Bicyclic pyridine derivatives

Abstract

This invention provides bicyclic pyridine derivatives. Compounds of formula I or pharmaceutically permissible salts thereof, wherein X is an oxygen atom, a sulfur atom, NR or CR'R", n is 0 or 1, and R... 1 R 2a R 2b R 2c R 2d R, R', and R" are, respectively, independently hydrogen atoms, halogen atoms, and optionally substituted carbon atoms. 1‑6 Alkyl or optionally substituted C 6‑10 aryl, or R 2a R 2b R 2c R 2d Two carbon or nitrogen atoms bonded to R, R', and R" together form a 3- to 6-membered saturated carbon ring or saturated heterocycle, R 3a R 3b R 3c and R 5a and R 5b As specified in the instruction manual.

Description

Technical Field

[0001] This disclosure relates to bicyclic pyridine derivatives or pharmaceutically permissible salts thereof that have agonist activity against the trace amine-associated receptor TAAR1, and to therapeutic agents for neuropsychiatric disorders in which such derivatives are active ingredients. Background Technology

[0002] Trace amines (TAs), which are types of amines in living organisms, include β-tyramine, β-phenylethylamine, tryptamine, and octopamine. Compared to traditional amines in living organisms, primarily serotonin, dopamine, and norepinephrine, they have similar structures and metabolisms, but exist in extremely small amounts under physiological conditions (Non-Patent Literature 1). TAs are known to play an important role in regulating nerve conduction in the central and peripheral nervous systems. Abnormal regulation of TAs has been shown to be associated with various central nervous system diseases, including schizophrenia, mood disorders, attention deficit hyperactivity disorder, Parkinson's disease, migraines, and eating disorders. There is a desire to develop new treatment methods for these diseases by improving their regulation (Non-Patent Literature 2).

[0003] Nine genes have been reported to act as receptors for TA in humans. The TAAR1 receptor is a G protein conjugated type, activated via Gαs with TA as a ligand. Other amines, catecholamine metabolites, and dopamine agonists have also been reported to act as ligands (Non-Patent Literature 1, 3). In downstream signaling, it is known to inhibit dopamine uptake by phosphorylating dopamine transporters via cAMP-PKA / PKC, and to promote dopamine release in a PKC-dependent manner (Non-Patent Literature 4, 5). In the central nervous system, TAAR1 receptor expression has been found in monoamine initiation nuclei including the ventral tegmental area, raphe nuclei, and the limbic system. It also regulates glutamate neurotransmission and serotonin neurotransmission, suggesting that the TAAR1 receptor can act on various monoamine functions (Non-Patent Literature 1).

[0004] Since the TAAR1-encoding locus 6q23 is a region associated with various mental illnesses, and TAAR1-regulated monoamine neurotransmission shows a strong correlation with neuropsychiatric disorders, selective TAAR1 receptor ligands are expected to be effective in treating these diseases. Furthermore, low-molecular-weight compounds demonstrating TAAR1 receptor agonism have shown antipsychotic and antidepressant effects in multiple rodent disease models and have also shown cognitive-improving effects in non-human primates. Therefore, antipsychotic, antidepressant, and cognitive-improving effects in humans are expected to be similarly observed (non-clinical literature 6).

[0005] Existing technical documents

[0006] Non-patent literature

[0007] Non-Patent Literature 1: Beth Borowsky, Proc Natl Acad Sci USA. 98, 8966-8971, 2001

[0008] Non-patent literature 2: Branchek, T.A. and Blackburn, T.P. Curr. Opin. Pharmacol. 3, 90-97, 2003

[0009] Non-patent literature 3: James R. Bunzow, Mol Pharmacol. 60, 1181-1188, 2001

[0010] Non-patent literature 4: Zhihua Xie and Gregory M. Miller, Journal of Pharmacology and Experimental Therapeutics 321, 128-136, 2007

[0011] Non-patent literature 5: Zhihua Xie and Gregory M. Miller, Journal of Pharmacology and Experimental Therapeutics, 330, 316-325, 2009

[0012] Non-patent literature 6: FG Revel, Molecular Psychiatry, 18, 543-556, 2013 Summary of the Invention

[0013] Methods for solving problems

[0014] This disclosure provides novel compounds that have agonist activity against the trace amine-associated receptor TAAR1 and are useful as therapeutic agents for neuropsychiatric disorders.

[0015] The inventors have discovered that compounds of Formula I or pharmaceutically permissible salts thereof (hereinafter sometimes referred to as "compounds of this disclosure") have agonist activity against trace amine-associated receptor TAAR1, and hereby provide this disclosure.

[0016] That is, this disclosure is as follows, for example.

[0017] [Item 1]

[0018] The compound represented by Formula I or its pharmaceutically permissible salt,

[0019] [Chemistry 1]

[0020]

[0021] [In the formula,

[0022] X represents an oxygen atom, a sulfur atom, NR, or CR'R.

[0023] n is 0 or 1,

[0024] R 1 Hydrogen atom, C atoms can be substituted. 1-6 Alkyl or optionally substituted C 3-6 alkenyl,

[0025] R 2a R 2b R 2c R 2d R, R', and R" are each independently a hydrogen atom, a halogen atom, or an optional substituted carbon atom. 1-6 Alkyl or optionally substituted C 6-10 Aryl, or R 2a R 2b R 2c R 2d Two carbon or nitrogen atoms from R, R', and R" bonded to them together form a 3- to 6-membered saturated carbon ring or saturated heterocycle.

[0026] R 3a R 3b and R 3c Each is an independent hydrogen atom, and the C atoms can be substituted at will. 1-6 Alkyl group, halogen atom, -OR 4 Or arbitrarily replaceable C 6-10 Aryl,

[0027] R 4 C is arbitrarily replaced 1-6 Alkyl groups or optionally substituted 3- to 6-membered saturated carbon rings,

[0028] R 5a and R 5b Each is independently a hydrogen atom or an optional substituted C atom. 1-6 Alkyl, or R 5a and R 5b Together with the carbon atoms they bond to, they form 3- to 6-membered saturated carbon rings.

[0029] Here,

[0030] The optional C is replaced 1-6 Alkyl groups and optionally substituted C 3-6 The alkenyl group may be replaced by a halogen atom, a hydroxyl group, or a C-aryl group. 1-6 Alkoxy substitution,

[0031] The optional C is replaced 6-10The aryl group and the optionally substituted 3- to 6-membered saturated carbon ring are optionally replaced by a halogen atom, hydroxyl group, or C. 1-6 Alkyl or C 1-6 Alkoxy substitution,

[0032] This excludes the following (1) to (19):

[0033] (1) n is 0, X is an oxygen atom, R 2a and R 2b Compounds containing hydrogen atoms

[0034] (2) n is 1, X is an oxygen atom, R 2a R 2b R 2c R 2d R 3a R 3b and R 3c Compounds containing hydrogen atoms

[0035] (3) n is 1, X is CH2, R 1 R 2a R 2b R 2c R 2d R 3b R 3c R 5a and R 5b For hydrogen atoms, R 3a Compounds consisting of hydrogen atoms or CH3,

[0036] (4) n is 1, X is an oxygen atom, R 1 R 2a R 2b R 2c R 2d R 3b R 3c R 5a and R 5b For hydrogen atoms, R 3a Compounds that are CH3

[0037] (5) n is 1, X is an oxygen atom, R 1 R 2a R 2b R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 2c and R 2d Compounds that are CH3

[0038] (6) n is 1, X is an oxygen atom, R 1 R2a R 2b R 2c R 2d R 3a R 3c R 5a and R 5b For hydrogen atoms, R 3b Compounds that are CH3

[0039] (7) n is 1, X is an oxygen atom, R 1 R 2a R 2b R 2d R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 2c Compounds that are CH3

[0040] (8) n is 0, X is CH2, R 1 R 2a R 2b R 3b R 3c R 5a and R 5b For hydrogen atoms, R 3a Compounds that are CH3

[0041] (9) n is 1, X is CH2, R 1 R 2a R 2b R 2d R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 2c Compounds that are CH3

[0042] (10) n is 1, X is CH2, R 1 R 2a R 2b R 2c R 2d R 3a R 3c R 5a and R 5b For hydrogen atoms, R 3b A compound consisting of CH3 and bromine atoms.

[0043] (11) n is 1, X is an oxygen atom, R 1 R 2a R2b R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 2c and R 2d The carbon atoms bonded to them together form compounds with cyclobutyl rings.

[0044] (12) n is 1, X is an oxygen atom, R 2a R 2b R 2c R 2d R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 1 Compounds that are CH3

[0045] (13) n is 0, X is CH2, R 2a R 2b R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 1 Hydrogen atom, C atoms can be substituted. 1-6 Alkyl or optionally substituted C 3-6 Alkenyl compounds,

[0046] (14) n is 1, X is CH2, R 2a R 2b R 2c R 2d R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 1 Hydrogen atom, C atoms can be substituted. 1-6 Alkyl or optionally substituted C 3-6 Alkenyl compounds,

[0047] (15) n is 0, X is CH2, R 2a R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 2b For hydrogen atoms and CH3, R 1 Compounds consisting of hydrogen atoms and CH3,

[0048] (16) n is 1, X is CH2, R 2c R 2d R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 2a and / or R 2b CH3, R 1 Compounds consisting of hydrogen atoms and CH3,

[0049] (17) n is 1, X is CH2, R 2c R 2d R 3a R 3b R 3c R 5a and R 5b For hydrogen atoms, R 2a and R 2b Together with carbon atoms, they form cyclopropane, R 1 Compounds consisting of hydrogen atoms and CH3,

[0050] (18) n is 0 or 1, X is CH2, R 5a Or R 5b C is arbitrarily replaced 1-6 Alkyl compounds,

[0051] (19) n is 0, X is CH2, R 1 R 2a R 2b R 3a R 3c R 5a and R 5b For hydrogen atoms, R 3b Compounds containing bromine atoms.

[0052] [Item 2]

[0053] The compound described in item 1, or a pharmaceutically permissible salt thereof, is represented by the following formula.

[0054] [Chemistry 2]

[0055]

[0056] [Item 3]

[0057] The compound described in item 1, or its pharmaceutically permissible salt, is represented by the following formula:

[0058] [Chemistry 3]

[0059]

[0060] [Item 4]

[0061] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 3, wherein R 1 It is a hydrogen atom.

[0062] [Item 5]

[0063] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 3, wherein R 1 C atoms that are optionally substituted with halogen atoms 1-6 alkyl.

[0064] [Item 6]

[0065] The compound described in item 5 or a pharmaceutically permissible salt thereof, wherein R 1 It is a methyl group.

[0066] [Item 7]

[0067] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 6, wherein R 2a and R 2b It is a hydrogen atom.

[0068] [Item 8]

[0069] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 6, wherein R 2a For hydrogen atoms, R 2b C is arbitrarily replaced 1-6 alkyl.

[0070] [Item 9]

[0071] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 6, wherein R 2a and R 2b C is arbitrarily replaced 1-6 alkyl.

[0072] [Item 10]

[0073] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 6, wherein R 2a and R 2b It is a halogen atom.

[0074] [Item 11]

[0075] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 6, wherein R 2a and R 2b Together with the carbon atoms they bond with, they form 3- to 6-membered saturated carbon rings.

[0076] [Item 12]

[0077] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 6, wherein R 2a C is arbitrarily replaced 6-10 Aryl, R 2b It is a hydrogen atom.

[0078] [Item 13]

[0079] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 6, wherein R 2a or R 2b For hydroxyl or C 1-6 Alkoxy-substituted groups.

[0080] [Item 13-1]

[0081] The compound or a pharmaceutically permissible salt thereof as described in any one of items 1 to 13, wherein X is CR'R", and R' and R" are hydrogen atoms.

[0082] [Item 13-2]

[0083] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 13, wherein X is CR'R", R' is a hydrogen atom, and R" is an optional substituted C atom. 1-6 alkyl.

[0084] [Item 13-3]

[0085] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 13, wherein X is CR'R", R' and R" are optionally substituted C 1-6 alkyl.

[0086] [Item 14]

[0087] The compound or pharmaceutically permissible salt thereof as described in any one of items 1, 3 to 13-3, wherein n is 1, R 2c and R 2d It is a hydrogen atom.

[0088] [Item 15]

[0089] The compound or pharmaceutically permissible salt thereof as described in any one of items 1, 3 to 13-3, wherein n is 1, R 2c For hydrogen atoms, R 2d C is arbitrarily replaced 1-6 alkyl.

[0090] [Item 16]

[0091] The compound or pharmaceutically permissible salt thereof as described in any one of items 1, 3 to 13-3, wherein n is 1, R 2c and R2d C is arbitrarily replaced 1-6 alkyl.

[0092] [Item 17]

[0093] The compound or pharmaceutically permissible salt thereof as described in any one of items 1, 3 to 13-3, wherein n is 1, R 2c and R 2d It is a halogen atom.

[0094] [Item 18]

[0095] The compound or pharmaceutically permissible salt thereof as described in any one of items 1, 3 to 13-3, wherein n is 1, R 2c and R 2d Together with the carbon atoms they bond with, they form 3- to 6-membered saturated carbon rings.

[0096] [Item 19]

[0097] The compound or pharmaceutically permissible salt thereof as described in any one of items 1, 3 to 13-3, wherein n is 1, R 2c C is arbitrarily replaced 6-10 Aryl, R 2d It is a hydrogen atom.

[0098] [Item 20]

[0099] The compound or pharmaceutically permissible salt thereof as described in any one of items 1, 3 to 13-3, wherein R 2c or R 2d For hydroxyl or C 1-6 Alkoxy-substituted groups.

[0100] [Item 21]

[0101] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 20, wherein R 3a R 3b and R 3c Each can be independently a hydrogen atom or a halogen atom.

[0102] [Item 22]

[0103] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 21, wherein R 3a R 3b and R 3c They are hydrogen atoms.

[0104] [Item 22-1]

[0105] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 21, wherein R 3a R 3b and R3c At least one of them is an optional C that is replaced. 1-6 Alkyl or halogen atom.

[0106] [Item 23]

[0107] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 22-1, wherein R 5a and R 5b They are hydrogen atoms.

[0108] [Item 24]

[0109] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 22-1, wherein R 5a For hydrogen atoms, R 5b C is arbitrarily replaced 1-6 alkyl.

[0110] [Item 25]

[0111] The compound or pharmaceutically permissible salt thereof as described in any one of items 1 to 22-1, wherein R 5a and R 5b C is arbitrarily replaced. 1-6 alkyl.

[0112] [Item 26]

[0113] The compound or a pharmaceutically permissible salt thereof as described in any one of items 1 to 25, wherein X is an oxygen atom.

[0114] [Item 27]

[0115] The compound or a pharmaceutically permissible salt thereof as described in any one of items 1 to 25, wherein X is a sulfur atom.

[0116] [Item 28]

[0117] The compound or a pharmaceutically permissible salt thereof as described in any one of items 1 to 25, wherein X is NR.

[0118] [Item 29]

[0119] The compound or a pharmaceutically permissible salt thereof as described in any one of items 1 to 25, wherein X is CR'R.

[0120] [Item 29-1]

[0121] The compound or pharmaceutically permissible salt thereof as described in any one of items 1-3, 5, 7-21, 22-1 and 23-29, wherein R 1 C atoms that are optionally substituted with halogen atoms 1-6 alkyl,

[0122] R3a R 3b and R 3c At least one of them is an optional C that is replaced. 1-6 Alkyl or halogen atom.

[0123] [Item 29-2]

[0124] The compound described in item 29-1 or a pharmaceutically permissible salt thereof, wherein R 1 It is methyl.

[0125] R 3a R 3b and R 3c At least one of them is a methyl, fluorine or chlorine atom.

[0126] [Item 30]

[0127] The compound described in item 1 or a pharmaceutically permissible salt thereof, wherein,

[0128] X is an oxygen atom.

[0129] When n is 0,

[0130] R 1 C atoms that are optionally substituted with halogen atoms 1-6 alkyl,

[0131] R 2a For hydrogen atoms, R 2b C is arbitrarily replaced 1-6 alkyl,

[0132] R 3a R 3b and R 3c At least one of them is an optional C that is replaced. 1-6 Alkyl or halogen atoms,

[0133] R 5a and R 5b They are hydrogen atoms.

[0134] [Item 31]

[0135] The compound or a pharmaceutically permissible salt thereof as described in any one of items 1-30, wherein the hydrogen atom of the aforementioned compound is deuterium.

[0136] [Item 32]

[0137] Compounds selected from item 1 of the following group of compounds, or pharmaceutically permissible salts thereof:

[0138] 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine,

[0139] 1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine,

[0140] N-Methyl-1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine,

[0141] 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]-N-methylmethylamine,

[0142] 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]-N-( 2 H3) Methyl methylamine,

[0143] rel-1-[(3'S)-5'-methyl-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine,

[0144] rel-1-[(3'S)-5'-fluoro-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine,

[0145] rel-1-[(3S)-2,2,5-trimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine,

[0146] rel-1-[(3'S)-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridin]-3'-yl]methylamine, and rac-1-(5-fluoro-2,2-dimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl)methylamine.

[0147] [Item 33]

[0148] A pharmaceutical composition comprising any one of the compounds described in items 1 to 32 or a pharmaceutically permissible salt thereof.

[0149] [Item 34]

[0150] The pharmaceutical composition of item 33, wherein the aforementioned pharmaceutical composition is used to treat or prevent diseases or disorders related to TAAR1.

[0151] [Item 35]

[0152] The pharmaceutical composition described in item 33 or 34, wherein the aforementioned pharmaceutical composition is used to treat or prevent neurological or psychiatric disorders.

[0153] [Item 36]

[0154] The pharmaceutical composition of item 35, wherein the aforementioned neurological or mental disorder is depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, poisoning, social disorder, attention deficit / hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, cognitive impairment, psychosis of Alzheimer's disease / Parkinson's disease, or anxiety / aggression or bulimia of Parkinson's disease.

[0155] [Item 37]

[0156] A method for treating or preventing a TAAR1-related disease or disorder in a subject, characterized in that an effective amount of any one of items 1 to 32, or a pharmaceutically permissible salt thereof, is administered to the subject.

[0157] [Item 38]

[0158] A method for treating or preventing neurological or mental disorders of a subject, characterized in that an effective amount of any one of items 1 to 32, or a pharmaceutically permissible salt thereof, is applied to the subject.

[0159] [Item 39]

[0160] The method described in item 38, wherein the aforementioned neurological or mental disorder is depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, poisoning, social disorder, attention deficit / hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, cognitive impairment, psychosis of Alzheimer's disease / Parkinson's disease, or anxiety / aggression or bulimia of Parkinson's disease.

[0161] [Item 40]

[0162] The compound or a pharmaceutically permissible salt thereof described in any one of items 1 to 32, used as a medicine.

[0163] [Item 41]

[0164] The compound described in item 40 or a pharmaceutically permissible salt thereof, wherein the aforementioned drug is used to treat or prevent diseases or disorders associated with TAAR1.

[0165] [Item 42]

[0166] The compound described in item 40 or 41, or a pharmaceutically permissible salt thereof, wherein the aforementioned compound or a pharmaceutically permissible salt thereof is used to treat or prevent neurological or psychiatric disorders.

[0167] [Item 43]

[0168] The compound described in item 42 or a pharmaceutically permissible salt thereof, wherein the aforementioned neurological or mental disorder is depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, poisoning, social disorder, attention deficit / hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, cognitive impairment, psychosis of Alzheimer's / Parkinson's disease, or anxiety / aggression or bulimia of Parkinson's disease.

[0169] [Item 44]

[0170] A TAAR1 agonist, which is any one of the compounds described in items 1 to 32 or a pharmaceutically permissible salt thereof.

[0171] [Item 45]

[0172] Use of any compound or pharmaceutically permissible salt thereof from any of items 1 to 32 in the regulation of TAAR1 receptor.

[0173] [Item 46]

[0174] A treatment agent for mental illness or central nervous system disorders, comprising any one of items 1 to 32 or a pharmaceutically permissible salt thereof as an active ingredient.

[0175] [Item 47]

[0176] The therapeutic agent described in item 46, wherein the mental illness or central nervous system disease includes symptomatic organic mental disorders; mental and behavioral disorders caused by the use of psychoactive substances; schizophrenia, schizophrenic-type disorders, and delusional disorders; mood [affective] disorders; neurotic disorders, stress-related disorders, and somatic symptom disorders; non-organic sleep disorders; sexual dysfunction not caused by organic disorders or diseases; pervasive developmental disorders; behavioral and emotional disorders that typically occur in childhood and adolescence; extrapyramidal disorders and abnormal movements; other degenerative diseases of the nervous system; or sleep disorders.

[0177] [Item 48]

[0178] The therapeutic agent described in item 46, wherein the mental illness or central nervous system disorder is schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, bipolar disorder with psychotic features, depressive disorder with psychotic features, psychotic symptoms with dementia, psychotic symptoms with Alzheimer's disease, psychotic symptoms with Lewy body dementia, psychotic symptoms with Parkinson's disease dementia, psychotic symptoms with Parkinson's disease, or agitation, excitement, or aggression with Alzheimer's disease.

[0179] [Item 49]

[0180] The therapeutic agent described in item 46, wherein the mental illness or central nervous system disorder is schizophrenia, psychotic symptoms associated with dementia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with Lewy body dementia, or agitation, excitement, or aggression associated with Alzheimer's disease.

[0181] [Item 50]

[0182] A method for treating mental illness or central nervous system disorders, comprising administering to a patient in need of treatment a therapeutically effective amount of any one of items 1 to 32, or a pharmaceutically permissible salt thereof.

[0183] [Item 51]

[0184] Use of any compound or pharmaceutically permissible salt thereof from any one of items 1 to 32 in the manufacture of a therapeutic agent for mental illness or central nervous system disorders.

[0185] [Item 52]

[0186] The compound or a pharmaceutically permissible salt thereof, as described in any one of items 1 to 32, is used to treat mental illness or central nervous system disorders.

[0187] [Item 53]

[0188] A treatment agent for mental illness or central nervous system disorders, comprising the compound or a pharmaceutically permissible salt thereof described in any one of items 1 to 32, and at least one drug selected from the group consisting of antidepressants, anxiolytics, schizophrenia treatments, dopamine supplements, dopamine receptor agonists, Parkinson's disease treatments, antiepileptics, analgesics, hormonal preparations, migraine treatments, adrenaline beta receptor antagonists, dementia treatments, mood disorder treatments, antiemetics, sleep inducers, and anticonvulsants.

[0189] [Item 54]

[0190] A therapeutic agent containing any one of the compounds described in items 1 to 32 or a pharmaceutically permissible salt thereof as an active ingredient, used in combination with at least one drug selected from antidepressants, anxiolytics, schizophrenia medications, dopamine supplements, dopamine receptor agonists, Parkinson's disease medications, antiepileptics, analgesics, hormonal preparations, migraine medications, adrenaline beta receptor antagonists, dementia medications, mood disorder medications, antiemetics, sleep inducers, and anticonvulsants, for the treatment of mental illness or central nervous system disorders.

[0191] Invention Effects

[0192] The compounds disclosed herein exhibit strong agonist activity against the TAAR1 receptor. Furthermore, in preferred embodiments, they demonstrate high selectivity for inhibition of other GPCRs, including the dopamine D2 receptor, adrenaline α1 receptor, adrenaline α2 receptor, and further, the hERG channel. Therefore, the preferred compounds of this disclosure can be used as highly safe therapeutic agents for neuropsychiatric disorders. Attached Figure Description

[0193] [ Figure 1 [Graph showing the results of the benzyl benzo ...

[0194] [ Figure 2 [Graph showing the results of the benzylpyridinin-induced hyperkinetic inhibition test (Experiment 2-2) of the compound of Example 8.]

[0195] [ Figure 3 [Graph showing the results of the benzyl benzo ... Detailed Implementation

[0196] The following describes the best mode of this disclosure. It should be understood that throughout this specification, unless otherwise indicated, singular expressions also include the concept of their plural forms. Therefore, it should be understood that, unless otherwise indicated, singular articles (e.g., "a," "an," "the," etc. in English) also include the concept of their plural forms. Furthermore, it should be understood that, unless otherwise indicated, the terms used in this specification generally use their meanings as commonly adopted in the art. Therefore, unless otherwise defined, all technical and technical terms used in this specification have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure pertains. In cases of conflict, this specification (including definitions) takes precedence.

[0197] The following provides appropriate definitions of terms and / or basic technical content used in this specification.

[0198] In this specification, "or" is used when referring to "at least one" of the items listed in the text. The same applies to "or". In this specification, when two values ​​are explicitly stated as being "within a range", that range also includes the two values ​​themselves.

[0199] The number of substituents in a group defined as "optionally substituted" or "substituted" is unlimited as long as it is substituted. Furthermore, unless otherwise specified, the description of each group also applies to cases where the group is part of another group or a substituent.

[0200] In this specification, the number of carbon atoms in the definition of "substituent" is also indicated by, for example, "C". 1-6"etc." Specifically, "C 1-6 The label "alkyl" is synonymous with alkyl groups having 1 to 6 carbon atoms.

[0201] Examples of "halogens" include fluorine, chlorine, bromine, and iodine.

[0202] “C 1-6 "Alkyl" refers to a straight-chain or branched saturated hydrocarbon group with 1 to 6 carbon atoms. As a C... 1-6 Alkyl groups, preferably listed as "C" 1-4 Alkyl", more preferably listed as "C" 1-3 Alkyl group. "As a C 1-3 Specific examples of "alkyl" include methyl, ethyl, propyl, 1-methylethyl, etc. As "C 1-4 Specific examples of "alkyl" include, for example, "C" as mentioned above. 1-3 Besides the specific examples listed for "alkyl", other examples include butyl, 1,1-dimethylethyl, 1-methylpropyl, 2-methylpropyl, etc. As for "C",... 1-6 Specific examples of "alkyl" include, for example, "C" as mentioned above. 1-4 In addition to the specific examples listed for "alkyl", other examples include pentyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 1-methylbutyl, 2-methylbutyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, hexyl, etc.

[0203] “C 3-6 "Alkenyl" refers to a straight-chain or branched saturated hydrocarbon group with 3 to 6 carbon atoms and 1 to 3 double bonds (wherein, in Formula I, R...). 1 For "C" 3-6 In the case of "alkenyl", and with R 1 The bonded nitrogen atom adjacent to the "C" 3-6 The "alkenyl" group does not have a double bond on the carbon atom, preferably listed as "C". 3-5 "Alkenyl", more preferably "C" 3-4 "Alkenyl". Specific examples of "alkenyl" include allyl, 2-methylallyl, etc.

[0204] “C 1-6 "Alkoxy" refers to "C 1-6 Alkyloxy, C 1-6 The "alkyl" part is related to the aforementioned "C" 1-6 Synonymous with "alkyl". As "C" 1-6 "alkoxy", preferably listed as "C" 1-4 Alkoxy, more preferably listed as "C 1-3 Alkyl groups. As "C 1-3 Specific examples of "alkoxy" include methoxy, ethoxy, propoxy, 1-methylethoxy, etc. As "C1-4 Specific examples of "alkoxy" include, for instance, in addition to the aforementioned "C" 1-3 In addition to the specific examples listed for "alkyl", other examples include butoxy, 1,1-dimethylethoxy, 1-methylpropoxy, 2-methylpropoxy, etc. As for "C", 1-6 Specific examples of "alkoxy" include, for instance, in addition to the aforementioned "C" 1-4 In addition to the specific examples listed for "alkyl", other examples include pentoxy, 1,1-dimethylpropoxy, 1,2-dimethylpropoxy, 1-methylbutoxy, 2-methylbutoxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 1-methylpentoxy, hexoxy, etc.

[0205] "3- to 6-membered saturated heterocycles" refer to saturated rings composed of 3 to 6 atoms, containing 1 to 2 atoms independently selected from nitrogen, oxygen, and sulfur atoms in addition to carbon atoms. This includes heterocycles with partially unsaturated bonds and heterocycles with cross-linked structures. Preferably, "4- to 6-membered monocyclic saturated heterocycles" are listed as "3- to 6-membered saturated heterocycles," and more preferably, "5- or 6-membered monocyclic saturated heterocycles" are listed. Specific examples of "5- or 6-membered monocyclic saturated heterocycles" include, for example, tetrahydrofuranyl, pyrrolylyl, imidazoyl, piperidinyl, morpholinyl, thiomorpholinyl, dioxothiomorpholinyl, hexamethyleneiminyl, oxazolyl, thiazoylyl, oxoimidazoylyl, dioxoimidazoylyl, oxooxazolylyl, dioxothiazoylylyl, tetrahydrofuranyltetrahydropyranyl, etc. As for "4- to 6-membered monocyclic saturated heterocycles", in addition to the specific examples listed above as "5- or 6-membered monocyclic saturated heterocycles", examples such as oxo-heterocyclic butyl and nitrogen-heterocyclic butyl can also be listed.

[0206] "3- to 6-membered saturated carbon rings" refer to cyclic saturated hydrocarbons with 3 to 6 carbon atoms, including some carbon rings with unsaturated bonds and cross-linked carbon rings. Preferably, "5- or 6-membered monocyclic saturated carbon rings" are listed as examples of "3- to 6-membered saturated carbon rings". Specific examples of "5- or 6-membered monocyclic saturated carbon rings" include cyclopentane and cyclohexane. In addition to the examples listed above, cyclopropane and cyclobutane can also be listed as specific examples of "3- to 6-membered saturated carbon rings".

[0207] “C 6-10 "Aryl" refers to a monocyclic or bicyclic aromatic hydrocarbon group with 6 to 10 carbon atoms. As "C..." 6-10 Specific examples of "aryl" include phenyl, 1-naphthyl, 2-naphthyl, etc. As "C 6-10 "Aryl", preferably phenyl. "C" 6-10 Aryl groups can adopt fused ring structures.

[0208] C is arbitrarily replaced 1-6 Alkyl groups, optionally substituted C 3-6 alkenyl, C 1-6 The "substituents" of alkoxy groups, optionally substituted 3- to 6-membered saturated carbocyclic rings, optionally substituted 3- to 6-membered saturated heterocyclic rings, and optionally substituted aryl groups are not particularly limited and can have one or more substituents of any kind at any chemically possible position. When there are two or more substituents, the substituents can be the same or different. Specific examples of substituents include halogen atoms, C atoms, etc. 1-6 Alkyl, C 1-4 Alkoxy, cyano, benzyloxy, phenyl, hydroxy, methanesulfonyl, substituted or unsubstituted amino groups.

[0209] C is arbitrarily replaced 1-6 Alkyl groups and optionally substituted C 3-6 Specific examples of substituents in an alkenyl group include halogen atoms, hydroxyl groups, or C atoms. 1-6 Alkoxy group, as an optional substituted C 6-10 Specific examples of substituents in the aryl group and the optionally substituted 3- to 6-membered saturated carbon ring include halogen atoms, hydroxyl groups, and C. 1-6 Alkyl or C 1-6 Alkyl group.

[0210] In the compounds of this disclosure represented by Formula I, X, n, and 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 are as follows, but the scope of this disclosure is not limited to the range of compounds listed below.

[0211] As a preferred embodiment, embodiments where n is 0 can be listed.

[0212] As a preferred embodiment, an embodiment in which n is 1 can be listed.

[0213] As a preferred embodiment, R can be listed as an example. 1 This is an implementation method for hydrogen atoms.

[0214] As a preferred embodiment, R can be listed as an example. 1 C atoms that are optionally substituted with halogen atoms 1-6 Implementation methods for alkyl groups.

[0215] As a preferred embodiment, R can be listed as an example.1 The embodiment of methyl is shown below.

[0216] As a preferred embodiment, R can be listed as an example. 2a and R 2b This is an implementation method for hydrogen atoms.

[0217] As a preferred embodiment, R can be listed as an example. 2a For hydrogen atoms, R 2b C is arbitrarily replaced 1-6 Implementation methods for alkyl groups.

[0218] As a preferred embodiment, R can be listed as an example. 2a and R 2b C is arbitrarily replaced 1-6 Implementation methods for alkyl groups.

[0219] As a preferred embodiment, R can be listed as an example. 2a and R 2b This is an implementation method for halogen atoms.

[0220] As a preferred embodiment, R can be listed as an example. 2a and R 2b Implementation method: The carbon atoms bonded to them together form 3- to 6-membered saturated carbon rings.

[0221] As a preferred embodiment, R can be listed as an example. 2a C is arbitrarily replaced 6-10 Aryl, R 2b This is an implementation method for hydrogen atoms.

[0222] As a preferred embodiment, R can be listed as an example. 2a or R 2b For hydroxyl or C 1-6 Implementation methods for alkoxy-substituted groups.

[0223] As a preferred implementation, an example can be n=1, R 2c and R 2d This is an implementation method for hydrogen atoms.

[0224] As a preferred implementation, an example can be n=1, R 2c For hydrogen atoms, R 2d C is arbitrarily replaced 1-6 Implementation methods for alkyl groups.

[0225] As a preferred implementation, an example can be n=1, R 2c and R 2d C is arbitrarily replaced 1-6 Implementation methods for alkyl groups.

[0226] As a preferred implementation, an example can be n=1, R 2c and R 2d This is an implementation method for halogen atoms.

[0227] As a preferred implementation, an example can be n=1, R 2c and R 2d Implementation method: The carbon atoms bonded to them together form 3- to 6-membered saturated carbon rings.

[0228] As a preferred implementation, an example can be n=1, R 2c C is arbitrarily replaced 6-10 Aryl, R 2d This is an implementation method for hydrogen atoms.

[0229] As a preferred embodiment, R can be listed as an example. 2c or R 2d For hydroxyl or C 1-6 Implementation methods for alkoxy-substituted groups.

[0230] As a preferred embodiment, R can be listed as an example. 3a R 3b and R 3c Each is an independent hydrogen atom, and the C atoms can be substituted at will. 1-6 Implementation methods for alkyl or halogen atoms.

[0231] As a preferred embodiment, R can be listed as an example. 3a R 3b and R 3c Each implementation is independently of a hydrogen atom or a halogen atom.

[0232] As a preferred embodiment, R can be listed as an example. 3a R 3b and R 3c These are implementation methods for hydrogen atoms.

[0233] As a preferred embodiment, R can be listed as an example. 3a R 3b and R 3c C is arbitrarily replaced. 1-6 Implementation methods for alkyl groups.

[0234] As a preferred embodiment, R can be listed as an example. 3a R 3b and R 3c At least one of them is an optional C that is replaced. 1-6 Implementation methods for alkyl or halogen atoms.

[0235] As a preferred embodiment, R can be listed as an example. 5a and R 5bThese are implementation methods for hydrogen atoms.

[0236] As a preferred embodiment, R can be listed as an example. 5a For hydrogen atoms, R 5b C is arbitrarily replaced 1-6 Implementation methods for alkyl groups.

[0237] As a preferred embodiment, R can be listed as an example. 5a and R 5b C is arbitrarily replaced. 1-6 Implementation methods for alkyl groups.

[0238] As a preferred embodiment, an embodiment in which X is an oxygen atom can be cited.

[0239] As a preferred embodiment, an embodiment in which X is a sulfur atom can be cited.

[0240] As a preferred embodiment, an embodiment where X is NR can be listed.

[0241] As a preferred embodiment, an embodiment in which X is CR'R” can be listed.

[0242] As a preferred embodiment, R can be listed as an example. 1 C atoms that are optionally substituted with halogen atoms 1-6 Alkyl, R 3a R 3b and R 3c At least one of them is an optional C that is replaced. 1-6 Implementation methods for alkyl or halogen atoms.

[0243] As a preferred embodiment, R can be listed as an example. 1 It is methyl, R 3a R 3b and R 3c An embodiment in which at least one of the atoms is a methyl, fluorine, or chlorine atom.

[0244] As a preferred embodiment, X can be an oxygen atom, n is 0, and R is... 1 C atoms that are optionally substituted with halogen atoms 1-6 Alkyl, R 2a For hydrogen atoms, R 2b C is arbitrarily replaced 1-6 Alkyl, R 3a R 3b and R 3c At least one of them is an optional C that is replaced. 1-6 Alkyl or halogen atom, R 5a and R 5b These are implementation methods for hydrogen atoms.

[0245] Compounds represented by Formula I can also exist as tautomers. Therefore, the compounds disclosed herein also include tautomers of compounds represented by Formula I.

[0246] Compounds represented by Formula I sometimes have at least one asymmetric carbon atom. Therefore, the compounds disclosed herein include not only racemates of compounds represented by Formula I, but also optically active forms of these compounds. When compounds represented by Formula I have two or more asymmetric carbon atoms, stereoisomers sometimes occur. Therefore, the compounds disclosed herein also include stereoisomers of these compounds and mixtures thereof. In the structural formulas, “rac.” indicates a racemate, “chiral” indicates an optically active form, and “abs.” indicates an absolute configuration.

[0247] In addition, derivatives in which one or more atoms of a compound represented by Formula I are transformed into isotopes are also included in the compound represented by Formula I.

[0248] For example, 1 H transform is 2 H(D) deuterium conversion agent, converted into 11 C 18 Transformers of radioactive isotopes such as F are also included in the compound shown in Formula I.

[0249] Compounds represented by Formula I and their pharmaceutically permissible salts sometimes exist as hydrates and / or solvates, and therefore these hydrates or solvates, such as ethanol solvates, are also included in the compounds disclosed herein. Furthermore, the compounds disclosed herein also include compounds of all crystalline forms.

[0250] As pharmaceutically permissible salts, compounds represented by Formula I that have acidic groups include, for example, alkali metal salts such as sodium and potassium salts; alkaline earth metal salts such as calcium and magnesium salts; inorganic metal salts such as zinc salts; and organic base salts such as triethylamine, triethanolamine, trihydroxymethylaminomethane, and amino acids.

[0251] When the compound represented by Formula I has a basic group, examples 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.

[0252] The following examples illustrate methods for manufacturing the compounds disclosed herein, but this disclosure is by no means limited thereto.

[0253] Manufacturing method

[0254] The compounds disclosed herein are synthesized by combining the following manufacturing methods with known synthetic methods.

[0255] This also includes cases where the compounds in the reaction formulas form salts, such as salts identical to those of the compounds represented by Formula I. Furthermore, these reactions are merely illustrative; based on the knowledge of those skilled in organic synthesis, the compounds disclosed herein can be prepared by other appropriate methods.

[0256] In the manufacturing methods described below, even without explicitly stating the use of a protecting group, if a functional group that needs to be protected is present, the functional group can be protected as needed, and deprotection can be performed after the reaction is completed or after a series of reactions to obtain the target product.

[0257] As protecting groups, conventional protecting groups described in references such as TW Greene and PGMWuts, “Protective Groups in Organic Synthesis,” 3rd Ed., John Wiley and Sons, Inc., New York (1999) can be used. More specifically, examples of protecting groups for amino groups include benzyloxycarbonyl, tert-butoxycarbonyl, acetyl, and benzyl. Additionally, examples of protecting groups for hydroxyl groups include trialkylsilyl, acetyl, and benzyl.

[0258] The introduction and removal of protecting groups can be carried out using methods commonly used in organic synthetic chemistry (e.g., the methods described in T.W. Greene and P. G.W. M. Uts, “Protective Groups in Organic Synthesis”, 3rd Ed., John Wiley and Sons, Inc., New York (1999)) or methods based on these methods.

[0259] Manufacturing Method 1

[0260] In the compounds represented by formula I, the compounds represented by formula (1a) are, for example, manufactured by the following method.

[0261] [Chemistry 4]

[0262]

[0263] [In the formula, n and R] 2a R 2b R 2c R 2d R 3a R 3b R 3c R 5a X is synonymous with item 1, R 6Indicates that C is arbitrarily replaced. 1-6 Alkyl, PG 1 [Refers to alkyl carbamates such as tert-butoxycarbonyl or benzyloxycarbonyl.]

[0264] In PG 1 In the case of a tert-butoxycarbonyl group, compound (1a) is prepared by treating compound (5) with a suitable acid. The treatment temperature is typically in the range of -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the acid used, the starting materials, and the solvent, and is typically from 10 minutes to 48 hours.

[0265] Specific examples of inactive 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; nonprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0266] Specific examples of acids include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0267] In PG 1 In the case of a benzyloxycarbonyl group, compound (1a) is prepared by hydrogenolysis of compound (5) in a suitable inert solvent under atmospheric or pressurized hydrogen atmosphere. Specific examples of catalysts used for this hydrogenolysis reaction include palladium-carbon and palladium hydroxide-carbon catalysts. The reaction temperature is typically in the range of 0°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the catalyst used, the raw materials, and the solvent, and is typically from 10 minutes to 48 hours.

[0268] Specific examples of inactive 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-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0269] Compound (5) is prepared by reacting compound (4) with diphenyl azidophosphate in a suitable inactive 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 it with alcohols such as benzyl alcohol and tert-butanol at a suitable temperature of 50°C to 100°C.

[0270] Alternatively, compound (5) can be prepared by reacting compound (4) with diphenyl azidophosphate in a suitable inactive solvent and 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, reacting with a base such as sodium hydroxide or potassium hydroxide in the presence of water, and then reacting with di-tert-butyl dicarbonate in the presence of a suitable base as needed.

[0271] The reaction time varies depending on the reaction temperature, the type of alkali, alcohol, raw materials, and solvent used, and is usually between 10 minutes and 48 hours.

[0272] Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0273] Specific examples of inactive 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-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0274] Compound (4) is produced by alkaline hydrolysis of compound (3) in a suitable solvent using potassium hydroxide, sodium hydroxide, sodium hydride, lithium hydroxide, etc. The processing temperature is typically in the range of approximately -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the alkali used, the raw materials, and the solvent, and is typically from 10 minutes to 48 hours.

[0275] Specific examples of solvents include lower alcohols such as methanol, ethanol, and 2-propanol, water, and their mixtures.

[0276] Compound (3) is prepared 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 typically from 50°C to the boiling point of the solvent. The reaction time varies depending on the reaction temperature, the raw materials used, and the solvent, and is typically from 10 minutes to 48 hours.

[0277] Specific examples of inactive solvents include aromatic hydrocarbons such as benzene and toluene; ether solvents such as diethyl ether, tetrahydrofuran (THF), and 1,4-dioxane; and mixed solvents thereof.

[0278] Manufacturing Method 2

[0279] The compounds represented by Formula I, and the compounds represented by Formula (1b), are manufactured, for example, by the method described below.

[0280] [Chemistry 5]

[0281]

[0282] [In the formula, n and R] 2a R 2b R 2c R 2d R 3a R 3b R 3c R 5a X is synonymous with item 1, PG 1 R represents alkyl carbamates such as tert-butoxycarbonyl or benzyloxycarbonyl. 7 Indicates that C is arbitrarily replaced. 1-6 alkyl.〕

[0283] In PG 1 In the case of a tert-butoxycarbonyl group, compound (1b) is prepared by treating compound (6) with a suitable acid. The treatment temperature is typically in the range of -20°C to 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, and is typically from 10 minutes to 48 hours.

[0284] Specific examples of inactive 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; nonprotic polar solvents such as acetonitrile, dimethylformamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0285] Specific examples of acids include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0286] In PG 1 In the case of a benzyloxycarbonyl group, compound (1b) is prepared by hydrogenolysis of compound (6) in a suitable inert solvent under atmospheric or pressurized hydrogen atmosphere. Specific examples of catalysts used for this hydrogenolysis reaction include palladium-carbon and palladium hydroxide-carbon catalysts. The reaction temperature is typically in the range of 0°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the catalyst used, the raw materials, and the solvent, and is typically from 10 minutes to 48 hours.

[0287] Specific examples of inactive 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-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0288] Compound (6) is prepared by reacting compound (5) with an alkylating agent such as iodomethane in the presence of a suitable base and in a suitable inactive solvent. The reaction may be carried out in the presence of a phase-transfer catalyst, if desired. The reaction temperature is typically in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the base used, the raw materials, and the solvent, and is typically from 10 minutes to 48 hours.

[0289] Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0290] Specific examples of phase transfer catalysts include tetrabutylammonium bisulfate.

[0291] Specific examples of inactive 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; nonprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0292] Manufacturing method 3

[0293] The compound shown in formula (2) is manufactured, for example, by the following method.

[0294] [Chemistry 6]

[0295]

[0296] [In the formula, n and R] 2a R 2b R 2c R 2d R 3a R 3b R 3c X is synonymous with item 1, R 6 Indicates that C is arbitrarily replaced. 1-6 alkyl〕

[0297] Compound (2) is prepared by reacting compound (8) with triphenylphosphine acetates such as ethyl(triphenylphosphine) acetate in a suitable inert solvent. Alternatively, compound (2) can also be prepared by reacting it with phosphonium salts such as ethoxyformylmethyltriphenylphosphine bromide and dialkylphosphine acetates such as diethylphosphine ethyl acetate in the presence of a suitable base. The reaction temperature is typically in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the base used, the raw materials, and the solvent, and is typically from 10 minutes to 48 hours.

[0298] Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0299] Specific examples of inactive 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-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0300] Compound (8) is prepared by reacting compound (7) with an oxidizing agent such as Dess-Martin Periodinane in a suitable inert solvent. Alternatively, compound (8) can also be prepared by reacting compound (7) with a sulfur trioxide pyridine complex in dimethyl sulfoxide in the presence of a tertiary alkylamine such as triethylamine. The reaction temperature is typically in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the reactants used, and the solvent, and is typically from 10 minutes to 48 hours.

[0301] Specific examples of inactive 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-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0302] Manufacturing method 4

[0303] In the compounds shown in formula (2), the compounds represented by formula (2a) are manufactured, for example, by the following method.

[0304] [Chemistry 7]

[0305]

[0306] [In the formula, n and R] 2a R 2b R 2c R 2d R 3a R 3b and R 3c Synonymous with item 1, R 6 Indicates that C is arbitrarily replaced. 1-6 alkyl.〕

[0307] Compound (2a) is prepared by reacting compound (9) and the alcohol represented by formula (10) in a suitable inert solvent in the presence of azodicarbonate such as triphenylphosphine and diisopropyl azodicarbonate. The reaction temperature is typically in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the raw materials used, and the solvent, and is typically from 10 minutes to 48 hours.

[0308] Specific examples of inactive 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-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0309] Manufacturing Method 5

[0310] The compounds represented by formula (7) are, for example, manufactured by the following method.

[0311] [Chemistry 8]

[0312]

[0313] [In the formula, n and R] 2a R 2b R 2c R 2d R 3a R 3b and R 3c Synonymous with item 1, R 8 Indicates that C is arbitrarily replaced. 1-6 Alkyl, PG 2 This indicates trialkylsilyl groups such as tert-butyldimethylsilyl, and LG indicates leaving groups (e.g., iodine, bromine, chlorine, substituted sulfonyl groups (e.g., methanesulfonyl, p-toluenesulfonyl, etc.)).

[0314] Compound (7a) is prepared by reacting compound (9) and the alcohol represented by formula (11) in a suitable inert solvent in the presence of an azodicarbonate such as triphenylphosphine and diisopropyl azodicarbonate, followed by treatment with a suitable acid. The reaction temperature is typically in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the raw materials used, and the solvent, and is typically from 10 minutes to 48 hours.

[0315] Specific examples of inactive 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-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0316] Specific examples of acids include inorganic acids such as hydrochloric acid and sulfuric acid, and organic acids such as trifluoroacetic acid.

[0317] Compound (7a) is prepared by reacting compound (13) with a suitable reducing agent in a suitable inert solvent. The reaction temperature is typically in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the raw materials used, and the solvent, and is typically from 10 minutes to 48 hours.

[0318] Specific examples of reducing agents include complex hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and diisobutylaluminum hydride; and borane complexes (borane-dimethyl sulfide complexes or borane-tetrahydrofuran complexes, etc.).

[0319] Specific examples of inactive 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.

[0320] Compound (13) is prepared by reacting compound (9) and the 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 desired. The reaction temperature is typically in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the base used, the starting materials, and the solvent, and is typically from 10 minutes to 48 hours.

[0321] Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0322] Specific examples of phase transfer catalysts include tetrabutylammonium bisulfate.

[0323] Specific examples of inactive 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; nonprotic polar solvents such as acetonitrile, acetone, methyl ethyl ketone, dimethylformamide, N-methyl-2-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0324] Manufacturing Method 6

[0325] The compounds represented by formula (7) are, for example, manufactured by the following method.

[0326] [Chemistry 9]

[0327]

[0328] [In the formula, n and R] 2a R 2b R 2c R 2d R 3a R 3b and R 3c Synonymous with item 1.

[0329] Compound (7b) is prepared by reacting compound (14) and the thiol represented by formula (15) in a suitable inert solvent in the presence of a suitable base. The reaction can be carried out in the presence of a phase-transfer catalyst, if desired. The reaction temperature is typically in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the base used, the starting materials, and the solvent, and is typically from 10 minutes to 48 hours.

[0330] Specific examples of bases include organic bases such as triethylamine, diisopropylethylamine, and pyridine; inorganic bases such as potassium carbonate, sodium carbonate, cesium carbonate, potassium bicarbonate, sodium bicarbonate, potassium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium phosphate, sodium dihydrogen phosphate, disodium hydrogen phosphate, sodium phosphate, potassium hydroxide, sodium hydroxide, and sodium hydride; and metal alkoxides such as sodium methoxide and potassium tert-butoxide.

[0331] Specific examples of phase transfer catalysts include tetrabutylammonium bisulfate.

[0332] Specific examples of inactive 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-pyrrolidone, and dimethyl sulfoxide; and mixtures thereof.

[0333] Manufacturing method 7

[0334] Of the compounds shown in Formula I, the compound shown in Formula (1c) is, for example, manufactured by the following method.

[0335] [Chemistry 10]

[0336]

[0337] [In the formula, n and R] 2a R 2b R 2c R 2d R 3a R 3b R 3c X is synonymous with item 1.

[0338] Compound (1c) is prepared by reacting compound (16) with a suitable reducing agent in a suitable inert solvent. The reaction temperature is typically in the range of about -20°C to the boiling point of the solvent used. The reaction time varies depending on the reaction temperature, the raw materials used, and the solvent, and is typically from 10 minutes to 48 hours.

[0339] Specific examples of reducing agents include complex hydrogen compounds such as lithium aluminum hydride, sodium borohydride, sodium cyanoborohydride, and diisobutylaluminum hydride; and borane complexes (borane-dimethyl sulfide complexes or borane-tetrahydrofuran complexes, etc.).

[0340] Specific examples of inactive 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.

[0341] By appropriately combining the above-described manufacturing methods, compounds of this disclosure having desired substituents at desired positions can be obtained. The separation and purification of intermediates and products in the above-described manufacturing methods can be carried out by appropriately combining methods commonly used in organic synthesis, such as filtration, extraction, washing, drying, concentration, crystallization, and various chromatographic processes. Alternatively, intermediates can be used in the next reaction without special purification.

[0342] The raw material compounds or intermediates used in the above manufacturing methods may also exist in the form of salts such as hydrochlorides, depending on the reaction conditions, and can be used directly or in free form. If the raw material compounds or intermediates are obtained in the form of salts, and it is desired to use or obtain them in free form, they can be dissolved or suspended in a suitable solvent, for example, by neutralization with an alkali such as an aqueous solution of sodium bicarbonate, to convert them into a free form.

[0343] In the compounds represented by Formula I or their pharmaceutically permissible salts, there are sometimes tautomers, positional isomers, geometric isomers or optical isomers, such as ketenol bodies, and all possible isomers including them and mixtures of such isomers in any proportion are also included in this disclosure.

[0344] Furthermore, optical isomers can be separated in appropriate steps of the above-described manufacturing method by performing known separation processes such as using optically active columns or fractional crystallization. Additionally, optically active substances can also be used as starting materials.

[0345] To obtain a salt of the compound represented by Formula I, it can be directly purified if the salt of the compound represented by Formula I is obtained. Alternatively, if the compound represented by Formula I is obtained in free form, it can be dissolved or suspended in a suitable solvent and an acid or base can be added to form a salt.

[0346] The compounds disclosed herein possess agonist activity against the trace amine-associated receptor TAAR1 and exhibit a mechanism of action distinct from existing drugs for treating mental illnesses, thus providing a new therapeutic option for various mental disorders. In other words, the compounds disclosed herein are effective in treating mental illnesses. Furthermore, the compounds disclosed herein are also effective against central nervous system disorders.

[0347] Examples of mental illnesses or central nervous system disorders for which efficacy is expected include, for example, those listed in the International Classification of Diseases, 10th Revision (ICD-10): F00-F09: including symptomatic organic mental disorders; F10-F19: mental and behavioral disorders caused by the use of psychoactive substances; F20-F29: schizophrenia, schizophrenic-type disorders, and delusional disorders; F30-F39: mood [affective] disorders; F40-F48: neurotic disorders, stress-related disorders, and somatic symptom disorders; F51: non-organic sleep disorders; F52: sexual dysfunction not caused by organic disorders or diseases; F84: pervasive developmental disorders; F90-F98: behavioral and emotional disorders that usually occur in childhood and adolescence; G20-G26: extrapyramidal disorders and abnormal movements; G30-G32: other degenerative diseases of the nervous system; and G47: sleep disorders.

[0348] F00-F09: Specific examples of symptomatic organic mental disorders include, for example, dementia in Alzheimer's disease, vascular dementia, Lewy body dementia, dementia in Parkinson's disease, mental disorders associated with brain injury or other diseases, and other mental disorders caused by brain dysfunction and physical illness.

[0349] F10-F19: Specific examples of mental and behavioral disorders caused by the use of psychoactive substances include delirium tremens, psychotic disorders, and amnesia caused by the use of various substances.

[0350] F20-F29: Specific examples of schizophrenia, schizophrenic disorder, and paranoid disorder, such as paranoid schizophrenia, simple schizophrenia, and paranoid disorder.

[0351] F30-F39: Specific examples of mood [emotional] disorders include manic episodes, bipolar disorder, and depressive episodes.

[0352] F40-F48: Specific examples of neurotic disorders, stress-related disorders, and somatic symptom disorders, such as phobic anxiety disorders, obsessive-compulsive disorders, and somatic symptom disorders.

[0353] F51: As specific examples of non-organic sleep disorders, non-organic insomnia, somnambulism, nightmares, etc. can be listed.

[0354] F52: As specific examples of sexual dysfunction not caused by organic disorders or diseases, examples include lack of or loss of libido, and sexual dysfunction with unclear details.

[0355] F84: Specific examples of pervasive developmental disorders include autism, intellectual disability, and hyperactivity disorder associated with stereotyped behaviors.

[0356] F90-F98: Specific examples of behavioral and emotional disorders that typically occur in childhood and adolescence, such as ADHD, behavioral disorders, and mixed behavioral and emotional disorders.

[0357] G20-G26: Specific examples of extrapyramidal disorders and abnormal movements include Parkinson's disease, secondary Parkinson's syndrome, movement disorders, spinocerebellar degeneration, etc.

[0358] G30-G32: Specific examples of other degenerative diseases of the nervous system, such as Alzheimer's disease, frontotemporal dementia, frontotemporal degeneration, Lewy body dementia, senile brain degeneration, and progressive supranuclear palsy.

[0359] G47: Specific examples of sleep disorders include sleep onset and maintenance disorders [insomnia], sleep-wake rhythm disorders, narcolepsy, and cataplexy.

[0360] The compounds disclosed herein can also be used to treat or prevent relapse of various symptoms accompanying these diseases (psychotic symptoms, anxiety, aggression, irritability and irritability, sleep disorders, depressive symptoms, anxiety symptoms, cognitive impairment, etc.).

[0361] As mental illnesses or central nervous system disorders for which effectiveness is expected, the following are preferred examples: schizophrenia, positive symptoms of schizophrenia, negative symptoms of schizophrenia, bipolar disorder with psychotic features, depressive disorder with psychotic features, psychotic symptoms with dementia, psychotic symptoms with Alzheimer's disease, psychotic symptoms with Lewy body dementia, psychotic symptoms with Parkinson's disease dementia, psychotic symptoms with Parkinson's disease, or agitation, excitement, or aggression with Alzheimer's disease. More preferably, schizophrenia, psychotic symptoms with dementia, psychotic symptoms with Alzheimer's disease and psychotic symptoms with Lewy body dementia, or agitation, excitement, or aggression with Alzheimer's disease.

[0362] The compounds disclosed herein exhibit agonist activity against trace amounts of the amine-associated receptor TAAR1 (Example 1). In a preferred embodiment of the compounds disclosed herein, since the hERG channel inhibitory activity, which is an expression indicator of arrhythmias caused by QT prolongation, is weak (Example 3), a small effect on the cardiovascular system can be expected. That is, the expression concentration of pharmacological effects and the expression concentration of side effects are divergent.

[0363] The compounds disclosed herein can be administered orally or non-orally. When administered orally, they can be administered using conventional methods of administration. Non-oral administration can be in the form of topical application, injections, transdermal formulations, nasal administration, etc. Examples of oral or rectal application formulations include capsules, tablets, pills, powders, suppositories, and liquid preparations. Examples of injection formulations include sterile solutions or suspensions. Examples of topical application formulations include creams, ointments, lotions, and transdermal formulations (typically patches and bases).

[0364] The above dosage forms are formulated using conventional methods with pharmaceutically permissible excipients and additives. Examples of pharmaceutically permissible excipients and additives include carriers, binders, fragrances, buffers, thickeners, colorants, stabilizers, emulsifiers, dispersants, suspending agents, and preservatives.

[0365] Examples of pharmaceutically permissible carriers include magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth gum, methylcellulose, sodium carboxymethyl cellulose, low-melting-point wax, and cocoa butter. Capsules can be formulated by incorporating the disclosed compounds together with a pharmaceutically permissible carrier. The disclosed compounds can be mixed with pharmaceutically permissible excipients or placed in capsules without excipients. Flat capsules can also be manufactured using the same method.

[0366] Examples of liquid formulations for injection include solutions, suspensions, and emulsions. Examples include aqueous solutions and water-propylene glycol solutions. Liquid formulations can also be manufactured as solutions containing water-containing polyethylene glycol and / or propylene glycol. Liquid formulations suitable for oral administration can be manufactured by adding the disclosed compound to water and, as needed, adding colorants, flavorings, stabilizers, sweeteners, solubilizers, thickeners, etc. Alternatively, liquid formulations suitable for oral administration can also be manufactured by adding the disclosed compound together with a dispersant to water to make it viscous. Thickeners include pharmaceutically permissible natural or synthetic gums, resins, methylcellulose, sodium carboxymethyl cellulose, or known suspending agents.

[0367] Dosage varies depending on the specific compound and the patient's disease, age, weight, sex, symptoms, route of administration, etc., but generally for adults (weighing 50 kg), the compounds disclosed herein are administered once daily at a dose of 0.1–1000 mg / day, preferably 1–300 mg / day, or divided into 2–3 doses. Alternatively, they may be administered every few days to several weeks.

[0368] The compounds disclosed herein can be used in combination with other drugs to enhance their effects and / or reduce side effects. Hereinafter, drugs that can be used in combination with the compounds disclosed herein are referred to as combination drugs.

[0369] Specific examples of combined medications include antidepressants, anti-anxiety medications, medications for schizophrenia, dopamine supplements, dopamine receptor agonists, medications for Parkinson's disease, antiepileptic drugs, analgesics, hormonal preparations, migraine medications, beta-adrenergic receptor antagonists, medications for dementia, medications for mood disorders, antiemetics, sleep aids, and anticonvulsants. Among the medications used in combination, anti-anxiety medications such as selective serotonin reuptake inhibitors (SSRIs) are preferred examples.

[0370] The administration period of the disclosed compounds and combined pharmaceutical agents is not limited; they can be administered to the recipient simultaneously or at intervals. Furthermore, a mixture of the disclosed compounds and combined pharmaceutical agents can be formulated. The dosage of the combined pharmaceutical agent can be appropriately selected based on clinically used dosages. Additionally, the ratio of the disclosed compounds to the combined pharmaceutical agents can be appropriately selected based on the recipient, route of administration, recipient's disease, symptoms, and combination. For example, when the recipient is a person, 0.01 to 100 parts by weight of the combined pharmaceutical agent can be used relative to 1 part by weight of the disclosed compound. Furthermore, to suppress side effects, it can be used in combination with antiemetics, sleep aids, anticonvulsants, and other agents (combined pharmaceutical agents).

[0371] Example

[0372] The present disclosure is described in more detail below with reference to examples, embodiments, and test examples. However, the present disclosure is not limited to the above description, nor to the following reference to examples, embodiments, and test examples. Therefore, the scope of the present disclosure is not limited to the specific embodiments and examples described in this specification, but is defined only by the claims. Furthermore, the compound names shown in the following reference to examples and embodiments do not necessarily follow the IUPAC nomenclature. Additionally, the compounds were identified using proton nuclear magnetic resonance absorption spectroscopy (PTB). 1 The measurements were performed using methods such as ¹H-NMR and LC-MS. LC-MS was performed using the conditions shown in the table below. Retention time (RT) indicates the time at which a mass spectrometric peak appears in the LC-MS measurement.

[0373] [Table 1]

[0374]

[0375] The following abbreviations are sometimes used in this instruction manual.

[0376] Me: Methyl

[0377] Et: Ethyl

[0378] DMF: N,N-dimethylformamide

[0379] THF: Tetrahydrofuran

[0380] tert-: Uncle

[0381] TBS:tert-butyldimethylsilyl

[0382] CDCl3: Deuterated chloroform

[0383] DMSO-D6: Deuterated dimethyl sulfoxide

[0384] CD3OD: Deuterated methanol

[0385] Proton NMR spectra were measured using a JEOL FT-NMR apparatus (400 MHz). Chemical shift values ​​were denoted as δ (ppm). In NMR, s represents a singlet, d represents a doublet, dd represents a doublet doublet, dt represents a double triplet, t represents a triplet, q represents a quartet, m represents a multiplet, br represents a broad peak, brs represents a broad singlet, and J represents the coupling constant.

[0386] Example 1

[0387] rac-1-[(3R,4S)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methylamine dihydrochloride

[0388] [Chemistry 11]

[0389]

[0390] Sodium hydroxide (235 mg) was added to a mixture of the compound from Reference Example 1-1 (461 mg), methanol (4.4 mL), and water (2.2 mL) 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. After concentrating the reaction solution, the concentrated residue was dissolved in methanol, the insoluble matter was filtered off, and the solution was concentrated.

[0391] Triethylamine (0.819 mL) and diphenyl azidophosphate (0.842 mL) were added to a toluene solution (28 mL) of the obtained concentrated residue (406 mg) 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. A 5 mol / L sodium hydroxide aqueous solution (6.66 mL) was added to a mixture of the concentrated residue and tetrahydrofuran (20 mL) 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, and the mixture was extracted with chloroform (20 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate).

[0392] To a mixture of the obtained 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 filtered off, washed with diethyl ether (1.0 mL), and dried under reduced pressure to give the title compound (26 mg).

[0393] 1H-NMR (400MHz, CD30D) 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, 3.1Hz), 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).

[0394] Example 2

[0395] rac-1-[(3S,4S)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methylamine dihydrochloride

[0396] [Chemistry 12]

[0397]

[0398] The title compound was obtained from the compounds of Reference Examples 1-2 using the same method as in Example 1.

[0399] 1 H-NMR (400MHz, CD30D) 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).

[0400] Example 3

[0401] rel-1-[(3R,4R)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methylamine dihydrochloride

[0402] [Chemistry 13]

[0403]

[0404] The compound of Reference Example 5 was optically resolved by chiral HPLC to obtain the compound with the first peak. A 4 mol / L hydrogen chloride-ethyl acetate solution (0.43 mL) of this compound (48.0 mg) in ethyl acetate was added to a solution (1.0 mL) at room temperature, and the mixture was stirred for 2 hours at room temperature. The precipitated solid was then filtered off and dried under reduced pressure to obtain the title compound.

[0405] [Chiral HPLC conditions]

[0406] Column: IC 4.6cm x 25cm

[0407] Solvent: Hexane (90%) - IPA (10%) containing diethylamine (0.1%)

[0408] Flow rate: 1.0 mL / min

[0409] Retention time = 3.8 min (first peak)

[0410] [α] D 22.4 -10.4(c0.1, MeOH)

[0411] 1 H-NMR (400MHz, DMSO-D6) δ: 8.21 (3H, brs), 8.21 (1H, dd, J = 4.6, 1.5Hz), 7.40 (1H, brd, J = 7.9Hz), 7.35 (1H, dd, J = 7.9, 4.6Hz), 4.20 (1H, dd, J = 1 1.6, 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).

[0412] Example 4

[0413] rel-1-[(3S,4S)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methylamine dihydrochloride

[0414] [Chemistry 14]

[0415]

[0416] The compound of Reference Example 5 was optically resolved by chiral HPLC to obtain the compound with the second peak. A 4 mol / L hydrogen chloride-ethyl acetate solution (0.40 mL) of this compound (44.8 mg) in ethyl acetate was added to a solution (1.0 mL) at room temperature, and the mixture was stirred for 2 hours at room temperature. The precipitated solid was then filtered off and dried under reduced pressure to obtain the title compound.

[0417] [Chiral HPLC conditions]

[0418] Column: IC 4.6cm x 25cm

[0419] Solvent: Hexane (90%) - IPA (10%) containing diethylamine (0.1%)

[0420] Flow rate: 1.0 mL / min

[0421] Retention time = 4.5 min (second peak)

[0422] [α] D 22.7 +14.4 (c0.1, MeOH)

[0423] 1 H-NMR (400MHz, DMSO-D6) δ: 8.21 (3H, brs), 8.21 (1H, dd, J = 4.6, 1.5Hz), 7.40 (1H, brd, J = 7.9Hz), 7.35 (1H, dd, J = 7.9, 4.6Hz), 4.20 (1H, dd, J = 1 1.6, 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).

[0424] Example 5

[0425] N-Methyl-1-[(2R,4S)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methylamine dihydrochloride

[0426] [Chemistry 15]

[0427]

[0428] A mixture of the compound from Reference Example 6-1 (203 mg, 0.728 mmol) and tetrahydrofuran (10.0 mL) was added to 55% sodium hydride (95.0 mg) under ice-cooling. After stirring under ice-cooling for 30 minutes, iodomethane (0.453 mL, 7.28 mmol) was added. After stirring at room temperature for 3 hours, a saturated aqueous solution of ammonium chloride (10 mL) was added, and the mixture was extracted with ethyl acetate (10 mL × 2 times). After drying with anhydrous magnesium sulfate, the mixture was filtered and concentrated. The concentrated residue was purified and concentrated by silica gel column chromatography (hexane / ethyl acetate).

[0429] The mixture of the obtained product (192 mg) and ethyl acetate (3.0 mL) was added to 4 mol / L ethyl chloride-ethyl acetate (3.0 mL) under ice cooling, and stirred at room temperature for 2 hours. The precipitated solid was then filtered off and dried under reduced pressure to give the title compound (142 mg).

[0430] 1 H-NMR (400MHz, DMSO-D6) δ: 9.56 (1H, brs), 9.13 (1H, brs), 8.29 (1H, d, J = 4.9Hz), 7.62 (1H, d, J = 7.9Hz), 7.52 (1H, dd, J = 7.9, 4.9Hz), 4.4 1-4.35 (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).

[0431] Examples 6-7

[0432] The compounds of Examples 6 and 7 were obtained from the corresponding reference examples using the method described in Example 5.

[0433] [Table 2]

[0434]

[0435] Example 8

[0436] 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0437] [Chemistry 16]

[0438]

[0439] A mixture of the compound of Reference Example 13 (98 mg, 3.47 mmol) and 2-propanol (3.5 mL) was added with 4 mol / L hydrochloride-cyclopentylmethyl ether (2 mL), and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction solution, the resulting solid was recrystallized from 2-propanol to give the title compound (39.7 mg).

[0440] [α] D 25.8 +46.8 (c0.005, MeOH)

[0441] 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).

[0442] Examples 9-25

[0443] The compounds of Examples 9 to 25 were obtained from the corresponding reference examples using the method described in Example 8.

[0444] [Table 3-1]

[0445]

[0446] [Table 3-2]

[0447]

[0448] [Table 3-3]

[0449]

[0450] Example 27

[0451] 1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0452] [Chemistry 17]

[0453]

[0454] 10% palladium-carbon (8.00 g) was added to a mixture of the compound of Reference Example 37 (23.6 g, 79.0 mmol) and methanol (158 mL) under a nitrogen atmosphere. After stirring for 5 hours at room temperature under a hydrogen atmosphere, the mixture was filtered through diatomaceous earth and concentrated.

[0455] Add 4 mol / L hydrogen chloride-cyclopentylmethyl ether (43.5 mL, 174 mmol) to a mixture of concentrated residue and 2-propanol (158 mL), and stir for 15 minutes at room temperature. After concentrating the reaction solution, recrystallize the resulting crude crystals from 2-propanol and methanol to give the title compound (9.57 g).

[0456] [α] D 25.3 +37.4 (c0.01, MeOH)

[0457] 1 H-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).

[0458] Examples 28-32

[0459] The compounds of Examples 28 to 32 were obtained from the corresponding reference examples by means of the method described in Example 27.

[0460] [Table 4]

[0461]

[0462] Example 33

[0463] rac-1-[(5aS, 9aR, 10S)-6,7,8,9,9a,10-hexahydro-5aH-[1]benzopyrano[3,2-b]pyridin-10-yl]methylamine dihydrochloride

[0464] [Chemistry 18]

[0465]

[0466] Triethylamine (0.208 mL, 1.49 mmol) and diphenyl azidophosphate (0.214 mL, 0.995 mmol) were added to a toluene solution (7.1 mL) of the compound of Reference Example 50 (123 mg, 0.497 mmol), and the mixture was stirred at room temperature for 30 minutes. After stirring at 90 °C for 1 hour, 5 mol / L sodium hydroxide aqueous 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 to pH 2 and the mixture was concentrated. Methanol was added to the concentrated residue, and after removing insoluble matter by filtration, the residue was concentrated. Triethylamine (0.208 mL, 1.49 mmol) and di-tert-butyl dicarbonate (0.346 mL, 1.49 mmol) were added to a chloroform solution (10 mL) of the residue. After stirring at room temperature for 1 hour, water (30 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL × 2 times). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate). To the ethyl acetate solution (1.0 mL) of the obtained product, 4 mol / L hydrogen chloride-ethyl acetate (1.0 mL) was added, and the mixture was stirred at room temperature for 2 hours. After concentrating the reaction mixture, it was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (13 mg).

[0467] 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, brs), 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).

[0468] Example 34

[0469] 1-[(2R,3S)-2,7-dimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0470] [Chemistry 19]

[0471]

[0472] The title compound was obtained from the compound of Reference Example 51 using the same method as in Example 33.

[0473] 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).

[0474] Example 35

[0475] 1-[(2R,3S)-2,5-dimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine

[0476] [Chemistry 20]

[0477]

[0478] To a 1.0 mL ethyl acetate solution (24.4 mg, 0.0878 mmol) of the compound from Reference Example 52, 4 mol / L hydrogen chloride-ethyl acetate (1.0 mL) was added. After stirring at room temperature for 2 hours, the precipitated solid was filtered off and dried. To a 1.0 mL chloroform suspension (20 mg) of the obtained solid, 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, and the mixture was extracted with chloroform (30 mL × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate). Potassium carbonate (55.0 mg, 0.398 mmol) was added to a mixture of the obtained product, methanol (0.9 mL), and water (0.1 mL), and the mixture was stirred at 50 °C for 2 hours. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL × 2 times). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated. The residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (8.2 mg).

[0479] 1H-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).

[0480] Example 36

[0481] rac-1-[(2R,3R)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0482] [Chemistry 21]

[0483]

[0484] Triethylamine (3.59 mL, 25.8 mmol) and diphenyl azidophosphate (3.69 mL, 17.2 mmol) were added to a toluene solution (57.3 mL) of a 10:1 diastereomer mixture (1.66 g, 8.59 mmol) from Reference Example 38 at room temperature, and the mixture was stirred for 30 minutes at room temperature. After stirring at 90 °C for 1 hour, a 5 mol / L aqueous solution of sodium hydroxide (29.2 mL) was added dropwise to the reaction mixture under ice cooling. The reaction mixture was heated 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, filtered to remove the insoluble matter, and concentrated. Then, triethylamine (3.59 mL, 25.8 mmol) and di-tert-butyl dicarbonate (5.63 g, 25.8 mmol) were added to a mixture of the concentrated residue and chloroform (100 mL). After stirring at room temperature for 1 hour, water (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (50 mL × 2 times). The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate). A fraction of the product (100 mg) was further purified by reversed-phase silica gel column chromatography (water / acetonitrile / trifluoroacetic acid).

[0485] 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 the mixture was stirred at room temperature for 1 hour. The precipitated solid was then filtered off and dried under reduced pressure to give the title compound (7.0 mg).

[0486] 1H-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).

[0487] Example 37

[0488] 1-[(2R,3S)-6-chloro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0489] [Chemistry 22]

[0490]

[0491] 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 diphenyl azidophosphate (0.388 mL, 1.80 mmol) were added at room temperature, and the mixture was stirred for 30 minutes at room temperature. After stirring at 90 °C for 1 hour, a 5 mol / L aqueous solution of sodium hydroxide (5.11 mL) was added dropwise to the reaction mixture under ice cooling. The reaction mixture was heated 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, filtered to remove the insoluble matter, and concentrated. Then, triethylamine (0.628 mL, 4.51 mmol) and di-tert-butyl dicarbonate (984 mg, 4.51 mmol) were added to a mixture of the concentrated residue and chloroform (2.2 mL). After stirring at room temperature for 1 hour, water (4.0 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (4 mL × 2 times). After drying with anhydrous magnesium sulfate, the mixture was filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate).

[0492] To a mixture of the obtained compound (219 mg) and 2-propanol (1.5 mL), 4 mol / L hydrogen chloride-cyclopentylmethyl ether (1.83 mL) was added, and the mixture was stirred at room temperature for 1 hour. After concentrating the reaction solution, the crude crystals were recrystallized from 2-propanol and methanol to give the title compound (66 mg).

[0493] 1H-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).

[0494] Example 38

[0495] 1-[(2R,3S)-5-chloro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0496] [Chemistry 23]

[0497]

[0498] The title compound was obtained from the compound of Reference Example 54 using the same method as in Example 37.

[0499] 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 (1 H, 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).

[0500] Example 39

[0501] rel-1-[(4R)-3,4-dihydro-2H-thiaro[3,2-b]pyridin-4-yl]methylamine dihydrochloride

[0502] [Chemistry 24]

[0503]

[0504] The compound of Reference Example 15 was optically resolved by chiral HPLC to obtain the compound with the first peak. A 4 mol / L hydrochloride-ethyl acetate solution (0.178 mL) was added to a 1.0 mL ethyl acetate solution of this compound (20.0 mg, 0.0713 mmol), and the mixture was stirred at room temperature for 2 hours. The precipitated solid was then filtered off and dried under reduced pressure to obtain the title compound (12 mg).

[0505] [Chiral HPLC conditions]

[0506] Column: IC

[0507] Solvent: Hexane (90%) - IPA (10%) containing diethylamine (0.1%)

[0508] Flow rate: 1.0 mL / min

[0509] Retention time = 7.7 min (first peak)

[0510] [α] D 24.0 -34.5 (c0.1, MeOH)

[0511] 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).

[0512] Example 40

[0513] rel-1-[(4S)-3,4-dihydro-2H-thiaro[3,2-b]pyridin-4-yl]methylamine dihydrochloride

[0514] [Chemistry 25]

[0515]

[0516] The compound of Reference Example 15 was optically separated by chiral HPLC to obtain the compound with the second peak. Then, the title compound was obtained by the same method as in Example 39.

[0517] [Chiral HPLC conditions]

[0518] Column: IC

[0519] Solvent: Hexane (90%) - IPA (10%) containing diethylamine (0.1%)

[0520] Flow rate: 1.0 mL / min

[0521] Retention time = 9.2 min (second peak)

[0522] [α] D 24.3 +22.6 (c0.1, MeOH)

[0523] 1H-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).

[0524] Example 41

[0525] rel-1-[(3R)-2,3-dihydrothiopheno[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0526] [Chemistry 26]

[0527]

[0528] The compound of Reference Example 18 was optically separated by chiral HPLC to obtain the compound with the first peak. Then, the title compound was obtained by the same method as in Example 39.

[0529] [Chiral HPLC conditions]

[0530] Column: IC

[0531] Solvent: Hexane (90%) - IPA (10%)

[0532] Flow rate: 1.0 mL / min

[0533] Retention time = 7.67 min (first peak)

[0534] 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).

[0535] Example 42

[0536] rel-1-[(3S)-2,3-dihydrothiopheno[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0537] [Chemistry 27]

[0538]

[0539] The compound of Reference Example 18 was optically separated by chiral HPLC to obtain the compound with the second peak. Then, the title compound was obtained by the same method as in Example 39.

[0540] [Chiral HPLC conditions]

[0541] Column: IC

[0542] Solvent: Hexane (90%) - IPA (10%)

[0543] Flow rate: 1.0 mL / min

[0544] Retention time = 9.19 min (second peak)

[0545] 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).

[0546] Example 43

[0547] rel-1-[(2R,3S)-2-ethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0548] [Chemistry 28]

[0549]

[0550] The compound of Reference Example 33 was optically separated by chiral HPLC to obtain the compound with the first peak. Then, the title compound was obtained by the same method as in Example 39.

[0551] [Chiral HPLC conditions]

[0552] Column: IC

[0553] Solvent: Hexane (95%) containing diethylamine (0.1%) - IPA (5%) containing diethylamine (0.1%)

[0554] Flow rate: 1.0 mL / min

[0555] Retention time = 9.72 min (first peak)

[0556] 1H-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).

[0557] Example 44

[0558] rel-1-[(2S,3R)-2-ethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0559] [Chemistry 29]

[0560]

[0561] The compound of Reference Example 33 was optically separated by chiral HPLC to obtain the compound with the second peak. Then, the title compound was obtained by the same method as in Example 39.

[0562] [Chiral HPLC conditions]

[0563] Column: IC

[0564] Solvent: Hexane (95%) containing diethylamine (0.1%) - IPA (5%) containing diethylamine (0.1%)

[0565] Flow rate: 1.0 mL / min

[0566] Retention time = 12.64 min (second peak)

[0567] 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).

[0568] Example 45

[0569] rac-1-(3,4-dihydro-2H-thiarano[3,2-b]pyridin-4-yl)-N-methylmethylamine dihydrochloride

[0570] [Chemistry 30]

[0571]

[0572] A mixture of the compound from Reference Example 15 (244 mg, 0.870 mmol) and N,N-dimethylformamide (2.2 mL) was added to 55% sodium hydride (144 mg) 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, a saturated aqueous solution of ammonium chloride (5 mL) was added, and the mixture was extracted with 2:1 hexane / ethyl acetate (5 mL × 3 times). The extract was dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate).

[0573] 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 the mixture was stirred at room temperature for 2 hours. The precipitated solid was then filtered off, washed with diethyl ether (4.0 mL), and dried under reduced pressure to give the title compound (101 mg).

[0574] 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).

[0575] Example 46

[0576] N-Methyl-1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0577] [Chemistry 31]

[0578]

[0579] Triethylamine (0.024 mL, 0.169 mmol) and di-tert-butyl dicarbonate (18 mg, 0.084 mmol) were added to a mixture of the compound from Example 27 (10 mg, 0.042 mmol) and chloroform (0.10 mL). After stirring at room temperature for 1 hour, the reaction mixture was concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate).

[0580] A mixture of the obtained compound (101 mg, 0.382 mmol) and N,N-dimethylformamide (0.764 mL) was added to 55% sodium hydride (50.0 mg) 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 × 3 times). After drying with anhydrous magnesium sulfate, the mixture was filtered and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate).

[0581] 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 the mixture was stirred at room temperature for 2 hours. The precipitated solid was then filtered off and dried under reduced pressure to obtain the title compound (45 mg).

[0582] 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), 5.11 (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).

[0583] Examples 47-48

[0584] The compounds of Examples 47 and 48 were obtained from the compounds of the corresponding examples according to the method described in Example 46.

[0585] [Table 5]

[0586]

[0587] Example 49

[0588] 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]-N-methylmethylamine dihydrobromide

[0589] [Chemistry 32]

[0590]

[0591] 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 the mixture was stirred and the solid was filtered off. The resulting solid was mixed with ethanol (211 mL) and heated at 75 °C with stirring until the solid was completely dissolved. The mixture was then cooled to 60 °C, and after confirming that the solid had precipitated, hexane (633 mL) was added dropwise. The mixture was then slowly cooled to 0 °C, the solid was filtered off, washed with hexane / ethanol = 9 / 1 (60 mL) cooled at 0 °C, and dried to give the title compound (34.2 g).

[0592] [α] D 23.7 +33.4 (c0.01, MeOH)

[0593] 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 (1H, 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).

[0594] Examples 50-51

[0595] The compounds of Examples 50 and 51 were obtained from the compounds of the corresponding examples according to the method described in Example 46.

[0596] [Table 6]

[0597]

[0598] Examples 52-61

[0599] The compounds of Examples 52 to 61 were obtained from the corresponding reference examples using the method described in Example 27.

[0600] [Table 7-1]

[0601]

[0602] [Table 7-2]

[0603]

[0604] Example 62

[0605] rac-1-[(2R,3R,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methylamine dihydrochloride

[0606] [Chemistry 33]

[0607]

[0608] 10% palladium-carbon (60 mg) was added to a methanol solution (1.2 mL) of the compound (120 mg, 0.368 mmol) from Reference Example 88-1. After stirring for 4 hours at room temperature under a hydrogen atmosphere, the mixture was filtered through diatomaceous earth and concentrated. 4 mol / L hydrochloric acid-ethyl acetate (0.5 mL) was added to the concentrated residue, and the mixture was prepared with diethyl ether to give the hydrochloride salt of the title compound as a mixture with impurities. Triethylamine (0.154 mL) and di-tert-butyl dicarbonate (96 mg) were added to a tetrahydrofuran suspension (3.68 mL) of the mixture. After stirring for 2 hours at room temperature, 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 a purified product (38.7 mg). 4 mol / L hydrochloric acid-ethyl acetate (0.331 mL) was added to a 0.4 mL ethyl acetate solution of the purified product (38.7 mg). After stirring at room temperature for 2 hours, the precipitated solid was filtered off and dried under reduced pressure to obtain the title compound (24.2 mg) hydrochloride as a white solid.

[0609] 1 H-NMR (400MHz, CD3OD) δ: 8.31-8.26 (1H, m), 7.75-7.60 (2H, m), 4.57-4.54 (1H, m), 3.8 0-3.76(2H,m), 3.36-3.33(1H,m), 2.33(1H,s), 1.48-1.47(3H,m), 0.92-0.89(3H,m).

[0610] Examples 63-66

[0611] The compounds of Examples 63 to 66 were obtained from the corresponding reference examples using the method described in Example 62.

[0612] [Table 8]

[0613]

[0614] Examples 67-79

[0615] The compounds of Examples 67 to 79 were obtained from the corresponding reference examples using the method described in Example 8.

[0616] [Table 9-1]

[0617]

[0618] [Table 9-2]

[0619]

[0620] Examples 80-87

[0621] The compounds of Examples 80 to 87 were obtained from the corresponding reference examples using the method described in Example 49.

[0622] [Table 10-1]

[0623]

[0624] [Table 10-2]

[0625]

[0626] Example 88

[0627] rac-1-(2-methoxy-5,6,7,8-tetrahydroquinoline-8-yl)methylamine dihydrochloride

[0628] [Chemistry 34]

[0629]

[0630] To a methanol solution (0.28 mL) of the compound of Reference Example 91 (9 mg, 0.028 mmol), hydrazine monohydrate (0.007 mL, 0.140 mmol) was added 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, the precipitated solid was filtered off, and the residue was washed with water and concentrated. The concentrated residue was washed with diethyl ether and dried under reduced pressure to give the title compound (7 mg).

[0631] 1 H-NMR (400MHz, CD30D) 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).

[0632] Example 89

[0633] rac-1-[4-(4-methylphenyl)-5,6,7,8-tetrahydroquinolin-8-yl]methylamine dihydrochloride

[0634] [Chemistry 35]

[0635]

[0636] The title compound was obtained from the compound of Reference Example 101 using the same method as in Example 88.

[0637] 1 H-NMR (400MHz, CD30D) 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).

[0638] Example 90

[0639] rac-1-(5'-methyl-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl)methylamine dihydrochloride

[0640] [Chemistry 36]

[0641]

[0642] To a mixture of the compound of Reference Example 95 (300 mg, 0.870 mmol), cesium carbonate (850 mg, 2.61 mmol), trimethylcyclotriboroxane (0.365 mL), toluene (2.9 mL), and water (1.45 mL), (2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) methanesulfonate (73.6 mg, 0.087 mmol) was added. After stirring at 90 °C for 5 hours, a saturated aqueous solution of ammonium chloride (30 mL) was added. Extraction was performed with ethyl acetate (30 mL × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give a purified product (128 mg). 5.1 mol / L hydrobromic acid-acetic acid (0.387 mL) was added to this purified product (128 mg) under ice-cooling. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The concentrated residue was purified by amino silica gel column chromatography (chloroform / methanol). 4 mol / L hydrochloric acid-ethyl acetate (3.0 mL) was added to a 1.0 mL solution of the purified 2-propanol, and the precipitated solid was filtered off to give the title compound (44.4 mg).

[0643] 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).

[0644] Example 91

[0645] rac-1-[4-(cyclobutoxy)-6,7-dihydro-5H-cyclopentano[b]pyridin-7-yl]methylamine dihydrochloride

[0646] [Chemistry 37]

[0647]

[0648] 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), cyanomethylenetributylphosphine (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, and the mixture was extracted with ethyl acetate (30 mL × 2 times). After drying with anhydrous sodium sulfate, the mixture was 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 purified product. After stirring at room temperature for 2 hours, the reaction mixture was concentrated. The concentrated residue was purified by reversed-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 purified product and concentrated to give the title compound (8.2 mg).

[0649] 1 H-NMR (400MHz, CD30D) 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).

[0650] Example 92

[0651] rac-1-(4-methyl-5,6,7,8-tetrahydroquinolin-8-yl)methylamine

[0652] [Chemistry 38]

[0653]

[0654] A 0.91 mol / L tetrahydrofuran solution (0.769 mL, 0.700 mmol) of the borane-tetrahydrofuran complex was added to a 1.2 mL tetrahydrofuran solution of the compound of Reference Example 104 (40.2 mg, 0.233 mmol) 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, and extraction was performed with chloroform / methanol = 4 / 1 (30 mL × 2 times). The extract was dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by amino silica gel column chromatography (chloroform / methanol) to give the title compound (33.5 mg).

[0655] 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).

[0656] Example 93-1, Example 93-2

[0657] Example 93-1

[0658] rac-1-[(5R,7S)-5-methyl-6,7-dihydro-5H-cyclopentano[b]pyridin-7-yl]methylamine

[0659] Example 93-2

[0660] rac-1-[(5R,7R)-5-methyl-6,7-dihydro-5H-cyclopentano[b]pyridin-7-yl]methylamine

[0661] [Chemistry 39]

[0662]

[0663] The title compound was obtained from the compound of Reference Example 108 in the form of a 1:1 diastereomer mixture of Examples 93-1 and 93-2 using the same method as in Example 92.

[0664] 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).

[0665] Example 94

[0666] rel-1-[(2S,3R)-2-methyl(2- 2 H)-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0667] [Chemistry 40]

[0668]

[0669] To a tetrahydrofuran solution (2.4 mL) of the compound from 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, and the mixture was extracted with ethyl acetate (30 mL × 2 times). After drying with anhydrous sodium sulfate, the mixture was 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 give the compound of the first peak (48.7 mg). Then, the title compound (42.9 mg) was obtained by the same method as in Example 39.

[0670] [Chiral HPLC conditions]

[0671] Column: IC

[0672] Solvent: Hexane (90%) containing diethylamine (0.1%) - IPA (10%) containing diethylamine (0.1%)

[0673] Flow rate: 1.0 mL / min

[0674] Retention time = 6.80 min (first peak)

[0675] 1 H-NMR (400MHz, DMSO-D6) δ: 8.23 ​​(3H, s), 8.07-8.06 (1H, m), 7.27-7.22 (2H, m), 3.47-3.45 (1H, m), 3.28-3.12 (2H, m), 1.47 (3H, s).

[0676] Example 95

[0677] rel-1-[(2R,3S)-2-methyl(2- 2 H)-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0678] [Chemistry 41]

[0679]

[0680] After obtaining the Boc body from the compound of Example 57 using the same method as in Example 94, the compound with the second peak was optically separated by chiral HPLC. Then, the title compound was obtained using the same method as in Example 39.

[0681] [Chiral HPLC conditions]

[0682] Column: IC

[0683] Solvent: Hexane (90%) containing diethylamine (0.1%) - IPA (10%) containing diethylamine (0.1%)

[0684] Flow rate: 1.0 mL / min

[0685] Retention time = 8.43 min (second peak)

[0686] 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).

[0687] Example 96

[0688] rel-1-[(3'R)-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine dihydrochloride

[0689] [Chemistry 42]

[0690]

[0691] Following the same method as in Example 94, the Boc body was obtained from the compound of Example 58, and then optically separated by chiral HPLC to obtain the compound with the first peak. The title compound was then obtained using the same method as in Example 39.

[0692] [Chiral HPLC conditions]

[0693] Column: IC

[0694] Solvent: Hexane (90%) - IPA (10%) containing diethylamine (0.1%)

[0695] Flow rate: 1.0 mL / min

[0696] Retention time = 7.41 min (first peak)

[0697] 1 H-NMR (400MHz, CD30D) 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).

[0698] Example 97

[0699] rel-1-[(3'S)-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine dihydrochloride

[0700] [Chemistry 43]

[0701]

[0702] Following the same method as in Example 94, the Boc body was obtained from the compound of Example 58, and then optically separated by chiral HPLC to obtain the compound with the second peak. The title compound was then obtained using the same method as in Example 39.

[0703] [Chiral HPLC conditions]

[0704] Column: IC

[0705] Solvent: Hexane (90%) - IPA (10%) containing diethylamine (0.1%)

[0706] Flow rate: 1.0 mL / min

[0707] Retention time = 8.21 min (second peak)

[0708] 1 H-NMR (400MHz, CD30D) 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).

[0709] Example 98

[0710] rel-1-[(3'R)-6'-chloro-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine dihydrochloride

[0711] [Chemistry 44]

[0712]

[0713] The compound of Reference Example 89 was optically separated by chiral HPLC to obtain the compound with the first peak. Then, the title compound was obtained by the same method as in Example 39.

[0714] [Chiral HPLC conditions]

[0715] Column: AY-H

[0716] Solvent: Hexane (90%) - IPA (10%)

[0717] Flow rate: 1.0 mL / min

[0718] Retention time = 5.04 min (first peak)

[0719] 1 H-NMR (400MHz, CD30D) 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).

[0720] Example 99

[0721] rel-1-[(3'S)-6'-chloro-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine dihydrochloride

[0722] [Chemistry 45]

[0723]

[0724] The compound of Reference Example 89 was optically separated by chiral HPLC to obtain the compound with the second peak. Then, the title compound was obtained by the same method as in Example 39.

[0725] [Chiral HPLC conditions]

[0726] Column: AY-H

[0727] Solvent: Hexane (90%) - IPA (10%)

[0728] Flow rate: 1.0 mL / min

[0729] Retention time = 7.34 min (second peak)

[0730] 1 H-NMR (400MHz, CD30D) 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).

[0731] Example 100

[0732] rel-1-[(3'R)-5'-methyl-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine dihydrochloride

[0733] [Chemistry 46]

[0734]

[0735] After obtaining the Boc body from the compound of Example 90 using the same method as in Example 94, optical separation was performed by chiral HPLC to obtain the compound with the first peak. Then, the title compound was obtained using the same method as in Example 39.

[0736] [Chiral HPLC conditions]

[0737] Column: AY-H

[0738] Solvent: Hexane (95%) - IPA (5%)

[0739] Flow rate: 1.0 mL / min

[0740] Retention time = 5.09 min (first peak)

[0741] 1H-NMR (400MHz, CD30D) δ: 7.60 (1H, d, J = 8.5Hz), 7.51 (1H, d, J = 8.5Hz), 3.98-3.97 (1H, m), 3.47-3.4 5(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).

[0742] Example 101

[0743] rel-1-[(3'S)-5'-methyl-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine dihydrochloride

[0744] [Chemistry 47]

[0745]

[0746] Following the same method as in Example 94, the Boc body was obtained from the compound of Example 90, and then optically separated by chiral HPLC to obtain the compound with the second peak. The title compound was then obtained using the same method as in Example 39.

[0747] [Chiral HPLC conditions]

[0748] Column: AY-H

[0749] Solvent: Hexane (95%) - IPA (5%)

[0750] Flow rate: 1.0 mL / min

[0751] Retention time = 6.03 min (second peak)

[0752] 1 H-NMR (400MHz, CD30D) δ: 7.49 (1H, d, J = 8.5Hz), 7.42 (1H, d, J = 9.2Hz), 3.91-3.8 8(1H,m), 3.45-3.41(2H,m), 2.64(3H,s), 1.29-1.21(3H,m), 0.92-0.89(1H,m).

[0753] Example 102

[0754] rel-1-[(3'R)-5'-fluoro-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine dihydrobromide

[0755] [Chemistry 48]

[0756]

[0757] The compound of Reference Example 96 was optically separated by chiral HPLC to obtain the compound with the first peak. Then, the title compound was obtained by the same method as in Example 49.

[0758] [Chiral HPLC conditions]

[0759] Pillar: IG

[0760] Solvent: Hexane (50%) - EtOH (50%)

[0761] Flow rate: 1.0 mL / min

[0762] Retention time = 5.36 min (first peak)

[0763] 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), 3.6 4(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).

[0764] Example 103

[0765] rel-1-[(3'S)-5'-fluoro-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine dihydrobromide

[0766] [Chemistry 49]

[0767]

[0768] The compound of Reference Example 96 was optically separated by chiral HPLC to obtain the compound with the second peak. Then, the title compound was obtained by the same method as in Example 49.

[0769] [Chiral HPLC conditions]

[0770] Pillar: IG

[0771] Solvent: Hexane (50%) - EtOH (50%)

[0772] Flow rate: 1.0 mL / min

[0773] Retention time = 7.14 min (first peak)

[0774] 1 H-NMR (400MHz, DMSO-D6) δ: 7.86 (3H, s), 7.46 (1H, dd, J=8.5, 6.1Hz), 7.04 (1H, dd, J=8.5, 1.8Hz), 3.6 4(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).

[0775] Example 104

[0776] rel-1-[(3R)-2,2,5-trimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0777] [Transformation 50]

[0778]

[0779] Following the same method as in Example 94, the Boc body was obtained from the compound of Example 83, and then optically separated by chiral HPLC to obtain the compound with the first peak. The title compound was then obtained using the same method as in Example 39.

[0780] [Chiral HPLC conditions]

[0781] Column: IC

[0782] Solvent: Hexane (95%) - IPA (5%)

[0783] Flow rate: 1.0 mL / min

[0784] Retention time = 5.575 min (first peak)

[0785] 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).

[0786] Example 105

[0787] rel-1-[(3S)-2,2,5-trimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine dihydrochloride

[0788] [Chemistry 51]

[0789]

[0790] Following the same method as in Example 94, the Boc body was obtained from the compound of Example 83, and then optically separated by chiral HPLC to obtain the compound with the second peak. The title compound was then obtained using the same method as in Example 39.

[0791] [Chiral HPLC conditions]

[0792] Column: IC

[0793] Solvent: Hexane (95%) - IPA (5%)

[0794] Flow rate: 1.0 mL / min

[0795] Retention time = 6.539 min (second peak)

[0796] 1 H-NMR (400MHz, DMSO-D6)S: 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).

[0797] Example 106

[0798] rac-1-(5-fluoro-2,2-dimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl)methylamine dihydrobromide

[0799] [Chemistry 52]

[0800]

[0801] The title compound was obtained from the compound of Reference Example 118 using the same method as in Example 49.

[0802] 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).

[0803] Refer to Example 1-1 and Example 1-2.

[0804] See Example 1-1

[0805] rac-ethyl[(3R,4R)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]acetate

[0806] See Example 1-2

[0807] rac-ethyl[(3S,4R)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]acetate

[0808] [Chemistry 53]

[0809]

[0810] 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 purified by silica gel column chromatography (hexane / ethyl acetate) to give Reference Example 1-1 (0.461 g) and Reference Example 1-2 (0.624 g) of the title compound.

[0811] See Example 1-1

[0812] 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).

[0813] See Example 1-2

[0814] 1H-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).

[0815] See Example 2

[0816] rac-ethyl(2E)-5-[(2-bromopyridin-3-yl)oxy]-4-methylpent-2-enoate

[0817] [Chemistry 54]

[0818]

[0819] Ethyl(triphenylphosphine) acetate (2.58 g, 7.40 mmol) was added to a mixture of the compound of Reference Example 3 (1.72 g, 7.05 mmol) and toluene (23.5 mL) at room temperature. After stirring at 90 °C for 2 hours, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.64 g).

[0820] 1 H-NMR (400MHz, CDCl3) δ: 7.98 (1H, dd, J=4.6, 1.2Hz), 7.18 (1H, dd, J=8.2, 4.6H z), 7.08 (1H, dd, J=8.2, 1.2Hz), 6.99 (1H, dd, J=15.8, 7.3Hz), 5.95 (1H, dd, J=1 5.8, 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).

[0821] See Example 3

[0822] rac-3-[(2-bromopyridin-3-yl)oxy]-2-methylpropanal

[0823] "Transformation 55"

[0824]

[0825] To a mixture of the compound of Reference Example 4 (3.65 g, 14.8 mmol) and chloroform (49.4 mL), Dysmart oxidant (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. The mixture was extracted with chloroform (50 mL × 2 times), 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).

[0826] 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).

[0827] See Example 4

[0828] rac-3-[(2-bromopyridin-3-yl)oxy]-2-methylpropane-1-ol

[0829] [Chemistry 56]

[0830]

[0831] Diisopropyl azodicarbonate (2.45 mL, 12.6 mmol) was added 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) 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).

[0832] 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, 5.2Hz), 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).

[0833] See Example 5

[0834] rac-tert-butyl{[(3S,4S)-3-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[0835] [Chemistry 57]

[0836]

[0837] 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) from Example 2. After stirring at room temperature for 2 hours, the compound was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (20.4 mg).

[0838] 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), 3.82-3.73 (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).

[0839] See Example 6-1 and Example 6-2.

[0840] See Example 6-1

[0841] tert-butyl{[(2R,4S)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[0842] See Example 6-2

[0843] tert-butyl{[(2R,4R)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[0844] [Chem.58]

[0845]

[0846] Sodium hydroxide (1.94 g, 48.5 mmol) was added to a mixture of the compound from Reference Example 7 (5.37 g, 24.3 mmol), methanol (53.9 mL), and water (27.0 mL) 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. After concentrating the reaction solution, the concentrated residue was dissolved in methanol, the insoluble matter was filtered off, and the solution was concentrated.

[0847] Triethylamine (11.7 mL, 84.0 mmol) and diphenyl azidophosphate (12.0 mL, 55.9 mmol) were added to a toluene solution (400 mL) of the obtained residue (5.79 g) 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 sodium hydroxide aqueous solution (84.0 mL) was added dropwise to the reaction mixture under ice cooling. The reaction mixture was heated to room temperature over 2 hours, and then concentrated by adding 6 mol / L hydrochloric acid to pH 7. The concentrated residue was dissolved in methanol, the insoluble matter was filtered off, and the mixture was concentrated. Triethylamine (11.7 mL, 84.0 mmol) and di-tert-butyl dicarbonate (18.3 g, 84.0 mmol) were added to a mixture of the concentrated residue and chloroform (100 mL). After stirring at room temperature for 1 hour, water (100 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (100 mL × 2 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated and purified by silica gel column chromatography (hexane / ethyl acetate) to obtain Reference Example 6-1 (1.32 g) and Reference Example 6-2 (3.34 g) of the title compound.

[0848] See Example 6-1

[0849] 1H-NMR (400MHz, CDCl3) δ: 8.06 (1H, dd, J=4.3, 1.2Hz), 7.04 (1H, dd, J=8.3, 1.2 Hz), 6.98 (1H, dd, J=8.3, 4.3Hz), 5.35 (1H, brs), 4.27-4.20 (1H, m), 3.56-3.5 0 (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).

[0850] See Example 6-2

[0851] 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), 3.37-3.31 (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).

[0852] See Example 7

[0853] Methyl[(2R)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]acetate

[0854] [Chemistry 59]

[0855]

[0856] 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 purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (5.37 g) as a 3:1 diastereomer mixture.

[0857] Main diastereomer

[0858] 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).

[0859] See Example 8

[0860] Ethyl(2E,5R)-5-[(2-bromopyridin-3-yl)oxy]hex-2-enoate

[0861] [Transformation 60]

[0862]

[0863] To a mixture of the compound of Reference Example 9 (8.91 g, 36.2 mmol) and chloroform (120 mL), Dysmart oxidant (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. The mixture was extracted with chloroform (75 mL × 2 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. To a mixture of the concentrated residue and toluene (100 mL), ethyl (triphenylphosphine) 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).

[0864] 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).

[0865] See Example 9

[0866] (3R)-3-[(2-bromopyridin-3-yl)oxy]butane-1-ol

[0867] [Chemistry 61]

[0868]

[0869] A mixture of the compound from Reference Example 10 (13.5 g, 37.5 mmol) and methanol (135 mL) was added to 6 mol / L hydrochloric acid (18.7 mL) under ice-cooling. After stirring at room temperature for 2 hours, a saturated aqueous solution of sodium bicarbonate (250 mL) was added to the reaction mixture under ice-cooling. The mixture was extracted with chloroform (150 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (8.91 g).

[0870] 1 H-NMR (400MHz, CDCl3) δ: 7.90 (1H, dd, J=4.0, 2.1Hz), 7.17-7.11 (2H, m), 4.6 0-4.58(1H,m), 3.84-3.71(2H,m), 2.01-1.83(2H,m), 1.30(3H,d,J=6.1Hz).

[0871] See Example 10

[0872] 2-Bromo-3-{[(2R)-4-{[tert-butyl(dimethyl)silyl]oxy}butane-2-yl]oxy}pyridine

[0873] [Chemistry 62]

[0874]

[0875] Diisopropyl azodicarbonate (8.60 mL, 44.3 mmol) was added 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) 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).

[0876] 1H-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).

[0877] See Example 11

[0878] tert-butyl{[(2S,4S)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[0879] [Chemistry 63]

[0880]

[0881] 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.

[0882] 1 H-NMR (400MHz, CDCl3) δ: 8.13-8.09 (1H, m), 7.10-7.04 (2H, m), 5.92 (1H, brs), 4.26-4.16 (1H, m), 3.80-3.71 (1H, m) ), 3.40-3.30 (1H, m), 3.16-3.07 (1H, m), 2.13-2.06 (1H, m), 1.70-1.57 (1H, m), 1.43 (9H, s), 1.40 (3H, d, J = 6.1Hz).

[0883] See Example 12

[0884] rac-tert-butyl{[(2R,4S)-2-methyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[0885] [Chemistry 64]

[0886]

[0887] The title compound was obtained from 4-((tert-butyldimethylsilyl)oxy)-2-butanol by the same method as in Reference Examples 6-1 to 10.

[0888] 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), 3.46-3.36 (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).

[0889] See Example 13

[0890] tert-butyl{[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[0891] [Chemistry 65]

[0892]

[0893] 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 diphenyl azidophosphate (0.57 mL, 2.67 mmol) were added at room temperature, and the mixture was stirred for 30 minutes at room temperature. After stirring at 90 °C for 1 hour, a 5 mol / L aqueous solution of sodium hydroxide (4.0 mL, 20.0 mmol) was added to the reaction mixture under ice cooling. After stirring at room temperature for 2 hours, 12 mol / L hydrochloric acid (1.7 mL) was added for neutralization, and 2-propanol (10 mL) was added for concentration. The concentrated residue was dissolved in methanol, the insoluble matter was filtered off, and the mixture was 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 purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (98 mg).

[0894] 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).

[0895] See Example 14

[0896] [(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]acetic acid

[0897] [Chemistry 66]

[0898]

[0899] 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) azodicarbonate (671 mg, 2.86 mmol) was added under ice-cooling. After stirring at room temperature for 2 hours, methanol was added to the reaction mixture and the mixture was concentrated. Toluene (500 mL) was added to the concentrated residue, which was washed with water (200 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. Tributyltin hydride (1.16 mL, 4.42 mmol) and azobisisobutyronitrile (42.7 mg, 0.26 mmol) were added to the toluene solution (9.0 mL) of the concentrated residue at room temperature. After stirring at 90 °C for 1 hour, the reaction mixture was concentrated. A mixture of concentrated residue and tetrahydrofuran (10 mL) was added to a 4 mol / L aqueous solution of sodium hydroxide (2.08 mL, 10.4 mmol) 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 ether (10 mL × 2 times). Then, 4 mol / L hydrochloric acid (10.4 mL) was added until the aqueous layer reached pH 5, and extraction was performed with chloroform (200 mL × 5 times). The combined organic layers were dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain the title compound (281 mg).

[0900] 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).

[0901] See Example 15

[0902] rac-tert-butyl[(3,4-dihydro-2H-thiaro[3,2-b]pyridin-4-yl)methyl]carbamate

[0903] [Chemistry 67]

[0904]

[0905] Sodium hydroxide (351 mg, 8.78 mmol) was added to a mixture of the compound from Reference Example 16 (980 mg, 4.39 mmol), methanol (9.8 mL), and water (4.9 mL) 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, filtered to remove the insoluble matter, and concentrated again.

[0906] Triethylamine (2.20 mL, 15.8 mmol) and diphenyl azidophosphate (2.26 mL, 10.5 mmol) were added to a toluene solution (35.0 mL) of the obtained compound (1.10 g) at room temperature, and the mixture was stirred at room temperature for 30 min. After stirring at 90 °C for 1 hour, a 5 mol / L sodium hydroxide aqueous solution (17.9 mL) was added dropwise to the reaction mixture under ice cooling. The reaction mixture was heated to room temperature over 2 hours, neutralized with 6 mol / L hydrochloric acid, and concentrated. The concentrated residue was dissolved in methanol, filtered to remove the insoluble matter, and concentrated. Triethylamine (2.20 mL, 15.8 mmol) and di-tert-butyl dicarbonate (3.66 g, 15.8 mmol) were added to a mixture of the concentrated residue and chloroform (30 mL). After stirring at room temperature for 1 hour, water (50 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (50 mL × 2 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (560 mg).

[0907] 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).

[0908] See Example 16

[0909] rac-methyl(3,4-dihydro-2H-thiarano[3,2-b]pyridin-4-yl)acetate

[0910] [Chemistry 68]

[0911]

[0912] To a mixture of the compound of Reference Example 17 (1.66 g, 6.69 mmol) and chloroform (22.3 mL), Dysmart oxidant (2.98 g, 7.02 mmol) was added under ice-cooling. After stirring under ice-cooling for 1 hour, ethyl (triphenylphosphine) acetate (2.46 g, 7.36 mmol) was added to the reaction mixture. After stirring at room temperature for 1 hour, 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 × 2 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified and concentrated by silica gel column chromatography (hexane / ethyl acetate).

[0913] 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 purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.980 g).

[0914] 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).

[0915] See Example 17

[0916] 3-[(2-bromopyridin-3-yl)thio]propane-1-ol

[0917] [Chemistry 69]

[0918]

[0919] Potassium carbonate (8.00 g) was added to a mixture of 2-bromo-3-fluoropyridine (3.00 g, 17.1 mmol), 3-mercapto-1-propanol (1.43 g, 15.5 mmol), and N,N-dimethylformamide (15.5 mL). After stirring at room temperature for 24 hours, the mixture was concentrated by diatomaceous earth filtration. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.66 g).

[0920] 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).

[0921] See Examples 18-22

[0922] The compounds of Reference Examples 18 to 22 were obtained from the corresponding compounds according to the methods described in Reference Examples 15 to 17.

[0923] [Table 11]

[0924]

[0925] See Example 25-1 and Example 25-2.

[0926] See Example 25-1

[0927] tert-butyl{[(2R,4R)-2,6-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[0928] See Example 25-2

[0929] tert-butyl{[(2R,4S)-2,6-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[0930] [Chemistry 70]

[0931]

[0932] Reference Examples 25-1 and 25-2, which yielded the title compounds from 2-bromo-3-hydroxy-6-methylpyridine, were obtained by the same method as in Reference Examples 6-1, 6-2 to Reference Examples 10.

[0933] See Example 25-1

[0934] LC-MS: RT=0.745min 0bsMS=293.0[M+1]

[0935] See Example 25-2

[0936] LC-MS: RT=0.650min ObsMS=294.3[M+2]

[0937] See Example 26-1 and Example 26-2.

[0938] See Example 26-1

[0939] tert-butyl{[(2S,3R)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[0940] See Example 26-2

[0941] tert-butyl{[(2S,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[0942] [Chemistry 71]

[0943]

[0944] Reference Examples 26-1 and 26-2, which are title compounds, were obtained from the compound of Reference Example 27 using the same method as Reference Examples 6-1, 6-2 to 7.

[0945] See Example 26-1

[0946] 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).

[0947] See Example 26-2

[0948] LC-MS: RT=1.42min 0bsMS=265[M+1]

[0949] See Example 27

[0950] Methyl(2E,4S)-4-[(2-bromopyridin-3-yl)oxy]pent-2-enoate

[0951] [Chemistry 72]

[0952]

[0953] A solution of 1.03 mol / L diisobutylaluminum hydride in toluene (17.47 mL, 17.99 mmol) was added to a mixture of the compound of Reference Example 28 (1.56 g, 6.00 mmol) and dichloromethane (12.0 mL) at -78 °C. After stirring at -78 °C for 2 hours, saturated ammonium chloride water (50 mL) was added, and the insoluble matter was removed by filtration through diatomaceous earth. After extraction with ethyl acetate, the mixture was dried over anhydrous magnesium sulfate, filtered, and concentrated. Ethyl(triphenylphosphine) acetate (2.005 g, 6.00 mmol) was added to a mixture of the concentrated residue and toluene 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).

[0954] 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).

[0955] See Example 28

[0956] Methyl (2S)-2-[(2-bromopyridin-3-yl)oxy]propionate

[0957] [Chemistry 73]

[0958]

[0959] Diisopropyl azodicarbonate (1.83 mL, 12.6 mmol) was added to a mixture of (R)-(+)-lactic acid methyl (1.20 g, 11.5 mmol), 2-bromo-3-hydroxypyridine (2.00 g, 11.5 mmol), triphenylphosphine (3.32 g, 12.6 mmol), and tetrahydrofuran (38 mL) under ice-cooling. After stirring at room temperature for 15 hours, methanol was added to the reaction mixture and the mixture was concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) and concentrated to give the title compound (13.5 g).

[0960] 1 H-NMR (400MHz, CDCl3) δ: 8.05-8.03 (1H, m), 7.18-7.17 (1H, m), 7.09-7.08 (1H, m), 4.78-4.76 (1H, m), 3.77 (3H, s), 1.72 (3H, d, J = 7.3Hz).

[0961] See Example 29

[0962] rac-tert-butyl{[(2R,3S)-2-(propane-2-yl)-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[0963] [Chemistry 74]

[0964]

[0965] The title compound was obtained from the compound of Reference Example 30 by the same method as in Reference Examples 6-1, 6-2 and 7.

[0966] 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).

[0967] See Example 30

[0968] rac-methyl(2E)-4-[(2-bromopyridin-3-yl)oxy]-5-methylhex-2-enoate

[0969] [Chemistry 75]

[0970]

[0971] Triethylamine (1.90 mL, 13.6 mmol) and a sulfur trioxide pyridine complex (2.17 g, 13.6 mmol) were added to a mixture of the compound of Reference Example 31 (1.18 g, 4.54 mmol) and dimethyl sulfoxide (15.0 mL) 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 × 2 times). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated. Ethyl(triphenylphosphine) acetate (1.72 g, 5.16 mmol) was added to a mixture of the concentrated residue and toluene (15 mL) at room temperature. After stirring at room temperature for 12 hours, the reaction solution was concentrated, and the residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (0.77 g).

[0972] 1H-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).

[0973] See Example 31

[0974] rac-2-[(2-bromopyridin-3-yl)oxy]-3-methylbutane-1-ol

[0975] [Chemistry 76]

[0976]

[0977] A 1.0 mol / L toluene solution of diisobutylaluminum hydride (4.88 mL, 4.88 mmol) was added to a mixture of the compound of Reference Example 32 (1.34 g, 4.43 mmol) and tetrahydrofuran (15.0 mL) at -78 °C. After stirring at room temperature for 3 hours, the 1.0 mol / L toluene solution of diisobutylaluminum hydride (4.88 mL, 4.88 mmol) was added under ice cooling. After stirring under ice cooling for 2 hours, water (30 mL) and a 10% potassium hydrogen sulfate aqueous solution (30 mL) were added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL × 2 times). 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).

[0978] 1 H-NMR (400MHz, CDCl3) δ: 7.97-7.96 (1H, m), 7.30-7.28 (1H, m), 7.18-7.16 (1H, m), 4.17-4.1 6(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).

[0979] See Example 32

[0980] rac-methyl 2-[(2-bromopyridin-3-yl)oxy]-3-methylbutyrate

[0981] [Chemistry 77]

[0982]

[0983] Potassium carbonate (1.91 g, 13.8 mmol) and ethyl 2-bromo-3-methylbutyrate (2.25 mL, 13.8 mmol) were added to a mixture of 2-bromo-3-hydroxypyridine (2.00 g, 11.5 mmol) and N,N-dimethylformamide (30 mL). 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 × 2 times). 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).

[0984] 1 H-NMR (400MHz, CDCl3) δ: 7.99-7.97 (1H, m), 7.15-7.13 (1H, m), 6.96-6.94 (1H, m), 4.39 (1H , d, J=4.9Hz), 4.22-4.19 (2H, m), 2.39-2.37 (1H, m), 1.23-1.22 (3H, m), 1.13-1.11 (6H, m).

[0985] See Examples 33-34

[0986] Following the method described in Reference Examples 29-32, the compounds of Reference Examples 33-34 were obtained from the corresponding compounds.

[0987] [Table 12]

[0988]

[0989] See Example 35-1 and Example 35-2.

[0990] See Example 35-1

[0991] rac-tert-butyl{[(2S,4R)-2-phenyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[0992] See Example 35-2

[0993] rac-tert-butyl{[(2S,4S)-2-phenyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[0994] [Chemistry 78]

[0995]

[0996] Reference Examples 35-1 and 35-2, which are title compounds, were obtained from 3-((tert-butyldimethylsilyl)oxy)-1-phenyl-1-propanol using the same method as Reference Examples 6-1, 6-2 to 10.

[0997] See Example 35-1

[0998] 1 H-NMR (400MHz, CDCl3) δ: 8.22-8.18 (1H, m), 7.46-7.31 (5H, m), 7.26-7.12 (2H, m), 6.01 (1H, brs), 5.14 (1H, dd, J=11.6 , 1.8Hz), 3.87-3.76 (1H, m), 3.51-3.40 (1H, m), 3.40-3.31 (1H, m), 2.40-2.32 (1H, m), 2.07-1.96 (1H, m), 1.44 (9H, s).

[0999] See Example 35-2

[1000] 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).

[1001] See Example 36

[1002] rac-tert-butyl{[(2S,3S)-2-(hydroxymethyl)-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[1003] [Chemistry 79]

[1004]

[1005] Triethylamine (0.044 mL, 0.314 mmol) and a 1.0 mol / L solution of boron tribromide in dichloromethane (0.330 mL, 0.330 mmol) were added to a 2.0 mL dichloromethane suspension of the compound from Example 32 (42.0 mg, 0.157 mmol) 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 under ice-cooling for 10 minutes, the reaction mixture was concentrated. Potassium carbonate (217 mg, 1.57 mmol) and di-tert-butyl dicarbonate (51.5 mg, 0.236 mmol) were added to a mixture of concentrated residue, tetrahydrofuran (1.0 mL), and water (1.0 mL). After stirring at room temperature for 3 hours, water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL × 2 times), 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).

[1006] 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).

[1007] See Example 37

[1008] Benzyl{[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[1009] [Chemistry 80]

[1010]

[1011] 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 diphenyl azidophosphate (37.5 mL, 175 mmol) were added at room temperature, and the mixture was stirred for 30 minutes at room temperature. 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, a saturated aqueous solution of sodium bicarbonate (250 mL) was added to the reaction mixture under ice cooling. The mixture was extracted with ethyl acetate (150 mL × 2 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified and concentrated by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (23.6 g) as a 10:1 diastereomer mixture.

[1012] Main diastereomer

[1013] 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).

[1014] See Example 38

[1015] tert-butyl{[(2S,4S)-2-phenyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1016] [Chemistry 81]

[1017]

[1018] 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. Sodium hydroxide (24.0 g, 599 mmol) was added to a mixture of the concentrated residue, tetrahydrofuran (333 mL), and water (167 mL) 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 times). Then, 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 times). 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 diastereomer mixture.

[1019] Main diastereomer

[1020] 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).

[1021] See Example 39

[1022] Ethyl(2E,4R)-4-[(2-bromopyridin-3-yl)oxy]pent-2-enoate

[1023] [Chemistry 82]

[1024]

[1025] 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, which was washed with water (200 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. Hexane / ethyl 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 and concentrated by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (45.0 g).

[1026] 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).

[1027] See Example 40

[1028] Ethyl(2E,4S)-4-hydroxypent-2-enoate

[1029] [Chemistry 83]

[1030]

[1031] Sodium borohydride (7.59 g, 201 mmol) was added to a mixture of the compound of Reference Example 41 (23.8 g, 167 mmol) and methanol (478 mL) at -35 °C. After heating to 0 °C over 1 hour, a saturated aqueous solution of ammonium chloride (500 mL) was added to the reaction mixture under ice cooling. The mixture was extracted with ethyl acetate (500 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified and concentrated by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (17.0 g).

[1032] 1H-NMR (400MHz, CDCl3) δ: 6.78 (1H, dd, J=15.8, 4.9Hz), 5.84 (1H, dd, J=15.8, 1.5Hz), 4 .35-4.26(1H,m), 4.02(2H,q,J=7.0Hz), 1.16(3H,d,J=6.7Hz), 1.11(3H,t,J=7.0Hz).

[1033] See Example 41

[1034] Ethyl(4S)-4-hydroxypent-2-enoate

[1035] [Chemistry 84]

[1036]

[1037] Concentrated sulfuric acid (0.110 mL) was added 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) 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 tetrahydrofuran solution of ethyl chloroformate (26.6 mL, 279 mmol) (59 mL) was added dropwise. After stirring at -78 °C for 1 hour, the reaction mixture was warmed to room temperature over 1 hour. 6 mol / L sulfuric acid (108 mL) was added to the reaction mixture, and the mixture was stirred at room temperature for 15 hours. Water (300 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (200 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was separated, purified, and concentrated by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (23.4 g).

[1038] 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).

[1039] See Examples 42-45

[1040] The compounds of Reference Examples 42 to 45 were obtained from the corresponding compounds by following the method described in Reference Examples 37 to 39.

[1041] [Table 13]

[1042]

[1043] See Example 46

[1044] rac-benzyl{[(2S,3S)-2-(methoxymethyl)-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[1045] [Chemistry 85]

[1046]

[1047] The title compound was obtained from Reference Example 47 by the same method as in Reference Example 37.

[1048] 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).

[1049] See Example 47

[1050] rac-[(2S,3S)-2-(methoxymethyl)-2,3-dihydrofurano[3,2-b]pyridin-3-yl]acetic acid

[1051] [Chemistry 86]

[1052]

[1053] 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. Then, 6 mol / L hydrochloric acid was added to the reaction mixture until pH 4 was reached, and the mixture was concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (258 mg).

[1054] 1H-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, 3.0Hz), 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).

[1055] See Example 48

[1056] rac-methyl[(2S,3S)-2-(methoxymethyl)-2,3-dihydrofurano[3,2-b]pyridin-3-yl]acetate

[1057] [Chemistry 87]

[1058]

[1059] The title compound was obtained from the compound of Reference Example 49 by the same method as in Reference Example 1-1.

[1060] 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), 3.70 (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).

[1061] See Example 49

[1062] rac-methyl(2E)-4-[(2-bromopyridin-3-yl)oxy]-5-methoxypent-2-enoate

[1063] [Chemistry 88]

[1064]

[1065] The title compound was obtained from methyl 2-bromo-3-methoxypropionate by the same method as in Reference Examples 30 to 32.

[1066] 1H-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).

[1067] See Example 50

[1068] rac-[(5aS, 9aR, 10R)-6,7,8,9,9a,10-hexahydro-5aH-[1]benzopyrano[3,2-b]pyridin-10-yl]acetic acid

[1069] [Chemistry 89]

[1070]

[1071] The title compound was obtained from 2-(((tert-butyldimethylsilyl)oxy)methyl)cyclohexane-1-ol by the same method as in Reference Examples 8 to 10 and Reference Example 14.

[1072] LC-MS: RT=1.353min 0bsMS=248.4[M+1]

[1073] See Example 51

[1074] [(2R,3S)-2,7-dimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]acetic acid

[1075] [Chemistry 90]

[1076]

[1077] The title compound was obtained from 2-bromo-3-hydroxy-4-methylpyridine using the same method as in Reference Examples 38 to 39.

[1078] LC-MS: RT=0.449min 0bsMS=208.1[M+1]

[1079] See Example 52

[1080] tert-butyl{[(2R,3S)-2,5-dimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[1081] [Chemistry 91]

[1082]

[1083] The title compound was obtained from 2-bromo-3-hydroxy-6-methylpyridine using the same method as in Reference Examples 13 to 14.

[1084] 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).

[1085] See examples 53-54

[1086] Following the method described in Reference Examples 38-39, the compounds of Reference Examples 53-54 were obtained from the corresponding compounds.

[1087] [Table 14]

[1088]

[1089] See Example 55

[1090] Benzyl{[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl} methylcarbamate

[1091] [Chemistry 92]

[1092]

[1093] A solution (123 mL) of N-methylpyrrolidone (58.2 g, 184 mmol) of the compound of Reference Example 56 was added to a suspension of N-methylpyrrolidone (491 mL) in 55% sodium hydride (12.0 g, 276 mmol) under ice-cooling. After stirring for 30 min, iodomethane (23.0 mL, 368 mmol) was added to the reaction mixture under ice-cooling, and the mixture was stirred at room temperature for 2 h. Then, water (500 mL) was added to the reaction mixture under ice-cooling, and the mixture was extracted with ethyl acetate (1000 mL), washed with water (200 mL × 2 times), 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).

[1094] 1H-NMR (400MHz, CDCl3) δ: 7.87 (1H, dd, J=2.4, 1.2Hz), 7.33-7.31 (5H, m), 6.75 -6.72(3H,m),5.12(2H,s),4.92-4.74(1H,m),3.80-3.65(2H,m),3.25(1H,br s), 2.92 (3H, d, J=14.6Hz), 1.40-1.35 (3H, m).

[1095] See Example 56

[1096] Benzyl{[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[1097] [Chemistry 93]

[1098]

[1099] Triethylamine (33.2 mL, 239 mmol) and diphenyl azidophosphate (41.0 mL, 191 mmol) were added to a toluene solution (227 mL) of the compound of Reference Example 14 (33.6 g, 159 mmol) 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, a saturated aqueous solution of sodium bicarbonate (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).

[1100] 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).

[1101] See examples 57-59

[1102] The compounds of Reference Examples 57 to 59 were obtained from the corresponding compounds by following the methods described in Reference Examples 7 to 10, 37 and 47.

[1103] [Table 15]

[1104]

[1105] See Example 60

[1106] rac-tert-butyl{[6-(trifluoromethyl)-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1107] [Chemistry 94]

[1108]

[1109] The title compound was obtained from propane-1,3-diol and 2-bromo-6-(trifluoromethyl)pyridine-3-ol by the same method as in Reference Examples 1 to 4 and Reference Example 6.

[1110] LC-MS: RT=1.133min 0bsMS=333.2[M+1]

[1111] See Example 61

[1112] rac-tert-butyl[(1,2,3,4-tetrahydro-1,5-naphthid-4-yl)methyl]carbamate

[1113] [Chemistry 95]

[1114]

[1115] To a mixture of the compound from 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, and the mixture was stirred for 15 minutes. After concentrating the reaction mixture, the concentrated residue was dissolved in 2.0 mol / L hydrochloric acid (2.52 mL, 5.03 mmol), and the mixture was stirred at 60 °C for 2 hours. After concentrating the reaction mixture, the concentrated residue was dissolved in chloroform (5.0 mL), and triethylamine (0.701 mL, 5.03 mmol) and di-tert-butyl dicarbonate (330 mg, 1.51 mmol) were added. After stirring at room temperature for 1 day, water (5.0 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (3.0 mL × 2 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to obtain the title compound (100 mg).

[1116] 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).

[1117] See Example 62

[1118] rac-tert-butyl-4-cyano-3,4-dihydro-1,5-naphthidine-1(2H)-carboxylate

[1119] [Chemistry 96]

[1120]

[1121] To a mixture of the compound of Reference Example 63 (660 mg, 2.11 mmol), trimethylcyanosilane (0.523 mL, 4.21 mmol), and acetonitrile (14 mL), 1.0 mol / L tetrabutylammonium fluoride (4.21 mL, 4.21 mmol) was added, and the mixture was stirred at 70 °C for 3 hours. The reaction mixture was concentrated, and the concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (261 mg) as a white solid.

[1122] 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).

[1123] See Example 63

[1124] rac-tert-butyl-4-bromo-3,4-dihydro-1,5-naphthidine-1(2H)-carboxylate

[1125] [Chemistry 97]

[1126]

[1127] A mixture of 1,1-dimethylethyl 3,4-dihydro-1,5-naphthyl-1(2H)-carboxylate (560 mg, 2.39 mmol), N-bromosuccinimide (510 mg, 2.87 mmol), and carbon tetrachloride (12 mL) was heated to reflux for 5 hours. After cooling the reaction mixture to room temperature, the precipitated solid was filtered off, 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).

[1128] 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).

[1129] See examples 64-65

[1130] Following the methods described in Reference Examples 37 to 39, the compounds of Reference Examples 64 to 65 were obtained from the corresponding compounds.

[1131] [Table 16]

[1132]

[1133] See Example 66

[1134] 2-Iodo-4,6-dimethylpyridin-3-ol

[1135] [Chem. 98]

[1136]

[1137] Iodine (247 mg, 0.972 mmol) was added to a mixture of 4,6-dimethyl-3-hydroxypyridine (99.8 mg, 0.810 mmol), water (12 mL), and tetrahydrofuran (2.0 mL) at 0 °C. After stirring at room temperature for 25 hours, 1 mol / L hydrochloric acid (4 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL × 3 times), dried over anhydrous magnesium sulfate, filtered, and concentrated. The organic layer was washed with 0.1 mol / L sodium thiosulfate aqueous solution (10 mL × 3 times), 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).

[1138] 1 H-NMR (400MHz, CDCl3) δ: 6.82 (1H, s), 2.42 (3H, s), 2.27 (3H, s).

[1139] See Example 67

[1140] Benzyl{2-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]propane-2-yl}carbamate

[1141] [Chemistry 99]

[1142]

[1143] Sodium hydroxide (37.5 mg, 0.939 mmol) was added to a mixture of the compound from Reference Example 68 (78.0 mg, 0.313 mmol), methanol (0.70 mL), and water (0.35 mL) 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. After concentrating the reaction solution, the concentrated residue was dissolved in methanol, the insoluble matter was filtered off, and the solution was concentrated again.

[1144] Triethylamine (0.130 mL, 0.936 mmol) and diphenyl azidophosphate (0.0800 mL, 0.374 mmol) were added to a toluene solution (0.45 mL) of the concentrated residue (69.0 mg) 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, a saturated aqueous solution of sodium bicarbonate (1.0 mL) was added to the reaction mixture under ice cooling. The mixture was extracted with ethyl acetate (1.0 mL × 2 times), 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).

[1145] 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).

[1146] See Example 68

[1147] Ethyl 2-methyl-2-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]propionate

[1148] [Chemistry 100]

[1149]

[1150] To a tetrahydrofuran solution (1.7 mL) of the compound of Reference Example 69 (150 mg, 0.678 mmol), a 1.0 mol / L solution of lithium bis(trimethylsilyl)aminotoluene (1.63 mL, 1.63 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 30 min, iodomethane (1.63 mL, 1.63 mmol) was added. After further stirring for 1 hour, the reaction mixture was heated to room temperature over 1 hour. A saturated aqueous solution of ammonium chloride (3.4 mL) was added to the reaction mixture under ice cooling, and the mixture was extracted with ethyl acetate (1.7 mL × 2 times), 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).

[1151] 1H-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 ), 4.69-4.63 (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).

[1152] See Example 69

[1153] Ethyl[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]acetate

[1154] [Chemistry 101]

[1155]

[1156] 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 purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (3.87 g) as a 5:1 diastereomer mixture.

[1157] Main diastereomer

[1158] 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).

[1159] See Example 70-1 and Example 70-2.

[1160] See Example 70-1

[1161] Benzyl{(1S)-1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]ethyl}carbamate

[1162] See Example 70-2

[1163] Benzyl{(1R)-1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]ethyl}carbamate

[1164] [Chemistry 102]

[1165]

[1166] Reference Examples 70-1 and 70-2, which are title compounds, were obtained from the compound of Reference Example 71 using the same method as in Reference Example 67.

[1167] See Example 70-1

[1168] 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).

[1169] See Example 70-2

[1170] 1 H-NMR (400MHz, CDCl3) δ: 8.01 (1H, d, J = 4.9Hz), 7.38-7.28 (5H, m), 7.08-6.99 (2H, m), 5.08 (1H, d, J = 12.2Hz), 5.03 (1H, d, J = 12.2H z), 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).

[1171] See Example 71-1 and Example 71-2.

[1172] See Example 71-1

[1173] Ethyl(2S)-2-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]propionate

[1174] See Example 71-2

[1175] Ethyl(2R)-2-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]propionate

[1176] [Chemistry 103]

[1177]

[1178] To a tetrahydrofuran solution (9.0 mL) of the compound of Reference Example 69 (800 mg, 3.62 mmol), a 1.0 mol / L solution of lithium bis(trimethylsilyl)aminotetrahydrofuran (3.80 mL, 3.80 mmol) was added dropwise at -78 °C. After stirring at -78 °C for 30 min, iodomethane (0.270 mL, 4.34 mmol) was added. After further stirring for 1 hour, the reaction mixture was heated to room temperature over 1 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 times), 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) in the form of a 1.4:1 diastereomer mixture of Reference Examples 71-1 and 71-2.

[1179] Main diastereomer

[1180] 1 H-NMR (400MHz, CDCl3) δ: 8.08-8.05 (1H, m), 7.07-7.00 (2H, m), 4.85 (1H, dq, J=7.3, 5.5Hz), 4.20-4.17 (2H, m) ), 3.53-3.52 (1H, m), 3.16-3.14 (1H, m), 1.37 (3H, d, J = 7.3Hz), 1.27 (3H, t, J = 7.0Hz), 1.01 (3H, d, J = 7.3Hz).

[1181] See Examples 72-73

[1182] The compounds of Reference Examples 72-73 were obtained from the corresponding compounds by following the methods described in Reference Examples 1 to 4 and Reference Example 6.

[1183] [Table 17]

[1184]

[1185] See Example 74

[1186] rac-benzyl{[(2R,3S)-2-methyl(2- 2 H)-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylcarbamate

[1187] [Chemistry 104]

[1188]

[1189] The title compound was obtained from the compound of Reference Example 75 by the same method as in Reference Examples 8 to 10 and Reference Examples 37 to 38.

[1190] 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 (1 H, 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).

[1191] See Example 75

[1192] rac-1-{[tert-butyl(dimethyl)silyl]oxy}(2- 2 H)Propan-2-ol

[1193] [Chemistry 105]

[1194]

[1195] To a chloroform solution (45 mL) of propane-2-d-1,2-diol (1.04 g, 13.5 mmol), imidazole (0.919 g, 13.5 mmol) and tert-butyldimethylchlorosilane (1.83 g, 12.2 mmol) were added at room temperature. After stirring at room temperature for 2 hours, water (200 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (200 mL × 2 times). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated. The residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (1.51 g).

[1196] 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).

[1197] See Example 76-1 and Example 76-2.

[1198] See Example 76-1

[1199] rac-benzyl{[(2R,4R)-2-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1200] See Example 76-2

[1201] rac-benzyl{[(2R,4S)-2-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1202] [Chemistry 106]

[1203]

[1204] Reference Examples 76-1 and 76-2, which are title compounds, were obtained from the compound of Reference Example 77 by the same method as in Reference Examples 8 and 37 to 38.

[1205] See Example 76-1

[1206] 1 H-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).

[1207] See Example 76-2

[1208] 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).

[1209] See Example 77

[1210] rac-3-[(2-bromopyridin-3-yl)oxy]pentane-1-ol

[1211] [Chemistry 107]

[1212]

[1213] A 1 mol / L solution of boron tribromide in dichloromethane (12.6 mL, 12.6 mmol) was added to a chloroform solution (13 mL) of the compound of Reference Example 78 (1.73 g, 6.31 mmol) under ice-cooling. After stirring at room temperature for 2 hours, a saturated aqueous solution of sodium bicarbonate (100 mL) was added to the reaction mixture, which was extracted with chloroform (100 mL × 2 times), 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).

[1214] 1 H-NMR (400MHz, CDCl3) δ: 7.97 (1H, dd, J=4.6, 1.5Hz), 7.25 (1H, dd, J=8.2, 1.5Hz), 7.20 (1H, dd, J=7.9, 4. 3Hz), 4.55-4.48 (1H, m), 3.90-3.79 (2H, m), 2.08-1.92 (2H, m), 1.82-1.72 (2H, m), 1.00 (3H, t, J = 7.3Hz).

[1215] See Example 78

[1216] rac-2-bromo-3-[(1-methoxypentan-3-yl)oxy]pyridine

[1217] [Chemistry 108]

[1218]

[1219] The title compound was obtained from 1-methoxypentane-3-ol by the same method as in Reference Example 10.

[1220] 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).

[1221] See Example 79

[1222] rac-benzyl[(3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl)methyl]carbamate

[1223] [Chemistry 109]

[1224]

[1225] The title compound was obtained from the compound of Reference Example 80 by the same method as in Reference Examples 30 to 31 and Reference Examples 37 to 38.

[1226] 1 H-NMR (400MHz, CDCl3) δ: 8.08-8.07 (1H, m), 7.35-7.33 (5H, m), 7.09-7.07 (1H, m), 7.02-7.00 (1H, m), 5.97 (1H, s), 5.14-5.1 0(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).

[1227] See Example 80

[1228] Methyl 1-[(2-bromopyridin-3-yl)oxo]cyclopropane-1-carboxylate

[1229] [Chemical 110]

[1230]

[1231] Potassium tert-butoxide (0.842 g, 7.51 mmol) was added to a tetrahydrofuran solution (75 mL) of the compound from Reference Example 81 at 0 °C. After stirring at room temperature for 90 min, potassium tert-butoxide (0.168 g, 1.50 mmol) was further added. After stirring at room temperature for 20 min, 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 (1.69 g).

[1232] 1H-NMR (400MHz, CDCl3) δ: 8.05-8.04 (1H, m), 7.24-7.18 (2H, m), 3.76 (3H, s), 1.71-1.69 (2H, m), 1.42-1.40 (2H, m).

[1233] See Example 81

[1234] rac-methyl 4-bromo-2-[(2-bromopyridin-3-yl)oxy]butyrate

[1235] [Chemistry 111]

[1236]

[1237] Potassium carbonate (2.66 g, 19.24 mmol) and methyl 2,4-dibromobutyrate (3.0 g, 11.54 mmol) were added to a solution of 2-bromo-3-hydroxypyridine (1.67 g, 9.62 mmol) in N,N-dimethylformamide (48.1 mL) at room temperature. After stirring at room temperature for 3 hours, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed three times with water, dried over anhydrous sodium sulfate, filtered, and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (2.75 g).

[1238] 1 H-NMR (400MHz, CDCl3) δ: 8.04-8.03 (1H, m), 7.20-7.15 (1H, m), 7.08-7.06 (1H, m), 4.9 1-4.88(1H,m), 3.77(3H,s), 3.75-3.61(2H,m), 2.63-2.58(1H,m), 2.51-2.46(1H,m).

[1239] See Example 82

[1240] tert-Butyl{[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}prop-2-en-1-ylcarbamate

[1241] [Chemistry 112]

[1242]

[1243] To a tetrahydrofuran solution (48.1 mL) of the compound of Reference Example 83 (50 mg, 0.189 mmol), 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).

[1244] 1 H-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).

[1245] See Example 83

[1246] tert-butyl{[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}carbamate

[1247] [Chemistry 113]

[1248]

[1249] The title compound was obtained from the compound of Example 27 using the same method as in Example 5.

[1250] 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), 4.68-4.60 (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).

[1251] See Example 84

[1252] tert-butyl{[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methyl}propylcarbamate

[1253] [Chemistry 114]

[1254]

[1255] 10% palladium / carbon (25 mg) was added to a methanol solution (1.0 mL) of the compound of Reference Example 82 (34.8 mg, 0.114 mmol). After stirring at room temperature for 2 hours under a hydrogen atmosphere, the mixture was filtered through diatomaceous earth and concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate) to give the title compound (32.0 mg).

[1256] 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).

[1257] See Examples 85-87

[1258] Following the method described in Reference Example 82, the compounds of Reference Examples 85-87 were obtained from the corresponding compounds.

[1259] [Table 18]

[1260]

[1261] See Examples 88-1, 88-2, 88-3, and 88-4.

[1262] See Example 88-1

[1263] rac-benzyl{[(2R,3R,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1264] See Example 88-2

[1265] rac-benzyl{[(2R,3S,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1266] See Example 88-3

[1267] rac-benzyl{[(2S,3R,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1268] See Example 88-4

[1269] rac-benzyl{[(2S,3S,4R)-2,3-dimethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1270] [Chemistry 115]

[1271]

[1272] Reference Examples 88-1, 88-2, 88-3 and 88-4, which are title compounds, were obtained from 2-methylbutane-1,3-diol by the same method as in Reference Examples 8 to 10, 37 to 38 and 75.

[1273] See Example 88-1

[1274] 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).

[1275] See Example 88-2

[1276] 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).

[1277] See Example 88-3

[1278] 1H-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).

[1279] See Example 88-4

[1280] 1 H-NMR (400MHz, CDCl3) δ: 8.13-8.11 (1H, m), 7.37-7.27 (5H, m), 7.10-7.06 (2H, m), 5.88 (1H, s), 5.09 (2H, s), 4.30-4.28 (1H, m), 3.80-3.73 (1H, m), 3.43-3.37 (1H, m), 2.70-2.68 (1H, m), 2.00-1.97 (1H, m), 1.31 (3H, d, J = 6.4Hz), 0.98 (3H, d, J = 6.9Hz).

[1281] See Example 89

[1282] rac-tert-butyl[(6'-chloro-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridin]-3'-yl)methyl]carbamate

[1283] [Chemistry 116]

[1284]

[1285] The title compound was obtained from the compound of Reference Example 90 by the same method as in Reference Examples 6 to 7 and Reference Examples 30 to 31.

[1286] 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).

[1287] Reference Example 90

[1288] Methyl 1-[(2-bromo-5-chloropyridin-3-yl)oxo]cyclopropane-1-carboxylate

[1289] [Chemistry 117]

[1290]

[1291] The title compound was obtained from 2-bromo-5-chloro-3-hydroxypyridine using the same method as in Reference Examples 80 to 81.

[1292] 1 H-NMR (400MHz, CDCl3) δ: 8.00 (1H, d, J = 1.8Hz), 7.16 (1H, d, J = 1.8Hz), 3.74 (3H, s), 1.70-1.68 (2H, m), 1.40-1.39 (2H, m).

[1293] See Example 91

[1294] rac-2-[(2-methoxy-5,6,7,8-tetrahydroquinolin-8-yl)methyl]-1H-isoindole-1,3(2H)-dione

[1295] [Chemistry 118]

[1296]

[1297] Sodium methoxide (364 mg, 6.73 mmol) was added 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) at room temperature. After stirring at 100 °C, water was added to the reaction mixture, 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 (9 mg).

[1298] 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) , 4.41-4.37(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).

[1299] See Example 92

[1300] rac-2-[(2-chloro-5,6,7,8-tetrahydroquinolin-8-yl)methyl]-1H-isoindole-1,3(2H)-dione

[1301] [Chemistry 119]

[1302]

[1303] Phosphoryl chloride (2.0 mL, 21.46 mmol) was added to the compound of Reference Example 93 (440 mg, 1.427 mmol) at room temperature. After stirring at 90 °C for 4 hours, ice water was added to the reaction mixture. Then, 4 mol / L sodium hydroxide was 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).

[1304] 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).

[1305] See Example 93

[1306] rac-2-[(1-oxo-5,6,7,8-tetrahydro-1λ] 5 [-quinolino-8-yl)methyl]-1H-isoindole-1,3(2H)-dione

[1307] [Chemistry 120]

[1308]

[1309] To a chloroform solution (10.4 mL) of the compound of Reference Example 94 (608 mg, 2.080 mmol), 70% 3-chloroperoxybenzoic acid (564 mg, 2.29 mmol) was added at 0 °C. After stirring at 0 °C for 4 hours, saturated sodium bicarbonate solution was added to the reaction mixture, followed by extraction with chloroform, drying with sodium sulfate, filtration, and concentration to give the title compound (646 mg).

[1310] 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).

[1311] See Example 94

[1312] rac-2-[(5,6,7,8-tetrahydroquinolin-8-yl)methyl]-1H-isoindole-1,3(2H)-dione

[1313] [Chemistry 121]

[1314]

[1315] Phthalic anhydride (548 mg, 3.70 mmol) was added to a chloroform solution (25 mL) of 5,6,7,8-tetrahydroquinoline-8-ylmethylamine (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).

[1316] 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).

[1317] See Examples 95-96

[1318] The compounds of Reference Examples 95-96 were obtained from the corresponding compounds by following the methods described in Reference Examples 79 to 81.

[1319] [Table 19]

[1320]

[1321] See Example 97

[1322] rac-tert-butyl[(4-chloro-6,7-dihydro-5H-cyclopentano[b]pyridin-7-yl)methyl]carbamate

[1323] [Chemistry 122]

[1324]

[1325] A toluene solution (1.374 mL) of the compound of Reference Example 98 (49.1 mg, 0.275 mmol) was added at 0 °C to a toluene solution of 1 mol / L diisobutylaluminum hydride (0.825 mL, 0.825 mmol). After stirring at room temperature for 3 hours, a 30% aqueous solution of potassium sodium tartrate, saturated sodium bicarbonate solution, and ethyl acetate were added to the reaction mixture. Di-tert-butyl dicarbonate (90 mg, 0.412 mmol) was added to the mixture 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.

[1326] 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).

[1327] See Example 98

[1328] rac-4-chloro-6,7-dihydro-5H-cyclopentano[b]pyridine-7-carboxynitrile

[1329] [Chemistry 123]

[1330]

[1331] To a toluene solution (1.965 mL) of 4-chloro-6,7-dihydro-5H-cyclopentano[B]pyridin-7-ol (100 mg, 0.590 mmol) and acetone cyanohydrin (0.081 mL, 0.884 mmol), cyanomethylenetributylphosphine (0.464 mL, 1.769 mmol) was added. After stirring at 60 °C for 1 hour, water was added to the reaction mixture, 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 (49.1 mg).

[1332] 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(1H,m), 3.00-2.94(1H,m), 2.65-2.55(1H,m), 2.42(1H, ddt, J=17.0, 9.4, 3.1Hz).

[1333] See Example 99

[1334] rac-tert-butyl[(4-ethoxy-6,7-dihydro-5H-cyclopentano[b]pyridin-7-yl)methyl]carbamate

[1335] [Chemistry 124]

[1336]

[1337] Bis(2-methoxyethyl) azodicarbonate was added 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, 0.284 mmol) at 0 °C. After stirring at room temperature for 1 hour, 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) to give the title compound (35 mg).

[1338] 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).

[1339] Reference Example 100

[1340] rac-tert-butyl[(4-hydroxy-6,7-dihydro-5H-cyclopentano[b]pyridin-7-yl)methyl]carbamate

[1341] [Chemistry 125]

[1342]

[1343] Acetyloxyxamic acid (198 mg, 2.63 mmol) was added to a suspension of N-methyl-2-pyrrolidone (1.46 mL) of the compound of Reference Example 97 (248 mg, 0.877 mmol) and potassium carbonate (606 mg, 4.39 mmol). After stirring at 100 °C for 6 hours, the reaction mixture was filtered through diatomaceous earth and concentrated. The concentrated residue was purified by silica gel column chromatography (chloroform / methanol) to give the title compound (128 mg).

[1344] 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).

[1345] See Example 101

[1346] rac-2-{[4-(4-methylphenyl)-5,6,7,8-tetrahydroquinolin-8-yl]methyl}-1H-isoindole-1,3(2H)-dione

[1347] [Chemistry 126]

[1348]

[1349] 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-dimethylxanthone (53.1 mg, 0.092 mmol), 4-methylphenylboronic acid (125 mg, 0.918 mmol), and cesium carbonate (199 mg, 0.612 mmol), tris(dibenzylacetone)dipalladium(0) (56 mg, 0.061 mmol) was added. After stirring at 130 °C, water was added to the reaction mixture, 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 (26.5 mg).

[1350] 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 = 7.9 Hz), 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).

[1351] See Example 102

[1352] rac-2-[(4-chloro-5,6,7,8-tetrahydroquinolin-8-yl)methyl]-1H-isoindole-1,3(2H)-dione

[1353] [Chemistry 127]

[1354]

[1355] Phosphoryl chloride (1.5 mL, 16.22 mmol) was added to the compound of Reference Example 93 (500 mg, 1.62 mmol) at room temperature. After stirring at 90 °C for 4 hours, ice water was added to the reaction mixture. Then, 4 mol / L sodium hydroxide was 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).

[1356] 1H-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).

[1357] See Example 103-1 and Example 103-2.

[1358] See Example 103-1

[1359] rac-benzyl{[(3R,4S)-3-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1360] See Example 103-2

[1361] rac-benzyl{[(3S,4S)-3-ethyl-3,4-dihydro-2H-pyrano[3,2-b]pyridin-4-yl]methyl}carbamate

[1362] [Chemistry 128]

[1363]

[1364] Reference Examples 103-1 and 103-2, which give the title compounds, were obtained from 2-ethylpropane-1,3-diol using the same method as in Reference Examples 2 to 4 and Reference Examples 37 to 38.

[1365] See Example 103-1

[1366] 1 H-NMR (400MHz, CDCl3) δ: 8.02 (1H, dd, J=3.7, 1.8Hz), 7.34-7.22 (5H, m), 7.04-6.97 (2H, m), 6.43-6.35 (1H, m), 5.04 (2H, s), 4.07-3.98 (2H, m), 3.74-3.66 (1H, m), 3.24-3.15 (1H, m), 3.11-3.04 (1H, m), 2.08-1.9 8(1H,m), 1.46-1.34(1H,m), 1.32-1.21(1H,m), 0.96(3H,t,J=7.3Hz).

[1367] See Example 103-2

[1368] 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), 5.92 (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).

[1369] See Example 104

[1370] rac-4-methyl-5,6,7,8-tetrahydroquinoline-8-carboxynitrile

[1371] [Chemistry 129]

[1372]

[1373] The title compound was obtained from the compound of Reference Example 105 by the same method as in Reference Example 62.

[1374] 1 H-NMR (400MHz, CDCl3) δ: 8.35 (1H, d, J = 4.9Hz), 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).

[1375] See Example 105

[1376] rac-8-bromo-4-methyl-5,6,7,8-tetrahydroquinoline

[1377] [Chemistry 130]

[1378]

[1379] 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 incubation at 70°C for 2 hours, saturated aqueous sodium bicarbonate solution (30 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL × 2 times). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated to give the title compound (118 mg).

[1380] 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, 5.5Hz), 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).

[1381] See Example 106

[1382] rac-4-methyl-5,6,7,8-tetrahydroquinoline-8-ol

[1383] [Chemistry 131]

[1384]

[1385] Sodium borohydride (30.1 mg, 0.796 mmol) was added to a methanol solution (5.3 mL) of the compound of Reference Example 107 (85.5 mg, 0.530 mmol) under ice-cooling. After stirring at room temperature for 3 hours, a saturated aqueous solution of ammonium chloride (30 mL) was added to the reaction mixture, which was extracted with chloroform (30 mL × 2 times), dried over anhydrous sodium sulfate, filtered, and concentrated to give the title compound (93.7 mg).

[1386] 1 H-NMR (400MHz, CDCl3) δ: 8.28 (1H, d, J = 4.9Hz), 6.99 (1H, d, J = 4.9Hz), 4.68 (1H, dd, J = 8.9, 5.2Hz), 4. 17(1H, brs), 2.74-2.62(2H, m), 2.33-2.26(1H, m), 2.23(3H, s), 2.10-2.02(1H, m), 1.87-1.70(2H, m).

[1387] See Example 107

[1388] 4-Methyl-6,7-dihydroquinoline-8(5H)-one

[1389] [Chemistry 132]

[1390]

[1391] A mixture of 4-chloro-6,7-dihydroquinoline-8(5H)-one (302 mg, 1.67 mmol), trimethylcycloboroxane (0.756 mL, 5.45 mmol), 1,1'-bis(diphenylphosphino)ferrocene palladium(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).

[1392] 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).

[1393] See Example 108-1 and Example 108-2.

[1394] See Example 108-1

[1395] rac-(5R,7R)-5-methyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-carboxynitrile

[1396] See Example 108-2

[1397] rac-(5R,7S)-5-methyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-carboxynitrile

[1398] [Chemistry 133]

[1399]

[1400] The title compound was obtained from the compound of Reference Example 109 in the form of a 1:1 diastereomer mixture of Reference Examples 108-1 and 108-2 by the same method as in Reference Examples 104 to 105.

[1401] 1H-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).

[1402] See Example 109-1 and Example 109-2.

[1403] See Example 109-1

[1404] rac-(5R,7R)-5-methyl-6,7-dihydro-5H-cyclopentano[b]pyridine-7-ol

[1405] See Example 109-2

[1406] rac-(5R,7S)-5-methyl-6,7-dihydro-5H-cyclopentano[b]pyridin-7-ol

[1407] [Chemistry 134]

[1408]

[1409] 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, 1 mol / L aqueous sodium hydroxide solution (30 mL) was added to the reaction mixture, and the mixture was extracted with chloroform (30 mL × 2 times). After drying with anhydrous sodium sulfate, the mixture was filtered and concentrated to give the title compound (125 mg) as a 1:1 diastereomer mixture of Reference Examples 109-1 and 109-2.

[1410] 1 H-NMR (400MHz, CDCl3) δ: 8.50-8.38 (1H, m), 7.61-7.47 (1H, m), 7.22-7.14 (1H, m), 5.32-5.11 (1H, m), 3.58-3.38 (0.5H, m) , 3.14-3.01(1H,m), 2.89-2.72(1H,m), 2.42-2.27(0.5H,m), 2.11-1.97(0.5H,m), 1.70-1.53(0.5H,m), 1.44-1.18(3H,m).

[1411] See Example 110

[1412] rac-5-methyl-1-oxo-6,7-dihydro-5H-1λ 5 -cyclopentano[b]pyridine

[1413] [Chemistry 135]

[1414]

[1415] The title compound was obtained from 5-methyl-6,7-dihydro-5H-cyclopentaned[b]pyridine using the same method as in Reference Example 93.

[1416] 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).

[1417] See Example 111-1 and Example 111-2.

[1418] See Example 111-1

[1419] rac-tert-butyl{[(5R,8S)-5-methyl-5,6,7,8-tetrahydroquinoline-8-yl]methyl}carbamate

[1420] See Example 111-2

[1421] rac-tert-butyl{[(5R,8R)-5-methyl-5,6,7,8-tetrahydroquinoline-8-yl]methyl}carbamate

[1422] [Chemistry 136]

[1423]

[1424] The title compound was obtained from the compound of Reference Example 112 in the form of a mixture of diastereomers of Reference Examples 111-1 and 111-2, using the same method as in Reference Example 61.

[1425] 1H-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), 3.71-3.5 7(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).

[1426] See Example 112-1 and Example 112-2.

[1427] See Example 112-1

[1428] rac-(5R,8R)-5-methyl-5,6,7,8-tetrahydroquinoline-8-carboxynitrile

[1429] See Example 112-2

[1430] rac-(5R,8S)-5-methyl-5,6,7,8-tetrahydroquinoline-8-carboxynitrile

[1431] [Chemistry 137]

[1432]

[1433] The title compound was obtained from 5-methyl-5,6,7,8-tetrahydroquinoline in the form of a mixture of diastereomers of Examples 112-1 and 112-2, using the same method as in Examples 104 to 105 and Examples 109 to 110.

[1434] 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, 4.9Hz), 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).

[1435] See Examples 113-114

[1436] The compounds of Reference Examples 113-114 were obtained from the compounds of the corresponding examples according to the methods described in Reference Examples 5 and 55.

[1437] [Table 20]

[1438]

[1439] See Example 115

[1440] rac-benzyl[(2,2,5-trimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl)methyl]carbamate

[1441] [Chemistry 138]

[1442]

[1443] The title compound was obtained from 2-bromo-6-methylpyridin-3-ol and ethyl 2-bromo-2-methylpropionate using the same method as in Reference Examples 30 to 32 and Reference Examples 37 to 38.

[1444] 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), 3.8 5-3.81(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).

[1445] See Example 116

[1446] rac-benzyl{[(6S,7S)-3-chloro-6-methyl-6,7-dihydro-5H-cyclopentano[b]pyridin-7-yl]methyl}carbamate

[1447] [Chemistry 139]

[1448]

[1449] The title compound was obtained from the compound of Reference Example 117 by the same method as in Reference Examples 30 and 37 to 38.

[1450] 1 H-NMR (400MHz, CDCl3) δ: 8.26 (1H, s), 7.44 (1H, s), 7.38-7.29 (5H, m), 6.07 (1H, brs), 5.11 (2H, s), 3.88-3.81 (1H, m), 3.34-3.28(1H,m), 3.03-2.99(1H,m), 2.83-2.80(1H,m), 2.56-2.49(1H,m), 2.30-2.18(1H,m), 1.26(3H,d,J=7.3Hz).

[1451] See Example 117

[1452] rac-3-(2-bromo-5-chloropyridin-3-yl)-2-methylpropane-1-ol

[1453] [Chemistry 140]

[1454]

[1455] Ethyl 2-(triphenylphosphino)propionate (1.64 g, 4.52 mmol) was added to a mixture of 2-bromo-5-chloronicotinaldehyde (999 mg, 4.30 mmol) and toluene (11 mL) under ice-cooling. The reaction mixture was stirred at 90 °C for 3 hours, and then concentrated. The concentrated residue was purified by silica gel column chromatography (hexane / ethyl acetate).

[1456] To a mixture of the obtained purified product (1.29 g) and tetrahydrofuran (42.5 mL), a 4 mol / L lithium borohydride tetrahydrofuran solution (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. 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 × 3 times), 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).

[1457] 1 H-NMR (400MHz, CDCl3) δ: 8.21 (1H, d, J = 2.4Hz), 7.51 (1H, d, J = 3.0Hz), 4.25 (1H, brs), 3.56-3 .55(2H,m), 2.94-2.90(1H,m), 2.53-2.49(1H,m), 2.14-2.09(1H,m), 0.98(3H,d,J=22.5Hz).

[1458] See Example 118

[1459] rac-benzyl[(5-fluoro-2,2-dimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl)methyl]carbamate

[1460] [Chemistry 141]

[1461]

[1462] The title compound was obtained from 2-bromo-6-fluoropyridine-3-ol and ethyl 2-bromo-2-methylpropionate using the same method as in Reference Examples 30 to 32 and Reference Examples 37 to 38.

[1463] 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).

[1464] Experimental Example 1: Evaluation of agonist activity of human TAAR1 receptor

[1465] TAAR1 is a G protein conjugate receptor that binds to G proteins (Gαs). Activation of the TAAR1 receptor by its agonists induces an increase in intracellular cAMP levels. Therefore, a cAMP assay was used to evaluate the agonist activity of the test compounds against the human TAAR1 receptor.

[1466] Purchased cAMP Hunter cells expressing the human TAAR1 receptor TM CHO-K1TAAR1 Gs Cell Line. CHO cells expressing human TAAR1 were seeded into 96-well plates and cultured for 24 hours. The test compound dissolved in DMSO was then added and incubated at 37°C for 30 minutes. Samples for cAMP assays were prepared according to the appendix of the cAMPHiRange kit. The cAMP production of the test compound was measured by time-resolved fluorescence (excitation wavelength: 330 nm, fluorescence wavelengths: 620 nm / 665 nm) using EnVision.

[1467] % of test compound = 100 × {(Csamp) - (Cblank)} / {(Ctyramine) - (Cblank)}

[1468] Csamp: Test compound count, Ctyramine: 100μM tyramine count, Cblank: Blank count

[1469] [Table 21-1]

[1470]

[1471] [Table 21-2]

[1472] 42 25 70 90 43 0 0 7 44 13 48 79 45 13 lead 77 46 31 70 80 47 13 52 84 48 38 74 86

[1473] [Table 21-3]

[1474]

[1475] [Table 21-4]

[1476]

[1477] [Table 21-5]

[1478] 86 1 8 40 87 4 25 63 88 11 38 65 89 0 23 48 90 54 85 94 91 0 14 49 92 0 0 0 93 0 12 45 94 1 4 28 95 59 90 96 96 3 28 66 97 70 101 96 98 1 9 37 99 9 39 62 100 0 17 50 101 62 79 84 102 1 18 59 103 60 84 89 104 0 5 31 105 64 77 79 106 38 70 78

[1479] Experimental Example 2-1: Benzophenone-induced hyperkinetic inhibition test

[1480] Eight-week-old male C57BL / 6J mice were used. In the preparation of the administration solutions for the test compounds, a 0.5% methylcellulose solution was used as the solvent for suspension, and in the preparation of the administration solution for phencyclidine, physiological saline was used as the solvent for dissolution.

[1481] The phenylcyclophenide-induced hyperkinetic inhibition test was conducted using a Supermex (manufactured by Muromachi Machinery Co., Ltd.), the data recording program CompACT AMS, and a transparent plastic cage as follows.

[1482] Animals were placed in the cages described above, and activity levels were measured. After 30 minutes, the mice were quietly removed and administered the compound administration solution (solvent or suspension of the test compound) orally, then returned to the cages. Thirty minutes after administration, phencyclidine administration solution or physiological saline was administered subcutaneously. After both administrations, the mice were quickly returned to their respective activity level measurement cages, and activity level measurements continued. During the activity level measurement, measurements were taken at 5-minute intervals, for a total of 120 minutes. Data from 30 minutes to 120 minutes after the start of the activity level measurement were used as the experimental results, and the activity levels of each individual over those 90 minutes were totaled.

[1483] Parametric Dunnett-type multiple comparisons (significance level: 5% on both sides) were performed in the test compound administration group and the solvent administration group. The test compound administration group was considered to have antipsychotic effects when it showed a significant inhibition of motor activity compared to the solvent administration group.

[1484] The results of the above tests using the compound of Example 27 are as follows: Figure 1 As shown.

[1485] Experimental Example 2-2: Benzophenone-induced hyperkinetic inhibition test

[1486] Eight-week-old male C57BL / 6J mice were used. Physiological saline was used as the solvent for suspension in the preparation of the administration solution for the test compounds, and physiological saline was used as the solvent for dissolution in the preparation of the administration solution for phencyclidine.

[1487] Using an activity meter equipped with photoelectric components and an electric counter, the benzylpyridin-induced hyperkinetic inhibition test was performed as follows.

[1488] Mice that had been subcutaneously administered the compound application solution (solvent or suspension of the test compound) were placed in the aforementioned device to begin the activity measurement. Thirty minutes after the start of the measurement, the mice were quietly removed and subcutaneously administered phencyclidine application solution or physiological saline. The mice were then quickly returned to the device, and activity was measured for 60 minutes. The measurement intervals were set to 5 minutes. Data from 30 minutes to 90 minutes after the start of the activity measurement were used as the experimental results, and the total activity for each individual over 60 minutes was calculated.

[1489] Parametric Dunnett-type multiple comparisons (significance level: 5% on both sides) were performed in the test compound administration group and the solvent administration group. The test compound administration group was considered to have antipsychotic effects when it showed a significant inhibition of motor activity compared to the solvent administration group.

[1490] The results of the above tests using the compounds from Examples 8 and 49 are as follows: Figure 2 and Figure 3 As shown.

[1491] Experimental Example 3: Evaluation of hERG channel inhibitory activity

[1492] The hERG channel inhibition of the compounds disclosed herein was measured using whole-cell patch-clamp methods with an automated patch-clamp system in CHO cells that were forced to express hERG channels associated with human fast-active delayed rectified potassium current (IKr).

[1493] (Preparation of cell suspension)

[1494] hERG-CHO cells purchased from ChanTest were cultured in a CO2 incubator at 37°C. Before measuring the hERG current, the cells were peeled off the flasks with trypsin to prepare a cell suspension.

[1495] (Solution preparation)

[1496] The extracellular and intracellular fluids used for the assay are prepared as follows.

[1497] Extracellular fluid: 2 mmol / L CaCl2, 1 mmol / L mgCl2, 10 mmol / L

[1498] HEPES, 4 mmol / L KCl, 145 mmol / L NaCl, 10 mmol / L glucose

[1499] Intracellular fluid: 10 mmol / L HEPES, 10 mmol / L EGTA, 20 mmol / L KCl, 130 mmol / L KF

[1500] Test substance solution: Dissolve the test substance in DMSO to a concentration of 2 mmol / L or 20 mmol / L to prepare the test substance solution. In addition, dilute the test substance solution 200-fold with extracellular fluid, and then further dilute it with extracellular fluid to prepare test substance solutions of various concentrations required for calculating the hERG inhibition IC50 value, and apply them.

[1501] (Current value measurement and data analysis)

[1502] Cell suspension, extracellular fluid, intracellular fluid, and assay plate were set up in an automated patch-clamp system, and hERG current measurements were performed using the whole-cell patch-clamp method. The voltage protocol set the hold potential to -80 mV. A depolarization pulse was applied from -50 mV to +20 mV for 5 seconds, followed by a repolarization pulse at -50 mV for 5 seconds, before returning to the hold potential. The interval between pulses was 15 seconds. Data analysis was performed using Qube analysis software (Sophion Sophion). Four concentrations of each test substance were applied incrementally, and the average of the maximum peaktail currents obtained from the final three stimuli at each applied concentration was used as the evaluation data.

[1503] In addition, based on the inhibition rate of the current to the applicable pre-value at each concentration of each tested substance, the software was used to calculate the IC using the Hill equation. 50 value.

[1504] The results are shown in the table below.

[1505] [Table 22-1]

[1506]

[1507] [Table 22-2]

[1508]

[1509] [Table 22-3]

[1510]

[1511] Experimental Example 4: Evaluation of the binding activity of receptors related to side effects

[1512] The binding affinity of the disclosed compounds to side-effect-related receptors (e.g., dopamine D2 receptor, adrenaline α1A receptor) can be determined by the following methods.

[1513] Binding evaluation assays were performed using CHO cell membrane components expressing human-type target receptors, as follows: The test compound dissolved in dimethyl sulfoxide (DMSO), various receptor membrane samples diluted with buffer, and [3H]-labeled ligands exhibiting strong binding activity to each target receptor were mixed and incubated separately at room temperature. The mixture was then rapidly added to a glass fiber filter plate (Multiscreen FB, Millipore) for vacuum filtration. The radioactivity remaining on the filter was measured using a liquid scintillation counter (PerkinElmer). Binding inhibition rates were calculated using the following formula. In the calculation of nonspecific binding amounts to receptor membrane samples, control compounds exhibiting strong binding activity to the target receptors were used instead of the test substance.

[1514] Binding inhibition rate of the target receptor (%) = 100 - 100 × {(in the presence of the test substance)} 3 H] Labeled ligand binding amount)}-(10μmol / L in the presence of control compound[ 3 H]labeled ligand binding amount)} / {(in the absence of the test substance[ 3 H] Labeled ligand binding amount)}-(10μmol / L in the presence of control compound[ 3 H] ligand binding amount)}

[1515] (Note)

[1516] As described above, this disclosure has been illustrated using preferred embodiments; however, it should be understood that the scope of this disclosure should be interpreted solely by the claims. This application claims priority to Japanese Patent Applications 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 patents, patent applications, scientific documents, and other documents cited in this specification contain the same content as specifically described herein, and their content should be incorporated by reference in connection with this specification.

[1517] Industrial practicality

[1518] The compounds disclosed herein possess agonist activity against the trace amine-associated receptor TAAR1, and are therefore effective in the treatment of mental illnesses. Furthermore, the compounds disclosed herein are also effective against central nervous system disorders.

Claims

1. The compound shown in the following formula or its pharmaceutically permissible salt, [Chemistry 1] In the formula, X is an oxygen atom or a sulfur atom. R 1 Hydrogen atom, C atoms can be substituted. 1-6 Alkyl or optionally substituted C 3-6 alkenyl, R 2a and R 2b Each is independently a hydrogen atom, or an optional substituted C atom. 1-6 Alkyl, or R 2a and R 2b Together with the carbon atoms bonded to them, they form 3- to 6-membered saturated carbon rings. R 3a R 3b and R 3c Each is an independent hydrogen atom, and the C atoms can be substituted at will. 1-6 Alkyl or halogen atoms, R 5a and R 5b Each is independently a hydrogen atom or an optional substituted C atom. 1-6 alkyl, Here, the arbitrarily replaced C 1-6 Alkyl groups and optionally substituted C 3-6 The alkenyl group may be replaced by a halogen atom, a hydroxyl group, or a C-aryl group. 1-6 Alkoxy substitution, in, Excluding the following (1): (1) X is an oxygen atom, R 2a and R 2b Compounds containing hydrogen atoms.

2. The compound according to claim 1 or a pharmaceutically permissible salt thereof, wherein, R 1 C is a hydrogen atom or optionally replaced by a halogen atom. 1-6 alkyl.

3. The compound according to claim 2 or a pharmaceutically permissible salt thereof, wherein, R 1 It is a methyl group.

4. The compound according to claim 1 or a pharmaceutically permissible salt thereof, wherein, R 2a For hydrogen atoms, R 2b C is arbitrarily replaced 1-6 alkyl.

5. The compound according to claim 1 or a pharmaceutically permissible salt thereof, wherein, R 3a R 3b and R 3c They are hydrogen atoms.

6. The compound according to claim 1 or a pharmaceutically permissible salt thereof, wherein, R 3a R 3b and R 3c At least one of them is an optional C that is replaced. 1-6 Alkyl or halogen atom.

7. The compound according to claim 1 or a pharmaceutically permissible salt thereof, wherein, R 5a and R 5b They are hydrogen atoms.

8. The compound according to claim 1 or a pharmaceutically permissible salt thereof, wherein, X is an oxygen atom.

9. The compound according to claim 1 or a pharmaceutically permissible salt thereof, wherein, R 1 C atoms that are optionally substituted with halogen atoms 1-6 alkyl, R 3a R 3b and R 3c At least one of them is an optional C that is replaced. 1-6 Alkyl or halogen atom.

10. The compound according to claim 9 or a pharmaceutically permissible salt thereof, wherein, R 1 It is methyl. R 3a R 3b and R 3c At least one of them is a methyl, fluorine or chlorine atom.

11. The compound according to claim 1 or a pharmaceutically permissible salt thereof, wherein, X is an oxygen atom. R 1 C atoms that are optionally substituted with halogen atoms 1-6 alkyl, R 2a For hydrogen atoms, R 2b C is arbitrarily replaced 1-6 alkyl, R 3a R 3b and R 3c At least one of them is an optional C that is replaced. 1-6 Alkyl or halogen atoms, R 5a and R 5b They are hydrogen atoms.

12. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is selected from the group consisting of: 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine, 1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine, N-Methyl-1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine, 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]-N-methylmethylamine, 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]-N-( 2 H3) Methyl methylamine, rel-1-[(3'S)-5'-methyl-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine, rel-1-[(3'S)-5'-fluoro-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine, rel-1-[(3S)-2,2,5-trimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine, rel-1-[(3'S)-3'H-spiro[cyclopropane-1,2'-furano[3,2-b]pyridine]-3'-yl]methylamine, and rac-1-(5-fluoro-2,2-dimethyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl)methylamine.

13. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is selected from the group consisting of: 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine, 1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine, N-Methyl-1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine, 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]-N-methylmethylamine, 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]-N-( 2 H3) Methyl methylamine.

14. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine.

15. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine.

16. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is N-methyl-1-[(2R,3S)-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]methylamine.

17. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]-N-methylmethylamine.

18. The compound of claim 1 or a pharmaceutically permissible salt thereof, wherein the compound is 1-[(2R,3S)-6-fluoro-2-methyl-2,3-dihydrofurano[3,2-b]pyridin-3-yl]-N-( 2 H3) Methyl methylamine.

19. A pharmaceutical composition comprising any one of the compounds of claims 1 to 18 or a pharmaceutically permissible salt thereof.

20. The pharmaceutical composition according to claim 19, wherein, The aforementioned pharmaceutical composition is used to treat or prevent diseases or disorders associated with TAAR1.

21. The pharmaceutical composition according to claim 19, wherein, The aforementioned pharmaceutical composition is used to treat or prevent neurological or psychiatric disorders.

22. The pharmaceutical composition according to claim 21, wherein, The aforementioned neurological or mental disorders include depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, poisoning, social disorder, attention deficit / hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, cognitive impairment, psychosis of Alzheimer's / Parkinson's disease, and anxiety / aggression or bulimia of Parkinson's disease.

23. Use of any compound of claims 1 to 18 or a pharmaceutically permissible salt thereof in the preparation of a therapeutic agent for a disease or disorder associated with TAAR1.

24. Use of any compound of claims 1 to 18 or a pharmaceutically permissible salt thereof in the preparation of a therapeutic agent for neurological or mental disorders.

25. The use according to claim 24, wherein, The aforementioned neurological or mental disorders include depression, bipolar disorder, pain, schizophrenia, obsessive-compulsive disorder, poisoning, social disorder, attention deficit / hyperactivity disorder, anxiety disorder, movement disorder, epilepsy, autism, cognitive impairment, psychosis of Alzheimer's / Parkinson's disease, and anxiety / aggression or bulimia of Parkinson's disease.

26. A TAAR1 agonist, which is the compound of any one of claims 1 to 18 or a pharmaceutically permissible salt thereof.

27. A treatment agent for mental illness or central nervous system disease, comprising the compound of any one of claims 1 to 18 or a pharmaceutically permissible salt thereof as an active ingredient.

28. The therapeutic agent according to claim 27, wherein, Mental illnesses or central nervous system disorders include symptomatic organic mental disorders; mental and behavioral disorders caused by the use of psychoactive substances; schizophrenia, schizophrenic-type disorders, and delusional disorders; mood [affective] disorders; neurotic disorders, stress-related disorders, and somatic symptom disorders; non-organic sleep disorders; sexual dysfunction not caused by organic disorders or diseases; pervasive developmental disorders; behavioral and emotional disorders that usually occur in childhood and adolescence; extrapyramidal disorders and abnormal movements; or sleep disorders.

29. The therapeutic agent according to claim 27, wherein, Mental illness or central nervous system disorder includes schizophrenia, bipolar disorder with psychotic features, depressive disorder with psychotic features, psychotic symptoms associated with dementia, psychotic symptoms associated with Parkinson's disease, or agitation, excitement, or aggression associated with Alzheimer's disease.

30. The therapeutic agent according to claim 29, wherein, Mental illness or central nervous system disease includes positive symptoms of schizophrenia, negative symptoms of schizophrenia, psychotic symptoms associated with Alzheimer's disease, psychotic symptoms associated with Lewy body dementia, or psychotic symptoms associated with Parkinson's disease dementia.

31. The therapeutic agent according to claim 29, wherein, Mental illness or central nervous system disorder includes schizophrenia, psychotic symptoms associated with dementia, or agitation, excitement, or aggression associated with Alzheimer's disease.

32. The therapeutic agent according to claim 30, wherein, Mental illness or central nervous system disease refers to psychotic symptoms associated with Alzheimer's disease or psychotic symptoms associated with Lewy body dementia.

33. Use of any compound of claims 1 to 18 or a pharmaceutically permissible salt thereof in the preparation of a therapeutic agent for neurological or mental disorders.

34. Use of any compound of claims 1 to 18 or a pharmaceutically permissible salt thereof in the manufacture of a therapeutic agent for mental illness or central nervous system disorders.

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