Bicyclic pyridine derivatives

Abstract

The present invention provides a compound that has agonist activity for the trace amine-associated receptor TAAR1, and is useful as a therapeutic agent for neuropsychiatric disorders. The present invention relates to a compound of the following formula I: TIFF2026035726000175.tif5858 In the formula, X is an oxygen atom, a sulfur atom, NR, or CR′R″, and n is 0 or 1.

Description

[Technical Field]

[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. [Background technology]

[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, TAs 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 monoamine nuclei of origin, including the ventral tegmental area and raphe nucleus, as well as in 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] Because the 6q23 locus encoding TAAR1 is associated with multiple psychiatric disorders and because there is a strong correlation between monoamine neurotransmission regulated by TAAR1 and neuropsychiatric disorders, TAAR1 receptor-selective ligands are expected to be effective in treating these disorders. Furthermore, small molecule compounds that exhibit TAAR1 receptor agonism have been reported to date, showing antipsychotic and antidepressant effects in multiple disease models using rodents and cognitive improvement effects in evaluations using non-human primates. Therefore, these compounds are expected to have antipsychotic, antidepressant, and cognitive improvement effects in humans as well (non-clinical literature 6). [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Written by Beth Borowsky Proc Natl Acad Sci USA.98,8966-8971,2001 [Non-patent document 2] Branchek, TA and Blackburn, TP Curr. Opin. Pharmacol. 3, 90-97, 2003 [Non-patent document 3] Written by James R. Bunzow Mol Pharmacol.60,1181-1188,2001 [Non-patent document 4] Zhihua Xie and Gregory M. Miller Journal of Pharmacology and Experimental Therapeutics 321,128-136,2007 [Non-patent document 5] Zhihua Xie and Gregory M. Miller Journal of Pharmacology and Experimental Therapeutics,330,316-325,2009 [Non-patent document 6] FG Revel Molecular Psychiatry,18,543-556,2013 Summary of the Invention [Means for solving the problem]

[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 discovered that a compound represented by the following formula I or a pharmaceutically acceptable salt thereof (hereinafter, sometimes 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] [Section 1] Formula I [ka] [In the formula, X is an oxygen atom, a sulfur atom, NR, or CR'R"; n is 0 or 1, R 1 is a hydrogen atom, optionally substituted C 1-6 Alkyl or optionally substituted C 3-6 is 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 optionally substituted C 6-10 aryl or R 2a , R 2b , R 2c , R 2dtwo 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 is aryl, R 4 may be 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, 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; 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 3cis a hydrogen atom, (3) n is 1, X is CH2, 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 CH3, (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, and R 3a Compounds in which is CH3, (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, and R 2c and R 2d Compounds in which is CH3, (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, and R 3b Compounds in which is CH3, (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 5bis a hydrogen atom, and R 2c Compounds in which is CH3, (8) n is 0, X is CH2, and R 1 , R 2a , R 2b , R 3b , R 3c , R 5a and R 5b is a hydrogen atom, and R 3a Compounds in which is CH3, (9) n is 1, X is CH2, 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 Compounds in which is CH3, (10) n is 1, X is CH2, 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 CH3 and bromine atom, (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, and R 2c and R 2d together with the carbon atoms to which they are attached to 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 , R5a and R 5b is a hydrogen atom, and R 1 Compounds in which is CH3, (13) n is 0, X is CH2, 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 a compound which is alkenyl, (14) n is 1, X is CH2, 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 a compound which is alkenyl, (15) n is 0, X is CH2, and R 2a , R 3a , R 3b , R 3c , R 5a and R 5b is a hydrogen atom, and R 2b are hydrogen atoms and CH3, and R 1 is a hydrogen atom and CH3, (16) n is 1, X is CH2, 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 CH3 and R 1 is a hydrogen atom and CH3, (17) n is 1, X is CH2, 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 CH3, (18) n is 0 or 1, X is CH2, and R 5a or R 5b optionally substituted C 1-6 a compound which is alkyl, (19) n is 0, X is CH2, 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] [Section 2] formula [ka] Item 1. The compound according to item 1, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof.

[0011] [Section 3] formula [ka] Item 1. The compound according to item 1, wherein the compound is represented by the following formula: or a pharmaceutically acceptable salt thereof.

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

[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 may be 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 may be 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 or a pharmaceutically acceptable salt thereof according to any one of Items 1 to 6, wherein is a halogen atom.

[0019] [Section 11] R 2a and R 2b 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.

[0020] [Section 12] R 2a may be 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 but hydroxy or C 1-6 Item 7. The compound according to any one of Items 1 to 6, wherein the group is substituted with alkoxy, or a pharmaceutically acceptable salt thereof. [Section 13-1] Item 14. The compound or pharmaceutically acceptable salt thereof according to any one of items 1 to 13, wherein X is CR'R'', and R' and R'' are hydrogen atoms. [Section 13-2] X is CR'R'', R' is a hydrogen atom, and R'' is an optionally substituted C 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. [Section 13-3] X is CR'R'', and R' and R'' are optionally substituted C 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] [Section 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 and 3 to 13-3, wherein is a hydrogen atom.

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

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

[0025] [Section 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 and 3 to 13-3, wherein is a halogen atom.

[0026] [Section 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] [Section 19] n is 1 and R 2c optionally substituted C 6-10 aryl, and R 2d The compound or a pharmaceutically acceptable salt thereof according to any one of Items 1 and 3 to 13-3, wherein is a hydrogen atom.

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

[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 is independently a hydrogen atom or a halogen atom.

[0030] [Section 22] R 3a , R 3b , and R 3c and R are each a hydrogen atom, or a pharmaceutically acceptable salt thereof. [Section 22-1] R 3a , R 3b , and R 3c At least one of the optionally substituted C 1-6 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 R are each a hydrogen atom, or a pharmaceutically acceptable salt thereof.

[0032] [Section 24] R 5a is a hydrogen atom, and R 5b may be 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 each of which may be 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] [Section 26] 26. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 25, wherein X is an oxygen atom.

[0035] [Section 27] 26. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 25, wherein X is a sulfur atom.

[0036] [Section 28] 26. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 25, wherein X is NR.

[0037] [Section 29] 26. The compound according to any one of items 1 to 25, wherein X is CR'R" or a pharmaceutically acceptable salt thereof. [Section 29-1] R 1 C optionally 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 items 1 to 3, 5, 7 to 21, 22-1, and 23 to 29, or a pharmaceutically acceptable salt thereof. [Section 29-2] R 1 is methyl, R 3a , R 3b , and R 3c at least one of is methyl, a fluorine atom, or a chlorine atom; The compound according to item 29-1 or a pharmaceutically acceptable salt thereof. [Section 30] X is an oxygen atom, n is 0, R 1 C optionally substituted with a halogen atom 1-6 is alkyl, R 2a is a hydrogen atom, and R 2b may be 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 R5b are hydrogen atoms, Item 1. The compound according to Item 1 or a pharmaceutically acceptable salt thereof. [Section 31] Item 31. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 30, wherein a hydrogen atom of the compound is deuterium. [Section 32] Item 1, wherein the compound is selected from the following group of compounds 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 H3) 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] [Section 33] 33. A pharmaceutical composition comprising the compound according to any one of items 1 to 32 or a pharmaceutically acceptable salt thereof.

[0039] [Section 34] 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] [Section 35] Item 35. The pharmaceutical composition according to Item 33 or 34, wherein the pharmaceutical composition is for treating or preventing a neurological or psychiatric disorder.

[0041] [Section 36] 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] [Section 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] [Section 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] [Section 39] 39. The method of claim 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] [Section 40] Item 33. The compound or a pharmaceutically acceptable salt thereof according to any one of items 1 to 32 for use as a pharmaceutical.

[0046] [Section 41] 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] [Section 42] 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] [Section 43] 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] [Section 44] Item 33. A TAAR1 agonist which is the compound according to any one of Items 1 to 32 or a pharmaceutically acceptable salt thereof.

[0050] [Section 45] Item 33. 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] [Section 46] 33. A therapeutic agent for treating 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] [Section 47] Item 47. The therapeutic agent according to Item 46, wherein the psychiatric or central nervous system disease is an organic mental disorder, including symptomatic; a mental or behavioral disorder due to the use of psychoactive substances; schizophrenia, schizophreniform disorder, and delusional disorder; a mood (affective) disorder; a neurotic disorder, a stress-related disorder, and a somatoform disorder; a non-organic sleep disorder; a sexual dysfunction not due to an organic disorder or disease; a pervasive developmental disorder; a behavioral and emotional disorder usually occurring in childhood and adolescence; an extrapyramidal disorder and abnormal movement; another degenerative disease of the nervous system; or a sleep disorder.

[0053] [Section 48] Item 47. 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] [Section 49] Item 47. 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] [Section 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] [Section 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] [Section 52] Item 33. 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] [Section 53] Item 33. 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] [Section 54] Item 33. A therapeutic agent for treating 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, 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. [Effects of the Invention]

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

[0061] [Figure 1] FIG. 1 shows the results of a test (Test Example 2-1) on the compound of Example 27 to inhibit phencyclidine-induced hyperactivity. [Figure 2] FIG. 1 shows the results of a test (Test Example 2-2) on the compound of Example 8 in inhibiting phencyclidine-induced hyperactivity. [Figure 3] FIG. 1 shows the results of a test (Test Example 2-2) on the compound of Example 49 to inhibit phencyclidine-induced hyperactivity. DETAILED DESCRIPTION OF THE INVENTION

[0062] The present disclosure will now be described, illustrating the best mode thereof. Throughout this specification, singular expressions should be understood to include the plural concept unless otherwise specified. Thus, singular articles (e.g., "a," "an," "the," etc. in English) should be understood to include the plural concept unless otherwise specified. Furthermore, terms used in this specification should be understood to have the meaning 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 one of ordinary skill 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 having 1 to 6 carbon atoms. 1-6 As the alkyl, preferably "C 1-4 alkyl" 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 "C3-6 In the case of "alkenyl", R 1 The "C" adjacent to the nitrogen atom bonded to 3-6 "Alkenyl" means a group having no double bond on the carbon atom of "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" portion 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 one example. 1-3 Specific 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 heterocycle" 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 heterocycle" is preferably a "4- to 6-membered monocyclic saturated heterocycle", and more preferably a "5- or 6-membered monocyclic saturated heterocycle". Specific examples of the "5- or 6-membered monocyclic saturated heterocycle" include 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 carbocyclic ring" refers to a cyclic saturated hydrocarbon having 3 to 6 carbon atoms, and includes those having a partial unsaturated bond and those having a bridged structure. A "3- to 6-membered saturated carbocyclic ring" is preferably a "5- or 6-membered monocyclic saturated carbocyclic ring." Specific examples of a "5- or 6-membered monocyclic saturated carbocyclic ring" include, for example, cyclopentane and cyclohexane. Specific examples of a "3- to 6-membered saturated carbocyclic ring" include those exemplified above as specific examples of the "5- or 6-membered monocyclic saturated carbocyclic ring," 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. 6-10The "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 type at any chemically possible position, and when there are two or more substituents, the respective substituents may be the same or different. Specific examples of the substituents include halogen atoms, 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 substituents in alkenyl include halogen atoms, hydroxyl, and C 1-6 alkoxy, optionally substituted C 6-10 Specific examples of the substituents in the aryl and 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 may be substituted C 1-6 Examples of the alkyl group include alkyl.

[0084] In a preferred embodiment, R 2a and R 2b may be substituted C 1-6 Examples 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 However, examples thereof include those which, together with the carbon atom to which they are attached, form a 3- to 6-membered saturated carbocyclic ring.

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

[0088] In a preferred embodiment, R 2a or R 2b but 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 may be substituted C 1-6 Examples include alkyl.

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

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

[0093] In a preferred embodiment, n is 1 and R 2c and R 2d However, examples thereof include those which, together with the carbon atom to which they are attached, form a 3- to 6-membered saturated carbocyclic ring.

[0094] In a preferred embodiment, n is 1 and R 2c optionally substituted C 6-10 aryl, and R2d is a hydrogen atom.

[0095] In a preferred embodiment, R 2c or R 2d but 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 optionally substituted C 1-6 Examples include alkyl.

[0100] In a preferred embodiment, 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.

[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 optionally substituted C 1-6 Examples include alkyl.

[0103] In a preferred embodiment, R 5a and R 5b are optionally substituted C 1-6 Examples 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 3c wherein 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 R1 C optionally substituted with a halogen atom 1-6 alkyl, and R 2a is a hydrogen atom, and R 2b may be 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, "rac." means a racemic compound, "chiral" means an optically active compound, and "abs." means an absolute configuration.

[0113] In addition, derivatives of the compounds represented by formula I in which any one or more atoms are converted to isotopes are also encompassed within the compounds 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] Manufacturing 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] Manufacturing 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. [ka] [In the formula, n, R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 3c , R 5a and X is the same as Item 1, and R 6is optionally substituted C 1-6 represents alkyl, PG 1 represents an alkyl carbamate such as tert-butoxycarbonyl or benzyloxycarbonyl.

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

[0125] 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, 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 (C) is benzyloxycarbonyl, it can be 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 between 0°C and the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, catalyst, raw materials, and solvent used, but is usually between 10 minutes and 48 hours.

[0128] Specific examples of inert solvents 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 compound 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 diphenylphosphoryl azide in an appropriate inert solvent in the presence of an appropriate base at room temperature for about 1 hour, heating and stirring at an appropriate temperature of 50°C to 100°C for about 1 hour, reacting the resulting mixture with a base such as sodium hydroxide or potassium hydroxide in the presence of water, and then reacting the resulting mixture with di-tert-butyl dicarbonate, if necessary, in the presence of an appropriate 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 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; 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 a suitable solvent. The treatment 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 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 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] Manufacturing 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. [ka] [In the formula, n, R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 3c , R 5a and X is synonymous with Term 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 PG 1 When is tert-butoxycarbonyl, it is prepared by treating compound (6) with an appropriate acid. The treatment temperature is usually between -20°C and the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, acid, raw materials, and solvent used, but is usually between 10 minutes and 48 hours.

[0140] 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, 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 PG 1When (C) is benzyloxycarbonyl, it can be 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 between 0°C and 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 between 10 minutes and 48 hours.

[0143] Specific examples of inert solvents 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 the reaction temperature, the base used, the starting materials, the solvent, and other conditions, but is usually 10 minutes to 48 hours.

[0145] 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. Specific examples of the phase transfer catalyst 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] Manufacturing method 3 The compound represented by formula (2) can be produced, for example, by the method shown below. [ka] [In the formula, n, R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 3c , and X is synonymous with term 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(carboethoxymethyl)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 10 minutes to 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 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; 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 typically 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, and solvent used, but is typically 10 minutes to 48 hours.

[0151] 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; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0152] Manufacturing method 4 Among the compounds represented by formula (2), the compound represented by formula (2a) is produced, for example, by the method shown below. [ka] [In the formula, n, R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c is synonymous with term 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 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 10 minutes to 48 hours.

[0154] 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; aprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidinone, and dimethyl sulfoxide; and mixed solvents thereof.

[0155] Manufacturing method 5 Among the compounds represented by formula (7), the compound represented by formula (7a) is produced, for example, by the method shown below. [ka] [In the formula, n, R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c is synonymous with term 1, and R 8 is optionally substituted C 1-6 represents alkyl, 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) can be 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 typically 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 typically 10 minutes to 48 hours.

[0157] 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; 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) can be prepared 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 the reaction temperature, the starting materials used, the solvent, and other conditions, but is usually 10 minutes to 48 hours.

[0160] Specific examples of the reducing agent include complex 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 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; 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 10 minutes to 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 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.

[0166] Manufacturing method 6 Among the compounds represented by formula (7), the compound represented by formula (7b) is produced, for example, by the method shown below. [ka] [In the formula, n, R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , and R 3c is synonymous with 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 10 minutes to 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 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.

[0171] Manufacturing method 7 Among the compounds represented by formula I, the compound represented by formula (1c) is produced, for example, by the method shown below. [ka] [In the formula, n, R 2a , R 2b , R 2c , R 2d , R 3a , R 3b , R 3c and X has the same meaning as in item 1.

[0172] Compound (1c) can be 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 the reaction temperature, starting materials, and solvent used, but is usually 10 minutes to 48 hours.

[0173] Specific examples of the reducing agent include complex 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 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; 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. Optically active substances can also be used as starting materials.

[0179] When a salt of a compound represented by formula I is desired to be obtained, 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, the compound represented by formula I 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 compounds have agonistic activity against the trace amine-associated receptor TAAR1 receptor and have a mechanism of action different from existing antipsychotic drugs, and therefore can provide new options for pharmacological treatment of various psychiatric disorders. That is, the disclosed compounds are effective in treating psychiatric disorders. The disclosed compounds are also effective for central nervous system disorders.

[0181] Examples of psychiatric disorders or central nervous system disorders for which efficacy is expected include, for example, the following 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, stress-related, 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 of 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, and somatoform disorders.

[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: 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 that typically occur 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, etc.

[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: 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 (Test Example 1). In a preferred embodiment of the disclosed compounds, the hERG channel inhibitory activity, which is an indicator of the onset 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 exhibited is different from the concentration at which side effects are exhibited.

[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 (normal 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 compound of the present disclosure together with a pharmaceutically acceptable carrier. The compound of the present disclosure 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, which may contain water. Liquids suitable for oral administration can be prepared by adding the disclosed compound 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 disclosed compound to water together with a dispersant 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, route of administration, 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 or 3 divided doses. It can also be administered once every few days to several 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 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, to suppress side effects, the compound of the present disclosure may be used in combination with drugs (concomitant drugs) such as antiemetics, hypnotics, and anticonvulsants. [Example]

[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 names of compounds shown in the following reference examples and examples do not necessarily conform to IUPAC nomenclature. Furthermore, the identification of compounds can be performed by proton nuclear magnetic resonance absorption spectroscopy ( 1 Measurements were performed using H-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. [Table 1]

[0206] The following abbreviations may be used in this specification: Me: Methyl Et: Ethyl DMF: N,N-dimethylformamide THF: tetrahydrofuran tert-: tertiary TBS: tert-butyldimethylsilyl CDCl3: deuterated chloroform DMSO-D6: deuterated dimethyl sulfoxide CD3OD: 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 [ka] 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 the concentrated residue was dissolved in methanol, and the 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 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 give the title compound (26 mg). 1 H-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 [ka] 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 [ka] The compound of Reference Example 5 was optically resolved by chiral HPLC to obtain the compound of Peak 1. 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 25cm Solvent: Hexane (90%) - IPA (10%) including diethylamine (0.1%) Flow rate: 1.0 mL / min Retention time = 3.8 min (first peak) [α] D 22.4 -10.4 (c0.1,MeOH) 1H-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 [ka] 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 25cm 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) 1H-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 [ka] 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. The precipitated solid was then collected by filtration and dried under reduced pressure to give the title compound (142 mg). 1H-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 6-7 According to the method described in Example 5, the compounds of Examples 6 and 7 were obtained from the corresponding compounds of Reference Examples. [Table 2]

[0217] Example 8 1-[(2R,3S)-6-Fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride [ka] 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. [Table 3-1] [Table 3-2] [Table 3-3]

[0219] Example 27 1-[(2R,3S)-2-Methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methanamine dihydrochloride [ka] 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. After stirring at room temperature under a hydrogen atmosphere for 5 hours, the mixture was 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 stirred at room temperature for 15 minutes. After concentrating the reaction solution, the obtained 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. [Table 4]

[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 [ka] 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 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 purified by silica gel column chromatography (hexane / ethyl acetate). 4 mol / L hydrogen chloride-ethyl acetate (1.0 mL) was added to an ethyl acetate solution (1.0 mL) of the obtained product, and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated, and then 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 [ka] 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 [ka] 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 resulting 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 purified by silica gel column chromatography (hexane / ethyl acetate). To a mixture of the resulting 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 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 [ka] To a toluene solution (57.3 mL) of the 10:1 diastereomeric mixture (1.66 g, 8.59 mmol) from 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 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 purified by silica gel column chromatography (hexane / ethyl acetate). A portion of the resulting product (100 mg) was further 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 give 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 [ka] 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 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 (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. After concentrating the reaction solution, the obtained crude crystals were recrystallized from 2-propanol and methanol to give 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 [ka] The title compound was obtained from the compound of Reference Example 54 by the same method as in Example 37. 1 H-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 [ka] 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 [ka] The compound of Reference Example 15 was optically resolved by chiral HPLC to obtain the compound of peak 2. Then, the title compound was 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 [ka] The compound of Reference Example 18 was optically resolved by chiral HPLC to obtain the compound of Peak 1. Then, the title compound was 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 [ka] The compound of Reference Example 18 was optically resolved by chiral HPLC to obtain the compound of peak 2. Then, the title compound was 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 [ka] The compound of Reference Example 33 was optically resolved by chiral HPLC to obtain the compound of Peak 1. Then, the title compound was 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 [ka] The compound of Reference Example 33 was optically resolved by chiral HPLC to obtain the compound of peak 2. Then, the title compound was 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 [ka] 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 give the title compound (101 mg). 1 H-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 [ka] 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 give the title compound (45 mg). 1 H-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 and 48 were obtained from the compounds of the corresponding Examples. [Table 5]

[0241] Example 49 1-[(2R,3S)-6-Fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]-N-methylmethanamine dihydrobromide [ka] 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 and 51 were obtained from the compounds of the corresponding Examples. [Table 6]

[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. [Table 7-1] [Table 7-2]

[0244] Example 62 rac-1-[(2R,3R,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methanamine dihydrochloride [ka] 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, which was then 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 purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the 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. [Table 8]

[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. [Table 9-1] [Table 9-2]

[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. [Table 10-1] [Table 10-2]

[0248] Example 88 rac-1-(2-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)methanamine dihydrochloride [ka] 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). 1H-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 [ka] 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 [ka] 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) was added (2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (73.6 mg, 0.087 mmol). 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 purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the 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 aminosilica 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 [ka] 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 extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate). 4 mol / L hydrobromic acid-acetic acid (0.500 mL) was added to the resulting purified product. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The concentrated residue was 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 resulting 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 [ka] To a tetrahydrofuran solution (1.2 mL) of the compound of Reference Example 104 (40.2 mg, 0.233 mmol), a tetrahydrofuran solution (0.769 mL, 0.700 mmol) of 0.91 mol / L borane-tetrahydrofuran complex 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 [ka] The title compound was obtained as a 1:1 diastereomeric mixture of Example 93-1 and Example 93-2 from the compound of Reference Example 108 by a method similar to that of Example 92. 1H-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 [ka] 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), di-tert-butyl dicarbonate (113 mg, 0.517 mmol) was added. 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), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain a purified product (120 mg). The 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) 1H-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 [ka] 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. Then, the title compound was 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 [ka] 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 peak 1. Then, the title compound was 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 [ka] 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. Then, the title compound was 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 [ka] The compound of Reference Example 89 was optically resolved by chiral HPLC to obtain the compound of Peak 1. Then, the title compound was 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 [ka] The compound of Reference Example 89 was optically resolved by chiral HPLC to obtain the compound of peak 2. Then, the title compound was 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 [ka] 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 peak 1. Then, the title compound was 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) 1H-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 [ka] 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. Then, the title compound was 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 [ka] The compound of Reference Example 96 was optically resolved by chiral HPLC to obtain the compound of Peak 1. Then, the title compound was 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 [ka] The compound of Reference Example 96 was optically resolved by chiral HPLC to obtain the compound of the second peak, followed by the same procedure as in Example 49 to obtain the title compound. [Chiral HPLC conditions] Column: IG Solvent: Hexane (50%) - EtOH (50%) Flow rate: 1.0 mL / min Retention time = 7.14 min (first peak) 1H-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 [ka] 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 peak 1. 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 [ka] 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. 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 = 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 [ka] The title compound was obtained from the compound of Reference Example 118 by the same method as 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 [ka] 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 give 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 [ka] 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 [ka] 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 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 [ka] 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 purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.65 g). 1H-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 [ka] Triethylamine (0.049 mL) and di-tert-butyl dicarbonate (0.041 mL) were added to a chloroform solution (1.0 mL) of the compound (22.0 mg) of Example 2. After stirring at room temperature for 2 hours, the mixture was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (20.4 mg). 1 H-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 [ka] 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 the concentrated residue was dissolved in methanol, and the insoluble matter was filtered off and concentrated.

[0273] To a toluene solution (400 mL) of the resulting 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. A 5 mol / L aqueous sodium hydroxide solution (84.0 mL) was added dropwise to the reaction mixture under ice cooling. The reaction mixture was warmed to room temperature over 2 hours, then adjusted to pH 7 with 6 mol / L hydrochloric acid and concentrated. The concentrated residue was dissolved in methanol, and the 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 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 1H-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 [ka] 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 give the title compound (5.37 g) as a 3:1 diastereomeric mixture. Major diastereomer 1H-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 [ka] 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 purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (7.90 g). 1 H-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 [ka] 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 [ka] 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 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 [ka] 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. 1H-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 [ka] 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 [ka] 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 the insoluble matter was filtered 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 [ka] 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, the reaction mixture was added with methanol and 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). 4 mol / L hydrochloric acid (10.4 mL) was then added until the aqueous layer reached pH 5, followed by extraction 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 [ka] 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. Insoluble matter was filtered off and the mixture was 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 allowed to warm to room temperature over 2 hours, neutralized with 6 mol / L hydrochloric acid, and concentrated. The concentrated residue was dissolved in methanol, and the insoluble matter was filtered and concentrated. A mixture of the concentrated residue and chloroform (30 mL) was added with triethylamine (2.20 mL, 15.8 mmol) and dicarbonic acid. Di-tert-butyl ether (3.66 g, 15.8 mmol) was 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). The extract was 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 (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 [ka] 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. The mixture was extracted with chloroform (20 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was 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 [ka] 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) was added potassium carbonate (8.00 g). After stirring at room temperature for 24 hours, the mixture was filtered through Celite and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.66 g). 1 H-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 18~22 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. [Table 11]

[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 [ka] The title compounds, Reference Examples 25-1 and 25-2, were obtained from Reference Examples 6-1, 6-2 and 10 in the same manner as in Reference Example 10 from 2-bromo-3-hydroxy-6-methylpyridine. 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 [ka] 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. Reference example 26-1 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). 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 [ka] 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 purified by silica gel column chromatography (hexane / ethyl acetate) to give 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 [ka] 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), diisopropyl azodicarboxylate (1.83 mL, 12.6 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 purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (13.5 g). 1H-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 [ka] 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 [ka] 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 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 [ka] 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 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 purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.19 g). 1 H-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 [ka] 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, and the mixture was extracted with ethyl acetate (200 mL x 2). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (1.36 g). 1H-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 33~34 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. [Table 12]

[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 [ka] 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 to Reference Example 10. Reference example 35-1 1H-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 [ka] 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 [ka] 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 purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (23.6 g) as a 10:1 diastereomeric mixture. Major 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 [ka] 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 × 2). Subsequently, 5 mol / L hydrochloric acid (120 mL) was added until the aqueous layer reached pH 5, and extraction was performed with chloroform (200 mL × 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. Major diastereomer 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 [ka] 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 [ka] To a mixture of the compound of Reference Example 41 (23.8 g, 167 mmol) and methanol (478 mL) was added sodium borohydride (7.59 g, 201 mmol) 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). 1 H-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 [ka] 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. 2.69 mol / L n-butyllithium (100 mL, 269 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 30 minutes, a solution of ethyl chloroformate (26.6 mL, 279 mmol) in tetrahydrofuran (59 mL) 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. The reaction mixture was added with water (300 mL), extracted with ethyl acetate (200 mL x 3), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was 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 42~45 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. [Table 13]

[0305] Reference example 46 rac-Benzyl {[(2S,3S)-2-(methoxymethyl)-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate [ka] 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 [ka] 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. 6 mol / L hydrochloric acid was then added to the reaction mixture until the pH reached 4, and the mixture was concentrated. The concentrated residue was 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 [ka] The title compound was obtained from the compound of Reference Example 49 by the same method as in Reference Example 1-1. 1 H-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 [ka] The title compound was obtained from methyl 2-bromo-3-methoxypropoate by methods similar to those in Reference Examples 30 and 32. 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 [ka] By the same procedures as in Reference Examples 8 to 10 and 14, the title compound was obtained from 2-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexan-1-ol. 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 [ka] 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 [ka] 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 53~54 According to the methods described in Reference Examples 38 and 39, the compounds of Reference Examples 53 and 54 were obtained from the corresponding compounds. [Table 14]

[0313] Reference example 55 Benzyl {[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl]methyl}methylcarbamate [ka] To a suspension of 55% sodium hydride (12.0 g, 276 mmol) in N-methylpyrrolidone (491 mL) was added a solution of the compound from 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). 1 H-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 [ka] 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 57~59 According to the methods described in Reference Examples 7 to 10, 37, and 47, the compounds of Reference Examples 57 to 59 were obtained from the corresponding compounds. [Table 15]

[0316] Reference example 60 rac-tert-butyl {[6-(trifluoromethyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate [ka] 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 [ka] To a mixture of the compound of Reference Example 62 (261 mg, 1.01 mmol) and tetrahydrofuran (5.0 mL), a 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, which was then stirred for 15 minutes. The reaction mixture was concentrated, and the 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 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). 1H-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 [ka] 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) was added 1.0 mol / L tetrabutylammonium fluoride (4.21 mL, 4.21 mmol), 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 [ka] 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 heated to reflux for 5 hours. After cooling to room temperature, the precipitated solid was filtered, and the filtrate was concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (510 mg). 1 H-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 64~65 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. [Table 16]

[0321] Reference example 66 2-Iodo-4,6-dimethylpyridin-3-ol [ka] 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 [ka] 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. Insoluble matter was filtered off, and the mixture was concentrated again. To a toluene solution (0.45 mL) of the resulting 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 (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 [ka] To a solution (1.7 mL) of the compound of Reference Example 69 (150 mg, 0.678 mmol) in tetrahydrofuran, 1.0 mol / L lithium bis(trimethylsilyl)amide toluene solution (1.63 mL, 1.63 mmol) was added dropwise at −78° C. After stirring for 30 minutes at −78° C., iodomethane (1.63 mL, 1.63 mmol) was added. After stirring for an additional hour, the reaction mixture was warmed to room temperature over an 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 [ka] 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 give the title compound (3.87 g) as a 5:1 diastereomeric mixture. Major diastereomer 1 H-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 [ka] The title compounds, Reference Example 70-1 and Reference Example 70-2, were obtained from the compound of Reference Example 71 by the same method as in Reference Example 67. Reference example 70-1 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 1H-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 [ka] To a solution (9.0 mL) of the compound of Reference Example 69 (800 mg, 3.62 mmol) in tetrahydrofuran, 1.0 mol / L lithium bis(trimethylsilyl)amide in tetrahydrofuran (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 an hour. A saturated aqueous solution of ammonium chloride (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 purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (826 mg) as a 1.4:1 diastereomeric mixture of Reference Example 71-1 and Reference Example 71-2. Major diastereomer 1H-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 72~73 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. [Table 17]

[0328] Reference example 74 rac-benzyl {[(2R,3S)-2-methyl(2- 2 H)-2,3-Dihydrofuro[3,2-b]pyridin-3-yl]methyl}carbamate [ka] 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 [ka] To a solution of propane-2-d-1,2-diol (1.04 g, 13.5 mmol) in chloroform (45 mL) was added imidazole (0.919 g, 13.5 mmol) and tert-butyldimethylsilyl chloride (1.83 g, 12.2 mmol) 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 [ka] 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. Reference example 76-1 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 [ka] To a chloroform solution (13 mL) of the compound of Reference Example 78 (1.73 g, 6.31 mmol), a 1 mol / L solution of boron tribromide in dichloromethane (12.6 mL, 12.6 mmol) was added under ice-cooling. After stirring at room temperature for 2 hours, saturated aqueous sodium bicarbonate (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). 1H-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 [ka] 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 [ka] 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. 1H-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 [ka] To a solution of the compound of Reference Example 81 (2.65 g, 7.51 mmol) in tetrahydrofuran (75 mL), 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 give the title compound (1.69 g). 1 H-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 [ka] 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 it 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 [ka] 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 [ka] 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 [ka] To a solution (1.0 mL) of the compound of Reference Example 82 (34.8 mg, 0.114 mmol) in methanol, 10% palladium on carbon (25 mg) was added. After stirring at room temperature for 2 hours under a hydrogen atmosphere, the mixture was 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 85~87 According to the method described in Reference Example 82, the compounds of Reference Examples 85 to 87 were obtained from the corresponding compounds. [Table 18]

[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 [ka] Reference Example 88-1, Reference Example 88-2, Reference Example 88-3, and Reference Example 88-4 of the title compound were obtained from 2-methylbutane-1,3-diol by the same method as in Reference Example 8 to Reference Example 10, Reference Example 37 to Reference Example 38, and Reference Example 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),3.79-3.73(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 1 H-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),3.80-3.75(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 1H-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 [ka] The title compound was obtained from the compound of Reference Example 90 by the same procedures as in Reference Examples 6 to 7 and Reference Examples 30 to 31. 1 H-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 [ka] The title compound was obtained from 2-bromo-5-chloro-3-hydroxypyridine by the same procedures as in Reference Examples 80 and 81. 1H-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 [ka] 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 [ka] 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 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 [ka] 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). 1H-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 [ka] 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 purified by silica gel chromatography (hexane / ethyl acetate) to give 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 95~96 According to the methods described in Reference Examples 79 to 81, the compounds of Reference Examples 95 and 96 were obtained from the corresponding compounds. [Table 19]

[0348] Reference example 97 rac-tert-butyl [(4-chloro-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl)methyl]carbamate [ka] 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 [ka] 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). 1 H-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 [ka] 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). 1H-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 [ka] 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 purified by silica gel column chromatography (chloroform / methanol) to give 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 [ka] 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). 1 H-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 [ka] To the compound of Reference Example 93 (500 mg, 1.62 mmol) was added phosphoryl chloride (1.5 mL, 16.22 mmol) 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 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 [ka] The title compounds, Reference Example 103-1 and Reference Example 103-2, were obtained from 2-ethylpropane-1,3-diol by the same procedures as in Reference Examples 2 to 4 and Reference Examples 37 and 38. Reference example 103-1 1H-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 [ka] 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 [ka] 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 solution of sodium bicarbonate (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 [ka] To a solution (5.3 mL) of the compound of Reference Example 107 (85.5 mg, 0.530 mmol) in methanol, sodium borohydride (30.1 mg, 0.796 mmol) was added under ice-cooling. After stirring at room temperature for 3 hours, a saturated aqueous solution of ammonium chloride (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 to give the title compound (93.7 mg). 1H-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 [ka] 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 at 120°C for 2 hours under microwave irradiation. The reaction mixture was then purified by silica gel column chromatography (chloroform / methanol) to give 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 [ka] The title compound was obtained as a 1:1 diastereomeric mixture of Reference Example 108-1 and Reference Example 108-2 from the compound of Reference Example 109 by the same method 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 [ka] Trifluoroacetic anhydride (3.0 mL, 21.4 mmol) was added to a chloroform solution (2.0 mL) of the compound of Reference Example 110 (232 mg, 1.55 mmol) 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. 1H-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 [ka] 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 [ka] The title compound was obtained as a diastereomeric mixture of Reference Example 111-1 and Reference Example 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, 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 [ka] 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 113~114 According to the methods described in Reference Examples 5 and 55, the compounds of Reference Examples 113 and 114 were obtained from the compounds of the corresponding Examples. [Table 20]

[0365] Reference example 115 rac-Benzyl [(2,2,5-trimethyl-2,3-dihydrofuro[3,2-b]pyridin-3-yl)methyl]carbamate [ka] 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 [ka] 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. 1H-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 [ka] 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). 1H-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 [ka] 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). Activation of the TAAR1 receptor by agonists 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 TMThe 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 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 compounds was measured by time-resolved fluorescence using EnVision (excitation wavelength: 330 nm, emission wavelength: 620 nm / 665 nm). Test compound % = 100 × {(Csamp) - (Cblank)} / {(Ctyramine) - (Cblank)} Csamp: counts of test compound, Ctyramine: counts of 100 μM tyramine, Cblank: counts of blank [Table 21-1] [Table 21-2] [Table 21-3] [Table 21-4] [Table 21-5]

[0372] Test Example 2-1: Phencyclidine-induced hyperactivity suppression test Eight-week-old C57BL / 6J male mice were used. A 0.5% methylcellulose solution was used as a solvent to prepare a turbid administration solution for the test compound, and a physiological saline solution was used as a solvent to prepare a phencyclidine administration solution.

[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 and the measurement of locomotion was started. After 30 minutes, the mice were gently removed and orally administered with a compound administration solution (solvent or test compound suspension), and then returned to their cages. 30 minutes after administration, the phencyclidine administration solution or saline solution was administered subcutaneously. After that, the mice were quickly returned to the locomotion measurement cages for each channel, and the locomotion measurement continued. The locomotion measurement was carried out for 120 minutes from the start of measurement, with measurement intervals of 5 minutes. The data for 90 minutes, from 30 minutes to 120 minutes after the start of the locomotion measurement, were used as the test results, and the 90-minute locomotion of each individual was calculated. The amounts were totaled.

[0375] Parametric Dunnett's multiple comparison (significant difference) was performed between the test compound and vehicle groups. The test compound-administered group showed no significant motor activity compared with the vehicle-administered group. If the amount of the drug was suppressed, it was determined to have an antipsychotic effect. The results of the above test using the compound of Example 27 are shown in FIG.

[0376] Test Example 2-2: Phencyclidine-induced hyperactivity suppression test Eight-week-old C57BL / 6J male mice were used. Physiological saline was used as a solvent to prepare a cloudy administration solution for the test compound, and physiological saline was used as a solvent to prepare a phencyclidine administration 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 and vehicle groups. If the test compound group showed a significant suppression of locomotion compared to the vehicle group, it was determined to have an antipsychotic effect. The results of the above test using the compounds of Example 8 and Example 49 are shown in FIGS.

[0380] Test Example 3: Evaluation of hERG channel inhibitory activity The hERG channel inhibitory activity of the disclosed compounds was evaluated using human rapidly activated delayed rectifier potassium current (I Kr We used CHO cells that overexpressed the hERG channel involved in autopatch Measurements were performed using the whole-cell patch clamp method using a clamp system.

[0381] (Preparation of cell suspension) hERG-CHO cells purchased from ChanTest were cultured at 37°C in a CO2 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 fluids used for the measurements were prepared as follows. Extracellular fluid: 2mmol / L CaCl2, 1mmol / LmgCl2, 10mmol / L HEPES, 4mmol / L KCl, 145mmol / L NaCl, 10mmol / Lglucose Intracellular fluid: 10mmol / L HEPES, 10mmol / L EGTA, 20mmol / L KCl, 130mmol / L KF Test substance solution: The test substance was dissolved in DMSO at 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 fluid, and then serially diluted with extracellular fluid 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) The cell suspension, extracellular solution, intracellular solution, and 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, followed by a depolarizing pulse from -50 mV to +20 mV for 5 seconds, followed by a repolarizing pulse at -50 mV for 5 seconds, followed by a return to the holding potential. The interval between pulses was 15 seconds. Data were analyzed using Qube analysis software (Sophion). Four concentrations of each test substance were applied incrementally, and the average peak current obtained after the final three stimulations of each applied concentration was used as the evaluation data. In addition, 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. [Table 22-1] [Table 22-2] [Table 22-3]

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

[0386] Binding evaluation tests are performed as follows using CHO cell membrane fractions expressing human target receptors. Test compounds dissolved in dimethyl sulfoxide (DMSO), various receptor membrane specimens diluted in buffer, and [3H]-labeled ligands 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 specimens, 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. [Industrial Applicability]

[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

[Claim 1] The invention described herein.

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