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] The present invention relates to a heterocyclic compound, and more particularly to a heterocyclic compound having a reuptake inhibitory effect on serotonin, norepinephrine and / or dopamine. [Background technology]

[0002] Attention-Deficit Hyperactivity Disorder (ADHD) is a developmental disorder whose core symptoms are inattention, hyperactivity, and impulsivity. The prevalence is estimated to be 5% in children and 2.5% in adults (Non-Patent Document 1), and it has been reported that more than 65% of patients diagnosed with ADHD in childhood continue to have ADHD symptoms in adulthood (Non-Patent Document 2). It has been reported that ADHD is not limited to its core symptoms, but can also cause various secondary and comorbid disorders as the patient grows (Non-Patent Document 3). In general, ADHD patients have a high prevalence of mood disorders, anxiety disorders, externalizing disorders, and substance use disorders, and are said to have many difficulties in daily life in terms of independence in daily life, education, employment status, economic situation, etc. (Non-Patent Document 4). In order to overcome such obstacles, it is necessary to confirm the diagnosis and begin treatment early. The pathology of ADHD is thought to involve the monoamine nervous system, including dopamine nerves, and the drug treatment of ADHD mainly involves central stimulants that act on the monoamine nervous system (such as amphetamine, methamphetamine, methylphenidate, and their derivatives) and non-central stimulants (such as atomoxetine, guanfacine, clonidine). Stimulants have excellent efficacy (fast acting and effective), but they have the risk of drug dependence and abuse, and their effects last for a short time. Non-stimulants have a low risk of drug dependence and abuse, but it takes time for their effects to stabilize. As for non-central stimulants, atomoxetine (norepinephrine reuptake inhibitor) is used as the first choice, or as the second choice when central stimulants are ineffective or their side effects are intolerable. In addition, the antidepressant bupropion (norepinephrine-dopamine reuptake inhibitor) may be used (Non-Patent Document 5). In addition, the involvement of the serotonin nervous system has been reported for impulsivity, one of the core symptoms of ADHD (Non-Patent Document 6), and there is also a report that impulsive-like symptoms in ADHD model animals are suppressed by serotonin reuptake inhibitors (Non-Patent Document 7). Patent Documents 1 and 2 disclose heterocyclic compounds as therapeutic agents for diseases relating to 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] The present invention aims to provide a therapeutic drug 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. Another object of the present invention is to provide a drug that has excellent pharmacokinetic properties (high metabolic stability, long duration of effective blood concentration, low protein binding rate, low CYP inhibition rate) and continuous pharmacological action, and therefore has a sustained effect at a lower dosage and at a lower drug blood concentration with fewer drug interactions. [Means for solving the problem]

[0006] As a result of intensive research aimed at solving the above problems, the present inventors have succeeded in synthesizing a heterocyclic compound having a structure in which a hydroxyethoxy group is bonded to an aryl moiety, which is represented by the following general formula and can be used to produce desired drugs. The present invention has been completed based on these findings.

[0007] That is, the present invention includes the following aspects. [1-1] Formula [I]: JPEG2024525719000002.jpg5088[In the formula, R 11 , R 12 and R 13 are the same or different and each independently represents hydrogen or C 1-6 alkyl or R 11 and R 12 forms a 3- to 8-membered cycloalkane together with adjacent carbon atoms; R 22 , R 23 , R 25 and R 26are the same or different and each independently represent hydrogen, halogen, C 1-6 Alkyl or C 1-6 Alkoxy or R 22 and R 23 forms, together with the adjacent benzene ring, a 9- to 10-membered bicyclic ring system further containing an oxygen atom as a ring-constituting element; R 31 and R 32 are the same or different and each independently represents hydrogen or halogen. A compound represented by the formula: [1-2] The compound according to [1-1], wherein the formula [I] is selected from the formula [Ia], the formula [Ib], the formula [Ic] or the formula [Id], or a salt thereof. JPEG2024525719000003.jpg84146[Each symbol in the formula is the same as above] [1-3] In formula [I], R 11 , R 12 and R 13 are the same or different and each independently represent hydrogen or methyl; 11 and R 12 forms a cyclobutyl with the adjacent carbon atom; R 22 , R 23 , R 25 and R 26 are the same or different and each independently represent hydrogen, fluorine, chlorine, methyl or methoxy; or R 22 and R 23 together with the adjacent benzene ring form a benzofuran; R 31 and R 32 are the same or different and each independently is hydrogen or fluorine; The compound or salt thereof according to [1-1] or [1-2]. [1-4] In formula [I], R 22 , R 23 , R 25 and R 26 wherein two or more of the above are hydrogen. [1-5] A compound or a salt thereof according to any one of [1-1] to [1-4] selected from the group consisting of the following compounds: JPEG2024525719000004.jpg124150[2] A pharmaceutical composition comprising a compound or a salt thereof according to any one of [1-1] to [1-5] as an active ingredient, and a pharma- ceutically acceptable carrier. [3-1] A therapeutic, preventive and / or diagnostic agent for disorders associated with dysfunction of serotonin, norepinephrine and / or dopamine nerves, comprising as an active ingredient a compound according to any one of [1-1] to [1-5] or a salt thereof. [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 illnesses, 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 dependency, pain, fibromyalgia, apathy, Alzheimer's disease, memory disorders, Parkinson's disease, restless legs syndrome, endocrinology, and chronic obstructive pulmonary disease. The therapeutic, prophylactic and / or diagnostic agent according to [3-1], wherein the disorder is selected from the group consisting of secretory disorders, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorders, negative symptoms of schizophrenia, affective disorders of schizophrenia, cognitive dysfunction of schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulse control disorders, trichotillomania, kleptomania, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, obstructive sleep apnea syndrome and headache. [3-3] The therapeutic, preventive and / or diagnostic agent according to [3-2], wherein the depression is selected from the group consisting of major depressive disorder, bipolar I disorder, bipolar II disorder, mixed state, dysthymic disorder, rapid cycler depression, atypical depression, seasonal affective disorder, postpartum depression, mild depression, recurrent brief depressive disorder, treatment-refractory depression / chronic depression, treatment-resistant depression, alcohol-induced mood disorder, mixed anxiety-depressive disorder, depression associated with various diseases such as Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactagogue syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc., middle-aged depression, geriatric depression, childhood / adolescent depression, and drug-induced depression such as interferon. [3-4] The therapeutic, preventive and / or diagnostic agent according to [3-2], wherein the anxiety associated with various diseases is anxiety selected from the group consisting of head trauma, brain infection, inner ear disorder, heart failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease. [3-5] The therapeutic, preventive and / or diagnostic agent according to [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 treating, preventing and / or diagnosing disorders associated with dysfunction of serotonin, norepinephrine and / or dopamine nerves, comprising a compound according to any one of [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 illnesses, 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 dependency, pain, fibromyalgia, apathy, Alzheimer's disease, memory disorders, Parkinson's disease, restless legs syndrome, endocrine disorders. The pharmaceutical composition for treatment, prevention and / or diagnosis according to [4-1], wherein the disorder is selected from the group consisting of disorders such as chronic obstructive pulmonary disease, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorders, negative symptoms of schizophrenia, affective disorders of schizophrenia, cognitive dysfunction of schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulse control disorders, trichotillomania, kleptomania, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, obstructive sleep apnea syndrome and headache. [4-3] The pharmaceutical composition for treatment, prevention and / or diagnosis according to [4-2], wherein the depression is selected from the group consisting of major depressive disorder, bipolar I disorder, bipolar II disorder, mixed state, dysthymic disorder, rapid cycler depression, atypical depression, seasonal affective disorder, postpartum depression, mild depression, recurrent brief depressive disorder, treatment-refractory depression / chronic depression, treatment-resistant depression, alcohol-induced mood disorder, mixed anxiety-depressive disorder, depression associated with various diseases such as Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea-galactagogue syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc., middle-aged depression, geriatric depression, childhood / adolescent depression, and drug-induced depression such as interferon. [4-4] The pharmaceutical composition for treatment, prevention and / or diagnosis according to [4-2], wherein the anxiety associated with various diseases is anxiety selected from the group consisting of head trauma, brain infection, inner ear disorder, heart failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease. [4-5] The pharmaceutical composition for treatment, prevention and / or diagnosis 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 a disorder associated with dysfunction of serotonin, norepinephrine and / or dopamine nerves, comprising administering to a subject an effective amount of a compound or a salt thereof according to any one of [1-1] to [1-5]. [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 illnesses, 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 dependency, pain, fibromyalgia, apathy, Alzheimer's disease, memory disorders, Parkinson's disease, restless legs syndrome, endocrinology, and chronic obstructive pulmonary disease. The method for treating, preventing and / or diagnosing the disorder described in [5-1], wherein the disorder is selected from the group consisting of secretory disorders, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorders, negative symptoms of schizophrenia, affective disorders of schizophrenia, cognitive dysfunction of schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulse control disorders, trichotillomania, kleptomania, gambling addiction, cluster headache, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, obstructive sleep apnea syndrome and headache. [5-3] The method for treating, preventing and / or diagnosing depression according to [5-2], wherein the depression is selected from the group consisting of major depressive disorder, bipolar I disorder, bipolar II disorder, mixed state, dysthymic disorder, rapid cycler depression, atypical depression, seasonal affective disorder, postpartum depression, mild depression, recurrent brief depressive disorder, treatment-refractory depression / chronic depression, treatment-resistant depression, alcohol-induced mood disorder, mixed anxiety-depressive disorder, depression associated with various diseases such as Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea / galactagogue syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc., middle-aged depression, geriatric depression, childhood / adolescent depression and drug-induced depression such as interferon. [5-4] The method for treatment, prevention and / or diagnosis described in [5-2], wherein the anxiety associated with various diseases is anxiety selected from the group consisting of head trauma, brain infection, inner ear disorder, heart failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease. [5-5] The method for treatment, prevention and / or diagnosis described in [5-2], wherein the pain is pain 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] The compound or salt thereof according to any one of [1-1] to [1-5] for use in the treatment, prevention and / or diagnosis of a disorder associated with dysfunction of serotonin, norepinephrine and / or dopamine nerves. [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 illnesses, 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 dependency, pain, fibromyalgia, and apathy. The compound or salt thereof according to [6-1], wherein the disorder is selected from the group consisting of Alzheimer's disease, memory disorder, Parkinson's disease, restless legs syndrome, endocrine disorder, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorder, negative symptoms of schizophrenia, affective disorder of schizophrenia, cognitive dysfunction 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. [6-3] The compound or salt thereof according to [6-2], wherein the depression is selected from the group consisting of major depressive disorder, bipolar I disorder, bipolar II disorder, mixed state, dysthymic disorder, rapid cycler disorder, atypical depression, seasonal affective disorder, postpartum depression, mild depression, recurrent brief depressive disorder, treatment-refractory depression / chronic depression, treatment-resistant depression, alcohol-induced mood disorder, mixed anxiety-depressive disorder, depression associated with various diseases such as Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea / galactagogue syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, and cancer, middle-aged depression, geriatric depression, childhood / adolescent depression, and drug-induced depression such as interferon. [6-4] The compound or salt thereof according to [6-2], wherein the anxiety associated with various diseases is anxiety selected from the group consisting of head trauma, brain infection, inner ear disorder, heart failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease. [6-5] The compound or salt thereof according to [6-2], 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. [7-1] Use of a compound or a salt thereof according to any one of [1-1] to [1-5] in the manufacture of a pharmaceutical for use in the treatment, prevention and / or diagnosis of disorders associated with dysfunction of serotonin, norepinephrine and / or dopamine nerves. [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 illnesses, 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 dependency, pain, fibromyalgia, apathy, Alzheimer's disease, memory disorders, Parkinson's disease, restlessness The use described in [7-1], wherein the disorder is selected from the group consisting of leg syndrome, endocrine disorder, hypertension, vasospasm, cerebellar ataxia, gastrointestinal disorder, negative symptoms of schizophrenia, affective disorder of schizophrenia, cognitive dysfunction 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. [7-3] The use according to [7-2], wherein the depression is selected from the group consisting of major depressive disorder, bipolar I disorder, bipolar II disorder, mixed state, dysthymic disorder, rapid cycling disorder, atypical depression, seasonal affective disorder, postpartum depression, mild depression, recurrent brief depressive disorder, treatment-refractory depression / chronic depression, treatment-resistant depression, alcohol-induced mood disorder, mixed anxiety-depressive disorder, depression associated with various diseases such as Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease, amenorrhea / galactagogue syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, cancer, etc., middle-aged depression, geriatric depression, childhood / adolescent depression, and drug-induced depression such as interferon. [7-4] The use described in [7-2], wherein the anxiety associated with various diseases is anxiety selected from the group consisting of head trauma, brain infection, inner ear disorder, heart failure, arrhythmia, hyperadrenalism, hyperthyroidism, asthma and chronic obstructive pulmonary disease. [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 the compound according to any one of [1-1] to [1-5] or a salt thereof as a serotonin reuptake inhibitor, a norepinephrine reuptake inhibitor and / or a dopamine reuptake inhibitor. Effect of the Invention

[0008] A drug that inhibits the reuptake of serotonin, norepinephrine and / or dopamine with an appropriate strength and ratio is expected to become a therapeutic drug that combines the excellent properties of both stimulants and non-stimulants. In in vitro tests, this compound potently and optimally inhibits the reuptake of the three types of monoamines mentioned above. In addition, in in vivo microdialysis tests in rats, this compound has the effect of persistently increasing the extracellular monoamine concentrations in the prefrontal cortex and striatum from low doses when orally administered. Furthermore, in evaluations of the effect of improving hyperactivity-like symptoms and impulsivity-like symptoms using stroke-prone spontaneously hypertensive rats (SHRSP), this compound shows effects from low doses when orally administered. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0009] The words and terms used in this specification are explained in detail below.

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

[0011] In this specification, "C 1-6 Alkyl" is a group with 1 to 6 carbon atoms (C 1-6 ) straight-chain or branched-chain alkyl, specific examples of which include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, and the like. Also, "C 1-6 "Alkyl" refers to a C alkyl group in which 1 to 7 hydrogen atoms have been replaced with deuterium atoms. 1-6 Alkyl is also included.

[0012] In this specification, "C 1-6 Alkoxy" is a group having 1 to 6 carbon atoms (C 1-6 ) straight-chain or branched-chain alkoxy, specific examples of which include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, n-pentoxy, isopentoxy, neopentoxy, n-hexyloxy, isohexyloxy, 3-methylpentoxy, and the like.

[0013] In the present specification, the term "3- to 8-membered cycloalkane" refers to a cycloalkane having 3 to 8 carbon atoms (C 3-8 ) is a cycloalkane, specific examples of which include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, and cyclooctane.

[0014] In this specification, the "9- to 10-membered bicyclic ring system containing an oxygen atom as a ring-constituting element in addition to a benzene ring" refers to a condensed ring consisting of a benzene ring and a saturated or unsaturated 5- to 6-membered heterocycle containing one oxygen atom as a ring-constituting element, and specific examples thereof include benzofuran, dihydrobenzofuran, benzopyran, dihydrobenzopyran, etc.

[0015] In the present specification, the term "protecting group" is not particularly limited as long as it functions as a protecting group, and examples thereof 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-toluoyl, 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl, ... 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);Aralkyl groups (e.g., benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl); carbamate groups (e.g., tert-butyl carbamate, allyl carbamate, benzyl carbamate); and the like.

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

[0017] In the present specification, the term "protecting agent" is not particularly limited as long as it can introduce a protecting group into a functional group of interest. Examples of the protecting agent 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, trifluoroacetyl chloride, ... acetic anhydride; arylcarbonylating agents (e.g., benzoyl chloride, benzoic 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, di-tert-butylisobutylsilyl triflate, and imidazole, pyridine, 2,6-lutidine, etc. as a base; alkoxymethylating agents (e.g., methoxymethyl chloride, methoxymethyl bromide, didimethoxymethane, ethoxymethyl chloride, 2-methoxyethoxymethyl chloride, 2, 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); carbamate groups (e.g., di-tert-butyl dicarbonate, allyl chloroformate, diallyl dicarbonate, benzyl chloroformate, dibenzyl dicarbonate).

[0018] In the present specification, the "deprotecting agent" is not particularly limited as long as it can deprotect the protecting group, and examples thereof include alkyl groups (e.g., trimethylsilyl iodide, boron tribromide, aluminum chloride / ethanethiol); alkyl(alkenyl)carbonyl groups (e.g., strong alkaline aqueous solution, ammonia water, methylamine, 2-aminoethanethiol, thiourea, tetrabutylammonium hydroxide, diisobutylaluminum hydride, lithium aluminum hydride, hydrazine, boron trifluoride diethyl ether complex / dimethyl sulfide); arylcarbonyl groups [a deprotecting agent 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); silyl aryl 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, tetrafluoroborate, zinc, zinc / copper, lithium / ammonia); aryl groups (e.g., hydrogen / palladium on carbon, ammonium formate / palladium on carbon, Raney nickel, trimethylsilyl iodide, boron tribromide, boron trichloride, dichlorodicyanoquinone, cerium ammonium nitrite);Examples of the deprotection of carbamate groups (for example, hydrochloric acid / ethyl acetate, trifluoroacetic acid, trimethylsilyl iodide, aluminum chloride / anisole, etc. can be used for deprotection of tert-butyl carbamate groups, and for example, a combination of a palladium(0) catalyst (tetrakistriphenylphosphinepalladium, trisdibenzylideneacetonedipalladium, etc.) with a nucleophile (morpholine, dimedone, formic acid, 2-ethylhexanoic acid, etc.), iodine / hydrated acetonitrile, etc. can be used for deprotection of benzyl carbamate groups, and for example, catalytic hydrogenolysis using palladium on carbon, trimethylsilyl iodide, trifluoroacetic acid, etc. can be used for deprotection of benzyl carbamate groups);

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

[0020] In this specification, the "desilylating protecting agent" is not particularly limited as long as it can deprotect a silyl protecting group, and examples thereof include formic acid, acetic acid, hydrochloric acid, trifluoroacetic acid, hydrofluoric acid, tetra-n-butylammonium fluoride, etc.

[0021] As used herein, the term "alkylating agent" is not particularly limited as long as it can alkylate a target functional group, and examples thereof include dimethyl sulfate, diazomethane, methyl bromide, methyl iodide, Meerwein reagent, methyl trifluoromethanesulfonate, ethyl bromide, isobutylene, and 2-hydroxyethyl bromide.

[0022] In this specification, the "peroxide" is not particularly limited as long as it can form an oxide, and examples thereof include potassium peroxymonosulfate (Oxone (registered trademark)), 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 the present specification, the term "palladium reagent" is not particularly limited, but examples thereof include tetravalent palladium catalysts such as sodium hexachloropalladate(IV) tetrahydrate and potassium hexachloropalladate(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 G3), palladium chloride (II), palladium bromide (II), palladium acetate (II), 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), 1,1'-bis(diphenylphosphino)ferrocenedichloropalladium (II)-dichloromethane complex and other divalent palladium catalysts; tris(dibenzylideneacetone)dipalladium(0) (Pd2(dba)3), tris(dibenzylideneacetone)dipalladium chloroform complex (0), tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3)4) and other zero-valent palladium catalysts. These palladium compounds may be used alone or in combination of two or more.

[0024] In the present specification, the "phosphine ligand" is not particularly limited, and examples thereof 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), Bis[2-(diphenylphosphino)phenyl] 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), 2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl (RuPhos), etc. are used.

[0025] As used herein, the "reducing agent" is not particularly limited as long as it can reduce a target functional group. For example, lithium aluminum hydride, diisobutylaluminum hydride, sodium dihydrobis(2-methoxyethoxy)aluminate, lithium borohydride, etc. may be used.

[0026] In the present specification, examples of the "base" include inorganic bases and organic bases. Examples of the "inorganic base" 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 hydrogen carbonates (e.g., sodium hydrogen carbonate, potassium hydrogen carbonate), alkali metal phosphates (e.g., sodium phosphate, potassium phosphate), alkaline earth metal phosphates (e.g., sodium phosphate, potassium phosphate), and the like. Examples of the "organic base" 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]undec-7-ene, and the like.

[0027] As used herein, a "leaving group" refers to, for example, halogen, C 1-18 Examples of the group include alkanesulfonyl, lower alkanesulfonyloxy, arylsulfonyloxy, aralkylsulfonyloxy, perhaloalkanesulfonyloxy, sulfonio, and toluenesulfoxy, and preferably, halogen.

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

[0029] The above "C 1-18 Examples of alkanesulfonyl include alkanesulfonyl with 1 to 18 carbon atoms (C 1-18 ) straight-chain or branched-chain alkanesulfonyl, specific examples of which are methanesulfonyl, 1-propanesulfonyl, 2-propanesulfonyl, butanesulfonyl, cyclohexanesulfonyl, dodecanesulfonyl, octadecanesulfonyl, and the like.

[0030] Examples of the above-mentioned "lower alkanesulfonyloxy" include alkanesulfonyloxy having 1 to 6 carbon atoms (C 1-6) straight-chain or branched-chain alkanesulfonyloxy, specific examples of which are methanesulfonyloxy, ethanesulfonyloxy, 1-propanesulfonyloxy, 2-propanesulfonyloxy, 1-butanesulfonyloxy, 3-butanesulfonyloxy, 1-pentanesulfonyloxy, 1-hexanesulfonyloxy, and the like.

[0031] Examples of the above-mentioned "arylsulfonyloxy" include arylsulfonyloxy having 1 to 6 carbon atoms (C 1-6 ) straight or branched alkyl, carbon number 1 to 6 (C 1-6 ) straight or branched alkoxy, nitro, and halogen, which may have 1 to 3 groups selected from the group consisting of phenylsulfonyloxy, naphthylsulfonyloxy, etc. Specific examples of the above "phenylsulfonyloxy which may have a substituent" include phenylsulfonyloxy, 4-methylphenylsulfonyloxy, 2-methylphenylsulfonyloxy, 4-nitrophenylsulfonyloxy, 4-methoxyphenylsulfonyloxy, 2-nitrophenylsulfonyloxy, 3-chlorophenylsulfonyloxy, etc. Specific examples of the above "naphthylsulfonyloxy" include α-naphthylsulfonyloxy, β-naphthylsulfonyloxy, etc.

[0032] Examples of the above-mentioned "aralkylsulfonyloxy" include arylsulfonyloxy having 1 to 6 carbon atoms (C 1-6 ) straight or branched alkyl, carbon number 1 to 6 (C 1-6 ) having 1 to 6 carbon atoms (C 1-6 ) straight or branched alkanesulfonyloxy, naphthyl-substituted alkanesulfonyloxy having 1 to 6 carbon atoms (C 1-6) straight or branched alkanesulfonyloxy. Specific examples of the above "alkanesulfonyloxy substituted with phenyl" include benzylsulfonyloxy, 2-phenylethylsulfonyloxy, 4-phenylbutylsulfonyloxy, 4-methylbenzylsulfonyloxy, 2-methylbenzylsulfonyloxy, 4-nitrobenzylsulfonyloxy, 4-methoxybenzylsulfonyloxy, 3-chlorobenzylsulfonyloxy, etc. Specific examples of the above "alkanesulfonyloxy substituted with naphthyl" include α-naphthylmethylsulfonyloxy, β-naphthylmethylsulfonyloxy, etc.

[0033] Specific examples of the above-mentioned "perhaloalkanesulfonyloxy" include trifluoromethanesulfonyloxy.

[0034] Specific examples of the above-mentioned "sulfonio" include dimethylsulfonio, diethylsulfonio, dipropylsulfonio, 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, and diphenylsulfonio.

[0035] In the present specification, the "solvent" may be any solvent inert to the reaction, and examples thereof include 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), polar solvents (e.g., N,N-dimethylformamide (DMF), N-methylpyrrolidone (NMP), dimethylsulfoxide (DMSO), hexamethylphosphoric acid triamide, acetonitrile). These solvents may be used alone or in combination of two or more. The reaction may also be carried out without a solvent.

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

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

[0038] R in compound [I] 11 , R 12 and R 13 are the same or different and each independently represents hydrogen or C 1-6 It is alkyl, preferably hydrogen, methyl, ethyl, 1-propyl or 2-propyl.

[0039] In another embodiment, R in compound [I] 11 and R 12 forms a 3- to 8-membered cycloalkane together with the adjacent carbon atom, and is 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 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, more preferably hydrogen, fluorine, chlorine or methyl.

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

[0042] R in compound [I] 31 and R 32 are the same or different and each independently hydrogen or halogen; preferably hydrogen, fluorine or chlorine.

[0043] As one aspect of the present invention, R 11 , R 12 and R 13 are the same or different and each independently represents 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.

[0044] In another aspect of the present invention, R 11 and R 12 forms a 3- to 8-membered cycloalkane together with the adjacent carbon atom, preferably cyclobutyl; R 13 is hydrogen or C 1-6 is 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 represents hydrogen or C 1-6 alkyl, preferably hydrogen or methyl; R 22 and R 23 forms a 9- to 10-membered bicyclic ring system together with the adjacent benzene ring further containing an oxygen atom as a ring-constituting element, preferably forms 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 forms a 3- to 8-membered cycloalkane together with the adjacent carbon atom, preferably cyclobutyl; R 13 is hydrogen or C 1-6 is alkyl, preferably hydrogen or methyl; R 22 and R 23 forms a 9- to 10-membered bicyclic ring system together with the adjacent benzene ring further containing an oxygen atom as a ring-constituting element, preferably forming 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.

[0047] In another preferred embodiment of the present invention, General formula [I] JPEG2024525719000005.jpg3956 is JPEG2024525719000006.jpg41145, R 11 , R 12 and R 13 are the same or different and each independently represents hydrogen or C 1-6 alkyl, preferably hydrogen or methyl; 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; --- is a single bond or a double bond, preferably a double bond.

[0048] In another aspect of the present invention, R 11 and R 12 forms a 3- to 8-membered cycloalkane together with the adjacent carbon atom, preferably cyclobutyl. R 13 is hydrogen or C 1-6 alkyl, preferably hydrogen or methyl; R 22 and R 23 forms a 9- to 10-membered bicyclic ring system together with the adjacent benzene ring and further contains an oxygen atom as a ring-constituting element, and is preferably 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.

[0049] In another preferred embodiment of the present invention, General formula [I] JPEG2024525719000007.jpg3856 is JPEG2024525719000008.jpg40145, R 11 and R 12 forms a 3- to 8-membered cycloalkane together with the adjacent carbon atom, preferably cyclobutyl; R 13 is hydrogen or C 1-6 is alkyl; R 25 and R 26 are the same or different and each independently represent hydrogen, halogen, C1-6 Alkyl or C 1-6 is alkoxy; R 31 and R 32 are the same or different and each independently represents hydrogen or halogen; --- is a single bond or a double bond.

[0050] Specific examples of the compound [I] of the present invention include the following compounds. JPEG2024525719000009.jpg124150

[0051] In this specification, the presentation of preferred aspects and options for different features of the compounds, methods, and compositions of the present invention also includes the presentation of combinations of preferred aspects and options for the different features, so long as they are combinable and not inconsistent.

[0052] The method for producing the compound [I] of the present invention will be described below. The compound [I] of the present invention can be produced, for example, based on the production method shown below. The production methods shown below are merely examples, and the production method of the compound [I] is not limited to these.

[0053] In the following reaction formulas, when an alkylation reaction, amination reaction, esterification reaction, amidation reaction, etherification reaction, nucleophilic substitution reaction, addition reaction, oxidation reaction, reduction reaction, etc. are carried out, these reactions are carried out according to a method known per se. Examples of such methods include those described in Experimental Chemistry Lectures (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, published by VCH Publishers Inc. in 1989, and "Greene's Protective Groups in Organic Synthesis" (4th Edition, 2006) by PGM Wuts and T.W. Greene.

[0054] General synthetic route for compound [I] 1) Method for producing compound [I] (1) JPEG2024525719000010.jpg40155 (wherein the symbols are as defined above.)

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

[0056] 2) Method for producing compound [I] (2) JPEG2024525719000011.jpg48161 (in the formula, R 33 is C 1-6 alkyl, and the other symbols are as defined above.

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

[0058] 3) Method for producing intermediate [2] (1) JPEG2024525719000012.jpg47160 (in the formula, Y 1 is a leaving group, and the other symbols are as defined above.)

[0059] The intermediate [2] of the compound [1] of the present invention can be produced by the reaction shown in the above synthetic route. Specifically, the intermediate [2] can be produced by condensing the compound [4] and the 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 intermediate [2] (2) JPEG2024525719000013.jpg41161 (in the formula, Y 2 is a leaving group, and the other symbols are as defined above.)

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

[0062] 5) Method for producing intermediate [3] JPEG2024525719000014.jpg43149 (in the formula, Y 2 is a leaving group, R 33 is C 1-6 alkyl, and the other symbols are as defined above.

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

[0064] 6) Method for producing intermediate [4] (1) JPEG2024525719000015.jpg41148 (in the formula, Y 1 , Y 2 is a leaving group, and the other symbols are as defined above.)

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

[0066] 7) Method for producing intermediate [4] (2) JPEG2024525719000016.jpg115142 (in the formula, Y 1 , Y 2 is a leaving group, R 33 is C 1-6 alkyl, and the other symbols are as defined above.

[0067] The reaction shown in the above synthetic route can produce intermediate [4] of compound [1] of the present invention. Specifically, intermediate

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

[11] can be produced by reducing intermediate

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

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

[0068] 8) Method for producing intermediate [6] (2) JPEG2024525719000017.jpg94110 (in the formula, Y 1 is a leaving group, and the other symbols are as defined above.)

[0069] By the reaction shown in the above synthetic route, intermediate [6] of compound [1] of the present invention can be produced. 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 peroxide in a reaction-inert solvent.

[0070] 9) Method for producing intermediate [5] JPEG2024525719000018.jpg76142 (wherein the symbols are as defined above.)

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

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

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

[16] can be produced by introducing an alkyl into intermediate

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

[16] with a deprotecting agent.

[0072] Other reaction conditions (such as reaction temperature and reaction time) for each reaction in the above reaction scheme can be appropriately determined based on known reactions.

[0073] In each reaction in the above reaction scheme, the product can be used in the next reaction as the reaction solution or as a crude product, or it can be isolated from the reaction mixture in a conventional manner or easily purified by conventional separation means such as recrystallization, distillation, and chromatography.

[0074] The starting compounds, intermediate compounds, and target compounds in each step, as well as the compound [I] of the present invention, include geometric isomers, stereoisomers, optical isomers, and tautomers. Various isomers can be separated by a general optical resolution method. They can also be produced from suitable optically active starting compounds.

[0075] The compound [I] of the present invention can be produced by the synthesis methods shown in the above reaction schemes or methods analogous thereto.

[0076] In the production of the compound [I] of the present invention, the starting compounds may be commercially available compounds, or compounds produced according to a method known per se or a method analogous thereto, unless a specific method is described.

[0077] The starting compounds and the target compounds in each step above can be used in the form of suitable salts. Examples of such salts include the same salts as those exemplified below as salts of compound [I] of the present invention.

[0078] The compound [I] of the present invention also includes salts thereof, and may form acid addition salts or salts with bases depending on the type of substituent. 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 hydrogen carbonate, potassium hydrogen carbonate, 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. In addition, it may form a salt with an amino acid such as lysine, arginine, aspartic acid, or glutamic acid.

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

[0080] The compound [I] of the present invention includes compounds in which one or more atoms are replaced with one or more isotope atoms. Examples of isotope atoms include deuterium ( 2 H), tritium ( 3 H), 13 C. 15 N, 18 Examples include O.

[0081] The compound [I] of the present invention also includes pharma- ceutically acceptable prodrugs. Substituents that can be modified to form prodrugs include reactive functional groups such as -OH, -COOH, and amino. Modification groups for these functional groups may be appropriately selected from the "substituents" in this specification.

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

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

[0084] In addition, compounds in the form of solvates (e.g., hydrates, ethanolates, etc.) added to the raw materials and target compounds shown in each reaction scheme are also included in each general formula. Preferred solvates include hydrates.

[0085] Each target compound obtained in each of the above reaction schemes can be isolated and purified from the reaction mixture by, for example, cooling the reaction mixture, separating the crude reaction product by an isolation procedure such as filtration, concentration, extraction, etc., and then subjecting the crude reaction product to a conventional purification procedure such as column chromatography, recrystallization, etc.

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

[0087] Various isomers can be isolated by a conventional method by utilizing the difference in physicochemical properties between isomers. For example, a racemic compound can be converted into a stereochemically pure isomer by a general optical resolution method [e.g., a method of converting a diastereomeric salt with a general optically active acid (e.g., tartaric acid) and then optically resolving the salt]. A mixture of diastereomers can be separated by, for example, fractional crystallization or chromatography. Optically active compounds can also be produced by using appropriate optically active raw materials.

[0088] Compound [I] of the present invention also includes isotopically labeled compounds identical to compound [I] except that one or more atoms are replaced by one or more atoms having a particular 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 The isotopes include hydrogen, carbon, nitrogen, oxygen, sulfur, fluorine, and chlorine isotopes, such as Cl. Certain isotopically labeled compounds of the invention [I], which contain the above isotopes and / or other isotopes of other atoms, e.g. 3 H and 14 Compounds incorporating a radioactive isotope, such as C, are useful in drug and / or substrate tissue distribution assays. 3 H), and carbon-14 (i.e. 14 C) isotopes are particularly preferred due to their ease of preparation and detectability. Additionally, deuterium (i.e., 2Substitution with heavier isotopes, such as H, can be expected to confer certain therapeutic advantages due to increased metabolic stability, e.g., increased in vivo half-life or reduced dosage requirements. Isotopically labeled compounds of the invention can generally be prepared by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent in the methods disclosed in the schemes above and / or examples below.

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

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

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

[0092] A wide variety of known carriers can be used as carriers for forming tablets, including excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; dry starch, sodium alginate, powdered agar, powdered laminaran, and sodium bicarbonate. disintegrants such as sucrose, stearic acid, cocoa butter, hydrogenated oils and the like; absorption promoters such as quaternary ammonium bases, sodium lauryl sulfate and the like; moisturizers such as glycerin and starch and the like; adsorbents such as starch, lactose, kaolin, bentonite and colloidal silicic acid and the like; and lubricants such as purified talc, stearates, powdered boric acid and polyethylene glycol and the like.

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

[0094] A wide variety of known carriers can be used as carriers for forming the tablet into a pill form, including, for example, excipients such as glucose, lactose, starch, cacao butter, hardened vegetable oil, kaolin, talc, etc.; binders such as powdered gum arabic, powdered tragacanth, gelatin, ethanol, etc.; disintegrants such as laminaran, agar, etc.

[0095] A wide variety of known carriers can be used for forming the suppository into a suppository, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, and the like.

[0096] When prepared as an injection, the liquid, emulsion and suspension are preferably sterilized and isotonic with blood. The diluent used in forming these liquids, emulsions and suspensions can be a wide variety of known diluents, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbetan fatty acid esters, etc. In this case, the pharmaceutical preparation may contain a sufficient amount of salt, glucose or glycerin to prepare an isotonic solution, and may also contain ordinary solubilizing agents, buffers, soothing agents, etc., and further, if necessary, colorants, preservatives, fragrances, flavorings, sweeteners, etc., and / or other pharmaceuticals.

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

[0098] The method of administration of the pharmaceutical composition of the present invention is not particularly limited, and it is administered according to various formulation forms, age, sex, disease state, and other conditions of the subject or patient (especially human). For example, tablets, pills, liquids, suspensions, emulsions, granules, and capsules are administered orally. In the case of injections, they can be administered intravenously alone or mixed with normal replacement fluids such as glucose and amino acids, or can be administered alone intramuscularly, intradermally, subcutaneously, or intraperitoneally as necessary. In the case of suppositories, they are administered rectally.

[0099] The dosage of the pharmaceutical composition may be appropriately selected depending on the method of use, the age and sex of the subject or patient (particularly humans), the severity of the disease, and other conditions, and is usually administered at about 0.001 to 100 mg, and preferably about 0.001 to 50 mg per kg of body weight per day, once or in divided doses.

[0100] The above dosage varies depending on various conditions, and therefore, in some cases, a dosage less than the above range is sufficient, and in other cases, a dosage exceeding the above range is required.

[0101] The compound [I] of the present invention or a salt thereof has an inhibitory effect on the reuptake of one, two or three types of monoamines (serotonin, norepinephrine, dopamine).

[0102] The compound [I] of the present invention or its salt has a significantly stronger inhibitory activity against one, two, or all of the three monoamines in an in vitro test than existing compounds having monoamine reuptake inhibitory activity. Also, in a brain microdialysis method (in vivo), the compound of the present invention or its salt shows a significantly stronger activity against the increase in one, two, or all of the three monoamines than existing compounds having monoamine reuptake inhibitory activity.

[0103] The serotonin inhibitory activity (IC 50 ) is 100 nM or less, preferably 30 nM or less.

[0104] The norepinephrine inhibitory activity (IC 50 ) is 100 nM or less, preferably 30 nM or less.

[0105] The dopamine inhibitory activity (IC 50 ) is 300 nM or less, preferably 150 nM or less. Dopamine inhibitory activity (IC 50 ) tends to be weaker than norepinephrine, which is preferable.

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

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

[0108] The compound [I] of the present invention or a salt thereof inhibits the metabolic enzyme in the liver by less than 50% or less than IC 50 value is 100 μM or more, and at 10 μM for CYP2D6, it is less than 50% or IC 50 value is 50 μM or more, and at 10 μM for CYP3A4, it is less than 50% or IC 50 The value is 50 μM or more.

[0109] The compound [I] of the present invention or a salt thereof has an inhibitory activity against serotonin, norepinephrine and dopamine (IC 50 ) is 1-20:1-2:1-100, preferably 1-5:1-2:1-50, and more preferably 1-5:1:5-25.

[0110] The compound [I] or its salt of the present invention has a low binding rate with plasma protein. If a drug binds to plasma protein, it cannot exert its pharmacological effect, so if the binding rate with plasma protein is low, it can be expected to be effective at a low dose. That is, it can be expected to be effective at a lower blood concentration.

[0111] The compound [I] of the present invention or a salt thereof has a weak inhibitory activity against metabolic enzymes in the liver, specifically, a weak inhibitory effect against cytochrome P450 (CYP), for example, CYP2C9, CYP2D6, and CYP3A4, and therefore has little effect on the metabolism of other drugs even when administered in combination with the other drugs.

[0112] The compound [I] of the present invention or a salt thereof has a broader therapeutic spectrum than known therapeutic agents for ADHD.

[0113] The compound [I] of the present invention or a salt thereof exerts a sufficient therapeutic effect even when administered for a short period of time.

[0114] The compound [I] of the present invention or a salt thereof has excellent intracerebral transportability.

[0115] The compound [I] of the present invention or a salt thereof exhibits an excellent improving effect on the increase in spontaneous locomotor activity in stroke-prone spontaneously hypertensive rats (SHRSP) used for screening of ADHD therapeutic drugs. The compound [I] of the present invention or a salt thereof also exhibits an excellent improving effect on the impulsive-like symptoms of SHRSP.

[0116] The compound [I] of the present invention or a salt thereof exhibits strong activity in a mouse marble-burying behavior test used as a model for anxiety / obsessive-compulsive disorder.

[0117] The compound [I] of the present invention or a salt thereof has an inhibitory effect on the reuptake of one, two or three types of monoamines (serotonin, norepinephrine, dopamine), and is therefore effective in treating various disorders associated with dysfunction of serotonin, norepinephrine and / or dopamine nerves.

[0118] Such disorders include attention-deficit hyperactivity disorder (ADHD), Tourette's disorder (also known as Tourette's syndrome), autism spectrum disorders, Asperger's syndrome, depression (e.g., major depressive disorder; bipolar I disorder; bipolar II disorder; mixed state; dysthymic disorder; rapid cycling; atypical depression; seasonal affective disorder; postpartum depression; mild depression; recurrent brief depressive disorder; treatment-resistant depression; chronic depression; treatment-resistant depression; overlapping depression; alcohol-induced mood disorder; mixed anxiety-depressive disorder; Cushing's syndrome, hypothyroidism, hyperparathyroidism, Addison's disease). , amenorrhea-galactagogue syndrome, Parkinson's disease, Alzheimer's disease, vascular dementia, cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, diabetes, viral infection, multiple sclerosis, chronic fatigue syndrome, coronary artery disease, pain, depression associated with various diseases such as cancer; depression in middle age; depression in geriatrics; depression in children and adolescents; depression induced by drugs such as interferon; depressive symptoms due to adjustment disorder; anxiety due to adjustment disorder, anxiety associated with various diseases [e.g., neurological disorders (head trauma, brain infections and inner ear disorders); cardiovascular disorders (heart failure, arrhythmia); endocrine disorders (hyperadrenalism, 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., binge eating disorder, bulimia nervosa, anorexia nervosa, and necrotic anorexia nervosa), obesity, chemical dependencies (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, etc.), These include memory disorders (e.g., dementia, amnesic disorders and age-related cognitive decline (ARCD)), Parkinson's disease (e.g., dementia in Parkinson's disease, neuroleptic-induced parkinsonism and tardive dyskinesia), restless legs syndrome, endocrine disorders (e.g., hyperprolactinemia), hypertension, vasospasm (particularly in the cerebral vasculature), cerebellar ataxia, gastrointestinal disorders (including motor and secretory changes), negative symptoms of schizophrenia, affective disorders in schizophrenia, cognitive impairment in schizophrenia, premenstrual syndrome, stress urinary incontinence, urge urinary incontinence, impulse control disorders, trichotillomania, kleptomania, gambling addiction, cluster headaches, migraine, chronic paroxysmal migraine, chronic fatigue, premature ejaculation, male impotence, narcolepsy, primary hypersomnia, cataplexy, sleep apnea and headaches (associated with vasculopathy);

[0119] The disclosures of all patent and non-patent publications cited herein are hereby incorporated by reference in their entirety. EXAMPLES

[0120] The present invention will be further explained in detail by the following Test Examples, Reference Examples and Examples, but these do not limit the present invention and may be modified without departing from the scope of the present invention. The following abbreviations may be used in this specification:

[0121] TIFF2024525719000019.tif240166 JPEG2024525719000020.jpg186166

[0122] In the following examples, "room temperature" generally refers to about 10° C. to about 35° C. Ratios shown in mixed solvents are volume ratios unless otherwise specified. % refers to weight % unless otherwise specified. 1 HNMR (proton nuclear magnetic resonance spectrum) was measured by Fourier transform NMR (either Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE III HD (500 MHz)). The spectrum was analyzed using MestReNova version: 14.1.2 (Mestrelab Research). Mass spectra were measured by LC / MS (ACQUITY UPLC H-Class). The ionization method used was ESI, and the data shown are the actual values ​​(found). Usually, the molecular ion peak ([M+H] + , [MH] - In the case of salts, the free molecular ion peak or fragment ion peak is usually observed. In silica gel column chromatography, aminopropylsilane-bonded silica gel was used when basic was mentioned. The absolute configuration of the compound was determined by a known X-ray crystal structure analysis method (for example, Shigeru Ohba and Shigenobu Yano, "Basic Lectures for Chemists 12: X-ray Crystal Structure Analysis" (1st edition, 1999)), or was estimated from the empirical rule 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: Preparation of (2-(4-bromo-2,6-difluorophenoxy)ethoxy)(tert-butyl)dimethylsilane To a solution of 4-bromo-2,6-difluorophenol (22.93 g) and (2-bromoethoxy)-tert-butyldimethylsilane (25.0 g) in DMF (120 mL), K2CO3 (28.9 g, fine powder) was added and stirred at 70°C for 3 hours. After cooling to room temperature, ice water was added to the reaction solution 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 (35.0 g).

[0124] Reference Example 2: Preparation of (4a'S,8a'S)-4'-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3,5-difluorophenyl)octahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline] To a solution of (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) in toluene (6 mL), Pd(OAc)2 (29.9 mg), t-Bu3P·HBF4 (38.6 mg), and t-BuONa (240 mg) were added and stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction solution 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 ethyl 2-(4-bromophenoxy)-2,2-difluoroacetate Bromodifluoroacetic acid ethyl ester (4.08 mL) was added to a solution of p-bromophenol (5 g) and DBU (5.23 mL) in DMF (25 mL) and stirred at room temperature overnight. Ice water was added to the reaction solution, 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 (7.2 g).

[0126] Reference Example 4. Preparation of 2-(4-bromophenoxy)-2,2-difluoroethan-1-ol A solution of 2-(4-bromophenoxy)-2,2-difluoroethyl acetate (13.9 g) in THF (150 mL) was added with LiBH4 (2.26 g) under ice-cooling and stirring, and the mixture was stirred at room temperature overnight. The reaction mixture was cooled, and a saturated aqueous solution of NaHSO4 was added, followed by extraction 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: Preparation of (2-(4-bromophenoxy)-2,2-difluoroethoxy)triisopropylsilane A solution of 2-(4-bromophenoxy)-2,2-difluoroethan-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 and stirred overnight. Ice water was added to the reaction solution, 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 (4.8 g).

[0128] Reference Example 6: Preparation of (4a'S,8a'S)-4'-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)phenyl)octahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline] To a solution of (4a'S,8a'S)-octahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline] (300 mg) and (2-(4-bromophenoxy)-2,2-difluoroethoxy)triisopropylsilane (749 mg) in toluene (6 mL), Pd(OAc)2 (29.9 mg), tBu3P·HBF4 (38.6 mg), and t-BuONa (192 mg) were added and stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction solution 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: Preparation of (3R,4aS,8aS)-1-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3-methyldecahydroquinoxaline To a solution of (2R,4aS,8aS)-2-methyldecahydroquinoxaline (500 mg) and (2-(4-bromo-2-chlorophenoxy)ethoxy)triisopropylsilane (1322 mg) in toluene (5 mL), Pd(OAc)2 (58.2 mg), tBu3P·HBF4 (75 mg), and t-BuONa (467 mg) were added and stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction solution 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 tert-butyl (4aS,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-carboxylate A solution of (4aS,8aS)-2,2-dimethyldecahydroquinoxaline (7.35 g) in MeOH (70 mL) was added to BocO (9.65 g) under ice-cooling and stirring, and the mixture was stirred at room temperature overnight. The reaction solution 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 tert-butyl (4aS,8aS)-3,3,4-trimethyloctahydroquinoxaline-1(2H)-carboxylate To a solution of (4aS,8aS)-3,3-dimethyloctahydroquinoxaline-1(2H)-tert-butyl carboxylate (10.0 g) in DCE (100 mL) and THF (50 mL), 37% formaldehyde solution (9.14 mL) was added, and the mixture was stirred at room temperature for 30 minutes. NaBH(OAc)3 (23.9 g) was added under ice-cooling and stirring. After stirring overnight at room temperature, the mixture was concentrated under reduced pressure and extracted with 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: Preparation 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 added to TFA (20 mL) under ice-cooling and stirring, and the mixture was stirred at room temperature overnight. The reaction mixture was concentrated, and a saturated aqueous solution of K2CO3 was added, followed by extraction 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: Preparation of (4aS,8aS)-4-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)phenyl)-1,2,2-trimethyldecahydroquinoxaline To a solution of (4aS,8aS)-1,2,2-trimethyldecahydroquinoxaline (200 mg) and (2-(4-bromophenoxy)-2,2-difluoroethoxy)triisopropylsilane (494 mg) in toluene (5 mL), Pd(OAc)2 (19.70 mg), tBu3P·HBF4 (25.5 mg), and t-BuONa (127 mg) were added and stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction solution 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: Preparation of (4aR,8aS)-1-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline To a solution of (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (250 mg) and (2-(4-bromo-2-chlorophenoxy)ethoxy)triisopropylsilane (697 mg) in toluene (5 mL), Pd(OAc)2 (26.7 mg), tBu3P·HBF4 (34.5 mg), and t-BuONa (157 mg) were added and stirred at 90°C for 1 hour under a nitrogen atmosphere. The reaction solution 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: Preparation of (4aS,8aR)-4-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-1,2,2-trimethyldecahydroquinoxaline To a solution of (4aR,8aS)-1-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline (180 mg) in DCM / THF (1:1) (4 mL), 36% aqueous formaldehyde solution (83 μL) was added 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-dimethyloctahydroquinoxalin-1(2H)-yl)-5-fluorobenzaldehyde DIPEA (445 μL) was added to a solution of (4aS,8aR)-2,2-dimethyldecahydroquinoxaline (343 mg) and 2-chloro-4,5-difluorobenzaldehyde (300 mg) in DMSO (3 mL), 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-dimethyloctahydroquinoxalin-1(2H)-yl)-5-fluorophenol 2-Chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-5-fluorobenzaldehyde (480 mg) in MeOH (8 mL) was added with 35% hydrogen peroxide (323 μL) and H2SO4 (118 μL) and stirred at room temperature for 3 days. Saturated NaHCO3 aqueous solution was added to the reaction solution, and the precipitated solid was collected by filtration. It was washed with water and hexane to obtain the target product (400 mg).

[0138] Reference Example 112: Preparation of (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-chloro-2-fluorophenyl)-3,3-dimethyldecahydroquinoxaline To a suspension of 2-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-5-fluorophenol (150 mg) and K2CO3 (133 mg, finely ground) in DMF (3 mL), (2-bromoethoxy)-tert-butyldimethylsilane (129 μL) was added and stirred at 60°C for 3 hours. Water was poured into the reaction solution, 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 (210 mg).

[0139] Reference Example 118. Preparation of ethyl 2-(4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-3-fluorophenoxy)-2,2-difluoroacetate To a solution of 4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-3-fluorophenol (150 mg) in DMF (3 mL), DBU (244 μL) and then bromodifluoroacetic acid ethyl ester (138 μL) were added and stirred at 60° C. for 3 hours. Water was poured into the reaction solution, and extraction was performed 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 of Reference Examples 7 to 40, 42 to 64, 69 to 81, 83 to 84, 86 to 109, 113 to 117 and 119 to 165 were produced in the same manner as in Reference Examples 1 to 6, 41, 65 to 68, 82, 85, 110 to 112 and 118. The structural formulas and physicochemical data of the compounds of Reference Examples 1 to 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. Preparation of 2-(2,6-difluoro-4-((4a'S,8a'S)-hexahydro-1'H-spiro[cyclobutane-1,2'-quinoxaline]-4'(3'H)-yl)phenoxy)ethan-1-ol A solution of (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 1M-TBAF / THF solution (1029 μL) was added. After stirring overnight at room temperature, the reaction solution 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[cyclobutane-1,2'-quinoxaline]-4'(3'H)-yl)phenoxy)ethan-1-ol A solution of (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 added to 1M-TBAF / THF solution (1317 μL) at room temperature under stirring. After stirring overnight at room temperature, the reaction solution 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-methyloctahydroquinoxalin-1(2H)-yl)phenoxy)ethan-1-ol 1 / 2 fumarate 1M-TBAF / THF solution (1302 μL) was added to a solution of (3R,4aS,8aS)-1-(3-chloro-5-fluoro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3-methyldecahydroquinoxaline (650 mg) in THF (5 mL), and the mixture was stirred at room temperature overnight. The reaction solution 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 a solution of fumaric acid (156 mg) in EtOH was added and the mixture was concentrated. 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-dimethyloctahydroquinoxalin-1(2H)-yl)phenoxy)-2,2-difluoroethan-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), 1M-TBAF / THF solution (2.17 mL) was added and 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). The product was recrystallized from AcOEt / Hexane to obtain the target product (324 mg).

[0146] Example 22. Preparation of 2-(4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-2-fluorophenoxy)-2,2-difluoroethan-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), 1M-TBAF / THF solution (2.18 mL) was added and 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). The product was recrystallized from AcOEt / Hexane to obtain the target product (347 mg).

[0147] Example 27. Preparation of 2-(2-chloro-4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)phenoxy)ethan-1-ol A 1M-TBAF / THF solution (3.94 mL) was added 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), and the mixture was stirred at room temperature for 1 hour. The reaction solution was decompressed, and the residue was purified by basic silica gel column chromatography (Hexane / AcOEt). The product was recrystallized from AcOEt / Hexane to obtain the target product (1.33 g).

[0148] Example 34. Preparation of 2-(4-((4aS,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-2,6-difluorophenoxy)ethan-1-ol A 1M-TBAF / THF solution (2.01 mL) was added to a solution of (4aS,8aS)-1-(3,5-difluoro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline (500 mg) in THF (5 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). The product was recrystallized from AcOEt / Hexane to obtain the target product (281 mg).

[0149] Example 37. Preparation of 2,2-difluoro-2-(4-((4aS,8aS)-3,3,4-trimethyloctahydroquinoxalin-1(2H)-yl)phenoxy)ethan-1-ol A 1M-TBAF / THF solution (940 μL) was added to a solution of (4aS,8aS)-4-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)phenyl)-1,2,2-trimethyldecahydroquinoxaline (480 mg) in THF (6 mL) and 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). The obtained 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-trimethyloctahydroquinoxalin-1(2H)-yl)phenoxy)ethan-1-ol dihydrochloride A 1M-TBAF / THF solution (805 μL) was added to a solution of (4aS,8aS)-4-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-1,2,2-trimethyldecahydroquinoxaline (410 mg) in THF (6 mL) and 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). The purified product was dissolved in EtOH, then 1N-HCl / EtOH was added, concentrated, 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-dimethyloctahydroquinoxalin-1(2H)-yl)phenoxy)ethan-1-ol 1 / 2 fumarate A 1M-TBAF / THF solution (7.27 mL) was added to a solution of (4aR,8aS)-1-(3-chloro-4-(2-((triisopropylsilyl)oxy)ethoxy)phenyl)-3,3-dimethyldecahydroquinoxaline (3.60 g) in THF (50 mL) and 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). The purified product was dissolved in AcOEt / EtOH, and an ethanol solution of fumaric acid (0.43 g) was added, followed by concentration, and recrystallization from EtOH to obtain the target product (2.5 g).

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

[0153] Example 56. Preparation of 2-(4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-3-methylphenoxy)-2,2-difluoroethan-1-ol A 1M-TBAF / THF solution (568 μL) was added to a solution of (4aR,8aS)-1-(4-(1,1-difluoro-2-((triisopropylsilyl)oxy)ethoxy)-2-methylphenyl)-3,3-dimethyldecahydroquinoxaline (290 mg) in THF (5 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). The product was recrystallized from hexane to obtain the target product (130 mg).

[0154] Example 59. Preparation of 2-(2-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-5-fluorophenoxy)ethan-1-ol 3 / 4 fumarate 1M-TBAF / THF solution (425 μL) was added to a solution of (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-5-chloro-2-fluorophenyl)-3,3-dimethyldecahydroquinoxaline (200 mg) in THF (3 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). The purified product was dissolved in AcOEt / EtOH, and a solution of fumaric acid (54 mg) in EtOH was added, followed by concentration, and recrystallization from EtOH / AcOEt to obtain the target product (160 mg).

[0155] Example 60. Preparation of 2-(2-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-3-fluorophenoxy)ethan-1-ol fumarate 1M-TBAF / THF solution (414 μL) was added to a solution of (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-3-chloro-2-fluorophenyl)-3,3-dimethyldecahydroquinoxaline (195 mg) in THF (3 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). The purified product was dissolved in EtOH, and an ethanol solution of fumaric acid (53.7 mg) was added and the mixture was concentrated. The product was recrystallized from EtOH / AcOEt to obtain the target product (150 mg).

[0156] Example 61. Preparation of 2-(4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-3-fluorophenoxy)-2,2-difluoroethan-1-ol 1 / 2 fumarate LiBH4 (19.75 mg) was added to a solution of 2-(4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-3-fluorophenoxy)-2,2-difluoroethyl acetate (165 mg) in THF (5 ml) under ice-cooling and stirring, and the mixture was stirred at room temperature for 20 hours. 5N-HCl / MeOH was added to the reaction solution under ice-cooling and stirring until no foaming occurred. 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, and an ethanol solution of fumaric acid (53 mg) was added and the mixture was concentrated, and the target product (120 mg) was obtained by recrystallization from EtOH / AcOEt.

[0157] Example 64. Preparation of 2-(3-chloro-4-((4aR,8aS)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)phenoxy)ethan-1-ol 1 / 2 fumarate To a solution of (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2-chlorophenyl)-3,3-dimethyldecahydroquinoxaline (540 mg) in THF (8 mL), 1M-TBAF / THF solution (1192 μL) was added and 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). The purified product was dissolved in EtOH, and an ethanol solution of fumaric acid (94 mg) was added and concentrated, and the product was recrystallized from EtOH / AcOEt to obtain the target product (400 mg).

[0158] Example 69. Preparation of 2-(4-((4aS,8aR)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-3-fluoro-2-methylphenoxy)-2,2-difluoroethan-1-ol 1 / 2 fumarate LiBH4 (53.2 mg) was added to a solution of 2-(4-((4aS,8aR)-3,3-dimethyloctahydroquinoxalin-1(2H)-yl)-3-fluoro-2-methylphenoxy)-2,2-difluoroethyl acetate (460 mg) in THF (12 mL) under ice-cooling and stirring, and the mixture was stirred at room temperature for 17 hours. The reaction was stopped by adding 5N HCl / MeOH to the reaction mixture, and then neutralized by adding 5N NaOH aqueous solution. 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 an ethanol solution of fumaric acid (70 mg) was added, 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-dimethyloctahydroquinoxalin-1(2H)-yl)-2,3-difluorophenoxy)ethan-1-ol 1 / 2 fumarate 1M-TBAF / THF solution (968 μL) was added to a solution of (4aR,8aS)-1-(4-(2-((tert-butyldimethylsilyl)oxy)ethoxy)-2,3-difluorophenyl)-3,3-dimethyldecahydroquinoxaline (440 mg) in THF (6 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). The purified product was dissolved in EtOH, and an ethanol solution of fumaric acid (124 mg) was added and the mixture was concentrated. The product was recrystallized from EtOH / AcOEt to obtain the target product (330 mg).

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

[0162] [Test example] The results of pharmacological tests on representative compounds of the present invention are shown below, and the pharmacological actions of the compounds are explained, but the present invention is not limited to these test examples.

[0163] Test Example 1 (Measurement of serotonin (5-HT) uptake inhibitory activity of test compounds using rat brain synaptosomes) Male Wistar rats were decapitated, the brains were removed, and the frontal cortices were excised. The isolated frontal cortices were placed in 20 times the weight of 0.32 molar (M) sucrose solution and homogenized using a Potter-type homogenizer. The homogenate was centrifuged at 1000 g for 10 minutes at 4°C, and the supernatant was further centrifuged at 20000 g for 20 minutes at 4°C. The 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 a crude synaptosome fraction. An uptake reaction was carried out in each well of a 96-well round-bottom plate with a total volume of 200 μL of a solution containing pargelin (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg / mL). In other words, the solvent, unlabeled 5-HT or serially diluted test compound was added to each well, and the synaptosome fraction was added in an amount of 1 / 10 of the final volume. After preincubation at 37°C for 10 minutes, a tritium-labeled 5-HT solution (final concentration 8 nM) was added to initiate the uptake reaction at 37°C. The uptake reaction was terminated 10 minutes later by suction filtration into a 96-well glass fiber filter plate. The filter was further washed with cold saline, thoroughly dried, and Microscinti 0 (PerkinElmer) was added to measure the remaining radioactivity on the filter.

[0164] The uptake value when only the solvent was added was taken as 100%, and the uptake value when unlabeled 5-HT (final concentration 10 μM) was added (non-specific uptake value) was taken as 0%, and 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, the brains removed, and the hippocampi dissected out. The isolated hippocampi were placed in 20 times the weight of 0.32 molar (M) sucrose solution and homogenized using a Potter homogenizer. The homogenate was centrifuged at 1000 g for 10 minutes at 4°C, and the supernatant was further centrifuged at 20000 g for 20 minutes at 4°C. The 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 a crude synaptosome fraction. An uptake reaction was carried out in each well of a 96-well round-bottom plate with a total volume of 200 μL of a solution containing pargelin (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg / mL). In other words, the solvent, unlabeled NE, or serially diluted test compound was added to each well, and then 1 / 10th the final volume of synaptosomal fraction was added to each well. After preincubation at 37°C for 10 minutes, tritium-labeled NE solution (final concentration 12 nM) was added to initiate the uptake reaction at 37°C. The uptake reaction was terminated 10 minutes later by suction filtration into a 96-well glass fiber filter plate. The filter was further washed with cold saline, thoroughly dried, and Microscinti 0 (PerkinElmer) was added to measure the remaining radioactivity on the filter.

[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%, and 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) uptake inhibitory activity of test compounds using rat brain synaptosomes) Male Wistar rats were decapitated, the brains removed, and the striatum dissected out. The isolated striatum was placed in 20 times its weight of 0.32 molar (M) sucrose solution and homogenized using a Potter-type homogenizer. The homogenate was centrifuged at 1000 g for 10 minutes at 4°C, and the supernatant was further centrifuged at 20000 g for 20 minutes at 4°C. The 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 a crude synaptosome fraction. An uptake reaction was carried out in each well of a 96-well round-bottom plate with a total volume of 200 μL of a solution containing pargelin (final concentration: 10 μM) and ascorbic acid (final concentration: 0.2 mg / mL). In other words, the solvent, unlabeled DA, or serially diluted test compound was added to each well, and then 1 / 10th of the final volume of synaptosomal fraction was added to each well. After preincubation at 37°C for 10 minutes, a tritium-labeled DA solution (final concentration 2 nM) was added to initiate the uptake reaction at 37°C. The uptake reaction was terminated 10 minutes later by suction filtration into a 96-well glass fiber filter plate. The filter was further washed with cold saline, thoroughly dried, and Microscinti 0 (PerkinElmer) was added to measure the remaining radioactivity on the filter.

[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%, and 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 started by adding and mixing the test compound solution (final concentration 0.001 mmol / L) and 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 microsome). In addition, a methanol solution of the internal standard was prepared and used as the reaction stop solution. In other words, 2.5 μL of the test compound acetonitrile solution was added to 222.5 μL of human liver microsome solution in ice water and mixed, and after preincubation at 37°C for 1 minute, 25 μL of NADH / NADPH solution was added and mixed to start 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 the reaction was stopped by adding and mixing with 500 μL of the reaction stop solution. The mixed solution was centrifuged (6130 g, 10 minutes, 4° C.), and the resulting supernatant was used as a sample for LC-MS / MS measurement.

[0173] The test compound and the internal standard were measured, and the peak area ratio ([peak area of ​​the test compound] / [peak area of ​​the internal standard]) was calculated. The remaining rate of the test compound was calculated from ([peak area ratio at each reaction time] / [peak area ratio at reaction time 0 min]). A nonlinear least squares analysis was performed on the residual rate and incubation time to determine the elimination rate constant ([0.693] / [half-life]), and the hepatic intrinsic 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 The metabolic reaction was started by adding and mixing the test compound solution (final concentration 0.01 mmol / L) and NADH / NADPH solution (final concentration 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 bufuralol (CYP2D6), 0.005 mmol / L midazolam (CYP3A4)). In addition, a methanol solution containing stable isotopes of the metabolic products (50 ng / mL [13C6] diclofenac hydroxyl, 5 ng / mL [2H9] bufuralol hydroxyl, and 5 ng / mL [13C6] midazolam hydroxyl (all stable isotopes)) was prepared as an internal standard solution and used as the reaction stop solution. In other words, 2 μL of the test compound acetonitrile solution (or acetonitrile as a control) was added to 178 μL of human liver microsome solution in ice water and mixed, and after preincubation at 37°C for 1 minute, 20 μL of NADH / NADPH solution was added and mixed to start the metabolic reaction. After incubation at 37°C for 10 minutes, 50 μL of the reaction solution was taken and added to 500 μL of the reaction 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 a sample for LC-MS / MS measurement.

[0176] The peak area ratio ([metabolite peak area] / [corresponding stable isotope peak area]) was calculated using metabolites and stable isotopes of metabolites as the measurement targets. The peak area ratio when each test compound solution was added was compared with that of the control, and 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]) x 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 Three Concentrations) The metabolic reaction was started by adding and mixing the test compound solution (final concentrations 0.01, 0.03, and 0.1 mmol / L) and NADH / NADPH solution (final concentration 1 mmol / L) to a human liver microsome solution containing three CYP-specific substrates (final concentrations 100 mmol / L potassium phosphate buffer (pH 7.4), 5 mmol / L magnesium chloride, 0.1 mg / mL human liver microsome, 0.005 mmol / L diclofenac (CYP2C9), 0.01 mmol / L bufuralol (CYP2D6), 0.005 mmol / L midazolam (CYP3A4)). In addition, a methanol solution containing stable isotopes of the metabolic products (50 ng / mL [13C6] diclofenac hydroxyl, 5 ng / mL [2H9] bufuralol hydroxyl, and 5 ng / mL [13C6] midazolam hydroxyl (all stable isotopes)) was prepared as an internal standard solution and used as the reaction stop solution. In other words, 2 μL of the test compound acetonitrile solution (or acetonitrile as a control) was added to 178 μL of human liver microsome solution in ice water and mixed, and after preincubation at 37°C for 1 minute, 20 μL of NADH / NADPH solution was added and mixed to start the metabolic reaction. After incubation at 37°C for 10 minutes, 50 μL of the reaction solution was taken and added to 500 μL of the reaction 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 a sample for LC-MS / MS measurement. The peak area ratio ([metabolite peak area] / [corresponding stable isotope peak area]) was calculated using metabolites and their stable isotopes as the measurement targets. The peak area ratio when each test compound solution was added was compared with that of the control, and 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]) x 100. For each CYP molecular species, the slope and intercept were calculated by linear regression of 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, and the concentration at which the inhibition rate (%) of each CYP molecular species was 50% was calculated, which was defined as the 50% inhibitory concentration. The results are shown in Table 8.

[0179] [Table 8]

[0180] Test Example 7 (Protein Binding Rate Test) A test compound solution was added to human serum to prepare a serum sample (final concentration of 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 the reaction stop solution. In other words, the dialysis membrane (molecular weight cutoff 12000-14000) was preconditioned by soaking in distilled water and then 20% ethanol. It was then washed with D-PBS(-) and set in an equilibrium dialysis kit. One of the two sections was divided by the dialysis membrane, and 150 μL of D-PBS(-) was added, and 150 μL of serum sample was added to the other section. All wells were sealed with a seal, and after incubation at 37°C for 6 hours, 30 μL of sample was taken from the serum side and 90 μL of sample was taken from the PBS side of each well, and the reaction was stopped by mixing with 90 μL of D-PBS(-) or 30 μL of blank serum and 480 μL of reaction stop solution. The mixed solution was centrifuged (6130 g, 10 minutes, 4° C.), and the resulting supernatant was used as a sample for LC-MS / MS measurement.

[0181] The peak area ratio ([peak area of ​​test compound] / [peak area of ​​internal standard]) was calculated using the test compound and the internal standard as the measurement objects. The peak area ratio of each test compound on the PBS side was compared with that on the serum side to calculate the protein binding rate (%) of the test compound from (1-[peak area ratio on the PBS side] / [peak area ratio on the serum side]) x 100. The results are shown in Table 9.

[0182] [Table 9] [Industrial Applicability]

[0183] The compound of the present invention or a salt thereof has a broad therapeutic spectrum.

Claims

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

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]. [wherein each symbol is the same as above]

3. In formula [I], R 11 , R 12 and R 13 are the same or different and each independently represent hydrogen or methyl; 11 and R 12 together with the adjacent carbon atom forms a cyclobutyl; R 22 , R 23 , R 25 and R 26 are the same or different and each independently represent hydrogen, fluorine, chlorine, methyl or methoxy; or R 22 and R 23 together with the adjacent benzene ring form a benzofuran; R 31 and R 32 are the same or different and each independently represents hydrogen or fluorine; The compound according to claim 2 or a salt thereof.

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

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

Images