidazole, pyridine, 2,6-lutidine, etc. are used as bases); alkoxymethylating agents (e.g., methoxymethyl chloride, methoxymethyl bromide, didimethoxymethane, ethoxymethyl chloride, 2-methoxyethoxymethyl chloride, 2, Examples include 2,2-trichloroethoxymethyl chloride, 2-trimethylsilylethoxymethyl chloride, benzyloxymethoxymethyl chloride, ethyl vinyl ether; aralkylating agents (e.g., benzyl chloride, benzyl bromide, benzyl 2,2,2-trichloroacetimidate, 4-methoxybenzyl chloride, triphenylmethyl chloride, triphenylmethyl bromide); and carbamate groups (e.g., di-tert-butyl dicarbonate, allyl chloroformate, diallyl dicarbonate, benzyl chloroformate, di-benzyl dicarbonate).

[0018] In this specification, "deprotecting agent" is not particularly limited as long as it can deprotect the protecting group, but examples include alkyl groups (e.g., trimethylsilyl iodide, boron tribromide, aluminum chloride / ethanethiol); alkyl (alkenyl) carbonyl groups (e.g., strong alkaline aqueous solution, aqueous ammonia, methylamine, 2-aminoethanethiol, thiourea, tetrabutylammonium hydroxide, diisobutylaluminum hydride, lithium aluminum hydride, hydrazine, boron trifluoride diethyl ether complex / dimethyl sulfide); aryl carbonyl groups [deprotecting agents for alkyl (alkenyl) carbonyl groups can be used]; tetrahydropyranyl (furanyl) groups (e.g., pyridinium p-toluenesulfonate, p-toluenesulfonic acid, acetic acid, hydrochloric acid, trifluoroacetic acid); sil Fluorine groups (e.g., tetra-n-butylammonium fluoride / tetrahydrofuran, potassium carbonate / methanol, 2% hydrofluoric acid, hydrofluoric acid / pyridine); alkoxymethyl groups (e.g., pyridinium p-toluenesulfonate, thiophenol / boron trifluoride diethyl ether complex, catecholboron bromide, trimethylsilyl bromide, bromodimethylborane, lithium tetrafluoroborate, hydrochloric acid, trifluoroacetic acid, zinc dibromide, titanium tetrachloride, trimethylsilyl chloride / sodium iodide, tetrafluoroboric acid, zinc, zinc / copper, lithium / ammonia); allyl groups (e.g., hydrogen / palladium carbon, ammonium formate / palladium carbon, Raney nickel, trimethylsilyl iodide, boron tribromide, boron trichloride, dichlorodicyanoquinone, cerium ammonium nitride);Examples of deprotection methods for carbamate groups include: deprotection of the tert-butylcarbamate group using hydrochloric acid / ethyl acetate, trifluoroacetic acid, trimethylsilyl iodide, and aluminum chloride / anisole; deprotection of the allylcarbamate group using a combination of a palladium(O) catalyst (such as tetrakistriphenylphosphinepalladium or trisdibenzylideneacetonedipalladium) and a nucleophile (such as morpholine, dimedone, formic acid, or 2-ethylhexanoic acid), and iodine / hydrated acetonitrile; and deprotection of the benzylcarbamate group using catalytic hydrogenation with palladium-carbon, trimethylsilyl iodide, and trifluoroacetic acid.

[0019] In this specification, "silyl protecting agent" is not particularly limited as long as it can introduce a silyl protecting group to the desired functional group, but examples include trimethylsilyl chloride, triethylsilyl chloride, isopropyldimethylsilyl chloride, tert-butyldimethylsilyl chloride, methyldiisopropylsilyl chloride, methylditert-butylsilyl chloride, triisopropylsilyl chloride, diphenylmethylsilyl chloride, diphenylbutylsilyl chloride, diphenylisopropylsilyl chloride, phenyldiisopropylsilyl chloride, triphenylsilyl chloride, and ditert-butylisobutylsilyl triflate.

[0020] In this specification, "desilyl protective agent" is not particularly limited as long as it can deprotect silyl protecting groups, but examples include formic acid, acetic acid, hydrochloric acid, trifluoroacetic acid, hydrofluoric acid, and tetra-n-butylammonium fluoride.

[0021] In this specification, the term "alkylating agent" is not particularly limited as long as it can alkylate the desired functional group, but examples include dimethyl sulfate, diazomethane, methyl bromide, methyl iodide, Meerwein reagent, methyl trifluoromethanesulfonate, ethyl bromide, isobutylene, and 2-hydroxyethyl bromide.

[0022] In this specification, "peroxide" is not particularly limited as long as it can form an oxide, but examples include potassium peroxymonosulfate (Oxone®), m-chloroperbenzoic acid (MCPBA), perbenzoic acid, peracetic acid, trifluoroperacetic acid, sodium periodate, hydrogen peroxide, 3,3-dimethyldioxirane, N-(benzenesulfonyl)-3-phenyloxaziridine, magnesium monoperoxyphthalate hexahydrate, tert-butyl hydroperoxide, sodium bromate, potassium permanganate, manganese dioxide, selenium dioxide, chromium trioxide, sodium perborate, tetrapropylammonium perruthenate, and the like.

[0023] In this specification, "palladium reagent" is not particularly limited, but includes, for example, tetravalent palladium catalysts such as sodium hexachloropalladium(IV) tetrahydrate and potassium hexachloropalladium(IV); [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride dichloromethane adduct (Pd(dppf)Cl2·CH2Cl2), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (XPhos Pd Examples include divalent palladium catalysts such as G3), palladium(II) chloride, palladium(II) bromide, palladium(II) acetate, palladium acetylacetonate(II), dichlorobis(benzonitrile)palladium(II), dichlorobis(acetonitrile)palladium(II), dichlorobis(triphenylphosphine)palladium(II), dichlorotetraamminepalladium(II), dichloro(cycloocta-1,5-diene)palladium(II), palladium trifluoroacetate(II), and 1,1'-bis(diphenylphosphine)ferrocenedichloropalladium(II)-dichloromethane complex; and zero-valent palladium catalysts such as tris(dibenzylideneacetone)dipalladium(O)(Pd2(dba)3), tris(dibenzylideneacetone)dipalladiumchloroform complex(O), and tetrakis(triphenylphosphine)palladium(O)(Pd(PPh3)4). These palladium compounds are used individually or in combination of two or more.

[0024] In this specification, "phosphine ligand" is not particularly limited, but examples include triphenylphosphine, tri(o-tolyl)phosphine, tri-tert-butylphosphonium tetrafluoroborate, tricyclohexylphosphonium tetrafluoroborate, pentaphenyl(di-tert-butylphosphino)ferrocene, 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (Xantphos), and Bis[2-(diphenylphosphino)phenyl] Examples of commonly used compounds include ether (DPEPhos), 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 1,1'-bis(diphenylphosphino)ferrocene (dppf), 2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl (XPhos), and 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos).

[0025] In this specification, the term "reducing agent" is not particularly limited as long as it can reduce the desired functional group, but examples of such agents include lithium aluminum hydride, diisobutylaluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminate, and lithium borohydride.

[0026] In this specification, "base" refers to, for example, inorganic bases, organic bases, etc. Examples of "inorganic bases" include alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate), alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate), alkali metal phosphates (e.g., sodium phosphate, potassium phosphate), alkaline earth metal phosphates (e.g., sodium phosphate, potassium phosphate), etc. Examples of "organic bases" include trialkylamines (e.g., trimethylamine, triethylamine, diisopropylethylamine), picoline, 1,5-diazabicyclo[4.3.0]non-5-ene, 1,4-diazabicyclo[2.2.2]octane, and 1,8-diazabicyclo[5.4.0]unde-7-ene, etc.

[0027] In this specification, "leaving group" refers to, for example, halogens, C 1-18 Examples include alkanesulfonyls, lower alkanesulfonyloxys, arylsulfonyloxys, aralkylsulfonyloxys, perhaloalkanesulfonyloxys, sulfonios, and toluenesulfoxys, with halogens being preferred.

[0028] The above "halogen" refers to fluorine, chlorine, bromine, or iodine.

[0029] The above "C 1-18 Examples of "alkanesulfonyls" include those with 1 to 18 carbon atoms (C 1-18 This includes linear or branched alkanesulfonyl compounds, specifically methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, etc.

[0030] Examples of the above "lower alkanesulfonyl oxy" include those with 1 to 6 carbon atoms (C 1-6This includes linear or branched alkanesulfonyloxy compounds, specifically methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy, etc.

[0031] An example of the above "arylsulfonyloxy" is a substituent with 1 to 6 carbon atoms on a phenyl ring (C 1-6 ) linear or branched alkyl groups, having 1 to 6 carbon atoms (C 1-6 This includes phenylsulfonyloxy, naphthylsulfonyloxy, etc., which may have 1 to 3 groups selected from the group consisting of linear or branched alkoxy, nitro, and halogen. Specific examples of the above "phenylsulfonyloxy that may have substituents" are phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, etc. Specific examples of the above "naphthylsulfonyloxy" are α-naphthylsulfonyloxy, β-naphthylsulfonyloxy, etc.

[0032] An example of the above "aralkylsulfonyloxy" is a substituent with 1 to 6 carbon atoms on a phenyl ring (C 1-6 ) linear or branched alkyl groups, having 1 to 6 carbon atoms (C 1-6 A phenyl-substituted carbon atom having 1 to 6 carbon atoms (C) and having 1 to 3 groups selected from the group consisting of linear or branched alkoxy, nitro, and halogen. 1-6 ) A linear or branched alkanesulfonyloxy or naphthyl-substituted alkanesulfonyloxy with 1 to 6 carbon atoms (C 1-6This includes linear or branched alkanesulfonyloxys of the above.Specific examples of the above "phenyl-substituted alkanesulfonyloxys" are benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, etc.Specific examples of the above "naphthyl-substituted alkanesulfonyloxys" are α-naphthylmethylsulfonyloxy, β-naphthylmethylsulfonyloxy, etc.

[0033] Examples of the "perhaloalkanesulfonyloxy" mentioned above include trifluoromethanesulfonyloxy.

[0034] Specific examples of the above-mentioned "sulfonio" include dimethyl sulfonio, diethyl sulfonio, dipropyl sulfonio, di(2-cyanoethyl) sulfonio, di(2-nitroethyl) sulfonio, di-(aminoethyl) sulfonio, di(2-methylaminoethyl) sulfonio, di-(2-dimethylaminoethyl) sulfonio, di-(2-hydroxyethyl) sulfonio, di-(3-hydroxypropyl) sulfonio, di-(2-methoxyethyl) sulfonio, di-(2-carbamoylethyl) sulfonio, di-(2-carbamoylethyl) sulfonio, di-(2-carboxyethyl) sulfonio, di-(2-methoxycarbonylethyl) sulfonio, or diphenyl sulfonio.

[0035] In this specification, "solvent" refers to any solvent that is inert to the reaction, and includes, for example, water, ethers (e.g., dioxane, tetrahydrofuran, diethyl ether, 1,2-dimethoxyethane, diethylene glycol dimethyl ether, ethylene glycol dimethyl ether), halohydrocarbons (e.g., methylene chloride, chloroform, 1,2-dichloroethane, carbon tetrachloride), aromatic hydrocarbons (e.g., benzene, toluene, xylene), lower alcohols (e.g., methanol, ethanol, isopropanol), and polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO), hexamethylphosphate triamide, acetonitrile). These solvents may be used individually or in combination of two or more. The reaction may also be carried out without a solvent.

[0036] Each substituent in the compound represented by the general formula [I] of the present invention (hereinafter referred to as "compound [I]") will be described below.

[0037] General formula [I] is preferably general formula [Ia], general formula [Ib], general formula [Ic], or general formula [Id], and more preferably general formula [Ia] or general formula [Ib].

[0038] R in compound [I] 11 , R 12 and R 13 These are identical or different, each independently of hydrogen or C 1-6 It is an alkyl group, preferably hydrogen, methyl, ethyl, 1-propyl, or 2-propyl.

[0039] In another aspect, R in compound [I] 11 and R 12 These atoms form a 3- to 8-membered cycloalkane with adjacent carbon atoms, preferably cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, or cyclooctane, and more preferably cyclobutane.

[0040] R in compound [I]22 , R 23 , R 25 and R 26 These are identical or different, each independently of hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 It is an alkoxy; preferably hydrogen, fluorine, chlorine, methyl or methoxy, and more preferably hydrogen, fluorine, chlorine or methyl.

[0041] In another aspect, R in compound [I] 22 and R 23 Together with the adjacent benzene ring, it forms a 9-10 membered bicyclic system containing an oxygen atom as a ring constituent element, preferably benzofuran, dihydrobenzofuran, benzopyran, or dihydrobenzopyran, and more preferably benzofuran or benzopyran.

[0042] R in compound [I] 31 and R 32 These are, either identical or distinct, hydrogen or halogen, independently; preferably hydrogen, fluorine, or chlorine.

[0043] In one aspect of the present invention, R 11 , R 12 and R 13 These are identical or different, each independently of hydrogen or C 1-6 It is alkyl, preferably hydrogen or methyl; R 22 , R 23 , R 25 and R 26 These are identical or different, each independently of hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 It is an alkoxy, preferably hydrogen, fluorine, chlorine, methyl, or methoxy; R 31 and R 32 These are, either identical or different, hydrogen or halogen, preferably hydrogen or fluorine, independently of each other.

[0044] In another aspect of the present invention, R 11 and R 12 , together with the adjacent carbon atom, form a 3- to 8-membered cycloalkane, preferably cyclobutyl, R 13 is hydrogen or C 1-6 alkyl, preferably hydrogen or methyl, R 22 , R 23 , R 25 and R 26 are the same or different and each independently represent hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen, fluorine, chlorine, methyl or methoxy; R 31 and R 32 are the same or different and each independently represent hydrogen or halogen, preferably hydrogen or fluorine;

[0045] In another aspect of the present invention, R 11 , R 12 and R 13 are the same or different and each independently represent hydrogen or C 1-6 alkyl, preferably hydrogen or methyl; R 22 and R 23 , together with the adjacent benzene ring, form a 9- to 10-membered bicyclic ring system further containing an oxygen atom as a ring constituent element, preferably form benzofuran; R 25 and R 26 are the same or different and each independently represent hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, preferably hydrogen, fluorine, chlorine, methyl or methoxy; R 31 and R 32 are the same or different and each independently represent hydrogen or halogen, preferably hydrogen or fluorine.

[0046] In another aspect of the present invention, R11 and R 12 It forms a 3- to 8-membered cycloalkane with adjacent carbon atoms, preferably cyclobutyl. R 13 is hydrogen or C 1-6 It is an alkyl group, preferably hydrogen or methyl, R 22 and R 23 Together with the adjacent benzene ring, it forms a 9-10 membered bicyclic system containing an oxygen atom as a ring constituent element, preferably forming a benzofuran; R 25 and R 26 These are identical or different, each independently of hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 It is an alkoxy, preferably hydrogen, fluorine, chlorine, methyl, or methoxy; R 31 and R 32 These are, either identical or different, hydrogen or halogen, preferably hydrogen or fluorine, independently of each other.

[0047] Another preferred embodiment of the present invention is, General formula [I] JPEG0007918251000004.jpg3956 is It is JPEG0007918251000005.jpg41145, R 11 , R 12 and R 13 These are identical or different, each independently of hydrogen or C 1-6 It is alkyl, preferably hydrogen or methyl; R 25 and R 26 These are identical or different, each independently of hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 It is an alkoxy, preferably hydrogen, fluorine, chlorine, methyl, or methoxy; R 31 and R 32 Each is either the same or different, independently of the others, hydrogen or a halogen, preferably hydrogen or fluorine; --- The bond is either a single bond or a double bond, preferably a double bond.

[0048] In another aspect of the present invention, R 11 and R 12 It forms a 3- to 8-membered cycloalkane with adjacent carbon atoms, preferably cyclobutyl. R 13 is hydrogen or C 1-6 It is an alkyl group, preferably hydrogen or methyl; R 22 and R 23 It forms a 9-10 membered bicyclic system with adjacent benzene rings, further containing oxygen atoms as ring constituent elements, and is preferably benzofuran; R 25 and R 26 These are identical or different, each independently of hydrogen, halogen, and C. 1-6 Alkyl or C 1-6 It is an alkoxy, preferably hydrogen, fluorine, chlorine, methyl, or methoxy; R 31 and R 32 These are, either identical or different, hydrogen or halogen, preferably hydrogen or fluorine, independently of each other.

[0049] Another preferred embodiment of the present invention is, General formula [I] JPEG0007918251000006.jpg3856 is It is JPEG0007918251000007.jpg40145, R 11 and R 12 It forms a 3- to 8-membered cycloalkane with adjacent carbon atoms, preferably cyclobutyl. R 13 is hydrogen or C 1-6 It is alkyl; R 25 and R 26 These are identical or different, each independently of hydrogen, halogen, and C.1-6 Alkyl or C 1-6 It is an alkoxy; R 31 and R 32 These are, either identical or distinct, hydrogen or halogen, independently of each other. --- It is either a single bond or a double bond.

[0050] The following compounds are examples of specific embodiments of compound [I] of the present invention. JPEG0007918251000008.jpg124150

[0051] In this specification, the presentation of preferred embodiments and options relating to different characteristics of the compounds, methods, and compositions of the present invention also includes the presentation of combinations of preferred embodiments and options relating to such different characteristics, provided that they are combinatorial and inconsistent.

[0052] The following describes a method for producing compound [I] of the present invention. Compound [I] of the present invention can be produced, for example, based on the production method shown below. The production method shown below is illustrative, and the method for producing compound [I] is not limited to these.

[0053] In the following reaction equations, when alkylation, hydrolysis, amination, esterification, amidation, etherification, nucleophilic substitution, addition, oxidation, reduction, etc., these reactions are carried out according to known methods. Examples of such methods include those described in "Experimental Chemistry Course" (5th edition, edited by the Chemical Society of Japan, Maruzen Co., Ltd.), "Organic Functional Group Preparations" 2nd edition, published by Academic Press, Inc. in 1989; "Comprehensive Organic Transformations" VCH Publishers Inc., published in 1989; and "Greene's Protective Groups in Organic Synthesis" (4th edition, 2006) by P.G. Wuts and T.W. Greene.

[0054] General synthetic route of compound [I] 1) Method for producing compound [I] (1) JPEG0007918251000009.jpg40155 (In the formula, the symbols are as defined above.)

[0055] Compound [1] of the present invention can be produced by the reaction shown in the above synthesis route. Specifically, compound [1] of the present invention can be produced by deprotecting the silyl protecting group of compound [2] with a desilyl protecting agent in a solvent inert to the reaction.

[0056] 2) Method for producing compound [I] (2) JPEG0007918251000010.jpg48161 (in the formula, R 33 is C 1-6 It is an alkyl group, and the other symbols are as defined above.

[0057] Compound [1] of the present invention can be produced by the reaction shown in the above synthesis route. Specifically, compound [1] of the present invention can be produced by reducing compound [3] in a solvent inert to the reaction in the presence of a reducing agent.

[0058] 3) Method for producing the intermediate [2] (1) JPEG0007918251000011.jpg47160 (in the formula, Y 1 (This is a leaving group, and the other symbols are as defined above.)

[0059] The reaction shown in the above synthesis route can produce an intermediate [2] of compound [1] of the present invention. Specifically, intermediate [2] can be produced by condensing compound [4] and compound [5] in a reaction-inert solvent in the presence of a palladium reagent, a phosphine ligand, and a base.

[0060] 4) Method for producing the intermediate [2] (2) JPEG0007918251000012.jpg41161 (in the formula, Y 2 (This is a leaving group, and the other symbols are as defined above.)

[0061] The reaction shown in the above synthesis route can produce an intermediate [2] of compound [1] of the present invention. Specifically, intermediate [2] can be produced by condensing compound [6] and compound [7] in a reaction-inert solvent in the presence of a base.

[0062] 5) Method for producing the intermediate [3] JPEG0007918251000013.jpg43149 (in the formula, Y 2 R is a leaving group. 33 is C 1-6 It is an alkyl group, and the other symbols are as defined above.

[0063] The reaction shown in the above synthesis route can produce an intermediate [3] of compound [1] of the present invention. Specifically, intermediate [3] can be produced by condensing compound [6] and compound [8] in a reaction-inert solvent in the presence of a base.

[0064] 6) Method for producing the intermediate [4] (1) JPEG0007918251000014.jpg41148 (in the formula, Y 1 , Y 2 (This is a leaving group, and the other symbols are as defined above.)

[0065] The reaction shown in the above synthesis route can produce an intermediate [4] of compound [1] of the present invention. Specifically, intermediate [4] can be produced by reacting compound [9] and compound [7] in a reaction-inert solvent in the presence of a base.

[0066] 7) Method for producing the intermediate [4] (2) JPEG0007918251000015.jpg115142 (in the formula, Y 1 , Y 2 R is a leaving group. 33 is C 1-6 It is an alkyl group, and the other symbols are as defined above.

[0067] Intermediate [4] of compound [1] of the present invention can be produced by the reaction shown in the above synthesis route. Specifically, intermediate

[10] can be produced by condensing compound [9] and compound [8] in a reaction-inert solvent in the presence of a base. Next, intermediate

[11] can be produced by reducing intermediate

[10] in a reaction-inert solvent in the presence of a reducing agent. Furthermore, intermediate [4] can be produced by introducing a silyl protecting group to intermediate

[11] using a silyl protecting agent in a reaction-inert solvent in the presence of a base.

[0068] 8) Method for producing the intermediate [6] (2) JPEG0007918251000016.jpg94110 (in the formula, Y 1 (This is a leaving group, and the other symbols are as defined above.)

[0069] Intermediate [6] of compound [1] of the present invention can be produced by the reaction shown in the above synthesis route. Specifically, intermediate

[13] can be produced by condensing compound

[12] and compound [5] in a reaction-inert solvent in the presence of a base. Next, intermediate [6] can be produced by reacting intermediate

[13] with a peroxide in a reaction-inert solvent.

[0070] 9) Method for producing the intermediate [5] JPEG0007918251000017.jpg76142 (In the formula, the symbols are as defined above.)

[0071] Intermediate [5] of compound [1] of the present invention can be produced by the reaction shown in the above synthesis route. Specifically, intermediate

[15] can be produced by introducing a protecting group to compound

[14] with a protecting agent in a reaction-inert solvent. Next, intermediate

[16] can be produced by introducing an alkyl group to intermediate

[15] with an alkylating agent in a reaction-inert solvent. Furthermore, intermediate [5] can be produced by deprotecting the protecting group of intermediate

[16] with a deprotecting agent.

[0072] Other reaction conditions (reaction temperature, reaction time, etc.) for each reaction in the above reaction equations can be appropriately determined based on known reactions.

[0073] In each reaction in the above reaction equation, the product can be used in the next reaction as is, or as a crude product. However, it can also be isolated from the reaction mixture according to conventional methods and easily purified by ordinary separation means. Examples of ordinary separation means include recrystallization, distillation, and chromatography.

[0074] The starting material compounds, intermediate compounds, and target compounds in each of the above processes, as well as compound [I] of the present invention, include geometric isomers, stereoisomers, optical isomers, and tautomers. These isomers can be separated by general optical resolution methods. Alternatively, the compound can be produced from suitable optically active starting material compounds.

[0075] Compound [I] of the present invention can be produced by the synthesis methods shown in the above reaction formulas or by similar methods.

[0076] Unless otherwise specified, the raw materials used in the production of compound [I] of the present invention may be commercially available or produced according to a known method or a similar method.

[0077] The starting material compounds and target compounds in each of the above processes can be used in appropriate salt forms. Examples of such salts are similar to those exemplified below as salts of compound [I] of the present invention.

[0078] Furthermore, the compound [I] of the present invention includes salt forms thereof, and depending on the type of acid addition salt or substituent, it may also form a salt with a base. Examples of such "acids" include inorganic acids (e.g., hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid, phosphoric acid, etc.) and organic acids (e.g., methanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, maleic acid, fumaric acid, malic acid, lactic acid, etc.). Examples of such "bases" include inorganic bases (e.g., sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc.) and organic bases (e.g., methylamine, diethylamine, trimethylamine, triethylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, picoline, choline, etc.) and ammonium salts. Furthermore, it may form salts with amino acids such as lysine, arginine, aspartic acid, and glutamic acid.

[0079] The present invention also includes various hydrates, solvates, and crystalline polymorphs of compound [I] and its salts.

[0080] Compounds [I] of the present invention include compounds in which one or more atoms are substituted with one or more isotopic atoms. Examples of isotopic atoms include deuterium ( 2 H), tritium ( 3 H), 13 C, 15 N, 18 Examples include O, etc.

[0081] Compounds [I] of the present invention also include pharmaceutically acceptable prodrugs. Substituents modified to form prodrugs include reactive functional groups such as -OH, -COOH, and amino. These functional group modifiers may be appropriately selected from the "substituents" as defined herein.

[0082] The compound [I] of the present invention or a salt thereof may be a cocrystal or a cocrystalline salt. Here, a cocrystal or cocrystalline salt means a crystalline substance composed of two or more unique solids at room temperature, each having different physical properties (e.g., structure, melting point, heat of fusion, etc.). Cocrystals and cocrystalline salts can be produced by applying known cocrystallization methods.

[0083] Suitable salts of compound [I] of the present invention are pharmaceutically acceptable salts, such as metal salts such as alkali metal salts (e.g., sodium salts, potassium salts, etc.), alkaline earth metal salts (e.g., calcium salts, magnesium salts, etc.), ammonium salts, alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal bicarbonates (e.g., lithium bicarbonate, sodium bicarbonate, potassium bicarbonate, etc.), and alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, etc.) and other inorganic base salts; for example, tri(lower)alkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine, etc.), pyridine, quinoline, piperidine, and imidazole. Examples include salts of organic bases such as picoline, dimethylaminopyridine, dimethylaniline, N-(lower) alkyl-morpholines (e.g., N-methylmorpholine), 1,5-diazabicyclo[4.3.0]nonene-5 (DBN), 1,8-diazabicyclo[5.4.0]undecene-7 (DBU), and 1,4-diazabicyclo[2.2.2]octane (DABCO); salts of inorganic acids such as hydrochloride, hydrobromide, hydroiodide, sulfate, nitrate, and phosphate; and salts of organic acids such as formate, acetate, propionate, oxalate, malonate, succinate, fumarate, maleate, lactate, malate, citrate, tartrate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, and glutamate.

[0084] Furthermore, compounds in which a solvate (e.g., hydrate, ethanolate, etc.) is added to the starting materials and target compound shown in each reaction equation are also included in the respective general formulas. Hydrates are a preferred solvate.

[0085] Each of the target compounds obtained in the above reaction equations can be isolated and purified from the reaction mixture by, for example, cooling the reaction mixture, separating the crude reaction product by isolation operations such as filtration, concentration, and extraction, and then performing conventional purification operations such as column chromatography and recrystallization.

[0086] Compound [I] of the present invention naturally includes isomers such as geometric isomers, stereoisomers, and optical isomers.

[0087] Various isomers can be isolated by conventional methods by utilizing the differences in physicochemical properties between them. For example, racemic compounds can be converted to sterically pure isomers by general optical resolution methods [for example, by deriving diastereomer salts with a common optically active acid (such as tartaric acid) and then optically resolving them]. Furthermore, mixtures of diastereomers can be separated by methods such as fractional crystallization or chromatography. Optically active compounds can also be produced by using appropriate optically active starting materials.

[0088] Compound [I] of the present invention also includes isotopically labeled compounds that are identical to compound [I] except that one or more atoms are replaced by one or more atoms having a specific atomic mass or mass number. Examples of isotopes that can be incorporated into compound [I] of the present invention include, 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 O, 18 F, 36 This includes hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine isotopes such as Cl. The compound [I] of the present invention is a specific isotope-labeled compound containing the above isotopes and / or other isotopes of other atoms, for example. 3 H and 14 Compounds incorporating radioactive isotopes such as 13C are useful in drug-tissue distribution assays and / or substrate-tissue distribution assays. Tritiation (i.e., 3 H), and carbon-14 (i.e., 14 C) Isotopes are particularly preferred due to their ease of preparation and detectability. Furthermore, deuterium (i.e., 2Substitution with heavier isotopes such as H) is expected to result in certain therapeutic benefits due to improved metabolic stability, such as an increased in vivo half-life or a reduced dose. The isotope-labeled compounds of the present invention can generally be prepared by substituting a non-isotope-labeled reagent with a readily available isotope-labeled reagent in the reaction formula and / or the examples disclosed below.

[0089] A pharmaceutical composition containing compound [I] of the present invention or a salt thereof as an active ingredient will be described.

[0090] The above-mentioned pharmaceutical composition is a formulation of compound [I] of the present invention or a salt thereof in the form of a conventional pharmaceutical composition, and is prepared using carriers, diluents and / or excipients (collectively referred to herein as "pharmaceutically acceptable carriers") such as commonly used fillers, bulking agents, binders, humectants, disintegrants, surfactants, and lubricants.

[0091] Such pharmaceutical compositions can be selected from a variety of forms depending on the therapeutic purpose, and typical examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions, etc.).

[0092] A wide range of known carriers can be used when forming tablets, such as excipients including lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders including water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; and dried starch, sodium alginate, agar powder, laminaran powder, and sodium bicarbonate. Examples of additives include disintegrants such as ammonium, calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, monoglyceride stearate, starch, and lactose; disintegration inhibitors such as sucrose, stearic acid, cocoa butter, and hydrogenated oil; absorption enhancers such as quaternary ammonium bases and sodium lauryl sulfate; humectants such as glycerin and starch; adsorbents such as starch, lactose, kaolin, bentonite, and colloidal silicic acid; and lubricants such as refined talc, stearate, boric acid powder, and polyethylene glycol.

[0093] Furthermore, the tablets may be coated with a conventional coating material as needed, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, or double-layered tablets.

[0094] A wide range of known carriers can be used when forming the product into pill form. Examples include excipients such as glucose, lactose, starch, cocoa butter, hydrogenated vegetable oil, kaolin, and talc; binders such as gum arabic powder, tragacanth powder, gelatin, and ethanol; and disintegrants such as laminaran and agar.

[0095] A wide range of known carriers can be used when forming the suppository, including polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin, and semi-synthetic glycerides.

[0096] When prepared as an injectable preparation, the liquid, emulsion, and suspension preparations are preferably sterilized and isotonic with blood. A wide range of known diluents can be used when forming these liquid, emulsion, and suspension preparations, including, for example, water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbetane fatty acid esters. In this case, a sufficient amount of sodium chloride, glucose, or glycerin to prepare an isotonic solution may be included in the pharmaceutical preparation, and conventional solubilizers, buffers, analgesics, and, if necessary, colorants, preservatives, fragrances, flavorings, sweeteners, and / or other pharmaceuticals may also be included.

[0097] The amount of compound [I] of the present invention or its salt contained in the pharmaceutical composition is not particularly limited and can be appropriately selected from a wide range, but it is generally preferable to contain compound [I] of the present invention or its salt in the pharmaceutical composition in an amount of about 1 to 70% by weight.

[0098] There are no particular limitations on the method of administering the pharmaceutical composition according to the present invention, and it may be administered in a manner appropriate to the various formulation forms, the age, sex, disease state, and other conditions of the target or patient (especially humans). For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules are administered orally. In the case of injections, they may be administered intravenously alone or mixed with conventional infusion fluids such as glucose and amino acids, or, if necessary, alone, intramuscularly, intradermally, subcutaneously, or intraperitoneally. In the case of suppositories, they are administered rectally.

[0099] The dosage of the above pharmaceutical composition may be appropriately selected depending on the method of use, target, or the age, sex, severity of the disease, and other conditions of the patient (especially a human). Typically, it is administered at a dose of approximately 0.001 to 100 mg per kg of body weight per day, preferably 0.001 to 50 mg, in one to several divided doses.

[0100] The above dosages vary depending on various conditions; therefore, a lower dosage may be sufficient in some cases, while a dosage exceeding the above range may be necessary in others.

[0101] Compound [I] of the present invention or a salt thereof has reuptake inhibitory activity for one, two, or three types of monoamines (serotonin, norepinephrine, dopamine).

[0102] Compound [I] of the present invention or its salt exhibits significantly stronger in vitro reuptake inhibitory activity against one, two, or all of the three monoamines compared to existing compounds with monoamine reuptake inhibitory activity. Furthermore, in intracerebral microdialysis (in vivo), compound [I] of the present invention or its salt exhibits significantly stronger activity against the increase of one, two, or all of the three monoamines compared to existing compounds with monoamine reuptake inhibitory activity.

[0103] The serotonin inhibitory activity (IC) of compound [I] or a salt thereof of the present invention 50 The ) is 100 nM or less, preferably 30 nM or less.

[0104] The inhibitory activity of compound [I] or a salt thereof of norepinephrine (IC) 50 The ) is 100 nM or less, preferably 30 nM or less.

[0105] The dopamine inhibitory activity (IC) of compound [I] or its salt of the present invention 50 The dopamine inhibitory activity (IC) is 300 nM or less, preferably 150 nM or less. 50 It is preferable that the effect of ) tends to be weaker compared to norepinephrine.

[0106] The intrinsic human liver clearance of compound [I] or a salt thereof of the present invention is 100 μL / min / mg or less, preferably 50 μL / min / mg or less.

[0107] The human serum protein binding rate of compound [I] or its salt of the present invention is 80% or less, preferably 70% or less, and more preferably 50% or less.

[0108] The inhibitory rate of metabolic enzymes in the liver of compound [I] of the present invention or its salt is less than 50% in CYP2C9 at 10 μM, or IC2C9. 50 The value is 100 μM or greater, and when it is 10 μM in CYP2D6, it is less than 50%, or IC 50 The value is 50 μM or greater, and when it is 10 μM in CYP3A4, it is less than 50%, or IC 50 The value is 50 μM or higher.

[0109] Compound [I] of the present invention or a salt thereof exhibits inhibitory activity (IC) on serotonin, norepinephrine, and dopamine, respectively. 50 The ratio of ) is 1-20:1-2:1-100, preferably 1-5:1-2:1-50, and even more preferably 1-5:1:5-25.

[0110] Compound [I] of the present invention or its salt has a low binding rate to plasma proteins. When a drug binds to plasma proteins, it cannot exert its therapeutic effect; therefore, a low binding rate to plasma proteins means that an effect can be expected with a lower dose. In other words, an effect can be expected at a lower blood concentration.

[0111] Compound [I] of the present invention or its salt exhibits weak metabolic enzyme inhibitory activity in the liver, specifically weak inhibitory activity against cytochrome P450 (CYP), such as CYP2C9, CYP2D6, and CYP3A4. Therefore, even when taken in combination with other drugs, it has little effect on the metabolism of those drugs.

[0112] Compound [I] of the present invention or its salt has a broader therapeutic spectrum compared to known ADHD medications.

[0113] Compound [I] of the present invention or a salt thereof exhibits sufficient therapeutic effects with short-term administration.

[0114] Compound [I] of the present invention or its salt exhibits excellent brain penetration.

[0115] Compound [I] of the present invention or a salt thereof exhibits excellent improvement in spontaneous motility enhancement in spontaneously hypertensive rats (SHRSP) prone to stroke, which are used for screening for ADHD treatment drugs. Furthermore, compound [I] of the present invention or a salt thereof also exhibits excellent improvement in impulsivity-like symptoms in SHRSP.

[0116] Compound [I] of the present invention or a salt thereof exhibits strong activity in the mouse marble-burying behavior test, which is used as a model for anxiety- and obsessive-compulsive disorder.

[0117] Compound [I] of the present invention or its salts have reuptake inhibitory effects on one, two, or three types of monoamines (serotonin, norepinephrine, dopamine), and are therefore effective in treating various disorders associated with dysfunction of serotonin, norepinephrine, and / or dopamine neurons.

[0118] These disorders include attention-deficit / hyperactivity disorder (ADHD), Tourette's syndrome, autism spectrum disorder, Asperger's syndrome, depression (e.g., major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymia; rapid cycler; atypical depression; seasonal affective disorder; postpartum depression; mild depression; recurrent short-term depressive disorder; treatment-resistant depression; chronic depression; treatment-resistant depression; multiple depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; Cushing's syndrome, hypothyroidism, hyperparathyroidism, and Addison's disease. Depression associated with various diseases such as amenorrhea / galactorrhea, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infections, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, and cancer; depression in middle age; depression in old age; depression in childhood and adolescence; drug-induced depression such as interferon-induced depression; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder; anxiety associated with various diseases [for example, neurological disorders (head injury, brain infections, and inner ear disorders); cardiovascular disorders (heart failure, arrhythmia); endocrine disorders (hyperadrenofunction, hyperthyroidism);Respiratory disorders (asthma, chronic obstructive pulmonary disease), generalized anxiety disorder, phobias (e.g., agoraphobia, social phobia and simple phobia), obsessive-compulsive disorder, panic disorder, post-traumatic stress disorder, acute stress disorder, hypochondriasis, dissociative amnesia, avoidant personality disorder, body dysmorphic disorder, eating disorders (e.g., bulimia nervosa, bulimia nervosa, anorexia nervosa and anorexia nervosa), obesity, chemical addiction (e.g., addiction to alcohol, cocaine, heroin, phenobarbital, nicotine and benzodiazepines), pain (e.g., chronic pain, psychogenic pain, neuropathic pain, phantom limb pain, postherpetic neuralgia, traumatic cervical syndrome, spinal cord injury pain, trigeminal neuralgia and diabetic neuropathy), fibromyalgia, apathy, Alzheimer's disease (e.g., dementia, cognitive impairment and behavioral disorders due to Alzheimer's disease), This includes memory impairment (e.g., dementia, amnesia, and age-related cognitive decline (ARCD)), Parkinson's disease (e.g., dementia in Parkinson's disease, neuroleptic-induced Parkinsonian syndrome, and tardive dyskinesia), restless legs syndrome, endocrine disorders (e.g., hyperprolactinemia), hypertension, vasospasm (especially in the cerebral vascular system), cerebellar ataxia, gastrointestinal disorders (including changes in motor and secretory functions), negative symptoms of schizophrenia, affective disorders of schizophrenia, cognitive impairment of schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulse control disorder, trichotillomania, kleptomania, gambling addiction, cluster headaches, migraines, chronic paroxysmal migraines, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea syndrome, and headaches (related to vascular disorders).

[0119] All patent and non-patent document disclosures cited herein are incorporated herein by reference as a whole. [Examples]

[0120] The present invention will be further described in detail by the following test examples, reference examples, and embodiments, but these are not intended to limit the present invention and may be modified without departing from the scope of the present invention. In this specification, the following abbreviations may be used.

[0121] TIFF0007918251000018.tif240166 JPEG0007918251000019.jpg186166

[0122] In the following examples, "room temperature" typically refers to a temperature range of approximately 10°C to 35°C. Ratios given for mixed solvents are volume ratios unless otherwise specified. Percentages (%) refer to weight percentages unless otherwise specified. 1 1H NMR (proton nuclear magnetic resonance spectroscopy) was measured using a Fourier transform NMR (either Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE III HD (500 MHz)). The spectra were analyzed using MestReNova version: 14.1.2 (Mestrelab Research). Mass spectra (MS) were measured using LC / MS (ACQUITY UPLC H-Class). ESI was used as the ionization method, and the data recorded are the found values. Typically, molecular ion peaks ([M+H]) are observed. + [MH] - (and so on) are observed. In the case of salts, the molecular ion peak or fragment ion peak of the free form is usually observed. In silica gel column chromatography, when basic conditions were mentioned, aminopropylsilane-bonded silica gel was used. The absolute configuration of the compounds was determined by known X-ray crystallography methods (e.g., Shigeru Ohba and Shigenobu Yano, "Basic Course for Chemists 12: X-ray Crystallography" (1st edition, 1999)), or estimated from empirical rules of asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401. Yuanming Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

[0123] [Reference example] Reference Example 1. Production of (2-(4-bromo-2,6-difluorophenoxy)ethoxy)(tert-butyl)dimethylsilane 4-bromo-2,6-difluorophenol (22.93 g) and (2-bromoethoxy)-tert-butyldimethylsilane (25.0 g) were dissolved in DMF (120 mL), to which K2CO3 (28.9 g, fine powder) was added and the mixture was stirred at 70°C for 3 hours. After cooling to room temperature, ice water was added to the reaction mixture and it was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target product (35.0 g).

[0124] Reference Example 2. Production of (4a'S,8a'S)-4'-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3,5-difluorophenyl)octahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline] (4a'S,8a'S)-octahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline] (300 mg) and (2-(4-bromo-2,6-difluorophenoxy)ethoxy)(tert-butyl)dimethylsilane (672 mg) were dissolved in toluene (6 mL). Pd(OAc)2 (29.9 mg), t-Bu3P·HBF4 (38.6 mg), and t-BuONa (240 mg) were added to the mixture and stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by basic silica gel chromatography (Hexane / AcOEt) to obtain the target product (490 mg).

[0125] Reference Example 3. Preparation of 2-(4-bromophenoxy)-2,2-difluoroethyl acetate To a solution of p-bromophenol (5 g) and DBU (5.23 mL) in DMF (25 mL), bromodifluoroethyl ester (4.08 mL) was added and stirred overnight at room temperature. Ice water was added to the reaction mixture and extracted with AcOEt. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target product (7.2 g).

[0126] Reference Example 4. Production of 2-(4-bromophenoxy)-2,2-difluoroethane-1-ol A solution of 2-(4-bromophenoxy)-2,2-difluoroethyl acetate (13.9 g) in THF (150 mL) was stirred under ice-cold conditions, and LiBH4 (2.26 g) was added. The mixture was stirred overnight at room temperature. The reaction mixture was cooled, saturated NaHSO4 aqueous solution was added, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target product (10.4 g).

[0127] Reference Example 5. Production of (2-(4-bromophenoxy)-2,2-difluoroethoxy)triisopropylsilane A solution of 2-(4-bromophenoxy)-2,2-difluoroethane-1-ol (3.00 g) and imidazole (1.21 g) in DMF (15 mL) was stirred at room temperature, and TIPSCl (2.76 mL) was added. The mixture was stirred overnight. Ice water was added to the reaction mixture, and it was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target product (4.8 g).

[0128] Reference Example 6. Production of (4a'S,8a'S)-4'-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)phenyl)octahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline] (4a'S,8a'S)-octahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline] (300 mg) and (2-(4-bromophenoxy)-2,2-difluoroethoxy)triisopropylsilane (749 mg) were dissolved in toluene (6 mL). Pd(OAc)2 (29.9 mg), tBu3P·HBF4 (38.6 mg), and t-BuONa (192 mg) were added to this solution and stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (Hexane / AcOEt) to obtain the target product (680 mg).

[0129] Reference Example 41. Production of (3R,4aS,8aS)-1-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3-methyldecahydroquinoxaline (2R,4aS,8aS)-2-methyldecahydroquinoxaline (500 mg) and (2-(4-bromo-2-chlorophenoxy)ethoxy)triisopropylsilane (1322 mg) were dissolved in toluene (5 mL). Pd(OAc)2 (58.2 mg), tBu3P·HBF4 (75 mg), and t-BuONa (467 mg) were added to this mixture and stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (Hexane / AcOEt) to obtain the target product (700 mg).

[0130] Reference Example 65. Preparation of (4aS,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-carboxylate tert-butyl A solution of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (7.35 g) in MeOH (70 mL) was stirred under ice-cold conditions, and Boc2O (9.65 g) was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt) to obtain the target product (11.0 g).

[0131] Reference Example 66. Preparation of (4aS,8aS)-3,3,4-trimethyloctahydroquinoxaline-1(2H)-carboxylate tert-butyl (4aS,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-carboxylate tert-butyl (10.0 g) was mixed with 37% formaldehyde solution (9.14 mL) in DCE (100 mL) and THF (50 mL). After stirring at room temperature for 30 minutes, NaBH(OAc)3 (23.9 g) was added under ice-cold stirring. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure and extracted by DCM. The organic layer was concentrated, and the residue was purified by basic silica gel column chromatography to obtain the target product (11.0 g).

[0132] Reference Example 67. Production of (4aS,8aS)-1,2,2-trimethyldecahydroquinoxaline A solution of (4aS,8aS)-3,3,4-trimethyloctahydroquinoxaline-1(2H)-carboxylate tert-butyl (10 g) in DCM (40 mL) was stirred on ice, and TFA (20 mL) was added. The mixture was stirred overnight at room temperature. The reaction mixture was concentrated, saturated K2CO3 aqueous solution was added, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt) to obtain the target product (4.68 g).

[0133] Reference Example 68. Production of (4aS,8aS)-4-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)phenyl)-1,2,2-trimethyldecahydroquinoxaline (4aS,8aS)-1,2,2-trimethyldecahydroquinoxaline (200 mg) and (2-(4-bromophenoxy)-2,2-difluoroethoxy)triisopropylsilane (494 mg) were dissolved in toluene (5 mL). Pd(OAc)2 (19.70 mg), tBu3P·HBF4 (25.5 mg), and t-BuONa (127 mg) were added, and the mixture was stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (Hexane / AcOEt) to obtain the target product (480 mg).

[0134] Reference Example 82. Production of (4aR,8aS)-1-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (250 mg) and (2-(4-bromo-2-chlorophenoxy)ethoxy)triisopropylsilane (697 mg) were dissolved in toluene (5 mL). Pd(OAc)2 (26.7 mg), tBu3P·HBF4 (34.5 mg), and t-BuONa (157 mg) were added to this mixture and stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by basic silica gel column chromatography (Hexane / AcOEt) to obtain the target product (400 mg).

[0135] Reference Example 85. Production of (4aS,8aR)-4-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-1,2,2-trimethyldecahydroquinoxaline (4aR,8aS)-1-(3-chloro-4-(2-((triisopropylsilyl l)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline (180 mg) was added to a 4 mL solution of DCM / THF (1:1) with 83 μL of 36% formaldehyde aqueous solution and stirred at room temperature. After 30 minutes, NaBH(OAc)3 (231 mg) was added and stirred at room temperature for two days. The solvent was concentrated, and the residue was purified by column chromatography (AcOEt / MeOH) to obtain the target product (170 mg).

[0136] Reference Example 110. Preparation of 2-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-5-fluorobenzaldehyde (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (343 mg) and 2-chloro-4,5-difluorobenzaldehyde (300 mg) were dissolved in DMSO (3 mL), to which DIPEA (445 μL) was added and the mixture was stirred at 100°C for 7 hours under a nitrogen atmosphere. After cooling to room temperature, 5N NaOH aqueous solution was added and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (AcOEt / MeOH) to obtain the target product (490 mg).

[0137] Reference Example 111. Preparation of 2-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-5-fluorophenol 2-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-5-fluorobenzaldehyde (480 mg) was dissolved in MeOH (8 mL), to which 323 μL of 35% hydrogen peroxide solution and 118 μL of H2SO4 were added and the mixture was stirred at room temperature for 3 days. Saturated NaHCO3 aqueous solution was added to the reaction mixture, and the precipitated solid was filtered off. The mixture was washed with water and hexane to obtain the target product (400 mg).

[0138] Reference Example 112. Production of (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-chloro-2-fluorophenyl)-3,3-dimethyldecahydroquinoxaline 2-Chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-5-fluorophenol (150 mg) and K2CO3 (133 mg, finely ground) were suspended in DMF (3 mL), to which (2-bromoethoxy)-tert-butyldimethylsilane (129 μL) was added and the mixture was stirred at 60°C for 3 hours. Water was added to the reaction mixture and extracted with AcOEt. The organic layer was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt) to obtain the target product (210 mg).

[0139] Reference Example 118. Preparation of 2-(4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-3-fluorophenoxy)-2,2-difluoroethyl acetate To a solution of 4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-3-fluorophenol (150 mg) in DMF (3 mL), DBU (244 μL) was added, followed by bromodifluoroethyl acetate (138 μL), and the mixture was stirred at 60°C for 3 hours. Water was added to the reaction mixture and extracted with AcOEt. The organic layer was concentrated, and the residue was purified by silica gel column chromatography (Hexane / AcOEt) to obtain the target product (175 mg).

[0140] Compounds 7-40, 42-64, 69-81, 83-84, 86-109, 113-117, and 119-165 were prepared in the same manner as in Reference Examples 1-6, 41, 65-68, 82, 85, 110-112, and 118. The structural formulas and physicochemical data of compounds 1-165 are shown in Tables 1-1 to 1-22, respectively.

[0141] [Table 1-1] [Table 1-2] [Table 1-3] [Table 1-4] [Table 1-5] [Table 1-6] [Table 1-7] [Table 1-8] Table 1-9 Table 1-10 Table 1-11 Table 1-12 Table 1-13 Table 1-14 Table 1-15 Table 1-16 Table 1-17 Table 1-18 Table 1-19 Table 1-20 Table 1-21 Table 1-22

[0142] Example 1. Production of 2-(2,6-difluoro-4-((4a'S,8a'S)-hexahydro-1'H-spiro[cyclobutan-1,2'-quinoxaline]-4'(3'H)-yl)phenoxy)ethane-1-ol (4a'S,8a'S)-4'-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3,5-difluorophenyl)octahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline] (480 mg) in THF (6 mL) was stirred at room temperature, and 1029 μL of 1M-TBAF / THF solution was added. After stirring overnight at room temperature, the reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was recrystallized from Hexane / AcOEt to obtain the target product (312 mg).

[0143] Example 2. Preparation of 2,2-difluoro-2-(4-((4a'S,8a'S)-hexahydro-1'H-spiro[cyclobutan-1,2'-quinoxaline]-4'(3'H)-yl)phenoxy)ethane-1-ol (4a'S,8a'S)-4'-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)phenyl)octahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline] (670 mg) in THF (6 mL) was stirred at room temperature, and 1317 μL of 1M-TBAF / THF solution was added. After stirring overnight at room temperature, the reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was recrystallized from AcOEt / Hexane to obtain the target product (436 mg).

[0144] Example 17. Preparation of 2-(2-chloro-6-fluoro-4-((3R,4aS,8aS)-3-methyloctahydroquinoxaline-1(2H)-yl)phenoxy)ethane-1-ol 1 / 2 fumarate (3R,4aS,8aS)-1-(3-chloro-5-fluoro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3-methyldecahydroquinoxaline (650 mg) was added to a solution of THF (5 mL) with 1M TBAF / THF solution (1302 μL) and stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was dissolved in EtOH, and then concentrated with a solution of fumaric acid (156 mg) in EtOH. The precipitated crystals were recrystallized from EtOH / AcOEt to obtain the target product (420 mg).

[0145] Example 20. Preparation of 2-(4-((4aS,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)phenoxy)-2,2-difluoroethane-1-ol To a solution of (4aS,8aS)-1-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline (540 mg) in THF (5 mL) was added 1 M TBAF / THF solution (2.17 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). Recrystallization from AcOEt / Hexane gave the target product (324 mg).

[0146] Example 22. Preparation of 2-(4-((4aS,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-2-fluorophenoxy)-2,2-difluoroethane-1-ol To a solution of (4aS,8aS)-1-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)-3-fluorophenyl)-3,3-dimethyldecahydroquinoxaline (560 mg) in THF (5 mL) was added 1 M TBAF / THF solution (2.18 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). Recrystallization from AcOEt / Hexane gave the target product (347 mg).

[0147] Example 27. Preparation of 2-(2-chloro-4-((4aS,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)phenoxy)ethane-1-ol To a solution of (4aS,8aS)-1-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline (1.95 g) in THF (20 mL) was added 1 M TBAF / THF solution (3.94 mL), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). Recrystallization from AcOEt / Hexane gave the target product (1.33 g).

[0148] Example 34. Preparation of 2-(4-((4aS,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-2,6-difluorophenoxy)ethane-1-ol (4aS,8aS)-1-(3,5-difluoro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline (500 mg) was added to a solution of THF (5 mL) with 1 M TBAF / THF solution (2.01 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The target product (281 mg) was obtained by recrystallization from AcOEt / Hexane.

[0149] Example 37. Preparation of 2,2-difluoro-2-(4-((4aS,8aS)-3,3,4-trimethyloctahydroquinoxaline-1(2H)-yl)phenoxy)ethane-1-ol (4aS,8aS)-4-(4-(1,1-difluoro-2-((triisopropylsilyl l)oxy)ethoxy)phenyl)-1,2,2-trimethyldecahydroquinoxaline (480 mg) was added to a solution of THF (6 mL) with 1 M TBAF / THF solution (940 μL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The resulting solid was recrystallized from AcOEt / Hexane to obtain the target product (296 mg).

[0150] Example 38. Preparation of 2-(2-chloro-4-((4aS,8aS)-3,3,4-trimethyloctahydroquinoxaline-1(2H)-yl)phenoxy)ethane-1-ol dihydrochloride (4aS,8aS)-4-(3-chloro-4-(2-((triisopropylsilyl l)oxy)ethoxy)phenyl)-1,2,2-trimethyldecahydroquinoxaline (410 mg) was added to a solution of THF (6 mL) with 1 M TBAF / THF solution (805 μL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was dissolved in EtOH, then concentrated with 1N HCl / EtOH, and recrystallized from EtOH / AcOEt to obtain the target product (285 mg).

[0151] Example 44. Preparation of 2-(2-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)phenoxy)ethane-1-ol 1 / 2 fumarate (4aR,8aS)-1-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline (3.60 g) was added to a solution of THF (50 mL) with 1 M TBAF / THF solution (7.27 mL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was dissolved in AcOEt / EtOH, concentrated with a solution of fumaric acid (0.43 g) in ethanol, and recrystallized from EtOH to obtain the target product (2.5 g).

[0152] Example 47. Preparation of 2-(2-chloro-4-((4aR,8aS)-3,3,4-trimethyloctahydroquinoxaline-1(2H)-yl)phenoxy)ethane-1-ol fumarate (4aS,8aR)-4-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-1,2,2-trimethyldecahydroquinoxaline (160 mg) was added to a solution of THF (4 ml) with 1 M TBAF / THF solution (314 μl) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was dissolved in AcOEt / EtOH, then a solution of fumaric acid (40 mg) in EtOH was added, concentrated, and washed with DCM / Hexane to obtain the target product (95 mg).

[0153] Example 56. Preparation of 2-(4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-3-methylphenoxy)-2,2-difluoroethane-1-ol (4aR,8aS)-1-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)-2-methylphenyl)-3,3-dimethyldecahydroquinoxaline (290 mg) was added to a solution of THF (5 mL) with 1 M TBAF / THF solution (568 μL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The target product (130 mg) was obtained by recrystallization from hexane.

[0154] Example 59. Preparation of 2-(2-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-5-fluorophenoxy)ethane-1-ol 3 / 4 fumarate (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-chloro-2-fluorophenyl)-3,3-dimethyldecahydroquinoxaline (200 mg) was added to a solution of THF (3 ml) with 1 M TBAF / THF solution (425 μL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was dissolved in AcOEt / EtOH, and a solution of fumaric acid (54 mg) in EtOH was added and concentrated. The product was recrystallized from EtOH / AcOEt to obtain the target product (160 mg).

[0155] Example 60. Preparation of 2-(2-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-3-fluorophenoxy)ethane-1-ol fumarate (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-chloro-2-fluorophenyl)-3,3-dimethyldecahydroquinoxaline (195 mg) was added to a solution of THF (3 mL) with 1 M TBAF / THF solution (414 μL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was dissolved in EtOH, concentrated with an ethanol solution of fumaric acid (53.7 mg), and recrystallized from EtOH / AcOEt to obtain the target product (150 mg).

[0156] Example 61. Preparation of 2-(4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-3-fluorophenoxy)-2,2-difluoroethane-1-ol 1 / 2 fumarate A solution of 2-(4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-3-fluorophenoxy)-2,2-difluoroethyl acetate (165 mg) in THF (5 ml) was stirred under ice-cold conditions, and LiBH4 (19.75 mg) was added. The mixture was stirred at room temperature for 20 hours. The reaction mixture was stirred under ice-cold conditions, and 5N-HCl / MeOH was added until the foaming stopped. Then, 5N NaOH aqueous solution was added to make the reaction system basic, and the mixture was extracted with AcOEt. The organic layer was concentrated, and the residue was purified by basic silica gel column chromatography. The purified product was dissolved in AcOEt / EtOH, concentrated with ethanol solution of fumaric acid (53 mg), and recrystallized from EtOH / AcOEt to obtain the target product (120 mg).

[0157] Example 64. Preparation of 2-(3-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)phenoxy)ethane-1-ol 1 / 2 fumarate (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-chlorophenyl)-3,3-dimethyldecahydroquinoxaline (540 mg) was added to a solution of THF (8 mL) with 1M TBAF / THF solution (1192 μL) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was dissolved in EtOH, concentrated with a solution of fumaric acid (94 mg) in ethanol, and recrystallized from EtOH / AcOEt to obtain the target product (400 mg).

[0158] Example 69. Preparation of 2-(4-((4aS,8aR)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-3-fluoro-2-methylphenoxy)-2,2-difluoroethane-1-ol 1 / 2 fumarate A solution of 2-(4-((4aS,8aR)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-3-fluoro-2-methylphenoxy)-2,2-difluoroethyl acetate (460 mg) in THF (12 mL) was stirred under ice-cold conditions, and LiBH4 (53.2 mg) was added. The mixture was stirred at room temperature for 17 hours. 5N HCl / MeOH was added to the reaction mixture to stop the reaction, and then 5N NaOH aqueous solution was added to neutralize it. The product was extracted with AcOEt, and the organic layer was concentrated. The residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was dissolved in EtOH, and a solution of fumaric acid (70 mg) in ethanol was added. The mixture was concentrated under reduced pressure, and recrystallized from EtOH / AcOEt to obtain the target product (340 mg).

[0159] Example 74. Preparation of 2-(4-((4aR,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-yl)-2,3-difluorophenoxy)ethane-1-ol 1 / 2 fumarate (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,3-difluorophenyl)-3,3-dimethyldecahydroquinoxaline (440 mg) was dissolved in THF (6 ml) and 1 M TBAF / THF solution (968 μL) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The purified product was dissolved in EtOH, and a solution of fumaric acid (124 mg) in ethanol was added and concentrated. The product was recrystallized from EtOH / AcOEt to obtain the target product (330 mg).

[0160] Compounds for Examples 3-16, 18-19, 21, 23-26, 28-33, 35-36, 39-43, 45-46, 48-55, 57-58, 62-63, 65-68, 70-73, and 75-80 were prepared in the same manner as in Examples 1, 2, 17, 20, 22, 27, 34, 37, 38, 44, 47, 56, 59-61, 64, 69, and 74. The structural formulas and physicochemical data for compounds in Examples 1-80 are shown in Tables 2-1 to 2-12, respectively.

[0161] [Table 2-1] [Table 2-2] [Table 2-3] [Table 2-4] Table 2-5 Table 2-6 Table 2-7 Table 2-8 Table 2-9 Table 2-10 Table 2-11 [Table 2-12]

[0162] [Example Test] The following shows the results of pharmacological tests on representative compounds of the present invention and explains their pharmacological effects, but the present invention is not limited to these test examples.

[0163] Test Example 1 (Measurement of serotonin (5-HT) reuptake inhibitory activity of test compounds using rat brain synaptosomes) Male Wistar rats were decapitated, their brains removed, and their frontal cortex was excised. The isolated frontal cortex was placed in a 0.32 Molar (M) sucrose solution 20 times its weight and homogenized using a Potter homogenizer. The homogenate was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4°C for 20 minutes. The resulting pellet was suspended in incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride) and used as the crude synaptosome fraction. Each well of a 96-well, round-bottom plate was used to carry out the reaction with a total volume of 200 μL of solution containing pergerin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / mL). Specifically, the solvent, unlabeled 5-HT, or serially diluted test compounds were added to each well, and then 1 / 10th of the final volume of synaptosome fraction was added to each well. After pre-incubation at 37°C for 10 minutes, tritium-labeled 5-HT solution (final concentration 8 nM) was added and the uptake reaction was started at 37°C. The uptake reaction was terminated after 10 minutes by suction filtration into a 96-well glass fiber filter plate. The filter was then washed with cold saline, thoroughly dried, and microscintigraphy (PerkinElmer) was added to measure the residual radioactivity on the filter.

[0164] The uptake value when only the solvent was added was set to 100%, and the uptake value when unlabeled 5-HT (final concentration 10 μM) was added (non-specific uptake value) was set to 0%. The 50% inhibitory concentration was calculated from the concentration of the test compound and its inhibitory activity. The results are shown in Table 3.

[0165] [Table 3]

[0166] Test Example 2 (Measurement of norepinephrine (NE) uptake inhibitory activity of test compounds using rat brain synaptosomes) Male Wistar rats were decapitated, their brains removed, and their hippocampi excised. The isolated hippocampi were placed in a 0.32 Molar (M) sucrose solution 20 times their weight and homogenized using a Potter homogenizer. The homogenate was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4°C for 20 minutes. The resulting pellet was suspended in incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride) and used as the crude synaptosome fraction. Each well of a 96-well, round-bottom plate was used to carry out the reaction with a total volume of 200 μL of solution containing pergerin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / mL). Specifically, the solvent, unlabeled NE, or serially diluted test compounds were added to each well, and then 1 / 10th of the final volume of synaptosome fraction was added to each well. After pre-incubation at 37°C for 10 minutes, tritium-labeled NE solution (final concentration 12 nM) was added and the uptake reaction was started at 37°C. The uptake reaction was terminated after 10 minutes by suction filtration into a 96-well glass fiber filter plate. After washing the filter with cold saline and drying it thoroughly, a microscintimeter (PerkinElmer) was added and the residual radioactivity on the filter was measured.

[0167] The uptake value when only the solvent was added was set to 100%, and the uptake value when unlabeled NE (final concentration 10 μM) was added (non-specific uptake value) was set to 0%. The 50% inhibitory concentration was calculated from the concentration of the test compound and its inhibitory activity. The results are shown in Table 4.

[0168] [Table 4]

[0169] Test Example 3 (Measurement of dopamine (DA) reuptake inhibitory activity of test compounds using rat brain synaptosomes) Male Wistar rats were decapitated, their brains removed, and their striatums excised. The separated striatums were placed in a 0.32 Molar (M) sucrose solution 20 times their weight and homogenized using a Potter homogenizer. The homogenate was centrifuged at 1000 g at 4°C for 10 minutes, and the supernatant was further centrifuged at 20000 g at 4°C for 20 minutes. The resulting pellet was suspended in incubation buffer (20 mM HEPES buffer (pH 7.4) containing 10 mM glucose, 145 mM sodium chloride, 4.5 mM potassium chloride, 1.2 mM magnesium chloride, and 1.5 mM calcium chloride) and used as the crude synaptosome fraction. Each well of a 96-well, round-bottom plate was used to carry out the reaction with a total volume of 200 μL of solution containing pergerin (final concentration 10 μM) and ascorbic acid (final concentration 0.2 mg / mL). Specifically, the solvent, unlabeled DA, or serially diluted test compounds were added to each well, and then one-tenth of the final volume of synaptosome fraction was added to each well. After pre-incubation at 37°C for 10 minutes, tritium-labeled DA solution (final concentration 2 nM) was added and the uptake reaction was started at 37°C. The uptake reaction was terminated after 10 minutes by suction filtration into a 96-well glass fiber filter plate. After washing the filter with cold saline and drying it thoroughly, a microscintimeter (PerkinElmer) was added and the residual radioactivity on the filter was measured.

[0170] The uptake value when only the solvent was added was set to 100%, and the uptake value when unlabeled DA (final concentration 10 μM) was added (non-specific uptake value) was set to 0%. The 50% inhibitory concentration was calculated from the concentration of the test compound and its inhibitory activity. The results are shown in Table 5.

[0171] [Table 5]

[0172] Test Example 4 (Metabolic Stability Test) The metabolic reaction was initiated by adding and mixing a test compound solution (final concentration 0.001 mmol / L) and an NADH / NADPH solution (final concentration 1 mmol / L) to a human liver microsome solution (final concentration 100 mmol / L potassium phosphate buffer (pH 7.4), 5 mmol / L magnesium chloride, 0.2 mg / mL human liver microsomes). A methanol solution of the internal standard was prepared and used as a reaction stop solution. Specifically, 222.5 μL of human liver microsome solution was added to ice water, 2.5 μL of acetonitrile solution of the test compound was added and mixed, and after pre-incubation at 37°C for 1 minute, 25 μL of NADH / NADPH solution was added and mixed to initiate the metabolic reaction. After incubation at 37°C for 0, 10, and 20 minutes, 25 μL of the reaction solution was taken at each reaction time and added to 500 μL of stop solution and mixed to stop the reaction. The mixed solution was centrifuged (6130 g, 10 minutes, 4°C), and the resulting supernatant was used as the sample for LC-MS / MS analysis.

[0173] The peak area ratio ([peak area of ​​the test compound] / [peak area of ​​the internal standard]) was calculated using the test compound and the internal standard as the measurement targets. The residual rate of the test compound was calculated from ([peak area ratio at each reaction time] / [peak area ratio at reaction time 0 minutes]). Nonlinear least squares analysis was performed on the survival rate and incubation time to determine the elimination rate constant ([0.693] / [half-life]), and the intrinsic liver clearance (μL / min / mg) was calculated from ([elimination rate constant] / [microsome concentration]). The results are shown in Table 6.

[0174] [Table 6]

[0175] Test Example 5 (CYP Inhibition Test (1): Inhibition Rate (%) at Concentration Evaluation) Metabolic reactions were initiated by adding and mixing a human liver microsome solution containing three CYP-specific substrates (final concentration 100 mmol / L potassium phosphate buffer (pH 7.4), 5 mmol / L magnesium chloride, 0.1 mg / mL human liver microsomes, 0.005 mmol / L diclofenac (CYP2C9), 0.01 mmol / L buflarol (CYP2D6), 0.005 mmol / L midazolam (CYP3A4)) with a test compound solution (final concentration 0.01 mmol / L) and an NADH / NADPH solution (final concentration 1 mmol / L). Furthermore, methanol solutions of stable isotopes of the metabolites (50 ng / mL [13C6] diclofenac hydroxylated, 5 ng / mL [2H9] buflalol hydroxylated, and 5 ng / mL [13C6] midazolam hydroxylated (all stable isotopes)) were prepared as internal standard solutions and used as reaction stop solutions. Specifically, 2 μL of acetonitrile solution of the test compound (or acetonitrile as a control) was added and mixed to 178 μL of human liver microsome solution in ice water. After pre-incubation at 37°C for 1 minute, 20 μL of NADH / NADPH solution was added and mixed to initiate the metabolic reaction. After incubation at 37°C for 10 minutes, 50 μL of the reaction solution was taken and added and mixed to 500 μL of stop solution to stop the reaction. The mixed solution was centrifuged (6130 g, 10 minutes, 4°C), and the resulting supernatant was used as the sample for LC-MS / MS analysis.

[0176] The peak area ratio ([peak area of ​​metabolite] / [peak area of ​​corresponding stable isotope]) was calculated for metabolites and their stable isotopes. By comparing the peak area ratio when each test compound solution was added with that of the control, the inhibition rate (%) of each CYP molecular species of the test compound was calculated from (1-[peak area ratio when each test compound solution was added] / [peak area ratio of the control]) × 100. The results are shown in Table 7.

[0177] [Table 7]

[0178] Test Example 6 (CYP Inhibition Test (2): Calculation of 50% inhibitory concentration from evaluation results of 3 concentrations) Metabolic reactions were initiated by adding and mixing test compound solutions (final concentrations of 0.01, 0.03, and 0.1 mmol / L) and an NADH / NADPH solution (final concentration of 1 mmol / L) to a human liver microsome solution containing three CYP-specific substrates (final concentration 100 mmol / L potassium phosphate buffer (pH 7.4), 5 mmol / L magnesium chloride, 0.1 mg / mL human liver microsomes, 0.005 mmol / L diclofenac (CYP2C9), 0.01 mmol / L buflarol (CYP2D6), 0.005 mmol / L midazolam (CYP3A4)). Furthermore, methanol solutions of stable isotopes of the metabolites (50 ng / mL [13C6] diclofenac hydroxylated, 5 ng / mL [2H9] buflalol hydroxylated, and 5 ng / mL [13C6] midazolam hydroxylated (all stable isotopes)) were prepared as internal standard solutions and used as reaction stop solutions. Specifically, 2 μL of acetonitrile solution of the test compound (or acetonitrile as a control) was added and mixed to 178 μL of human liver microsome solution in ice water. After pre-incubation at 37°C for 1 minute, 20 μL of NADH / NADPH solution was added and mixed to initiate the metabolic reaction. After incubation at 37°C for 10 minutes, 50 μL of the reaction solution was taken and added and mixed to 500 μL of stop solution to stop the reaction. The mixed solution was centrifuged (6130 g, 10 minutes, 4°C), and the resulting supernatant was used as the sample for LC-MS / MS analysis. The peak area ratio ([peak area of ​​metabolite] / [peak area of ​​corresponding stable isotope]) was calculated for metabolites and their stable isotopes. By comparing the peak area ratio when each test compound solution was added with that of the control, the inhibition rate (%) of each CYP molecular species of the test compound was calculated from (1-[peak area ratio when each test compound solution was added] / [peak area ratio of the control]) × 100. For each CYP molecule, the slope and intercept of a linear regression between the logarithm of the final concentration of the test compound (0.01, 0.03, and 0.1 mmol / L) and the inhibition rate (%) at each concentration were calculated. The concentration at which the inhibition rate (%) of each CYP molecule was 50% was then determined and defined as the 50% inhibition concentration. The results are shown in Table 8.

[0179] [Table 8]

[0180] Test Example 7 (Protein Binding Rate Test) A serum sample was prepared by adding a test compound solution to human serum (final concentration of the test compound: 0.001 mmol / L). The serum sample and Dulbecco's Phosphate-Buffered Saline (D-PBS(-)) were added to wells separated by a dialysis membrane to initiate the reaction. A methanol solution of the internal standard was also prepared and used as a reaction stop solution. Specifically, a dialysis membrane (molecular weight cutoff 12000-14000) was pre-conditioned by immersing it in distilled water and then 20% ethanol. Afterward, it was washed with D-PBS(-) and placed in an equilibrium dialysis kit. 150 μL of D-PBS(-) was added to one half of the dialysis membrane, and 150 μL of serum sample was added to the other half. All wells were sealed and incubated at 37°C for 6 hours. Then, 30 μL of sample was taken from the serum side and 90 μL from the PBS side of each well. The reaction was stopped by mixing these samples with 90 μL of D-PBS(-) or 30 μL of blank serum and 480 μL of stop solution. The mixed solution was centrifuged (6130 g, 10 minutes, 4°C), and the resulting supernatant was used as the sample for LC-MS / MS analysis.

[0181] The peak area ratio ([peak area of ​​test compound] / [peak area of ​​internal standard]) was calculated for both the test compound and the internal standard substance. By comparing the peak area ratio on the PBS side of each test compound with that on the serum side, the protein binding rate (%) of the test compound was calculated from (1-[peak area ratio on PBS side] / [peak area ratio on serum side])×100. The results are shown in Table 9.

[0182] [Table 9] [Industrial applicability]

[0183] The compounds or salts thereof of the present invention have a broad therapeutic spectrum.

Claims

1. Formula [I]: [In the formula, R 11 , R 12 and R 13 These are identical or different, each independently of hydrogen or C 1-6 It is alkyl, or R 11 and R 12 It forms a 3- to 8-membered cycloalkane with adjacent carbon atoms; R 22 , R 23 , R 25 and R 26 are the same or different, each independently represent hydrogen, halogen, C 1-6 alkyl or C 1-6 alkoxy, or R 22 and R 23 together with the adjacent benzene ring form a 9- to 10-membered bicyclic system further containing an oxygen atom as a ring-constituting atom; R 31 and R 32 [These are either the same or different, and each is independently hydrogen or halogen.] A compound represented by or a salt thereof.

2. The compound or salt thereof according to claim 1, wherein formula [I] is selected from formula [Ia], formula [Ib], formula [Ic], or formula [Id]. [The symbols in the formula are the same as above.]

3. In formula [I], R 11 , R 12 and R 13 These are either the same or different, independently of each other, hydrogen or methyl, or R 11 and R 12 It forms cyclobutyl with adjacent carbon atoms; R 22 , R 23 , R 25 and R 26 These are, either identical or different, independently hydrogen, fluorine, chlorine, methyl, or methoxy, or R 22 and R 23 Together with the adjacent benzene ring, it forms a benzofuran; R 31 and R 32 These are, either identical or distinct, hydrogen or fluorine, each independently; The compound or salt thereof according to claim 2.

4. In formula [I], R 22 , R 23 , R 25 and R 26 A compound or salt thereof according to any one of claims 1 to 3, wherein two or more of the atoms are hydrogen.

5. A compound according to claim 1, or a salt thereof, selected from the group consisting of the following compounds.

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