Compounds having s1p5 receptor agonistic activity

Abstract

Provided is a compound in which the balance of the agonist activity against the S1P5 receptor relative to the S1P1 receptor has been improved in order to develop a pharmaceutical useful for the treatment of S1P5-mediated diseases such as schizophrenia and Binswanger's disease and other neurodegenerative diseases. This compound represented by general formula (V) (in the formula, all symbols are as defined in the specification) has an improved balance of the agonist activity against the S1P5 receptor relative to the S1P1 receptor, and can thus serve as a therapeutic for S1P5-mediated diseases such as schizophrenia and Binswanger's disease and other neurodegenerative diseases.

Description

Compounds having S1P5 receptor agonist activity

[0001] In one embodiment, the present invention relates to general formula (V) This invention relates to a compound represented by (wherein all symbols have the same meaning as described below) or a pharmaceutically acceptable salt thereof (hereinafter sometimes abbreviated as the "inventive compound").

[0002] Sphingosine-1-phosphate [(2S,3R,4E)-2-amino-3-hydroxyoctadeca-4-enyl-1-phosphate; sometimes abbreviated as S1P] is a lipid synthesized through the metabolic turnover of sphingolipids within cells and the action of secreted sphingosine kinases outside cells, and it has been proposed to function as an intercellular signaling molecule and an intracellular secondary signaling molecule.

[0003] Among S1P receptors, the S1P5 (EDG-8) receptor is known to be highly expressed in oligodendrocytes and oligodendrocyte progenitor cells. ５ It has been shown that activating the receptor promotes the differentiation of oligodendrocyte precursor cells into oligodendrocytes (see Non-Patent Documents 1 and 2). Oligodendrocytes are a type of glial cell that binds to the axons of nerve cells and forms myelin sheaths. Therefore, S1P ５ Compounds that possess receptor agonist activity are thought to be useful in the treatment of demyelinating diseases such as multiple sclerosis and neurodegenerative diseases because they promote the regeneration of myelin that has been lost in nerve cells (demyelination).

[0004] Also, S1P ５ The receptor is known to be highly expressed in natural killer (NK) cells, and S1P ５ It is known that activation of the receptor induces the migration of NK cells (see Non-Patent Document 3).

[0005] Furthermore, S1P ５ The receptor is highly expressed in patrolling monocytes, which are known to be involved in tumor immunity, therefore S1P ５Activation of the receptor may induce tumor immunological activation (see Non-Patent Documents 4 and 5).

[0006] On the other hand, S1P １ receptors are receptors expressed on the cardiovascular system and lymphocytes. Compounds having S1P １ receptor agonist activity are known to have concerns about lymphocyte reduction effects and heart rate reduction effects.

[0007] By the way, as prior art of the present invention, the following compounds are known. As a dihydronaphthalene compound having S1P receptor binding ability, general formula (a) (In the formula, ring A ａ represents a cyclic group, ring B ａ represents a cyclic group which may further have a substituent, X ａ represents a bond or a spacer having 1 to 8 atoms in the main chain, Y ａ represents a bond or a spacer having 1 to 10 atoms in the main chain, na represents 0 or 1, when na is 0, ma represents 1, and R １ａ represents a hydrogen atom or a substituent, when na is 1, ma represents 0 or an integer of 1 to 7, and R １ａ represents a substituent (when ma is 2 or more, a plurality of R １ａ may be the same or different.) (However, the definitions of each group are excerpted.)), and the compound represented by is disclosed to specifically bind to EDG-1 (S1P １ ) and EDG-6 (S1P ４ ) receptors (see Patent Document 1).

[0008] Further, as a dihydronaphthalene compound having S1P receptor binding ability, general formula (b) (In the formula, ring A ｂ represents a cyclic group, ring B ｂ represents a cyclic group which may further have a substituent, X ｂ represents a bond or a spacer having 1 to 8 atoms in the main chain, Y ｂ represents a bond or a spacer having 1 to 10 atoms in the main chain, Z ｂ represents an acidic group which may be protected, nb represents 0 or 1, when nb is 0, mb represents 1, and R １ｂrepresents a hydrogen atom or substituent, and when nb is 1, mb represents 0 or an integer from 1 to 7, and R １ｂ is a substituent (when mb is 2 or more, there are multiple R １ｂ They may be the same or different. ) represents (however, the definitions of each group are excerpts). ) is a compound that is particularly EDG-1 (S1P １ ), EDG-6 (S1P ４ ) and / or EDG-8 (S1P ５ It has been disclosed that it binds to receptors (see Patent Document 2).

[0009] In compounds having a dihydronaphthalene skeleton, the compound of the present invention is S1P １ S1P for receptors ５ None of the prior art documents describe or suggest that this method improves the balance of receptor agonist activity.

[0010] International Publication No. 2005 / 020882 Brochure International Publication No. 2006 / 064757 Brochure

[0011] The Journal of Neuroscience, Vol. 25, No. 6, pp. 1459–1469, 2005; The FASEB Journal, Vol. 21, pp. 1503–1514, 2007; Nature Immunology, Vol. 8, No. 12, pp. 1337–1344, 2007; European Journal of Immunology, Vol. 43, pp. 1667–1675, 2013; Science, Vol. 350, No. 6263, pp. 985–990, 2015.

[0012] The problem of the present invention is S1P １ S1P for receptors ５ The objective is to provide compounds that improve the balance of receptor agonist activity.

[0013] As a result of diligent research to solve the aforementioned problems, the inventors have found that the aforementioned problems can be solved by a compound represented by the following general formula (V) or a pharmaceutically acceptable salt thereof.

[0014] In other words, the present invention relates to, for example, [1] General formula (V) [In the formula, L is a branched or linear chain group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms, the number of atoms in its main chain is 3 to 8, and the chain group may contain 1 to 3 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms, where the carbon atoms in L may be substituted with 1 to 13 halogen atoms, and Y is, or This represents, where each group is bonded to Z by the bonds indicated by the arrows, A represents an optional C3-7 cycloalkylene group or an optional C1-4 alkylene group, and R １ R represents a C1-4 alkyl group, a C3-6 cycloalkyl group which may be substituted with a halogen, a C1-4 alkoxy group which may be substituted with a halogen, a C1-4 haloalkyl group, a halogen atom, or a hydroxyl group. ２ R represents a C1-4 alkyl group, a C1-4 alkoxy group which may be substituted with a halogen, a C1-4 haloalkyl group, a halogen atom, or a hydroxyl group. ３ , R ４ and R ５Each of these independently represents a hydrogen atom, a C1-4 alkyl group, a C3-6 cycloalkyl group which may be substituted with a halogen, or a C1-4 haloalkyl group. Z represents (1) a carboxyl group which may be substituted with one C1-8 alkyl group, (2) a hydroxyl group which may be substituted with one C1-8 alkyl group, (3) a hydroxamic acid group which may be substituted with one or two C1-8 alkyl groups, (4) a sulfonic acid group which may be substituted with one C1-8 alkyl group, (5) a boronic acid group which may be substituted with one or two C1-8 alkyl groups, (6) a carbamoyl group which may be substituted with (i) one or two C1-8 alkyl groups or (ii) one or two sulfonyl groups which may be substituted with a C1-4 alkyl group, (7) a sulfamoyl group which may be substituted with (i) one or two C1-8 alkyl groups or (ii) one or two C2-8 acyl groups, (8) a sulfoximine group which may be substituted with one or two C1-8 alkyl groups, or (9) a tetrazolyl group. ring2 represents a 3- to 7-membered nitrogen-containing heteroring, m represents an integer from 0 to 6, n represents an integer from 0 to 5, and when m is 2 or greater, multiple R １ The R values ​​may be the same or different, and when n is 2 or greater, there may be multiple R values. ２ [1] The compounds represented by [1] or a pharmaceutically acceptable salt thereof, [2] A pharmaceutical composition containing the compound represented by the general formula (V) described in [1] above or a pharmaceutically acceptable salt thereof, [3] S1P characterized by administering an effective amount of the compound represented by the general formula (V) described in [1] above or a pharmaceutically acceptable salt thereof to a mammal. ５ Methods for the prevention and / or treatment of intermediary diseases, [4] S1P ５ Compounds represented by the general formula (V) described in [1] above, or pharmaceutically acceptable salts thereof, used for the prevention and / or treatment of intermittent diseases, and [5] S1P ５ The present invention provides embodiments such as the use of a compound represented by general formula (V) described in [1] above, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the prevention and / or treatment of a disease-mediated disease.

[0015] The compound of the present invention is S1P １ High S1P for receptors ５ Because it has receptor-selective agonistic activity, S1P ５ It is useful in treating indirect diseases, such as neurodegenerative diseases, autoimmune diseases, infections, and cancer.

[0016] The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments and can be implemented in any form without departing from the spirit of the invention.

[0017] s In the present invention, "S1P １ S1P for receptors ５ "To improve the balance of receptor agonist activity" means "S1P １ S1P for receptors ５ This means "to enhance the selectivity of receptor agonist activity."

[0018] In this invention, the term "halogen atom" means fluorine, chlorine, bromine, or iodine.

[0019] In the present invention, C1-8 alkyl groups include linear or branched C1-8 alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 1-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, 2-methyl-3-hexyl, 1,2-dimethylbutyl Lupentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1-ethyl-1-methylbutyl, 1-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1-dimethylpentyl, 1,1,3-trimethylbutyl, 1,1-diethylpropyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 3-ethylpentyl, 1-methylheptyl, 2- Examples include methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 1-propylpentyl, 2-propylpentyl, 1,5-dimethylhexyl, 1-ethyl-4-methylpentyl, 1-propyl-3-methylbutyl, 1,1-dimethylhexyl, 1-ethyl-1-methylpentyl, or 1,1-diethylbutyl group.

[0020] In the present invention, the C1-6 alkyl group includes linear or branched C1-6 alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2,3-dimethylbutyl group.

[0021] In the present invention, the C1-5 alkyl group includes linear or branched C1-5 alkyl groups, such as methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, or 2,2-dimethylpropyl group.

[0022] In the present invention, the C1-4 alkyl group includes linear or branched C1-4 alkyl groups, such as methyl, ethyl, propyl, butyl, isopropyl, isobutyl, sec-butyl, or tert-butyl groups.

[0023] In the present invention, C2-7 alkyl groups include linear or branched C2-7 alkyl groups, for example, ethyl, propyl, butyl, pentyl, hexyl, heptyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl Examples include 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 1-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, 2-methyl-3-hexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1-ethyl-1-methylbutyl, 1-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1-dimethylpentyl, 1,1,3-trimethylbutyl, 1,1-diethylpropyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, or the 3-ethylpentyl group.

[0024] In the present invention, the C2-5 alkyl group includes linear or branched C2-5 alkyl groups, such as ethyl, propyl, butyl, pentyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, or 2,2-dimethylpropyl group.

[0025] In the present invention, C3-8 alkyl groups include linear or branched C3-8 alkyl groups, for example, propyl, butyl, pentyl, hexyl, heptyl, octyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 2,3-dimethylbutyl, 1-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, 2-methyl-3-hexyl, 1,2-dimethylpentyl 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1-ethyl-1-methylbutyl, 1-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1-dimethylpentyl, 1,1,3-trimethylbutyl, 1,1-diethylpropyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, 3-ethylpentyl, 1-methylheptyl, 2-methyl Examples include methylheptyl, 3-methylheptyl, 4-methylheptyl, 5-methylheptyl, 6-methylheptyl, 1-ethylhexyl, 2-ethylhexyl, 3-ethylhexyl, 1-propylpentyl, 2-propylpentyl, 1,5-dimethylhexyl, 1-ethyl-4-methylpentyl, 1-propyl-3-methylbutyl, 1,1-dimethylhexyl, 1-ethyl-1-methylpentyl, or 1,1-diethylbutyl group.

[0026] In the present invention, the C3-6 alkyl group includes linear or branched C3-6 alkyl groups, such as propyl, butyl, pentyl, hexyl, isopropyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, or 2,3-dimethylbutyl group.

[0027] In the present invention, C4-7 alkyl groups include linear or branched C4-7 alkyl groups, such as butyl, pentyl, hexyl, heptyl, isobutyl, sec-butyl, tert-butyl, 1-methylbutyl, 1-ethylpropyl, 1,1-dimethylpropyl, 1,2-dimethylpropyl, 2-methylbutyl, 3-methylbutyl, 2,2-dimethylpropyl, 1-methylpentyl, 1-ethylbutyl, 2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 2-methylpentyl, 3-methyl Examples include pentyl, 4-methylpentyl, 2,3-dimethylbutyl, 1-methylhexyl, 1-ethylpentyl, 2-ethylpentyl, 1-propylbutyl, 2-methyl-3-hexyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1-ethyl-1-methylbutyl, 1-methyl-2-ethylbutyl, 1-ethyl-2-methylbutyl, 1-ethyl-3-methylbutyl, 1,1-dimethylpentyl, 1,1,3-trimethylbutyl, 1,1-diethylpropyl, 2-methylhexyl, 3-methylhexyl, 4-methylhexyl, 5-methylhexyl, or 3-ethylpentyl.

[0028] In the present invention, the C2-7 alkenyl group includes linear or branched C2-7 alkenyl groups, such as ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, heptadienyl groups, or their isomers.

[0029] In the present invention, the C2-6 alkenyl group includes linear or branched C2-6 alkenyl groups, such as ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl groups, or their isomers.

[0030] In the present invention, the C2-5 alkenyl group includes linear or branched C2-5 alkenyl groups, such as ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl groups, or their isomers.

[0031] In the present invention, the C2-4 alkenyl group includes linear or branched C2-4 alkenyl groups, such as ethenyl, propenyl, butenyl, butadienyl groups, or their isomers.

[0032] In the present invention, the C3-8 alkenyl group includes linear or branched C3-8 alkenyl groups, such as propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, heptadienyl, octenyl, octadienyl groups, or their isomers.

[0033] In the present invention, the C3-6 alkenyl group includes linear or branched C3-6 alkenyl groups, such as propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl groups, or their isomers.

[0034] In the present invention, the C4-7 alkenyl group includes linear or branched C4-7 alkenyl groups, such as butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, hexadienyl, heptenyl, heptadienyl groups, or their isomers.

[0035] In the present invention, the C2-7 alkynyl group includes linear or branched C2-7 alkynyl groups, such as ethynyl, propynyl, butynyl, butadiinyl, pentynyl, pentadinyl, hexynyl, hexadinyl, heptynyl, heptadinyl groups, or their isomers.

[0036] In the present invention, the C2-6 alkynyl group includes linear or branched C2-6 alkynyl groups, such as ethynyl, propynyl, butynyl, butadiinyl, pentynyl, pentadinyl, hexynyl, hexadinyl groups, or their isomers.

[0037] In the present invention, the C2-5 alkynyl group includes linear or branched C2-5 alkynyl groups, such as ethynyl, propynyl, butynyl, butadiinyl, pentynyl, pentadinyl groups, or their isomers.

[0038] In the present invention, the C2-4 alkynyl group includes linear or branched C2-4 alkynyl groups, such as ethynyl, propynyl, butynyl, butadiinyl groups, or their isomers.

[0039] In the present invention, the C3-8 alkynyl group includes linear or branched C3-8 alkynyl groups, such as propynyl, butynyl, butadiinyl, pentynyl, pentadinyl, hexynyl, hexadinyl, heptynyl, heptadiinyl, octinyl, octadiinyl groups, or their isomers.

[0040] In the present invention, the C3-6 alkynyl group includes linear or branched C3-6 alkynyl groups, such as propynyl, butynyl, butadiinyl, pentynyl, pentadinyl, hexynyl, hexadinyl groups, or their isomers.

[0041] In the present invention, the C4-7 alkynyl group includes linear or branched C4-7 alkynyl groups, such as butynyl, butadiinyl, pentynyl, pentadinyl, hexynyl, hexadinyl, heptynyl, heptadinyl groups, or their isomers.

[0042] In the present invention, the C1-5 alkylene group includes linear or branched C1-5 alkylenes, such as methylene, ethylene, propylene, butylene, pentylene, or their isomers.

[0043] In the present invention, the C1-4 alkylene group includes linear or branched C1-4 alkylenes, such as methylene, ethylene, propylene, butylene, or their isomers.

[0044] In the present invention, the C1-3 alkylene group includes linear or branched C1-3 alkylenes, such as methylene, ethylene, propylene, or their isomers.

[0045] In the present invention, the C2-4 alkylene group includes linear or branched C2-4 alkylenes, such as ethylene, propylene, butylene, or their isomers.

[0046] In the present invention, the C2-3 alkylene group includes linear or branched C2-3 alkylenes, such as ethylene, propylene, or their isomers.

[0047] In the present invention, the C3-6 cycloalkyl group refers to, for example, a cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl group.

[0048] In the present invention, the C3-7 cycloalkylene group refers to, for example, cyclopropylene, cyclobutylene, cyclopentylene, cyclohexylene, or cycloheptylene.

[0049] In the present invention, the C1-4 alkoxy group refers to, for example, a methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, or tert-butoxy group.

[0050] In the present invention, examples of C1-4 haloalkyl groups include fluoromethyl group, chloromethyl group, bromomethyl group, iodomethyl group, difluoromethyl group, trifluoromethyl group, 1-fluoroethyl group, 2-fluoroethyl group, 2-chloroethyl group, pentafluoroethyl group, 1-fluoropropyl group, 2-chloropropyl group, 3-fluoropropyl group, 3-chloropropyl group, 4,4,4-trifluorobutyl group, or 4-bromobutyl group.

[0051] In the present invention, the C2-8 acyl group refers to, for example, ethanol, propanoyl, butanoyl, pentanoyl, hexanoyl, heptanol, octanoyl groups, or their isomers.

[0052] In the present invention, a 3- to 7-membered nitrogen-containing heterocycle means an unsaturated or saturated 3- to 7-membered monocyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and which always contains at least one nitrogen atom. For example, aziridine, pyrrole, imidazole, triazole, tetrazole, pyrazole, azepine, diazepine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazolline, pyrazolidine, dihydrolyzine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydro Examples include rothiazole (thiazolidine), tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, perhydrooxazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiadin, dihydrothiadiazine, tetrahydrothiadiazine, perhydrothiadiazine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, or azabicyclo[3.2.1]octane.

[0053] In the present invention, a 4- to 7-membered nitrogen-containing heterocycle means an unsaturated or saturated 4- to 7-membered monocyclic heterocycle containing 1 to 5 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and which always contains at least one nitrogen atom. For example, pyrrole, imidazole, triazole, tetrazole, pyrazole, azepine, diazepine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazolline, pyrazolidine, dihydrolyzine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothia Examples include zole (thiazolidine), tetrahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, perhydrooxazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiadin, dihydrothiadiazine, tetrahydrothiadiazine, perhydrothiadiazine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, or azabicyclo[3.2.1]octane.

[0054] In the present invention, a 3- to 7-membered nitrogen-containing saturated heterocycle means a 3- to 7-membered monocyclic heterocycle that is partially or fully saturated and contains 1 to 5 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and which always contains at least one nitrogen atom. For example, aziridine, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazolin, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), te Examples include trahydroisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, perhydrooxazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiadin, dihydrothiadiazine, tetrahydrothiadiazine, perhydrothiadiazine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, or azabicyclo[3.2.1]octane.

[0055] In the present invention, a 4- to 7-membered nitrogen-containing saturated heterocycle means a 4- to 7-membered monocyclic heterocycle that is partially or fully saturated and contains 1 to 5 heteroatoms selected from oxygen, nitrogen, and sulfur atoms, and which always contains at least one nitrogen atom. For example, azetidine, pyrroline, pyrrolidine, imidazoline, imidazolidine, triazoline, triazolidine, tetrazoline, tetrazolidine, pyrazolin, pyrazolidine, dihydropyridine, tetrahydropyridine, piperidine, dihydropyrazine, tetrahydropyrazine, piperazine, dihydropyrimidine, tetrahydropyrimidine, perhydropyrimidine, dihydropyridazine, tetrahydropyridazine, perhydropyridazine, dihydroazepine, tetrahydroazepine, perhydroazepine, dihydrodiazepine, tetrahydrodiazepine, perhydrodiazepine, dihydrooxazole, tetrahydrooxazole (oxazolidine), tetrahydroisoxazole (isoxazolidine), tetrahydrothiazole (thiazolidine), tetrahydro Examples include diisothiazole (isothiazolidine), dihydrofurazan, tetrahydrofurazan, dihydrooxadiazole, tetrahydrooxadiazole (oxadiazolidine), tetrahydrooxazine, dihydrooxadiazine, tetrahydrooxadiazine, perhydrooxazepine, tetrahydrooxadiazepine, perhydrooxadiazepine, dihydrothiadiazole, tetrahydrothiadiazole (thiadiazolidine), tetrahydrothiadin, dihydrothiadiazine, tetrahydrothiadiazine, perhydrothiadiazine, tetrahydrothiadiazepine, perhydrothiadiazepine, morpholine, thiomorpholine, azabicyclo[2.2.1]heptane, azabicyclo[3.1.1]heptane, or azabicyclo[3.2.1]octane.

[0056] In the present invention, a chain-like group means a linear or branched chain-like group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms.

[0057] In this invention, the main chain refers to the longest linearly linked portion of the atoms constituting the chain group, which includes atoms bonded to the mother skeleton (dihydronaphthalene skeleton).

[0058] In this invention, the number of atoms in the main chain refers to the total number of carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms contained in the main chain. For example, if L is the group shown in the figure below, the number of atoms in the main chain is 5.

[0059] In the present invention, L can also be represented as a linear or branched chain hydrocarbon group having 3 to 8 carbon atoms in the main chain, or as a heteroatom-containing chain hydrocarbon group containing 1 to 3 heteroatoms independently selected from oxygen, nitrogen, and sulfur atoms, respectively, instead of 1 to 3 carbon atoms in the chain hydrocarbon group.

[0060] In the present invention, a linear or branched chain hydrocarbon group having 3 to 8 carbon atoms in the main chain means, for example, a C3-8 alkyl group, a C3-8 alkenyl group, or a C3-8 alkynyl group.

[0061] [Compound of the present invention] In the present invention, R １ The preferred elements are C1-4 alkyl groups, C3-6 cycloalkyl groups which may be substituted with halogens, C1-4 haloalkyl groups, or halogen atoms; more preferably C1-4 alkyl groups, C3-6 cycloalkyl groups, or halogen atoms; and particularly preferably methyl groups, cyclopropyl groups, or fluorine.

[0062] In the present invention, R ２ The preferred elements are C1-4 alkyl groups, halogen atoms, C1-4 alkoxy groups which may be substituted with halogens, or hydroxyl groups; more preferably C1-4 alkyl groups, halogen atoms, C1-4 alkoxy groups, or hydroxyl groups; and particularly preferably fluorine, methyl groups, methoxy groups, or hydroxyl groups.

[0063] In the present invention, R ３ Preferably, the element is a hydrogen atom or a C1-4 alkyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.

[0064] In the present invention, R ４ Preferably, the element is a hydrogen atom or a C1-4 alkyl group, more preferably a hydrogen atom or a methyl group, and particularly preferably a hydrogen atom.

[0065] In the present invention, R ５ Preferably, the element is a hydrogen atom or a C1-4 alkyl group, and more preferably a hydrogen atom or a methyl group.

[0066] In the present invention, fluorine is preferred as the halogen atom.

[0067] In the present invention, L is preferably a branched or linear chain group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms, wherein the number of atoms in the main chain is 4 to 7, and the chain group may contain 1 to 3 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms (where the carbon atoms in L may be substituted with 1 to 13 halogen atoms), and is (1)-O-(C3-6 alkyl), (2)-O-(C3-6 alkenyl), (3)-O-(C3-6 alkynyl), (4)-O-(C1-4 alkylene)-OCH ３ (5)-O-(C1-3 alkylene)-OCH ２ CH ３ (6)-CH ２ O-(C2-5 alkyl),(7)-CH ２ O-(C2-5 alkenyl),(8)-CH ２ O-(C2-5 alkynyl),(9)-CH ２ CH ２ O-(C1-4 alkyl),(10)-CH ２ CH ２ O-(C2-4 alkenyl),(11)-CH ２ CH ２ O-(C2-4 alkynyl), (12)-S-(C3-6 alkyl), (13)-S-(C3-6 alkenyl), (14)-S-(C3-6 alkynyl), (15)-NR ６ -(C3-6 alkyl),(16)-NR ６ -(C3-6 alkenyl), (17)-NR ６ - A chain-like group which is (C3-6 alkynyl), (18) C4-7 alkyl, (19) C4-7 alkenyl, or (20) C4-7 alkynyl (where R ６(where represents a hydrogen atom or a C1-4 alkyl group, and the carbon atoms in each group may be substituted with 1 to 13 halogen atoms) is more preferable. (Here, the carbon atoms in each group may be substituted with 1 to 13 halogen atoms, and each group is bonded to the dihydronaphthalene ring by the bonds indicated by the arrows) is particularly preferred.

[0068] In the present invention, L is (1)-O-(C2-7 alkyl), (2)-O-(C2-7 alkenyl), (3)-O-(C2-7 alkynyl), (4)-O-(C1-5 alkylene)-OCH ３ (5)-O-(C1-4 alkylene)-OCH ２ CH ３ (6)-CH ２ O-(C1-6 alkyl),(7)-CH ２ O-(C2-6 alkenyl),(8)-CH ２ O-(C2-6 alkynyl),(9)-CH ２ CH ２ O-(C1-5 alkyl),(10)-CH ２ CH ２ O-(C2-5 alkenyl),(11)-CH ２ CH ２ O-(C2-5 alkynyl), (12)-S-(C2-7 alkyl), (13)-S-(C2-7 alkenyl), (14)-S-(C2-7 alkynyl), (15)-NR ６ -(C2-7 alkyl),(16)-NR ６ -(C2-7 alkenyl), (17)-NR ６ - (C2-7 alkynyl), (18) C3-8 alkyl group, (19) C3-8 alkenyl group, or (20) C3-8 alkynyl group (where R ６ (where represents a hydrogen atom or a C1-4 alkyl group, and the carbon atoms in each group may be substituted with 1 to 13 halogen atoms) is also preferred.

[0069] In the present invention, L is, (It is also preferable that the carbon atoms in each group are substituted with 1 to 13 halogen atoms, and each group is bonded to the dihydronaphthalene ring by the bonds indicated by the arrows.)

[0070] In the present invention, Z is preferably a carboxyl group which may be substituted with a C1-8 alkyl group, or a tetrazolyl group which is more preferably a carboxyl group which is more preferably a tetrazolyl group which is more preferably a carboxyl group which is particularly preferably a carboxyl group.

[0071] In the present invention, ring 2 is preferably a 3- to 7-membered nitrogen-containing saturated heterocycle, more preferably a 4- to 7-membered nitrogen-containing saturated heterocycle, particularly preferably azetidine, pyrrolidine, piperidine, or perhydroazepine, and even more preferably azetidine or pyrrolidine.

[0072] In the present invention, ring 1 is preferably a 4- to 7-membered nitrogen-containing saturated heterocycle, more preferably azetidine, pyrrolidine, piperidine, or perhydroazepine, and particularly preferably azetidine or pyrrolidine.

[0073] In the present invention, R １ When R is bonded to the chiral carbon on dihydronaphthalene, １ The following arrangement is preferred for the three-dimensional configuration. R can adopt this three-dimensional configuration. １ C1-4 alkyl groups are more preferred, and methyl groups are particularly preferred.

[0074] In the present invention, when there is an oxygen atom at the end of the chain group represented by L, that oxygen atom may be either =O or -OH.

[0075] In the present invention, Y is, It is preferable.

[0076] In the present invention, A is preferably (1) a C3-7 cycloalkylene group which may be substituted with a C1-4 alkyl, C1-4 alkoxy, halogen, or hydroxyl group, or (2) a C1-4 alkylene group which may be substituted with a C1-4 alkyl, C1-4 alkoxy, halogen, or hydroxyl group, more preferably a C3-7 cycloalkylene group or a C1-4 alkylene group, and particularly preferably a cyclobutane or ethylene group.

[0077] In the present invention, m is preferably an integer of 0 to 3, more preferably an integer of 0 to 2.

[0078] In the present invention, n is preferably an integer of 0 to 2, more preferably an integer of 0 to 1.

[0079] In the present invention, general formula (V-1) [wherein all symbols have the same meaning as described above, and here, each hydrogen atom may be a deuterium atom or a tritium atom.] The compound represented by is preferred.

[0080] In the present invention, general formula (V-2) [wherein L １ is a branched or linear chain group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms and sulfur atoms, the number of atoms in the main chain thereof is 4 to 7, and the chain group may contain 1 to 3 hetero atoms selected from oxygen atoms, nitrogen atoms and sulfur atoms. Here, the carbon atoms in L １ may be substituted with 1 to 13 halogen atoms, ring2-1 represents a 3- to 7-membered nitrogen-containing saturated heterocyclic ring, m-1 represents an integer of 0 to 2, n-1 represents an integer of 0 to 2, when m-1 is 2, a plurality of R １ may be the same or different, when n-1 is 2, a plurality of R ２ may be the same or different, and other symbols have the same meaning as described above. Here, each hydrogen atom may be a deuterium atom or a tritium atom.] The compound represented by is preferred.

[0081] In the present invention, general formula (I) [wherein ring1 represents a 4- to 7-membered nitrogen-containing heterocyclic ring, and other symbols have the same meaning as described above. Here, each hydrogen atom may be a deuterium atom or a tritium atom.] The compound represented by is preferred.

[0082] In the present invention, general formula (I-1) [In the formula, ring1-1 represents a 4- to 7-member nitrogen-containing saturated heterocycle, and the other symbols have the same meanings as described above. Here, each hydrogen atom may be a deuterium atom or a tritium atom.] A compound represented by this is more preferable.

[0083] In the present invention, general formula (I-1-1) [In the formula, all symbols have the same meanings as described above. Here, each hydrogen atom may be a deuterium atom or a tritium atom.] A compound represented by this is also preferable.

[0084] In the present invention, in general formula (I-1), general formula (V-2) or general formula (I-1-1), L １ is preferably (1) -O-(C3-6 alkyl), (2) -O-(C3-6 alkenyl), (3) -O-(C3-6 alkynyl), (4) -O-(C1-4 alkylene)-OCH ３ (5) -O-(C1-3 alkylene)-OCH ２ CH ３ (6) -CH ２ O-(C2-5 alkyl), (7) -CH ２ O-(C2-5 alkenyl), (8) -CH ２ O-(C2-5 alkynyl), (9) -CH ２ CH ２ O-(C1-4 alkyl), (10) -CH ２ CH ２ O-(C2-4 alkenyl), (11) -CH ２ CH ２ O-(C2-4 alkynyl), (12) -S-(C3-6 alkyl), (13) -S-(C3-6 alkenyl), (14) -S-(C3-6 alkynyl), (15) -NR ６ -(C3-6 alkyl), (16) -NR ６ -(C3-6 alkenyl), (17) -NR ６ -(C3-6 alkynyl), (18) a C4-7 alkyl group, (19) a C4-7 alkenyl group, or (20) a C4-7 alkynyl group (where R ６ represents a hydrogen atom or a C1-4 alkyl group, and the carbon atoms in each group may be substituted with 1 to 13 halogen atoms) is preferable. (Here, the carbon atoms in each group may be substituted with 1 to 13 halogen atoms, and each group is more preferably bonded to the dihydronaphthalene ring by the bonds indicated by the arrows.)

[0085] In the present invention, in general formula (I-1), general formula (V-2), or general formula (I-1-1), ring1-1 or ring2-1 is preferably azetidine, pyrrolidine, piperidine, or perhydroazepine, and azetidine or pyrrolidine is more preferably.

[0086] In the above general formula, it is also preferable to arbitrarily combine each of the preferred groups listed above.

[0087] In the present invention, the compounds described in the examples are preferred: (1) 1-[((3R)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid, (2) 1-[((3S)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid, (3) 1-[((3S)-3-methyl-6-pentoxy-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid, (4) 1-[[(3S)-3-methyl-6-(4,4 (4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (5) 3-fluoro-1-[[(3S)-3-methyl-6-(3,4,4-trifluorobuta-3-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (6) 1-[[(3S)-3-methyl-6-(1,1,2,2,3,3,4,4,4-nonaduteriobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (7) (3R) (3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]pyrrolidine-3-carboxylic acid, (8) 1-[[(3S)-3-methyl-6-((R)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (9) 1-[[(3S)-3-methyl-6-((S)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine Zin-3-carboxylic acid, (10) 3-fluoro-1-[[(3S)-3-methyl-6-[(E)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid, (11) 3-fluoro-1-{[(3S)-3-methyl-6-(3,3,3-trifluoropropoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid, (12) cis-3-({1-[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydro-2-naphthalenyl]ethyl}amino)cyclobutanecarboxylic acid, or (13)1-{[(3S)-3-methyl-6-(propoxymethyl)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid is more preferred.

[0088] In the present invention, compounds having a clearance of 10 mL / min / kg or less, as measured by the method in Biological Experiment Example 2, are preferred, and compounds having a clearance of 5 mL / min / kg or less are more preferred.

[0089] In the present invention, compounds having an effective dose of 100 mg / kg or less, measured by the method described in Biological Experiment Example 4, are preferred, compounds having an effective dose of 10 mg / kg or less are more preferred, and compounds having an effective dose of 1 mg / kg or less are particularly preferred.

[0090] In this invention, isomers are encompassed unless otherwise specified. For example, alkyl groups include both linear and branched groups. Furthermore, geometric isomers (E, Z, cis, and trans isomers) in double bonds, rings, and fused rings, optical isomers (R, S, α, β configurations, enantiomers, and diastereomers) due to the presence of chiral carbon atoms, etc., optically active isomers with optical activity (D, L, d, and l isomers), polar isomers (highly polar and low polar isomers) determined by chromatographic separation, equilibrium compounds, rotational isomers, mixtures of these in any proportion, and racemic mixtures are all included in this invention. In addition, isomers due to tautomerism are also encompassed in this invention.

[0091] Furthermore, the optical isomers in this invention may not be 100% pure, but may also contain less than 50% of other optical isomers.

[0092] In this invention, unless otherwise specified, symbols will be used as will be obvious to those skilled in the art. This indicates that it is connected to the other side of the paper (i.e., in an α configuration). This indicates that it is coupled to the front side of the page (i.e., β configuration). This indicates an α configuration, a β configuration, or a mixture of any ratio thereof.

[0093] In the present invention, all references to the compounds of the present invention include the compound represented by general formula (V), its salt, its solvate, its N-oxide, or its cocrystal, or the solvate of a salt of the compound represented by general formula (V), or its cocrystal.

[0094] Compounds represented by general formula (V) are converted to corresponding salts by known methods. Water-soluble salts are preferred. Furthermore, pharmaceutically acceptable salts are preferred. Such salts include alkali metal salts (lithium, potassium, sodium, etc.), alkaline earth metal salts (calcium, magnesium, etc.), salts of other metals (silver, zinc, etc.), ammonium salts, and pharmaceutically acceptable organic amines (tetramethylammonium, choline, triethylamine, methylamine, dimethylamine, ethylamine, diethylamine, cyclopentylamine, benzylamine, phenethylamine, tert-butylamine, ethylenediamine, piperidine, piperazine, monoethanolamine, diethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-2-phenethylamine). Examples include salts of amines, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, lysine, arginine, N-methyl-D-glucamine, etc., acid adduct salts (inorganic salts (hydrochloride, hydrobromide, hydroiodide, sulfate, phosphate, nitrate, etc.), organic salts (acetate, trifluoroacetate, lactate, tartrate, oxalate, fumarate, maleate, benzoate, hydroxybenzoate, citrate, methanesulfonate, ethanesulfonate, benzenesulfonate, toluenesulfonate, isethionate, napadisylate, glucuronate, gluconate, etc.)).

[0095] Compounds represented by general formula (V) or pharmaceutically acceptable salts thereof can also be converted to solvates. The solvates are preferably low in toxicity and water-soluble. Examples of such solvates include those with water or alcoholic solvents (e.g., ethanol). In one embodiment, a hydrate is used.

[0096] The N-oxide form of a compound represented by general formula (V) refers to a compound in which the nitrogen atom of the compound represented by general formula (V) has been oxidized. Furthermore, the N-oxide form of a compound represented by general formula (V) may also be an alkali (earth) metal salt, ammonium salt, organic amine salt, or acid adduct salt.

[0097] Compounds represented by general formula (V) or pharmaceutically acceptable salts thereof can form cocrystals with suitable cocrystal-forming agents. Preferably, the cocrystals are pharmaceutically acceptable and formed with pharmaceutically acceptable cocrystal-forming agents. A cocrystal is typically defined as a crystal formed by two or more different intermolecular interactions. Alternatively, the cocrystal may be a complex of a neutral molecule and a salt. Cocrystals can be prepared by known methods, such as by melt crystallization, recrystallization from a solvent, or by physically grinding the components together. Suitable cocrystal-forming agents include organic acids (malic acid, succinic acid, adipic acid, gluconic acid, tartaric acid, benzoic acid, 4-hydroxybenzoic acid, 3-hydroxybenzoic acid, nicotinic acid, isonicotinic acid, etc.), organic amines (imidazole, diethanolamine, triethanolamine, tris(hydroxymethyl)aminomethane, N-benzyl-phenethylamine, deanol, 2-(diethylamino)ethanol, 1-(2-hydroxyethyl)pyrrolidine, 4-(2-hydroxyethyl)morpholine, N-methyl-D-glucamine, glycine, histidine, proline, etc.), and other organic compounds (caffeine, saccharin, etc.). Suitable cocrystal-forming agents include those described in WO2006 / 007448.

[0098] Furthermore, compounds represented by general formula (V) can be administered as prodrugs. For example, a prodrug of a compound represented by general formula (V) is a compound that is converted in the body by reactions involving enzymes, gastric acid, etc., to the compound represented by general formula (V). Examples of prodrugs of the compound represented by general formula (V) include, when the compound represented by general formula (V) has a hydroxyl group, compounds in which the hydroxyl group is acylated, alkylated, phosphorylated, or borated (for example, compounds in which the hydroxyl group of the compound of the present invention is acetylated, palmitoylated, propanoylated, pivaloylated, succinylated, fumalylated, alanylated, or dimethylaminomethylcarbonylated); compounds in which the carboxyl group of the compound represented by general formula (V) is esterified or amidized (for example, compounds in which the carboxyl group of the compound represented by general formula (V) is ethyl esterified, isopropyl esterified, phenyl esterified, carboxymethyl esterified, dimethylaminomethyl esterified, pivaloyloxymethyl esterified, ethoxycarbonyloxyethyl esterified, phthalidyl esterified, (5-methyl-2-oxo-1,3-dioxolene-4-yl)methyl esterified, cyclohexyloxycarbonylethyl esterified, or methylamidized); and so on. These compounds can be produced by known methods. Furthermore, the prodrug of the compound represented by general formula (V) may be either a hydrate or an unhydrated form. Also, the prodrug of the compound represented by general formula (V) may be one that transforms into the compound represented by general formula (V) under physiological conditions, as described on pages 163-198 of "Molecular Design," Volume 7 of "Pharmaceutical Development," published by Hirokawa Shoten in 1990.

[0099] Furthermore, compounds represented by general formula (V) contain isotopes (for example, ２ H, ３ H, １１ C, １３ C, １４ C, １３ N, １５ N, １５ O, １７ O, １８ O, ３５ S, １８ F, ３６ Cl, １２３ I,１２５ They may be marked with I, etc.

[0100] [Method for Producing the Compound of the Present Invention] The compound of the present invention can be produced by appropriately modifying and combining known methods, such as the method described in Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition (Richard C. Larock, John Wiley & Sons Inc, 2018), or the method shown in the examples.

[0101] Of the general formula (V), R ３ and R ４ A compound in which is a hydrogen atom, one of the atoms constituting L is an oxygen atom, and ring 1 is a 4-7 member nitrogen-containing saturated heteroring, i.e., the general formula (I-A) (In the formula, L Ａ L is a branched or linear chain group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms, wherein the number of atoms in the main chain is 2 to 7, and the chain group may contain 1 to 2 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms, where L Ａ The carbon atoms inside may be substituted with 1 to 13 halogen atoms, ring1 Ａ The symbol represents a 4-7 member nitrogen-containing saturated heterocycle, and the other symbols have the same meaning as above. The compound represented by ) can be produced by the reaction process formula 1 shown below. Note that in general formula (I-A), ring 1 Ａ Compounds in which the ring is a 3- to 7-membered nitrogen-containing saturated heterocycle can also be produced in the same manner according to reaction step formula 1. (In the formula, X １ The symbols represent a halogen atom, a trifluoromethanesulfonyloxy group (OTf group), a methanesulfonyloxy group (OMs group), or a toluenesulfonyloxy group (OTs), and the other symbols have the same meaning as above.

[0102] In reaction step formula 1, reaction 1 can be carried out by subjecting a compound represented by general formula (A) and a compound represented by general formula (II) to a reductive amination reaction. This reductive amination reaction is well known and is carried out, for example, in an organic solvent (dichloroethane, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, acetic acid, tetrahydrofuran, methanol, and mixtures thereof) in the presence of a reducing agent (sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride, etc.) at a temperature of 0 to 40°C.

[0103] In reaction step 1, reaction 2 can be carried out by subjecting the compound represented by general formula (B) and the compound represented by general formula (III) to an etherification reaction, or by subjecting the compound represented by general formula (B) and the compound represented by general formula (IV) to a Mitsunobu reaction. This etherification reaction is well known and is carried out at 0 to 100°C in an organic solvent (N,N-dimethylformamide, dimethyl sulfoxide, chloroform, dichloromethane, diethyl ether, tetrahydrofuran, methyl t-butyl ether, etc.) in the presence of alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.), or carbonates (sodium carbonate, potassium carbonate, etc.), or aqueous solutions thereof, or mixtures thereof. This Mitsunobu reaction is well known and is carried out at 0 to 60°C in an organic solvent (dichloromethane, diethyl ether, tetrahydrofuran, acetonitrile, benzene, toluene, etc.) in the presence of azo compounds (diethyl azodicarboxylate (DEAD), diisopropyl azodicarboxylate, 1,1'-(azodicarbonyl)dipiperidine, 1,1'-azobis(N,N-dimethylformamide), etc.) and phosphine compounds (triphenylphosphine, tributylphosphine, trimethylphosphine, polymer-supported triphenylphosphine, etc.).

[0104] Compounds in which one of the atoms constituting L in general formula (V) is a carbon atom, a nitrogen atom, or a sulfur atom, i.e., general formula (V-A) The compound represented by (wherein E represents a carbon atom, a nitrogen atom, or a sulfur atom, and the other symbols have the same meaning as above) can be produced by the reaction process formula 2 shown below. (In the formula, X ２ The symbol represents a halogen atom or a trifluoromethanesulfonyloxy group (OTf group), and the other symbols have the same meaning as above.

[0105] In reaction step 2, reaction 3 can be carried out by subjecting the compound represented by general formula (C) and the compound represented by general formula (VI) to a transition metal-catalyzed cross-coupling reaction. This transition metal-catalyzed cross-coupling reaction is well known, and examples of transition metal catalysts include palladium catalysts, copper catalysts, nickel catalysts, ruthenium catalysts, iridium catalysts, rhodium catalysts, iron catalysts, platinum catalysts, silver catalysts, or gold catalysts.

[0106] Among transition metal catalyzed cross-coupling reactions, the Suzuki coupling reaction involves, for example, an organic solvent (benzene, toluene, dimethylformamide, dioxane, tetrahydrofuran, methanol, acetonitrile, dimethoxyethane, acetone, etc.), a base (sodium ethylate, sodium hydroxide, potassium hydroxide, triethylamine, sodium carbonate, sodium bicarbonate, potassium carbonate, cesium carbonate, thallium carbonate, tripotassium phosphate, cesium fluoride, barium hydroxide, tetrabutylammonium fluoride, etc.) or an aqueous solution thereof, or a mixture thereof, and a catalyst (tetrakis(triphenylphosphine)palladium (Pd(PPh) ３ ) ４ ), bis(triphenylphosphine)palladium(PdCl) dichloride ２ (PPh ３ ) ２ ), palladium acetate (Pd(OAc) ２ ), palladium black, 1,1'-bis(diphenylphosphinoferrocene)dichloropalladium (PdCl ２ (dppf) ２ ), diallylpalladium dichloride (PdCl ２ (allyl) ２), phenylbis(triphenylphosphine)palladium iodide (PhPdI(PPh ３ ) ２ ), Tris(dibenzylideneacetone) dipalladium(Pd ２ (dba) ３ This can be carried out at room temperature to 120°C in the presence of (etc.).

[0107] If a protecting group is present in the compound represented by each general formula in reaction step formula 1 or 2, for example, if Z is protected, a deprotection reaction may be carried out as necessary.

[0108] Examples of protecting groups for carboxyl groups include methyl, ethyl, allyl, t-butyl, trichloroethyl, benzyl (Bn), and phenacyl groups.

[0109] Examples of hydroxyl group protecting groups include methyl group, trityl group, methoxymethyl (MOM) group, 1-ethoxyethyl (EE) group, methoxyethoxymethyl (MEM) group, 2-tetrahydropyranyl (THP) group, trimethylsilyl (TMS) group, triethylsilyl (TES) group, t-butyldimethylsilyl (TBDMS) group, t-butyldiphenylsilyl (TBDPS) group, acetyl (Ac) group, pivaloyl group, benzoyl group, benzyl (Bn) group, p-methoxybenzyl group, allyloxycarbonyl (Alloc) group, and 2,2,2-trichloroethoxycarbonyl (Troc) group.

[0110] The protecting group is not particularly limited as long as it is a group that can be easily and selectively eliminated, in addition to those mentioned above. For example, those described in TW Greene, Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014 can be used.

[0111] Deprotection reactions of protecting groups are well known and include, for example, (1) alkaline hydrolysis, (2) deprotection reactions under acidic conditions, (3) deprotection reactions by hydrolysis, (4) deprotection reactions of silyl groups, (5) deprotection reactions using metals, and (6) deprotection reactions using metal complexes.

[0112] To explain these methods in detail: (1) Deprotection reactions by alkaline hydrolysis are carried out at a temperature of 0 to 40°C in an organic solvent (methanol, tetrahydrofuran, dioxane, etc.) using alkali metal hydroxides (sodium hydroxide, potassium hydroxide, lithium hydroxide, etc.), alkaline earth metal hydroxides (barium hydroxide, calcium hydroxide, etc.), or carbonates (sodium carbonate, potassium carbonate, etc.), or aqueous solutions thereof, or mixtures thereof. (2) Deprotection reactions under acidic conditions are carried out at a temperature of 0 to 100°C in an organic solvent (dichloromethane, chloroform, dioxane, ethyl acetate, anisole, etc.), organic acids (acetic acid, trifluoroacetic acid, methanesulfonic acid, p-tosylic acid, etc.), or inorganic acids (hydrochloric acid, sulfuric acid, etc.) or mixtures thereof (hydrogen bromide / acetic acid, etc.). (3) Deprotection reactions by hydrolysis are carried out, for example, in a solvent (ether-based (tetrahydrofuran, dioxane, dimethoxyethane, diethyl ether, etc.), alcohol-based (methanol, ethanol, etc.), benzene-based (benzene, toluene, etc.), ketone-based (acetone, methyl ethyl ketone, etc.), nitrile-based (acetonitrile, etc.), amide-based (dimethylformamide, etc.), water, ethyl acetate, acetic acid, or a mixture of two or more of these solvents, etc.) in the presence of a catalyst (palladium-carbon, palladium black, palladium hydroxide, platinum oxide, Raney nickel, etc.), under atmospheric pressure or under a pressurized hydrogen atmosphere, or in the presence of ammonium formate, at a temperature of 0 to 200°C. (4) Deprotection reactions of silyl groups are carried out, for example, in an organic solvent miscible with water (tetrahydrofuran, acetonitrile, etc.) using tetrabutylammonium fluoride at a temperature of 0 to 40°C. (5) Deprotection reactions using metals are carried out, for example, in an acidic solvent (acetic acid, a buffer solution with a pH of 4.2 to 7.2, or a mixture of these solutions with an organic solvent such as tetrahydrofuran) in the presence of zinc powder, and with sonication if necessary, at a temperature of 0 to 40°C.(6) Deprotection reactions using metal complexes are carried out at a temperature of 0 to 40°C, for example, in an organic solvent (dichloromethane, dimethylformamide, tetrahydrofuran, ethyl acetate, acetonitrile, dioxane, ethanol, etc.), water, or a mixture thereof, in the presence of a trap reagent (tributyltin hydride, triethylsilane, dimedone, morpholine, diethylamine, pyrrolidine, etc.), an organic acid (acetic acid, formic acid, 2-ethylhexanoic acid, etc.) and / or an organic acid salt (sodium 2-ethylhexanoate, potassium 2-ethylhexanoate, etc.), in the presence or absence of a phosphine reagent (triphenylphosphine, etc.), and using a metal complex (tetrakistriphenylphosphine palladium (O), bis(triphenylphosphine)palladium (II) chloride, palladium (II) acetate, tris(triphenylphosphine)rhodium (I) chloride, etc.).

[0113] In addition to the methods described above, deprotection reactions can also be carried out by methods such as those described in TW Greene, Protective Groups in Organic Synthesis, Fifth Edition, Wiley, New York, 2014.

[0114] As will be easily understood by those skilled in the art, the target compound of the present invention can be easily produced by selectively using these deprotection reactions.

[0115] In each reaction described herein, the compounds used as starting materials, for example, compounds represented by general formula (A), general formula (II), general formula (III), general formula (IV), general formula (C), or general formula (VI), are known or can be readily produced by known methods.

[0116] In each of the reactions described herein, reactions involving heating can be carried out using a water bath, an oil bath, a sand bath, or a microwave, as will be obvious to those skilled in the art.

[0117] In each reaction described herein, a solid-phase supported reagent supported on a polymer (e.g., polystyrene, polyacrylamide, polypropylene, polyethylene glycol, etc.) may be used as appropriate.

[0118] In each reaction described herein, the reaction product can be purified by conventional purification methods, such as distillation under atmospheric or reduced pressure, high-performance liquid chromatography using silica gel or magnesium silicate, thin-layer chromatography, ion exchange resin, scavenger resin, or column chromatography, or by washing and recrystallization. Purification may be performed after each reaction or after several reactions have been completed.

[0119] [Toxicity] The toxicity of the compound of the present invention is sufficiently low and it can be safely used as a pharmaceutical product.

[0120] [Application to Pharmaceuticals] The compound of the present invention is S1P ５ (EDG-8) has receptor agonist activity, therefore S1P ５ It is useful as a preventive and / or therapeutic agent for indirect diseases. S1P ５ Examples of mediating diseases include neurodegenerative diseases, autoimmune diseases, infectious diseases, and cancer.

[0121] Furthermore, the compound of the present invention is S1P ５ Because it possesses (EDG-8) receptor agonist activity, it is useful as a cancer preventive and / or therapeutic agent through its tumor immune activation effect.

[0122] In this invention, neurodegenerative diseases include anxiety-related disorders (social anxiety disorder, anxiety neurosis, obsessive-compulsive disorder, post-traumatic stress disorder (PTSD)), polyglutamine diseases, retinitis pigmentosa, neuroses, seizures, panic disorder, sleep disorders, depression, reactive depression, epilepsy, Parkinson's disease, Parkinsonian syndromes, Down syndrome, schizophrenia, autonomic dysfunction, Huntington's disease, Alzheimer's disease, affective disorders (including depressive or bipolar disorder), cognitive impairment, migraines, tension headaches, cluster headaches, dissociative disorders, amyotrophic lateral sclerosis, neuromyelitis optica, optic neuritis, acute disseminated encephalomyelitis, allergic encephalomyelitis, Marchifava-Bignami disease, and Binswanger's disease. Diseases, progressive multifocal leukoencephalopathy, post-infectious encephalitis, central pontine myelin breakdown, adrenoleukodystrophy, multiple system atrophy, Krabbe disease, metachromatic leukodystrophy, Alexander disease, Canavan disease, Cockayne syndrome, Pelizaues-Merzbacher disease, Hurler syndrome, Lowe syndrome, spinal cord injury, transverse myelitis, spinocerebellar degeneration, chronic inflammatory demyelinating polyneuropathy (CIDP), Guillain-Barré syndrome, phenylketonuria, Refsum's disease Examples include Charcot-Marie-Tooth disease, Gaucher disease, Niemann-Pick disease, multiple sclerosis, fragile X syndrome, autism, insomnia, nervous cough, psychogenic seizures, psychogenic syncope, writer's cramp, spasmodic torticollis, neuropathy, neurodegenerative diseases with cerebral iron accumulation, and Lewy body dementia.

[0123] In the present invention, preferred neurodegenerative diseases are Alzheimer's disease, Parkinson's disease, multiple system atrophy, multiple sclerosis, or Lewy body dementia.

[0124] In the present invention, examples of autoimmune diseases include inflammatory bowel disease, arthritis, lupus, rheumatism, psoriatic arthritis, osteoarthritis, Still's disease, juvenile arthritis, type 1 diabetes, myasthenia gravis, Hashimoto's thyroiditis, Audrey's thyroiditis, Graves' disease, Sjögren's syndrome, Addison's disease, opsoclonus-myoclonus syndrome, ankylosing spondylitis, antiphospholipid antibody syndrome, aplastic anemia, autoimmune hepatitis, celiac disease, Goodpasture syndrome, idiopathic thrombocytopenic purpura, scleroderma, primary biliary cirrhosis, Reiter's disease, Takayasu's arteritis, temporal arteritis, warm autoimmune hemolytic anemia, Wegner's granuloma, psoriasis, alopecia generalis, Burchet's disease, chronic fatigue syndrome, autonomic neuropathy, endometriosis, interstitial cystitis, myotonia, vulvodynia, and systemic lupus erythematosus.

[0125] In the present invention, infectious diseases include symptoms that develop when normal cells in the body become infected and proliferate with one or more pathogenic microorganisms, such as viruses, bacteria, and fungi. The above-mentioned pathogenic microorganisms also include rickettsiae, chlamydia, protozoa, parasites, and the like.

[0126] In the present invention, the viruses related to infectious diseases include human hepatitis viruses (e.g., hepatitis B, hepatitis C, hepatitis A, and hepatitis E), human retroviruses, human immunodeficiency viruses (e.g., HIV1 and HIV2), human T-cell leukemia viruses or human T-lymphotropic viruses (e.g., HTLV1 and HTLV2), herpes simplex virus type 1 or 2, Epstein-Barr (EB) virus, cytomegalovirus, varicella-zoster virus, human herpesviruses (e.g., human herpesvirus 6), poliovirus, measles virus, rubella virus, Japanese encephalitis virus, and mumps virus. Examples include influenza viruses, common cold viruses (e.g., adenovirus, enterovirus, rhinovirus, etc.), viruses that cause severe acute respiratory syndrome (SARS), Ebola virus, West Nile virus, flavivirus, echovirus, coxsackievirus, coronavirus, respiratory multinuclear (syntiocytotic) viruses, rotavirus, norovirus, sapovirus, parvovirus, vaccinia virus, HTL virus, dengue virus, hapillomavirus, molluscum contagiosum virus, rabies virus, JC virus, arbovirus, encephalitis virus, hantavirus, and Ebola virus.

[0127] In the present invention, the bacteria involved in infectious diseases include Vibrio cholerae, Salmonella, Escherichia coli, Legionella, Bacillus anthrax, Helicobacter pylori, Listeria monocytogenes, Mycobacterium tuberculosis, non-tuberculous mycobacteria, Staphylococcus, Streptococcus, Streptococcus pneumoniae, Neisseria meningitidis, Klebsiella pneumoniae, Serratia marcescens, Neisseria diphtheriae, Brucella, Bartonella henselae, Erytheperothrix luciopathie, Actinomycetes, Lyme disease bacteria, Clostridium perfringens, Shigella, Plague bacillus, Neisseria tetanus, Enterobacter, and the like.

[0128] In the present invention, fungi related to infectious diseases include Candida, Aspergillus, Cryptococcus, Blastomyces, Coccidioides, Histoplasma, Paracoccidioides, Sporotrichus, and the like.

[0129] In the present invention, examples of protozoa related to infectious diseases include malaria parasites and toxoplasma parasites.

[0130] In the present invention, examples of parasites related to infectious diseases include Entamoeba histolytica, roundworms, Babesia, Cryptosporidium, Giardia lamblia, hookworms, pinworms, schistosomiasis, tapeworms, Trichinella, and whipworms.

[0131] In the present invention, other microorganisms related to infectious diseases include mycoplasma, spirochetes, and the like.

[0132] In this invention, cancers include cancers related to the brain and nerves (for example, pediatric brain tumors (e.g., neuroblastoma, medulloblastoma, astrocytoma (juvenile trichoroidal astrocytoma), ependymoma, craniopharyngioma, germ cell tumor, optic nerve glioma, choroid plexus papilloma, brainstem glioma), adult brain tumors (e.g., adult astrocytoma, adult malignant astrocytoma, adult glioblastoma, adult ventriculospondyloplasm, adult malignant ventriculospondyloplasm, adult malignant oligodendroma, adult medulloblastoma, adult meningioma, adult malignant meningioma), gliomas (e.g., astrocytoma, oligodendroma, ependymoma, brainstem glioma), pituitary adenoma, acoustic neuroma, retinoblastoma, uveal melanoma, etc.), and respiratory cancers. (For example, pharyngeal cancer (e.g., nasopharyngeal cancer, oropharyngeal cancer, hypopharyngeal cancer), laryngeal cancer, paranasal sinus cancer, lung cancer (e.g., small cell carcinoma, non-small cell carcinoma), thymoma, mesothelioma, etc.), gastrointestinal cancer (e.g., esophageal cancer, gastric cancer, duodenal cancer, colorectal cancer (e.g., colon cancer, rectal cancer, anal cancer), oral cancer (e.g., gingival cancer, tongue cancer, salivary gland cancer, etc.), urinary tract cancer (e.g., penile cancer, renal pelvis / ureteral cancer, renal cell carcinoma, testicular tumor, prostate cancer, bladder cancer, etc.), cancers affecting women (vulvar cancer, uterine cancer (e.g., cervical cancer, endometrial cancer), uterine sarcoma, gestational trophoblastic disease (e.g., hydatidiform mole, choriocarcinoma, placental trophoblastic tumor, persistent trophoblastic disease) , vaginal cancer, breast cancer, breast sarcoma, ovarian cancer, ovarian germ cell tumor, etc.), skin cancer (e.g., melanoma (malignant melanoma) (e.g., lentigo malignant melanoma, superficial spreading melanoma, nodular melanoma, acral lentiginous melanoma, erosive melanoma), mycosis fungoides, squamous cell carcinoma, basal cell carcinoma, precancerous and intraepidermal carcinoma (e.g., actinic keratosis, Bowen's disease, Paget's disease), lymphomatoid papulosis, anaplastic large cell lymphoma of the skin, Sézary syndrome, cutaneous B-cell lymphoma, etc.), bone and muscle cancer (e.g., osteosarcoma, soft tissue sarcoma, rhabdomyosarcoma, synovial sarcoma, liposarcoma, etc.), thyroid cancer, carcinoma This includes liver cancer (hepatocellular carcinoma), hepatoblastoma, cholangiocarcinoma, gallbladder cancer, pancreatic cancer, pancreatic endocrine tumors (e.g., insulinoma, gastrinoma, VIP-producing adenoma, etc.), cancer of unknown primary origin, hereditary tumors / familial tumors (e.g., hereditary nonpolyposis colorectal cancer, familial adenomatous polyposis, hereditary breast cancer, ovarian cancer syndrome, Lie-Fraumeni syndrome, hereditary melanoma, Wilms' tumor, hereditary papillary renal cell carcinoma, von Hipper-Lindau syndrome, multiple endocrine neoplasia, etc.), leukemia (e.g., acute myeloid leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, chronic myeloid leukemia / chronic myeloproliferative disorders,Examples include adult T-cell leukemia / lymphoma, chronic lymphocytic leukemia / small cell lymphoma, etc.), multiple myeloma, primary macroglobulinemia, and malignant lymphoma (e.g., Hodgkin lymphoma, non-Hodgkin lymphoma (intermediate-to-high grade lymphoma, Burkitt lymphoma, lymphoblastic lymphoma, follicular lymphoma, mantle cell lymphoma, MALT (Mucosa-Associated Lymphoid Tissue) lymphoma, NK (Natural Killer) cell lymphoma, etc.)).

[0133] The compounds of the present invention may be administered as concomitant agents in combination with other drugs for the following purposes: 1) to complement and / or enhance the preventive and / or therapeutic effects of the compound; 2) to improve the kinetics and absorption of the compound, reduce the dosage, and / or 3) to mitigate the side effects of the compound.

[0134] The compound of the present invention and other drugs may be administered in the form of a combination preparation containing both components in a single formulation, or they may be administered as separate formulations. When administered as separate formulations, this includes simultaneous administration and administration with a time difference. Furthermore, in the case of administration with a time difference, the compound of the present invention may be administered first and the other drug afterward, or the other drug may be administered first and the compound of the present invention afterward. The respective administration methods may be the same or different.

[0135] The diseases for which the above-mentioned concomitant drugs provide preventive and / or therapeutic effects are not particularly limited, and any disease that complements and / or enhances the preventive and / or therapeutic effects of the compound of the present invention is acceptable.

[0136] Furthermore, the concomitant drugs to be used in combination with the compounds of the present invention include not only those that have been discovered to date, but also those that may be discovered in the future.

[0137] Other drugs for complementing and / or enhancing the preventive and / or therapeutic effects of the compounds of the present invention on neurodegenerative diseases include acetylcholinesterase inhibitors, nicotinic receptor modulators, β-amyloid protein production, secretion, accumulation, aggregation and / or deposition inhibitors (e.g., β-secretase inhibitors, γ-secretase inhibitors, β-amyloid protein aggregation inhibitors, β-amyloid vaccines, β-amyloid-degrading enzymes, etc.), brain function activators (e.g., brain metabolism activators, cerebral circulation improvers, etc.), dopamine receptor agonists (dopamine receptor stimulants), dopamine release promoters (dopamine secretion promoters or dopamine release promoters), dopamine reuptake inhibitors, dopamine agonists, dopamine antagonists, lithium carbonate, serotonin agonists, serotonin antagonists (e.g., 5-HT ２Ａ Antagonist, 5-HT ３ Antagonist, 5-HT ４ Antagonist, 5-HT ７Antagonists), monoamine oxidase (MAO) inhibitors, aromatic L-amino acid decarboxylase inhibitors (DCIs), norepinephrine (norepinephrine) replacement therapy, anticholinergics, catechol-O-methyltransferase (COMT) inhibitors, amyotrophic lateral sclerosis (ALS) treatments, hyperlipidemia treatments, apoptosis inhibitors, nerve regeneration and differentiation promoters, antihypertensives, diabetes treatments, diabetic complication treatments, antidepressants (e.g., tricyclic antidepressants, tetracyclic antidepressants, etc.), anxiolytics, antiepileptics, anticonvulsants, antispasmodics, nonsteroidal anti-inflammatory drugs, anticytokine drugs (e.g., TNF inhibitors) Harmful drugs, MAP kinase inhibitors, etc.), steroids, sex hormones or their derivatives (e.g., progesterone, estradiol, estradiol benzoate, etc.), thyroid hormones, parathyroid hormones (e.g., PTH, etc.), calcium channel blockers (calcium channel blockers), calcium receptor antagonists, opioid receptor agonists, N-methyl-D-2-amino-5-D-aspartate (NMDA) receptor antagonists, VR-1 receptor agonists, neuromuscular junction blockers, cannabinoid-2 receptor agonists, GABAA receptor modulators (e.g., GABAA receptor agonists) Drugs, etc.), GABAB receptor modulators, prostaglandins, cholecystokinin antagonists, nitric oxide synthase (NOS) inhibitors, local anesthetics, neurotrophic factors (e.g., neurotrophins, TGF-β superfamily, neurokine family, growth factors, etc.), sympathomimetic agents, parasympathomimetic agents, sympathomimetic inhibitors, prostaglandin receptor antagonists, prostaglandin receptor agonists, carbonic anhydrase inhibitors, hypertonic osmotic agents, vasodilators, metabolic stimulants, diuretics (e.g., thiazide diuretics, loop diuretics, potassium-sparing diuretics, etc.), peripheral blood flow improvers Drugs, immunosuppressants (e.g., dimethyl fumarate, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod), immunoglobulins, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) / kainate receptor antagonists, Rho-kinase inhibitors, vitamins (e.g., vitamin B6, vitamin B12, etc.), cyclooxygenase (COX)-2 inhibitors, anti-vertigo drugs, anemia treatments, heavy metal poisoning treatments, muscarinic receptor agonists, aldose reductase inhibitors, nerve regeneration promoters,Examples include protein kinase C (PKC) inhibitors, advanced glycation end product (AGE) inhibitors, reactive oxygen species scavengers, and muscle relaxants. Other drugs for complementing and / or enhancing the preventive and / or therapeutic effects of the compounds of the present invention on autoimmune diseases include immunosuppressants (e.g., dimethyl fumarate, glatiramer acetate, interferon beta-1a, interferon beta-1b, fingolimod), steroids, disease-modifying antirheumatic drugs, elastase inhibitors, cannabinoid-2 receptor agonists, prostaglandins, prostaglandin synthase inhibitors, phosphodiesterase inhibitors, metalloproteinase inhibitors, adhesion molecule inhibitors, anti-cytokine protein preparations such as anti-TNF-α preparations, anti-IL-1 preparations, and anti-IL-6 preparations, cytokine inhibitors, nonsteroidal anti-inflammatory drugs, and anti-CD20 antibodies.

[0138] Other drugs that complement and / or enhance the preventive and / or therapeutic effects of the compound of the present invention against infectious diseases include antiviral drugs, antibiotics, antifungal drugs, antiparasitic drugs, and antiprotozoal drugs.

[0139] Other drugs for complementing and / or enhancing the cancer-preventive and / or therapeutic effects of the compounds of the present invention include alkylating agents, antimetabolites, anticancer antibiotics, plant alkaloids, hormones, platinum compounds, anti-CD20 antibodies, and other anticancer agents.

[0140] The compounds of the present invention are usually administered systemically or topically, either orally or parenterally. Examples of oral preparations include oral liquid preparations (e.g., elixirs, syrups, pharmaceutically acceptable aqueous preparations, suspensions, emulsions), oral solid preparations (e.g., tablets (including sublingual tablets and orally disintegrating tablets), pills, capsules (including hard capsules, soft capsules, gelatin capsules, and microcapsules), powders, granules, and lozenges). Examples of parenteral preparations include liquid preparations (e.g., injections (subcutaneous injections, intravenous injections, intramuscular injections, intraperitoneal injections, drips, etc.), eye drops (e.g., aqueous eye drops (aqueous eye solutions, aqueous suspension eye drops, viscous eye drops, solubilized eye drops, etc.), non-aqueous eye drops (non-aqueous eye solutions, non-aqueous suspension eye drops, etc.)), topical preparations (e.g., ointments (eye ointments, etc.)), ear drops, patches, etc.). These formulations may also be release-controlled agents such as immediate-release formulations or sustained-release formulations. These formulations can be manufactured by known methods, for example, by methods described in the Japanese Pharmacopoeia.

[0141] Oral preparations are prepared, for example, by dissolving, suspending, or emulsifying the active ingredient in a commonly used diluent (e.g., purified water, ethanol, or a mixture thereof). Furthermore, these preparations may contain wetting agents, suspending agents, emulsifiers, sweeteners, flavoring agents, fragrances, preservatives, buffering agents, etc.

[0142] For oral solid preparations, for example, the active ingredient is mixed with excipients (e.g., lactose, mannitol, glucose, microcrystalline cellulose, starch, etc.), binders (e.g., hydroxypropyl cellulose, polyvinylpyrrolidone, magnesium aluminometasilicate, etc.), disintegrants (e.g., calcium cellulose glycolate, etc.), lubricants (e.g., magnesium stearate, etc.), stabilizers, solubilizers (glutamic acid, aspartic acid, etc.), etc., and formulated according to conventional methods. Furthermore, if necessary, the preparation may be coated with a coating agent (e.g., sucrose, gelatin, hydroxypropyl cellulose, hydroxypropyl methylcellulose phthalate, etc.), or coated with two or more layers.

[0143] Topical preparations for parenteral use are manufactured by known methods or commonly used formulations. For example, ointments are manufactured by grinding or melting the active ingredient into a base. The ointment base is selected from known or commonly used ones. For example, higher fatty acids or higher fatty acid esters (e.g., adipic acid, myristic acid, palmitic acid, stearic acid, oleic acid, adipic acid ester, myristic acid ester, palmitic acid ester, stearic acid ester, oleic acid ester, etc.), waxes (e.g., beeswax, whale wax, ceresin, etc.), surfactants (e.g., polyoxyethylene alkyl ether phosphate ester, etc.), higher alcohols (e.g., cetanol, stearyl alcohol, cetostearyl alcohol, etc.), silicone oils (e.g., dimethylpolysiloxane, etc.), hydrocarbons (e.g., hydrophilic petrolatum, white petrolatum, refined lanolin, liquid paraffin, etc.), glycols (e.g., ethylene glycol, diethylene glycol, propylene glycol, polyethylene glycol, macrogol, etc.), vegetable oils (e.g., castor oil, olive oil, sesame oil, turpentine oil, etc.), animal oils (e.g., mink oil, egg yolk oil, squalane, squalene, etc.), water, absorption enhancers, and anti-rash agents may be used individually or in combination of two or more. Furthermore, it may contain humectants, preservatives, stabilizers, antioxidants, fragrances, etc.

[0144] Parenteral injectable preparations include solutions, suspensions, emulsions, and solid injectable preparations that are dissolved or suspended in a solvent before use. Injectable preparations are used, for example, by dissolving, suspending, or emulsifying the active ingredient in a solvent. Solvents include, for example, distilled water for injection, physiological saline, vegetable oil, propylene glycol, polyethylene glycol, alcohols such as ethanol, and combinations thereof. Furthermore, these injectable preparations may contain stabilizers, solubilizers (e.g., glutamic acid, aspartic acid, polysorbate 80®, etc.), suspending agents, emulsifiers, analgesics, buffers, preservatives, etc. These are sterilized in the final step or manufactured using aseptic techniques. Alternatively, sterile solid preparations, such as lyophilized products, can be manufactured and sterilized before use or dissolved in sterile distilled water for injection or other solvents.

[0145] To use the compound of the present invention, or a combination of the compound of the present invention and other agents, for the above purposes, it is usually administered systemically or topically, orally or parenterally. The dosage varies depending on age, weight, symptoms, therapeutic effect, method of administration, processing time, etc., but is usually administered orally once to several times a day in the range of 1 ng to 1000 mg per adult, or parenterally once to several times a day in the range of 0.1 ng to 10 mg per adult, or continuously administered intravenously for a range of 1 to 24 hours per day. Of course, as mentioned above, the dosage will vary depending on various conditions, so in some cases a smaller amount than the above dosage may be sufficient, and in other cases it may be necessary to administer more than the range.

[0146] The present invention provides, for example, the following embodiments: [1] General formula (V) [In the formula, L is a branched or linear chain group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms, the number of atoms in its main chain is 3 to 8, and the chain group may contain 1 to 3 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms, where the carbon atoms in L may be substituted with 1 to 13 halogen atoms, and Y is, or This represents, where each group is bonded to Z by the bonds indicated by the arrows, A represents an optional C3-7 cycloalkylene group or an optional C1-4 alkylene group, and R １ R represents a C1-4 alkyl group, a C3-6 cycloalkyl group which may be substituted with a halogen, a C1-4 alkoxy group which may be substituted with a halogen, a C1-4 haloalkyl group, a halogen atom, or a hydroxyl group. ２ R represents a C1-4 alkyl group, a C1-4 alkoxy group which may be substituted with a halogen, a C1-4 haloalkyl group, a halogen atom, or a hydroxyl group. ３ , R ４ and R ５Each of these independently represents a hydrogen atom, a C1-4 alkyl group, a C3-6 cycloalkyl group which may be substituted with a halogen, or a C1-4 haloalkyl group. Z represents (1) a carboxyl group which may be substituted with one C1-8 alkyl group, (2) a hydroxyl group which may be substituted with one C1-8 alkyl group, (3) a hydroxamic acid group which may be substituted with one or two C1-8 alkyl groups, (4) a sulfonic acid group which may be substituted with one C1-8 alkyl group, (5) a boronic acid group which may be substituted with one or two C1-8 alkyl groups, (6) a carbamoyl group which may be substituted with (i) one or two C1-8 alkyl groups or (ii) one or two sulfonyl groups which may be substituted with a C1-4 alkyl group, (7) a sulfamoyl group which may be substituted with (i) one or two C1-8 alkyl groups or (ii) one or two C2-8 acyl groups, (8) a sulfoximine group which may be substituted with one or two C1-8 alkyl groups, or (9) a tetrazolyl group. ring2 represents a 3- to 7-membered nitrogen-containing heteroring, m represents an integer from 0 to 6, n represents an integer from 0 to 5, and when m is 2 or greater, multiple R １ The R values ​​may be the same or different, and when n is 2 or greater, there may be multiple R values. ２ The hydrogen atoms may be the same or different, and each hydrogen atom may be a deuterium atom or a tritium atom. [2] Compounds represented by ] or pharmaceutically acceptable salts thereof, [2] General formula (V-1) [In the formula, all symbols have the same meaning as in [1] above, where each hydrogen atom may be a deuterium atom or a tritium atom.] The compound described in [1] above, or a pharmaceutically acceptable salt thereof, [3] L is (1)-O-(C2-7 alkyl), (2)-O-(C2-7 alkenyl), (3)-O-(C2-7 alkynyl), (4)-O-(C1-5 alkylene)-OCH ３ (5)-O-(C1-4 alkylene)-OCH ２ CH ３ (6)-CH ２ O-(C1-6 alkyl),(7)-CH ２ O-(C2-6 alkenyl),(8)-CH ２O-(C2-6 alkynyl),(9)-CH ２ CH ２ O-(C1-5 alkyl),(10)-CH ２ CH ２ O-(C2-5 alkenyl),(11)-CH ２ CH ２ O-(C2-5 alkynyl), (12)-S-(C2-7 alkyl), (13)-S-(C2-7 alkenyl), (14)-S-(C2-7 alkynyl), (15)-NR ６ -(C2-7 alkyl),(16)-NR ６ -(C2-7 alkenyl), (17)-NR ６ - (C2-7 alkynyl), (18) C3-8 alkyl group, (19) C3-8 alkenyl group, or (20) C3-8 alkynyl group, R ６ is a hydrogen atom or a C1-4 alkyl group, where the carbon atoms in each group may be substituted with 1 to 13 halogen atoms, the compound described in [1] or [2] above, or a pharmaceutically acceptable salt thereof; [4] L is a branched or linear chain group having 4 to 7 atoms in the main chain, the compound described in [1] or [2] above, or a pharmaceutically acceptable salt thereof; [5] L is (1)-O-(C3-6 alkyl), (2)-O-(C3-6 alkenyl), (3)-O-(C3-6 alkynyl), (4)-O-(C1-4 alkylene)-OCH ３ (5)-O-(C1-3 alkylene)-OCH ２ CH ３ (6)-CH ２ O-(C2-5 alkyl),(7)-CH ２ O-(C2-5 alkenyl),(8)-CH ２ O-(C2-5 alkynyl),(9)-CH ２ CH ２ O-(C1-4 alkyl),(10)-CH ２ CH ２ O-(C2-4 alkenyl),(11)-CH ２ CH ２ O-(C2-4 alkynyl), (12)-S-(C3-6 alkyl), (13)-S-(C3-6 alkenyl), (14)-S-(C3-6 alkynyl), (15)-NR６ -(C3-6 alkyl),(16)-NR ６ -(C3-6 alkenyl), (17)-NR ６ - (C3-6 alkynyl), (18) C4-7 alkyl group, (19) C4-7 alkenyl group, or (20) C4-7 alkynyl group, R ６ [1] or [2] above, or a pharmaceutically acceptable salt thereof, wherein represents a hydrogen atom or a C1-4 alkyl group, where the carbon atoms in each group may be substituted with 1 to 13 halogen atoms; [6] The compound according to any one of [1] to [5] above, or a pharmaceutically acceptable salt thereof, wherein ring2 is a 3-7 member nitrogen-containing saturated heterocycle (preferably azetidine, pyrrolidine, piperidine, or perhydroazepine); [7] General formula (V-2) [In the formula, L １ L is a branched or linear chain group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms, wherein the number of atoms in the main chain is 4 to 7, and the chain group may contain 1 to 3 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms, where L １ The carbon atoms inside may be substituted with 1 to 13 halogen atoms, ring2-1 represents a 3 to 7-membered nitrogen-containing saturated heteroring, m-1 represents an integer from 0 to 2, n-1 represents an integer from 0 to 2, and when m-1 is 2, multiple R １ They can be the same or different, and when n-1 is 2, there are multiple R ２ [1] The compounds described in [1] or [2] above, which are compounds represented by [2], or pharmaceutically acceptable salts thereof, [8] The compounds described in any one of [1] to [7] above, in which Z is a carboxyl group which may be substituted with one C1-8 alkyl group, or a tetrazolyl group, or pharmaceutically acceptable salts thereof, [9] L １However, (1)-O-(C3-6 alkyl), (2)-O-(C3-6 alkenyl), (3)-O-(C3-6 alkynyl), (4)-O-(C1-4 alkylene)-OCH ３ (5)-O-(C1-3 alkylene)-OCH ２ CH ３ (6)-CH ２ O-(C2-5 alkyl),(7)-CH ２ O-(C2-5 alkenyl),(8)-CH ２ O-(C2-5 alkynyl),(9)-CH ２ CH ２ O-(C1-4 alkyl),(10)-CH ２ CH ２ O-(C2-4 alkenyl),(11)-CH ２ CH ２ O-(C2-4 alkynyl), (12)-S-(C3-6 alkyl), (13)-S-(C3-6 alkenyl), (14)-S-(C3-6 alkynyl), (15)-NR ６ -(C3-6 alkyl),(16)-NR ６ -(C3-6 alkenyl), (17)-NR ６ - (C3-6 alkynyl), (18) C4-7 alkyl group, (19) C4-7 alkenyl group, or (20) C4-7 alkynyl group, R ６ represents a hydrogen atom or a C1-4 alkyl group, where the carbon atoms in each group may be substituted with 1 to 13 halogen atoms, the compound described in [7] or [8] above, or a pharmaceutically acceptable salt thereof,

[10] R １However, the compound according to any one of the above [1] to [9], which is a C1-4 alkyl group or a halogen atom, or a pharmaceutically acceptable salt thereof,

[11] The compound according to any one of the above [7] to

[10] , which is azetidine, pyrrolidine, piperidine, or perhydroazepine, or a pharmaceutically acceptable salt thereof,

[12] (1) 1-[((3R)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid, (2) 1-[((3S)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid, (3) 1-[((3S)-3-methyl-6-pentoxy-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid, (4) 1-[[(3S)-3-methyl-6-(4 (4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (5) 3-fluoro-1-[[(3S)-3-methyl-6-(3,4,4-trifluorobuta-3-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (6) 1-[[(3S)-3-methyl-6-(1,1,2,2,3,3,4,4,4-nonaduteriobutoxy)-3,4-dihydronaphthalene-2 (7) (3R)-1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]pyrrolidine-3-carboxylic acid, (8) 1-[[(3S)-3-methyl-6-((R)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (9) 1-[[(3S)-3-methyl-6- ((S)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (10)3-fluoro-1-[[(3S)-3-methyl-6-[(E)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (11)3-fluoro-1-{[(3S)-3-methyl-6-(3,3,3-trifluoropropoxy)-3,[1] or [2], which is 4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid, (12) cis-3-({1-[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydro-2-naphthalenyl]ethyl}amino)cyclobutanecarboxylic acid, or (13) 1-{[(3S)-3-methyl-6-(propoxymethyl)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid, or a pharmaceutically acceptable salt thereof,

[13] a pharmaceutical composition containing a compound represented by the general formula (V) described in [1], or a pharmaceutically acceptable salt thereof,

[14] S1P, ５ The pharmaceutical composition described in

[13] above, which is an activator,

[15] S1P ５ The pharmaceutical composition described in

[13] or

[14] above, which is an agent for the prevention and / or treatment of mediating diseases,

[16] S1P ５ The pharmaceutical composition according to

[15] , wherein the intervening disease is a neurodegenerative disease, an autoimmune disease, an infectious disease, or cancer.

[17] S1P ５ The pharmaceutical composition according to

[16] , wherein the intervening disease is a neurodegenerative disease, and the neurodegenerative disease is schizophrenia, Binswanger's disease, multiple sclerosis, neuromyelitis optica, Alzheimer's disease, cognitive impairment, amyotrophic lateral sclerosis, spinocerebellar degeneration, multiple system atrophy, Parkinson's disease, or Lewy body dementia;

[18] S1P, characterized by administering an effective amount of a compound represented by general formula (V) according to [1], or a pharmaceutically acceptable salt thereof, to a mammal. ５ Methods for the prevention and / or treatment of intermediary diseases,

[19] S1P ５ Compounds represented by general formula (V) as described in [1] above, or pharmaceutically acceptable salts thereof, used for the prevention and / or treatment of intermittent diseases,

[20] S1P ５ Use of a compound represented by general formula (V) as described in [1] above, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the prevention and / or treatment of a disease-mediated disease,

[21] General formula (I) [In the formula, L is a branched or linear chain group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms, the number of atoms in its main chain is 3 to 8, and the chain group may contain 1 to 3 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms, where the carbon atoms in L may be substituted with 1 to 13 halogen atoms, R １ R represents a C1-4 alkyl group, a C3-6 cycloalkyl group which may be substituted with a halogen, a C1-4 alkoxy group which may be substituted with a halogen, a C1-4 haloalkyl group, a halogen atom, or a hydroxyl group. ２ This represents a C1-4 alkyl group, a C1-4 alkoxy group which may be substituted with a halogen, a C1-4 haloalkyl group, a halogen atom, or a hydroxyl group. Z represents (1) a carboxyl group which may be substituted with one C1-8 alkyl group, (2) a hydroxyl group which may be substituted with one C1-8 alkyl group, (3) a hydroxamic acid group which may be substituted with one or two C1-8 alkyl groups, (4) a sulfonic acid group which may be substituted with one C1-8 alkyl group, (5) a boronic acid group which may be substituted with one or two C1-8 alkyl groups, (6) a carbamoyl group which may be substituted with (i) one or two C1-8 alkyl groups or (ii) one or two sulfonyl groups which may be substituted with a C1-4 alkyl group, (7) a sulfamoyl group which may be substituted with (i) one or two C1-8 alkyl groups or (ii) one or two C2-8 acyl groups, (8) a sulfoximine group which may be substituted with one or two C1-8 alkyl groups, or (9) a tetrazolyl group. ring1 represents a 4-7 member nitrogen-containing heteroring, m represents an integer from 0 to 6, n represents an integer from 0 to 5, and when m is 2 or greater, multiple R １ The R values ​​may be the same or different, and when n is 2 or greater, there may be multiple R values. ２[1] may be the same or different, where each hydrogen atom may be a deuterium atom or a tritium atom.

[22] The compound represented by

[21] or a pharmaceutically acceptable salt thereof,

[23] The compound according to

[21] or a pharmaceutically acceptable salt thereof, wherein L is a branched or linear chain group having 4 to 7 atoms in the main chain,

[24] The compound according to

[21] or

[22] or a pharmaceutically acceptable salt thereof, wherein ring1 is a 4 to 7-membered nitrogen-containing saturated heterocycle,

[25] General formula (I-1) [In the formula, L １ L is a branched or linear chain group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms, wherein the number of atoms in the main chain is 4 to 7, and the chain group may contain 1 to 3 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms, where L １ The carbon atoms inside may be substituted with 1 to 13 halogen atoms, ring1-1 represents a 4 to 7-membered nitrogen-containing saturated heteroring, m-1 represents an integer from 0 to 2, n-1 represents an integer from 0 to 2, and when m-1 is 2, multiple R １ They can be the same or different, and when n-1 is 2, there are multiple R ２

[21] The compound described in

[21] , which is the compound represented by

[21] , or a pharmaceutically acceptable salt thereof;

[25] The compound described in

[24] , which is a carboxyl group which may be substituted with one C1-8 alkyl group, or a pharmaceutically acceptable salt thereof;

[26] L １ However, -O-(C3-6 alkyl group), -O-(C3-6 alkenyl group), -O-(C3-6 alkynyl group), -O-(C2-4 alkylene group)-OCH ３ , or -O-(C2-3 alkylene group)-OCH ２ CH ３ Herein, the carbon atoms in each group may be substituted with 1 to 13 halogen atoms, the compounds described in

[24] or

[25] , or pharmaceutically acceptable salts thereof,

[27] R １

[24] to

[26] , which is a C1-4 alkyl group or a halogen atom, or a pharmaceutically acceptable salt thereof;

[28] A compound according to any of

[24] to

[27] , which is azetidine, pyrrolidine, piperidine, or perhydroazepine, or a pharmaceutically acceptable salt thereof;

[29] (1) 1-[((3R)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid, (2) 1-[((3S)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid, (3) 1-[((3S)-3-methyl-6-pentoxy-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid, (4 ) 1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (5) 3-fluoro-1-[[(3S)-3-methyl-6-(3,4,4-trifluorobut-3-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (6) 1-[[(3S)-3-methyl-6-(1,1,2, 2,3,3,4,4,4-nonaduteriobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (7)(3R)-1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]pyrrolidine-3-carboxylic acid, (8)1-[[(3S)-3-methyl-6-((R)-3,3,3-trifluoro-2-methylpro (poxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, (9) 1-[[(3S)-3-methyl-6-((S)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid, or (10) 3-fluoro-1-[[(3S)-3-methyl-6-[(E)-4,4,4-trifluorobuta-2-enoxy]-3,

[21] The compound described above, which is 4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid, or a pharmaceutically acceptable salt thereof;

[30] A pharmaceutical composition comprising the compound represented by general formula (I) described above, or a pharmaceutically acceptable salt thereof;

[31] S1P, ５ The pharmaceutical composition described in

[30] above, which is an activator,

[32] S1P ５ The pharmaceutical composition described in

[30] or

[31] above, which is an agent for the prevention and / or treatment of a disease,

[33] S1P ５ A pharmaceutical composition according to

[32] wherein the intervening disease is a neurodegenerative disease, an autoimmune disease, an infection, or cancer;

[34] A pharmaceutical composition according to

[33] wherein the neurodegenerative disease is schizophrenia, Binswanger's disease, multiple sclerosis, neuromyelitis optica, Alzheimer's disease, cognitive impairment, amyotrophic lateral sclerosis, spinocerebellar degeneration, multiple system atrophy, Parkinson's disease, or Lewy body dementia;

[35] S1P characterized by administering an effective amount of a compound represented by general formula (I) according to

[21] or a pharmaceutically acceptable salt thereof to a mammal. ５ Methods for the prevention and / or treatment of intermediary diseases,

[36] S1P ５ Compounds represented by general formula (I) as described in

[21] above, or pharmaceutically acceptable salts thereof, for the prevention and / or treatment of intermittent diseases, and

[37] S1P ５ Use of a compound represented by general formula (I) as described in

[21] above, or a pharmaceutically acceptable salt thereof, for the manufacture of an agent for the prevention and / or treatment of a disease-mediated disease.

[0147] The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

[0148] The solvents in parentheses in the sections on chromatography separation and TLC indicate the elution or developing solvent used, and the percentages represent volume ratios. The solvents in parentheses in the NMR section indicate the solvent used for the measurement.

[0149] The compound names used herein are generally named using computer programs that name compounds according to IUPAC rules, such as ACD / Name® from Advanced Chemistry Development, Lexichem Toolkit 1.4.2 from OpenEye Scientific Software, or ChemDraw® Ultra from PerkinElmer, or in accordance with IUPAC nomenclature.

[0150] LCMS was performed using the Waters i-class system under the following conditions: Column: YMC Triart C １８ 2.0 mm × 30 mm, 1.9 μm; flow rate: 1.0 mL / min; temperature: 30°C; mobile phase A: 0.1% TFA aqueous solution; mobile phase B: 0.1% TFA acetonitrile solution; gradient (ratio of mobile phase (A): mobile phase (B) indicated): 0 to 0.10 min: (95%:5%); 0.10 to 1.20 min: (95%:5%) to (5%:95%); 1.20 to 1.50 min: (5%:95%).

[0151] Example 1: 6-(benzyloxy)-3,4-dihydronaphthalene-1(2H)-one. 24.3 g of 6-hydroxy-3,4-dihydronaphthalene-1(2H)-one (CAS registration number: 3470-50-6) was dissolved in 160 mL of acetone. 29.4 mL of benzyl bromide and 31.1 g of potassium carbonate were added at room temperature, and the mixture was stirred at 40°C for 3.5 hours. Insoluble matter was filtered off, and the mixture was concentrated. The residue was washed with a tert-butyl methyl ether (MTBE)-hexane (1:4) mixed solvent to obtain the title compound (34.5 g) with the following physical properties: TLC: Rf 0.38 (hexane:ethyl acetate = 3:1).

[0152] Example 2: 7-(benzyloxy)-4-methyl-1,2-dihydronaphthalene. A solution of the compound prepared in Example 1 (34.5 g) in tetrahydrofuran (THF) (300 mL) was mixed with methylmagnesium bromide (3 mol / L diethyl ether solution, 55 mL) at 0°C and stirred at room temperature for 1 hour. The reaction mixture was cooled to 0°C and poured into an ice-saturated ammonium chloride aqueous solution. After adding 2 mol / L hydrochloric acid, the solution was stirred at room temperature for 3 hours. Extraction was performed with ethyl acetate, and the organic layer was sequentially washed with water and saturated brine. After drying over magnesium sulfate, the mixture was concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) to obtain the title compound (24.8 g) with the following physical properties: TLC: Rf 0.57 (hexane:ethyl acetate = 15:1).

[0153] Example 3: 6-(benzyloxy)-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde oxyphosphorus chloride (26.7 g) was mixed dropwise with N,N-dimethylformamide (DMF) (60 mL) at 0°C and stirred for 20 minutes. Then, a solution of the compound prepared in Example 2 (24.8 g) in methylene chloride (DCM) (60 mL) was slowly added dropwise and stirred at room temperature for 90 minutes. The reaction mixture was cooled to 0°C, poured into ice, stirred for 30 minutes, and then extracted with a hexane-ethyl acetate (1:2) mixed solvent. The organic layer was sequentially washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The resulting residue was washed with MTBE and dried to obtain the title compound (19.9 g) with the following physical properties: TLC: Rf 0.50 (hexane:ethyl acetate = 3:1).

[0154] Example 4: 6-hydroxy-1-methyl-3,4-dihydronaphthalene-2-carbaldehyde thioanisole (35 mL) was mixed with trifluoroacetic acid (140 mL) at 0°C, and the compound prepared in Example 3 (9.17 g) was gradually added. The mixture was stirred at room temperature for 4 hours. After pouring the reaction mixture onto ice, a 5 mol / L sodium hydroxide aqueous solution was added and the mixture was washed with MTBE. 1 mol / L hydrochloric acid was added to the aqueous layer and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and then concentrated. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1 → 2:1) to obtain the title compound (6.03 g) with the following physical properties. TLC: Rf 0.26 (hexane:ethyl acetate = 3:1).

[0155] Example 5: Methyl 1-((6-hydroxy-1-methyl-3,4-dihydronaphthalene-2-yl)methyl)azetidine-3-carboxylate A solution of the compound prepared in Example 4 (8.0 g) in DCM (340 mL) was mixed with methylazetidine-3-carboxylate hydrochloride (8.4 g) (CAS registration number: 100202-39-9) and diisopropylethylamine (9.6 mL) and stirred at room temperature for 30 minutes. Sodium triacetoxyborohydride (11.7 g) was added to the reaction mixture and stirred at room temperature for 16 hours. After adding saturated sodium bicarbonate aqueous solution to the reaction mixture, it was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (DIOL silica gel, hexane:ethyl acetate = 65:35 → 35:65) to obtain the title compound (10.6 g) having the following physical properties. 1 H-NMR (CDCl3): δ 7.11, 6.63, 6.57, 3.70, 3.58, 3.45-3.25, 2.60, 2.23, 2.07.

[0156] Example 6: Methyl 1-((1-methyl-6-(pentyloxy)-3,4-dihydronaphthalene-2-yl)methyl)azetidine-3-carboxylate A solution of the compound prepared in Example 5 (123 mg) in DMF (4 mL) was mixed with sodium hydride (60% in mineral oil, 17 mg) and stirred at room temperature under a nitrogen atmosphere for 15 minutes. 1-bromopentane (62 mg) was added to the reaction mixture and stirred for 6 hours. The reaction mixture was diluted with ethyl acetate, washed with water and 5% lithium chloride aqueous solution, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 8:2 → 2:8) to obtain the title compound (108 mg) having the following physical properties. 1 H-NMR (CDCl3): δ 7.18, 6.71, 6.68, 3.95, 3.70, 3.53, 3.35-3.27, 2.67, 2.26, 2.08, 1.78, 1.45-1.35, 0.93.

[0157] Example 7: 1-[(1-methyl-6-pentoxy-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid To a methanol (3 mL) solution of the compound (104 mg) prepared in Example 6, 2N sodium hydroxide aqueous solution (3 mL) was added, and the reaction mixture was stirred at room temperature for 2 hours. After concentration under reduced pressure, the resulting residue was purified by silica gel column chromatography (DCM: (DCM: methanol: concentrated ammonium hydroxide aqueous solution = 80:18:2) = 9:1 → 0:10) to obtain the title compound (84 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ7.16, 6.74, 6.71, 3.94, 3.40, 3.19, 2.59, 2.16, 2.02, 1.70, 1.36, 0.90; LCMS: Retention time 0.91 minutes.

[0158] Examples 7(1) to 7(10) By using the compound produced in Example 4 or an equivalent aldehyde derivative, methylazetidine-3-carboxylate hydrochloride, and an alkyl halide equivalent to 1-bromopentane, the same reaction as in Example 5 → Example 6 → Example 7 was performed, or by using the compound produced in Example 4 or an equivalent aldehyde derivative, methylazetidine-3-carboxylate hydrochloride, and an alcohol equivalent to 1-butanol, the same reaction as in Example 5 → Example 8 → Example 7 described below was performed, to obtain example compounds having the following physical properties.

[0159] Example 7(1): 1-[(6-butoxy-1-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylate ammonia salt 1 LCMS: Retention time 0.90 minutes.

[0160] Example 7(2): 1-[[1-methyl-6-[(2S)-pentan-2-yl]oxy-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (Acetic Acid-d4): δ 7.29, 6.76, 6.72, 4.64, 4.43-4.41, 4.18, 3.83-3.80, 2.71, 2.30, 2.21, 1.72-1.68, 1.59-1.37, 1.28, 0.94; LCMS: Retention time 0.93 minutes.

[0161] Example 7(3): 1-[[6-(1,1,2,2,3,3,3-heptaduteriopropoxy)-1-methyl-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.16, 6.74, 6.71, 3.40, 3.18, 2.59, 2.16, 2.02; LCMS: Retention time 0.79 minutes.

[0162] Example 7(4): 1-[[1-methyl-6-(2,2,3,3-tetrafluoropropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.21, 6.87, 6.86, 6.67, 4.56, 3.60-3.00, 2.61, 2.18, 2.03; LCMS: Retention time 0.79 minutes.

[0163] Example 7(5): 1-[[1-methyl-6-(3,4,4-trifluorobuta-3-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.18, 6.77, 6.75, 4.14, 3.60-3.00, 2.80, 2.60, 2.17, 2.03; LCMS: Retention time 0.82 minutes.

[0164] Example 7(6): 1-[[1-methyl-6-(3,3,4,4,4-pentaduteriobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.16, 6.74, 6.71, 3.94, 3.40, 3.19, 2.59, 2.16, 2.02, 1.66; LCMS: Retention time 0.85 minutes.

[0165] Example 7(7): 1-[[1-methyl-6-(1,1,2,2,3,3,4,4,4-nonaduteriobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.16, 6.74, 6.71, 3.40, 3.19, 2.59, 2.16, 2.02; LCMS: Retention time 0.85 minutes.

[0166] Example 7(8): 1-[[6-[(E)-buta-2-enoxy]-1-methyl-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 7.18, 6.75, 6.73, 5.83, 5.68, 4.46, 3.60-3.00, 2.60, 2.16, 2.04, 1.70; LCMS: Retention time 0.81 min.

[0167] Example 7(9): 1-[(6-butoxy-1-ethyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (CDCl3): δ 7.24, 6.73, 6.68, 4.35, 4.05, 3.96, 3.91, 3.52-3.35, 2.66, 2.30, 1.76, 1.48, 1.11, 0.97; LCMS: Retention time 0.89 minutes.

[0168] Example 7(10): 1-[[6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.72, 6.69, 6.28, 4.00, 3.20, 3.07, 2.68, 2.13, 1.91; LCMS: Retention time 0.82 minutes.

[0169] Example 8: 6-Butoxy-3,4-dihydronaphthalene-1(2H)-one A solution of 6-hydroxy-3,4-dihydronaphthalene-1(2H)-one (CAS registration number: 3470-50-6) (2.0 g) in THF (40 mL) was mixed with 1-butanol (2.3 mL), triphenylphosphine (6.5 g), and a toluene solution of 2.2 mol / L diethyl azodicarboxylate, and the mixture was stirred at room temperature for 5 hours. After concentrating the reaction mixture, the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 8:2) to obtain the title compound (2.7 g) having the following physical properties. 1 H-NMR (CDCl3): δ 8.00, 6.81, 6.70, 4.01, 2.91, 2.60, 2.11, 1.78, 1.49, 0.98.

[0170] Example 9: 1-bromo-6-butoxy-3,4-dihydronaphthalene-2-carbaldehyde A chloroform (12 mL) / DMF (1.37 mL) solution of the compound prepared in Example 8 (770 mg) was cooled on ice, and tribromide phosphate (0.83 mL) was added and the mixture was stirred at room temperature for 72 hours. Saturated sodium bicarbonate aqueous solution was added to the reaction mixture and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 7:3) to obtain the title compound (621 mg) having the following physical properties. 1 H-NMR (CDCl3): δ 10.20, 7.82, 6.82, 6.72, 4.02, 2.80, 2.61, 1.79, 1.50, 0.99.

[0171] Example 10: 6-Butoxy-1-cyclopropyl-3,4-dihydronaphthalene-2-carbaldehyde A solution of the compound prepared in Example 9 (320 mg) in toluene (5 mL) was mixed with cyclopropylboric acid (133 mg), 2 mol / L potassium phosphate aqueous solution (1.6 mL), tricyclohexylphosphine (0.064 mL), and palladium acetate (23 mg), and the mixture was stirred at 90°C for 5 hours. The reaction mixture was filtered through Celite (trade name), and the filtrate was extracted twice with ethyl acetate. The organic layer was washed with water and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 8:2) to obtain the title compound (271 mg) having the following physical properties. 1 H-NMR (CDCl3): δ 10.66, 7.78, 6.80, 6.71, 4.00, 2.67, 2.47, 1.89, 1.78, 1.50, 1.15, 0.98, 0.59.

[0172] Example 11: 1-[(6-butoxy-1-cyclopropyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid The compound prepared in Example 10 (270 mg) and methylazetidine-3-carboxylate hydrochloride (197 mg) were subjected to the same reaction as in Example 5 → Example 7 to obtain the title compound (92 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 7.44, 6.74, 6.67, 3.94, 3.84-2.91, 2.14, 1.67, 1.54, 1.42, 0.96-0.91, 0.24; LCMS: Retention time 0.96 minutes.

[0173] Example 12: 6-Methoxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde 1 g of 6-methoxy-3-methyl-3,4-dihydronaphthalene-1(2H)-one (CAS registration number: 5563-21-3) was added to a methanol (100 mL) solution at 0°C with 398 mg of sodium borohydride. The reaction solution was heated to room temperature and stirred for 2 hours, then aqueous ammonium chloride solution was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation. The resulting residue was crudely purified by silica gel column chromatography (hexane:ethyl acetate = 10:1) and used directly in the next reaction. 2.2 g of phosphorus oxychloride was added to a DMF (100 mL) solution of the obtained crudely purified product. The reaction solution was heated to 60°C and stirred for 8 hours. The reaction solution was then poured into ice water and stirred for 5 minutes, after which the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:1 → 5:1) to obtain the title compound (299 mg) with the following physical properties. 1 H-NMR (CDCl3): δ 9.57, 7.30-7.24, 6.82-6.78, 3.85, 3.08, 2.65, 0.92.

[0174] Example 13: 6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde A solution of the compound prepared in Example 12 (299 mg) in dichloromethane (100 mL) was to which boron tribromide (815 mg) was added dropwise at 0°C. After stirring at 0°C for 3 hours, the reaction solution was poured into ice water and stirred for 5 minutes, after which the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed by distillation. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1) to obtain the title compound (200 mg) having the following physical properties. 1 H-NMR (CDCl3): δ 9.57, 7.18, 6.72, 3.08, 2.60, 0.94.

[0175] Example 14: (R)-6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde The compound prepared in Example 13 was optically resolved using HPLC (column used: Daicel Corporation CHIRALCEL OJ-H (4.6 mm I.D. × 250 mm L), mobile phase: n-hexane:2-propanol = 80:20, flow rate: 1 mL / min, temperature: 40°C, wavelength: 245 nm), and the title compound was obtained as the first peak (retention time approximately 6.9 minutes).

[0176] Example 14(1): (S)-6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde. Optical resolution of Example 14 yielded the title compound as the second peak (retention time approximately 8.1 minutes).

[0177] Example 15: 1-[((3S)-3-methyl-6-pentoxy-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid Using the compound prepared in Example 14(1) (2.5 g) and methylazetidine-3-carboxylate hydrochloride (2.6 g), the reaction was carried out in the same manner as in Example 5 to obtain (S)-methyl 1-((6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl)azetidine-3-carboxylate (3.8 g). Using (S)-methyl 1-((6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl)azetidine-3-carboxylate (30 mg) and 1-pentanol (13.8 mg), the reaction was carried out in the same manner as in Example 8 → Example 7 to obtain the title compound (19.5 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 6.97, 6.71, 6.68, 6.26, 3.92, 3.60-3.00, 2.84, 2.34, 1.68, 1.45-1.26, 0.89, 0.84; LCMS: Retention time 0.91 minutes.

[0178] Examples 15(1) to (87) The following example compounds were obtained by using the compound produced in Example 14 or Example 14(1), methylazetidine-3-carboxylate hydrochloride or an equivalent amine derivative, and an alkyl halide equivalent to 1-bromopentane, and subjecting them to the same reaction as in Example 5 → Example 6 → Example 7, or by using the compound produced in Example 14 or Example 14(1), methylazetidine-3-carboxylate hydrochloride or an equivalent amine derivative, and an alcohol equivalent to 1-butanol, and subjecting them to the same reaction as in Example 5 → Example 8 → Example 7.

[0179] Example 15(1): 1-[((3R)-3-methyl-6-pentoxy-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.71, 6.68, 6.26, 3.92, 3.60-3.00, 2.84, 2.34, 1.68, 1.45-1.26, 0.89, 0.84; LCMS: Retention time 0.91 minutes.

[0180] Example 15(2): 1-[((3S)-6-hexoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.71, 6.67, 6.22, 3.92, 3.42, 3.21, 2.98, 2.84, 2.33, 1.68, 1.41, 1.31, 0.86; LCMS: Retention time 0.97 minutes.

[0181] Example 15(3): 1-[((3R)-6-hexoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.71, 6.67, 6.22, 3.92, 3.42, 3.21, 2.98, 2.84, 2.33, 1.68, 1.41, 1.31, 0.86; LCMS: Retention time 0.97 minutes.

[0182] Example 15(4): 1-[[(3S)-3-methyl-6-(3-methylpentoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.72, 6.69, 6.25, 3.96, 3.65-3.00, 2.85, 2.34, 1.72, 1.59-1.47, 1.38, 1.18, 0.90, 0.88-0.83; LCMS: Retention time 0.95 minutes.

[0183] Example 15(5): 1-[[(3R)-3-methyl-6-(3-methylpentoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.72, 6.69, 6.25, 3.96, 3.65-3.00, 2.85, 2.34, 1.72, 1.59-1.47, 1.38, 1.18, 0.90, 0.88-0.83; LCMS: Retention time 0.95 minutes.

[0184] Example 15(6): 1-[((3S)-3-methyl-6-propoxy-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.71, 6.68, 6.24, 3.89, 3.60-2.90, 2.84, 2.32, 1.70, 0.96, 0.85; LCMS: Retention time 0.79 minutes.

[0185] Example 15(7): 1-[((3R)-3-methyl-6-propoxy-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.71, 6.68, 6.24, 3.89, 3.60-2.90, 2.84, 2.32, 1.70, 0.96, 0.85; LCMS: Retention time 0.79 minutes.

[0186] Example 15(8): 1-[((3S)-6-heptoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.71, 6.68, 6.25, 3.92, 3.60-3.00, 2.84, 2.33, 1.68, 1.39, 1.35-1.20, 0.87, 0.85; LCMS: Retention time 1.02 minutes.

[0187] Example 15(9): 1-[((3R)-6-heptoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.71, 6.68, 6.25, 3.92, 3.60-3.00, 2.84, 2.33, 1.68, 1.39, 1.35-1.20, 0.87, 0.85; LCMS: Retention time 1.02 minutes.

[0188] Example 15(10): 1-[[(3S)-3-methyl-6-[(2R)-pentan-2-yl]oxy-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.95, 6.68, 6.66, 6.22, 4.40, 3.60-2.95, 2.83, 2.32, 1.61, 1.50, 1.45-1.28, 1.20, 0.89, 0.85; LCMS: Retention time 0.88 minutes.

[0189] Example 15(11): 1-[[(3R)-3-methyl-6-[(2R)-pentan-2-yl]oxy-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.95, 6.68, 6.66, 6.22, 4.40, 3.60-2.95, 2.83, 2.32, 1.61, 1.50, 1.45-1.28, 1.20, 0.89, 0.85; LCMS: Retention time 0.88 minutes.

[0190] Example 15(12): 1-[[(3S)-3-methyl-6-[(2S)-pentan-2-yl]oxy-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (CDCl3): δ 6.97, 6.70-6.60, 6.45, 4.46-4.22, 4.15-3.97, 3.92, 3.60-3.30, 3.02, 2.61-2.47, 1.69, 1.59-1.31, 1.28, 0.93; LCMS: retention time 0.88 minutes.

[0191] Example 15 (13): 1-[[(3R)-3-methyl-6-[(2S)-pentan-2-yl]oxy-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid s 1 H-NMR (CDCl3): δ 6.97, 6.70-6.60, 6.45, 4.46-4.22, 4.15-3.97, 3.92, 3.60-3.30, 3.02, 2.61-2.47, 1.69, 1.59-1.31, 1.28, 0.93; LCMS: retention time 0.88 minutes.

[0192] Example 15(14): 1-[[(3S)-3-methyl-6-(3-methylbutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid1 H-NMR (DMSO-d6): δ 6.96, 6.72, 6.69, 6.23, 3.96, 3.60-3.00, 2.84, 2.33, 1.77, 1.59, 0.93, 0.85; LCMS: Retention time 0.91 min.

[0193] Example 15 (15): 1-[[(3R)-3-methyl-6-(3-methylbutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.72, 6.69, 6.23, 3.96, 3.60-3.00, 2.84, 2.33, 1.77, 1.59, 0.93, 0.85; LCMS: Retention time 0.91 min.

[0194] Example 15(16): 1-[((3S)-6-hexane-2-yloxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.95, 6.68, 6.67, 6.23, 4.39, 3.60-2.97, 2.83, 2.33, 1.62, 1.52, 1.43-1.25, 1.20, 0.89-0.83; LCMS: Retention time 0.94 minutes.

[0195] Example 15(17): 1-[((3R)-6-hexane-2-yloxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.95, 6.68, 6.67, 6.23, 4.39, 3.60-2.97, 2.83, 2.33, 1.62, 1.52, 1.43-1.25, 1.20, 0.89-0.83; LCMS: Retention time 0.94 minutes.

[0196] Example 15(18): 1-[[(3S)-3-methyl-6-(2-methylpentoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.97, 6.72, 6.68, 6.25, 3.80, 3.72, 3.60-2.97, 2.85, 2.34, 1.86, 1.48-1.24, 1.18, 0.96, 0.88, 0.85; LCMS: Retention time 0.96 minutes.

[0197] Example 15(19): 1-[[(3R)-3-methyl-6-(2-methylpentoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.72, 6.68, 6.25, 3.80, 3.72, 3.60-2.97, 2.85, 2.34, 1.86, 1.48-1.24, 1.18, 0.96, 0.88, 0.85; LCMS: Retention time 0.96 minutes.

[0198] Example 15(20): 1-[[(3S)-3-methyl-6-(4-methylpentoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.71, 6.68, 6.26, 3.92, 3.60-3.01, 2.85, 2.33, 1.69, 1.57, 1.29, 0.89, 0.85; LCMS: Retention time 0.95 minutes.

[0199] Example 15(21): 1-[[(3R)-3-methyl-6-(4-methylpentoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.71, 6.68, 6.26, 3.92, 3.60-3.01, 2.85, 2.33, 1.69, 1.57, 1.29, 0.89, 0.85; LCMS: Retention time 0.95 minutes.

[0200] Example 15(22): 1-[[(3S)-6-(2,2-dimethylpropoxy)-3-methyl-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.96, 6.72, 6.68, 6.21, 3.59, 3.21, 2.96, 2.84, 2.55, 2.32, 0.99, 0.84; LCMS: Retention time 0.92 minutes.

[0201] Example 15(23): 1-[[(3R)-6-(2,2-dimethylpropoxy)-3-methyl-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.72, 6.68, 6.21, 3.59, 3.21, 2.96, 2.84, 2.55, 2.32, 0.99, 0.84; LCMS: Retention time 0.92 minutes.

[0202] Example 15 (24): 1-[[(3S)-3-methyl-6-[(2S)-4-methylpentan-2-yl]oxy-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.68, 6.66, 6.22, 4.46, 3.60-2.90, 2.83, 2.33, 1.73, 1.59, 1.33, 1.19, 0.91, 0.88, 0.85; LCMS: Retention time 0.93 minutes.

[0203] Example 15 (25): 1-[[(3R)-3-methyl-6-[(2S)-4-methylpentan-2-yl]oxy-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.69, 6.67, 6.22, 4.46, 3.60-2.90, 2.84, 2.33, 1.73, 1.59, 1.34, 1.20, 0.91, 0.88, 0.85; LCMS: Retention time 0.93 minutes.

[0204] Example 15 (26): 1-[[(3S)-6-(3,3-dimethylbutoxy)-3-methyl-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.95, 6.71, 6.68, 6.22, 3.98, 3.24, 3.02, 2.84, 2.55, 2.33, 1.63, 0.95, 0.84; LCMS: retention time 0.94 minutes.

[0205] Example 15(27): 1-[[(3R)-6-(3,3-dimethylbutoxy)-3-methyl-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.95, 6.71, 6.68, 6.22, 3.98, 3.24, 3.02, 2.84, 2.55, 2.33, 1.63, 0.95, 0.84; LCMS: retention time 0.94 minutes.

[0206] Example 15(28): 1-[[(3S)-3-methyl-6-[(2R)-4-methylpentan-2-yl]oxy-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.69, 6.67, 6.22, 4.46, 3.60 - 2.90, 2.84, 2.33, 1.73, 1.59, 1.34, 1.20, 0.91, 0.88, 0.85; LCMS: retention time 0.93 minutes.

[0207] Example 15(29): 1-[[(3R)-3-methyl-6-[(2R)-4-methylpentan-2-yl]oxy-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.68, 6.66, 6.22, 4.46, 3.60 - 2.90, 2.83, 2.33, 1.73, 1.59, 1.33, 1.19, 0.91, 0.88, 0.85; LCMS: retention time 0.93 minutes.

[0208] Example 15(30): 1-(((3S)-6-hexan-3-yloxy-3-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.95, 6.69, 6.67, 6.23, 4.24, 3.60 - 2.90, 2.84, 2.33, 1.56, 1.34, 0.88; LCMS: retention time 0.94 minutes.

[0209] Example 15(31): 1 - [((3R)-6-hexan-3-yloxy-3-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.95, 6.69, 6.67, 6.23, 4.24, 3.60 - 2.90, 2.84, 2.33, 1.56, 1.34, 0.88; LCMS: retention time 0.94 minutes.

[0210] Example 15(32): 1 - [[(3S)-3-methyl-6-(2-methylhexan-3-yloxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.93, 6.69, 6.68, 6.21, 4.12, 3.60 - 2.90, 2.83, 2.32, 1.91, 1.51, 1.39, 1.29, 0.91, 0.88, 0.86; LCMS: retention time 0.98 minutes.

[0211] Example 15(33): 1 - [[(3R)-3-methyl-6-(2-methylhexan-3-yloxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.93, 6.69, 6.68, 6.21, 4.12, 3.60 - 2.90, 2.83, 2.32, 1.91, 1.51, 1.39, 1.29, 0.91, 0.88, 0.86; LCMS: retention time 0.98 minutes.

[0212] Example 15(34): 1 - [[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.95, 6.71, 6.68, 6.20, 3.98, 3.46-3.36, 3.24-3.12, 2.96, 2.82, 2.49, 2.39, 2.31, 1.89, 0.83; LCMS: Retention time 0.85 minutes.

[0213] Example 15 (35): 1-[[(3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.95, 6.71, 6.68, 6.20, 3.98, 3.46-3.36, 3.24-3.12, 2.96, 2.82, 2.49, 2.39, 2.31, 1.89, 0.83; LCMS: Retention time 0.85 minutes.

[0214] Example 15 (36): 1-[[(3S)-6-[(E)-buta-2-enoxy]-3-methyl-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.71, 6.68, 6.23, 5.82, 5.68, 4.44, 3.90-2.95, 2.84, 2.33, 1.70, 0.85; LCMS: Retention time 0.82 minutes.

[0215] Example 15 (37): 1-[[(3R)-6-[(E)-buta-2-enoxy]-3-methyl-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.71, 6.68, 6.23, 5.82, 5.68, 4.44, 3.90-2.95, 2.84, 2.33, 1.70, 0.85; LCMS: Retention time 0.82 minutes.

[0216] Example 15 (38): 1-[[(3S)-3-methyl-6-(3-methylbuta-2-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.96, 6.72, 6.68, 6.23, 5.41, 4.48, 3.80-2.95, 2.84, 2.33, 1.74, 1.70, 0.85; LCMS: Retention time 0.85 minutes.

[0217] Example 15 (39): 1-[[(3R)-3-methyl-6-(3-methylbuta-2-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.96, 6.72, 6.68, 6.23, 5.41, 4.48, 3.80-2.95, 2.84, 2.33, 1.74, 1.70, 0.85; LCMS: Retention time 0.85 minutes.

[0218] Example 15 (40): 1-[[(3S)-3-methyl-6-(3,4,4-trifluorobuta-3-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.99, 6.74, 6.71, 6.24, 4.13, 3.75-2.95, 2.84, 2.78, 2.33, 0.84; LCMS: Retention time 0.83 minutes.

[0219] Example 15 (41): 1-[[(3R)-3-methyl-6-(3,4,4-trifluorobuta-3-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.99, 6.74, 6.71, 6.24, 4.13, 3.75-2.95, 2.84, 2.78, 2.33, 0.84; LCMS: Retention time 0.83 minutes.

[0220] Example 15 (42): 1-[((3S)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]-3-fluoroazetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.99, 6.72, 6.65, 6.31, 3.93, 3.85-3.05, 2.87, 2.37, 1.68, 1.48, 0.92, 0.85; LCMS: Retention time 0.84 minutes.

[0221] Example 15 (43): 1-[((3R)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]-3-fluoroazetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.99, 6.72, 6.65, 6.31, 3.93, 3.85-3.05, 2.87, 2.37, 1.68, 1.48, 0.92, 0.85; LCMS: Retention time 0.84 minutes.

[0222] Example 15 (44): 3-Fluoro-1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.01, 6.74, 6.71, 6.31, 4.01, 3.94-3.01, 2.87, 2.40, 1.92, 0.85; LCMS: Retention time 0.83 minutes.

[0223] Example 15 (45): 3-Fluoro-1-[[(3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.01, 6.74, 6.71, 6.31, 4.01, 3.94-3.01, 2.87, 2.40, 1.92, 0.85; LCMS: Retention time 0.83 minutes.

[0224] Example 15 (46): 1-[[(3S)-6-[(E)-buta-2-enoxy]-3-methyl-3,4-dihydronaphthalene-2-yl]methyl]-3-fluoroazetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.99, 6.72, 6.69, 6.29, 5.83, 5.68, 4.44, 3.85-3.00, 2.87, 2.40-2.34, 1.70, 0.86; LCMS: Retention time 0.79 minutes.

[0225] Example 15 (47): 1-[[(3R)-6-[(E)-buta-2-enoxy]-3-methyl-3,4-dihydronaphthalene-2-yl]methyl]-3-fluoroazetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.99, 6.72, 6.69, 6.29, 5.83, 5.68, 4.44, 3.85-3.00, 2.87, 2.40-2.34, 1.70, 0.86; LCMS: Retention time 0.79 minutes.

[0226] Example 15 (48): 1-[((3S)-6-buta-2-inoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]-3-fluoroazetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.01, 6.76-6.71, 6.30, 4.70, 3.84-2.98, 2.87, 2.42-2.34, 1.83, 0.86; LCMS: Retention time 0.74 minutes.

[0227] Example 15 (49): 1-[((3R)-6-buta-2-inoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]-3-fluoroazetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.01, 6.76-6.71, 6.30, 4.70, 3.84-2.98, 2.87, 2.42-2.34, 1.83, 0.86; LCMS: Retention time 0.74 minutes.

[0228] Example 15 (50): 3-fluoro-1-[[(3S)-3-methyl-6-(3-methylbuta-2-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 6.99, 6.73, 6.69, 6.29, 5.41, 4.49, 3.85-3.04, 2.87, 2.41-2.34, 1.74, 1.70, 0.86; LCMS: retention time 0.84 min.

[0229] Example 15 (51): 3-Fluoro-1-[[(3R)-3-methyl-6-(3-methylbuta-2-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.99, 6.73, 6.69, 6.29, 5.41, 4.49, 3.85-3.04, 2.87, 2.41-2.34, 1.74, 1.70, 0.86; LCMS: Retention time 0.84 minutes.

[0230] Example 15 (52): 3-Fluoro-1-[[(3S)-3-methyl-6-(3,4,4-trifluorobuta-3-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.01, 6.75, 6.72, 6.29, 4.13, 3.82-3.08, 2.87, 2.78, 2.41-2.34, 0.85; LCMS: Retention time 0.81 min.

[0231] Example 15 (53): 3-Fluoro-1-[[(3R)-3-methyl-6-(3,4,4-trifluorobuta-3-enoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.01, 6.75, 6.72, 6.29, 4.13, 3.82-3.08, 2.87, 2.78, 2.41-2.34, 0.85; LCMS: Retention time 0.81 min.

[0232] Example 15 (54): 3-Fluoro-1-[[(3S)-3-methyl-6-[(2S)-pentan-2-yl]oxy-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.98, 6.69, 6.67, 6.29, 4.41, 3.85-2.98, 2.86, 2.41-2.34, 1.61, 1.49, 1.44-1.31, 1.20, 0.89, 0.86; LCMS: Retention time 0.87 minutes.

[0233] Example 15 (55): 3-Fluoro-1-[[(3R)-3-methyl-6-[(2S)-pentan-2-yl]oxy-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.98, 6.69, 6.67, 6.29, 4.41, 3.85-2.98, 2.86, 2.41-2.34, 1.61, 1.49, 1.44-1.31, 1.20, 0.89, 0.86; LCMS: Retention time 0.87 minutes.

[0234] Example 15 (56): 1-[((3S)-6-ethoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]-3-fluoroazetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.98, 6.71, 6.68, 6.29, 3.99, 3.60-2.97, 2.87, 2.38, 1.30, 0.86; LCMS: Retention time 0.71 min.

[0235] Example 15 (57): 1-[((3R)-6-ethoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]-3-fluoroazetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.98, 6.71, 6.68, 6.29, 3.99, 3.60-2.97, 2.87, 2.38, 1.30, 0.86; LCMS: Retention time 0.71 min.

[0236] Example 15(58): 3-Fluoro-1-(((3S)-3-methyl-6-propoxy-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylic acid 1 H-NMR(DMSO-d6): δ 6.99, 6.72, 6.69, 6.31, 3.89, 3.60 - 3.00, 2.87, 2.38, 1.70, 0.96, 0.86; LCMS: retention time 0.78 minutes.

[0237] Example 15(59): 3-Fluoro-1-(((3R)-3-methyl-6-propoxy-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylic acid 1 H-NMR(DMSO-d6): δ 6.99, 6.72, 6.69, 6.31, 3.89, 3.60 - 3.00, 2.87, 2.38, 1.70, 0.96, 0.86; LCMS: retention time 0.78 minutes.

[0238] Example 15(60): 3-Fluoro-1-(((3S)-3-methyl-6-propoxy-3,4-dihydronaphthalen-2-yl)methyl)pyrrolidine-3-carboxylic acid 1 H-NMR(DMSO-d6): δ 6.96, 6.72, 6.68, 6.29, 3.90, 3.70 - 3.10, 2.89, 2.36, 2.10, 1.70, 0.97, 0.88; LCMS: retention time 0.80 minutes.

[0239] Example 15(61): 3-Fluoro-1-(((3R)-3-methyl-6-propoxy-3,4-dihydronaphthalen-2-yl)methyl)pyrrolidine-3-carboxylic acid 1 H-NMR(DMSO-d6): δ 6.96, 6.72, 6.68, 6.29, 3.90, 3.70 - 3.10, 2.89, 2.36, 2.10, 1.70, 0.97, 0.88; LCMS: retention time 0.80 minutes.

[0240] Example 15(62): 1-(((3S)-3-methyl-6-((2R)-2-methylbutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 7.03, 6.75, 6.73, 6.41, 3.81, 3.74, 3.10, 2.89, 1.81-1.75,1.62-1.56, 1.53-1.47, 1.43-1.38, 1.37-1.33, 1.28-1.20, 1.18, 0.96, 0.90, 0.85; LCMS: retention time 0.93 minutes.

[0241] Example 15 (63): 1-[[(3R)-3-methyl-6-[(2R)-2-methylbutoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.03, 6.76, 6.73, 6.42, 3.82, 3.73, 3.09, 2.89, 2.55, 1.82-1.75, 1.62-1.57,1.52-1.47, 1.45-1.33, 1.26-1.19, 1.18, 0.96, 0.90, 0.88, 0.85; LCMS: retention time 0.92 minutes.

[0242] Example 15 (64): 1-[[(3S)-3-methyl-6-[(2S)-2-methylbutoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.03, 6.76, 6.73, 6.42, 3.82, 3.73, 3.09, 2.89, 2.55, 1.82-1.75, 1.62-1.57,1.52-1.47, 1.45-1.33, 1.26-1.19, 1.18, 0.96, 0.90, 0.88, 0.85; LCMS: retention time 0.92 minutes.

[0243] Example 15 (65): 1-[[(3R)-3-methyl-6-[(2S)-2-methylbutoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 7.03, 6.75, 6.73, 6.41, 3.81, 3.74, 3.10, 2.89, 1.81-1.75,1.62-1.56, 1.53-1.47, 1.43-1.38, 1.37-1.33, 1.28-1.20, 1.18, 0.96, 0.90, 0.85; LCMS: retention time 0.93 minutes.

[0244] Example 15 (66): 3-Fluoro-1-[[(3S)-3-methyl-6-(2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.00, 6.73, 6.69, 6.29, 3.71, 3.10, 2.88, 2.02-1.95, 1.18, 0.97, 0.85; LCMS: Retention time 0.84 minutes.

[0245] Example 15 (67): 3-Fluoro-1-[[(3R)-3-methyl-6-(2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.00, 6.73, 6.69, 6.29, 3.71, 3.10, 2.88, 2.02-1.95, 1.18, 0.97, 0.85; LCMS: Retention time 0.84 minutes.

[0246] Example 15 (68): 1-[[(3S)-3-methyl-6-(2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.04, 6.75, 6.72, 6.43, 3.72, 3.09, 2.89, 2.54, 2.03-1.95, 1.18, 0.96, 0.85; LCMS: Retention time 0.86 minutes.

[0247] Example 15 (69): 1-[[(3R)-3-methyl-6-(2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1H-NMR (DMSO-d6): δ 7.04, 6.75, 6.72, 6.43, 3.72, 3.09, 2.89, 2.54, 2.03-1.95, 1.18, 0.96, 0.85; LCMS: Retention time 0.86 minutes.

[0248] Example 15 (70): 1-[[(3S)-3-methyl-6-(1,1,2,2,3,3,4,4,4-nonaduteriobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (CD3OD): δ 6.97, 6.72-6.65, 6.37, 3.94, 3.87, 3.71, 3.62, 3.45, 3.38-3.29, 2.98, 2.59, 2.37, 0.92; LCMS: Retention time 0.85 minutes.

[0249] Example 15 (71): 1-[[(3R)-3-methyl-6-(1,1,2,2,3,3,4,4,4-nonaduteriobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (CD3OD): δ 6.97, 6.72-6.65, 6.37, 3.94, 3.87, 3.71, 3.62, 3.45, 3.38-3.29, 2.98, 2.59, 2.37, 0.92; LCMS: Retention time 0.85 minutes.

[0250] Example 15 (72): (3R)-1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]pyrrolidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.75, 6.70, 6.28, 4.01, 3.60-3.10, 3.00-2.80, 2.60-2.35, 2.05-1.85, 0.86; LCMS: Retention time 0.84 minutes.

[0251] Example 15 (73): (3R)-1-[[(3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]pyrrolidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.75, 6.70, 6.28, 4.01, 3.60-3.10, 3.00-2.80, 2.60-2.35, 2.05-1.85, 0.86; LCMS: Retention time 0.84 minutes.

[0252] Example 15 (74): (3S)-3-fluoro-1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]pyrrolidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.75, 6.70, 6.31, 4.01, 3.65-2.80, 2.60-2.30, 2.20-2.03, 1.91, 0.88; LCMS: Retention time 0.84 minutes.

[0253] Example 15 (75): (3S)-3-fluoro-1-[[(3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]pyrrolidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.97, 6.75, 6.70, 6.31, 4.01, 3.65-2.80, 2.60-2.30, 2.20-2.03, 1.91, 0.88; LCMS: Retention time 0.84 minutes.

[0254] Example 15 (76): 1-[[(3S)-3-methyl-6-[(E)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.00, 6.79, 6.75-6.70, 6.27-6.20, 4.72, 3.60-3.24, 2.86, 2.33, 0.85; LCMS: Retention time 0.84 minutes.

[0255] Example 15 (77): 1-[[(3R)-3-methyl-6-[(E)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.00, 6.79, 6.75-6.70, 6.27-6.20, 4.72, 3.60-3.24, 2.86, 2.33, 0.85; LCMS: Retention time 0.84 minutes.

[0256] Example 15 (78): 1-[[(3S)-3-methyl-6-[(Z)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.00, 6.79, 6.76-6.70, 6.25-6.21, 4.72, 2.86, 2.52, 2.35, 0.85; LCMS: Retention time 0.85 minutes.

[0257] Example 15 (79): 1-[[(3R)-3-methyl-6-[(Z)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.00, 6.79, 6.76-6.70, 6.25-6.21, 4.72, 2.86, 2.52, 2.35, 0.85; LCMS: Retention time 0.85 minutes.

[0258] Example 15(80): 3-Fluoro-1-[[(3S)-6-(4-methoxybutan-2-yloxy)-3-methyl-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.98, 6.70, 6.67, 6.29, 4.60, 3.81-3.67, 3.21, 2.86, 2.87, 1.88-1.83, 1.80-1.73, 1.23, 0.87; LCMS: Retention time 0.78 minutes.

[0259] Example 15(81): 3-Fluoro-1-[[(3R)-6-(4-methoxybutan-2-yloxy)-3-methyl-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 6.98, 6.70, 6.67, 6.29, 4.60, 3.81-3.67, 3.21, 2.86, 2.87, 1.88-1.83, 1.80-1.73, 1.23, 0.87; LCMS: Retention time 0.78 minutes.

[0260] Example 15 (82): 3-Fluoro-1-[[(3S)-3-methyl-6-[(E)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.03, 6.80, 6.75, 6.71, 6.30, 6.25-6.20, 4.73, 2.89, 2.55, 2.52. 2.39, 0.87; LCMS: Retention time 0.83 minutes.

[0261] Example 15 (83): 3-Fluoro-1-[[(3R)-3-methyl-6-[(E)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.03, 6.80, 6.75, 6.71, 6.30, 6.25-6.20, 4.73, 2.89, 2.55, 2.52. 2.39, 0.87; LCMS: Retention time 0.83 minutes.

[0262] Example 15 (84): 3-Fluoro-1-[[(3S)-3-methyl-6-[(Z)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.04, 6.80, 6.76, 6.71, 6.32, 6.26-6.16, 4.72, 2.90, 0.85; LCMS: Retention time 0.83 minutes.

[0263] Example 15 (85): 3-Fluoro-1-[[(3R)-3-methyl-6-[(Z)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid 1 H-NMR (DMSO-d6): δ 7.04, 6.80, 6.76, 6.71, 6.32, 6.26-6.16, 4.72, 2.90, 0.85; LCMS: Retention time 0.83 minutes.

[0264] Example 15 (86): 3-Fluoro-1-{[(3S)-3-methyl-6-(3,3,3-trifluoropropoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid 1 H-NMR (DMSO-d6): δ 7.05, 6.79, 6.75, 6.41, 4.19, 3.50-3.10, 2.91, 2.77, 2.60-2.53, 2.52, 2.45-2.36, 0.86; LCMS: Retention time 0.78 minutes.

[0265] Example 15 (87): 3-Fluoro-1-{[(3R)-3-methyl-6-(3,3,3-trifluoropropoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid 1 H-NMR (DMSO-d6): δ 7.05, 6.79, 6.75, 6.41, 4.19, 3.50-3.10, 2.91, 2.77, 2.60-2.53, 2.52, 2.45-2.36, 0.86; LCMS: Retention time 0.78 minutes.

[0266] Example 16: Methyl 1-(((3S)-3-methyl-6-(3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalene-2-yl)methyl)azetidine-3-carboxylate The compound prepared in Example 14(1) (2.5 g) and methylazetidine-3-carboxylate hydrochloride (2.6 g) were subjected to the same reaction as in Example 5 to obtain (S)-methyl 1-((6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl)azetidine-3-carboxylate (3.8 g). The title compound (18.0 mg) was obtained by subjecting (S)-methyl 1-((6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl)azetidine-3-carboxylate (50 mg) and 3,3,3-trifluoro-2-methyl-propan-1-ol (31.7 mg) to the same reaction as in Example 8.

[0267] Example 17: Methyl 1-(((S)-3-methyl-6-((R)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylate and methyl 1-(((S)-3-methyl-6-((S)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylate The compounds prepared in Example 16 were subjected to SFC (Column used: Daicel Corporation CHIRALPAK IC (10 mm x 250 mm), Mobile phase: CO ２ Optical resolution was performed using the following conditions: (0.1% DEA / EA / IPA) = 9:1, flow rate: 30 mL / min, pressure: 100 bar, wavelength: 254 nm, column temperature: 35°C). Under these optical resolution conditions, the optically active compounds of the compound prepared in Example 16 were obtained as the first peak (retention time: approximately 9.00 min) and the second peak (retention time: approximately 12.16 min), respectively.

[0268] Example 18: 1-[[(3S)-3-methyl-6-((R)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid and 1-[[(3S)-3-methyl-6-((S)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid The first peak compound (5.0 mg) or the second peak compound (6.0 mg) optically resolved in Example 17 were subjected to the same reaction as in Example 7 to obtain the title compound (derived from the first peak: 4.2 mg, derived from the second peak: 4.7 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 7.03, 6.75, 6.73, 6.41, 3.80, 3.75, 3.40, 3.10, 2.89, 2.62, 2.57-2.46, 2.42-2.36, 1.80-1.75, 1.62-1.57, 1.53-1.47, 1.43-1.38, 1.38-1.33, 1.25-1.20, 1.18, 0.96, 0.90, 0.85; LCMS: retention time 0.84 min. Origin of second peak 1 H-NMR (DMSO-d6): δ 6.99, 6.75, 6.71, 6.22, 6.10, 4.02, 3.23-3.12, 2.95, 2.91-2.87,2.85, 2.33, 1.19, 0.85; LCMS: Retention time 0.85 minutes.

[0269] Example 18(1): Using the compound prepared in Example 14, methylazetidine-3-carboxylate hydrochloride, and 3,3,3-trifluoro-2-methylpropan-1-ol, the title compound having the following physical properties was obtained by subjecting them to the same reaction as in Example 5 → Example 8 → Example 17 → Example 7. 1 ¹H-NMR (DMSO-d6): δ 7.03, 6.75, 6.73, 6.41, 3.80, 3.75, 3.40, 3.10, 2.89, 2.62, 2.57-2.46, 2.42-2.36, 1.80-1.75, 1.62-1.57, 1.53-1.47, 1.43-1.38, 1.38-1.33, 1.25-1.20, 1.18, 0.96, 0.90, 0.85; LC-MS: Retention time 0.84 min. Or 1 H-NMR (DMSO-d6): δ 6.99, 6.75, 6.71, 6.22, 6.10, 4.02, 3.23-3.12, 2.95, 2.91-2.87,2.85, 2.33, 1.19, 0.85; LCMS: Retention time 0.85 minutes.

[0270] Example 19: Methyl 1-[(6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylate] The compound prepared in Example 13 (250 mg) and methylazetidine-3-carboxylate hydrochloride (242 mg) were subjected to the same reaction as in Example 5 to obtain the corresponding ester derivative. The obtained ester derivative (100 mg) and 1-butanol (39 mg) were subjected to the same reaction as in Example 8 to obtain the title compound (120 mg).

[0271] Example 20: (R)-methyl 1-((6-butoxy-3-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylate and (S)-methyl 1-((6-butoxy-3-methyl-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylate. The compounds prepared in Example 19 were subjected to SFC (Column used: Daicel Corporation CHIRALPAK ID (10 mm I.D. × 250 mm L), Mobile phase: CO2). ２ Optical resolution was performed using the following conditions: (0.1% DEA / MeOH) = 95:5, flow rate: 30 mL / min, pressure: 100 bar, wavelength: 220 nm, column temperature: 35 °C). Under these optical resolution conditions, the optically active compounds of the compound prepared in Example 19 were obtained as the first peak (retention time: approximately 4.62 min) and the second peak (retention time: approximately 7.02 min), respectively.

[0272] Example 21: 1-[((3R)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid and 1-[((3S)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid In Example 20, the first peak compound (41 mg) or the second peak compound (38 mg) obtained by optical resolution were subjected to the same reaction as in Example 7 to obtain the title compound (derived from the first peak: 21 mg, derived from the second peak: 19 mg) having the following physical properties. 1 H-NMR(CDCl3): δ 6.96, 6.73-6.61, 6.45, 4.34, 4.24, 4.11, 4.05, 3.98-3.86, 3.60-3.38, 3.02, 2.62-2.48, 1.75, 1.48, 0.97, 0.91; LCMS: Retention time 0.86 minutes. Origin of second peak 1 H-NMR (DMSO-d6): δ 6.96, 6.71, 6.68, 6.24, 3.93, 3.60-2.90, 2.84, 2.34, 1.67, 1.43, 0.93, 0.85; LCMS: Retention time 0.86 minutes.

[0273] Example 22: 5-Fluoro-6-methoxy-3-methyl-3,4-dihydronaphthalene-1(2H)-one 10.0 g of 6-methoxy-3-methyl-3,4-dihydronaphthalene-1(2H)-one (CAS registration number: 5563-21-3) (10.0 g) was added to a solution of acetonitrile (60 mL) and SelectFluor (trade name) (21.6 g) was stirred at 40°C for 25 hours. Water was added to the reaction mixture and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 8:2) to obtain a mixture containing the title compound (3.68 g).

[0274] Example 23: 5-Fluoro-6-methoxy-3-methyl-1,2,3,4-tetrahydronaphthalene-1-ol A mixture (3.68 g) prepared in Example 22 was dissolved in methanol (35 mL) and sodium borohydride (1.34 g) was added at 0°C. The mixture was stirred at room temperature for 1.5 hours. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was used in the next reaction without purification.

[0275] Example 24: 5-Fluoro-6-methoxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde A solution of the compound prepared in Example 23 (3.71 g) in DMF (35 mL) was mixed with phosphorus oxychloride (5.0 mL) and stirred at 70°C for 16 hours. The reaction mixture was poured into an aqueous sodium hydroxide solution under ice cooling and stirred at room temperature for 30 minutes. After extraction twice with ethyl acetate, the organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 7:3) to obtain the title compound (419 mg) with the following physical properties. 1 H-NMR (CDCl3): δ9.59, 7.15, 7.07, 6.83, 3.93, 3.11, 3.05, 2.78, 0.94.

[0276] Example 25: Methyl 1-((5-fluoro-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl)methyl)azetidine-3-carboxylate. The compound prepared in Example 24 (460 mg), methylazetidine-3-carboxylate hydrochloride (226 mg), and 4,4,4-trifluorobutan-1-ol (84 mg) were subjected to the same reaction as in Example 13 → Example 5 → Example 8 to obtain the title compound (150 mg). 1 H-NMR (CDCl3): δ 6.78-6.68, 6.22, 4.06, 3.72, 3.65-3.50, 3.43-3.22, 3.05, 2.85, 2.75, 2.50-2.25, 2.08, 0.94.

[0277] Example 26: (R)-methyl 1-((5-fluoro-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylate and (S)-methyl 1-((5-fluoro-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl)methyl)azetidine-3-carboxylate. The compounds prepared in Example 25 were subjected to SFC (Column used: Daicel Corporation CHIRALPAK IC (10 mm x 250 mm), Mobile phase: CO2). ２ Optical resolution was performed using the following conditions: (0.1% DEA / EA) = 95:5, flow rate: 30 mL / min, pressure: 100 bar, wavelength: 254 nm, column temperature: 35°C. Under these optical resolution conditions, the optically active product of Example 25 was obtained as the first peak (retention time: approximately 5.99 min) and the second peak (retention time: approximately 7.67 min), respectively.

[0278] Example 27: (R)-1-[[5-fluoro-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid and (S)-1-[[5-fluoro-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid. The first peak compound (72 mg) or the second peak compound (52 mg) obtained by optical resolution in Example 26 were subjected to the same reaction as in Example 7 to obtain the title compound (from the first peak: 43 mg, from the second peak: 39 mg) having the following physical properties. First peak 1 H-NMR (CDCl3): δ 6.80, 6.71, 6.47, 4.39, 4.30, 4.09-3.97, 3.91, 3.54, 3.44, 2.90, 2.81, 2.62, 2.33, 2.07, 0.94; LCMS: Retention time 0.86 minutes. second peak 1 H-NMR (CDCl3): δ 6.80, 6.71, 6.47, 4.38, 4.29, 4.09-3.97, 3.90, 3.53, 3.43, 2.90, 2.81, 2.62, 2.33, 2.07, 0.93; LCMS: Retention time 0.85 minutes.

[0279] Example 28: 3-Fluoro-1-[[5-Fluoro-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid The compound prepared in Example 24 (370 mg), 4,4,4-trifluorobutan-1-ol (124 mg), and methyl 3-fluoroazetidine-3-carboxylate hydrochloride (48.8 mg) were subjected to the same reaction as in Example 13 → Example 8 → Example 5 → Example 7 to obtain the title compound (34.9 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 6.95-6.86, 6.32, 4.08, 3.80-2.89, 2.73, 2.47-2.37, 1.94, 0.87; LCMS: Retention time 0.82 minutes.

[0280] Example 29: 2,4,6-Triisopropylbenzenesulfonohydrazide 2,4,6-Triisopropylbenzenesulfonyl chloride (CAS registration number: 6553-96-4) (10 g) was gradually added to a solution of 2,4,6-triisopropylbenzenesulfonyl chloride (CAS registration number: 6553-96-4) (30 mL) in THF (0°C) and stirred at 0°C for 2 hours. Water was added to the reaction mixture and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was washed with hexane and dried to obtain the title compound (7.1 g) having the following physical properties. 1 H-NMR (CDCl3): δ 5.46, 4.18, 2.92, 1.30-1.24.

[0281] Example 30: (E)-2,4,6-triisopropyl-N'-(6-methoxy-3-methyl-3,4-dihydronaphthalene-1(2H)-ylidene)benzenesulfonohydrazide. 6-methoxy-3-methyl-3,4-dihydronaphthalene-1(2H)-one (CAS registration number: 5563-21-3) (4.0 g) was added to a methanol (40 mL) solution to which the compound prepared in Example 29 (7.0 g) was added and stirred at room temperature for 72 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (NH₄ silica gel, hexane:ethyl acetate = 8:2 → 5:5) to obtain the title compound (4.2 g) having the following physical properties. 1 H-NMR (DMSO-d6): δ 10.45, 7.69, 7.23, 6.72-6.67, 4.34, 3.73, 2.91, 2.84, 2.72, 2.40, 2.04-1.80, 1.26-1.17, 1.02.

[0282] Example 31: 4-Fluoro-7-methoxy-2-methyl-1,2-dihydronaphthalene A solution of the compound prepared in Example 30 (2.0 g) in THF (21 mL) was added to a hexane solution of 1.55 M n-butyllithium at -78°C (6.0 mL) and stirred at -78°C for 30 minutes and then at 0°C for 20 minutes. After cooling again to -78°C, a THF solution of N-fluorobenzenesulfonimide (3.3 g) (6.0 mL) was added and stirred at -78°C for 30 minutes and then at room temperature for 18 hours. Saturated aqueous sodium bicarbonate solution was added to the reaction mixture and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 8:2) to obtain a mixture containing the title compound (550 mg).

[0283] Example 32: 1-Fluoro-6-methoxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde A solution of the mixture prepared in Example 31 (550 mg) in DMF (5 mL) was mixed with phosphorus oxychloride (1.2 g) and stirred at room temperature for 16 hours. Water was added to the reaction mixture and extracted twice with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 10:0 → 7:3) to obtain the title compound (154 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 10.11, 7.59, 6.99, 6.96, 3.84, 3.10-2.95, 2.69, 0.86.

[0284] Example 33: 1-[[1-fluoro-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid Using the compound prepared in Example 32 (150 mg), methylazetidine-3-carboxylate hydrochloride (64.1 mg), and 4,4,4-trifluorobutan-1-ol (8.2 mg), the same reaction as in Example 13 → Example 5 → Example 8 → Example 7 was carried out to obtain the title compound (8.1 mg) having the following physical properties. 1H-NMR (DMSO-d6): δ 7.22, 6.85, 6.81, 4.05, 3.60-3.00, 2.92, 2.42, 1.93, 0.89; LCMS: Retention time 0.86 minutes.

[0285] Example 34: 1-bromo-6-methoxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde A mixed solution of DCM (7.5 L) and DMF (1.5 L) was to be to which phosphorus tribromide (1.5 L) was added dropwise at 0-5°C and stirred at 25-30°C for 1 hour. A solution of 6-methoxy-3-methyl-3,4-dihydronaphthalene-1(2H)-one (CAS registration number: 5563-21-3) (750 g) in DCM (3.75 L) was added dropwise at 25-30°C and then heated at 90°C for 1 hour. The reaction mixture was cooled to 25°C and poured onto crushed ice. The resulting solution was adjusted to pH 7-8 with 2N sodium hydroxide solution and then extracted with DCM. The organic layer was washed with cold water, dried over sodium sulfate, and the solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography to obtain the title compound (500 g) having the following physical properties. 1 H-NMR (CDCl3): δ 10.18, 7.82, 6.82, 6.74, 3.85, 3.21, 3.07, 2.60, 0.84.

[0286] Example 35: 1-bromo-6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde A 4.2 L solution of the compound prepared in Example 34 (525 g) was added dropwise to a 4.2 L solution of DCM containing 1 mol / L boron tribromide (5.6 L) at 10-20°C, and the mixture was stirred at 20-30°C for 6 hours. The reaction mixture was poured into ice-cold water and stirred for 30 minutes. After adding DCM to the reaction mixture, the organic layer was separated. The aqueous layer was extracted with DCM containing 10% methanol. The combined organic layers were washed with water, dried over sodium sulfate, and the solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography to obtain the title compound (350 g) having the following physical properties. 1 H-NMR (CDCl3): δ 10.18, 7.81, 6.79, 6.67, 5.22, 3.22, 3.04, 2.58, 0.85.

[0287] Example 36: 6-hydroxy-1,3-dimethyl-3,4-dihydronaphthalene-2-carbaldehyde A solution of the compound prepared in Example 35 (350 g) in 1,4-dioxane (4.9 L) was mixed with methylboronic acid (235.2 g), potassium carbonate (726 g), and Rac BINAP (2,2'-bis(diphenylphosphin)-1,1'-binaphthyl, 40.78 g) under an argon atmosphere and stirred for 30 minutes. Palladium acetate (17.64 g) was added at 25-30°C, and the reaction mixture was heated at 90°C for 4 hours. The resulting reaction mixture was cooled to 25°C and then poured into ice water. The reaction mixture was filtered through Celite and washed with ethyl acetate. The filtrate was adjusted to pH 2-3 with 2N hydrochloric acid solution, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with saturated saline solution, dried over sodium sulfate, and the solvent was removed by distillation. The resulting residue was purified by silica gel column chromatography to obtain the title compound (151 g) with the following physical properties. 1 H-NMR (DMSO-d6): δ 10.21, 9.89, 7.48, 6.70, 6.65, 2.97, 2.81, 2.58-2.45, 2.44, 0.71.

[0288] Example 37: (R)-6-hydroxy-1,3-dimethyl-3,4-dihydronaphthalene-2-carbaldehyde and (S)-6-hydroxy-1,3-dimethyl-3,4-dihydronaphthalene-2-carbaldehyde. The compounds prepared in Example 36 were subjected to SFC (Column used: Daicel Corporation CHIRALCEL OJ-H (30 mm x 250 mm), Mobile phase: CO2). ２ Optical resolution was performed using 2-propanol (85:15, flow rate: 90 g / min, pressure: 100.0 bar, wavelength: 320 nm). The optically active product of Example 36 obtained under the above optical resolution conditions was subjected to SFC (column used: Daicel Corporation CHIRALPAK-IG (46 mm x 250 mm), mobile phase: CO2). ２ Analysis using methanol (80:20, flow rate: 3 mL / min, pressure: 100 bar, wavelength: 214 nm, column temperature: 30°C) showed retention times of 2.45 minutes and 4.77 minutes for the first and second peaks, respectively.

[0289] Example 38: 1-[[(3R)-1,3-dimethyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid or 1-[[(3S)-1,3-dimethyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid The optically active first peak product (1.0 g) prepared in Example 37, methylazetidine-3-carboxylate hydrochloride (970 mg), and 4,4,4-trifluorobutan-1-ol (85 mg) were subjected to the same reaction as in Example 5 → Example 8 → Example 7 to obtain the title compound (112 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 7.19, 6.77-6.72, 4.02, 3.90-2.88, 2.80, 2.48-2.36, 2.02, 1.92, 0.74; LCMS: Retention time 0.81 min.

[0290] Example 39: (3S)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde. The compound prepared in Example 14(1) (300 mg) and 1-bromobutane (240 mg) were subjected to the same reaction as in Example 6 to obtain the title compound (351 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 9.54, 7.42, 7.37, 6.88, 6.85, 4.03, 3.01-2.84, 2.67, 1.71, 1.44, 0.94, 0.82; LCMS: Retention time 1.25 minutes.

[0291] Example 39(1): (3R)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-carbaldehyde. The compound prepared in Example 14 and 1-bromobutane were subjected to the same reaction as in Example 6 to obtain the title compound having the following physical properties. 1H-NMR (DMSO-d6): δ 9.54, 7.42, 7.37, 6.88, 6.85, 4.03, 3.01-2.84, 2.67, 1.71, 1.44, 0.94, 0.82; LCMS: Retention time 1.25 minutes.

[0292] Example 40: 1-{[(3S)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-methyl-3-azetidinecarboxylic acid The compound prepared in Example 39 (55 mg) and ethyl 3-methylazetidine-3-carboxylate (25 mg) were subjected to the same reaction as in Example 5 → Example 7 to obtain the title compound (28.6 mg) having the following physical properties. 1 H-NMR (CD3OD): δ 7.06, 6.78-6.70, 6.56, 4.40, 4.34, 4.07-3.94, 3.93-3.83, 3.04, 2.66, 2.42, 1.77, 1.60-1.46, 1.01, 0.96; LCMS: Retention time 0.89 minutes.

[0293] Examples 40(1) to (3): The compounds prepared in Example 39 or Example 39(1), and ethyl azetidine-3-carboxylate or an equivalent amine derivative were subjected to the same reaction as in Example 5 to Example 7 to obtain the following example compounds.

[0294] Example 40(1): 1-{[(3R)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-methyl-3-azetidinecarboxylic acid 1 H-NMR (CD3OD): δ 7.06, 6.78-6.70, 6.56, 4.40, 4.34, 4.07-3.94, 3.93-3.83, 3.04, 2.66, 2.42, 1.77, 1.60-1.46, 1.01, 0.96; LCMS: Retention time 0.89 minutes.

[0295] Example 40(2): 1-{[(3S)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-methoxy-3-azetidinecarboxylic acid 1H-NMR (CD3OD): δ 7.07, 6.78-6.70, 6.58, 4.46, 4.40, 4.23-4.06, 4.03-3.92, 3.36, 3.05, 2.66, 2.44, 1.77, 1.52, 1.01, 0.97; LCMS: Retention time 0.88 minutes.

[0296] Example 40(3): 1-{[(3R)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-methoxy-3-azetidinecarboxylic acid 1 H-NMR (CD3OD): δ 7.07, 6.78-6.70, 6.58, 4.46, 4.40, 4.23-4.06, 4.03-3.92, 3.36, 3.05, 2.66, 2.44, 1.77, 1.52, 1.01, 0.97; LCMS: Retention time 0.88 minutes.

[0297] Example 41: (3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-carbaldehyde. The compound prepared in Example 14(1) (312 mg) and 1-bromo-4,4,4-trifluorobutane (348 mg) were subjected to the same reaction as in Example 6 to obtain the title compound (502 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 9.55, 7.43, 7.39, 6.90, 6.87, 4.10, 3.02-2.85, 2.68, 2.47-2.35, 1.95, 0.82; LCMS: Retention time 1.13 minutes.

[0298] Example 41(1): (3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-carbaldehyde. The compound prepared in Example 14 and 1-bromo-4,4,4-trifluorobutane were subjected to the same reaction as in Example 6 to obtain the title compound having the following physical properties. 1 H-NMR (DMSO-d6): δ 9.55, 7.43, 7.39, 6.90, 6.87, 4.10, 3.02-2.85, 2.68, 2.47-2.35, 1.95, 0.82; LCMS: Retention time 1.13 minutes.

[0299] Example 42: 3-hydroxy-1-{[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid The compound prepared in Example 41 (50 mg) and methyl 3-hydroxyazetidine-3-carboxylate hydrochloride (42 mg) were subjected to the same reaction as in Example 5 → Example 7 to obtain the title compound (8.0 mg) having the following physical properties. 1 H-NMR (CD3OD): δ 6.94, 6.69-6.60, 6.41, 4.22, 3.99-3.79, 2.92, 2.53, 2.38-2.17, 1.92, 0.85; LCMS: Retention time 0.81 min.

[0300] Example 42(1): 3-hydroxy-1-{[(3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid The compound prepared in Example 41(1) and methyl 3-hydroxyazetidine-3-carboxylate hydrochloride were subjected to the same reaction as in Example 5 → Example 7 to obtain the title compound having the following physical properties. 1 H-NMR (CD3OD): δ 6.94, 6.69-6.60, 6.41, 4.22, 3.99-3.79, 2.92, 2.53, 2.38-2.17, 1.92, 0.85; LCMS: Retention time 0.81 min.

[0301] Example 43: Using tert-butyl N-{[(3S)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl]methyl}-N-methyl-β-alaninate, the compound prepared in Example 39 (55 mg) and tert-butyl 3-(methylamino)propanoate (47 mg) were subjected to the same reaction as in Example 5 to obtain a mixture containing the title compound (23.9 mg).

[0302] Example 43(1): tert-butyl N-{[(3R)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl]methyl}-N-methyl-β-alaninate The compound prepared in Example 39(1) and tert-butyl 3-(methylamino)propanoate were subjected to the same reaction as in Example 5 to obtain a mixture containing the title compound.

[0303] Example 44: 3-[{[(3S)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}(methyl)amino]propanoic acid A mixture (23.9 mg) prepared in Example 43 was dissolved in dichloromethane (0.48 mL) and trifluoroacetic acid (0.15 mL) was added and the mixture was stirred at room temperature. After concentrating the reaction solution under reduced pressure, the resulting residue was purified by silica gel column chromatography (DCM:(DCM:methanol:concentrated ammonium hydroxide aqueous solution = 80:18:2) = 9:1 → 0:10) to obtain the title compound (12.0 mg) having the following physical properties. 1 H-NMR (CD3OD): δ 7.04, 6.77-6.70, 6.57, 3.99, 3.85, 3.73, 3.32-3.24, 3.23-3.14, 3.10, 2.67, 2.59, 2.56-2.47, 1.77, 1.53, 1.04-0.97; LCMS: retention time 0.95 minutes.

[0304] Examples 44(1) to (3): The compounds prepared in Example 39 or Example 39(1), and tert-butyl 3-(methylamino)propanoate or a comparable amine derivative were subjected to the same reaction as in Example 5 → Example 44 to obtain the following example compounds.

[0305] Example 44(1): 3-[{[(3R)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}(methyl)amino]propanoic acid 1H-NMR (CD3OD): δ 7.04, 6.77-6.70, 6.57, 3.99, 3.85, 3.73, 3.32-3.24, 3.23-3.14, 3.10, 2.67, 2.59, 2.56-2.47, 1.77, 1.53, 1.04-0.97; LCMS: retention time 0.95 minutes.

[0306] Example 44(2): 3-({[(3S)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}aminopropanoic acid 1 H-NMR (CD3OD): δ 7.06, 6.79-6.70, 6.62, 4.08-3.94, 3.71, 3.46-3.40, 3.28-3.17, 3.11, 2.87, 2.75-2.50, 1.77, 1.53, 1.05-0.94; LCMS: Retention time 0.93 minutes.

[0307] Example 44(3): 3-({[(3R)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}aminopropanoic acid 1 H-NMR (CD3OD): δ 7.06, 6.79-6.70, 6.62, 4.08-3.94, 3.71, 3.46-3.40, 3.28-3.17, 3.11, 2.87, 2.75-2.50, 1.77, 1.53, 1.05-0.94; LCMS: Retention time 0.93 minutes.

[0308] Example 45: 1-[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]ethane-1-ol A solution of the compound (502 mg) prepared in Example 41 in THF (2.5 mL) was cooled to -78°C, and a solution of 3 mol / L methylmagnesium chloride in THF (2.8 mL) was added and stirred. A saturated aqueous solution of ammonium chloride was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 5:1 → 1:1) to obtain the title compound (410 mg) having the following physical properties. 1H-NMR (DMSO-d6): δ 7.02-6.95, 6.74, 6.70, 6.32, 6.23, 4.81, 4.74, 4.25-4.13, 4.10-3.94, 2.86, 2.45-2.31, 1.93, 1.26, 1.24, 0.88, 0.86.

[0309] Example 45(1): 1-[(3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalene-2-yl]ethane-1-ol The compound prepared in Example 41(1) was subjected to the same reaction as in Example 45 to obtain the title compound having the following physical properties. 1 H-NMR (DMSO-d6): δ 7.02-6.95, 6.74, 6.70, 6.32, 6.23, 4.81, 4.74, 4.25-4.13, 4.10-3.94, 2.86, 2.45-2.31, 1.93, 1.26, 1.24, 0.88, 0.86.

[0310] Example 46: 1-[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl]ethane-1-one A solution of the compound prepared in Example 45 (410 mg) in dichloromethane (4.1 mL) was mixed with Des-Martin periodinane (CAS registration number: 87413-09-0) (1.5 g) under ice cooling and stirred at room temperature for 24 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with aqueous sodium thiosulfate solution, saturated aqueous sodium bicarbonate solution, and saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The obtained residue was used in the next reaction without purification.

[0311] Example 46(1): 1-[(3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydronaphthalen-2-yl]ethane-1-one The title compound was obtained by subjecting the compound prepared in Example 45(1) to the same reaction as in Example 46.

[0312] Example 47: 1-{1-[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydro-2-naphthalenyl]ethyl}-3-azetidinecarboxylic acid The compound prepared in Example 46 (40 mg) and methylazetidine-3-carboxylate hydrochloride (39 mg) were subjected to the same reaction as in Example 5 → Example 7 to obtain the title compound (14.2 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 7.03-6.95, 6.73, 6.72-6.66, 6.27, 6.25, 4.01, 3.50-2.99, 2.93-2.70, 2.46-2.28, 1.92, 1.07, 1.03, 0.89, 0.83; LCMS: retention time 0.96 minutes.

[0313] Examples 47(1) to (3) The compounds prepared in Example 46 or Example 46(1), and methylazetidine-3-carboxylate hydrochloride or an equivalent amine derivative were subjected to the same reaction as in Example 5 to Example 7 to obtain the following example compounds.

[0314] Example 47(1): 1-{1-[(3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydro-2-naphthalenyl]ethyl}-3-azetidinecarboxylic acid 1 H-NMR (DMSO-d6): δ 7.03-6.95,6.73, 6.72-6.66, 6.27, 6.25, 4.01, 3.50-2.99, 2.93-2.70, 2.46-2.28, 1.92, 1.07, 1.03, 0.89, 0.83; LCMS: retention time 0.96 minutes.

[0315] Example 47(2): cis-3-({1-[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydro-2-naphthalenyl]ethyl}amino)cyclobutanecarboxylic acid 1H-NMR (CD3OD): δ7.07, 6.83-6.74, 6.62, 6.49, 4.07, 3.94-3.72, 3.20-3.03, 3.02-2.86, 2.75-2.26, 2.09-1.96, 1.57, 1.53, 1.00; LCMS: retention time 0.65 minutes.

[0316] Example 47(3): cis-3-({1-[(3R)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-dihydro-2-naphthalenyl]ethyl}amino)cyclobutanecarboxylic acid 1 H-NMR (CD3OD): δ7.07, 6.83-6.74, 6.62, 6.49, 4.07, 3.94-3.72, 3.20-3.03, 3.02-2.86, 2.75-2.26, 2.09-1.96, 1.57, 1.53, 1.00; LCMS: retention time 0.65 minutes.

[0317] Example 48: 1-{[(3S)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl]methyl}azetidine-3-carbonitride The compound prepared in Example 39 (80 mg) and azetidine-3-carbonitride hydrochloride (CAS registration number: 345954-83-8) (58 mg) were subjected to the same reaction as in Example 5 to obtain the title compound (38 mg) having the following physical properties. 1 ¹H-NMR (CDCl3): δ 6.93, 6.70-6.64, 6.22, 3.95, 3.71-3.55, 3.39-3.24, 3.02, 2.95, 2.53, 2.39, 1.75, 1.49, 0.97, 0.93. Example 48(1): 1-{[(3R)-6-butoxy-3-methyl-3,4-dihydronaphthalene-2-yl]methyl}azetidine-3-carbonitrilate. The compound prepared in Example 39(1) and azetidine-3-carbonitrilate hydrochloride were subjected to the same reaction as in Example 5 to obtain the title compound having the following physical properties. 1H-NMR (CDCl3): δ 6.93, 6.70-6.64, 6.22, 3.95, 3.71-3.55, 3.39-3.24, 3.02, 2.95, 2.53, 2.39, 1.75, 1.49, 0.97, 0.93.

[0318] Example 49: 5-(1-{[(3S)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinyl)-1H-tetrazole A solution of the compound prepared in Example 48 (36 mg) in toluene (2.0 mL) was mixed with dibutyltine oxide (CAS registration number: 818-08-6) (87 mg) and trimethylsilyl azide (CAS registration number: 4648-54-8) (40 mg) and stirred at 110°C for 4 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (Diol silica gel, dichloromethane:methanol = 100:0 → 95:5) to obtain the title compound (5.0 mg) having the following physical properties. 1 H-NMR (CD3OD): δ 6.94, 6.69-6.57, 6.48, 4.51-4.40, 4.40-4.13, 3.97, 3.90-3.81, 2.94, 2.55, 2.33, 1.65, 1.41, 0.92-0.84; LCMS: Retention time 0.85 minutes.

[0319] Example 49(1): 5-(1-{[(3R)-6-butoxy-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinyl)-1H-tetrazole The compound prepared in Example 48(1) was subjected to the same reaction as in Example 49 to obtain the title compound having the following physical properties. 1 H-NMR (CD3OD): δ 6.94, 6.69-6.57, 6.48, 4.51-4.40, 4.40-4.13, 3.97, 3.90-3.81, 2.94, 2.55, 2.33, 1.65, 1.41, 0.92-0.84; LCMS: Retention time 0.85 minutes.

[0320] Example 50: Methyl 1-{[(3S)-6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-yl]methyl}azetidine-3-carboxylate. The compound prepared in Example 14(1) (1.0 g) and methylazetidine-3-carboxylate hydrochloride (1.0 g) were subjected to the same reaction as in Example 5 to obtain the title compound (1.5 g) having the following physical properties. 1 H-NMR (DMSO-d6): δ 9.24, 6.84, 6.53, 6.50, 6.16, 3.63, 3.48-3.24, 3.23-3.07, 2.92, 2.80, 2.43, 2.36-2.26, 0.85.

[0321] Example 50(1): Methyl 1-{[(3R)-6-hydroxy-3-methyl-3,4-dihydronaphthalene-2-yl]methyl}azetidine-3-carboxylate. The compound prepared in Example 14 and methylazetidine-3-carboxylate hydrochloride were subjected to the same reaction as in Example 5 to obtain the title compound having the following physical properties. 1 H-NMR (DMSO-d6): δ 9.24, 6.84, 6.53, 6.50, 6.16, 3.63, 3.48-3.24, 3.23-3.07, 2.92, 2.80, 2.43, 2.36-2.26, 0.85.

[0322] Example 51: Methyl 1-({(3S)-3-methyl-6-[(trifluoromethanesulfonyl)oxy]-3,4-dihydronaphthalen-2-yl}methyl)azetidine-3-carboxylate A solution of the compound prepared in Example 50 (1250 mg) in dichloromethane (12.5 mL) was mixed with diisopropylethylamine (2.3 mL) and N-phenylbis(trifluoromethanesulfonimide) (CAS registration number: 37595-74-7) (1.7 g) under ice cooling and stirred at room temperature for 24 hours. Water was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 7:3 → 5:5) to obtain the title compound (1630 mg) having the following physical properties. 1H-NMR (CDCl3): δ 7.09-6.98, 6.26, 3.64-3.52, 3.41-3.25, 3.08, 3.00, 2.60, 2.43, 0.94.

[0323] Example 51(1): Methyl 1-({(3R)-3-methyl-6-[(trifluoromethanesulfonyl)oxy]-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylate. The compound prepared in Example 50(1) was subjected to the same reaction as in Example 51 to obtain the title compound having the following physical properties. 1 H-NMR (CDCl3): δ 7.09-6.98, 6.26, 3.64-3.52, 3.41-3.25, 3.08, 3.00, 2.60, 2.43, 0.94.

[0324] Example 52: Methyl 1-({(3S)-6-[butyl(methyl)amino]-3-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylate. To a solution of the compound prepared in Example 51 (50 mg) in 1,4-dioxane (0.5 mL), N-methylbutylamine (13.5 mg), cesium carbonate (51 mg), XPhos (11 mg), and dibenzylideneacetone dipalladium (5.5 mg) were added and the mixture was stirred at 80°C for 16 hours. Ethyl acetate was added to the reaction mixture, filtered through aminosilica, and the filtrate was concentrated. The obtained residue was subjected to silica gel column chromatography (NH₄). ２ A mixture containing the title compound was obtained by purification using silica gel (hexane:ethyl acetate = 1:2).

[0325] Example 52(1): Methyl 1-({(3R)-6-[butyl(methyl)amino]-3-methyl-3,4-dihydronaphthalene-2-yl}methyl)azetidine-3-carboxylate. The compound prepared in Example 51(1) and N-methylbutylamine were subjected to the same reaction as in Example 52 to obtain a mixture containing the title compound.

[0326] Example 53: 1-({(3S)-6-[butyl(methyl)amino]-3-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid The mixture (21 mg) prepared in Example 52 was subjected to the same reaction as in Example 7 to obtain the title compound (4.4 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 6.84, 6.46, 6.42, 6.14, 3.50-3.07, 3.00-2.87, 2.86, 2.84-2.76, 2.52, 2.47-2.42, 2.35-2.22, 1.47, 1.30, 0.90, 0.85; LCMS: retention time 0.79 minutes.

[0327] Example 53(1): 1-({(3R)-6-[butyl(methyl)amino]-3-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidinecarboxylic acid The mixture prepared in Example 52(1) was subjected to the same reaction as in Example 7 to obtain the title compound having the following physical properties. 1 H-NMR (DMSO-d6): δ 6.84, 6.46, 6.42, 6.14, 3.50-3.07, 3.00-2.87, 2.86, 2.84-2.76, 2.52, 2.47-2.42, 2.35-2.22, 1.47, 1.30, 0.90, 0.85; LCMS: retention time 0.79 minutes.

[0328] Example 54: Methyl 1-{[(3S)-6-(butylsulfanyl)-3-methyl-3,4-dihydronaphthalene-2-yl]methyl}azetidine-3-carboxylate A solution of the compound prepared in Example 51 (150 mg) in 1,4-dioxane (1.5 mL) was mixed with 1-butanethiol (64.5 mg), diisopropylethylamine (0.15 mL), Xantphos (41 mg), and dibenzylideneacetone dipalladium (33 mg) and stirred at 100°C for 24 hours. The reaction mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 8:2 → 5:5) to obtain the title compound (83 mg) having the following physical properties. 1H-NMR (CDCl3): δ 7.09, 7.06, 6.93, 6.23, 3.71, 3.65-3.52, 3.42-3.22, 3.04, 2.96, 2.90, 2.53, 2.40, 1.68-1.56, 1.51-1.37, 0.97-0.88.

[0329] Example 54(1): Methyl 1-{[(3R)-6-(butylsulfanyl)-3-methyl-3,4-dihydronaphthalene-2-yl]methyl}azetidine-3-carboxylate. The compound prepared in Example 51(1) and 1-butanethiol were subjected to the same reaction as in Example 54 to obtain the title compound having the following physical properties. 1 H-NMR (CDCl3): δ 7.09, 7.06, 6.93, 6.23, 3.71, 3.65-3.52, 3.42-3.22, 3.04, 2.96, 2.90, 2.53, 2.40, 1.68-1.56, 1.51-1.37, 0.97-0.88.

[0330] Example 55: 1-{[(3S)-6-(butylthio)-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid The compound (77 mg) prepared in Example 54 was subjected to the same reaction as in Example 7 to obtain the title compound (57 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 7.10-7.04, 7.00, 6.27, 3.55-3.17, 3.05, 2.94, 2.86, 2.57-2.52, 2.42-2.31, 1.55, 1.40, 0.88, 0.85; LCMS: Retention time 0.98 minutes.

[0331] Example 55(1): 1-{[(3R)-6-(butylthio)-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid The compound prepared in Example 54(1) was subjected to the same reaction as in Example 7 to obtain the title compound having the following physical properties. 1H-NMR (DMSO-d6): δ 7.10-7.04, 7.00, 6.27, 3.55-3.17, 3.05, 2.94, 2.86, 2.57-2.52, 2.42-2.31, 1.55, 1.40, 0.88, 0.85; LCMS: Retention time 0.98 minutes.

[0332] Example 56: Methyl 1-{[(3S)-3-methyl-6-pentyl-3,4-dihydronaphthalene-2-yl]methyl}azetidine-3-carboxylate. A mixture of the compound (95 mg) prepared in Example 51 with 1,4-dioxane (1.0 mL), tetrahydrofuran (0.95 mL), and water (0.19 mL) was mixed with pentylboronic acid (31.5 mg), cesium carbonate (221 mg), and 1,1'-bis(diphenylphosphin)ferrocene-palladium(II) dichloride dichloromethane adduct (18.5 mg), and the mixture was stirred at 90°C for 19 hours. Saturated saline solution was added to the reaction mixture and extracted with ethyl acetate. The organic layer was washed with 5% aqueous potassium carbonate solution, dried over sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate = 6:4 → 4:6) to obtain a mixture (23 mg) containing the title compound. LCMS: Retention time 1.01 min.

[0333] Example 56(1): Methyl 1-{[(3R)-3-methyl-6-pentyl-3,4-dihydronaphthalene-2-yl]methyl}azetidine-3-carboxylate. The compound prepared in Example 51(1) and pentylboronic acid were subjected to the same reaction as in Example 56 to obtain a mixture containing the title compound. LCMS: Retention time 1.01 min.

[0334] Example 57: 1-{[(3S)-3-methyl-6-pentyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid The compound prepared in Example 56 (23 mg) was subjected to the same reaction as in Example 7 to obtain the title compound (10.7 mg) having the following physical properties. 1H-NMR (DMSO-d6): δ 6.97-6.92, 6.25, 3.50-3.15, 3.02, 2.86, 2.48-2.44, 2.40-2.29, 1.54, 1.17-1.21, 0.90-0.82; LCMS: Retention time 1.00 minutes.

[0335] Examples 57(1) to (5) The compounds produced in Example 51 or Example 51(1), and pentylboronic acid or a boronic acid derivative equivalent thereto, were subjected to the same reaction as in Example 56 → Example 7 to obtain the following example compounds.

[0336] Example 57(1): 1-{[(3R)-3-methyl-6-pentyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid 1 H-NMR (DMSO-d6): δ 6.97-6.92, 6.25, 3.50-3.15, 3.02, 2.86, 2.48-2.44, 2.40-2.29, 1.54, 1.17-1.21, 0.90-0.82; LCMS: Retention time 1.00 minutes.

[0337] Example 57(2): 1-{[(3S)-3-methyl-6-(propoxymethyl)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid 1 H-NMR (DMSO-d6): δ 7.09-7.05, 7.02, 6.27, 4.38, 3.50-3.10, 2.98, 2.88, 2.52, 2.46-2.32, 1.54, 0.88, 0.86; LCMS: Retention time 0.89 minutes.

[0338] Example 57(3): 1-{[(3R)-3-methyl-6-(propoxymethyl)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid 1 H-NMR (DMSO-d6): δ 7.09-7.05, 7.02, 6.27, 4.38, 3.50-3.10, 2.98, 2.88, 2.52, 2.46-2.32, 1.54, 0.88, 0.86; LCMS: Retention time 0.89 minutes.

[0339] Example 57(4): 1-{[(3S)-6-(2-ethoxyethyl)-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid 1 H-NMR (CDCl3): δ 7.05-6.95, 6.50, 4.55-4.08, 3.92, 3.69, 3.60, 3.49, 3.00, 2.83, 2.57, 2.49, 1.19, 0.91; LCMS: Retention time 0.86 minutes.

[0340] Example 57(5): 1-{[(3R)-6-(2-ethoxyethyl)-3-methyl-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid 1 H-NMR (CDCl3): δ 7.05-6.95, 6.50, 4.55-4.08, 3.92, 3.69, 3.60, 3.49, 3.00, 2.83, 2.57, 2.49, 1.19, 0.91; LCMS: Retention time 0.86 minutes.

[0341] Comparative Example: (S)-3-fluoro-1-[(6-methoxy-3-methyl-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid. Using the compound prepared in Example 14(1) (300 mg), methyl 3-fluoroazetidine-3-carboxylate hydrochloride (297 mg), and methanol (6.3 mg), the same reaction as in Example 5 → Example 8 → Example 7 was carried out to obtain the title compound (17 mg) having the following physical properties. 1 H-NMR (DMSO-d6): δ 6.99, 6.71, 6.68, 6.27, 3.82-3.64, 3.63-3.35, 3.30-3.15, 2.86, 2.52, 2.36, 0.85; LCMS: Retention time 0.65 minutes.

[0342] The following are examples of biological experiments, and the effects of the compound of the present invention were confirmed based on these experimental methods.

[0343] Biological Experiment Example 1: Evaluation of the S1P receptor agonist activity of the present invention compound by monitoring intracellular calcium concentration Human S1P １ (EDG-1) or Human S1P ５Chinese hamster Owley (CHO) cells, each overexpressing the (EDG-8) gene, were cultured in Ham's F-12 medium containing 10% FBS (fetal bovine serum), penicillin / streptomycin, and Geneticin (0.25 mg / mL). The medium was changed one day before the calcium assay and on the day of the assay. Four hours after the medium change, the medium was removed and washed once with phosphate-buffered saline. After detaching the cells with 0.05% Trypsin EDTA, the medium was added and the cells were collected. The collected cell suspension was centrifuged, the supernatant was removed, and the cells were resuspended in phosphate-buffered saline and counted. 1.1 × 10 ６ Cells were suspended in Hanks solution containing Calcium 6 Assay Reagent (Molecular Devices), 20 mM HEPES, and 2.5 mM Probenecid to a concentration of cells / mL, and incubated at 37°C for approximately 1 hour. The supernatant was then removed by centrifugation, yielding 2.2 × 10⁶ cells. ６ The compounds were suspended in Hanks solution containing 20 mM HEPES, 2.5 mM Probenecid, and 0.1% BSA to a concentration of cells / mL. The suspension was seeded into 96-well plates at 80 μL / well. The plates were placed in a fluorescent drug screening system (FDSS6000), and the compounds and S1P were added sequentially. The increase in intracellular calcium concentration before and after addition was measured at an excitation wavelength of 480 nm and an fluorescence wavelength of 540 nm. The increase in intracellular calcium concentration was evaluated by the signal intensity at the fluorescence wavelength, and the activating activity of each compound was calculated, with the signal intensity when S1P was added instead of the compound being considered 100% activity.

[0344] [Results] S1P of the compound of the present invention １ Receptor or S1P ５ Receptor agonist activity (EC) ５０The values ​​are shown in Table 1. In addition to the comparative examples described herein, comparative compound A was 1-{[1-methyl-6-(octyloxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidine carboxylic acid hydrochloride as described in Example 31 (58) of Patent Document 1, and comparative compound B was 1-({6-[(2-methoxy-4-propylbenzyl)oxy]-1-methyl-3,4-dihydro-2-naphthalenyl}methyl)-3-azetidine carboxylic acid as described in Example 37 of Patent Document 2. Comparative example S1P １ and S1P ５ They did not possess receptor agonist activity. Comparative compound A and comparative compound B were S1P １ and S1P ５ Both possess receptor agonist activity, S1P ５ S1P is more important than receptor agonist activity. １ The receptor agonist activity was stronger. In contrast, all of the compounds of the present invention were S1P ５ It has selective agonistic activity against the receptor, S1P １ S1P for receptors ５ It was found that the balance of receptor agonist activity had improved.

[0345] Biological Experiment Example 2: Measurement of Clearance in Rats A compound solution was administered intravenously to fasted male SD rats. After administration, the rats were manually restrained at regular intervals, and blood was collected from the jugular vein with heparin sodium. The blood was centrifuged at 10,000 g, 3 min, and 4°C to obtain plasma. The compound concentration in the plasma was measured by LC / MS / MS. Clearance was calculated from the plasma concentration profile using the pharmacokinetic analysis software Phoenix WinNonlin (Certara USA, Inc.).

[0346] [Results] Because the compound of the present invention has low clearance, high bioavailability can be expected.

[0347] Biological experiment example 3: [ ３３ P] - S1P of S1P ５ Measurement of the inhibitory effect of comparative compound C on binding to (EDG-8) in human S1P １ (EDG-1) or Human S1P５ Using membrane fractions of Chinese hamster Overley (CHO) cells in which each gene was overexpressed, the reaction was carried out in a 96-well assay plate with 60 μg protein / mL of membrane fraction. Bending Buffer (50 mmol / L, Tris pH 7.5, 5 mmol / L, MgCl) was added to each well. ２ 100 μL of a vehicle (DMSO) solution diluted with 0.5% BSA, Complete EDTA free (1 table / 50 mL) or a compound solution at twice the concentration, and 50 μL of 0.16 nmol / L diluted with Binder Buffer. ３３ After adding P-S1P (American Radiolabeled Chemicals), 50 μL of membrane fraction solution was added and the mixture was reacted at room temperature for 60 minutes. After the reaction, the mixture was filtered by suction using a 96-well UNIFILTER, washed with washing buffer (50 mmol / L, Tris pH 7.5, 0.5% BSA) (150 mL), and then dried at 50-60°C for 30-60 minutes. MicroScint (trade name) 20 (50 μL / well) was added, the plate was covered with TopSeal-A, and the radioactivity was measured using TopCount (Perkin Elmer).

[0348] [Evaluation] Human S1P １ and human S1P ５ to ３３ Compound concentration (IC) that replaces 50% of the specific bond of [P]-S1P ５０ The value was used as an evaluation item. The specific binding amount was [ ３３ [P]-S1P total binding amount (cpm) and [ in vehicle or compound treatment ３３ From the average value (cpm) of the P-S1P binding amount (cpm) [ ３３ [P] - S1P nonspecific binding amount (cpm) was subtracted to determine the result. ３３ The specific binding amount of P-S1P was set to 100%, and the relative value (%) of the specific binding amount at each concentration of the compound was calculated. Among the vehicle or compound treatment concentrations that show a relative value (%) of 25-75%, the treatment concentration that shows the relative value closest to 50% was selected, and the relative value (%) was substituted into Y and the treatment concentration into X in the following formula, and IC was calculated. ５０The value was calculated. Y = 100 / (1 + 10 Ｘ－ｌｏｇＩＣ５０ )

[0349] [Results] As comparative compound C, 3-({[6-(3-cyclohexylpropoxy)-1-methyl-3,4-dihydro-2-naphthalenyl]methyl}amino)propanoate salt described in Example 31 (45) of Patent Document 1 was used. Comparative compound C is, ３３ P] - S1P of S1P １ Or S1P ５ The inhibitory activity (IC) against binding to was 1.0 nmol / L or 8.5 nmol / L, respectively. ５０ The value was shown.

[0350] Biological Experiment Example 4: Efficacy in a Mouse Experimental Autoimmune Encephalomyelitis Model Female C57BL / J mice (Charles River Co., Ltd., age at the start of the experiment: 7 or 8 weeks) were used. Myelin Oligodendrocyte Glycoprotein [sequence 35-55 MEVGWYRSPFSRVVHLYRNGK (AnaSpec Inc, hereafter MOG35-55)] was dissolved in physiological saline (Otsuka Pharmaceutical Factory Co., Ltd.) to prepare a 2 mg / mL solution. An emulsion was prepared by mixing the 2 mg / mL solution of MOG35-55 with an equal volume of FCA H37Ra (Difco Laboratories) and used as an inducer. The mice were immunized by subcutaneous administration of 0.2 mL of the inciter agent into the flank using a glass syringe fitted with a 26G needle. The day of immunization was designated as immunization day 0, and on immunization days 0 and 2, 0.2 mL of a 1 μg / mL solution of Pertussis toxin (List Biological Laboratories) was administered intravenously into the tail vein (see Cell Mol Immunol, Vol. 2, pp. 439-448, 2005).

[0351] Body weight was measured the day before immunization, and participants were divided into groups to ensure that there were no significant differences in the average body weight of each group. After group division, administration of the test substance (compound of the present invention), positive control compound (FTY720; fingolimod), or medium (0.5 w / v% methylcellulose 400 cP solution) was started on the same day. All test substances were administered orally once daily for 30 days, from the day before immunization until day 28 of immunization. The amount of solution administered was calculated based on the individual's body weight on the day of administration.

[0352] Neurological symptoms were evaluated by scoring the degree of paralysis into a neurological symptom score (0: normal, 1: tail flaccidity, 2: hind limb weakness, 3: hind limb paralysis, 4: quadriplegia, 5: mortally ill). Observation was conducted daily from the day before immunization and from days 5 to 29 of immunization, before administration of the test substance, etc. (Reference: Proc. Natl. Acad. Sci. USA, Vol. 103, pp. 13451-13456, 2006).

[0353] [Results] The compound of the present invention demonstrates efficacy in this model.

[0354] [Formulation Example] Formulation Example 1 By mixing the following components by conventional methods and then compressing them into tablets, approximately 10,000 tablets containing 10 mg of the active ingredient per tablet are obtained. • 1-[((3S)-3-methyl-6-pentoxy-3,4-dihydronaphthalene-2-yl)methyl]azetidine-3-carboxylic acid…100 g • Carboxymethylcellulose calcium (disintegrant)…20 g • Magnesium stearate (lubricant)…10 g • Microcrystalline cellulose…870 g

[0355] Formulation Example 2 After mixing the following components by conventional methods, the mixture is filtered through a dust removal filter, filled into 5 ml ampoules, and sterilized by heating in an autoclave to obtain approximately 10,000 ampoules containing 20 mg of the active ingredient per ampoule. • 3-Fluoro-1-[[(3S)-3-methyl-6-[(E)-4,4,4-trifluorobuta-2-enoxy]-3,4-dihydronaphthalene-2-yl]methyl]azetidine-3-carboxylic acid…200 g • Mannitol…20 g • Distilled water…50 L

[0356] The compound of the present invention is selective S1P ５ Because it has receptor agonist activity, S1P ５ It is useful in treating mediated diseases, such as neurodegenerative diseases.

Claims

1. General formula (V) wherein each group is bonded to Z via a bond indicated by an arrow, A represents an optionally substituted C3-7 cycloalkylene group or an optionally substituted C1-4 alkylene group, R １ represents a C1-4 alkyl group, a C3-6 cycloalkyl group which may be substituted with halogen, a C1-4 alkoxy group which may be substituted with halogen, a C1-4 haloalkyl group, a halogen atom, or a hydroxyl group; R ２ represents a C1-4 alkyl group, a C1-4 alkoxy group optionally substituted with halogen, a C1-4 haloalkyl group, a halogen atom, or a hydroxyl group; R ３ , R ４ and R ５ each independently represents a hydrogen atom, a C1-4 alkyl group, a C3-6 cycloalkyl group optionally substituted with halogen, or a C1-4 haloalkyl group, Z represents (1) a carboxyl group optionally substituted with one C1-8 alkyl group, (2) a hydroxyl group optionally substituted with one C1-8 alkyl group, (3) a hydroxamic acid group optionally substituted with one or two C1-8 alkyl groups, (4) a sulfonic acid group optionally substituted with one C1-8 alkyl group, (5) a boronic acid group optionally substituted with one or two C1-8 alkyl groups, (6) a carbamoyl group optionally substituted with (i) one or two C1-8 alkyl groups or (ii) one or two sulfonyl groups optionally substituted with a C1-4 alkyl group, (7) a sulfamoyl group optionally substituted with (i) one or two C1-8 alkyl groups or (ii) one or two C2-8 acyl groups, (8) a sulfoximine group optionally substituted with one or two C1-8 alkyl groups, or (9) a tetrazolyl group; ring2 represents a 3- to 7-membered nitrogen-containing heterocycle, m represents an integer of 0 to 6, n represents an integer of 0 to 5, and when m is 2 or more, a plurality of R １ may be the same or different, and when n is 2 or more, a plurality of R ２ may be the same or different, and wherein each hydrogen atom may be a deuterium atom or a tritium atom, or a pharmaceutically acceptable salt thereof.

2. General formula (V-1) [wherein all symbols have the same meaning as in claim 1, and wherein each hydrogen atom may be a deuterium atom or a tritium atom], or a pharmaceutically acceptable salt thereof.

3. L is (1) —O—(C2-7 alkyl), (2) —O—(C2-7 alkenyl), (3) —O—(C2-7 alkynyl), or (4) —O—(C1-5 alkylene)-OCH ３ , (5) —O—(C1-4 alkylene)-OCH ２ CH ３ , (6)-CH ２ O—(C1-6 alkyl), (7)—CH ２ O—(C2-6 alkenyl), (8)—CH ２ O—(C2-6 alkynyl), (9)—CH ２ CH ２ O—(C1-5 alkyl), (10)—CH ２ CH ２ O—(C2-5 alkenyl), (11)—CH ２ CH ２ O—(C2-5 alkynyl), (12) —S—(C2-7 alkyl), (13) —S—(C2-7 alkenyl), (14) —S—(C2-7 alkynyl), (15) —NR ６ -(C2-7 alkyl), (16)-NR ６ —(C2-7 alkenyl), (17)-NR ６ -(C2-7 alkynyl), (18) a C3-8 alkyl group, (19) a C3-8 alkenyl group, or (20) a C3-8 alkynyl group; R ６ represents a hydrogen atom or a C1-4 alkyl group, wherein the carbon atoms in each group are optionally substituted with 1 to 13 halogen atoms, or a pharmaceutically acceptable salt thereof.

4. The compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, wherein L is a branched or straight chain group having 4 to 7 atoms in the main chain.

5. L is (1) —O—(C3-6 alkyl), (2) —O—(C3-6 alkenyl), (3) —O—(C3-6 alkynyl), or (4) —O—(C1-4 alkylene)-OCH ３ , (5) —O—(C1-3 alkylene)-OCH ２ CH ３ , (6)-CH ２ O—(C2-5 alkyl), (7)—CH ２ O—(C2-5 alkenyl), (8)—CH ２ O—(C2-5 alkynyl), (9)—CH ２ CH ２ O—(C1-4 alkyl), (10)—CH ２ CH ２ O—(C2-4 alkenyl), (11)—CH ２ CH ２ O—(C2-4 alkynyl), (12)—S—(C3-6 alkyl), (13)—S—(C3-6 alkenyl), (14)—S—(C3-6 alkynyl), (15)—NR ６ —(C3-6 alkyl), (16)-NR ６ —(C3-6 alkenyl), (17)-NR ６ -(C3-6 alkynyl), (18) a C4-7 alkyl group, (19) a C4-7 alkenyl group, or (20) a C4-7 alkynyl group; R ６ represents a hydrogen atom or a C1-4 alkyl group, wherein the carbon atoms in each group are optionally substituted with 1 to 13 halogen atoms, or a pharmaceutically acceptable salt thereof.

6. The compound according to any one of 1 to 5, wherein ring 2 is a 3- to 7-membered nitrogen-containing saturated heterocycle, or a pharmaceutically acceptable salt thereof.

7. General formula (V-2) [In the formula, L １ is a branched or linear chain group composed of atoms selected from carbon atoms, oxygen atoms, nitrogen atoms, and sulfur atoms, the main chain of which has 4 to 7 atoms, and the chain group may contain 1 to 3 heteroatoms selected from oxygen atoms, nitrogen atoms, and sulfur atoms, １ carbon atoms in the ring may be substituted with 1 to 13 halogen atoms; ring2-1 represents a 3- to 7-membered nitrogen-containing saturated heterocycle; m-1 represents an integer of 0 to 2; n-1 represents an integer of 0 to 2; and when m-1 is 2, a plurality of R １ may be the same or different, and when n-1 is 2, a plurality of R ２ may be the same or different, other symbols have the same meanings as in claim 1, and each hydrogen atom may be a deuterium atom or a tritium atom.], or a pharmaceutically acceptable salt thereof.

8. The compound according to any one of claims 1 to 7, wherein Z is a carboxyl group optionally substituted with one C1-8 alkyl group, or a tetrazolyl group, or a pharmaceutically acceptable salt thereof.

9. L １ (1) —O—(C3-6 alkyl), (2) —O—(C3-6 alkenyl), (3) —O—(C3-6 alkynyl), (4) —O—(C1-4 alkylene)-OCH ３ , (5) —O—(C1-3 alkylene)-OCH ２ CH ３ , (6)-CH ２ O—(C2-5 alkyl), (7)—CH ２ O—(C2-5 alkenyl), (8)—CH ２ O—(C2-5 alkynyl), (9)—CH ２ CH ２ O—(C1-4 alkyl), (10)—CH ２ CH ２ O—(C2-4 alkenyl), (11)—CH ２ CH ２ O—(C2-4 alkynyl), (12)—S—(C3-6 alkyl), (13)—S—(C3-6 alkenyl), (14)—S—(C3-6 alkynyl), (15)—NR ６ —(C3-6 alkyl), (16)-NR ６ —(C3-6 alkenyl), (17)-NR ６ -(C3-6 alkynyl), (18) a C4-7 alkyl group, (19) a C4-7 alkenyl group, or (20) a C4-7 alkynyl group; R ６ represents a hydrogen atom or a C1-4 alkyl group, wherein the carbon atoms in each group are optionally substituted with 1 to 13 halogen atoms, or a pharmaceutically acceptable salt thereof.

10. R １ The compound according to any one of claims 1 to 9, wherein is a C1-4 alkyl group or a halogen atom, or a pharmaceutically acceptable salt thereof.

11. The compound according to any one of claims 7 to 10, or a pharmaceutically acceptable salt thereof, wherein ring 2-1 is azetidine, pyrrolidine, piperidine, or perhydroazepine.

12. (1) 1-[((3R)-6-butoxy-3-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylic acid, (2) 1-[((3S)-6-butoxy-3-methyl-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylic acid, (3) 1-[((3S)-3-methyl-6-pentoxy-3,4-dihydronaphthalen-2-yl)methyl]azetidine-3-carboxylic acid, (4) 1-[[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,4-di (5) 3-fluoro-1-[[(3S)-3-methyl-6-(3,4,4-trifluorobut-3-enoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid, (6) 1-[[(3S)-3-methyl-6-(1,1,2,2,3,3,4,4,4-nonaduteriobutoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid, (7) (3R)-1-[[(3S)-3-methyl (8) 1-[[(3S)-3-methyl-6-((R)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid, (9) 1-[[(3S)-3-methyl-6-((S)-3,3,3-trifluoro-2-methylpropoxy)-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid, carboxylic acid, or (10) 3-fluoro-1-[[(3S)-3-methyl-6-[(E)-4,4,4-trifluorobut-2-enoxy]-3,4-dihydronaphthalen-2-yl]methyl]azetidine-3-carboxylic acid, (11) 3-fluoro-1-{[(3S)-3-methyl-6-(3,3,3-trifluoropropoxy)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid, (12) cis-3-({1-[(3S)-3-methyl-6-(4,4,4-trifluorobutoxy)-3,The compound according to claim 1 or 2, which is (13) 1-{[(3S)-3-methyl-6-(propoxymethyl)-3,4-dihydro-2-naphthalenyl]methyl}-3-azetidinecarboxylic acid, or a pharmaceutically acceptable salt thereof.

13. A pharmaceutical composition containing the compound represented by formula (V) according to claim 1 or a pharmaceutically acceptable salt thereof.

14. S1P ５ The pharmaceutical composition of claim 13, which is an agonist.

15. S1P ５ The pharmaceutical composition according to claim 13 or 14, which is an agent for preventing and / or treating an intervening disease.

16. S1P ５ 16. The pharmaceutical composition of claim 15, wherein the mediated disease is a neurodegenerative disease, an autoimmune disease, an infectious disease, or cancer.

17. S1P ５ 17. The pharmaceutical composition of claim 16, wherein the intervening disease is a neurodegenerative disease, and the neurodegenerative disease is schizophrenia, Binswanger's disease, multiple sclerosis, neuromyelitis optica, Alzheimer's disease dementia, cognitive impairment, amyotrophic lateral sclerosis, spinocerebellar degeneration, multiple system atrophy, Parkinson's disease, or dementia with Lewy bodies.

18. A method for treating S1P, comprising administering to a mammal an effective amount of a compound represented by general formula (V) according to claim 1 or a pharmaceutically acceptable salt thereof. ５ A method for preventing and / or treating an intervening disease.

19. S1P ５ 2. A compound of formula (V) according to claim 1, or a pharmaceutically acceptable salt thereof, for use in the prevention and / or treatment of an intervening disease.

20. S1P ５ Use of a compound represented by formula (V) according to claim 1 or a pharmaceutically acceptable salt thereof for the manufacture of an agent for the prophylaxis and / or treatment of an intervening disease.