Bicyclic pyridine derivative

Abstract

Provided is a bicyclic pyridine derivative. A compound represented by formula I [wherein: X represents an oxygen atom, a sulfur atom, NR or CR'R"; n is 0 or 1; R1, R2a, R2b, R2c, R2d, R, R' and R" independently represent a hydrogen atom, a halogen atom, an optionally substituted C1-6 alkyl or an optionally substituted C6-10 aryl, or two of R2a, R2b, R2c, R2d, R, R' and R", together with the carbon or nitrogen atom to which these groups are attached, form a 3- to 6-membered saturated carbon ring or saturated heterocyclic ring; and R3a, R3b, R3c, R5a and R5b are as defined in the description] or a pharmaceutically acceptable salt thereof.

Description

Bicyclic pyridine derivatives

[0001] The present disclosure relates to a bicyclic pyridine derivative or a pharmaceutically acceptable salt thereof that has agonistic activity against the trace amine-associated receptor TAAR1, and a therapeutic agent for neuropsychiatric disorders that contains the derivative as an active ingredient.

[0002] Trace amines (TAs), a type of biogenic amine, include p-tyramine, β-phenylethylamine, tryptamine, and octopamine. Although their structure and metabolism are similar to classical biogenic amines such as serotonin, dopamine, and norepinephrine, they exist in extremely small amounts under physiological conditions in vivo (Non-Patent Document 1). TAs are known to play an important role in regulating neurotransmission in the central and peripheral nervous systems. Dysregulation of TAs has been suggested to be involved in various central nervous system disorders, including schizophrenia, mood disorders, attention deficit hyperactivity disorder, Parkinson's disease, migraine, and eating disorders. Improving this dysregulation is expected to lead to the establishment of new treatments for these disorders (Non-Patent Document 2).

[0003] Nine genes for TA receptors have been reported in humans. The TAAR1 receptor is G protein-coupled and is activated via Gas with TA as a ligand. It has also been reported that other amines, catecholamine metabolites, and dopamine agonists act as ligands (Non-Patent Documents 1 and 3). Its downstream signaling is known to inhibit dopamine uptake by phosphorylating the dopamine transporter via cAMP-PKA / PKC and promote dopamine release in a PKC-dependent manner (Non-Patent Documents 4 and 5). In the central nervous system, TAAR1 receptors are expressed in the ventral tegmental area, the nuclei of monoamine origin, including the raphe nucleus, and the limbic system. These receptors also regulate glutamate and serotonin neurotransmission, suggesting that the TAAR1 receptor may affect various monoamine functions (Non-Patent Document 1).

[0004] Since 6q23, the gene locus encoding TAAR1, is a region associated with multiple psychiatric disorders, and since there is a strong correlation between monoamine neurotransmission regulated by TAAR1 and neuropsychiatric disorders, it is expected that TAAR1 receptor-selective ligands will be effective in treating these diseases. Furthermore, small molecule compounds that have been reported to exhibit TAAR1 receptor agonism have shown antipsychotic and antidepressant effects in multiple disease models using rodents, and have also shown cognitive function improving effects in evaluations using non-human primates, so they can be expected to have antipsychotic, antidepressant, and cognitive function improving effects in humans as well (non-clinical literature 6).

[0005] Beth Borowsky, Proc Natl Acad Sci USA.98,8966-8971,2001Branchek,TAand Blackburn,TP,Curr.Opin.Pharmacol.3,90-97,2003James R.Bunzow, Mol Pharmacol.60,1181-1188,2001Zhihua Xie and Gregory M.Miller, Journal of Pharmacology and Experimental Therapeutics 321,128-136,2007Zhihua Xie and Gregory M.Miller Journal of Pharmacology and Experimental Therapeutics,330,316-325,2009FG Revel Molecular Psychiatry,18,543-556,2013

[0006] The present disclosure provides novel compounds that have agonist activity for the trace amine-associated receptor TAAR1 receptor and are useful as therapeutic agents for neuropsychiatric disorders.

[0007] The present inventors have found that a compound represented by the following formula I or a pharmaceutically acceptable salt thereof (hereinafter, may be referred to as the "disclosed compound") has agonist activity for the trace amine-associated receptor TAAR1 receptor, and provide the present disclosure.

[0008] That is, the present disclosure is, for example, as follows.

[0009] [Term 1] Formula I [Wherein, X is an oxygen atom, a sulfur atom, NR, or CR'R"; n is 0 or 1; R １ represents a hydrogen atom, an optionally substituted C １－６ Alkyl or optionally substituted C ３－６ alkenyl, and R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R, R′ and R″ are each independently a hydrogen atom, a halogen atom, an optionally substituted C １－６ Alkyl or optionally substituted C ６－１０ aryl or R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ two of R, R' and R" taken together with the carbon or nitrogen atom to which they are attached form a 3- to 6-membered saturated carbocyclic or saturated heterocyclic ring; R ３ａ , R ３ｂ , and R ３ｃ are each independently a hydrogen atom, an optionally substituted C １－６ Alkyl, halogen atom, —OR ４ or optionally substituted C ６－１０ aryl, R ４ is an optionally substituted C １－６ alkyl or an optionally substituted 3- to 6-membered saturated carbocyclic ring, R ５ａ and R ５ｂ are each independently a hydrogen atom or an optionally substituted C １－６ alkyl or R ５ａ and R ５ｂ together with the carbon atoms to which they are attached form a 3- to 6-membered saturated carbocyclic ring, wherein said optionally substituted C １－６ Alkyl and optionally substituted C ３－６ Alkenyl is a halogen atom, hydroxy or C １－６ Optionally substituted with alkoxy, ６－１０The aryl and optionally substituted 3- to 6-membered saturated carbocyclic rings are substituted with halogen atoms, hydroxy, C １－６ Alkyl or C １－６ and optionally substituted with alkoxy, except for the following (1) to (19): (1) n is 0, X is an oxygen atom, and R ２ａ and R ２ｂ is a hydrogen atom, (2) a compound in which n is 1, X is an oxygen atom, and R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ and R ３ｃ is a hydrogen atom, (3) a compound in which n is 1 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ３ａ is a hydrogen atom or CH ３ (4) a compound in which n is 1, X is an oxygen atom, and R １ , R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ３ａ is CH ３ (5) a compound in which n is 1, X is an oxygen atom, and R １ , R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ２ｃ and R ２ｄ is CH ３ (6) a compound in which n is 1, X is an oxygen atom, and R １ , R ２ａ, R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ３ｂ is CH ３ (7) a compound in which n is 1, X is an oxygen atom, and R １ , R ２ａ , R ２ｂ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ２ｃ is CH ３ (8) a compound in which n is 0 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ３ａ is CH ３ (9) a compound in which n is 1 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ２ｃ is CH ３ (10) a compound in which n is 1 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ３ｂ is CH ３and a bromine atom; (11) a compound in which n is 1, X is an oxygen atom, and R １ , R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ２ｃ and R ２ｄ together with the carbon atom to which they are attached form a cyclobutyl ring; (12) a compound in which n is 1, X is an oxygen atom, and R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R １ is CH ３ (13) a compound in which n is 0 and X is CH ２ and R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R １ is a hydrogen atom, optionally substituted C １－６ Alkyl or optionally substituted C ３－６ (14) a compound in which n is 1 and X is CH ２ and R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R １ is a hydrogen atom, optionally substituted C １－６ Alkyl or optionally substituted C ３－６ (15) a compound in which n is 0 and X is CH ２ and R ２ａ , R３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ２ｂ is a hydrogen atom and CH ３ and R １ is a hydrogen atom and CH ３ (16) a compound in which n is 1 and X is CH ２ and R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ２ａ and / or R ２ｂ is CH ３ and R １ is a hydrogen atom and CH ３ (17) a compound in which n is 1 and X is CH ２ and R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ２ａ and R ２ｂ together with the carbon atom to form cyclopropane, and R １ is a hydrogen atom and CH ３ (18) a compound in which n is 0 or 1 and X is CH ２ and R ５ａ or R ５ｂ is optionally substituted C １－６ (19) Compounds in which n is 0 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ３ａ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, and R ３ｂ is a bromine atom.] or a pharmaceutically acceptable salt thereof.

[0010] [Term 2] Formula Item 2. The compound according to item 1, represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0011] [Term 3] Formula Item 2. The compound according to item 1, represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0012] [Section 4] R １ Item 4. The compound according to any one of Items 1 to 3, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

[0013] [Section 5] R １ C optionally substituted with a halogen atom １－６ Item 4. The compound according to any one of Items 1 to 3, wherein R is alkyl, or a pharmaceutically acceptable salt thereof.

[0014] [Section 6] R １ Item 6. The compound according to Item 5, or a pharmaceutically acceptable salt thereof, wherein is methyl.

[0015] [Section 7] R ２ａ and R ２ｂ Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

[0016] [Section 8] R ２ａ is a hydrogen atom, and R ２ｂ is optionally substituted C １－６ Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0017] [Section 9] R ２ａ and R ２ｂ is optionally substituted C １－６ Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0018] [Section 10] R ２ａ and R ２ｂ Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is a halogen atom.

[0019] [Section 11] R ２ａ and R ２ｂand R 1 and R 2 together with the carbon atom to which they are attached form a 3- to 6-membered saturated carbocyclic ring, or a pharmaceutically acceptable salt thereof.

[0020] [Section 12] R ２ａ is optionally substituted C ６－１０ aryl, and R ２ｂ Item 7. The compound according to any one of Items 1 to 6, or a pharmaceutically acceptable salt thereof, wherein is a hydrogen atom.

[0021] [Section 13] R ２ａ or R ２ｂ is hydroxy or C １－６ The compound according to any one of items 1 to 6, wherein X is a group substituted with alkoxy, or a pharmaceutically acceptable salt thereof. [Item 13-1] The compound according to any one of items 1 to 13, wherein X is CR'R'', and R' and R'' are hydrogen atoms. [Item 13-2] The compound according to any one of items 1 to 13, wherein X is CR'R'', R' is a hydrogen atom, and R'' is an optionally substituted C １－６ [Item 13-3] The compound according to any one of items 1 to 13, wherein X is CR'R'', and R' and R'' are optionally substituted C, or a pharmaceutically acceptable salt thereof. １－６ Item 14. The compound according to any one of Items 1 to 13, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0022] [Item 14] n is 1, and R ２ｃ and R ２ｄ The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1, 3 to 13-3, wherein is a hydrogen atom.

[0023] [Item 15] n is 1, and R ２ｃ is a hydrogen atom, and R ２ｄ is optionally substituted C １－６ The compound according to any one of Items 1, 3 to 13-3, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0024] [Item 16] n is 1, and R ２ｃ and R ２ｄ is optionally substituted C１－６ The compound according to any one of Items 1, 3 to 13-3, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0025] [Item 17] n is 1, and R ２ｃ and R ２ｄ The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1, 3 to 13-3, wherein is a halogen atom.

[0026] [Item 18] n is 1, and R ２ｃ and R ２ｄ and R 1 and R 2 are, taken together with the carbon atom to which they are attached, to form a 3- to 6-membered saturated carbocyclic ring, or a pharmaceutically acceptable salt thereof.

[0027] [Item 19] n is 1, and R ２ｃ is optionally substituted C ６－１０ aryl, and R ２ｄ The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1, 3 to 13-3, wherein is a hydrogen atom.

[0028] [Section 20] R ２ｃ or R ２ｄ is hydroxy or C １－６ The compound according to any one of Items 1 and 3 to 13-3, wherein the group is substituted with alkoxy, or a pharmaceutically acceptable salt thereof.

[0029] [Section 21] R ３ａ , R ３ｂ , and R ３ｃ Item 21. The compound according to any one of Items 1 to 20, or a pharmaceutically acceptable salt thereof, wherein each of the groups independently represents a hydrogen atom or a halogen atom.

[0030] [Section 22] R ３ａ , R ３ｂ , and R ３ｃ [Item 22-1] The compound according to any one of items 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R ３ａ , R ３ｂ , and R ３ｃ At least one of the optionally substituted C １－６Item 22. The compound according to any one of Items 1 to 21, or a pharmaceutically acceptable salt thereof, wherein R is an alkyl or halogen atom.

[0031] [Section 23] R ５ａ and R ５ｂ and each represent a hydrogen atom, or a pharmaceutically acceptable salt thereof.

[0032] [Section 24] R ５ａ is a hydrogen atom, and R ５ｂ is optionally substituted C １－６ The compound according to any one of Items 1 to 22-1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0033] [Section 25] R ５ａ and R ５ｂ are each optionally substituted C １－６ The compound according to any one of Items 1 to 22-1, or a pharmaceutically acceptable salt thereof, wherein R is alkyl.

[0034] [Item 26] The compound according to any one of items 1 to 25, or a pharmaceutically acceptable salt thereof, wherein X is an oxygen atom.

[0035] [Item 27] ​​The compound according to any one of items 1 to 25, or a pharmaceutically acceptable salt thereof, wherein X is a sulfur atom.

[0036] [Item 28] The compound according to any one of items 1 to 25, or a pharmaceutically acceptable salt thereof, wherein X is NR.

[0037] [Item 29] The compound according to any one of items 1 to 25, wherein X is CR'R'', or a pharmaceutically acceptable salt thereof. [Item 29-1] R １ C optionally substituted with a halogen atom １－６ alkyl, R ３ａ , R ３ｂ , and R ３ｃ At least one of the optionally substituted C １－６[Item 29-2] R is an alkyl or halogen atom, or a pharmaceutically acceptable salt thereof. １ is methyl, R ３ａ , R ３ｂ , and R ３ｃ [Item 30] The compound according to Item 29-1, or a pharmaceutically acceptable salt thereof, wherein at least one of R is methyl, a fluorine atom, or a chlorine atom. １ C optionally substituted with a halogen atom １－６ alkyl, R ２ａ is a hydrogen atom, and R ２ｂ is optionally substituted C １－６ alkyl, R ３ａ , R ３ｂ , and R ３ｃ At least one of the optionally substituted C １－６ is an alkyl or halogen atom, R ５ａ and R ５ｂ and each represent a hydrogen atom. [Item 31] The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 30, wherein the hydrogen atom of the compound is deuterium. [Item 32] The compound according to item 1, selected from the following compound group, or a pharmaceutically acceptable salt thereof: 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine, 1-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine, N-methyl-1-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine, 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]-N-methylmethanamine, 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]-N-( ２ H ３) methylmethanamine, rel-1-[(3'S)-5'-methyl-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine, rel-1-[(3'S)-5'-fluoro-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine, rel-1-[(3S)-2,2,5-trimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine, rel-1-[(3'S)-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine, and rac-1-(5-fluoro-2,2-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl)methanamine.

[0038] [Item 33] A pharmaceutical composition comprising the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof.

[0039] [Item 34] The pharmaceutical composition according to Item 33, wherein the pharmaceutical composition is for treating or preventing a disease or disorder associated with TAAR1.

[0040] [Item 35] The pharmaceutical composition according to Item 33 or 34, which is for treating or preventing a neurological or psychiatric disorder.

[0041] [Item 36] The pharmaceutical composition according to Item 35, wherein the neurological or psychiatric disorder is depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, addiction, social disorder, attention-deficit hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, cognitive impairment, Alzheimer's disease / Parkinson's disease psychosis, Parkinson's disease agitation / aggression, or bulimia.

[0042] [Item 37] A method for treating or preventing a disease or disorder associated with TAAR1 in a subject, comprising administering to the subject an effective amount of the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof.

[0043] [Item 38] A method for treating or preventing a neurological or psychiatric disorder in a subject, comprising administering to the subject an effective amount of the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof.

[0044] [Item 39] The method according to Item 38, wherein the neurological or psychiatric disorder is depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, addiction, social disorder, attention deficit hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, cognitive impairment, Alzheimer's disease / Parkinson's disease psychosis, Parkinson's disease agitation / aggression, or bulimia.

[0045] [Item 40] The compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof for use as a pharmaceutical.

[0046] [Item 41] The compound or a pharmaceutically acceptable salt thereof according to Item 40, wherein the medicament is for treating or preventing a disease or disorder associated with TAAR1.

[0047] [Item 42] The compound or pharmaceutically acceptable salt thereof according to Item 40 or 41, wherein the compound or pharmaceutically acceptable salt thereof is used for treating or preventing a neurological or psychiatric disorder.

[0048] [Item 43] The compound or a pharmaceutically acceptable salt thereof according to Item 42, wherein the neurological or psychiatric disorder is depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, addiction, social disorder, attention-deficit hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, cognitive dysfunction, Alzheimer's disease / Parkinson's disease psychosis, Parkinson's disease agitation / aggression, or bulimia.

[0049] [Item 44] A TAAR1 agonist which is the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof.

[0050] [Item 45] Use of the compound according to any one of items 1 to 32 or a pharmaceutically acceptable salt thereof in modulating the TAAR1 receptor.

[0051] [Item 46] A therapeutic agent for a psychiatric disorder or a central nervous system disorder, comprising the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof as an active ingredient.

[0052] [Item 47] The therapeutic agent according to Item 46, wherein the psychiatric disease or central nervous system disease is an organic mental disorder including symptomatic ones; mental and behavioral disorders due to the use of psychoactive substances; schizophrenia, schizophreniform disorders and delusional disorders; mood (affective) disorders; neurotic disorders, stress-related disorders and somatoform disorders; non-organic sleep disorders; sexual dysfunction not caused by organic disorders or diseases; pervasive developmental disorders; behavioral and emotional disorders usually occurring in childhood and adolescence; extrapyramidal disorders and abnormal movements; other degenerative diseases of the nervous system; or sleep disorders.

[0053] [Item 48] The therapeutic agent according to Item 46, wherein the psychiatric disorder or central nervous system disease is schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, bipolar disorder with psychotic features, depressive disorder with psychotic features, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with dementia with Lewy bodies, psychotic symptoms associated with Parkinson's disease dementia, psychotic symptoms associated with Parkinson's disease, or agitation, excitement or aggression associated with Alzheimer's disease.

[0054] [Item 49] The therapeutic agent according to Item 46, wherein the psychiatric disorder or central nervous system disorder is schizophrenia, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with dementia with Lewy bodies, or agitation, excitement or aggression associated with Alzheimer's disease.

[0055] [Item 50] A method for treating a psychiatric disorder or a central nervous system disorder, comprising administering to a patient in need of treatment a therapeutically effective amount of the compound according to any one of items 1 to 32, or a pharmaceutically acceptable salt thereof.

[0056] [Item 51] Use of the compound according to any one of Items 1 to 32, or a pharmaceutically acceptable salt thereof, for the manufacture of a therapeutic agent for a psychiatric disorder or a central nervous system disorder.

[0057] [Item 52] The compound according to any one of Items 1 to 32, or a pharmaceutically acceptable salt thereof, for use in the treatment of a psychiatric disorder or a central nervous system disorder.

[0058] [Item 53] A therapeutic agent for a psychiatric disorder or a central nervous system disorder, comprising a compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof in combination with at least one drug selected from the group consisting of antidepressants, anti-anxiety drugs, drugs for treating schizophrenia, dopamine supplements, dopamine receptor agonists, drugs for treating Parkinson's disease, antiepileptics, analgesics, hormone preparations, drugs for treating migraine, adrenergic β-receptor antagonists, drugs for treating dementia, drugs for treating mood disorders, antiemetics, sleep-inducing agents, and anticonvulsants.

[0059] [Item 54] A therapeutic agent for treating a psychiatric disorder or a central nervous system disorder, comprising as an active ingredient the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof, in combination with at least one drug selected from the group consisting of antidepressants, anti-anxiety drugs, drugs for treating schizophrenia, dopamine supplements, dopamine receptor agonists, drugs for treating Parkinson's disease, antiepileptics, analgesics, hormone preparations, drugs for treating migraine, adrenergic β-receptor antagonists, drugs for treating dementia, drugs for treating mood disorders, antiemetics, sleep-inducing drugs, and anticonvulsants.

[0060] The compounds disclosed herein have potent agonist activity against the TAAR1 receptor. In addition, in a preferred embodiment, they have high selectivity for inhibiting other GPCRs, such as the dopamine D2 receptor, the adrenergic α1 receptor, the adrenergic α2 receptor, and the hERG channel. Therefore, preferred compounds of the disclosed herein are useful as highly safe therapeutic agents for neuropsychiatric disorders.

[0061] 1 shows the results of a test (Test Example 2-1) on the inhibition of phencyclidine-induced hyperlocomotion of the compound of Example 27. FIG. 2 shows the results of a test (Test Example 2-2) on the inhibition of phencyclidine-induced hyperlocomotion of the compound of Example 8. FIG. 3 shows the results of a test (Test Example 2-2) on the inhibition of phencyclidine-induced hyperlocomotion of the compound of Example 49.

[0062] The present disclosure will now be described with reference to the best mode. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Therefore, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, it should be understood that terms used in this specification are used in the sense commonly used in the art unless otherwise specified. Therefore, unless otherwise defined, all technical and scientific terms used in this specification have the same meaning as commonly understood by those skilled in the art to which this disclosure belongs. In the event of conflict, the present specification (including definitions) will prevail.

[0063] The following provides definitions of terms particularly used in this specification and / or explains basic technical content as appropriate.

[0064] In this specification, "or" is used when "at least one or more" of the items listed in the sentence can be employed. The same applies to "alternative." When the term "within a range" of two values ​​is specified in this specification, the range includes the two values ​​themselves.

[0065] The number of substituents in a group defined as "optionally substituted" or "substituted" is not particularly limited as long as substitution is possible. In addition, unless otherwise specified, the description of each group also applies when that group is a part or substituent of another group.

[0066] In the present specification, the number of carbon atoms in the definition of "substituent" is, for example, "C １－６ " It may also be written as "C １－６ The term "alkyl" is synonymous with an alkyl group having 1 to 6 carbon atoms.

[0067] "Halogen" includes fluorine, chlorine, bromine and iodine.

[0068] "C １－６ "Alkyl" means a straight or branched chain saturated hydrocarbon group containing from 1 to 6 carbon atoms. １－６ As the alkyl, preferably "C １－４alkyl", and more preferably "C １－３ "C alkyl" is an example. １－３ Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. １－４ Specific examples of "alkyl" include the above-mentioned "C １－３ In addition to the specific examples of "alkyl", butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. are also included. １－６ Specific examples of "alkyl" include the above-mentioned "C １－４ In addition to the specific examples of "alkyl", pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, etc. are included.

[0069] "C ３－６ "Alkenyl" means a linear or branched saturated hydrocarbon group having 3 to 6 carbon atoms and having 1 to 3 double bonds (provided that in Formula I, R １ "C ３－６ In the case of "alkenyl", R １ The "C" adjacent to the nitrogen atom bonded to ３－６ There is no double bond on the carbon of "alkenyl" and preferably "C ３－５ alkenyl", more preferably "C ３－４ Specific examples of "alkenyl" include allyl and 2-methylallyl.

[0070] "C １－６ "Alkoxy" means "C １－６ "C alkyloxy" １－６ The "C alkyl" moiety is １－６ "C" is synonymous with "alkyl." １－６ The "alkoxy" is preferably "C １－４ Alkoxy" is preferred, and "C １－３ "Alkoxy" is an example. １－３Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. １－４ Specific examples of "alkoxy" include the above-mentioned "C １－３ In addition to the specific examples of "alkyl", butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. are also included. １－６ Specific examples of "alkoxy" include the above-mentioned "C １－４ In addition to the specific examples of "alkyl", pentyloxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentyloxy, 3-methylpentyloxy, 2-methylpentyloxy, 1-methylpentyloxy, hexyloxy, and the like are included.

[0071] The term "3- to 6-membered saturated heterocyclic ring" refers to a saturated ring composed of 3 to 6 atoms, including, in addition to carbon atoms, 1 to 2 atoms independently selected from the group consisting of nitrogen atoms, oxygen atoms, and sulfur atoms, and includes rings having a partially unsaturated bond and rings having a bridged structure. The "3- to 6-membered saturated heterocyclic ring" is preferably a "4- to 6-membered monocyclic saturated heterocyclic ring," and more preferably a "5- or 6-membered monocyclic saturated heterocyclic ring." Specific examples of the "5- or 6-membered monocyclic saturated heterocycle" include, for example, tetrahydrofuryl, pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolidinyl, thiazolidinyl, oxoimidazolidinyl, dioxoimidazolidinyl, oxooxazolidinyl, dioxooxazolidinyl, dioxothiazolidinyl, tetrahydrofuranyltetrahydropyranyl, etc. Examples of the "4- to 6-membered monocyclic saturated heterocycle" include, in addition to the specific examples of the "5- or 6-membered monocyclic saturated heterocycle", oxetanyl, azetidinyl, etc.

[0072] "3- to 6-membered saturated carbocycle" means a cyclic saturated hydrocarbon having 3 to 6 carbon atoms, and includes those having a partially unsaturated bond and those having a bridged structure. Preferred examples of "3- to 6-membered saturated carbocycle" include "5- or 6-membered monocyclic saturated carbocycle". Specific examples of "5- or 6-membered monocyclic saturated carbocycle" include cyclopentane and cyclohexane. Specific examples of "3- to 6-membered saturated carbocycle" include those given above as specific examples of "5- or 6-membered monocyclic saturated carbocycle", as well as cyclopropane and cyclobutane.

[0073] "C ６－１０ "Aryl" means a monocyclic or bicyclic aromatic hydrocarbon group having 6 to 10 carbon atoms. ６－１０ Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. ６－１０ "Aryl" preferably includes phenyl. ６－１０ The "aryl" may have a fused ring structure.

[0074] Optionally substituted C １－６ Alkyl, optionally substituted C ３－６ Alkenyl, C １－６ Unless otherwise specified, the "substituents" of alkoxy, optionally substituted 3- to 6-membered saturated carbocyclic ring, optionally substituted 3- to 6-membered saturated heterocyclic ring, and optionally substituted aryl group may have one or more substituents of any kind at any chemically possible positions, and when there are two or more substituents, the respective substituents may be the same or different. Specific examples of the substituents include a halogen atom, C １－６ Alkyl, C １－４ Examples include an alkoxy group, a cyano group, a benzyloxy group, a phenyl group, a hydroxy group, a methanesulfonyl group, and a substituted or unsubstituted amino group.

[0075] Optionally substituted C １－６ Alkyl and optionally substituted C ３－６ Specific examples of the substituent in the alkenyl include a halogen atom, hydroxy or C １－６alkoxy, optionally substituted C ６－１０ Specific examples of the substituents in the aryl and the optionally substituted 3- to 6-membered saturated carbocyclic ring include a halogen atom, hydroxy, C １－６ Alkyl or C １－６ It is an alkoxy.

[0076] In the compounds of the present disclosure represented by formula I, X, n, R １ , R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R, R ’ , R”, R ３ａ , R ３ｂ , R ３ｃ , R ４ , R ５ａ , and R ５ｂ Preferred examples of the compounds are as follows, but the technical scope of the present disclosure is not limited to the range of the compounds listed below.

[0077] Preferred embodiments include those in which n is 0.

[0078] Preferred embodiments include those in which n is 1.

[0079] In a preferred embodiment, R １ is a hydrogen atom.

[0080] In a preferred embodiment, R １ C optionally substituted with a halogen atom １－６ Examples of the alkyl group include alkyl.

[0081] In a preferred embodiment, R １ However, examples thereof include those in which the aryl group is methyl.

[0082] In a preferred embodiment, R ２ａ and R ２ｂ is a hydrogen atom.

[0083] In a preferred embodiment, R ２ａ is a hydrogen atom, and R ２ｂ is optionally substituted C １－６ Examples of the alkyl group include alkyl.

[0084] In a preferred embodiment, R ２ａ and R ２ｂ is optionally substituted C １－６ Examples of the alkyl group include alkyl.

[0085] In a preferred embodiment, R ２ａ and R ２ｂ is a halogen atom.

[0086] In a preferred embodiment, R ２ａ and R ２ｂ may be combined with the carbon atom to form a 3- to 6-membered saturated carbocyclic ring.

[0087] In a preferred embodiment, R ２ａ is optionally substituted C ６－１０ aryl, and R ２ｂ is a hydrogen atom.

[0088] In a preferred embodiment, R ２ａ or R ２ｂ is hydroxy or C １－６ Examples include groups substituted with alkoxy.

[0089] In a preferred embodiment, n is 1 and R ２ｃ and R ２ｄ is a hydrogen atom.

[0090] In a preferred embodiment, n is 1 and R ２ｃ is a hydrogen atom, and R ２ｄ is optionally substituted C １－６ Examples of the alkyl group include alkyl.

[0091] In a preferred embodiment, n is 1 and R ２ｃ and R ２ｄ is optionally substituted C １－６ Examples of the alkyl group include alkyl.

[0092] In a preferred embodiment, n is 1 and R ２ｃ and R ２ｄis a halogen atom.

[0093] In a preferred embodiment, n is 1 and R ２ｃ and R ２ｄ may be combined with the carbon atom to form a 3- to 6-membered saturated carbocyclic ring.

[0094] In a preferred embodiment, n is 1 and R ２ｃ is optionally substituted C ６－１０ aryl, and R ２ｄ is a hydrogen atom.

[0095] In a preferred embodiment, R ２ｃ or R ２ｄ is hydroxy or C １－６ Examples include groups substituted with alkoxy.

[0096] In a preferred embodiment, R ３ａ , R ３ｂ , and R ３ｃ are each independently a hydrogen atom, an optionally substituted C １－６ Examples of the alkyl group include those which are alkyl or halogen atoms.

[0097] In a preferred embodiment, R ３ａ , R ３ｂ , and R ３ｃ are each independently a hydrogen atom or a halogen atom.

[0098] In a preferred embodiment, R ３ａ , R ３ｂ , and R ３ｃ are each a hydrogen atom.

[0099] In a preferred embodiment, R ３ａ , R ３ｂ , and R ３ｃ are each optionally substituted C １－６ Examples of the alkyl group include alkyl.

[0100] In a preferred embodiment, R ３ａ , R ３ｂ , and R３ｃ At least one of the optionally substituted C １－６ Examples include those which are alkyl or halogen atoms.

[0101] In a preferred embodiment, R ５ａ and R ５ｂ are each a hydrogen atom.

[0102] In a preferred embodiment, R ５ａ is a hydrogen atom, and R ５ｂ is optionally substituted C １－６ Examples of the alkyl group include alkyl.

[0103] In a preferred embodiment, R ５ａ and R ５ｂ are each optionally substituted C １－６ Examples of the alkyl group include alkyl.

[0104] Preferred embodiments include those in which X is an oxygen atom.

[0105] Preferred embodiments include those in which X is a sulfur atom.

[0106] Preferred embodiments include those in which X is NR.

[0107] Preferred embodiments include those in which X is CR'R''.

[0108] In a preferred embodiment, R １ C optionally substituted with a halogen atom １－６ alkyl, and R ３ａ , R ３ｂ , and R ３ｃ At least one of the optionally substituted C １－６ Examples include those which are alkyl or halogen atoms.

[0109] In a preferred embodiment, R １ is methyl, and R ３ａ , R ３ｂ , and R ３ｃwherein at least one of is a methyl, a fluorine atom, or a chlorine atom.

[0110] In a preferred embodiment, X is an oxygen atom, n is 0, and R １ C optionally substituted with a halogen atom １－６ alkyl, and R ２ａ is a hydrogen atom, and R ２ｂ is optionally substituted C １－６ alkyl, and R ３ａ , R ３ｂ , and R ３ｃ At least one of the optionally substituted C １－６ is an alkyl or halogen atom, and R ５ａ and R ５ｂ are each a hydrogen atom.

[0111] The compounds of formula I may exist as tautomers. Therefore, the compounds of the present disclosure also include tautomers of the compounds of formula I.

[0112] The compound represented by formula I may have at least one asymmetric carbon atom. Therefore, the disclosed compounds include not only the racemic compounds of formula I but also the optically active compounds of these compounds. When the compound represented by formula I has two or more asymmetric carbon atoms, stereoisomerism may occur. Therefore, the disclosed compounds also include the stereoisomers of these compounds and mixtures thereof. In the structural formulas, those marked with "rac." mean racemic compounds, those marked with "chiral" mean optically active compounds, and those marked with "abs." mean absolute configuration.

[0113] In addition, derivatives in which any one or more atoms of the compound represented by formula I are converted to isotopes are also encompassed in the compound represented by formula I. For example, １ H ２ Deuterium conversion products converted to H(D) １１ C and １８ Compounds of formula I also include radioisotopes such as F.

[0114] The compound represented by Formula I and its pharmaceutically acceptable salts may exist in the form of a hydrate and / or solvate, and these hydrates or solvates such as ethanol solvates are also included in the compounds disclosed herein. Furthermore, the compounds disclosed herein also include all crystalline forms.

[0115] When the compound represented by Formula I has an acidic group, pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium salts and potassium salts; alkaline earth metal salts such as calcium salts and magnesium salts; inorganic metal salts such as zinc salts; and salts of organic bases such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids.

[0116] When the compound represented by formula I has a basic group, examples of the salt include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; and organic acid salts such as acetate, propionate, succinate, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, benzenesulfonate, and ascorbate.

[0117] Examples of methods for producing the compounds of the present disclosure will be described below, but the present disclosure is not limited to these.

[0118] Production Method The compounds of the present disclosure are synthesized by a combination of the production method shown below and known synthesis methods.

[0119] The compounds in the reaction schemes may each form a salt, and examples of such salts include the same as the salts of the compound represented by formula I. Note that these reactions are merely illustrative, and the compounds of the present disclosure may also be produced by other appropriate methods based on the knowledge of those skilled in organic synthesis.

[0120] In each of the production methods described below, even if the use of a protecting group is not specifically specified, when a functional group that requires protection is present, the functional group may be protected as necessary, and the target product may be obtained by deprotecting the functional group after completion of the reaction or after performing a series of reactions.

[0121] As the protecting group, a conventional protecting group described in the literature (T.W. Greene and P.G.M. Buts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, Inc., New York (1999)) can be used. More specifically, protecting groups for amino include, for example, benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl. Protecting groups for hydroxy include, for example, trialkylsilyl, acetyl, and benzyl.

[0122] Introduction and removal of a protecting group can be carried out by a method commonly used in organic synthetic chemistry (e.g., the method described in T.W. Greene and P.G.M. Butts, "Protective Groups in Organic Synthesis", 3rd Ed., John Wiley and Sons, Inc., New York (1999)) or a method similar thereto.

[0123] Production Method 1 Among the compounds represented by formula I, the compound represented by formula (1a) can be produced, for example, by the method shown below. [In the formula, n, R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and X are the same as those in item 1, and R ６ is optionally substituted C １－６ represents alkyl, and PG １ represents an alkyl carbamate such as tert-butoxycarbonyl or benzyloxycarbonyl.

[0124] Compound (1a) is a PG １When is tert-butoxycarbonyl, it is produced by treating compound (5) with an appropriate acid. The treatment temperature is usually in the range of -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw materials, and the solvent, but is usually 10 minutes to 48 hours.

[0125] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; lower alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof.

[0126] Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0127] Compound (1a) is a PG １ When is benzyloxycarbonyl, it is produced by hydrogenolysis of compound (5) in a suitable inert solvent under atmospheric or pressurized hydrogen atmosphere. Specific examples of catalysts used in this hydrogenolysis reaction include palladium-based catalysts such as palladium-carbon and palladium hydroxide-carbon. The reaction temperature is usually in the range of 0°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, catalyst, raw materials, and solvent used, but is usually 10 minutes to 48 hours.

[0128] Specific examples of the inert solvent include ester solvents such as ethyl acetate; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and 2-propanol; aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0129] Compound (5) can be produced by reacting compound (4) with diphenylphosphoryl azide in a suitable inert solvent in the presence of a suitable base at room temperature for about 1 hour, heating and stirring at a suitable temperature of 50°C to 100°C for about 1 hour, and then reacting the resulting mixture with an alcohol such as benzyl alcohol or tert-butanol at a suitable temperature of 50°C to 100°C.

[0130] Alternatively, compound (5) can be produced by reacting compound (4) with diphenylphosphoric acid azide in a suitable inert solvent in the presence of a suitable base at room temperature for about 1 hour, heating and stirring the mixture at a suitable temperature of 50°C to 100°C for about 1 hour, reacting the mixture with a base such as sodium hydroxide or potassium hydroxide in the presence of water, and then reacting the mixture with di-tert-butyl dicarbonate, if necessary, in the presence of a suitable base.

[0131] The reaction time varies depending on conditions such as the reaction temperature, the base, alcohol, raw materials, and solvent used, but is usually from 10 minutes to 48 hours.

[0132] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate, potassium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0133] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0134] Compound (4) is produced by hydrolyzing compound (3) with a base such as potassium hydroxide, sodium hydroxide, sodium hydride, or lithium hydroxide in an appropriate solvent. The treatment temperature is usually within the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw materials, and the solvent, but is usually 10 minutes to 48 hours.

[0135] Specific examples of the solvent include lower alcohols such as methanol, ethanol, and 2-propanol, water, and mixed solvents thereof.

[0136] Compound (3) is produced by reacting compound (2) with tributyltin hydride in a suitable inert solvent in the presence of a catalytic amount of azobisisobutyronitrile. The reaction temperature is usually between 50°C and the boiling point of the solvent. The reaction time varies depending on conditions such as the reaction temperature, raw materials, and solvent used, but is usually between 10 minutes and 48 hours.

[0137] Specific examples of the inert solvent include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF) and 1,4-dioxane; and mixed solvents thereof.

[0138] Production Method 2 Among the compounds represented by formula I, the compound represented by formula (1b) can be produced, for example, by the method shown below. [In the formula, n, R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and X has the same meaning as in item 1, and PG １ represents an alkyl carbamate such as tert-butoxycarbonyl or benzyloxycarbonyl, and R ７ is optionally substituted C １－６ represents alkyl.

[0139] Compound (1b) is a PG １When is tert-butoxycarbonyl, it is produced by treating compound (6) with an appropriate acid. The treatment temperature is usually in the range of -20°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the acid used, the raw materials, and the solvent, but is usually 10 minutes to 48 hours.

[0140] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran, 1,4-dioxane and 1,2-dimethoxyethane; lower alcohols such as methanol, ethanol and 2-propanol; aprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidinone and dimethyl sulfoxide; and mixed solvents thereof.

[0141] Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0142] Compound (1b) is a PG １ When is benzyloxycarbonyl, it is produced by hydrogenolysis of compound (6) in a suitable inert solvent under atmospheric or pressurized hydrogen atmosphere. Specific examples of catalysts used in this hydrogenolysis reaction include palladium-based catalysts such as palladium-carbon and palladium hydroxide-carbon. The reaction temperature is usually in the range of 0°C to the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, catalyst, raw materials, and solvent used, but is usually 10 minutes to 48 hours.

[0143] Specific examples of the inert solvent include ester solvents such as ethyl acetate; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), 1,4-dioxane, and 1,2-dimethoxyethane; alcohol solvents such as methanol, ethanol, and 2-propanol; aprotic polar solvents such as dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0144] Compound (6) is produced by reacting compound (5) with an alkylating agent such as iodomethane in a suitable inert solvent in the presence of a suitable base. The reaction may be carried out in the presence of a phase transfer catalyst, if necessary. The reaction temperature is usually between about −20° C. and the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the starting materials, and the solvent, but is usually between 10 minutes and 48 hours.

[0145] Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide. Specific examples of phase transfer catalysts include tetrabutylammonium hydrogen sulfate. Specific examples of inert solvents include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; lower alcohols such as methanol, ethanol, and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0146] Production Method 3 The compound represented by formula (2) can be produced, for example, by the following method. [In the formula, n, R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , and X are the same as those in item 1, and R ６ is optionally substituted C １－６ represents alkyl.

[0147] Compound (2) can be produced by reacting compound (8) with a (triphenylphosphoranylidene)acetic acid ester such as ethyl (triphenylphosphoranylidene)acetate in a suitable inert solvent. Compound (2) can also be produced by reacting compound (8) with a phosphonium salt such as triphenyl(carbethoxymethyl)phosphonium bromide or a dialkylphosphonoacetic acid ester such as ethyl diethylphosphonoacetate in the presence of a suitable base. The reaction temperature is usually between about −20° C. and the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, base, raw materials, and solvent used, but is usually between 10 minutes and 48 hours.

[0148] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate, potassium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0149] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0150] Compound (8) can be produced by reacting compound (7) with an oxidizing agent such as Dess-Martin periodinane in a suitable inert solvent. Compound (8) can also be produced by reacting compound (7) with a sulfur trioxide-pyridine complex in the presence of a tertiary alkylamine such as triethylamine in dimethyl sulfoxide. The reaction temperature is usually between about -20°C and the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, raw materials used, and solvent, but is usually between 10 minutes and 48 hours.

[0151] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0152] Production Method 4 Among the compounds represented by formula (2), the compound represented by formula (2a) can be produced, for example, by the method shown below. [In the formula, n, R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , and R ３ｃ is the same as Item 1, and R ６ is optionally substituted C １－６ represents alkyl.

[0153] Compound (2a) is produced by reacting compound (9) with an alcohol represented by formula (10) in a suitable inert solvent in the presence of triphenylphosphine and an azodicarboxylate ester such as diisopropyl azodicarboxylate. The reaction temperature is usually between about -20°C and the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, raw materials used, and solvent, but is usually between 10 minutes and 48 hours.

[0154] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0155] Production Method 5 Among the compounds represented by formula (7), the compound represented by formula (7a) can be produced, for example, by the method shown below. [In the formula, n, R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , and R ３ｃ is the same as Item 1, and R ８ is optionally substituted C １－６ represents alkyl, and PG ２ represents a trialkylsilyl such as tert-butyldimethylsilyl, and LG represents a leaving group (e.g., iodine, bromine, chlorine, substituted sulfonyl (e.g., methanesulfonyl, p-toluenesulfonyl, etc.)).

[0156] Compound (7a) is produced by reacting compound (9) with an alcohol represented by formula (11) in a suitable inert solvent in the presence of triphenylphosphine and an azodicarboxylate such as diisopropyl azodicarboxylate, followed by treatment with a suitable acid. The reaction temperature is usually between about -20°C and the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, raw materials used, and solvent, but is usually between 10 minutes and 48 hours.

[0157] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0158] Specific examples of the acid include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0159] Compound (7a) is produced by reacting compound (13) with a suitable reducing agent in a suitable inert solvent. The reaction temperature is usually between about -20°C and the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, starting materials, and solvent used, but is usually between 10 minutes and 48 hours.

[0160] Specific examples of the reducing agent include composite hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and diisobutylaluminum hydride; and borane complexes (such as borane-dimethyl sulfide complex or borane-tetrahydrofuran complex).

[0161] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and mixed solvents thereof.

[0162] Compound (13) is produced by reacting compound (9) with an alkylating agent represented by formula (12) in a suitable inert solvent in the presence of a suitable base. The reaction may be carried out in the presence of a phase transfer catalyst, if necessary. The reaction temperature is usually between about −20° C. and the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the raw materials, and the solvent, but is usually between 10 minutes and 48 hours.

[0163] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate, potassium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0164] Specific examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate.

[0165] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; lower alcohols such as methanol, ethanol, and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0166] Production Method 6 Among the compounds represented by formula (7), the compound represented by formula (7b) can be produced, for example, by the method shown below. [In the formula, n, R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , and R ３ｃ has the same meaning as item 1.

[0167] Compound (7b) is produced by reacting compound (14) with a thiol represented by formula (15) in a suitable inert solvent in the presence of a suitable base. The reaction may be carried out in the presence of a phase transfer catalyst, if necessary. The reaction temperature is usually between about −20° C. and the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, the base used, the starting materials, and the solvent, but is usually between 10 minutes and 48 hours.

[0168] Specific examples of the base include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium hydrogencarbonate, sodium hydrogencarbonate, potassium dihydrogenphosphate, dipotassium hydrogenphosphate, potassium phosphate, sodium dihydrogenphosphate, disodium hydrogenphosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0169] Specific examples of the phase transfer catalyst include tetrabutylammonium hydrogen sulfate.

[0170] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; lower alcohols such as methanol, ethanol, and 2-propanol; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0171] Production Method 7 Among the compounds of formula I, the compound of formula (1c) can be produced, for example, by the method shown below. [In the formula, n, R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃand X has the same meaning as in item 1.

[0172] Compound (1c) is produced by reacting compound (16) with a suitable reducing agent in a suitable inert solvent. The reaction temperature is usually between about -20°C and the boiling point of the solvent used. The reaction time varies depending on conditions such as the reaction temperature, starting materials, and solvent used, but is usually between 10 minutes and 48 hours.

[0173] Specific examples of the reducing agent include composite hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and diisobutylaluminum hydride; and borane complexes (such as borane-dimethyl sulfide complex or borane-tetrahydrofuran complex).

[0174] Specific examples of the inert solvent include halogenated hydrocarbons such as chloroform and dichloromethane; aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and mixed solvents thereof.

[0175] By appropriately combining the above-mentioned production methods, it is possible to obtain the disclosed compound having the desired substituents at the desired positions. The isolation and purification of the intermediates and products in the above-mentioned production methods can be carried out by appropriately combining methods used in ordinary organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, various types of chromatography, etc. Furthermore, the intermediates can also be subjected to the next reaction without any particular purification.

[0176] In the above-mentioned production methods, the starting compounds or intermediates may exist in the form of a salt such as a hydrochloride depending on the reaction conditions, etc., but can be used as is or in a free form. When the starting compounds or intermediates are obtained in the form of a salt and it is desired to use or obtain the starting compounds or intermediates in a free form, they can be converted to the free form by dissolving or suspending them in an appropriate solvent and neutralizing them with a base such as an aqueous solution of sodium bicarbonate.

[0177] Some of the compounds represented by formula I or pharmaceutically acceptable salts thereof may exist in the form of isomers such as tautomers (e.g., keto-enol forms), positional isomers, geometric isomers, or optical isomers, and all possible isomers, including these, and mixtures of such isomers in any ratio are encompassed in the present disclosure.

[0178] In addition, optical isomers can be separated by carrying out a known separation step such as a method using an optically active column, fractional crystallization, etc. in an appropriate step of the above-mentioned production method. Also, optically active substances can be used as starting materials.

[0179] When it is desired to obtain a salt of the compound represented by formula I, if a salt of the compound represented by formula I is obtained, it can be purified as it is. Alternatively, if the compound represented by formula I is obtained in a free form, it can be dissolved or suspended in an appropriate solvent and an acid or a base can be added to form a salt.

[0180] The disclosed compound has agonistic activity against the trace amine-associated receptor TAAR1 receptor and has a mechanism of action different from that of existing antipsychotic drugs, and therefore can provide a new option for drug treatment of various psychiatric disorders. That is, the disclosed compound is effective in treating psychiatric disorders. The disclosed compound is also effective for central nervous system disorders.

[0181] Examples of psychiatric disorders or central nervous system disorders for which the present invention is expected to be effective include, in the International Classification of Diseases, 10th edition (ICD-10), F00-F09: organic mental disorders including symptomatic, F10-F19: mental and behavioral disorders due to psychoactive substance use, F20-F29: schizophrenia, schizophreniform disorders, and delusional disorders, F30-F39: mood [affective] disorders, F40-F48: neurotic disorders, stress-related disorders, and somatoform disorders, F51: non-organic sleep disorders, F52: sexual dysfunction, not due to organic disorder or disease, F84: pervasive developmental disorders, F90-F98: behavioral and emotional disorders usually occurring in childhood and adolescence, G20-G26: extrapyramidal disorders and abnormal movements, G30-G32: other degenerative diseases of the nervous system, and G47: sleep disorders.

[0182] F00-F09: Specific examples of organic mental disorders, including symptomatic ones, include Alzheimer's disease dementia, vascular dementia, Lewy body dementia, Parkinson's disease dementia, mental disorders associated with diseases such as brain injury, brain dysfunction, and other mental disorders due to physical illness.

[0183] F10-F19: Examples of mental and behavioral disorders due to psychoactive substance use include delirium tremens, psychotic disorders, and amnesic syndromes due to various substance use disorders.

[0184] F20-F29: Specific examples of schizophrenia, schizophreniform disorder, and delusional disorder include paranoid schizophrenia, simple schizophrenia, and delusional disorder.

[0185] F30-F39: Specific examples of mood [affective] disorders include manic episodes, bipolar disorder, and depressive episodes.

[0186] F40-F48: Specific examples of neurotic disorders, stress-related disorders and somatoform disorders include phobic anxiety disorders, obsessive-compulsive disorders, somatoform disorders, etc.

[0187] F51: Specific examples of non-organic sleep disorders include non-organic insomnia, sleepwalking, and nightmares.

[0188] F52: Specific examples of sexual dysfunction not due to organic disorder or disease include lack of libido or loss of libido, and unspecified sexual dysfunction.

[0189] F84: Specific examples of pervasive developmental disorders include autism, mental retardation, and hyperkinetic disorder associated with stereotypic movements.

[0190] F90-F98: Hyperactivity Disorders Examples of behavioral and emotional disorders usually occurring in childhood and adolescence include, for example, hyperactivity disorder, conduct disorder, and mixed conduct and emotional disorder.

[0191] G20-G26: Specific examples of extrapyramidal disorders and abnormal movements include Parkinson's disease, secondary parkinsonism, dyskinesia, spinocerebellar degeneration, and the like.

[0192] G30-G32: Specific examples of other degenerative diseases of the nervous system include Alzheimer's disease, frontotemporal dementia, frontotemporal lobar degeneration, dementia with Lewy bodies, senile cerebral degeneration, and progressive supranuclear palsy.

[0193] G47: Specific examples of sleep disorders include, for example, disorders of sleep initiation and maintenance [insomnia], sleep-wake schedule disorders, narcolepsy, and cataplexy.

[0194] The disclosed compounds are also useful for treating or preventing recurrence of various symptoms associated with these diseases, such as psychotic symptoms, restlessness, aggression, irritability and irritability, sleep disorders, depression, anxiety, and cognitive impairment.

[0195] The psychiatric disorders or central nervous system disorders for which the present invention is expected to be effective preferably include schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, bipolar disorder with psychotic features, depressive disorder with psychotic features, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with dementia with Lewy bodies, psychotic symptoms associated with Parkinson's disease dementia, psychotic symptoms associated with Parkinson's disease, or agitation, excitement, or aggression associated with Alzheimer's disease, and more preferably include schizophrenia, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with dementia with Lewy bodies, or agitation, excitement, or aggression associated with Alzheimer's disease.

[0196] The disclosed compounds exhibit agonistic activity against the trace amine-associated receptor TAAR1 receptor (Test Example 1). In a preferred embodiment of the disclosed compounds, the hERG channel inhibitory activity, which is an indicator of arrhythmia due to QT prolongation, is weak (Test Example 3), and therefore, it is expected that the effects on the cardiovascular system are small. In other words, the concentration at which the pharmacological effect is expressed is different from the concentration at which side effects are expressed.

[0197] The compounds of the present disclosure can be administered orally or parenterally. When administered orally, they can be administered in a commonly used dosage form. When administered parenterally, they can be administered in the form of topical preparations, injections, transdermal preparations, nasal preparations, etc. Oral or rectal preparations include, for example, capsules, tablets, pills, powders, cachets, suppositories, liquid preparations, etc. Injectable preparations include, for example, sterile solutions or suspensions, etc. Topical preparations include, for example, creams, ointments, lotions, transdermal preparations (ordinary patches, matrix preparations), etc.

[0198] The above dosage forms are prepared in a conventional manner with pharmaceutically acceptable excipients and additives, such as carriers, binders, flavorings, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersing agents, suspending agents, preservatives, etc.

[0199] Pharmaceutically acceptable carriers include, for example, magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, low-melting wax, cocoa butter, etc. Capsules can be prepared by placing the disclosed compound together with a pharmaceutically acceptable carrier. The disclosed compound can be mixed with a pharmaceutically acceptable excipient or placed in a capsule without an excipient. Cachets can also be prepared in a similar manner.

[0200] Injectable liquids include solutions, suspensions, emulsions, and the like. Examples include aqueous solutions and water-propylene glycol solutions. Liquids can also be prepared in the form of polyethylene glycol and / or propylene glycol solutions that may contain water. Liquids suitable for oral administration can be prepared by adding the compound of the present disclosure to water and optionally adding colorants, flavors, stabilizers, sweeteners, solubilizers, thickeners, and the like. Liquids suitable for oral administration can also be prepared by adding the compound of the present disclosure together with a dispersant to water to thicken the solution. Examples of thickeners include pharmaceutically acceptable natural or synthetic gums, resins, methylcellulose, sodium carboxymethylcellulose, and known suspending agents.

[0201] The dosage varies depending on the individual compound, the patient's disease, age, weight, sex, symptoms, administration route, etc., but typically, for an adult (body weight 50 kg), the compound of the present disclosure is administered at 0.1 to 1000 mg / day, preferably 1 to 300 mg / day, once a day or in 2 to 3 divided doses. It can also be administered once every few days to every few weeks.

[0202] The compounds of the present disclosure can be used in combination with other drugs for the purpose of enhancing their effects and / or reducing their side effects. Hereinafter, drugs that can be used in combination with the compounds of the present disclosure will be abbreviated as "concomitant drugs."

[0203] Specific examples of concomitant medications include antidepressants, anti-anxiety drugs, drugs for treating schizophrenia, dopamine supplements, dopamine receptor agonists, drugs for treating Parkinson's disease, anti-epileptic drugs, analgesics, hormone preparations, drugs for treating migraine, adrenergic β-receptor antagonists, drugs for treating dementia, drugs for treating mood disorders, antiemetics, sleep-inducing drugs, anticonvulsants, etc. Preferable concomitant medications include anti-anxiety drugs such as selective serotonin reuptake inhibitors.

[0204] The administration period of the compound of the present disclosure and the concomitant drug is not limited, and they may be administered to the subject simultaneously or at staggered times. The compound of the present disclosure and the concomitant drug may also be used as a combination drug. The dose of the concomitant drug can be appropriately selected based on clinically used doses. The compounding ratio of the compound of the present disclosure to the concomitant drug can be appropriately selected depending on the subject, administration route, target disease, symptoms, combination, etc. For example, when the subject is a human, 0.01 to 100 parts by weight of the concomitant drug may be used per 1 part by weight of the compound of the present disclosure. Furthermore, for the purpose of suppressing side effects, the compound of the present disclosure may be used in combination with drugs (concomitant drugs) such as antiemetics, hypnotics, and anticonvulsants.

[0205] The present disclosure will be explained in more detail below with reference examples, examples, and test examples. However, the present disclosure is not limited to the following reference examples, examples, test examples, etc., including the above explanation. Therefore, the scope of the present disclosure is not limited to the embodiments or examples specifically described in this specification, but is limited only by the claims. The compound names shown in the following reference examples and examples do not necessarily conform to the IUPAC nomenclature. Furthermore, the identification of the compounds can be performed by proton nuclear magnetic resonance absorption spectroscopy ( １ Measurements were performed using 1H-NMR, LC-MS, etc. LC-MS measurements were performed under the various conditions shown in the table below. The retention time (RT) indicates the time at which a mass spectrum peak appears in the LC-MS measurement.

[0206] The following abbreviations may be used in the present specification: Me: methyl, Et: ethyl, DMF: N,N-dimethylformamide, THF: tetrahydrofuran, tert-: tertiary, TBS: tert-butyldimethylsilyl, CDCl ３ : deuterated chloroform DMSO-D ６ : deuterated dimethyl sulfoxide CD ３ OD: deuterated methanol

[0207] Proton nuclear magnetic resonance spectra were measured using a JEOL FT-NMR spectrometer (400 MHz). Chemical shift values ​​are reported as δ values ​​(ppm). Symbols used in NMR include s for singlet, d for doublet, dd for double doublet, dt for double triplet, t for triplet, q for quartet, m for multiplet, br for broad, brs for broad singlet, and J for coupling constant.

[0208] Example 1 rac-1-[(3R,4S)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methanamine dihydrochloride To a mixture of the compound of Reference Example 1-1 (461 mg), methanol (4.4 mL), and water (2.2 mL), sodium hydroxide (235 mg) was added at room temperature. After stirring at 60°C for 5 hours, 3 mol / L hydrochloric acid was added until the aqueous layer reached pH 5. The reaction solution was concentrated, and then the concentrated residue was dissolved in methanol, and insoluble matter was filtered off and concentrated.

[0209] To a toluene solution (28 mL) of the resulting concentrated residue (406 mg), triethylamine (0.819 mL) and diphenylphosphoryl azide (0.842 mL) were added at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was heated to 100°C. After stirring at 100°C for 1 hour, the reaction solution was concentrated. To a mixture of the concentrated residue and tetrahydrofuran (20 mL), 5 mol / L aqueous sodium hydroxide solution (6.66 mL) was added under ice cooling. After stirring at room temperature for 3 hours, di-tert-butyl dicarbonate (1.28 g) was added to the reaction mixture. After stirring at room temperature for 15 hours, water (20 mL) was added to the reaction mixture, which was then extracted with chloroform (20 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate).

[0210] To a mixture of the purified product (31 mg) and ethyl acetate (1.0 mL), 4 mol / L hydrogen chloride-ethyl acetate (1.0 mL) was added and the mixture was stirred at room temperature for 2 hours. The precipitated solid was then collected by filtration, washed with diethyl ether (1.0 mL), and dried under reduced pressure to obtain the title compound (26 mg). 1H-NMR(400MHz,CD3OD) δ:8.31(1H,dd,J=5.5,1.2Hz),7.74(1H,dd,J=8.6,1.2Hz),7.65(1H,dd,J=8.6,5.5Hz),4.36(1H,dd,J=11.0,3.1 Hz),4.21(1H,dd,J=11.0,6.7Hz),3.72-3.66(1H,m),3.48-3.36(2H,m),2.55-2.45(1H,m),1.12(3H,d,J=7.3Hz).

[0211] Example 2 rac-1-[(3S,4S)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methanamine dihydrochloride The title compound was obtained from the compound of Reference Example 1-2 by the same method as in Example 1. 1 H-NMR(400MHz,CD3OD) δ:8.46(1H,dd,J=5.5,1.2Hz),8.00(1H,dd,J=7.9,1.2Hz),7.85(1H,dd,J=7.9,5.5Hz),4.40(1H,dd,J= 11.6,2.4Hz),4.27(1H,dd,J=11.6,3.7Hz),3.53-3.43(3H,m),2.50-2.40(1H,m),1.15(3H,d,J=6.7Hz).

[0212] Example 3 rel-1-[(3R,4R)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methanamine dihydrochloride The compound of Reference Example 5 was optically resolved by chiral HPLC to obtain the compound of the first peak. To a solution (1.0 mL) of this compound (48.0 mg) in ethyl acetate, 4 mol / L hydrogen chloride-ethyl acetate (0.43 mL) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was then collected by filtration and dried under reduced pressure to obtain the title compound. [Chiral HPLC Conditions] Column: IC 4.6 cm x 25 cm Solvent: Hexane (90%) - IPA (10%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 3.8 min (first peak) [α] D22.4 -10.4 (c0.1,MeOH) 1 H-NMR(400MHz,DMSO-D6) δ:8.21(3H,brs),8.21(1H,dd,J=4.6,1.5Hz),7.40(1H,brd,J=7.9Hz),7.35(1H,dd,J=7.9,4.6Hz),4.20(1H,dd,J=11.6,3.0Hz) ,3.93(1H,dd,J=11.3,7.0Hz),3.33-3.27(1H,m),3.18-3.11(1H,m),2.98-2.92(1H,m),2.23-2.15(1H,m),1.01(3H,d,J=6.7Hz).

[0213] Example 4 rel-1-[(3S,4S)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methanamine dihydrochloride The compound of Reference Example 5 was optically resolved by chiral HPLC to obtain the compound of the second peak. To a solution (1.0 mL) of this compound (44.8 mg) in ethyl acetate, 4 mol / L hydrogen chloride-ethyl acetate (0.40 mL) was added at room temperature, and the mixture was stirred at room temperature for 2 hours. The precipitated solid was then collected by filtration and dried under reduced pressure to obtain the title compound. [Chiral HPLC Conditions] Column: IC 4.6 cm x 25 cm Solvent: Hexane (90%) - IPA (10%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 4.5 min (second peak) [α] D 22.7 +14.4 (c0.1,MeOH) 1 H-NMR(400MHz,DMSO-D6) δ:8.21(3H,brs),8.21(1H,dd,J=4.6,1.5Hz),7.40(1H,brd,J=7.9Hz),7.35(1H,dd,J=7.9,4.6Hz),4.20(1H,dd,J=11.6,3.0Hz) ,3.93(1H,dd,J=11.3,7.0Hz),3.33-3.27(1H,m),3.18-3.11(1H,m),2.98-2.92(1H,m),2.23-2.15(1H,m),1.01(3H,d,J=6.7Hz).

[0214] Example 5 N-methyl-1-[(2R,4S)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methanamine dihydrochloride To a mixture of the compound of Reference Example 6-1 (203 mg, 0.728 mmol) and tetrahydrofuran (10.0 mL), 55% sodium hydride (95.0 mg) was added under ice-cooling. After stirring for 30 minutes under ice-cooling, iodomethane (0.453 mL, 7.28 mmol) was added. After stirring at room temperature for 3 hours, saturated aqueous ammonium chloride solution (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated.

[0215] To a mixture of the obtained product (192 mg) and ethyl acetate (3.0 mL), 4 mol / L hydrogen chloride-ethyl acetate (3.0 mL) was added under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Thereafter, the precipitated solid was collected by filtration and dried under reduced pressure to obtain the title compound (142 mg). 1 H-NMR(400MHz,DMSO-D6) δ:9.56(1H,brs),9.13(1H,brs),8.29(1H,d,J=4.9Hz),7.62(1H,d,J=7.9Hz),7.52(1H,dd,J=7.9,4.9Hz),4.41-4.35(1H,m ),3.56-3.54(1H,m),3.40-3.29(2H,m),2.61(3H,t,J=4.9Hz),2.45-2.35(1H,m),1.88-1.80(1H,m),1.38(3H,d,J=6.1Hz).

[0216] Examples 6 to 7 According to the method described in Example 5, the compounds of Examples 6 to 7 were obtained from the corresponding compounds of Reference Examples.

[0217] Example 8 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride To a mixture of the compound of Reference Example 13 (98 mg, 3.47 mmol) and 2-propanol (3.5 mL), 4 mol / L hydrogen chloride-cyclopentyl methyl ether (2 mL) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated, and the resulting solid was recrystallized from 2-propanol to give the title compound (39.7 mg). [α] D 25.8 +46.8 (c0.005,MeOH) 1 H-NMR(400MHz,DMSO-D6) δ:8.12-8.02(4H,m),7.30-7.25(1H,m),5.01-4.95(1H,m),3.41-3.31(1H,m),3.22-3.08(2H,m),1.46(3H,d,J=6.7Hz).

[0218] Examples 9 to 25 According to the method described in Example 8, the compounds of Examples 9 to 25 were obtained from the corresponding compounds of Reference Examples.

[0219] Example 27 1-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride To a mixture of the compound of Reference Example 37 (23.6 g, 79.0 mmol) and methanol (158 mL), 10% palladium-carbon (8.00 g) was added under a nitrogen atmosphere. The mixture was stirred at room temperature under a hydrogen atmosphere for 5 hours, filtered through Celite, and concentrated. To a mixture of the concentrated residue and 2-propanol (158 mL), 4 mol / L hydrogen chloride-cyclopentyl methyl ether (43.5 mL, 174 mmol) was added, and the mixture was stirred at room temperature for 15 minutes. The reaction solution was concentrated, and the resulting crude crystals were recrystallized from 2-propanol and methanol to give the title compound (9.57 g). [α] D 25.3 +37.4 (c0.01,MeOH) 1H-NMR(400MHz,DMSO-D6) δ:8.54-8.33(3H,s),8.11(1H,dd,J=4.6,1.5Hz),7.37(1H,dd,J=7.9,1.5Hz),7.33(1H,dd,J=7.9,4.6Hz), 5.03(1H,dq,J=6.7,6.1Hz),3.60-3.57(1H,m),3.32-3.29(1H,m),3.21-3.16(1H,m),1.47(3H,d,J=6.1Hz).

[0220] Examples 28 to 32 According to the method described in Example 27, the compounds of Examples 28 to 32 were obtained from the corresponding compounds of Reference Examples.

[0221] Example 33 rac-1-[(5aS,9aR,10S)-6,7,8,9,9a,10-hexahydro-5aH-[1]benzopyrano[3,2-b]pyridin-10-yl]methanamine dihydrochloride To a toluene solution (7.1 mL) of the compound of Reference Example 50 (123 mg, 0.497 mmol), triethylamine (0.208 mL, 1.49 mmol) and diphenylphosphoryl azide (0.214 mL, 0.995 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. After stirring at 90°C for 1 hour, 5 mol / L aqueous sodium hydroxide solution (1.69 mL) was added dropwise to the reaction mixture under ice cooling, and the mixture was stirred at room temperature for 2 hours. 6 mol / L hydrochloric acid was added to the reaction mixture until the pH reached 2, and the mixture was concentrated. Methanol was added to the concentrated residue, and insoluble matter was removed by filtration, followed by concentration. To a chloroform solution (10 mL) of the residue, triethylamine (0.208 mL, 1.49 mmol) and di-tert-butyl dicarbonate (0.346 mL, 1.49 mmol) were added. After stirring at room temperature for 1 hour, water (30 mL) was added to the reaction mixture, which was then extracted with chloroform (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate). To an ethyl acetate solution (1.0 mL) of the obtained product, 4 mol / L hydrogen chloride-ethyl acetate (1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then separated and purified by amino silica gel column chromatography (chloroform / methanol) to obtain the title compound (13 mg).1 H-NMR(400MHz, CDCl3) δ:8.06(1H,dd,J=4.6,1.5Hz),7.03(1H,dd,J=8.6,1.5Hz),6.99(1H,dd,J=8.6,4.6Hz),3.62( 1H,dt,J=10.5,4.5Hz),3.50(1H,dd,J=12.5,3.1Hz),2.90(1H,dd,J=12.5,6.4Hz),2.86(2H,br s),2.68(1H,ddd,J=11.0,6.1,3.1Hz),2.17-2.08(2H,m),1.84-1.79(1H,m),1.74-1.68(1H,m ),1.59(1H,ddd,J=10.4,10.4,3.1Hz),1.47-1.18(4H,m),1.02(1H,ddd,J=12.5,12.5,3.7Hz).

[0222] Example 34 1-[(2R,3S)-2,7-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride The title compound was obtained from the compound of Reference Example 51 by the same method as in Example 33. 1 H-NMR(400MHz,DMSO-D6) δ:8.45(3H,brs),8.10(1H,d,J=5.5Hz),7.37(1H,d,J=5.5Hz),5.10(1H,dq,J=6.7,6.7Hz), 3.74-3.67(1H,m),3.43-3.37(1H,m),3.27-3.18(1H,m),2.25(3H,s),1.49(3H,d,J=6.7Hz).

[0223] Example 35 1-[(2R,3S)-2,5-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine To a solution (1.0 mL) of the compound of Reference Example 52 (24.4 mg, 0.0878 mmol) in ethyl acetate, 4 mol / L hydrogen chloride-ethyl acetate (1.0 mL) was added. After stirring at room temperature for 2 hours, the precipitated solid was collected by filtration and dried. To a suspension (1.0 mL) of the obtained solid (20 mg) in chloroform, triethylamine (0.039 mL, 0.279 mmol) and trifluoroacetic anhydride (0.013 mL, 0.096 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water (30 mL) was added to the reaction mixture, which was then extracted with chloroform (30 mL x 2). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate). To a mixture of the obtained product, methanol (0.9 mL), and water (0.1 mL), potassium carbonate (55.0 mg, 0.398 mmol) was added, and the mixture was stirred at 50°C for 2 hours. The reaction mixture was added with water (30 mL), extracted with chloroform (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was separated and purified by aminosilica gel column chromatography (chloroform / methanol) to give the title compound (8.2 mg). 1 H-NMR(400MHz, CDCl3) δ:6.85(1H,d,J=8.6Hz),6.81(1H,d,J=8.6Hz),4.65-4.58(1H,dq,J=6.1,6 .1Hz),3.03-2.99(3H,m),2.40(3H,s),2.10(2H,s),1.43(3H,d,J=6.1Hz).

[0224] Example 36 rac-1-[(2R,3R)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride To a toluene solution (57.3 mL) of the 10:1 diastereomeric mixture (1.66 g, 8.59 mmol) of Reference Example 38, triethylamine (3.59 mL, 25.8 mmol) and diphenylphosphoryl azide (3.69 mL, 17.2 mmol) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After stirring at 90°C for 1 hour, 5 mol / L aqueous sodium hydroxide solution (29.2 mL) was added dropwise to the reaction mixture under ice cooling. The reaction mixture was warmed to room temperature over 2 hours, and then 6 mol / L hydrochloric acid was added until the aqueous layer reached pH 5. The reaction mixture was concentrated, and the concentrated residue was dissolved in methanol, and the insoluble matter was filtered and concentrated. Subsequently, to a mixture of the concentrated residue and chloroform (100 mL), triethylamine (3.59 mL, 25.8 mmol) and di-tert-butyl dicarbonate (5.63 g, 25.8 mmol) were added. After stirring at room temperature for 1 hour, water (100 mL) was added to the reaction mixture, which was then extracted with chloroform (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate). A portion of the resulting product (100 mg) was further separated and purified by reverse-phase silica gel column chromatography (water / acetonitrile / trifluoroacetic acid).

[0225] To a mixture of the obtained product (10 mg) and ethyl acetate (1.0 mL), 4 mol / L hydrogen chloride-ethyl acetate (0.1 mL) was added and stirred at room temperature for 1 hour. The precipitated solid was then collected by filtration and dried under reduced pressure to obtain the title compound (7.0 mg). 1 H-NMR(400MHz,DMSO-D6) δ:8.13-7.99(3H,brs),8.04(1H,dd,J=3.7,2.4Hz),7.23-7.20(2H,m),5.15(1H,dq, J=9.2,6.1Hz),3.77(1H,dd,J=7.9,7.9Hz),3.24-3.17(2H,m),1.34(3H,d,J=6.1Hz).

[0226] Example 37 1-[(2R,3S)-6-chloro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride To a toluene solution (2.2 mL) of the compound of Reference Example 53 (342 mg, 1.50 mmol), triethylamine (0.314 mL, 2.25 mmol) and diphenylphosphoryl azide (0.388 mL, 1.80 mmol) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After stirring at 90°C for 1 hour, 5 mol / L aqueous sodium hydroxide solution (5.11 mL) was added dropwise to the reaction mixture under ice cooling. The reaction mixture was warmed to room temperature over 2 hours, and then 6 mol / L hydrochloric acid was added until the aqueous layer reached pH 5. The reaction mixture was concentrated, and the concentrated residue was dissolved in methanol, and insoluble matter was filtered off and concentrated. Subsequently, to a mixture of the concentrated residue and chloroform (2.2 mL), triethylamine (0.628 mL, 4.51 mmol) and di-tert-butyl dicarbonate (984 mg, 4.51 mmol) were added. After stirring at room temperature for 1 hour, water (4.0 mL) was added to the reaction mixture, which was then extracted with chloroform (4 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate).

[0227] To a mixture of the obtained compound (219 mg) and 2-propanol (1.5 mL), 4 mol / L hydrogen chloride-cyclopentyl methyl ether (1.83 mL) was added and stirred at room temperature for 1 hour. The reaction solution was concentrated, and the obtained crude crystals were recrystallized from 2-propanol and methanol to obtain the title compound (66 mg). 1 H-NMR(400MHz,DMSO-D6) δ:8.14(3H,brs),8.08(1H,d,J=1.8Hz),7.44(1H,d,J=1.8Hz),4.97(1H,dq, J=6.1,6.1Hz),3.43-3.38(1H,m),3.23-3.11(2H,m),1.47(3H,d,J=6.1Hz).

[0228] Example 38 1-[(2R,3S)-5-chloro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride The title compound was obtained from the compound of Reference Example 54 by the same method as in Example 37. 1H-NMR(400MHz,DMSO-D6) δ:8.11(3H,brs),7.29(2H,s),5.01-4.92(1H,m),3.47-3.39(1H,m),3.20( 1H,dd,J=13.1,5.2Hz),3.14(1H,dd,J=13.1,8.2Hz),1.45(3H,d,J=6.7Hz).

[0229] Example 39 rel-1-[(4R)-3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-4-yl]methanamine dihydrochloride The compound of Reference Example 15 was optically resolved by chiral HPLC to obtain the compound of the first peak. To a solution of this compound (20.0 mg, 0.0713 mmol) in ethyl acetate (1.0 mL), 4 mol / L hydrogen chloride-ethyl acetate (0.178 mL) was added and stirred at room temperature for 2 hours. The precipitated solid was then collected by filtration and dried under reduced pressure to obtain the title compound (12 mg). [Chiral HPLC Conditions] Column: IC Solvent: Hexane (90%) - IPA (10%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 7.7 min (first peak) [α] D 24.0 -34.5 (c0.1,MeOH) 1 H-NMR(400MHz,DMSO-D6) δ:8.27(1H,dd,J=4.6,1.5Hz),8.13(3H,brs),7.65(1H,dd,J=7.9,1.5Hz),7.24(1H,dd,J =7.9,4.6Hz),3.32-3.19(2H,m),3.16-3.07(3H,m),2.32-2.22(1H,m),2.09-2.00(1H,m).

[0230] Example 40 rel-1-[(4S)-3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-4-yl]methanamine dihydrochloride The compound of Reference Example 15 was optically resolved by chiral HPLC to obtain the compound of the second peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (90%) - IPA (10%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 9.2 min (second peak) [α] D 24.3 +22.6 (c0.1,MeOH) 1 H-NMR(400MHz,DMSO-D6) δ:8.27(1H,dd,J=4.6,1.5Hz),8.13(3H,brs),7.65(1H,dd,J=7.9,1.5Hz),7.24(1H,dd,J =7.9,4.6Hz),3.32-3.19(2H,m),3.16-3.07(3H,m),2.32-2.22(1H,m),2.09-2.00(1H,m).

[0231] Example 41 rel-1-[(3R)-2,3-dihydrothieno[3,2-b]pyridin-3-yl]methanamine dihydrochloride The compound of Reference Example 18 was optically resolved by chiral HPLC to obtain the compound of the first peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (90%) - IPA (10%) Flow rate: 1.0 mL / min Retention time = 7.67 min (first peak) 1 H-NMR(400MHz,DMSO-D6) δ:8.32(3H,brs),8.24-8.24(1H,m),7.80-7.78(1H,m),7.26-7.24(1H,m), 3.84-3.81(1H,m),3.64-3.57(1H,m),3.40-3.34(2H,m),3.17-3.10(1H,m).

[0232] Example 42 rel-1-[(3S)-2,3-dihydrothieno[3,2-b]pyridin-3-yl]methanamine dihydrochloride The compound of Reference Example 18 was subjected to optical resolution by chiral HPLC to obtain the compound of the second peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (90%) - IPA (10%) Flow rate: 1.0 mL / min Retention time = 9.19 min (second peak) 1 H-NMR(400MHz,DMSO-D6) δ:8.24-8.23(1H,m),8.21(3H,brs),7.76(1H,d,J=7.3Hz),7.24-7.22(1H,m) ,3.80-3.78(1H,m),3.62-3.59(1H,m),3.38-3.35(2H,m),3.17-3.11(1H,m).

[0233] Example 43 rel-1-[(2R,3S)-2-ethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride The compound of Reference Example 33 was optically resolved by chiral HPLC to obtain the compound of the first peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (95%) including diethylamine (0.1%) - IPA (5%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 9.72 min (first peak) 1 H-NMR(400MHz,DMSO-D6) δ:8.11-8.03(4H,m),7.25-7.15(2H,m),4.76-4.66(1H,m),3.53-3.44(1H,s),3.25-3.10(2H,m),1.85-1.67(2H,m),0.99(3H,t,J=7.3Hz).

[0234] Example 44 rel-1-[(2S,3R)-2-ethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride The compound of Reference Example 33 was optically resolved by chiral HPLC to obtain the compound of the second peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (95%) including diethylamine (0.1%) - IPA (5%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 12.64 min (second peak) 1 H-NMR(400MHz,DMSO-D6) δ:8.30-8.02(4H,m),7.24-7.19(2H,m),4.75-4.65(1H,s),3.53-3.48(1H,m),3.23-3.13(2H,m),1.81-1.70(2H,m),0.97(3H,t,J=6.7Hz).

[0235] Example 45 rac-1-(3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-4-yl)-N-methylmethanamine dihydrochloride To a mixture of the compound of Reference Example 15 (244 mg, 0.870 mmol) and N,N-dimethylformamide (2.2 mL), 55% sodium hydride (144 mg) was added under ice-cooling. After stirring for 10 minutes under ice-cooling, iodomethane (0.544 mL, 8.70 mmol) was added. After stirring at room temperature for 2 hours, saturated aqueous ammonium chloride solution (5 mL) was added, and the mixture was extracted with 2:1-hexane / ethyl acetate (5 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate).

[0236] To a mixture of the obtained compound (150 mg) and ethyl acetate (1.1 mL), 4 mol / L hydrogen chloride-ethyl acetate (1.1 mL) was added and stirred at room temperature for 2 hours. The precipitated solid was then collected by filtration, washed with diethyl ether (4.0 mL), and dried under reduced pressure to obtain the title compound (101 mg). 1H-NMR(400MHz,DMSO-D6) δ:8.87(2H,brs),8.26(1H,dd,J=4.6,1.2Hz),7.64(1H,dd,J=7.9,1.2Hz),7.24(1H,dd,J=7.9,4.6Hz ),3.36-3.32(2H,m),3.23-3.10(3H,m),2.62(3H,t,J=5.5Hz),2.29-2.25(1H,m),2.04-2.02(1H,m).

[0237] Example 46 N-methyl-1-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride To a mixture of the compound of Example 27 (10 mg, 0.042 mmol) and chloroform (0.10 mL), triethylamine (0.024 mL, 0.169 mmol) and di-tert-butyl dicarbonate (18 mg, 0.084 mmol) were added. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate).

[0238] To a mixture of the obtained compound (101 mg, 0.382 mmol) and N,N-dimethylformamide (0.764 mL), 55% sodium hydride (50.0 mg) was added under ice-cooling. After stirring for 10 minutes under ice-cooling, iodomethane (0.239 mL, 3.82 mmol) was added. After stirring at room temperature for 1 hour, water (2 mL) was added, and the mixture was extracted with chloroform (2 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate).

[0239] To a mixture of the obtained compound (50 mg) and ethyl acetate (1.0 mL), 4 mol / L hydrogen chloride-ethyl acetate (0.955 mL) was added and stirred at room temperature for 2 hours. The precipitated solid was then collected by filtration and dried under reduced pressure to obtain the title compound (45 mg). 1H-NMR(400MHz,DMSO-D6) δ:9.42(2H,brs),8.12(1H,dd,J=4.6,1.5Hz),7.38(1H,dd,J=8.5,1.5Hz),7.34(1H,dd,J=8.5,4.6Hz),5.1 1(1H,dq,J=6.7,6.1Hz),3.72-3.67(1H,m),3.42-3.25(2H,m),2.59(3H,t,J=5.2Hz),1.48(3H,d,J=6.7Hz).

[0240] Examples 47-48 According to the method described in Example 46, the compounds of Examples 47-48 were obtained from the compounds of the corresponding Examples.

[0241] Example 49 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]-N-methylmethanamine dihydrobromide A mixture of the compound of Reference Example 55 (39.5 g, 120 mmol) and 30% hydrobromic acid / acetic acid (117 mL) was stirred at room temperature for 3 hours. The mixture was then concentrated. Ethyl acetate was added to the concentrated residue, and after stirring, the solid was collected by filtration. A mixture of the obtained solid and ethanol (211 mL) was heated and stirred at 75°C. After confirming that the solid was completely dissolved, the mixture was cooled to 60°C. After confirming the precipitation of a solid, hexane (633 mL) was added dropwise. The mixture was then gradually cooled to 0°C, and the solid was collected by filtration, washed with hexane / ethanol = 9 / 1 (60 mL) cooled at 0°C, and dried to obtain the title compound (34.2 g). [α] D 23.7 +33.4 (c0.01,MeOH) 1 H-NMR(400MHz,DMSO-D6) δ:8.62(3H,brs),8.04(1H,dd,J=2.4,1.2Hz),7.30(1H,dd,J=9.8,2.4Hz),5.04-4.96(1 H,m),3.51-3.43(1H,m),3.35-3.22(2H,m),2.64(3H,t,J=5.5Hz),1.48(3H,d,J=6.1Hz).

[0242] Examples 50-51 According to the method described in Example 46, the compounds of Examples 50-51 were obtained from the compounds of the corresponding Examples.

[0243] Examples 52 to 61 According to the method described in Example 27, the compounds of Examples 52 to 61 were obtained from the corresponding compounds of Reference Examples.

[0244] Example 62 rac-1-[(2R,3R,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methanamine dihydrochloride To a methanol solution (1.2 mL) of the compound of Reference Example 88-1 (120 mg, 0.368 mmol), 10% palladium-carbon (60 mg) was added. After stirring at room temperature under a hydrogen atmosphere for 4 hours, the mixture was filtered through Celite and concentrated. 4 mol / L hydrochloric acid-ethyl acetate (0.5 mL) was added to the concentrated residue, and the mixture was triturated with diethyl ether to obtain the hydrochloride salt of the title compound as a mixture with impurities. To a suspension of the mixture in tetrahydrofuran (3.68 mL), triethylamine (0.154 mL) and di-tert-butyl dicarbonate (96 mg) were added. After stirring at room temperature for 2 hours, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a purified product (38.7 mg). To a solution of this purified product (38.7 mg) in ethyl acetate (0.4 mL), 4 mol / L hydrochloric acid-ethyl acetate (0.331 mL) was added. After stirring at room temperature for 2 hours, the precipitated solid was collected by filtration and dried under reduced pressure to obtain the hydrochloride salt of the title compound (24.2 mg) as a white solid. 1 H-NMR(400MHz,CD3OD) δ:8.31-8.26(1H,m),7.75-7.60(2H,m),4.57-4.54(1H,m),3.80-3.76(2H ,m),3.36-3.33(1H,m),2.33(1H,s),1.48-1.47(3H,m),0.92-0.89(3H,m).

[0245] Examples 63 to 66 According to the method described in Example 62, the compounds of Examples 63 to 66 were obtained from the corresponding compounds of Reference Examples.

[0246] Examples 67 to 79 According to the method described in Example 8, the compounds of Examples 67 to 79 were obtained from the corresponding compounds of Reference Examples.

[0247] Examples 80 to 87 According to the method described in Example 49, the compounds of Examples 80 to 87 were obtained from the corresponding compounds of Reference Examples.

[0248] Example 88 rac-1-(2-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)methanamine dihydrochloride Hydrazine monohydrate (0.007 mL, 0.140 mmol) was added to a methanol solution (0.28 mL) of the compound of Reference Example 91 (9 mg, 0.028 mmol) at room temperature. After stirring at 50°C for 2 hours, the reaction mixture was concentrated. 1 mol / L hydrochloric acid was added to the concentrated residue, and the precipitated solid was removed by filtration. After washing with water, the filtrate was concentrated. The concentrated residue was washed with diethyl ether and dried under reduced pressure to obtain the title compound (7 mg). 1 H-NMR(400MHz,CD3OD)δ:7.82(1H,d,J=8.5Hz),7.03(1H,d,J=8.5Hz),4.04(3H,s),3.35- 3.24(3H,m),2.81-2.79(2H,m),2.05-2.02(1H,m),1.95-1.91(1H,m),1.84-1.83(2H,m).

[0249] Example 89 rac-1-[4-(4-methylphenyl)-5,6,7,8-tetrahydroquinolin-8-yl]methanamine dihydrochloride The title compound was obtained from the compound of Reference Example 101 by the same method as in Example 88. 1 H-NMR(400MHz,CD3OD)δ:8.62(1H,d,J=5.5Hz),7.67(1H,d,J=6.1Hz),7.39-7.33(4H,m),3.67-3.64(1H,m), 3.53-3.48(1H,m),3.37-3.34(1H,m),2.86-2.84(2H,m),2.43(3H,s),2.19-2.11(1H,m),2.01-1.82(3H,m).

[0250] Example 90 rac-1-(5'-methyl-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl)methanamine dihydrochloride To a mixture of the compound of Reference Example 95 (300 mg, 0.870 mmol), cesium carbonate (850 mg, 2.61 mmol), trimethylboroxine (0.365 mL), toluene (2.9 mL), and water (1.45 mL), (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (73.6 mg, 0.087 mmol) was added. After stirring at 90°C for 5 hours, saturated aqueous ammonium chloride solution (30 mL) was added. The mixture was extracted with ethyl acetate (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a purified product (128 mg). To this purified product (128 mg), 5.1 mol / L hydrobromic acid-acetic acid (0.387 mL) was added under ice-cooling. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The concentrated residue was separated and purified by amino silica gel column chromatography (chloroform / methanol). To a 2-propanol solution (1.0 mL) of the obtained purified product, 4 mol / L hydrochloric acid-ethyl acetate (3.0 mL) was added, and the precipitated solid was collected by filtration to obtain the title compound (44.4 mg). 1 H-NMR(400MHz,CD3OD)δ:7.03-7.02(2H,m),3.39-3.27(1H,m),3.04-3.00(1 H,m),2.88-2.85(1H,m),2.47(3H,s),1.13-1.08(3H,m),0.91-0.89(1H,m).

[0251] Example 91 rac-1-[4-(cyclobutyloxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]methanamine dihydrochloride To a toluene solution (1.89 mL) of the compound of Reference Example 100 (50.0 mg, 0.189 mmol) and cyclobutanol (0.045 mL, 0.567 mmol), cyanomethylenetributylphosphorane (0.149 mL, 0.567 mmol) was added. After stirring at 100°C for 3 hours, water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 2). The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate). 4 mol / L hydrobromic acid-acetic acid (0.500 mL) was added to the obtained purified product. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The concentrated residue was separated and purified by reverse-phase silica gel column chromatography (water / acetonitrile). 4 mol / L hydrochloric acid-ethyl acetate (1.0 mL) was added to a 2-propanol solution (1.0 mL) of the obtained purified product, and the mixture was concentrated to give the title compound (8.2 mg). 1 H-NMR(400MHz,CD3OD)δ:8.51(1H,d,J=6.7Hz),7.29(1H,d,J=6.7Hz),5.14-5.07(1H,m),3.94-3.90(1H,m),3.59-3.56( 1H,m),3.24-3.21(1H,m),3.16-2.98(2H,m),2.64-2.55(3H,m),2.27-2.21(3H,m),1.99-1.94(1H,m),1.86-1.78(1H,m).

[0252] Example 92 rac-1-(4-methyl-5,6,7,8-tetrahydroquinolin-8-yl)methanamine To a tetrahydrofuran solution (1.2 mL) of the compound of Reference Example 104 (40.2 mg, 0.233 mmol), a tetrahydrofuran solution of 0.91 mol / L borane-tetrahydrofuran complex (0.769 mL, 0.700 mmol) was added under ice-cooling. After stirring at room temperature for 2 hours, methanol (1.0 mL) was added to the reaction mixture, followed by concentrated hydrochloric acid (1.0 mL). After stirring at 50°C for 1 hour, a 1 mol / L aqueous sodium hydroxide solution was added to the reaction mixture, which was then extracted with chloroform / methanol = 4 / 1 (30 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by aminosilica gel column chromatography (chloroform / methanol) to give the title compound (33.5 mg). 1 H-NMR(400MHz,CDCl3)δ:8.26(1H,d,J=4.9Hz),6.90(1H,d,J=4.9Hz),3.13(1H,dd,J=12.8,5.5Hz),3 .01(1H,dd,J=12.8,6.7Hz),2.90-2.84(1H,m),2.63(2H,t,J=6.1Hz),2.20(3H,s),1.98-1.74(4H,m).

[0253] Example 93-1, Example 93-2 Example 93-1 rac-1-[(5R,7S)-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]methanamine Example 93-2 rac-1-[(5R,7R)-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]methanamine The title compound was obtained from the compound of Reference Example 108 by a method similar to that of Example 92 as a 1:1 diastereomeric mixture of Example 93-1 and Example 93-2. 1 H-NMR(400MHz,CDCl3)δ:8.37-8.36(1H,m),7.47-7.44(1H,m),7.10-7.06(1H,m),3.31-1.85(6H,m),1.40-1.26(3H,m).

[0254] Example 94 rel-1-[(2S,3R)-2-methyl(2- ２ H) -2,3-Dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride Di-tert-butyl dicarbonate (113 mg, 0.517 mmol) was added to a tetrahydrofuran solution (2.4 mL) of the compound of Example 57 (112 mg, 0.470 mmol) and triethylamine (0.328 mL, 2.35 mmol). After stirring at room temperature for 15 hours, water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 2). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a purified product (120 mg). The obtained purified product was optically resolved by chiral HPLC to obtain the compound of the first peak (48.7 mg). The title compound (42.9 mg) was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane(90%) including diethylamine (0.1%) - IPA (10%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 6.80 min (first peak) 1 H-NMR(400MHz,DMSO-D6) δ:8.23(3H,s),8.07-8.06(1H,m),7.27-7.22(2H,m),3.47-3.45(1H,m),3.28-3.12(2H,m),1.47(3H,s).

[0255] Example 95 rel-1-[(2R,3S)-2-methyl(2- ２ H) -2,3-Dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride The Boc compound was obtained from the compound of Example 57 by the same method as in Example 94, and then optically resolved by chiral HPLC to obtain the compound of the second peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (90%) including diethylamine (0.1%) - IPA (10%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 8.43 min (second peak) 1 H-NMR(400MHz,DMSO-D6) δ:8.27(3H,s),8.08-8.07(1H,m),7.28-7.25(2H,m),3.49-3.47(1H,m),3.29-3.12(2H,m),1.46(3H,s).

[0256] Example 96 rel-1-[(3'R)-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine dihydrochloride The Boc compound was obtained from the compound of Example 58 by the same method as in Example 94, and then optically resolved by chiral HPLC to obtain the compound of the first peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (90%) - IPA (10%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 7.41 min (first peak) 1 H-NMR(400MHz,CD3OD) δ:8.34-8.34(1H,m),7.67-7.65(2H,m),4.06-4.04(1H,m),3.48-3.45(1H,m),3.37-3.33(1H,m),1.37-1.21(3H,m),0.95-0.93(1H,m).

[0257] Example 97 rel-1-[(3'S)-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine dihydrochloride The Boc compound was obtained from the compound of Example 58 by the same method as in Example 94, and then optically resolved by chiral HPLC to obtain the compound of the second peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (90%) - IPA (10%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 8.21 min (second peak) 1 H-NMR(400MHz,CD3OD) δ:8.34-8.34(1H,m),7.67-7.64(2H,m),4.05-4.04(1H,m),3.49-3.45(1H,m),3.38-3.33(1H,m),1.37-1.22(3H,m),0.95-0.93(1H,m).

[0258] Example 98 rel-1-[(3'R)-6'-chloro-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine dihydrochloride The compound of Reference Example 89 was optically resolved by chiral HPLC to obtain the compound of the first peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: AY-H Solvent: Hexane (90%) - IPA (10%) Flow rate: 1.0 mL / min Retention time = 5.04 min (first peak) 1 H-NMR(400MHz,CD3OD) δ:8.12-8.12(1H,m),7.29-7.29(1H,m),3.70-3.69(1H,m),3.30-3.29(1H,m) ,3.20-3.18(1H,m),1.26-1.24(1H,m),1.20-1.08(2H,m),0.87-0.86(1H,m).

[0259] Example 99 rel-1-[(3'S)-6'-chloro-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine dihydrochloride The compound of Reference Example 89 was optically resolved by chiral HPLC to obtain the compound of the second peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: AY-H Solvent: Hexane (90%) - IPA (10%) Flow rate: 1.0 mL / min Retention time = 7.34 min (second peak) 1 H-NMR(400MHz,CD3OD) δ:8.13(1H,d,J=1.8Hz),7.30(1H,d,J=1.8Hz),3.72-3.70(1H,m),3.34-3.27(1H ,m),3.21-3.18(1H,m),1.29-1.24(1H,m),1.17-1.13(2H,m),0.90-0.86(1H,m).

[0260] Example 100 rel-1-[(3'R)-5'-methyl-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine dihydrochloride The Boc compound was obtained from the compound of Example 90 by the same method as in Example 94, and then optically resolved by chiral HPLC to obtain the compound of the first peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: AY-H Solvent: Hexane (95%) - IPA (5%) Flow rate: 1.0 mL / min Retention time = 5.09 min (first peak) 1 H-NMR(400MHz,CD3OD) δ:7.60(1H,d,J=8.5Hz),7.51(1H,d,J=8.5Hz),3.98-3.97(1H,m),3.47-3.45(1H,m),3 .35-3.33(1H,m),2.67(3H,s),1.38-1.34(1H,m),1.27-1.24(2H,m),0.92-0.90(1H,m).

[0261] Example 101 rel-1-[(3'S)-5'-methyl-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine dihydrochloride The Boc compound was obtained from the compound of Example 90 by the same method as in Example 94, and then optically resolved by chiral HPLC to obtain the compound of the second peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: AY-H Solvent: Hexane (95%) - IPA (5%) Flow rate: 1.0 mL / min Retention time = 6.03 min (second peak) 1 H-NMR(400MHz,CD3OD) δ:7.49(1H,d,J=8.5Hz),7.42(1H,d,J=9.2Hz),3.91-3.88(1H,m),3.45-3.41(2H,m),2.64(3H,s),1.29-1.21(3H,m),0.92-0.89(1H,m).

[0262] Example 102 rel-1-[(3'R)-5'-fluoro-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine dihydrobromide The compound of Reference Example 96 was optically resolved by chiral HPLC to obtain the compound of the first peak. The title compound was then obtained by the same method as in Example 49. [Chiral HPLC conditions] Column: IG Solvent: Hexane (50%) - EtOH (50%) Flow rate: 1.0 mL / min Retention time = 5.36 min (first peak) 1 H-NMR(400MHz,DMSO-D6) δ:7.85(3H,s),7.46(1H,dd,J=8.8,6.4Hz),7.05(1H,dd,J=8.8,1.5Hz),3.64(1H,dd,J= 8.2,5.2Hz),3.17-3.15(1H,m),3.07-3.05(1H,m),1.19-1.05(3H,m),0.83-0.80(1H,m).

[0263] Example 103 rel-1-[(3'S)-5'-fluoro-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine dihydrobromide The compound of Reference Example 96 was optically resolved by chiral HPLC to obtain the compound of the second peak. The title compound was then obtained by the same method as in Example 49. [Chiral HPLC conditions] Column: IG Solvent: Hexane (50%) - EtOH (50%) Flow rate: 1.0 mL / min Retention time = 7.14 min (first peak) 1 H-NMR(400MHz,DMSO-D6) δ:7.86(3H,s),7.46(1H,dd,J=8.5,6.1Hz),7.04(1H,dd,J=8.5,1.8Hz),3.64(1H,dd,J= 7.9,5.5Hz),3.17-3.14(1H,m),3.07-3.04(1H,m),1.20-1.05(3H,m),0.83-0.81(1H,m).

[0264] Example 104 rel-1-[(3R)-2,2,5-trimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride The Boc compound was obtained from the compound of Example 83 by the same method as in Example 94, and then optically resolved by chiral HPLC to obtain the compound of the first peak. Then, the title compound was obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (95%) - IPA (5%) Flow rate: 1.0 mL / min Retention time = 5.575 min (first peak) 1 H-NMR(400MHz,DMSO-D6) δ:8.11(3H,brs),7.08-7.06(2H,m),3.44-3.42(1H,m),3.25-3.24(2H,m),2.41(3H,s),1.53(3H,s),1.32(3H,s).

[0265] Example 105 rel-1-[(3S)-2,2,5-trimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride The Boc compound was obtained from the compound of Example 83 by the same method as in Example 94, and then optically resolved by chiral HPLC to obtain the compound of the second peak. The title compound was then obtained by the same method as in Example 39. [Chiral HPLC conditions] Column: IC Solvent: Hexane (95%) - IPA (5%) Flow rate: 1.0 mL / min Retention time = 6.539 min (second peak) 1 H-NMR(400MHz,DMSO-D6) δ:8.03(3H,brs),7.08-7.04(2H,m),3.42-3.40(1H,m),3.24-3.20(2H,m),2.40(3H,s),1.52(3H,s),1.32(3H,s).

[0266] Example 106 rac-1-(5-fluoro-2,2-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl)methanamine dihydrobromide The title compound was obtained from the compound of Reference Example 118 by a method similar to that in Example 49. 1 H-NMR(400MHz,DMSO-D6) δ:7.95(3H,brs),7.39-7.37(1H,m),6.99-6.97(1H,m),3.45-3.43(1H,m),3.21-3.18(2H,m),1.52(3H,s),1.36(3H,s).

[0267] Reference Example 1-1, Reference Example 1-2 Reference Example 1-1 rac-ethyl [(3R,4R)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]acetate Reference Example 1-2 rac-ethyl [(3S,4R)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]acetate To a toluene solution (26.0 mL) of the compound of Reference Example 2 (1.64 g, 5.22 mmol), tributyltin hydride (2.58 mL, 8.87 mmol) and azobisisobutyronitrile (0.086 g, 0.522 mmol) were added at room temperature. After stirring at 90°C for 1 hour, the reaction mixture was concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compounds Reference Example 1-1 (0.461 g) and Reference Example 1-2 (0.624 g). Reference Example 1-1 1 H-NMR(400MHz, CDCl3) δ:8.09(1H,dd,J=3.7,2.4Hz),7.04-7.02(2H,m),4.24-4.15(3H,m),4.03(1H,dd,J=10.7,4.6Hz),3.65(1H,dt,J=10.2,4.3Hz ),3.13(1H,dd,J=15.8,6.1Hz),2.41(1H,dd,J=15.8,8.8Hz),2.39-2.32(1H,m),1.27(3H,t,J=7.3Hz),0.97(3H,d,J=7.3Hz). Reference example 1-2 1 H-NMR(400MHz, CDCl3) δ:8.12(1H,dd,J=4.6,1.5Hz),7.07(1H,dd,J=8.2,1.5Hz),7.02(1H,dd,J= 8.2,4.6Hz),4.19-4.08(3H,m),3.85(1H,dd,J=11.0,6.7Hz),3.10(1H,dt, J=8.5,5.5Hz),2.93(1H,dd,J=16.1,5.2Hz),2.67(1H,dd,J=16.1,8.2Hz), 2.11(1H,dq,J=13.4,3.3Hz),1.23(3H,t,J=7.0Hz),1.08(3H,d,J=6.7Hz).

[0268] Reference Example 2 rac-ethyl (2E)-5-[(2-bromopyridin-3-yl)oxy]-4-methylpent-2-enoate To a mixture of the compound of Reference Example 3 (1.72 g, 7.05 mmol) and toluene (23.5 mL), ethyl (triphenylphosphoranylidene)acetate (2.58 g, 7.40 mmol) was added at room temperature. After stirring at 90°C for 2 hours, the reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.64 g). 1 H-NMR(400MHz, CDCl3) δ:7.98(1H,dd,J=4.6,1.2Hz),7.18(1H,dd,J=8.2,4.6Hz),7.08(1H,dd,J=8.2,1.2Hz),6.99(1H,dd,J=15.8,7.3Hz),5.95(1H,dd,J=15.8,1.2Hz ),4.19(2H,q,J=7.1Hz),3.97(1H,dd,J=8.8,6.4Hz),3.91(1H,dd,J=8.8,6.4Hz),2.97-2.86(1H,m),1.28(3H,t,J=7.1Hz),1.26(3H,d,J=7.3Hz).

[0269] Reference Example 3 rac-3-[(2-bromopyridin-3-yl)oxy]-2-methylpropanal To a mixture of the compound of Reference Example 4 (3.65 g, 14.8 mmol) and chloroform (49.4 mL), Dess-Martin periodinane (3.59 g, 8.45 mmol) was added at room temperature. After stirring at room temperature for 1 hour, saturated aqueous sodium bicarbonate solution (30 mL) and saturated aqueous sodium thiosulfate solution (30 mL) were added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.72 g). 1 H-NMR(400MHz, CDCl3) δ:9.83(1H,t,J=2.4Hz),8.00(1H,dd,J=4.9,1.8Hz),7.21(1H,dd,J=7.9,4.9Hz),7.16(1H,dd,J=7.9,1.8Hz) ,4.25(1H,dd,J=9.1,5.5Hz),4.16(1H,dd,J=9.1,5.5Hz),2.94(1H,dq,J=7.3,5.5Hz),1.35(3H,d,J=7.3Hz).

[0270] Reference Example 4 rac-3-[(2-bromopyridin-3-yl)oxy]-2-methylpropan-1-ol To a mixture of 2-methyl-1,3-propanediol (1.13 g, 12.6 mmol), 2-bromo-3-hydroxypyridine (2.19 g, 12.6 mmol), triphenylphosphine (3.30 g, 12.6 mmol), and N,N-dimethylformamide (9.75 mL) was added diisopropyl azodicarboxylate (2.45 mL, 12.6 mmol) under ice-cooling. After stirring at room temperature for 5 hours, methanol was added and the mixture was concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.65 g). 1 H-NMR(400MHz, CDCl3) δ:7.96(1H,dd,J=4.6,1.5Hz),7.19(1H,dd,J=7.9,4.6Hz),7.13(1H,dd,J=7.9,1.5Hz),4.05(1H,dd,J=8.8,5.2 Hz),3.98(1H,dd,J=8.8,6.7Hz),3.78-3.69(2H,m),2.32-2.21(1H,m),1.30-1.20(1H,m),1.07(3H,d,J=6.7Hz).

[0271] Reference Example 5 rac-tert-butyl {[(3S,4S)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate Triethylamine (0.049 mL) and di-tert-butyl dicarbonate (0.041 mL) were added to a chloroform solution (1.0 mL) of the compound of Example 2 (22.0 mg). After stirring at room temperature for 2 hours, the mixture was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (20.4 mg). 1H-NMR(400MHz, CDCl3) δ:8.17(1H,dd,J=4.6,1.5Hz),7.30-7.15(2H,m),5.71(1H,brs),4.30-4.20(1H,m),3.96-3.86(1H,m),3.8 2-3.73(1H,m),3.49-3.40(1H,m),2.90-2.79(1H,m),2.15-2.08(1H,m),1.42(9H,s),1.12(3H,d,J=6.7Hz).

[0272] Reference Example 6-1, Reference Example 6-2 Reference Example 6-1 tert-butyl {[(2R,4S)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate Reference Example 6-2 tert-butyl {[(2R,4R)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate To a mixture of the compound of Reference Example 7 (5.37 g, 24.3 mmol), methanol (53.9 mL), and water (27.0 mL) was added sodium hydroxide (1.94 g, 48.5 mmol) at room temperature. After stirring at 60°C for 2 hours, 3 mol / L hydrochloric acid was added to the reaction mixture until the aqueous layer reached pH 5. The reaction solution was concentrated, and then the concentrated residue was dissolved in methanol, and insoluble matter was filtered off and concentrated.

[0273] To a toluene solution (400 mL) of the obtained residue (5.79 g), triethylamine (11.7 mL, 84.0 mmol) and diphenylphosphoryl azide (12.0 mL, 55.9 mmol) were added at room temperature. After stirring at room temperature for 30 minutes, the reaction mixture was stirred at 90°C for 1 hour. To the reaction mixture, 5 mol / L aqueous sodium hydroxide solution (84.0 mL) was added dropwise under ice cooling. The reaction mixture was warmed to room temperature over 2 hours, then 6 mol / L hydrochloric acid was added to adjust the pH to 7 and concentrated. The concentrated residue was dissolved in methanol, and insoluble matter was filtered and concentrated. To a mixture of the concentrated residue and chloroform (100 mL), triethylamine (11.7 mL, 84.0 mmol) and di-tert-butyl dicarbonate (18.3 g, 84.0 mmol) were added. After stirring at room temperature for 1 hour, water (100 mL) was added to the reaction mixture, which was then extracted with chloroform (100 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compounds Reference Example 6-1 (1.32 g) and Reference Example 6-2 (3.34 g). Reference Example 6-1 1 H-NMR(400MHz, CDCl3) δ:8.06(1H,dd,J=4.3,1.2Hz),7.04(1H,dd,J=8.3,1.2Hz),6.98(1H,dd,J=8.3,4.3Hz),5.35(1H,brs),4.27-4.20(1H,m),3.56-3.50(1H,m),3 .36-3.30(1H,m),2.94-2.88(1H,m),1.94(1H,ddd,J=14.8,6.0,2.4Hz) ,1.79(1H,ddd,J=14.8,7.2,6.4Hz),1.38(9H,s),1.32(3H,d,J=6.1Hz). Reference example 6-2 1 H-NMR(400MHz, CDCl3) δ:8.11(1H,dd,J=3.7,2.4Hz),7.07-7.06(2H,m),5.95(1H,brs),4.23(1H,ddd,J=11.6,6.7,1.6Hz),3.79-3.73(1H,m),3.3 7-3.31(1H,m),3.16-3.08(1H,m),2.10(1H,ddd,J=13.4,5.5,1.8Hz),1.69-1.60(1H,m),1.45(9H,s),1.41(3H,d,J=6.7Hz).

[0274] Reference Example 7 Methyl [(2R)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]acetate To a toluene solution (132 mL) of the compound of Reference Example 8 (7.90 g, 26.3 mmol), tributyltin hydride (11.7 mL, 44.7 mmol) and azobisisobutyronitrile (0.432 g, 2.63 mmol) were added at room temperature. After stirring at 90°C for 1 hour, the reaction mixture was concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (5.37 g) as a 3:1 diastereomeric mixture. Main diastereomer 1 H-NMR(400MHz, CDCl3) δ:8.09(1H,dd,J=4.3,1.8Hz),7.09-7.03(2H,m),4.27-4.18(1H,m),3.70(3H,s),3.53-3.45(1H,m),3.36(1H,dd ,J=16.2,4.6Hz),2.26(1H,ddd,J=13.4,6.1,1.8Hz),2.00-1.96(1H,m),1.64-1.53(1H,m),1.40(3H,d,J=6.1Hz).

[0275] Reference Example 8 Ethyl (2E,5R)-5-[(2-bromopyridin-3-yl)oxy]hex-2-enoate To a mixture of the compound of Reference Example 9 (8.91 g, 36.2 mmol) and chloroform (120 mL), Dess-Martin periodinane (21.5 g, 50.7 mmol) was added under ice-cooling. After stirring at room temperature for 1 hour, saturated aqueous sodium bicarbonate solution (75 mL) and saturated aqueous sodium thiosulfate solution (75 mL) were added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform (75 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. To a mixture of the concentrated residue and toluene (100 mL), ethyl (triphenylphosphoranylidene)acetate (12.7 g, 38.0 mmol) was added at room temperature. After stirring at 80°C for 2 hours, the reaction mixture was concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (7.90 g). 1H-NMR(400MHz, CDCl3) δ:7.98(1H,dd,J=4.6,1.8Hz),7.18(1H,dd,J=7.9,4.6Hz),7.11(1H,dd,J=7.9,1.8Hz),7.02-6.94(1H,m),5.95-5.91(1H,m) ,4.52-4.48(1H,m),4.17(2H,q,J=7.1Hz),2.71-2.64(1H,m),2.60-2.53(1H,m),1.37(3H,d,J=6.1Hz),1.27(3H,t,J=7.3Hz).

[0276] Reference Example 9 (3R)-3-[(2-bromopyridin-3-yl)oxy]butan-1-ol To a mixture of the compound of Reference Example 10 (13.5 g, 37.5 mmol) and methanol (135 mL), 6 mol / L hydrochloric acid (18.7 mL) was added under ice-cooling. After stirring at room temperature for 2 hours, saturated aqueous sodium bicarbonate solution (250 mL) was added to the reaction mixture under ice-cooling, and the mixture was extracted with chloroform (150 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (8.91 g). 1 H-NMR(400MHz, CDCl3) δ:7.90(1H,dd,J=4.0,2.1Hz),7.17-7.11(2H,m),4.60-4.58(1H,m),3.84-3.71(2H,m),2.01-1.83(2H,m),1.30(3H,d,J=6.1Hz).

[0277] Reference Example 10 2-bromo-3-{[(2R)-4-{[tert-butyl(dimethyl)silyl]oxy}butan-2-yl]oxy}pyridine To a mixture of (S)-4-((tert-butyldimethylsilyl)oxy)-2-butanol (8.22 g, 40.2 mmol), 2-bromo-3-hydroxypyridine (7.00 g, 40.2 mmol), triphenylphosphine (11.6 g, 44.3 mmol), and tetrahydrofuran (134 mL), diisopropyl azodicarboxylate (8.60 mL, 44.3 mmol) was added under ice-cooling. After stirring at room temperature for 15 hours, methanol was added to the reaction mixture and the mixture was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (13.5 g). 1 H-NMR(400MHz, CDCl3) δ:7.93(1H,dd,J=4.6,1.8Hz),7.21(1H,dd,J=8.2,1.8Hz),7.15(1H,dd,J=8.2,4.6Hz),4.65-4.57(1H,m),3.83- 3.69(2H,m),2.05-1.95(1H,m),1.85-1.77(1H,m),1.37(3H,d,J=6.1Hz),0.84(9H,s),0.00(3H,s),-0.04(3H,s).

[0278] Reference Example 11 tert-Butyl {[(2S,4S)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate The title compound was obtained from (R)-4-((tert-butyldimethylsilyl)oxy)-2-butanol by the same method as in Reference Examples 6-2 to 10. 1 H-NMR(400MHz, CDCl3) δ:8.13-8.09(1H,m),7.10-7.04(2H,m),5.92(1H,brs),4.26-4.16(1H,m),3.80-3.71(1H,m),3.40-3. 30(1H,m),3.16-3.07(1H,m),2.13-2.06(1H,m),1.70-1.57(1H,m),1.43(9H,s),1.40(3H,d,J=6.1Hz).

[0279] Reference Example 12 rac-tert-butyl {[(2R,4S)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate The title compound was obtained from 4-((tert-butyldimethylsilyl)oxy)-2-butanol by the same method as in Reference Examples 6-1 to 10. 1 H-NMR(400MHz, CDCl3) δ:8.12(1H,dd,J=4.6,1.5Hz),7.22-7.09(2H,m),5.54(1H,brs),4.39-4.28(1H,m),3.64-3.54(1H,m),3.4 6-3.36(1H,m),3.14-3.03(1H,m),2.04-1.97(1H,m),1.88-1.79(1H,m),1.42(9H,s),1.40(3H,d,J=6.1Hz).

[0280] Reference Example 13 tert-Butyl {[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate To a toluene solution (13 mL) of the compound of Reference Example 14 (282 mg, 1.33 mmol), triethylamine (0.56 mL, 4.00 mmol) and diphenylphosphoryl azide (0.57 mL, 2.67 mmol) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After stirring at 90°C for 1 hour, 5 mol / L aqueous sodium hydroxide solution (4.0 mL, 20.0 mmol) was added to the reaction mixture under ice cooling. After stirring at room temperature for 2 hours, the mixture was neutralized with 12 mol / L hydrochloric acid (1.7 mL), and 2-propanol (10 mL) was added and the mixture was concentrated. The concentrated residue was dissolved in methanol, and insoluble matter was filtered off and concentrated. To a mixture of the concentrated residue and chloroform (5.0 mL), triethylamine (0.56 mL, 4.0 mmol) and di-tert-butyl dicarbonate (873 mg, 4.0 mmol) were added. After stirring at room temperature for 4 hours, the reaction mixture was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (98 mg). 1 H-NMR(400MHz, CDCl3) δ:7.91(1H,s),6.80-6.75(1H,m),5.33-5.23(1H,m),4.79-4.72(1H,m),3. 69-3.59(1H,m),3.405-3.35(1H,m),3.19-3.12(1H,m),1.54(3H,d,J=6.7).

[0281] Reference Example 14 [(2R,3S)-6-Fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]acetic acid To a mixture of the compound of Reference Example 40 (375 mg, 2.6 mmol), 2-bromo-5-fluoropyridin-3-ol (500 mg, 2.60 mmol), triphenylphosphine (751 mg, 2.86 mmol), and tetrahydrofuran (8.7 mL), bis(2-methoxyethyl) azodicarboxylate (671 mg, 2.86 mmol) was added under ice-cooling. After stirring at room temperature for 2 hours, methanol was added to the reaction mixture and the mixture was concentrated. To the concentrated residue, toluene (500 mL) was added, washed with water (200 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated. To a toluene solution (9.0 mL) of the concentrated residue, tributyltin hydride (1.16 mL, 4.42 mmol) and azobisisobutyronitrile (42.7 mg, 0.26 mmol) were added at room temperature. After stirring at 90°C for 1 hour, the reaction mixture was concentrated. To a mixture of the concentrated residue and tetrahydrofuran (10 mL), 4 mol / L aqueous sodium hydroxide solution (2.08 mL, 10.4 mmol) was added at room temperature. After stirring at 60°C for 4 hours, water (10 mL) was added to the reaction mixture, and the aqueous layer was washed with diethyl ether (10 mL x 2). Then, 4 mol / L hydrochloric acid (10.4 mL) was added until the aqueous layer reached pH 5, and extraction was performed with chloroform (200 mL x 5). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to give the title compound (281 mg). 1 H-NMR(400MHz, CDCl3) δ:7.91(1H,s),6.88-6.84(1H,m),4.75-4.67(1H,m),3.50-3.42(1H,m),2.94 (1H,dd,J=16.0,8.0Hz),2.68(1H,dd,J=16.0,6.4Hz),1.37(3H,d,J=6.7Hz).

[0282] Reference Example 15 rac-tert-butyl [(3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-4-yl)methyl]carbamate To a mixture of the compound of Reference Example 16 (980 mg, 4.39 mmol), methanol (9.8 mL), and water (4.9 mL), sodium hydroxide (351 mg, 8.78 mmol) was added at room temperature. After stirring at 60°C for 2 hours, 3 mol / L hydrochloric acid was added under ice cooling until the aqueous layer reached pH 5. The reaction mixture was concentrated, and the concentrated residue was dissolved in methanol, and insoluble matter was filtered off and concentrated.

[0283] To a toluene solution (35.0 mL) of the obtained compound (1.10 g), triethylamine (2.20 mL, 15.8 mmol) and diphenylphosphoryl azide (2.26 mL, 10.5 mmol) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After stirring at 90°C for 1 hour, 5 mol / L aqueous sodium hydroxide solution (17.9 mL) was added dropwise to the reaction mixture under ice cooling. The reaction mixture was warmed to room temperature over 2 hours, neutralized by adding 6 mol / L hydrochloric acid, and concentrated. The concentrated residue was dissolved in methanol, and insoluble matter was filtered and concentrated. To a mixture of the concentrated residue and chloroform (30 mL), triethylamine (2.20 mL, 15.8 mmol) and di-tert-butyl dicarbonate (3.66 g, 15.8 mmol) were added. After stirring at room temperature for 1 hour, water (50 mL) was added to the reaction mixture, which was then extracted with chloroform (50 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (560 mg). 1 H-NMR(400MHz, CDCl3) δ:8.17(1H,dd,J=4.9,1.8Hz),7.34(1H,dd,J=7.9,1.8Hz),6.94(1H,dd,J=7.9,4.9Hz),5.46(1H,brs),3. 65-3.61(1H,m),3.37-3.34(1H,m),3.06-2.88(3H,m),2.24-2.19(1H,m),2.04-2.00(1H,m),1.37(9H,s).

[0284] Reference Example 16 rac-methyl (3,4-dihydro-2H-thiopyrano[3,2-b]pyridin-4-yl)acetate To a mixture of the compound of Reference Example 17 (1.66 g, 6.69 mmol) and chloroform (22.3 mL), Dess-Martin periodinane (2.98 g, 7.02 mmol) was added under ice-cooling. After stirring for 1 hour under ice-cooling, methyl (triphenylphosphoranylidene)acetate (2.46 g, 7.36 mmol) was added to the reaction mixture. After stirring for 1 hour at room temperature, saturated aqueous sodium bicarbonate solution (15 mL) and saturated aqueous sodium thiosulfate solution (15 mL) were added to the reaction mixture under ice-cooling, followed by extraction with chloroform (20 mL x 2), drying over anhydrous magnesium sulfate, filtration, and concentration. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated.

[0285] To a toluene solution (26.8 mL) of the obtained compound (1.62 g, 5.36 mmol), tributyltin hydride (2.39 mL, 9.11 mmol) and azobisisobutyronitrile (0.088 g, 0.536 mmol) were added at room temperature. After stirring at 90°C for 1 hour, the reaction mixture was concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.980 g). 1 H-NMR(400MHz, CDCl3) δ:8.21(1H,dd,J=4.6,1.5Hz),7.43-7.37(1H,m),7.02-6.96(1H,m),3.69(3H,s),3.09(1H,dd ,J=15.8,5.5Hz),3.06-3.01(3H,m),2.60-2.57(1H,m),2.32-2.30(1H,m),2.15-2.12(1H,m).

[0286] Reference Example 17 3-[(2-bromopyridin-3-yl)sulfanyl]propan-1-ol Potassium carbonate (8.00 g) was added to a mixture of 2-bromo-3-fluoropyridine (3.00 g, 17.1 mmol), 3-mercapto-1-propanol (1.43 g, 15.5 mmol), and N,N-dimethylformamide (15.5 mL). After stirring at room temperature for 24 hours, the mixture was filtered through Celite and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.66 g). 1H-NMR(400MHz, CDCl3) δ:8.13(1H,dd,J=4.6,1.5Hz),7.51(1H,dd,J=7.9,4.6Hz),7.22(1H,dd,J=7 .9,1.5Hz),3.81(2H,t,J=6.1Hz),3.06(2H,t,J=7.3Hz),1.98-1.92(2H,m).

[0287] Reference Examples 18 to 22 According to the methods described in Reference Examples 15 to 17, the compounds of Reference Examples 18 to 22 were obtained from the corresponding compounds.

[0288] Reference Example 25-1, Reference Example 25-2 Reference Example 25-1 tert-butyl {[(2R,4R)-2,6-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate Reference Example 25-2 tert-butyl {[(2R,4S)-2,6-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate The title compounds Reference Examples 25-1 and 25-2 were obtained from Reference Examples 6-1 and 6-2 and 2-bromo-3-hydroxy-6-methylpyridine in the same manner as in Reference Example 10. Reference Example 25-1 LC-MS: RT=0.745 min ObsMS=293.0 [M+1] Reference Example 25-2 LC-MS: RT=0.650 min ObsMS=294.3 [M+2]

[0289] Reference Example 26-1, Reference Example 26-2 Reference Example 26-1 tert-butyl {[(2S,3R)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate Reference Example 26-2 tert-butyl {[(2S,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate The title compounds, Reference Examples 26-1 and 26-2, were obtained from the compound of Reference Example 27 by the same procedures as in Reference Examples 6-1, 6-2, and 7. 1H-NMR(400MHz, CDCl3) δ:8.06-8.04(1H,m),7.11-7.08(2H,m),5.48-5.46(1H,m),4.75-4.72(1H,m ),3.72-3.48(2H,m),3.26-3.23(1H,m),1.55(3H,d,J=6.1Hz),1.44(9H,s). Reference example 26-2 LC-MS: RT=1.42 min ObsMS=265 [M+1]

[0290] Reference Example 27 Methyl (2E,4S)-4-[(2-bromopyridin-3-yl)oxy]pent-2-enoate To a mixture of the compound of Reference Example 28 (1.56 g, 6.00 mmol) and dichloromethane (12.0 mL), a 1.03 mol / L solution of diisobutylaluminum hydride in toluene (17.47 mL, 17.99 mmol) was added at −78° C. After stirring at −78° C. for 2 hours, saturated aqueous ammonium chloride (50 mL) was added, and insoluble matter was removed by filtration through Celite. After extraction with ethyl acetate, the mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated. To a mixture of the concentrated residue and toluene, ethyl (triphenylphosphoranylidene)acetate (2.005 g, 6.00 mmol) was added at room temperature. After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.54 g). 1 H-NMR(400MHz, CDCl3) δ:7.97-7.96(1H,m),7.17-7.14(2H,m),6.29-6.26(1H,m),6.07-6.06(1H,m),5.90(1H,d,J=11.6Hz),3.78(3H,s),1.57(5H,d,J=6.1Hz).

[0291] Reference Example 28 Methyl (2S)-2-[(2-bromopyridin-3-yl)oxy]propanoate Diisopropyl azodicarboxylate (1.83 mL, 12.6 mmol) was added to a mixture of (R)-(+)-methyl lactate (1.20 g, 11.5 mmol), 2-bromo-3-hydroxypyridine (2.00 g, 11.5 mmol), triphenylphosphine (3.32 g, 12.6 mmol), and tetrahydrofuran (38 mL) under ice-cooling. After stirring at room temperature for 15 hours, methanol was added to the reaction mixture and the mixture was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (13.5 g). 1 H-NMR(400MHz,CDCl3) δ:8.05-8.03(1H,m),7.18-7.17(1H,m),7.09-7.08(1H,m),4.78-4.76(1H,m),3.77(3H,s),1.72(3H,d,J=7.3Hz).

[0292] Reference Example 29 rac-tert-butyl {[(2R,3S)-2-(propan-2-yl)-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate The title compound was obtained from the compound of Reference Example 30 by the same procedures as in Reference Examples 6-1, 6-2 and 7. 1 H-NMR (400MHz, CDCl3) δ:8.06-8.04(1H,m),7.11-7.08(2H,m),5.48-5.46(1H,m),4.75-4.72(1H,m ),3.72-3.48(2H,m),3.26-3.23(1H,m),1.55(3H,d,J=6.1Hz),1.44(9H,s).

[0293] Reference Example 30 rac-methyl (2E)-4-[(2-bromopyridin-3-yl)oxy]-5-methylhex-2-enoate To a mixture of the compound of Reference Example 31 (1.18 g, 4.54 mmol) and dimethyl sulfoxide (15.0 mL), triethylamine (1.90 mL, 13.6 mmol) and sulfur trioxide pyridine complex (2.17 g, 13.6 mmol) were added at room temperature. After stirring at room temperature for 3 hours, water (200 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. To a mixture of the concentrated residue and toluene (15 mL), ethyl (triphenylphosphoranylidene)acetate (1.72 g, 5.16 mmol) was added at room temperature. After stirring at room temperature for 12 hours, the reaction solution was concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (0.77 g). 1 H-NMR(400MHz, CDCl3) δ:7.92-7.91(1H,m),7.16-7.14(1H,m),7.11-7.09(1H,m),6.17-6.14(1H,m),6.00-5.97(1H,m) ,5.76-5.75(1H,m),3.77(3H,s),2.14-2.10(1H,m),1.10(3H,d,J=7.3Hz),1.05(3H,d,J=7.3Hz).

[0294] Reference Example 31 rac-2-[(2-bromopyridin-3-yl)oxy]-3-methylbutan-1-ol To a mixture of the compound of Reference Example 32 (1.34 g, 4.43 mmol) and tetrahydrofuran (15.0 mL), a 1.0 mol / L toluene solution of diisobutylaluminum hydride (4.88 mL, 4.88 mmol) was added at -78°C. After stirring at room temperature for 3 hours, a 1.0 mol / L toluene solution of diisobutylaluminum hydride (4.88 mL, 4.88 mmol) was added under ice-cooling. After stirring under ice-cooling for 2 hours, water (30 mL) and a 10% aqueous potassium hydrogen sulfate solution (30 mL) were added to the reaction mixture, which was then extracted with ethyl acetate (50 mL x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.19 g). 1H-NMR(400MHz, CDCl3) δ:7.97-7.96(1H,m),7.30-7.28(1H,m),7.18-7.16(1H,m),4.17-4.16(1H,m),3. 87-3.81(2H,m),2.14-2.06(1H,m),1.05(3H,d,J=7.3Hz),1.00(3H,d,J=6.7Hz).

[0295] Reference Example 32 rac-methyl 2-[(2-bromopyridin-3-yl)oxy]-3-methylbutanoate To a mixture of 2-bromo-3-hydroxypyridine (2.00 g, 11.5 mmol) and N,N-dimethylformamide (30 mL) were added potassium carbonate (1.91 g, 13.8 mmol) and ethyl 2-bromo-3-methylbutyrate (2.25 mL, 13.8 mmol). After stirring at 50°C for 4 hours, water (200 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (200 mL x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (1.36 g). 1 H-NMR(400MHz, CDCl3) δ:7.99-7.97(1H,m),7.15-7.13(1H,m),6.96-6.94(1H,m),4.39(1H,d,J=4.9H z),4.22-4.19(2H,m),2.39-2.37(1H,m),1.23-1.22(3H,m),1.13-1.11(6H,m).

[0296] Reference Examples 33 to 34 According to the methods described in Reference Examples 29 to 32, the compounds of Reference Examples 33 to 34 were obtained from the corresponding compounds.

[0297] Reference Example 35-1, Reference Example 35-2 Reference Example 35-1 rac-tert-butyl {[(2S,4R)-2-phenyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate Reference Example 35-2 rac-tert-butyl {[(2S,4S)-2-phenyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate The title compounds, Reference Example 35-1 and Reference Example 35-2, were obtained from 3-((tert-butyldimethylsilyl)oxy)-1-phenyl-1-propanol by the same procedures as in Reference Example 6-1, Reference Example 6-2, and Reference Example 10. 1 H-NMR(400MHz, CDCl3) δ:8.22-8.18(1H,m),7.46-7.31(5H,m),7.26-7.12(2H,m),6.01(1H,brs),5.14(1H,dd,J=11.6,1.8Hz),3 .87-3.76(1H,m),3.51-3.40(1H,m),3.40-3.31(1H,m),2.40-2.32(1H,m),2.07-1.96(1H,m),1.44(9H,s). Reference example 35-2 1 H-NMR(400MHz, CDCl3) δ:8.23-8.18(1H,m),7.53-7.30(7H,m),5.68-5.47(1H,m),5.44-5.30(1H,m),3.81-3.71(1H,m) ,3.69-3.51(1H,m),3.44-3.09(1H,m),2.34-2.25(1H,m),2.22-2.11(1H,m),1.45-1.41(9H,m).

[0298] Reference Example 36 rac-tert-butyl {[(2S,3S)-2-(hydroxymethyl)-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate To a dichloromethane suspension (2.0 mL) of the compound of Example 32 (42.0 mg, 0.157 mmol), triethylamine (0.044 mL, 0.314 mmol) and a 1.0 mol / L dichloromethane solution of boron tribromide (0.330 mL, 0.330 mmol) were added under ice cooling. After stirring at room temperature for 4 hours, methanol (2.0 mL) was added to the reaction mixture under ice cooling. After stirring for 10 minutes under ice cooling, the reaction mixture was concentrated. To a mixture of the concentrated residue, tetrahydrofuran (1.0 mL), and water (1.0 mL), potassium carbonate (217 mg, 1.57 mmol) and di-tert-butyl dicarbonate (51.5 mg, 0.236 mmol) were added. After stirring at room temperature for 3 hours, water (30 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (30 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (22.9 mg). 1 H-NMR(400MHz, CDCl3) δ:8.06(1H,dd,J=4.3,2.4Hz),7.19-7.13(2H,m),5.44(1H,brs),4.79(1H,m),3.98(1H,dd,J= 12.5,3.4Hz),3.86(1H,dd,J=12.2,4.9Hz),3.79-3.69(1H,m),3.67-3.53(2H,m),1.41(9H,s).

[0299] Reference Example 37 Benzyl {[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate To a toluene solution (208 mL) of the compound of Reference Example 38 (28.1 g, 145 mmol), triethylamine (30.4 mL, 218 mmol) and diphenylphosphoryl azide (37.5 mL, 175 mmol) were added at room temperature, and the mixture was stirred at room temperature for 30 minutes. After stirring at 90°C for 1 hour, benzyl alcohol (22.5 mL, 218 mmol) was added to the reaction mixture. After stirring at 90°C for 3 hours, saturated aqueous sodium bicarbonate solution (250 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate (150 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to obtain the title compound (23.6 g) as a 10:1 diastereomeric mixture. Main diastereomer 1 H-NMR(400MHz, CDCl3) δ:8.00(1H,dd,J=4.6,1.5Hz),7.40-7.29(5H,m),7.17-7.05(2H,m),5.84(1H,brs),5.09(2H,s), 4.76-4.68(1H,m),3.84-3.76(1H,m),3.54-3.46(1H,m),3.31-3.25(1H,m),1.52(3H,d,J=6.1Hz).

[0300] Reference Example 38 tert-Butyl {[(2S,4S)-2-phenyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate To a toluene solution (499 mL) of the compound of Reference Example 39 (45.0 g, 150 mmol), tributyltin hydride (66.8 mL, 255 mmol) and azobisisobutyronitrile (2.46 g, 15.0 mmol) were added at room temperature. After stirring at 90°C for 1 hour, the reaction mixture was concentrated. To a mixture of the concentrated residue, tetrahydrofuran (333 mL), and water (167 mL), sodium hydroxide (24.0 g, 599 mmol) was added at room temperature. After stirring at 60°C for 3 hours, water (333 mL) was added to the reaction mixture, and the aqueous layer was washed with diethyl ether (167 mL x 2). Thereafter, 5 mol / L hydrochloric acid (120 mL) was added until the aqueous layer reached pH 5, and extraction was performed with chloroform (200 mL x 5). The combined organic layers were dried over anhydrous magnesium sulfate, filtered and concentrated to give the title compound (28.1 g) as a 10:1 diastereomeric mixture. 1 H-NMR(400MHz, CDCl3) δ:8.02(1H,dd,J=4.9,1.2Hz),7.18-7.11(2H,m),4.61-4.53(1H,m),3.51(1H,dt,J=9.4, 4.9Hz),2.89(1H,dd,J=15.8,9.4Hz),2.71(1H,dd,J=15.8,4.9Hz),1.61(3H,d,J=6.7Hz).

[0301] Reference Example 39 Ethyl (2E,4R)-4-[(2-bromopyridin-3-yl)oxy]pent-2-enoate To a mixture of the compound of Reference Example 40 (26.0 g, 180 mmol), 2-bromo-3-hydroxypyridine (31.4 g, 180 mmol), triphenylphosphine (52.0 g, 198 mmol), and tetrahydrofuran (515 mL), bis(2-methoxyethyl) azodicarboxylate (46.5 g, 198 mmol) was added under ice-cooling. After stirring at room temperature for 2 hours, methanol was added to the reaction mixture and the mixture was concentrated. Toluene (500 mL) was added to the concentrated residue, washed with water (200 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated. Hexane / diethyl ether (4 / 1, 250 mL) was added to the concentrated residue, the precipitated solid was filtered off, and the filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (45.0 g). 1 H-NMR(400MHz, CDCl3) δ:7.99(1H,dd,J=4.9,1.8Hz),7.16(1H,dd,J=8.2,4.9Hz),7.06(1H,dd,J=8.2,1.8Hz),6.96(1H,dd,J=15.2,4.9Hz),6. 06(1H,dd,J=15.2,1.8Hz),4.96-4.92(1H,m),4.18(2H,dq,J=7.0,1.2Hz),1.55(3H,d,J=6.1Hz),1.27(3H,t,J=7.0Hz).

[0302] Reference Example 40 Ethyl (2E,4S)-4-hydroxypent-2-enoate To a mixture of the compound of Reference Example 41 (23.8 g, 167 mmol) and methanol (478 mL), sodium borohydride (7.59 g, 201 mmol) was added at -35°C. After warming to 0°C over 1 hour, saturated aqueous ammonium chloride solution (500 mL) was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate (500 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (17.0 g). 1H-NMR(400MHz, CDCl3) δ:6.78(1H,dd,J=15.8,4.9Hz),5.84(1H,dd,J=15.8,1.5Hz),4.35-4.26( 1H,m),4.02(2H,q,J=7.0Hz),1.16(3H,d,J=6.7Hz),1.11(3H,t,J=7.0Hz).

[0303] Reference Example 41 Ethyl (4S)-4-hydroxypent-2-ynoate To a mixture of (S)-(-)-3-butyn-2-ol (14.5 g, 207 mmol), bis(trimethylsilyl)amine (18.4 g, 114 mmol), and tetrahydrofuran (104 mL) was added concentrated sulfuric acid (0.110 mL) at room temperature. After stirring at 65°C for 3 hours, the reaction mixture was cooled to -78°C. At -78°C, 2.69 mol / L n-butyllithium (100 mL, 269 mmol) was added dropwise. After stirring at -78°C for 30 minutes, a tetrahydrofuran solution (59 mL) of ethyl chloroformate (26.6 mL, 279 mmol) was added dropwise. After stirring at -78°C for 1 hour, the reaction mixture was allowed to warm to room temperature over 1 hour. 6 mol / L sulfuric acid (108 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. Water (300 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (200 mL x 3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (23.4 g). 1 H-NMR (400MHz, CDCl3) δ:4.64(1H,q,J=6.7Hz),4.25(2H,q,J=7.0Hz),1.52(3H,d,J=6.7Hz),1.32(3H,t,J=7.0Hz).

[0304] Reference Examples 42 to 45 According to the methods described in Reference Examples 37 to 39, the compounds of Reference Examples 42 to 45 were obtained from the corresponding compounds.

[0305] Reference Example 46 rac-benzyl {[(2S,3S)-2-(methoxymethyl)-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate The title compound was obtained from Reference Example 47 by the same method as in Reference Example 37. 1 H-NMR(400MHz, CDCl3) δ:8.02(1H,dd,J=3.4,3.4Hz),7.36-7.26(5H,m),7.10-7.06(2H,m),5.75(1H,brs),5.09(2H ,s),4.78-4.70(1H,m),3.83-3.72(1H,m),3.69-3.62(2H,m),3.60-3.47(2H,m),3.40(3H,s).

[0306] Reference Example 47 rac-[(2S,3S)-2-(methoxymethyl)-2,3-dihydrofuro[3,2-b]pyridin-3-yl]acetic acid To a methanol solution (5.0 mL) of the compound of Reference Example 48 (324 mg, 1.37 mmol), water (5.0 mL) and sodium hydroxide (546 mg, 13.7 mmol) were added, and the mixture was stirred at room temperature for 30 minutes. Thereafter, 6 mol / L hydrochloric acid was added to the reaction mixture until the pH reached 4, and the mixture was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (258 mg). 1 H-NMR(400MHz, CDCl3) δ:8.05-7.98(1H,m),7.23-7.16(2H,m),4.69-4.64(1H,m),3.89-3.83(1H,m),3.79(1H,dd,J=11.0,3.0H z),3.70(1H,dd,J=11.0,5.5Hz),3.42(3H,s),2.99(1H,dd,J=16.5,8.5Hz),2.86(1H,dd,J=16.1,5.2Hz).

[0307] Reference Example 48 rac-methyl [(2S,3S)-2-(methoxymethyl)-2,3-dihydrofuro[3,2-b]pyridin-3-yl]acetate The title compound was obtained from the compound of Reference Example 49 by the same method as in Reference Example 1-1. 1H-NMR(400MHz, CDCl3) δ:8.04(1H,dd,J=4.3,1.8Hz),7.06-7.00(2H,m),4.71(1H,td,J=6.7,3.0Hz),3.78-3.72(1H,m),3.7 0(3H,s),3.69-3.60(2H,m),3.42(3H,s),3.08(1H,dd,J=16.8,4.0Hz),2.64(1H,dd,J=16.8,10.1Hz).

[0308] Reference Example 49 rac-methyl (2E)-4-[(2-bromopyridin-3-yl)oxy]-5-methoxypent-2-enoate By the same procedures as in Reference Examples 30 and 32, the title compound was obtained from methyl 2-bromo-3-methoxypropoate. 1 H-NMR(400MHz, CDCl3) δ:8.00(1H,dd,J=4.3,1.8Hz),7.18-7.12(2H,m),6.97(1H,dd,J=15.8,4.9Hz),6.17(1H,dd ,J=15.8,1.8Hz),5.00-4.94(1H,m),3.73(3H,s),3.70(2H,dd,J=5.5,3.7Hz),3.43(3H,s).

[0309] Reference Example 50 rac-[(5aS,9aR,10R)-6,7,8,9,9a,10-hexahydro-5aH-[1]benzopyrano[3,2-b]pyridin-10-yl]acetic acid The title compound was obtained from 2-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexan-1-ol by the same procedures as in Reference Examples 8 to 10 and 14. LC-MS: RT=1.353 min ObsMS=248.4 [M+1]

[0310] Reference Example 51 [(2R,3S)-2,7-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]acetic acid The title compound was obtained from 2-bromo-3-hydroxy-4-methylpyridine by the same procedures as in Reference Examples 38 and 39. LC-MS: RT = 0.449 min ObsMS = 208.1 [M+1]

[0311] Reference Example 52 tert-Butyl {[(2R,3S)-2,5-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate The title compound was obtained from 2-bromo-3-hydroxy-6-methylpyridine by the same procedures as in Reference Examples 13 and 14. 1 H-NMR(400MHz, CDCl3) δ:6.91-6.84(2H,m),5.37(1H,brs),4.66-4.58(1H,m),3.71-3.58(1H,m),3.45-3.34 (1H,m),3.10(1H,dd,J=12.8,7.3Hz),2.45(3H,s),1.49(3H,d,J=6.1Hz),1.43(9H,s).

[0312] Reference Examples 53 to 54 According to the methods described in Reference Examples 38 to 39, the compounds of Reference Examples 53 to 54 were obtained from the corresponding compounds.

[0313] Reference Example 55 Benzyl {[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}methylcarbamate To a suspension of 55% sodium hydride (12.0 g, 276 mmol) in N-methylpyrrolidone (491 mL) was added a solution of the compound of Reference Example 56 (58.2 g, 184 mmol) in N-methylpyrrolidone (123 mL) under ice-cooling. After stirring for 30 minutes, methyl iodide (23.0 mL, 368 mmol) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 hours. Water (500 mL) was then added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate (1000 mL), washed with water (200 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate) to give the title compound (39.5 g). 1H-NMR(400MHz,CDCl3)δ:7.87(1H,dd,J=2.4,1.2Hz),7.33-7.31(5H,m),6.75 -6.72(3H,m),5.12(2H,s),4.92-4.74(1H,m),3.80-3.65(2H,m),3.25(1H,br s),2.92(3H,d,J=14.6Hz),1.40-1.35(3H,m).

[0314] Reference Example 56 Benzyl {[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate To a toluene solution (227 mL) of the compound of Reference Example 14 (33.6 g, 159 mmol), triethylamine (33.2 mL, 239 mmol) and diphenylphosphoryl azide (41.0 mL, 191 mmol) were added at room temperature. After stirring at room temperature for 1 hour, the reaction solution was heated to 90°C. After stirring at 90°C for 20 minutes, benzyl alcohol (18.0 mL, 175 mmol) was added to the reaction solution. After stirring at 90°C for 3.5 hours, saturated aqueous sodium bicarbonate solution (400 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate (200 mL). The organic layer was washed with water (400 mL), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (52 g). 1 H-NMR(400MHz,CDCl3)δ:7.86-7.86(1H,m),7.32(5H,m),6.75(1H,dd,J=9.1,2.4Hz),5.60(1H,s),5.11-5.0 9(2H,m),4.74-4.72(1H,m),3.73-3.72(1H,m),3.46-3.44(1H,m),3.16-3.15(1H,m),1.52(3H,d,J=6.1Hz).

[0315] Reference Examples 57 to 59 According to the methods described in Reference Examples 7 to 10, Reference Example 37, and Reference Example 47, the compounds of Reference Examples 57 to 59 were obtained from the corresponding compounds.

[0316] Reference Example 60 rac-tert-butyl {[6-(trifluoromethyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate The title compound was obtained from propane-1,3-diol and 2-bromo-6-(trifluoromethyl)pyridin-3-ol by the same procedures as in Reference Examples 1 to 4 and Reference Example 6. LC-MS: RT=1.133 min ObsMS=333.2 [M+1]

[0317] Reference Example 61 rac-tert-butyl [(1,2,3,4-tetrahydro-1,5-naphthyridin-4-yl)methyl]carbamate To a mixture of the compound of Reference Example 62 (261 mg, 1.01 mmol) and tetrahydrofuran (5.0 mL), 0.90 mol / L tetrahydrofuran-borane tetrahydrofuran solution (2.24 mL, 2.01 mmol) was added. After stirring at 60°C for 2 hours, methanol (2.5 mL) was added to the reaction mixture and stirred for 15 minutes. The reaction mixture was concentrated, and the concentrated residue was dissolved in 2.0 mol / L hydrochloric acid (2.52 mL, 5.03 mmol) and stirred at 60°C for 2 hours. The reaction mixture was concentrated, and the concentrated residue was dissolved in chloroform (5.0 mL), and triethylamine (0.701 mL, 5.03 mmol) and di-tert-butyl dicarbonate (330 mg, 1.51 mmol) were added. After stirring at room temperature for 1 day, water (5.0 mL) was added to the reaction mixture, which was then extracted with chloroform (3.0 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (100 mg). 1 H-NMR(400MHz, CDCl3) δ:7.87(1H,dd,J=4.6,1.5Hz),6.92(1H,dd,J=7.9,4.6Hz),6.74(1H,dd,J=7.9,1.5Hz),5.75(1H,brs),3.84(1H, brs),3.72-3.62(1H,m),3.40-3.27(3H,m),3.02-2.95(1H,m),2.08-1.99(1H,m),1.92-1.83(1H,m),1.44(9H,s).

[0318] Reference Example 62 rac-tert-butyl 4-cyano-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate To a mixture of the compound of Reference Example 63 (660 mg, 2.11 mmol), trimethylsilyl cyanide (0.523 mL, 4.21 mmol), and acetonitrile (14 mL), 1.0 mol / L tetrabutylammonium fluoride (4.21 mL, 4.21 mmol) was added, and the mixture was stirred for 3 hours at 70° C. The reaction mixture was concentrated, and the concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (261 mg) as a white solid. 1 H-NMR(400MHz, CDCl3) δ:8.31(1H,dd,J=4.6,1.5Hz),8.22(1H,dd,J=8.5,1.5Hz),7.23(1H,dd,J=8.5,4 .6Hz),4.16(1H,t,J=6.4Hz),3.92-3.87(2H,m),2.38-2.33(2H,m),1.54(9H,s).

[0319] Reference Example 63 rac-tert-butyl 4-bromo-3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate Azobisisobutyronitrile (7.85 mg, 0.0480 mmol) was added to a mixture of 1,1-dimethylethyl 3,4-dihydro-1,5-naphthyridine-1(2H)-carboxylate (560 mg, 2.39 mmol), N-bromosuccinimide (510 mg, 2.87 mmol), and carbon tetrachloride (12 mL), and the mixture was heated to reflux for 5 hours. After the reaction mixture was cooled to room temperature, the precipitated solid was filtered, and the filtrate was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (510 mg). 1H-NMR(400MHz, CDCl3) δ:8.33(1H,dd,J=8.8,1.5Hz),8.27(1H,dd,J=4.6,1.5Hz),7.20(1H,dd,J=8.8,4.6Hz),5.53(1H,t,J=3.0Hz ),4.32-4.27(1H,m),3.88-3.81(1H,m),2.50(1H,ddd,J=15.1,3.3,3.3Hz),2.44-2.35(1H,m),1.55(9H,s).

[0320] Reference Examples 64 to 65 According to the methods described in Reference Examples 37 to 39, the compounds of Reference Examples 64 to 65 were obtained from the corresponding compounds.

[0321] Reference Example 66 2-iodo-4,6-dimethylpyridin-3-ol To a mixture of 4,6-dimethyl-3-hydroxypyridine (99.8 mg, 0.810 mmol), water (12 mL), and tetrahydrofuran (2.0 mL) was added iodine (247 mg, 0.972 mmol) at 0°C. After stirring at room temperature for 25 hours, 1 mol / L hydrochloric acid (4 mL) was added to the reaction mixture, which was then extracted with ethyl acetate (10 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The organic layer was washed with 0.1 mol / L aqueous sodium thiosulfate solution (10 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (140 mg). 1 H-NMR (400MHz, CDCl3) δ:6.82(1H,s),2.42(3H,s),2.27(3H,s).

[0322] Reference Example 67 Benzyl {2-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]propan-2-yl}carbamate To a mixture of the compound of Reference Example 68 (78.0 mg, 0.313 mmol), methanol (0.70 mL), and water (0.35 mL), sodium hydroxide (37.5 mg, 0.939 mmol) was added at room temperature. After stirring at 60°C for 2 hours, 3.0 mol / L hydrochloric acid was added until the aqueous layer reached pH 5. The reaction solution was concentrated, and the concentrated residue was dissolved in methanol, and insoluble matter was filtered off and concentrated again. To a toluene solution (0.45 mL) of the obtained concentrated residue (69.0 mg), triethylamine (0.130 mL, 0.936 mmol) and diphenylphosphoryl azide (0.0800 mL, 0.374 mmol) were added at room temperature. After stirring at room temperature for 30 minutes, the reaction solution was heated to 90°C. After stirring at 90°C for 1 hour, benzyl alcohol (0.0482 mL, 0.468 mmol) was added to the reaction solution. After stirring at 90°C for 3 hours, saturated aqueous sodium bicarbonate solution (1.0 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate (1.0 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (53.0 mg). 1 H-NMR(400MHz, CDCl3) δ:8.00(1H,dd,J=4.6,1.5Hz),7.40-7.29(5H,m),7.06(1H,dd,J=8.2,4.6Hz),7.01(1H,dd,J=8.2,1.5Hz),6.18(1H,brs),5.11(1H,d, J=12.8Hz), 5.07(1H,d,J=12.8Hz),4.80(1H,dq,J=6.7,4.3Hz),3.42(1H,d,J=4.3Hz),1.39(3H,d,J=6.7Hz),1.33(3H,s),1.31(3H,s).

[0323] Reference Example 68 Ethyl 2-methyl-2-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]propanoate To a tetrahydrofuran solution (1.7 mL) of the compound of Reference Example 69 (150 mg, 0.678 mmol), 1.0 mol / L lithium bis(trimethylsilyl)amide toluene solution (1.63 mL, 1.63 mmol) was added dropwise at −78°C. After stirring at −78°C for 30 minutes, iodomethane (1.63 mL, 1.63 mmol) was added. After stirring for an additional hour, the reaction mixture was warmed to room temperature over 1 hour. A saturated aqueous ammonium chloride solution (3.4 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate (1.7 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (78.0 mg). 1 H-NMR(400MHz, CDCl3) δ:8.06(1H,dd,J=4.6,1.5Hz),7.04(1H,dd,J=7.9,4.6Hz),6.99(1H,dd,J=7.9,1.5Hz),4.67(1H,dq,J=6.0,3.7Hz),4.69-4.6 3(2H,m),3.34(1H,d,J=3.7Hz),1.59(2H,d,J=7.3Hz),1.41(3H,d,J=6.0Hz),1.40(3H,s),1.26(3H,t,J=7.3Hz),1.05(3H,s).

[0324] Reference Example 69 Ethyl [(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]acetate To a toluene solution (73 mL) of the compound of Reference Example 39 (6.58 g, 21.9 mmol), tributyltin hydride (9.77 mL, 37.3 mmol) and azobisisobutyronitrile (0.360 g, 2.19 mmol) were added at room temperature. After stirring at 90°C for 1 hour, the reaction mixture was concentrated. The residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (3.87 g) as a 5:1 diastereomeric mixture. The main diastereomer 1H-NMR(400MHz, CDCl3) δ:8.05-8.01(1H,m),7.13-7.01(2H,m),4.76-4.67(1H,m),4.21-4.09(2H,m),3.58-3.48(1H,m ),3.07(1H,dd,J=16.5,3.7Hz),2.75-2.62(1H,m),1.53(3H,d,J=6.1Hz),1.24(3H,t,J=6.7Hz).

[0325] Reference Example 70-1, Reference Example 70-2 Reference Example 70-1 Benzyl {(1S)-1-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]ethyl}carbamate Reference Example 70-2 Benzyl {(1R)-1-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]ethyl}carbamate The title compounds Reference Example 70-1 and Reference Example 70-2 were obtained from the compound of Reference Example 71 in the same manner as in Reference Example 67. 1 H-NMR(400MHz, CDCl3) δ:8.03(1H,d,J=3.7Hz),7.40-7.30(5H,m),7.10-7.00(2H,m),6.29(1H,d,J=8.5Hz),5.14(1H,d,J=12.2Hz),5.09(1H,d,J =12.2Hz),4.67(1H,dq,J=6.7,4.3Hz),4.12-4.07(1H,m),3.32-3.29(1H,m),1.49(4H,d,J=6.7Hz),1.03(3H,d,J=6.7Hz). Reference example 70-2 1 H-NMR(400MHz, CDCl3) δ:8.01(1H,d,J=4.9Hz),7.38-7.28(5H,m),7.08-6.99(2H,m),5.08(1H,d,J=12.2Hz),5.03(1H,d,J=12.2Hz),4.79-4. 73(1H,dq,J=6.7,6.7Hz),4.13-4.03(1H,m),3.19(1H,dd,J=5.5,5.5Hz),1.47(3H,d,J=6.7Hz),1.43(3H,d,J=6.1Hz).

[0326] Reference Example 71-1, Reference Example 71-2 Reference Example 71-1 Ethyl (2S)-2-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]propanoate Reference Example 71-2 Ethyl (2R)-2-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]propanoate To a tetrahydrofuran solution (9.0 mL) of the compound of Reference Example 69 (800 mg, 3.62 mmol), 1.0 mol / L lithium bis(trimethylsilyl)amide tetrahydrofuran solution (3.80 mL, 3.80 mmol) was added dropwise at −78° C. After stirring for 30 minutes at −78° C., iodomethane (0.270 mL, 4.34 mmol) was added. After stirring for an additional hour, the reaction mixture was warmed to room temperature over 1 hour. A saturated aqueous ammonium chloride solution (18 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate (18 mL × 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (826 mg) as a 1.4:1 diastereomeric mixture of Reference Example 71-1 and Reference Example 71-2. Major diastereomer 1 H-NMR(400MHz, CDCl3) δ:8.08-8.05(1H,m),7.07-7.00(2H,m),4.85(1H,dq,J=7.3,5.5Hz),4.20-4.17(2H,m),3.53-3. 52(1H,m),3.16-3.14(1H,m),1.37(3H,d,J=7.3Hz),1.27(3H,t,J=7.0Hz),1.01(3H,d,J=7.3Hz).

[0327] Reference Examples 72 to 73 According to the methods described in Reference Examples 1 to 4 and Reference Example 6, the compounds of Reference Examples 72 to 73 were obtained from the corresponding compounds.

[0328] Reference Example 74 rac-benzyl {[(2R,3S)-2-methyl(2- ２ H) -2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate The title compound was obtained from the compound of Reference Example 75 by the same procedures as in Reference Examples 8 to 10 and Reference Examples 37 to 38. 1 H-NMR(400MHz, CDCl3) δ:8.01-7.97(1H,m),7.37-7.27(5H,m),7.08-7.03(2H,m),5.79(1H,s),5.10 (2H,s),3.81-3.77(1H,m),3.50-3.40(1H,m),3.23-3.19(1H,m),1.53(3H,s).

[0329] Reference Example 75 rac-1-{[tert-butyl(dimethyl)silyl]oxy}(2- ２ H) Propan-2-ol To a chloroform solution (45 mL) of propane-2-d-1,2-diol (1.04 g, 13.5 mmol), imidazole (0.919 g, 13.5 mmol) and tert-butyldimethylsilyl chloride (1.83 g, 12.2 mmol) were added at room temperature. After stirring at room temperature for 2 hours, water (200 mL) was added to the reaction mixture, which was then extracted with chloroform (200 mL x 2). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.51 g). 1 H-NMR(400MHz,CDCl3) δ:3.64-3.58(1H,m),3.40-3.33(1H,m),1.15-1.10(3H,m),0.96-0.88(9H,m),0.13-0.05(6H,m).

[0330] Reference Example 76-1, Reference Example 76-2 Reference Example 76-1 rac-benzyl {[(2R,4R)-2-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate Reference Example 76-2 rac-benzyl {[(2R,4S)-2-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate The title compounds, Reference Example 76-1 and Reference Example 76-2, were obtained from the compound of Reference Example 77 by the same procedures as in Reference Example 8, and Reference Examples 37 and 38. 1H-NMR(400MHz, CDCl3) δ:8.13-8.10(1H,m),7.35-7.29(5H,m),7.13(2H,d,J=8.5Hz),6.33(1H,s),5.08(2H,s),3.99-3.95(1H,m),3. 89-3.86(1H,m),3.46-3.44(1H,m),3.18-3.15(1H,m),2.14-2.12(1H,m),1.80-1.60(3H,m),1.04-1.02(3H,m). Reference example 76-2 1 H-NMR(400MHz, CDCl3) δ:8.10(1H,s),7.35-7.34(5H,m),7.10-7.05(2H,m),5.93(1H,s),5.09(2H,s),4.04-4.01(1H,m ),3.68-3.66(1H,m),3.42-3.39(1H,m),3.01-2.99(1H,m),1.91-1.66(4H,m),1.03-1.01(3H,m).

[0331] Reference Example 77 rac-3-[(2-bromopyridin-3-yl)oxy]pentan-1-ol To a chloroform solution (13 mL) of the compound of Reference Example 78 (1.73 g, 6.31 mmol), a 1 mol / L dichloromethane solution of boron tribromide (12.6 mL, 12.6 mmol) was added under ice-cooling. After stirring at room temperature for 2 hours, saturated aqueous sodium bicarbonate solution (100 mL) was added to the reaction mixture, which was then extracted with chloroform (100 mL x 2), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.541 g). 1 H-NMR(400MHz, CDCl3) δ:7.97(1H,dd,J=4.6,1.5Hz),7.25(1H,dd,J=8.2,1.5Hz),7.20(1H,dd,J=7.9,4.3Hz),4.55 -4.48(1H,m),3.90-3.79(2H,m),2.08-1.92(2H,m),1.82-1.72(2H,m),1.00(3H,t,J=7.3Hz).

[0332] Reference Example 78 rac-2-bromo-3-[(1-methoxypentan-3-yl)oxy]pyridine The title compound was obtained from 1-methoxypentan-3-ol by a method similar to that of Reference Example 10. 1 H-NMR(400MHz, CDCl3) δ:7.97-7.93(1H,m),7.27-7.22(1H,m),7.21-7.16(1H,m),4.50-4.42(1H,m),3.50(2H ,t,J=5.5Hz),3.30(3H,s),2.03-1.88(2H,m),1.80-1.70(2H,m),1.00(3H,t,J=7.0Hz).

[0333] Reference Example 79 rac-benzyl [(3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl)methyl]carbamate The title compound was obtained from the compound of Reference Example 80 by the same procedures as in Reference Examples 30 to 31 and Reference Examples 37 to 38. 1 H-NMR(400MHz, CDCl3) δ:8.08-8.07(1H,m),7.35-7.33(5H,m),7.09-7.07(1H,m),7.02-7.00(1H,m),5.97(1H,s),5.14-5.10(2H,m),3 .76-3.69(1H,m),3.51-3.49(1H,m),3.33-3.27(1H,m),1.24-1.19(1H,m),1.12-1.02(2H,m),0.76-0.70(1H,m).

[0334] Reference Example 80 Methyl 1-[(2-bromopyridin-3-yl)oxy]cyclopropane-1-carboxylate To a solution (75 mL) of the compound of Reference Example 81 (2.65 g, 7.51 mmol), potassium tert-butoxide (0.842 g, 7.51 mmol) was added at 0°C. After stirring at room temperature for 90 minutes, potassium tert-butoxide (0.168 g, 1.50 mmol) was further added. After stirring at room temperature for 20 minutes, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (1.69 g). 1H-NMR(400MHz,CDCl3) δ:8.05-8.04(1H,m),7.24-7.18(2H,m),3.76(3H,s),1.71-1.69(2H,m),1.42-1.40(2H,m).

[0335] Reference Example 81 rac-methyl 4-bromo-2-[(2-bromopyridin-3-yl)oxy]butanoate Potassium carbonate (2.66 g, 19.24 mmol) and methyl 2,4-dibromobutyrate (3.0 g, 11.54 mmol) were added to a solution of 2-bromo-3-hydroxypyridine (1.67 g, 9.62 mmol) in N,N-dimethylformamide (48.1 mL) at room temperature. After stirring at room temperature for 3 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.75 g). 1 H-NMR(400MHz, CDCl3) δ:8.04-8.03(1H,m),7.20-7.15(1H,m),7.08-7.06(1H,m),4.91-4.88(1H ,m),3.77(3H,s),3.75-3.61(2H,m),2.63-2.58(1H,m),2.51-2.46(1H,m).

[0336] Reference Example 82 tert-butyl {[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}prop-2-en-1-ylcarbamate To a solution (48.1 mL) of the compound of Reference Example 83 (50 mg, 0.189 mmol) in tetrahydrofuran, 55% sodium hydride (24.76 mg, 0.567 mmol) was added at 0°C. After stirring at room temperature for 90 minutes, allyl bromide (0.048 mL, 0.567 mmol) was added. After stirring at room temperature for 90 minutes, water was added, and the mixture was extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (34.8 mg). 1H-NMR(400MHz, CDCl3) δ:8.00-7.94(1H,m),6.99-6.89(2H,m),5.78-5.60(1H,m),5.13-4.98(2H,m) ,4.90-4.70(1H,m),3.86-3.51(4H,m),3.29-3.15(1H,m),1.43-1.37(12H,m).

[0337] Reference Example 83 tert-Butyl {[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate The title compound was obtained from the compound of Example 27 by the same method as in Example 5. 1 H-NMR(400MHz, CDCl3) δ:8.02(1H,dd,J=4.6,1.5Hz),7.03(1H,dd,J=8.2,4.6Hz),6.98(1H,dd,J=7.9,1.2Hz),5.40(1H,brs),4.6 8-4.60(1H,m),3.73-3.62(1H,m),3.44-3.33(1H,m),3.19-3.13(1H,m),1.52(3H,d,J=6.7Hz),1.43(9H,s).

[0338] Reference Example 84 tert-butyl {[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}propylcarbamate To a methanol solution (1.0 mL) of the compound of Reference Example 82 (34.8 mg, 0.114 mmol), 10% palladium / carbon (25 mg) was added. The mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours, filtered through Celite, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (32.0 mg). 1 H-NMR(400MHz, CDCl3) δ:7.97(1H,d,J=3.7Hz),6.98-6.91(2H,m),4.83(1H,brs),3.73-3.58(2H,m),3.23-3. 12(3H,m),1.53-1.41(2H,m),1.40(3H,d,J=6.1Hz),1.39(9H,s),0.78(3H,t,J=7.3Hz).

[0339] Reference Examples 85 to 87 According to the method described in Reference Example 82, the compounds of Reference Examples 85 to 87 were obtained from the corresponding compounds.

[0340] Reference Example 88-1, Reference Example 88-2, Reference Example 88-3, Reference Example 88-4 Reference Example 88-1 rac-benzyl {[(2R,3R,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate Reference Example 88-2 rac-benzyl {[(2R,3S,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate Reference Example 88-3 rac-benzyl {[(2S,3R,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate Reference Example 88-4 rac-benzyl {[(2S,3S,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate The title compounds Reference Examples 88-1, 88-2, 88-3 and 88-4 were obtained from 2-methylbutane-1,3-diol in the same manner as in Reference Examples 8 to 10, 37 to 38 and 75. Reference Example 88-1 1 H-NMR(400MHz, CDCl3) δ:8.05-8.05(1H,m),7.36-7.30(5H,m),7.05-6.98(2H,m),6.72(1H,brs),5.15-5.07(2H,m),4.31-4.30(1H,m),3.7 9-3.73(1H,m),3.37-3.34(1H,m),3.24-3.19(1H,m),2.11-2.09(1H,m),1.35(3H,d,J=6.7Hz),0.79(3H,d,J=6.7Hz). Reference example 88-2 1H-NMR(400MHz, CDCl3) δ:8.09-8.08(1H,m),7.34-7.26(5H,m),7.06-7.03(2H,m),6.07(1H,brs),5.09-5.05(2H,m),4.03-3.99(1H,m),3.8 0-3.75(1H,m),3.43-3.37(1H,m),2.66-2.61(1H,m),1.65-1.60(1H,m),1.40(3H,d,J=6.1Hz),1.16(3H,d,J=6.1Hz). Reference example 88-3 1 H-NMR(400MHz, CDCl3) δ:8.02-8.01(1H,m),7.33-7.22(5H,m),7.02-7.00(2H,m),6.47(1H,d,J=6.7Hz),5.06-5.03(2H,m),4.08-4.04(1H,m), 3.75-3.68(1H,m),3.22-3.16(1H,m),2.99-2.94(1H,m),2.02-1.98(1H,m),1.27(3H,d,J=6.7Hz),0.97(3H,d,J=7.3Hz). Reference example 88-4 1 H-NMR(400MHz, CDCl3) δ:8.13-8.11(1H,m),7.37-7.27(5H,m),7.10-7.06(2H,m),5.88(1H,s),5.09(2H,s),4.30-4.28(1H,m),3.80-3. 73(1H,m),3.43-3.37(1H,m),2.70-2.68(1H,m),2.00-1.97(1H,m),1.31(3H,d,J=6.4Hz),0.98(3H,d,J=6.9Hz).

[0341] Reference Example 89 rac-tert-butyl [(6'-chloro-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl)methyl]carbamate The title compound was obtained from the compound of Reference Example 90 by the same procedures as in Reference Examples 6 and 7, and Reference Examples 30 and 31. 1H-NMR(400MHz, CDCl3) δ:7.99(1H,d,J=1.8Hz),6.95(1H,d,J=1.8Hz),5.38(1H,s),3.58-3.52(1H,m),3.36-3.34(1H ,m),3.16-3.12(1H,m),1.37(9H,s),1.22-1.11(1H,m),1.02-0.99(2H,m),0.69-0.63(1H,m).

[0342] Reference Example 90 Methyl 1-[(2-bromo-5-chloropyridin-3-yl)oxy]cyclopropane-1-carboxylate By the same procedures as in Reference Examples 80 and 81, the title compound was obtained from 2-bromo-5-chloro-3-hydroxypyridine. 1 H-NMR(400MHz,CDCl3) δ:8.00(1H,d,J=1.8Hz),7.16(1H,d,J=1.8Hz),3.74(3H,s),1.70-1.68(2H,m),1.40-1.39(2H,m).

[0343] Reference Example 91 rac-2-[(2-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl]-1H-isoindole-1,3(2H)-dione To a mixture of the compound of Reference Example 92 (110 mg, 0.337 mmol), dimethyl sulfoxide (1.68 mL), and methanol (1.68 mL) was added sodium methoxide (364 mg, 6.73 mmol) at room temperature. After stirring at 100°C, water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (9 mg). 1 H-NMR(400MHz, CDCl3) δ:7.84-7.83(2H,m),7.70-7.69(2H,m),7.25-7.24(1H,m),6.49(1H,d,J=8.5Hz),4.41-4.3 7(1H,m),3.79-3.76(1H,m),3.66(3H,s),3.33(1H,s),2.68-2.66(2H,m),1.81-1.72(4H,m).

[0344] Reference Example 92 rac-2-[(2-chloro-5,6,7,8-tetrahydroquinolin-8-yl)methyl]-1H-isoindole-1,3(2H)-dione To the compound of Reference Example 93 (440 mg, 1.427 mmol), phosphoryl chloride (2.0 mL, 21.46 mmol) was added at room temperature. After stirring at 90°C for 4 hours, ice water was added to the reaction mixture. 4 mol / L sodium hydroxide was then added, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (110 mg). 1 H-NMR(400MHz, CDCl3) δ:7.85-7.81(2H,m),7.72-7.68(2H,m),7.30(1H,d,J=8.5Hz),7.01(1H,d,J=7.9Hz),4.26-4.23(1H ,m),3.82-3.78(1H,m),3.44-3.42(1H,m),2.75-2.70(2H,m),1.93-1.88(2H,m),1.75-1.66(2H,m).

[0345] Reference Example 93 rac-2-[(1-oxo-5,6,7,8-tetrahydro-1λ ５ -quinolin-8-yl)methyl]-1H-isoindole-1,3(2H)-dione To a chloroform solution (10.4 mL) of the compound of Reference Example 94 (608 mg, 2.080 mmol), 70% 3-chloroperbenzoic acid (564 mg, 2.29 mmol) was added at 0° C. After stirring at 0° C. for 4 hours, saturated aqueous sodium bicarbonate was added to the reaction mixture, which was then extracted with chloroform, dried over sodium sulfate, filtered, and concentrated to give the title compound (646 mg). 1 H-NMR(400MHz, CDCl3) δ:8.30-8.29(1H,m),7.86-7.83(2H,m),7.73-7.70(2H,m),7.18(2H,d,J=4.3Hz),4.37-4.34(1H,m),4.15- 4.14(1H,m),4.00-3.97(1H,m),2.93-2.88(1H,m),2.83-2.74(1H,m),2.03-1.93(2H,m),1.83-1.74(2H,m).

[0346] Reference Example 94 rac-2-[(5,6,7,8-tetrahydroquinolin-8-yl)methyl]-1H-isoindole-1,3(2H)-dione Phthalic anhydride (548 mg, 3.70 mmol) was added to a chloroform solution (25 mL) of 5,6,7,8-tetrahydroquinolin-8-ylmethanamine (400 mg, 2.47 mmol). After stirring at 70°C for 5 hours, the reaction mixture was concentrated. The concentrated residue was separated and purified by silica gel chromatography (hexane / ethyl acetate) to obtain the title compound (608 mg). 1 H-NMR(400MHz, CDCl3) δ:8.31(1H,d,J=4.3Hz),7.84-7.83(2H,m),7.71-7.68(2H,m),7.38(1H,d,J=7.3Hz),7.05-7.03(1H,m),4.34 -4.30(1H,m),3.87-3.84(1H,m),3.47-3.44(1H,m),2.85-2.70(2H,m),2.00-1.82(2H,m),1.77-1.68(2H,m).

[0347] Reference Examples 95 to 96 According to the methods described in Reference Examples 79 to 81, the compounds of Reference Examples 95 to 96 were obtained from the corresponding compounds.

[0348] Reference Example 97 rac-tert-butyl [(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)methyl]carbamate To a toluene solution (1.374 mL) of the compound of Reference Example 98 (49.1 mg, 0.275 mmol), a 1 mol / L toluene solution of diisobutylaluminum hydride (0.825 mL, 0.825 mmol) was added at 0°C. After stirring at room temperature for 3 hours, 30% aqueous potassium sodium tartrate, saturated sodium bicarbonate water, and ethyl acetate were added to the reaction mixture. To this mixture, di-tert-butyl dicarbonate (90 mg, 0.412 mmol) was added at room temperature. After stirring at room temperature for 1 hour, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (30.9 mg) as a pale yellow oil. 1 H-NMR(400MHz, CDCl3) δ:8.24(1H,d,J=5.5Hz),7.08(1H,d,J=5.5Hz),5.64(1H,s),3.68-3.65(1H,m),3.34-3.29(2H ,m),3.01-2.97(1H,m),2.92-2.84(1H,m),2.33-2.30(1H,m),1.84-1.79(1H,m),1.43(9H,s).

[0349] Reference Example 98 rac-4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile To a toluene solution (1.965 mL) of 4-chloro-6,7-dihydro-5H-cyclopenta[B]pyridin-7-ol (100 mg, 0.590 mmol) and acetone cyanohydrin (0.081 mL, 0.884 mmol), cyanomethylenetributylphosphorane (0.464 mL, 1.769 mmol) was added. After stirring at 60°C for 1 hour, water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (49.1 mg). 1H-NMR(400MHz, CDCl3) δ:8.33(1H,d,J=5.5Hz),7.17(1H,d,J=5.5Hz),4.20-4.18(1H,m),3.20-3.09(1 H,m),3.00-2.94(1H,m),2.65-2.55(1H,m),2.42(1H,ddt,J=17.0,9.4,3.1Hz).

[0350] Reference Example 99 rac-tert-butyl [(4-ethoxy-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)methyl]carbamate To a toluene solution (1.89 mL) of the compound of Reference Example 100 (50 mg, 0.189 mmol), ethanol (0.055 mL, 0.946 mmol), and triphenylphosphine (74.4 mg, 0284 mmol), bis(2-methoxyethyl) azodicarboxylate was added at 0°C. After stirring at room temperature for 1 hour, methanol was added to the reaction mixture, which was then concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (35 mg). 1 H-NMR(400MHz, CDCl3) δ:8.23(1H,d,J=5.5Hz),6.56(1H,d,J=5.5Hz),5.79(1H,s),4.10-4.06(2H,m),3.67-3.65(1H,m),3.27-3.22(2H, m),2.89-2.85(1H,m),2.78-2.69(1H,m),2.28-2.25(1H,m),1.80-1.73(1H,m),1.43(9H,s),1.41(3H,t,J=6.6Hz).

[0351] Reference Example 100 rac-tert-butyl [(4-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)methyl]carbamate Acetohydroxamic acid (198 mg, 2.63 mmol) was added to a suspension (1.46 mL) of the compound of Reference Example 97 (248 mg, 0.877 mmol) and potassium carbonate (606 mg, 4.39 mmol) in N-methyl-2-pyrrolidone. After stirring at 100°C for 6 hours, the reaction mixture was filtered through Celite and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (128 mg). 1 H-NMR(400MHz, CDCl3) δ:7.39(1H,s),6.32(1H,s),5.22(1H,s),4.26(1H,s),3.36-3.26(3H,m),2.87-2 .83(1H,m),2.70-2.62(1H,m),2.31-2.27(1H,m),1.75-1.67(1H,m),1.42(9H,s).

[0352] Reference Example 101 rac-2-{[4-(4-methylphenyl)-5,6,7,8-tetrahydroquinolin-8-yl]methyl}-1H-isoindole-1,3(2H)-dione To a toluene suspension (2.3 mL) of the compound of Reference Example 102 (100 mg, 0.306 mmol), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (53.1 mg, 0.092 mmol), 4-methylphenylboronic acid (125 mg, 0.918 mmol), and cesium carbonate (199 mg, 0.612 mmol), tris(dibenzylideneacetone)dipalladium(0) (56 mg, 0.061 mmol) was added. After stirring at 130°C, water was added to the reaction mixture, which was then extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (26.5 mg). 1H-NMR(400MHz, CDCl3) δ:8.40(1H,d,J=4.9Hz),7.86-7.84(2H,m),7.72-7.69(2H,m),7.23(2H,d,J=4.9Hz),7.17(2H,d,J=7.9Hz),7.05- 7.04(1H,m),4.40-4.37(1H,m),4.00-3.97(1H,m),3.63(1H,s),2.66-2.61(2H,m),2.39(3H,s),1.90-1.60(4H,m).

[0353] Reference Example 102 rac-2-[(4-chloro-5,6,7,8-tetrahydroquinolin-8-yl)methyl]-1H-isoindole-1,3(2H)-dione To the compound of Reference Example 93 (500 mg, 1.62 mmol), phosphoryl chloride (1.5 mL, 16.22 mmol) was added at room temperature. After stirring at 90°C for 4 hours, ice water was added to the reaction mixture. 4 mol / L sodium hydroxide was then added, and the mixture was extracted with ethyl acetate, dried over sodium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (256 mg). 1 H-NMR(400MHz, CDCl3) δ:8.21(1H,d,J=4.9Hz),7.87-7.84(2H,m),7.73-7.70(2H,m),7.15(1H,d,J=4.9Hz),4.35-4.30(1H ,m),3.86-3.84(1H,m),3.49-3.46(1H,m),2.87-2.75(2H,m),2.03-2.00(1H,m),1.85-1.79(3H,m).

[0354] Reference Example 103-1, Reference Example 103-2 Reference Example 103-1 rac-benzyl {[(3R,4S)-3-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate Reference Example 103-2 rac-benzyl {[(3S,4S)-3-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate The title compounds, Reference Examples 103-1 and 103-2, were obtained from 2-ethylpropane-1,3-diol in the same manner as in Reference Examples 2 to 4 and Reference Examples 37 and 38. Reference Example 103-1 1 H-NMR(400MHz, CDCl3) δ:8.02(1H,dd,J=3.7,1.8Hz),7.34-7.22(5H,m),7.04-6.97(2H,m),6.43-6.35(1H,m),5.04(2H,s),4.07-3.98(2H,m),3.74-3. 66(1H,m),3.24-3.15(1H,m),3.11-3.04(1H,m),2.08-1.98(1H,m),1.46-1.34(1H,m),1.32-1.21(1H,m),0.96(3H,t,J=7.3Hz). Reference example 103-2 1 H-NMR(400MHz, CDCl3) δ:8.11(1H,dd,J=4.3,1.2Hz),7.37-7.27(5H,m),7.11-7.02(2H,m),5.9 2(1H,brs),5.09(2H,s),4.20(1H,dd,J=11.0,3.0Hz),3.93(1H,dd,J=11. 0,6.1Hz),3.86-3.77(1H,m),3.42-3.33(1H,m),2.77-2.70(1H,m),1.84- 1.75(1H,m),1.66-1.56(1H,m),1.44-1.32(1H,m),0.98(3H,t,J=7.3Hz).

[0355] Reference Example 104 rac-4-methyl-5,6,7,8-tetrahydroquinoline-8-carbonitrile The title compound was obtained from the compound of Reference Example 105 by the same method as in Reference Example 62. 1 H-NMR(400MHz,CDCl3) δ:8.35(1H,d,J=4.9 Hz),7.04(1H,d,J=4.9Hz),4.11(1H,t,J=6.1Hz),2.78-2.61(2H,m),2.28-2.15(2H,m),2.24(3H,s),2.14-2.04(1H,m),1.97-1.88(1H,m).

[0356] Reference Example 105 rac-8-bromo-4-methyl-5,6,7,8-tetrahydroquinoline Phosphorus tribromide (0.0747 mL, 0.795 mmol) was added to a chloroform solution (5.3 mL) of the compound of Reference Example 106 (87.0 mg, 0.530 mmol). After 2 hours at 70° C., a saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture, which was then extracted with chloroform (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (118 mg). 1 H-NMR(400MHz, CDCl3) δ:8.34(1H,d,J=4.9Hz),6.99(1H,d,J=4.9Hz),5.55-5.53(1H,m),2.87(1H,dd,J=17.7,5.5H z),2.70-2.61(1H,m),2.49-2.44(1H,m),2.36-2.13(2H,m),2.23(3H,s),2.04-1.96(1H,m).

[0357] Reference Example 106 rac-4-methyl-5,6,7,8-tetrahydroquinolin-8-ol Sodium borohydride (30.1 mg, 0.796 mmol) was added to a methanol solution (5.3 mL) of the compound of Reference Example 107 (85.5 mg, 0.530 mmol) under ice-cooling. After stirring at room temperature for 3 hours, a saturated aqueous ammonium chloride solution (30 mL) was added to the reaction mixture, which was then extracted with chloroform (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (93.7 mg). 1 H-NMR(400MHz, CDCl3) δ:8.28(1H,d,J=4.9Hz),6.99(1H,d,J=4.9Hz),4.68(1H,dd,J=8.9,5.2Hz),4.17(1H,brs) ,2.74-2.62(2H,m),2.33-2.26(1H,m),2.23(3H,s),2.10-2.02(1H,m),1.87-1.70(2H,m).

[0358] Reference Example 107 4-methyl-6,7-dihydroquinolin-8(5H)-one A mixture of 4-chloro-6,7-dihydroquinolin-8(5H)-one (302 mg, 1.67 mmol), trimethylboroxine (0.756 mL, 5.45 mmol), 1,1'-bis(diphenylphosphino)ferrocenepalladium(II) chloride (130 mg, 0.159 mmol), potassium carbonate (388 mg, 2.81 mmol), and dichloroethane (2.0 mL) was stirred under microwave irradiation at 120°C for 2 hours. The reaction mixture was then separated and purified by silica gel column chromatography (chloroform / methanol) to obtain the title compound (85.5 mg). 1 H-NMR (400MHz, CDCl3) δ:8.57(1H,d,J=4.3Hz),7.24(1H,d,J=4.9Hz),2.94(2H,t,J=6.1Hz),2.79(2H,t,J=6.7Hz),2.36(3H,s),2.24-2.18(2H,m).

[0359] Reference Example 108-1, Reference Example 108-2 Reference Example 108-1 rac-(5R,7R)-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile Reference Example 108-2 rac-(5R,7S)-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine-7-carbonitrile The title compound was obtained as a 1:1 diastereomeric mixture of Reference Examples 108-1 and 108-2 from the compound of Reference Example 109 by the same procedures as in Reference Examples 104 and 105. 1 H-NMR(400MHz, CDCl3) δ:8.51-8.48(1H,m),7.58-7.54(1H,m),7.25-7.22(1H,m),4.23-4.12(1H,m) ,3.54-3.21(1H,m),2.87-2.65(1H,m),2.17-1.96(1H,m),1.41-1.31(3H,m).

[0360] Reference Example 109-1, Reference Example 109-2 Reference Example 109-1 rac-(5R,7R)-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol Reference Example 109-2 rac-(5R,7S)-5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-ol To a chloroform solution (2.0 mL) of the compound of Reference Example 110 (232 mg, 1.55 mmol), trifluoroacetic anhydride (3.0 mL, 21.4 mmol) was added under ice-cooling. After stirring at room temperature for 20 hours, a 1 mol / L aqueous sodium hydroxide solution (30 mL) was added to the reaction mixture, which was then extracted with chloroform (30 mL × 2), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (125 mg) as a 1:1 diastereomeric mixture of Reference Example 109-1 and Reference Example 109-2. 1 H-NMR(400MHz, CDCl3) δ:8.50-8.38(1H,m),7.61-7.47(1H,m),7.22-7.14(1H,m),5.32-5.11(1H,m),3.58-3.38(0.5H,m),3.14-3.01 (1H,m),2.89-2.72(1H,m),2.42-2.27(0.5H,m),2.11-1.97(0.5H,m),1.70-1.53(0.5H,m),1.44-1.18(3H,m).

[0361] Reference Example 110 rac-5-methyl-1-oxo-6,7-dihydro-5H-1λ ５ -cyclopenta[b]pyridine The title compound was obtained from 5-methyl-6,7-dihydro-5H-cyclopenta[b]pyridine by a method similar to that of Reference Example 93. 1 H-NMR(400MHz, CDCl3) δ:8.06(1H,d,J=6.1Hz),7.12-7.07(2H,m),3.36-3.18(2H,m),3.10-3. 01(1H,m),2.47-2.37(1H,m),1.77-1.68(1H,m),1.31(3H,d,J=6.7Hz).

[0362] Reference Example 111-1, Reference Example 111-2 Reference Example 111-1 rac-tert-butyl {[(5R,8S)-5-methyl-5,6,7,8-tetrahydroquinolin-8-yl]methyl}carbamate Reference Example 111-2 rac-tert-butyl {[(5R,8R)-5-methyl-5,6,7,8-tetrahydroquinolin-8-yl]methyl}carbamate The title compound was obtained as a diastereomeric mixture of Reference Examples 111-1 and 111-2 from the compound of Reference Example 112 by the same method as in Reference Example 61. 1 H-NMR(400MHz, CDCl3) δ:8.39-8.36(1H,m),7.53-7.46(1H,m),7.09(1H,dd,J=7.6,4.6Hz),5.87(1H,brs),3.71-3.57(1H,m),3. 38-3.27(1H,m),2.98-2.85(2H,m),2.10-1.87(2H,m),1.67-1.59(2H,m),1.45(9H,s),1.28-1.26(3H,m).

[0363] Reference Example 112-1 and Reference Example 112-2 Reference Example 112-1 rac-(5R,8R)-5-methyl-5,6,7,8-tetrahydroquinoline-8-carbonitrile Reference Example 112-2 rac-(5R,8S)-5-methyl-5,6,7,8-tetrahydroquinoline-8-carbonitrile By the same procedures as in Reference Examples 104 and 105, and Reference Examples 109 and 110, the title compound was obtained as a diastereomeric mixture of Reference Examples 112-1 and 112-2 from 5-methyl-5,6,7,8-tetrahydroquinoline. 1 H-NMR(400MHz,CDCl3) δ:8.48-8.47(1H,m),7.60-7.57(1H,m),7.22(1H,dd,J=7.9,4.9 Hz),4.13-4.07(1H,m),3.06-2.89(1H,m),2.40-2.28(1H,m),2.23-1.55(3H,m),1.35-1.29(3H,m).

[0364] Reference Examples 113 to 114 According to the methods described in Reference Examples 5 and 55, the compounds of Reference Examples 113 to 114 were obtained from the compounds of the corresponding Examples.

[0365] Reference Example 115 rac-benzyl [(2,2,5-trimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl)methyl]carbamate The title compound was obtained from 2-bromo-6-methylpyridin-3-ol and ethyl 2-bromo-2-methylpropanoate by the same procedures as in Reference Examples 30 to 32 and Reference Examples 37 and 38. 1 H-NMR(400MHz, CDCl3) δ:7.41-7.28(5H,m),6.90(2H,s),6.39-6.37(1H,m),5.14(2H,s),3.85-3.81(1H ,m),3.27-3.24(1H,m),3.18-3.16(1H,m),2.45(3H,s),1.52(3H,s),1.37(3H,s).

[0366] Reference Example 116 rac-benzyl {[(6S,7S)-3-chloro-6-methyl-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl]methyl}carbamate The title compound was obtained from the compound of Reference Example 117 by the same procedures as in Reference Example 30, and Reference Examples 37 and 38. 1 H-NMR(400MHz, CDCl3) δ:8.26(1H,s),7.44(1H,s),7.38-7.29(5H,m),6.07(1H,brs),5.11(2H,s),3.88-3.81(1H,m),3.34-3.28 (1H,m),3.03-2.99(1H,m),2.83-2.80(1H,m),2.56-2.49(1H,m),2.30-2.18(1H,m),1.26(3H,d,J=7.3Hz).

[0367] Reference Example 117 rac-3-(2-bromo-5-chloropyridin-3-yl)-2-methylpropan-1-ol To a mixture of 2-bromo-5-chloronicotinaldehyde (999 mg, 4.30 mmol) and toluene (11 mL), ethyl 2-(triphenylphosphoranylidene)propionate (1.64 g, 4.52 mmol) was added under ice cooling. After stirring at 90°C for 3 hours, the reaction mixture was concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate).

[0368] To a mixture of the purified product (1.29 g) and tetrahydrofuran (42.5 mL), a 4 mol / L solution of lithium borohydride in tetrahydrofuran (1.28 mL, 5.10 mmol) was added dropwise over 5 minutes under ice cooling. After stirring at room temperature for 15 minutes, the mixture was stirred at 60°C for 2 hours, and then methanol (5 mL) and 1 mol / L hydrochloric acid (10 mL) were added under ice cooling. The mixture was extracted with ethyl acetate (20 mL x 3), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by aminosilica gel column chromatography (hexane / ethyl acetate) to give the title compound (469 mg). 1 H-NMR(400MHz, CDCl3) δ:8.21(1H,d,J=2.4Hz),7.51(1H,d,J=3.0Hz),4.25(1H,brs),3.56-3.55(2H,m) ,2.94-2.90(1H,m),2.53-2.49(1H,m),2.14-2.09(1H,m),0.98(3H,d,J=22.5Hz).

[0369] Reference Example 118 rac-benzyl [(5-fluoro-2,2-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl)methyl]carbamate The title compound was obtained from 2-bromo-6-fluoropyridin-3-ol and ethyl 2-bromo-2-methylpropanoate by the same procedures as in Reference Examples 30 to 32 and Reference Examples 37 and 38. 1 H-NMR(400MHz, CDCl3) δ:7.40-7.29(5H,m),7.08-7.06(1H,m),6.69-6.67(1H,m),5.87-5.85(1H,brm),5.17-5.09 (2H,m),3.83-3.79(1H,m),3.31-3.25(1H,m),3.22-3.20(1H,m),1.54(3H,s),1.38(3H,s).

[0370] Test Example 1: Evaluation of agonist activity against human TAAR1 receptor TAAR1 is a G protein-coupled receptor that binds to G protein (Gαs), and activation of the TAAR1 receptor by an agonist induces an increase in intracellular cAMP levels. Therefore, the agonist activity of test compounds against the human TAAR1 receptor was evaluated using a cAMP assay.

[0371] cAMP Hunter cells expressing the human TAAR1 receptor TM The CHO-K1 TAAR1 Gs Cell Line was purchased. Human TAAR1-expressing CHO cells were seeded onto a 96-well plate and cultured for 24 hours. After 24 hours of incubation, test compounds dissolved in DMSO were added and incubated at 37°C for 30 minutes. Samples for cAMP measurement were prepared according to the cAMPHiRange kit protocol. The amount of cAMP produced by the test compound was measured using time-resolved fluorescence using EnVision (excitation wavelength: 330 nm, emission wavelength: 620 nm / 665 nm). Test compound % = 100 × {(Csamp) - (Cblank)} / {(Ctyramine) - (Cblank)} Csamp: test compound counts, Ctyramine: 100 μM tyramine counts, Cblank: blank counts.

[0372] Test Example 2-1: Test for suppressing phencyclidine-induced hyperactivity Eight-week-old C57BL / 6J male mice were used. A 0.5% methylcellulose solution was used as a solvent to prepare a dosing solution of the test compound, which was then clouded. A physiological saline solution was used as a solvent to prepare a dosing solution of phencyclidine, which was then dissolved.

[0373] The phencyclidine-induced hyperactivity inhibition test was carried out using Supermex manufactured by Muromachi Kikai Co., Ltd., the data acquisition program CompACT AMS, and a transparent plastic cage as follows.

[0374] The animals were placed in the cages mentioned above, and locomotion measurement began. 30 minutes later, the mice were gently removed, orally administered the compound administration solution (solvent or test compound suspension), and then returned to their cages. 30 minutes after this administration, the phencyclidine administration solution or saline was administered subcutaneously. After both administrations, the mice were promptly returned to their locomotion measurement cages for each channel, and locomotion measurement continued. Locomotion measurements were conducted for 120 minutes from the start of measurement, with measurement intervals of 5 minutes. Data from 30 minutes to 120 minutes after the start of locomotion measurement were used as the test results, and the locomotion of each individual for the 90 minutes was totaled.

[0375] A parametric Dunnett's multiple comparison (significance level: two-sided 5%) was performed between the test compound and vehicle groups. If the test compound group showed a significant suppression of locomotion compared to the vehicle group, it was determined to have antipsychotic effects. The results of the above test using the compound of Example 27 are shown in Figure 1.

[0376] Test Example 2-2: Test for suppressing phencyclidine-induced hyperactivity Eight-week-old C57BL / 6J male mice were used. Physiological saline was used as a solvent to prepare a dosing solution for the test compound, and physiological saline was used as a solvent to prepare a dosing solution for phencyclidine, which was then dissolved in the solution.

[0377] The phencyclidine-induced hyperlocomotion suppression test was carried out using an activity meter equipped with a photo assembly and an electric counter as follows.

[0378] Mice that had been subcutaneously administered with a compound administration solution (vehicle or test compound suspension) were placed in the aforementioned device, and locomotion measurement began. 30 minutes after the start of measurement, the mice were gently removed, and either the phencyclidine administration solution or physiological saline solution was administered subcutaneously. After administration, the mice were promptly returned to the device, and locomotion measurement continued for 60 minutes. Measurement intervals for locomotion measurement were 5 minutes. Data from 30 to 90 minutes after the start of locomotion measurement were used as the test results, and the locomotion of each individual over the 60 minutes was totaled.

[0379] A parametric Dunnett's multiple comparison (significance level: two-sided 5%) was performed between the test compound administration group and the vehicle administration group. If the test compound administration group showed a significant suppression of locomotion compared to the vehicle administration group, it was determined to have antipsychotic effects. The results of the above test using the compounds of Example 8 and Example 49 are shown in Figures 2 and 3.

[0380] Test Example 3: Evaluation of hERG channel inhibitory activity The hERG channel inhibitory activity of the compounds of the present disclosure was evaluated using human rapidly activated delayed rectifier potassium current (I Ｋｒ We used CHO cells in which the hERG channel involved in ATPase activity was forcibly expressed, and measurements were made by the whole-cell patch clamp method using an autopatch clamp system.

[0381] (Preparation of cell suspension) hERG-CHO cells purchased from ChanTest were cultured in CO ２ The cells were cultured at 37°C in an incubator, and immediately before measuring the hERG current, the cells were detached from the flask using trypsin to prepare a cell suspension.

[0382] (Solution Preparation) The extracellular and intracellular solutions used for the measurements were prepared as follows: Extracellular solution: 2 mmol / L CaCl ２ , 1 mmol / LmgCl ２ , 10 mmol / L HEPES, 4 mmol / L KCl, 145 mmol / L NaCl, 10 mmol / L glucose Intracellular solution: 10 mmol / L HEPES, 10 mmol / L EGTA, 20 mmol / L KCl, 130 mmol / L KF Test substance solution: The test substance was dissolved in DMSO to a concentration of 2 mmol / L or 20 mmol / L to prepare a test substance solution. The test substance solution was further diluted 200-fold with extracellular solution, and the resulting solution was serially diluted with extracellular solution to obtain the hERG inhibitory IC ５０ Test substance solutions of the various concentrations required for calculating values ​​were prepared and applied.

[0383] (Current Measurement and Data Analysis) Cell suspension, extracellular solution, intracellular solution, and a measurement plate were placed in an automated patch clamp system, and hERG current measurements were performed using the whole-cell patch clamp method. The voltage protocol consisted of a holding potential of -80 mV, a depolarizing pulse from -50 mV to +20 mV for 5 seconds, a repolarizing pulse at -50 mV for 5 seconds, and a return to the holding potential. The interval between pulses was 15 seconds. Data analysis was performed using Qube analysis software (Sophion, Sophion). Four concentrations of each test substance were applied incrementally, and the average value of the maximum outward current (Peaktail current) obtained after the final three stimulations of each applied concentration was used as the evaluation data. Furthermore, the IC was calculated using the Hill equation using the software from the current inhibition rate at each concentration of each test substance relative to the pre-application value. ５０ The value was calculated.

[0384] The results are shown in the table below.

[0385] Test Example 4: Evaluation of binding activity to side effect-related receptors The binding affinity of the compounds of the present disclosure to side effect-related receptors (for example, dopamine D2 receptor and adrenaline α1A receptor) can be measured by the following method.

[0386] A binding evaluation test is performed as follows using a CHO cell membrane fraction expressing a human target receptor. A test compound dissolved in dimethyl sulfoxide (DMSO), various receptor membrane specimens diluted with buffer, and a [3H]-labeled ligand with strong binding activity to each target receptor are mixed and incubated at room temperature. The mixture is then quickly added to a glass fiber filter plate (Multiscreen FB, Millipore) and filtered under reduced pressure. The radioactivity remaining on the filter is measured using a liquid scintillation counter (PerkinElmer). The binding inhibition rate is calculated using the following formula: To calculate the amount of nonspecific binding to the receptor membrane specimen, a control compound with strong binding activity to the target receptor is used instead of the test substance.

[0387] Binding inhibition rate to target receptor (%) = 100 - 100 × {(in the presence of test substance)} ３ H]-labeled ligand binding amount)}-(10 μmol / L in the presence of control compound [ ３ H]-labeled ligand binding amount)} / {(in the absence of test substance [ ３ H]-labeled ligand binding amount)}-(10 μmol / L in the presence of control compound [ ３ H] labeled ligand binding amount)

[0388] (Note) While the present disclosure has been illustrated using preferred embodiments thereof, it is understood that the scope of the present disclosure should be interpreted solely by the claims. This application claims priority to Japanese Patent Application Nos. 2021-66825 (filed April 10, 2021) and 2021-150394 (filed September 15, 2021), the contents of which are incorporated herein by reference in their entirety. It is understood that the patents, patent applications, scientific literature, and other literature cited herein are incorporated herein by reference in their entirety as if the contents themselves were specifically set forth herein.

[0389] The compounds of the present disclosure have agonistic activity against the trace amine-associated receptor TAAR1, and are therefore effective in treating psychiatric disorders and central nervous system disorders.

Claims

1. Formula I 【Chemistry 1】 [In the formula, X is an oxygen atom, a sulfur atom, or NR; n is 0 or 1; R １ is a hydrogen atom, an optionally substituted C １－６ Alkyl or optionally substituted C ３－６ alkenyl, R ２ａ , R ２ｂ , R ２ｃ , R 2d and R each independently represent a hydrogen atom, a halogen atom, or an optionally substituted C １－６ Alkyl or optionally substituted C ６－１０ aryl or R ２ａ , R ２ｂ , R ２ｃ two of R 2d and R together with the carbon or nitrogen atom to which they are attached form a 3- to 6-membered saturated carbocyclic or saturated heterocyclic ring; R ３ａ , R ３ｂ , and R ３ｃ each independently represents a hydrogen atom or an optionally substituted C １－６ Alkyl, halogen atom, -OR ４ or optionally substituted C ６－１０ is aryl, R ４ is an optionally substituted C １－６ alkyl or an optionally substituted 3- to 6-membered saturated carbocyclic ring; R ５ａ and R ５ｂ each independently represents a hydrogen atom or an optionally substituted C １－６ alkyl or R ５ａ and R ５ｂ together with the carbon atom to which they are attached form a 3- to 6-membered saturated carbocyclic ring, Where: The optionally substituted C １－６ Alkyl and optionally substituted C ３－６ Alkenyl is a halogen atom, hydroxy or C １－６ optionally substituted with alkoxy; The optionally substituted C ６－１０ Aryl and optionally substituted 3- to 6-membered saturated carbocyclic rings are substituted with halogen atoms, hydroxy, C １－６ Alkyl or C １－６ optionally substituted with alkoxy; or, X is CR'R'', n is 0 or 1; R 1 is a hydrogen atom, an optionally substituted C 1-6 alkyl or an optionally substituted C 3-6 alkenyl; R 2a , R 2b , R 2c , R 2d , R, R' and R" are each independently a hydrogen atom, a halogen atom, an optionally substituted C 1-6 alkyl, or an optionally substituted C 6-10 aryl, or two of R 2a , R 2b , R 2c , R 2d , R, R' and R" together with the carbon atom or nitrogen atom to which they are attached form a 3-6 membered saturated carbocyclic or saturated heterocyclic ring; R 3a , R 3b and R 3c each independently represent a hydrogen atom, an optionally substituted C 1-6 alkyl, a halogen atom, —OR 4 or an optionally substituted C 6-10 aryl; R 4 is an optionally substituted C 1-6 alkyl or an optionally substituted 3- to 6-membered saturated carbocyclic ring; R 5a and R 5b each independently represent a hydrogen atom or an optionally substituted C 1-6 alkyl; Where: The optionally substituted C 1-6 alkyl and the optionally substituted C 3-6 alkenyl are optionally substituted by a halogen atom, hydroxy or C 1-6 alkoxy; the optionally substituted C 6-10 aryl and the optionally substituted 3- to 6-membered saturated carbocyclic ring are optionally substituted by a halogen atom, hydroxy, C 1-6 alkyl or C 1-6 alkoxy; However, the following (1) to (19) are excluded: (1) n is 0, X is an oxygen atom, and R ２ａ and R ２ｂ is a hydrogen atom, (2) n is 1, X is an oxygen atom, and R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ and R ３ｃ is a hydrogen atom, (3) n is 1 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ３ａ is a hydrogen atom or CH ３ A compound, (4) n is 1, X is an oxygen atom, and R １ , R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ３ａ CH ３ A compound, (5) n is 1, X is an oxygen atom, and R １ , R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ２ｃ and R ２ｄ CH ３ A compound, (6) n is 1, X is an oxygen atom, and R １ , R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ３ｂ CH ３ A compound, (7) n is 1, X is an oxygen atom, and R １ , R ２ａ , R ２ｂ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ２ｃ CH ３ A compound, (8) n is 0 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ３ａ CH ３ A compound, (9) n is 1 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ２ｃ CH ３ A compound, (10) n is 1 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ３ｂ CH ３ and a compound in which the bromine atom is (11) n is 1, X is an oxygen atom, and R １ , R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ２ｃ and R ２ｄ taken together with the carbon atom to which they are attached form a cyclobutyl ring, (12) n is 1, X is an oxygen atom, and R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R １ CH ３ A compound, (13) n is 0 and X is CH ２ and R ２ａ , R ２ｂ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R １ is a hydrogen atom, optionally substituted C １－６ Alkyl or optionally substituted C ３－６ Compounds which are alkenyl, (14) n is 1 and X is CH ２ and R ２ａ , R ２ｂ , R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R １ is a hydrogen atom, optionally substituted C １－６ Alkyl or optionally substituted C ３－６ Compounds which are alkenyl, (15) n is 0 and X is CH ２ and R ２ａ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ２ｂ is a hydrogen atom and CH ３ and R １ is a hydrogen atom and CH ３ A compound, (16) n is 1 and X is CH ２ and R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ２ａ and / or R ２ｂ CH ３ and R １ is a hydrogen atom and CH ３ A compound, (17) n is 1 and X is CH ２ and R ２ｃ , R ２ｄ , R ３ａ , R ３ｂ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ２ａ and R ２ｂ together with the carbon atom to form a cyclopropane, R １ is a hydrogen atom and CH ３ A compound, (18) n is 0 or 1 and X is CH ２ and R ５ａ Or R ５ｂ is optionally substituted C １－６ Compounds which are alkyl, (19) n is 0 and X is CH ２ and R １ , R ２ａ , R ２ｂ , R ３ａ , R ３ｃ , R ５ａ and R ５ｂ is a hydrogen atom, R ３ｂ is a bromine atom. or a pharma- ceutically acceptable salt thereof.

2. formula 【Chemistry 2】 2. The compound of claim 1, wherein:

3. formula 【Chemistry 3】 2. The compound of claim 1, wherein:

4. R １ is a hydrogen atom or a C optionally substituted with a halogen atom １－６ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl group.

5. R １ is methyl, or a pharma- ceutically acceptable salt thereof.

6. R ２ａ and R ２ｂ are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl, or R 2a and R 2b together with the carbon atom to which they are attached form a 3-6 membered saturated carbocyclic ring, or a pharma- ceutically acceptable salt thereof.

7. R ２ａ is a hydrogen atom, R ２ｂ is optionally substituted C １－６ 7. The compound of claim 6, or a pharma- ceutically acceptable salt thereof, wherein: R is an alkyl group;

8. The compound according to any one of claims 1 to 3, wherein X is CR'R'', and R' and R'' are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl, or a pharma- ceutically acceptable salt thereof.

9. n is 1, R ２ｃ and R ２ｄ are each independently a hydrogen atom or an optionally substituted C 1-6 alkyl, or R 2c and R 2d together with the carbon atom to which they are attached form a 3- to 6-membered saturated carbocyclic ring, or a pharma- ceutically acceptable salt thereof.

10. R ３ａ , R ３ｂ , and R ３ｃ each independently represents a hydrogen atom or an optionally substituted C １－６ The compound according to any one of claims 1 to 3, wherein R is an alkyl or halogen atom, or a pharma- ceutically acceptable salt thereof.

11. R ３ａ , R ３ｂ , and R ３ｃ The compound according to claim 10, or a pharma- ceutically acceptable salt thereof, wherein each of is a hydrogen atom.

12. R ３ａ , R ３ｂ , and R ３ｃ At least one of the optionally substituted C １－６ 11. The compound of claim 10, or a pharma- ceutically acceptable salt thereof, wherein R is an alkyl or halogen atom.

13. R ５ａ and R ５ｂ The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein each of is a hydrogen atom.

14. The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof, wherein X is an oxygen atom.

15. R １ C which may be substituted with a halogen atom １－６ is alkyl, R ３ａ , R ３ｂ , and R ３ｃ At least one of the optionally substituted C １－６ is an alkyl or halogen atom; The compound according to any one of claims 1 to 3, or a pharma- ceutically acceptable salt thereof.

16. R １ is methyl, R ３ａ , R ３ｂ , and R ３ｃ at least one of is methyl, a fluorine atom, or a chlorine atom; 16. The compound of claim 15 or a pharma- ceutically acceptable salt thereof.

17. X is an oxygen atom; n is 0, R １ C which may be substituted with a halogen atom １－６ is alkyl, R ２ａ is a hydrogen atom, R ２ｂ is optionally substituted C １－６ is alkyl, R ３ａ , R ３ｂ , and R ３ｃ At least one of the optionally substituted C １－６ is an alkyl or halogen atom, R ５ａ and R ５ｂ are hydrogen atoms, 2. The compound of claim 1 or a pharma- ceutically acceptable salt thereof.

18. The compound according to claim 1, selected from the following group of compounds or a pharma- ceutically acceptable salt thereof: 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine, 1-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine, N-methyl-1-[(2R,3S)-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine, 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]-N-methylmethanamine, 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]-N-( ２ H ３ ) methylmethanamine, rel-1-[(3'S)-5'-methyl-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine, rel-1-[(3'S)-5'-fluoro-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine, rel-1-[(3S)-2,2,5-trimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine, rel-1-[(3'S)-3'H-spiro[cyclopropane-1,2'-furo[3,2-b]pyridin]-3'-yl]methanamine, and rac-1-(5-fluoro-2,2-dimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl)methanamine.

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