Azabicyclo[3.1.0]hexane compound

Abstract

The present invention provides a new azabicyclo[3.1.0]hexane compound that is represented by the following formula and that is for use in treating central nervous system (CNS) disorders. In the formula, X represents -C(=O)-O- or the like, and R represents H, an optionally substituted C1-C18 alkyl, or the like.

Description

Azabicyclo[3.1.0]hexane compounds

[0001] The present invention relates to novel azabicyclo[3.1.0]hexane compounds and salts thereof, and their use in the treatment of central nervous system (CNS) disorders.

[0002] (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, also known as (+)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, inhibits the reuptake of three biogenic amines: norepinephrine, serotonin, and dopamine (Patent Document 1). (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane is a useful compound as an unbalanced triple reuptake inhibitor (TRI), being most effective against norepinephrine reuptake (NE), six times less effective against dopamine reuptake (DA), and fourteen times less effective against serotonin reuptake (5-HT). Based on these actions, the compounds are useful as therapeutic agents for CNS disorders such as depression, anxiety, and attention-deficit hyperactivity disorder (ADHD).

[0003] In the field of pharmaceuticals, one approach to drug design is to chemically convert or modify some functional groups of known drug molecules in order to improve their efficacy and slow their metabolism in the body. These newly designed compounds may be more stable than known drugs or may be released for a longer period of time in the patient's body, thereby prolonging their efficacy.

[0004] The discovery of novel azabicyclo[3.1.0]hexane compounds to provide new options for therapeutic agents for various CNS disorders is highly desired by patients suffering from these disorders.

[0005] Patent No. 5184354

[0006] One of the problems to be solved by the present invention is to provide a novel therapeutic agent for CNS disorders.

[0007] As a result of extensive research, the present inventors have succeeded in developing novel azabicyclo[3.1.0]hexane compounds and salts thereof represented by the following formula [I], and have found that they can be used as new therapeutic agents for CNS disorders. The present invention was completed based on this finding.

[0008] One embodiment of the present invention is a compound of the following formula [I]: [Wherein, X is: 1) —C(═O)—O—, 2) —C(═O)—O—C(X １１ａ ) (X １２ａ )-OC(=O)-, 3)-C(=O)-OC(X １１ｂ ) (X １２ｂ )-OP(=O)(-OR ２ｂ )-O-, 4)-C(=O)-, 5)-C(=O)-C(X １１ｃ ) (X １２ｃ )-N(X １３ｃ )-C(=O)-, 6)-C(X １１ｄ ) (X １２ｄ )-OC(=O)-, 7)-C(X １１ｅ ) (X １２ｅ )-N(X １３ｅ )-C(=O)-, 8)-C(X １１ｆ ) (X １２ｆ )-OP(=O)(-OR ２ｆ )-O-, 9)-C(X １１ｇ ) (X １２ｇ )-OP(=O)(-OR ２ｇ )-O-C(X １１ｈ ) (X １２ｈ )-O-C(=O)-, or 10)-P(=O)(-OR ２ｉ )-O-; X １１ａ , X １１ｂ , X １１ｃ , X １１ｄ , X １１ｅ , X １１ｆ , X １１ｇ , X １１ｈ , X １２ａ , X １２ｂ , X １２ｃ , X １２ｄ , X １２ｅ , X １２ｆ , X １２ｇ , and X １２ｈare each independently H or optionally substituted C １ -C ６ alkyl or X １１ａ and X １２ａ , X １１ｂ and X １２ｂ , X １１ｃ and X １２ｃ , X １１ｄ and X １２ｄ , X １１ｅ and X １２ｅ , X １１ｆ and X １２ｆ , X １１ｇ and X １２ｇ , and X １１ｈ and X １２ｈ are each, together with the carbon atom to which they are attached, C ３ -C ６ may form a cycloalkane ring or a 3- to 6-membered heterocycloalkane ring; X １３ｃ and X １３ｅ are each independently H or optionally substituted C １ -C ６ alkyl; R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ are each independently: i) H, ii) optionally substituted C １ -C １８ alkyl, iii) optionally substituted C ２ -C １８ alkenyl, iv) optionally substituted C ２ -C １８ a) an optionally substituted 3- to 15-membered hydrocarbon ring group; b) an optionally substituted 3- to 15-membered alkynyl group; c) an optionally substituted 3- to 15-membered hydrocarbon ring group; or d) an optionally substituted 3- to 15-membered heterocyclic group (herein also referred to as "compound of formula [I]").

[0009] By appropriately chemically modifying the nitrogen atom at position 3 of the (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, the compound of formula [I] can have a longer metabolic half-life, primarily in the intestine and liver, than when administered to the body as (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, thereby improving bioavailability. Furthermore, administering the compound of formula [I] can also enhance the duration of its efficacy. Prolonging the metabolic half-life can also lead to a reduction in the number and dose of clinical administration to patients, potentially improving patient compliance.

[0010] The words and terms used in this specification are explained in more detail below.

[0011] Examples of "alkyl" include straight or branched chain alkyls having 1 to 18 carbon atoms (C １ -C １８ alkyl), for example, C １ -C １４ It is an alkyl, and specific examples thereof include methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl, hexyl, isohexyl, 3-methylpentyl, heptyl, octyl, nonyl, decyl, and tetradecyl.

[0012] Examples of "alkenyl" include straight or branched chain alkenyl (C ２ -C １８ alkenyl), and preferably C ２ -C ６ Alkenyl, specifically, vinyl (ethenyl), 1-propenyl, 2-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 3-hexenyl, 5-hexenyl, and the like.

[0013] Examples of "alkynyl" include straight or branched alkynyl (C ２ -C １８ alkynyl), preferably C ２ -C ６ Alkynyl, specifically 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 4-methyl-2-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.

[0014] Examples of "alkoxy" include straight or branched chain alkoxy having 1 to 6 carbon atoms (C １ -C ６ Specific examples thereof include methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy, and 3-methylpentyloxy.

[0015] "Hydroxyalkyl" refers to the above "alkyl" substituted by a hydroxyl group, e.g., hydroxy C １ -C １８ Alkyl, hydroxy C １ -C １４ Alkyl, hydroxy C １ -C １０ Alkyl, hydroxy C １ -C ８ Alkyl, hydroxy C １ -C ６ Alkyl, hydroxy C １ -C ４ Specific examples include hydroxymethyl, hydroxyethyl, and hydroxypropyl.

[0016] Examples of "cycloalkyl" include cyclic alkyls having 3 to 6 carbon atoms (C ３ -C ６Specific examples include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.

[0017] Examples of "cycloalkenyl" include cyclic alkenyl (C) having 3 to 6 carbon atoms and 1 to 3 double bonds. ３ -C ６ Specific examples include 2-cyclopentenyl, 3-cyclopentenyl, 2-cyclohexenyl, and 3-cyclohexenyl.

[0018] Examples of "cycloalkoxy" include cyclic alkoxy having 3 to 6 carbon atoms (C ３ -C ６ Specific examples include cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy, etc.

[0019] Examples of "cycloalkane" or "cycloalkane ring" include saturated monocyclic hydrocarbon rings having 3 to 6 carbon atoms, specifically cyclopropane, cyclobutane, cyclopentane, cyclohexane, and the like.

[0020] Examples of "heterocycloalkane" or "heterocycloalkane ring" include 3- to 6-membered saturated monocyclic rings containing carbon atoms and 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur, and specifically include aziridine, oxirane, thiirane, azetidine, oxetane, thietane, azolidine, oxolane, thiolane, adinane, oxane, thiane, dioxolane, dioxane, morpholine, and the like.

[0021] "Alkanoyl" or "acyl" refers to any group such as the above-mentioned "alkyl", "alkenyl", "alkynyl", or "cycloalkyl" bonded to a carbonyl group, and is also represented as, for example, R'-C(=O)- (where R' represents any group). Specific examples include acetyl, propionyl, acryloyl, and cyclohexanecarbonyl.

[0022] "Alkanoyloxy" or "acyloxy" refers to an "alkanoyl" or "acyl" group having an oxygen atom bonded thereto, and is also represented by, for example, R'-C(=O)-O- (wherein R' represents any group). １ -C ６ Examples thereof include alkyl-C(=O)-O-.

[0023] Examples of "aryl" include monocyclic, bicyclic, or tricyclic aromatic hydrocarbons having 6 to 14 carbon atoms (C ６ -C １４ aryl), preferably C ６ -C １０ Examples thereof include aryl, specifically phenyl, naphthyl, anthryl, phenanthryl, and the like.

[0024] Examples of "aralkyl" include straight or branched alkyl groups having 1 to 3 carbon atoms substituted with a monocyclic, bicyclic, or tricyclic aromatic hydrocarbon group having 6 to 14 carbon atoms (C ７ -C １７ aralkyl), preferably C ７ -C １２ Examples include aralkyl, and specific examples include benzyl, 1-phenylethyl, 2-phenylethyl, 1-naphthylmethyl, and 2-naphthylmethyl.

[0025] Examples of the "hydrocarbon ring" include saturated or unsaturated monocyclic or polycyclic hydrocarbon rings, such as saturated or unsaturated 3- to 15-membered hydrocarbon rings, preferably 3- to 14-membered saturated hydrocarbon rings or 6- to 14-membered unsaturated hydrocarbon rings. More preferably, it includes a 6- to 10-membered monocyclic, bicyclic, or tricyclic unsaturated hydrocarbon ring; or a 3- to 10-membered monocyclic, bicyclic, or tricyclic saturated hydrocarbon ring. An "unsaturated" ring refers to an aromatic ring or a ring in which the bonds between ring atoms of an aromatic ring are partially hydrogenated. Ring atoms of the hydrocarbon ring may be substituted with oxo to form oxide. Specific examples of the "hydrocarbon ring" include: (a) saturated or unsaturated 3- to 8-membered, preferably 5- or 6-membered, more preferably 6-membered monocyclic hydrocarbon ring; specific examples include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cycloheptane, cyclooctane, cyclobutene, cyclopentene, cyclohexene, cycloheptene, cyclooctene, benzene, etc.; (b) saturated or unsaturated 7- to 15-membered bicyclic or tricyclic hydrocarbon ring, preferably saturated or unsaturated 7- to 14-membered, more preferably 7- to 10-membered bicyclic hydrocarbon ring; specific examples include indene, dihydroindene, naphthalene, dihydronaphthalene, tetrahydronaphthalene, decahydronaphthalene, anthracene, phenanthrene, etc.

[0026] Examples of "heterocycles" include saturated or unsaturated monocyclic or polycyclic heterocycles containing 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur as ring-constituting atoms, including, for example, saturated or unsaturated 3- to 15-membered, preferably 5- to 10-membered, monocyclic, bicyclic, or tricyclic heterocycles. An "unsaturated" ring refers to an aromatic ring or a ring in which the bonds between ring atoms of an aromatic ring are partially hydrogenated. A "nitrogen-containing heterocycle" refers to a heterocycle containing at least one nitrogen atom as a ring-constituting atom. A ring atom of a heterocycle may be substituted with oxo to form an oxide or dioxide. Specific examples of the "heterocycle" include: (a) saturated or unsaturated 3- to 8-membered, preferably 3- to 6-membered, more preferably 5- or 6-membered monocyclic heterocycles containing 1 to 4 nitrogen atoms as ring-constituting atoms; specifically, pyrrole, imidazole, pyrazole, pyridine, dihydropyridine, tetrahydropyridine, pyrimidine, pyrazine, pyridazine, triazole, tetrazole, dihydrotriazine, azetidine, pyrrolidine, imidazolidine, piperidine, pyrazolidine, piperazine, azepane, 1,4-diazepane, etc.; (b) saturated or unsaturated 7- to 15-membered bicyclic or tricyclic heterocycles containing 1 to 5 nitrogen atoms as ring-constituting atoms, preferably saturated or unsaturated 7- to 12-membered, more preferably 7- to 10-membered bicyclic or tricyclic heterocycles containing 1 to 3 nitrogen atoms as ring-constituting atoms;Specific examples thereof include indole, indoline (dihydroindole), isoindole, isoindoline (dihydroisoindole), benzimidazole, dihydrobenzimidazole, indazole, indazoline (dihydroindazole), quinoline, dihydroquinoline, tetrahydroquinoline, decahydroquinoline, isoquinoline, dihydroisoquinoline, tetrahydroisoquinoline, benzotriazole, tetrazolopyridine, tetrazolopyridazine, dihydrotriazolopyridazine, imidazopyridine, naphthyridine, tetrahydronaphthyridine, hexahydronaphthyridine, cinnoline, quinoxaline, dihydroquinoxaline, tetrahydroquinoxaline, quinazoline, dihydroquinazoline, tetrahydroquinazoline, pyrazolopyridine, tetrahydropyridoindole, benzazepine, tetrahydrobenzazepine, carbazole, phenanthridine, and dihydrophenanthridine; (c) saturated or unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic heterocycles containing one or two oxygen atoms as ring-constituting atoms; specifically, furan, tetrahydropyran, tetrahydrofuran, dioxane, etc.; (d) saturated or unsaturated 7- to 12-membered, preferably 7- to 10-membered bicyclic heterocycles containing one to three oxygen atoms as ring-constituting atoms; specifically, benzofuran, dihydrobenzofuran, chroman, benzodioxole, benzodioxane, etc.; (e) saturated or unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic heterocycles containing one sulfur atom as a ring-constituting atom; specifically, thiophene, etc.; (f) saturated or unsaturated 7- to 12-membered, preferably 7- to 10-membered bicyclic heterocycles containing one to three sulfur atoms as ring-constituting atoms; specifically, benzothiophene, etc.; (g) saturated or unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic heterocycles containing one or two oxygen atoms and one to three nitrogen atoms as ring-constituting atoms; specifically, oxazole, isoxazole, oxadiazole, morpholine, etc.; (h) saturated or unsaturated 7- to 12-membered, preferably 7- to 10-membered bicyclic heterocycles containing one or two oxygen atoms and one to three nitrogen atoms as ring-constituting atoms;Specific examples include benzoxazole, dihydrobenzoxazole, benzoxadiazole, benzisoxazole, benzoxazine, dihydrobenzoxazine, furopyridine, furopyrrole, benzoxazepine, tetrahydrobenzoxazepine, etc.; (i) saturated or unsaturated 3- to 8-membered (preferably 5- or 6-membered) monocyclic heterocycles containing one or two sulfur atoms and one to three nitrogen atoms as ring-constituting atoms; specific examples include thiazole, thiazoline (dihydrothiazole), thiadiazole, isothiazole, thiazolidine, etc.; (j) saturated or unsaturated 7- to 12-membered, preferably 7- to 10-membered, bicyclic heterocycles containing one or two sulfur atoms and one to three nitrogen atoms as ring-constituting atoms; specific examples include benzothiazole, dihydrobenzothiazole, benzothiadiazole, thienopyridine, imidazothiazole, dihydroimidazothiazole, thienopyrazine, benzothiazine, dihydrobenzothiazine, benzothiazepine, tetrahydrobenzothiazepine, etc.; and (k) saturated or unsaturated 7- to 12-membered, preferably 7- to 10-membered, bicyclic heterocycles containing one or two oxygen atoms and one to three sulfur atoms as ring-constituting atoms; specific examples include benzoxathiin, etc.;

[0027] Examples of "heteroaryl" include monocyclic or polycyclic aromatic rings containing 1 to 5 heteroatoms independently selected from the group consisting of nitrogen, oxygen, and sulfur as ring-constituting atoms, including, for example, 3- to 15-membered monocyclic, bicyclic, or tricyclic aromatic rings. Preferred heteroaryls are 5- to 10-membered heteroaryls. Specific examples of heteroaryls include pyridyl, imidazolyl, triazolyl, indolyl, quinolinyl, oxazolyl, thiazolyl, and the like.

[0028] Examples of "halogen" include fluorine, chlorine, bromine, and iodine, and preferably fluorine, chlorine, or bromine. More preferred examples are fluorine and chlorine.

[0029] Each group defined in the present specification may be bonded to another group as appropriate via a linker such as —O—, —C(═O)—, —C(═O)—O—, —S—, —S(═O)—, —S(═O)(═O)—, or —O—C(═O)—.

[0030] As used herein, examples of the "substituent" in the term "optionally substituted α" (wherein α means any group described herein) include: (A) halogen, (B) -CN, (C) -NO. ２ , (D)=N-OH, (E)-OH, (F)-CHO, (G)-COOH, (H)-SO ３ H, (I)-SO ２H, (J) -SH, (K) = O, (L) = S, (M) alkyl which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (N) alkenyl which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (O) alkynyl which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (P) alkoxy which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (Q) alkenyl-O- which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (R) alkynyl-O- which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (S) alkyl-CO- which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (T) alkenyl-CO— which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (U) alkynyl-CO— which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (V) alkyl-COO— which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (W) alkoxy-CO— which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (X) alkyl-S— which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (Y) alkyl-SO— which may have at least one group independently selected from the substituent groups (Ia) and (Ib), (Z) alkyl-SO— which may have at least one group independently selected from the substituent groups (Ia) and (Ib). ２-, (AA) cycloalkyl optionally having at least one group independently selected from the substituent groups (Ia), (Ib), (Ic) and ═O, (BB) cycloalkoxy optionally having at least one group independently selected from the substituent groups (Ia), (Ib), (Ic) and ═O, (CC) cycloalkenyl optionally having at least one group independently selected from the substituent groups (Ia), (Ib), (Ic) and ═O, (DD) cycloalkenyl-O— optionally having at least one group independently selected from the substituent groups (Ia), (Ib), (Ic) and ═O, (EE) cycloalkyl-CO— optionally having at least one group independently selected from the substituent groups (Ia), (Ib), (Ic) and ═O, (FF) cycloalkoxy-CO— optionally having at least one group independently selected from the substituent groups (Ia), (Ib), (Ic) and ═O, (GG) aryl optionally having at least one group independently selected from the substituent groups (Ia), (Ib) and (Ic), (HH) aryl-O- optionally having at least one group independently selected from the substituent groups (Ia), (Ib) and (Ic), (II) aryl-CO- optionally having at least one group independently selected from the substituent groups (Ia), (Ib) and (Ic), (JJ) aryl-O-CO- optionally having at least one group independently selected from the substituent groups (Ia), (Ib) and (Ic), (KK) aralkyl optionally having at least one group independently selected from the substituent groups (Ia), (Ib) and (Ic), (LL) aralkyl-O- optionally having at least one group independently selected from the substituent groups (Ia), (Ib) and (Ic), (MM) aralkyl-CO- optionally having at least one group independently selected from the substituent groups (Ia), (Ib) and (Ic), (NN) an aralkyl-O—CO— group which may have at least one group independently selected from the substituent groups (Ia), (Ib), and (Ic); (OO) a heterocyclic group which may have at least one group independently selected from the substituent groups (Ia), (Ib), (Ic), and ═O;(PP) heterocycle-O- optionally having at least one group independently selected from the substituent groups (Ia), (Ib), (Ic) and ═O, (QQ) heterocycle-CO- optionally having at least one group independently selected from the substituent groups (Ia), (Ib), (Ic) and ═O, (RR) heterocycle-O-CO- optionally having at least one group independently selected from the substituent groups (Ia), (Ib), (Ic) and ═O, (SS) amino optionally having at least one group independently selected from the substituent groups (Ia) and (Ic), and (TT) carbamoyl optionally having at least one group independently selected from the substituent groups (Ia) and (Ic). The number of substituents in the compound of formula [I] is not limited as long as it is chemically permissible, and examples thereof include 1 to 10, 1 to 8, 1 to 6, 1 to 4, and 1 to 3. When α is amino or carbamoyl, the number of substituents on α is 1 or 2. The substituent may be bonded to any atom, such as a carbon atom or a heteroatom, as long as it is chemically permissible.

[0031] "Substituent group (Ia)" means (a) alkyl-CO- which may have at least one group independently selected from substituent groups (IIa) and (IIb), (b) alkenyl-CO- which may have at least one group independently selected from substituent groups (IIa) and (IIb), (c) alkynyl-CO- which may have at least one group independently selected from substituent groups (IIa) and (IIb), (d) alkoxy-CO- which may have at least one group independently selected from substituent groups (IIa) and (IIb), (e) alkyl-S- which may have at least one group independently selected from substituent groups (IIa) and (IIb), (f) alkyl-SO- which may have at least one group independently selected from substituent groups (IIa) and (IIb), (g) alkyl-SO- which may have at least one group independently selected from substituent groups (IIa) and (IIb). ２-, (h) cycloalkyl optionally having at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and ═O, (i) cycloalkoxy optionally having at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and ═O, (j) cycloalkenyl optionally having at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and ═O, (k) cycloalkyl-CO— optionally having at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and ═O, (l) cycloalkoxy-CO— optionally having at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and ═O, (m) aryl optionally having at least one group independently selected from the substituent groups (IIa), (IIb) and (IIc), (n) aryl-CO— optionally having at least one group independently selected from the substituent groups (IIa), (IIb) and (IIc), (o) aryl-O-CO- optionally having at least one group independently selected from the substituent groups (IIa), (IIb) and (IIc), (p) aralkyl optionally having at least one group independently selected from the substituent groups (IIa), (IIb) and (IIc), (q) aralkyl-CO- optionally having at least one group independently selected from the substituent groups (IIa), (IIb) and (IIc), (r) aralkyl-O-CO- optionally having at least one group independently selected from the substituent groups (IIa), (IIb) and (IIc), (s) a heterocyclic group optionally having at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and ═O, (t) heterocycle-CO- optionally having at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and ═O, (v) heterocycle -O-CO- which may have at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and ═O, and (w) carbamoyl which may have at least one group independently selected from the substituent groups (IIa) and (IIc).

[0032] The "substituent group (Ib)" includes: (a) halogen, (b) -CN, and (c) -NO. ２ , (d)-OH, (e)-CHO, (f)-COOH, (g)-SO ３ H, (h) -SH, (i) alkoxy optionally having at least one group independently selected from the substituent groups (IIa) and (IIb), (j) alkenyl-O- optionally having at least one group independently selected from the substituent groups (IIa) and (IIb), (k) alkynyl-O- optionally having at least one group independently selected from the substituent groups (IIa) and (IIb), (l) alkyl-COO- optionally having at least one group independently selected from the substituent groups (IIa) and (IIb), (m) cycloalkenyl-O- optionally having at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and =O, (n) aryl-O- optionally having at least one group independently selected from the substituent groups (IIa), (IIb) and (IIc), (o) aralkyl-O- optionally having at least one group independently selected from the substituent groups (IIa), (IIb) and (IIc), (p) heterocycle-O- which may have at least one group independently selected from the substituent groups (IIa), (IIb), (IIc) and ═O, and (q) amino which may have at least one group independently selected from the substituent groups (IIa) and (IIc).

[0033] "Substituent group (Ic)" is a group consisting of: (a) alkyl which may have at least one group independently selected from substituent groups (IIa) and (IIb); (b) alkenyl which may have at least one group independently selected from substituent groups (IIa) and (IIb); and (c) alkynyl which may have at least one group independently selected from substituent groups (IIa) and (IIb).

[0034] "Substituent group (IIa)" includes -CHO, alkyl-CO-, alkenyl-CO-, alkynyl-CO-, alkoxy-CO-, alkyl-SO ２-, cycloalkyl, cycloalkoxy, cycloalkenyl, cycloalkyl-CO-, cycloalkoxy-CO-, aryl, aryl-CO-, aryl-O-CO-, aralkyl, aralkyl-CO-, aralkyl-O-CO-, heterocycle, heterocycle-CO-, heterocycle-O-CO-, mono- or di-(alkyl-CO)-carbamoyl, and mono- or di-alkylcarbamoyl.

[0035] "Substituent group (IIb)" includes halogen, -CN, -NO ２ , -OH, -COOH, -SO ３ H, -SH, -NH ２ , alkoxy, alkenyl-O—, alkynyl-O—, alkyl-COO—, alkyl-S—, alkyl-SO—, cycloalkenyl-O—, aryl-O—, aralkyl-O—, heterocycle-O—, mono- or di-alkylamino, mono- or di-(alkyl-CO)-amino, mono- or di-alkoxycarbonylamino, mono- or di-arylcarbonylamino, and mono- or di-aralkylcarbonylamino.

[0036] "Substituent group (IIc)" is a group consisting of alkyl, alkenyl, and alkynyl.

[0037] The present invention includes the following exemplary embodiments: Item 1. Formula [I]: [Wherein, X is: 1) —C(═O)—O—, 2) —C(═O)—O—C(X １１ａ ) (X １２ａ )-OC(=O)-, 3)-C(=O)-OC(X １１ｂ ) (X １２ｂ )-OP(=O)(-OR ２ｂ )-O-, 4)-C(=O)-, 5)-C(=O)-C(X １１ｃ ) (X １２ｃ )-N(X １３ｃ )-C(=O)-, 6)-C(X １１ｄ ) (X １２ｄ )-OC(=O)-, 7)-C(X １１ｅ ) (X １２ｅ )-N(X １３ｅ )-C(=O)-, 8)-C(X １１ｆ ) (X１２ｆ )-OP(=O)(-OR ２ｆ )-O-, 9)-C(X １１ｇ ) (X １２ｇ )-OP(=O)(-OR ２ｇ )-O-C(X １１ｈ ) (X １２ｈ )-O-C(=O)-, or 10)-P(=O)(-OR ２ｉ )-O-; X １１ａ , X １１ｂ , X １１ｃ , X １１ｄ , X １１ｅ , X １１ｆ , X １１ｇ , X １１ｈ , X １２ａ , X １２ｂ , X １２ｃ , X １２ｄ , X １２ｅ , X １２ｆ , X １２ｇ , and X １２ｈ are each independently H or optionally substituted C １ -C ６ alkyl or X １１ａ and X １２ａ , X １１ｂ and X １２ｂ , X １１ｃ and X １２ｃ , X １１ｄ and X １２ｄ , X １１ｅ and X １２ｅ , X １１ｆ and X １２ｆ , X １１ｇ and X １２ｇ , and X １１ｈ and X １２ｈ are each, together with the carbon atom to which they are attached, C ３ -C ６ may form a cycloalkane ring or a 3- to 6-membered heterocycloalkane ring; X １３ｃ and X １３ｅ are each independently H or optionally substituted C １ -C ６ alkyl; R, R ２ｂ , R ２ｆ , R ２ｇ and R２ｉ are each independently: i) H, ii) optionally substituted C １ -C １８ alkyl, iii) optionally substituted C ２ -C １８ alkenyl, iv) optionally substituted C ２ -C １８ v) an optionally substituted 3- to 15-membered hydrocarbon ring group, or vi) an optionally substituted 3- to 15-membered heterocyclic group, or a salt thereof.

[0038] Item 2. R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ When substituted, each independently represents: 1) C １ -C ６ Alkyl, 2) Hydroxy C １ -C ６ alkyl, 3) optionally substituted C ３ -C ６ cycloalkyl, 4)-C(=O)-O-R １１ａ , 5)-OC(=O)-R １１ｂ , 6)-C(=O)-N(R １２ａ )-R １３ａ , 7)-N(R １２ｂ )-C(=O)-R １３ｂ , 8)-N (R １２ｃ )-C(=O)-OR ２０ , 9)-SR １４ , 10)-OR １５ , 11)-N(R １２ｄ )-R １６ , 12)-S(=O)(=O)-OR １７ , 13)-OP(=O)(OR １８ ) -OR １９ 14) optionally substituted 6- to 14-membered aryl, 15) optionally substituted 3- to 15-membered heterocyclic group, 16) halogen, and 17) cyano, wherein R, R ２ｂ , R ２ｆ , R ２ｇ or R２ｉ ii) optionally substituted C １ -C １８ alkyl, iii) optionally substituted C ２ -C １８ alkenyl, or iv) optionally substituted C ２ -C １８ When R is alkynyl, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ The substituents of are: 1) C １ -C ６ Alkyl, or 2) hydroxy C １ -C ６ Not alkyl; R １１ａ , R １１ｂ , R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １３ａ , R １３ｂ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ are each independently H, optionally substituted C １ -C ６ Item 2. The compound or salt thereof according to Item 1, wherein R is alkyl, an optionally substituted 3- to 15-membered hydrocarbon ring group, or an optionally substituted 3- to 15-membered heterocyclic group.

[0039] Item 3. R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ are each independently: i) H, ii) optionally substituted C １ -C １８ alkyl, iii) optionally substituted C ２ -C ６ alkenyl, iv) optionally substituted C ２ -C ６ alkynyl, v) optionally substituted C ３ -C ６vi) an optionally substituted 6- to 10-membered aryl, or vii) an optionally substituted 5- to 10-membered heterocyclic group; where R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ When substituted, each independently represents: 1) C １ -C ６ Alkyl, 2) Hydroxy C １ -C ６ alkyl, 3) 1 to 3 C １ -C ６ C optionally substituted with alkyl ３ -C ６ cycloalkyl, 4)-C(=O)-O-R １１ａ , 5)-OC(=O)-R １１ｂ , 6)-C(=O)-N(R １２ａ )-R １３ａ , 7)-N(R １２ｂ )-C(=O)-R １３ｂ , 8)-N (R １２ｃ )-C(=O)-OR ２０ , 9)-SR １４ , 10)-OR １５ , 11)-N(R １２ｄ )-R １６ , 12)-S(=O)(=O)-OR １７ , 13)-OP(=O)(OR １８ ) -OR １９ 14) optionally substituted 6- to 10-membered aryl (wherein the optionally substituted 6- to 10-membered aryl is C １ -C ６ Alkyl, hydroxy C １ -C ６ Alkyl and C １ -C ６ alkanoyloxy), 15) an optionally substituted 5- to 10-membered heterocyclic group (wherein the optionally substituted 5- to 10-membered heterocyclic group is selected from the group consisting of C １ -C ６ Alkyl and C １ -C６ 15) a 5- to 10-membered heterocyclic group optionally substituted with 1 to 3 groups of the same or different kind selected from the group consisting of alkanoyloxy), 16) halogen, and 17) cyano, provided that R, R are preferably substituted with 1 to 3 groups of the same or different kind selected from the group consisting of ２ｂ , R ２ｆ , R ２ｇ or R ２ｉ ii) optionally substituted C １ -C １８ alkyl, iii) optionally substituted C ２ -C ６ alkenyl, or iv) optionally substituted C ２ -C ６ When R is alkynyl, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ The substituents of are: 1) C １ -C ６ Alkyl, or 2) hydroxy C １ -C ６ Not alkyl; R １１ａ , R １１ｂ , R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １３ａ , R １３ｂ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ are each independently H, optionally substituted C １ -C ６ alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, wherein said optionally substituted C １ -C ６ The alkyl may be substituted with 1 to 2 groups, the same or different, selected from the group consisting of optionally substituted phenyl and amino, and the optionally substituted 6- to 10-membered aryl may be substituted with hydroxyC１ -C ６ Alkyl and C １ -C ６ and the optionally substituted 5- to 10-membered heteroaryl is optionally substituted with 1 to 3 groups selected from the group consisting of alkoxy, the same or different, and 1 to 3 groups selected from the group consisting of hydroxy, C １ -C ６ Item 3. The compound or salt thereof according to Item 1 or 2, which may be substituted with alkyl.

[0040] Item 4. X is -C(=O)-O-, -C(=O)-O-C(X １１ａ ) (X １２ａ )-O-C(=O)-, -C(=O)-, -C(=O)-C(X １１ｃ ) (X １２ｃ )-N(X １３ｃ )-C(=O)-, or -P(=O)(-OR ２ｉ )-O-; X １１ａ , X １１ｃ , X １２ａ and X １２ｃ are each independently H or C １ -C ６ is alkyl; １３ｃ is C １ -C ６ alkyl; R and R ２ｉ each independently represents an optionally substituted C １ -C １８ Alkyl or optionally substituted C ３ -C ６ cycloalkyl, where R and R ２ｉ is substituted, -C(=O)-O-R １１ａ , -NH-C(=O)-OR ２０ , -NH-R １６ and optionally substituted 6- to 10-membered aryl, wherein the optionally substituted 6- to 10-membered aryl is C １ -C ６ Alkyl and C １ -C ６alkanoyloxy; R １１ａ is H or optionally substituted C １ -C ６ alkyl, wherein the optionally substituted C １ -C ６ The alkyl group may be the same or different, and may be 1 to 3 C １ -C ６ optionally substituted with phenyl optionally substituted with alkoxy; R １６ is H or C １ -C ６ alkyl; R ２０ is C １ -C ６ Item 4. The compound or salt thereof according to any one of Items 1 to 3, wherein R is alkyl.

[0041] Item 5. X is -C(=O)-O-, -C(=O)-O-C(X １１ａ ) (X １２ａ )-O-C(=O)-, or -C(=O)-; X １１ａ and X １２ａ Item 5. The compound or salt thereof according to Item 4, wherein each of R, R, and R is independently H or methyl.

[0042] Item 6. The compound or salt thereof according to any one of Items 1 to 5 for use in treating a central nervous system (CNS) disorder.

[0043] Item 7. A pharmaceutical composition comprising the compound or salt thereof according to any one of Items 1 to 5 and a pharmaceutically acceptable carrier.

[0044] Item 8. The pharmaceutical composition according to Item 7, for use in treating a central nervous system (CNS) disorder.

[0045] Item 9. Use of the compound or salt thereof according to any one of Items 1 to 5, or the pharmaceutical composition according to Item 7, in the manufacture of a therapeutic agent for a central nervous system (CNS) disorder.

[0046] Item 10. A method for treating a central nervous system (CNS) disorder, comprising administering a therapeutically effective amount of the compound or salt thereof according to any one of items 1 to 5, or the composition according to item 7, to a subject.

[0047] Item 11. An agent for treating and / or preventing a central nervous system (CNS) disorder, comprising the compound according to any one of items 1 to 5 or a salt thereof.

[0048] In a preferred embodiment, R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ are each independently: i) H, ii) optionally substituted C １ -C １８ alkyl, iii) optionally substituted C ２ -C ６ alkenyl, iv) optionally substituted C ２ -C ６ alkynyl, v) optionally substituted C ３ -C ６ vi) an optionally substituted 6- to 10-membered aryl; or vii) an optionally substituted 5- to 10-membered heterocyclic group.

[0049] In a preferred embodiment, the compound of formula [I]: [Wherein, X is: 1) —C(═O)—O—, 2) —C(═O)—O—C(X １１ａ ) (X １２ａ )-OC(=O)-, 3)-C(=O)-OC(X １１ｂ ) (X １２ｂ )-OP(=O)(-OR ２ｂ )-O-, 4)-C(=O)-, 5)-C(=O)-C(X １１ｃ ) (X １２ｃ )-N(X １３ｃ )-C(=O)-, 6)-C(X １１ｄ ) (X １２ｄ )-OC(=O)-, 7)-C(X １１ｅ ) (X １２ｅ )-N(X １３ｅ )-C(=O)-, 8)-C(X １１ｆ ) (X １２ｆ )-OP(=O)(-OR ２ｆ )-O-, 9)-C(X １１ｇ ) (X １２ｇ )-OP(=O)(-OR ２ｇ )-O-C(X１１ｈ ) (X １２ｈ )-O-C(=O)-, or 10)-P(=O)(-OR ２ｉ )-O-; X １１ａ , X １１ｂ , X １１ｃ , X １１ｄ , X １１ｅ , X １１ｆ , X １１ｇ , X １１ｈ , X １２ａ , X １２ｂ , X １２ｃ , X １２ｄ , X １２ｅ , X １２ｆ , X １２ｇ , and X １２ｈ are each independently H or optionally substituted C １ -C ６ alkyl or X １１ａ and X １２ａ , X １１ｂ and X １２ｂ , X １１ｃ and X １２ｃ , X １１ｄ and X １２ｄ , X １１ｅ and X １２ｅ , X １１ｆ and X １２ｆ , X １１ｇ and X １２ｇ , and X １１ｈ and X １２ｈ are each, together with the carbon atom to which they are attached, C ３ -C ６ may form a cycloalkane ring or a 3- to 6-membered heterocycloalkane ring; X １３ｃ and X １３ｅ are each independently H or optionally substituted C １ -C ６ alkyl; R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ are each independently: i) H, ii) optionally substituted C １ -C １８ alkyl, iii) optionally substituted C ２ -C６ alkenyl, iv) optionally substituted C ２ -C ６ alkynyl, v) optionally substituted C ３ -C ６ vi) an optionally substituted 6- to 10-membered aryl, or vii) an optionally substituted 5- to 10-membered heterocyclic group; where R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ When substituted, each independently represents: 1) C １ -C ６ Alkyl, 2) Hydroxy C １ -C ６ alkyl, 3) optionally substituted C ３ -C ６ Cycloalkyl (preferably 1 to 3 (preferably 1) C, which may be the same or different) １ -C ６ C optionally substituted with alkyl ３ -C ６ cycloalkyl), 4) -C(=O)-O-R １１ａ , 5)-OC(=O)-R １１ｂ , 6)-C(=O)-N(R １２ａ )-R １３ａ , 7)-N(R １２ｂ )-C(=O)-R １３ｂ , 8)-N (R １２ｃ )-C(=O)-OR ２０ , 9)-SR １４ , 10)-OR １５ , 11)-N(R １２ｄ )-R １６ , 12)-S(=O)(=O)-OR １７ , 13)-OP(=O)(OR １８ ) -OR １９ 14) optionally substituted 6- to 10-membered aryl (wherein the optionally substituted 6- to 10-membered aryl is preferably C １ -C ６ Alkyl, hydroxy C １ -C ６ Alkyl and C １ -C６ alkanoyloxy, wherein a preferred example of the 6- to 10-membered aryl is phenyl); 15) an optionally substituted 5- to 10-membered heterocyclic group (wherein the optionally substituted 5- to 10-membered heterocyclic group is preferably C １ -C ６ Alkyl and C １ -C ６ alkanoyloxy, wherein a preferred 5- to 10-membered heterocyclic group is a 5- to 6-membered heterocyclic group, for example, selected from the group consisting of pyridyl and dihydropyridyl), 16) halogen, and 17) cyano, which may be substituted with one or more groups, preferably 1 to 3 groups, more preferably 1 to 2 groups, of the same or different types, selected from the group consisting of R, R ２ｂ , R ２ｆ , R ２ｇ or R ２ｉ ii) optionally substituted C １ -C １８ alkyl, iii) optionally substituted C ２ -C ６ alkenyl, or iv) optionally substituted C ２ -C ６ When R is alkynyl, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ The substituents of are: 1) C １ -C ６ Alkyl, or 2) hydroxy C １ -C ６ Not alkyl; R １１ａ , R １１ｂ , R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １３ａ , R １３ｂ , R １４ , R １５ , R １６ , R１７ , R １８ , R １９ , and R ２０ are each independently H, optionally substituted C １ -C ６ alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl, wherein said optionally substituted C １ -C ６ Alkyl is C １ -C ６ C optionally substituted with 1 to 2 identical or different groups selected from the group consisting of alkyl, or optionally substituted phenyl and amino １ -C ６ alkyl, wherein the optionally substituted phenyl is selected from the group consisting of 1 to 3 (preferably 1) C １ -C ６ The optionally substituted 6- to 10-membered aryl is preferably hydroxyC １ -C ６ Alkyl and C １ -C ６ phenyl optionally substituted with 1 to 3 (preferably 1) groups of the same or different kind selected from the group consisting of alkoxy, and the optionally substituted 5- to 10-membered heteroaryl is preferably selected from the group consisting of 1 to 3 (preferably 1) hydroxy C １ -C ６ and pyridyl optionally substituted with alkyl, or a salt thereof.

[0050] In some embodiments, X is —C(═O)—O—, —C(═O)—O—C(X １１ ) (X １２ )-O-C(=O)-, -C(=O)-, -C(=O)-C(X １１ ) (X １２ ) N (X １３ )-C(=O)-, or -P(=O)(-OR ２ )-O-; X １１ and X １２ are each independently H or C１ -C ６ is alkyl; １３ is C １ -C ６ It is alkyl.

[0051] In some embodiments, R １１ａ , R １１ｂ , R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １３ａ , R １３ｂ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ are each independently H, optionally substituted C １ -C ６ alkyl, an optionally substituted 3- to 15-membered hydrocarbon ring group, or an optionally substituted 3- to 15-membered heterocyclic group. １１ａ , R １１ｂ , R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １３ａ , R １３ｂ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ are each independently H, optionally substituted C １ -C ６ alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl. １ -C ６ Alkyl is C １ -C ６alkyl, or, when substituted, may be substituted with 1 to 2 groups, the same or different, selected from the group consisting of optionally substituted phenyl and amino; said optionally substituted 6- to 10-membered aryl may be substituted with 1 to 3 hydroxy C groups, the same or different １ -C ６ Alkyl, or C １ -C ６ and the optionally substituted 5- to 10-membered heteroaryl may be substituted with 1 to 3 hydroxy C １ -C ６ It may be substituted with alkyl.

[0052] In a more preferred embodiment, R １１ａ , R １１ｂ , and R １３ｂ are each independently H; amino, phenyl, or C １ -C ６ C optionally substituted with alkoxyphenyl １ -C ６ Alkyl; C １ -C ６ Alkyl, hydroxy C １ -C ６ Alkyl, or C １ -C ６ phenyl optionally substituted with alkoxy; or hydroxy C １ -C ６ and pyridinyl optionally substituted with alkyl.

[0053] In some embodiments, R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １３ａ , R １４ , R １５ , R １６ , and R １７ are each independently H or optionally substituted C １ -C ６ Preferably, R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １３ａ , R１４ , R １５ , R １６ , and R １７ are each independently H or C １ -C ６ It is alkyl.

[0054] In some embodiments, R １８ and R １９ are each independently H or optionally substituted C １ -C ６ Preferably, R １８ and R １９ are each independently H or C １ -C ６ It is alkyl.

[0055] In some embodiments, R ２０ is H or optionally substituted C １ -C ６ Preferably, R ２０ is H, C １ -C ６ C optionally substituted with alkyl or phenyl １ -C ６ More preferably, R ２０ is C １ -C ６ C optionally substituted with alkyl or phenyl １ -C ６ It is alkyl.

[0056] In some embodiments, R, R ２ｂ , R ２ｆ , R ２ｇ , or R ２ｉ is an optionally substituted 3- to 15-membered hydrocarbon ring group, or has an optionally substituted 3- to 15-membered hydrocarbon ring group, the 3- to 15-membered hydrocarbon ring group is preferably an optionally substituted 6- to 14-membered aryl (for example, a 6- to 10-membered aryl); or an optionally substituted 3- to 14-membered saturated hydrocarbon ring (for example, a 3- to 10-membered saturated hydrocarbon ring). More preferably, the 3- to 15-membered hydrocarbon ring group is １ -C ６ Alkyl, hydroxy C１ -C ６ Alkyl, C １ -C ６ Alkoxy, and C １ -C ６ phenyl optionally substituted with 1 to 3 groups, the same or different, selected from the group consisting of alkanoyloxy; or C １ -C ６ Alkyl, C １ -C ６ Alkoxy-(C═O)-, C １ -C ６ C optionally substituted with 1 to 3 identical or different groups selected from the group consisting of alkoxy-(C═O)—NH— and amino ３ -C ６ More preferably, the 3- to 15-membered hydrocarbon ring group is phenyl, hydroxymethylphenyl, methoxyphenyl, acetoxyphenyl, dimethylacetoxyphenyl, cyclopropyl, methylcyclopropyl, methoxycarbonylcyclopropyl, C １ -C ６ It is alkoxy-(C═O)—NH-cyclopropyl, or aminocyclopropyl.

[0057] In some embodiments, R, R ２ｂ , R ２ｆ , R ２ｇ , or R ２ｉ is an optionally substituted 3- to 15-membered heterocyclic group, or has an optionally substituted 3- to 15-membered heterocyclic group, the 3- to 15-membered heterocyclic group is preferably an optionally substituted 5- to 10-membered heterocyclic group. More preferably, the 3- to 15-membered heterocyclic group is １ -C ６ Alkyl, hydroxy C １ -C ６ Alkyl, or C １ -C ６ and pyridinyl or dihydropyridinyl optionally substituted by alkanoyloxy. Preferably, the 3- to 15-membered heterocyclic group is pyridinyl, methylpyridinyl, methyldihydropyridinyl, hydroxymethylpyridinyl, or acetoxypyridinyl.

[0058] After administration to a living body, the compound of formula [I] is chemically or enzymatically converted to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane under physiological conditions. The compound of formula [I] can, for example, improve the water solubility of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, improve its bioavailability, and improve the selectivity of the drug for the target site.

[0059] In certain embodiments, diseases that may be treated by the compounds of formula [I] include diseases that may be treated by inhibiting the reuptake of several biogenic amines that are causally implicated in target central nervous system disorders, such as those listed below: (i) Attention Deficit Hyperactivity Disorder (ADHD, both in children and adults) and related behavioral disorders, as well as forms and symptoms of alcohol abuse, drug abuse, obsessive-compulsive disorder, learning disabilities, reading comprehension disorders, gambling addiction, manic symptoms, phobias, panic attacks, oppositional defiant disorder, conduct disorder, disruptive behavior disorders, academic problems at school, smoking, abnormal sexual behavior, schizophrenic behavior, somatization, depression (such as, but not limited to, major depressive disorder, recurrent; dysthymic disorder; depressive disorder not otherwise specified (NOS); major depressive disorder, single episode; bipolar disorder, depression associated with Alzheimer's disease, psychosis or Parkinson's disease; postpartum depression; and seasonal affective disorder), sleep disorders, generalized anxiety disorder, stuttering, and tic disorders (such as Tourette's syndrome); (ii) ADHD, substance abuse, depression, anxiety disorders (such as, but not limited to, panic disorder, generalized anxiety disorder, obsessive-compulsive disorder, post-traumatic stress disorder, and social phobia), autism, traumatic brain injury, cognitive impairment, schizophrenia (especially regarding cognition), obesity, chronic pain disorders, personality disorders, and mild cognitive impairment; (iii) anxiety disorders, panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia and related disorders, obesity, tic disorders, addiction, Parkinson's disease, and chronic pain; (iv) substance abuse disorders (such as, but not limited to, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen-use disorders, inhalant-related disorders, and opioid-related disorders); (v) cognitive impairment, bipolar disorder, anorexia nervosa, bulimia nervosa, cyclothymic disorder, chronic fatigue syndrome, chronic or acute stress, fibromyalgia and other somatoform disorders (such as somatization disorder, conversion disorder, pain disorder, hypochondriasis, body dysmorphic disorder, undifferentiated somatoform disorder, somatoform NOS), incontinence (i.e., stress urinary incontinence, true stress urinary incontinence, and mixed urinary incontinence), inhalation disorders, mania, migraine, peripheral neuropathy;(vi) addictive disorders (including, but not limited to, eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, and opioid-related disorders); (vii) fragile X syndrome-associated disorders; (viii) autism spectrum disorders (ASD), such as in patients with fragile X syndrome-associated disorders; (ix) ADHD in patients with fragile X syndrome-associated disorders; (x) comorbidity of ADHD and depression; (xi) comorbidity of ADHD and substance abuse; (xii) comorbidity of ADHD and anxiety disorders;

[0060] In another embodiment, diseases that may be treated by the compounds of formula [I] include any of the following disorders: attention deficit hyperactivity disorder (ADHD) and related behavioral disorders, as well as types and symptoms of substance abuse (alcohol abuse, drug abuse), obsessive-compulsive behavior, learning disabilities, reading comprehension disorders, gambling addiction, manic symptoms, phobias, panic attacks, oppositional attitudes, conduct disorders, academic problems at school, smoking, abnormal sexual behavior, schizophrenic behavior, somatization, depression, sleep disorders, generalized anxiety disorder, stuttering and tic disorders; depression, anxiety disorders, autism, traumatic brain injury, cognitive disorders and schizophrenia (particularly cognitive disorders), obesity, chronic pain disorders, personality disorders and mild cognitive impairment; panic disorder, post-traumatic stress disorder, obsessive-compulsive disorder, schizophrenia and related disorders, obesity, tic disorders, Parkinson's disease; fragile X syndrome-related disorders; fragile X syndrome-related disorders in which the patient has failed previous treatments for the disorder; Attention-deficit / hyperactivity disorder (ADHD), which is comorbid with anxiety and / or depression (e.g., depression), for example in patients with Fragile X syndrome-related disorders; Autism spectrum disorder (ASD).

[0061] In yet another embodiment, disorders contemplated for treatment with compounds of formula [I] include those described in the Quick Reference to Diagnostic Criteria according to DSM-IV (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition) American Psychiatric Association, Washington, D.C., 1994. These target disorders include, but are not limited to, attention-deficit / hyperactivity disorder, predominantly inattentive type; attention-deficit / hyperactivity disorder, predominantly hyperactive-impulsive type; attention-deficit / hyperactivity disorder, combined type; attention-deficit / hyperactivity disorder not otherwise specified (NOS); conduct disorder; oppositional defiant disorder; and disruptive behavior disorder not otherwise specified (NOS).

[0062] As used herein, depressive disorders include, but are not limited to, major depressive disorder, recurrent; dysthymic disorder; depressive disorder not otherwise specified (NOS); and major depressive disorder, single episode.

[0063] As used herein, addictive disorders include, but are not limited to, eating disorders, impulse control disorders, alcohol-related disorders, nicotine-related disorders, amphetamine-related disorders, cannabis-related disorders, cocaine-related disorders, hallucinogen use disorders, inhalant-related disorders, and opioid-related disorders.

[0064] In addition to the embodiments exemplified above, the present invention also includes any combination of preferred embodiments or alternatives for different elements or features herein, unless inconsistent.

[0065] [General Production Method] The compound of formula [I] can be produced, for example, by the general production method shown below, but is not limited thereto. Commercially available starting compounds may be used, or the compound may be synthesized according to a method known per se or a method similar thereto. The solvent, acid, base, protecting group, and leaving group appropriately used in the production of the compound of formula [I] are not particularly limited as long as they are commonly used in the field of organic synthetic chemistry. In the production of the compound of formula [I], the product can be used in the next reaction as a reaction solution or as a crude product. However, it can also be isolated from the reaction mixture according to a conventional method, and can also be easily purified by a conventional separation means. Typical separation means include, for example, filtration, extraction, concentration, evaporation, crystallization, recrystallization, reprecipitation, distillation, chromatography, and optical resolution. When alkylation, hydrolysis, amination, esterification, amidation, etherification, oxidation, reduction, etc. are performed in the production of the compound of formula [I], these reactions can be carried out according to a method known per se. These commonly used various reagents and methods are described, for example, in ORGANIC FUNCTIONAL GROUP PREPARATIONS, 2nd ed., ACADEMIC PRESS, INC., 1989; Comprehensive Organic Transformations, VCH Publishers Inc., 1989, PGM Wuts; "Greene's Protective Groups in Organic Synthesis" by T.W. Greene, 4th ed., 2006; John Wiley & Sons; New York, 1991, p. 309, etc. In the general production method of the compound of formula [I], the starting compounds, intermediate compounds, and the compound of formula [I] may be in the form of salts, and the target compound obtained in each reaction may also form a salt.When each compound is a free compound, it can be converted into the desired salt by a method known per se, and when the compound is a salt, it can be converted into the free form or another desired salt by a method known per se.

[0066] [Common Scheme] The compound of formula [I] can be synthesized by using a method classified into the following step A or step B.

[0067] Step A: Coupling reaction [In the formula, LG represents a leaving group; other symbols are the same as above] Step B: Dehydration condensation reaction [wherein each symbol is the same as above] The compound of formula [I] can be obtained by reacting compound (1) with compound (2) in an inert solvent in the presence or absence of a base or an acid depending on the reaction conditions (Step A). ​​Alternatively, the compound of formula [I] can be obtained by dehydration condensation reaction of compound (1) with compound (3) in an inert solvent in the presence or absence of a base and a condensing agent (Step B). Compound (1) can be produced according to the method described in Patent Document 1, and can be used in free form or in salt form. Examples of salt forms of compound (1) include inorganic acid salts such as hydrochloride, sulfate, carbonate, phosphate, hydrobromide, hydroiodide, and nitrate; organic acid salts such as formate, propionate, oxalate, carbonate, picrate, methanesulfonate, ethanesulfonate, p-toluenesulfonate, acetate, citrate, tartrate, malonate, succinate, maleate, fumarate, malate, and lactate; and amino acid salts such as aspartate and glutamate.

[0068] Examples of the leaving group include a halogen atom (e.g., chlorine, bromine, iodine), alkylsulfonyloxy groups (e.g., methylsulfonyloxy, ethylsulfonyloxy, trifluoromethylsulfonyloxy), arylsulfonyloxy groups (e.g., benzenesulfonyloxy, p-toluenesulfonyloxy, 2,4,6-trimethylbenzenesulfonyloxy, 2-nitrobenzenesulfonyloxy, 4-nitrobenzenesulfonyloxy), etc. Examples of the inert solvent include water; alcoholic solvents such as MeOH, EtOH, isopropanol, n-butanol, trifluoroethanol, ethylene glycol, etc.; ketone solvents such as acetone, methyl ethyl ketone, etc.; THF, dioxane, Et ２ Examples of the base include ether solvents such as hexane, diisopropyl ether, cyclopentyl methyl ether, and diglyme; ester solvents such as AcOMe and AcOEt; aprotic polar solvents such as MeCN, DMF, and DMSO; hydrocarbon solvents such as n-pentane, n-hexane, n-heptane, and cyclohexane; halogenated hydrocarbon solvents such as methylene chloride, ethylene chloride, and DCM; other organic solvents; and mixed solvents thereof. Examples of the base include, for example, known inorganic and organic bases, which can be widely used. Examples of the inorganic base include alkali metals (e.g., sodium, potassium, etc.), alkali metal hydrogen carbonates (e.g., lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, etc.), alkali metal hydroxides (e.g., LiOH, NaOH, KOH, etc.), alkali metal carbonates (e.g., Li ２ CO ３ , Na ２ CO ３ , K. ２ CO ３ , Cs ２ CO ３Examples of the organic base include trialkylamines (e.g., trimethylamine, triethylamine, N-ethyldiisopropylamine (DIPEA)), pyridine, quinoline, piperidine, imidazole, picoline, dimethylaminopyridine, dimethylaniline, N-methylmorpholine, DBN, DABCO, DBU, and the like. When these bases are liquid, they can also be used as solvents. These bases can be used alone or in combination of two or more. The amount of the base used is usually 0.1 to 10 mol, preferably 0.1 to 5 mol, per 1 mol of compound (1). Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and phosphoric acid; and organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid. Two or more of these acids may be mixed in an appropriate ratio. The amount of the acid used is usually 1 molar equivalent to an excess amount relative to compound (1). The reaction conditions are not particularly limited, and the reaction can usually proceed under cooling, room temperature, or heating. The reaction is preferably carried out at a temperature of room temperature to 100°C for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.

[0069] Step B Examples of the inert solvent include the inert solvents described above. Examples of the base include the bases described above. Examples of the condensing agent include HATU; DCC; N-cyclohexyl-N'-morpholinoethylcarbodiimide; N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide; N,N'-diethylcarbodiimide; N,N'-diisopropylcarbodiimide; N,N-diisopropylethylamine; WSC or its HCl salt; N,N'-carbonylbis(2-methylimidazole); pentamethyleneketene-N-cyclohexylimine; diphenylketene-N-cyclohexylimine; ethoxyacetylene, 1-alkoxy-1-chloroethylene; trialkyl phosphite; ethyl polyphosphate; isopropyl polyphosphate; phosphorus oxychloride (phosphoryl chloride); trialkyl phosphate; Examples of suitable condensing agents include phosphorus chloride; diphenyl phosphoryl azide; thionyl chloride; oxalyl chloride; alkyl haloformates such as ethyl chloroformate and isopropyl chloroformate; triphenylphosphine; 2-ethyl-7-hydroxybenzisoxazolium salt; 2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide inner salt; benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate; 1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benzotriazole; and the so-called Vilsmeier reagent prepared by reacting DMF with thionyl chloride, phosgene, trichloromethyl chloroformate, phosphorus oxychloride, or the like. The amount of the condensing agent used is typically 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to compound (1). In addition to the condensing agent, a condensation promoter may also be added. Examples of condensation promoters include 1-hydroxybenzotriazole (HOBt), N-hydroxysuccinimide (HOSu), 1-hydroxy-7-azabenzotriazole (HOAt), and hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt). The amount of the condensation promoter used is usually 0.1 to 10 molar equivalents, and preferably 1 to 5 molar equivalents, relative to compound (1). The reaction conditions are not particularly limited, and the reaction can usually proceed under cooling, at room temperature, or under heating.Preferably, the reaction is carried out at a temperature of from room temperature to 100° C. for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.

[0070] Synthesis of carbamate represented by formula [I-1] Among the compounds of formula [I], the compound represented by formula [I-1] can be synthesized more specifically by the method shown in the following step A-1.

[0071] Step A-1: ​​Coupling reaction [wherein each symbol is the same as above] (Step A-1: ​​(1) + (2-1) → [I-1]) The compound of formula [I-1] can be obtained by reacting compound (1) with compound (2-1) in an inert solvent in the presence of a base. Examples of the leaving group include the above-mentioned leaving groups. Examples of the inert solvent include the above-mentioned inert solvents, preferably halogenated hydrocarbon solvents such as dichloromethane. Examples of the base include the above-mentioned bases, preferably triethylamine. The reaction conditions are not particularly limited, and the reaction can usually proceed under cooling, at room temperature, or under heating. Preferably, the reaction is carried out at room temperature to 100°C for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.

[0072] Synthesis of acyloxymethyl carbamate represented by formula [I-2] Among the compounds of formula [I], the compound represented by formula [I-2] can be synthesized more specifically by the methods shown in the following steps C-2 and D-2.

[0073] Steps C-2 and D-2: Coupling Reaction [Wherein LG and LG ２are each a leaving group, and each symbol is the same as above] (Step C-2: (1) + (4-2) → (5-2)) (Step D-2: (5-2) + (3-2) → [I-2]) The compound of formula [I-2] can be obtained by reacting compound (1) with compound (4-2) in an inert solvent in the presence of a base to obtain compound (5-2), and then reacting this with compound (3-2) in an inert solvent in the presence of a base.

[0074] Step C-2: Coupling Reaction (First Step) Examples of the leaving group represented by LG include the leaving groups described above. Examples of the inert solvent include the inert solvents described above, preferably halogenated hydrocarbon solvents such as dichloromethane. Examples of the base include the bases described above, preferably triethylamine. The reaction conditions are not particularly limited, and the reaction can generally proceed under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of 0°C to room temperature for 30 minutes to 30 hours, preferably 1 hour to 15 hours.

[0075] Step D-2: Coupling reaction (second step) LG ２ Examples of the leaving group represented by the formula (I) include the leaving groups described above. Examples of the inert solvent include the inert solvents described above, preferably N,N-dimethylformamide. Examples of the base include the bases described above, preferably cesium carbonate. The reaction conditions are not particularly limited, and the reaction can usually proceed under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of 0°C to room temperature for 30 minutes to 30 hours, preferably 1 hour to 15 hours.

[0076] Synthesis of amide represented by formula [I-4] Among the compounds of formula [I], the compound represented by formula [I-4] can be synthesized more specifically by either the following step A-4 or step B-4.

[0077] Step A-4: Coupling reaction [wherein each symbol is the same as above] (Step A-4: (1) + (2-4) → [I-4]) The compound of formula [I-4] can be obtained by reacting compound (1) with compound (2-4) in an inert solvent in the presence of a base. Examples of the leaving group include the leaving groups described above. Examples of the inert solvent include the inert solvents described above, preferably halogenated hydrocarbon solvents such as dichloromethane. Examples of the base include the bases described above, preferably triethylamine. The reaction conditions are not particularly limited, and the reaction can usually proceed under cooling, at room temperature, or under heating. The reaction is preferably carried out at a temperature of room temperature to 100°C for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.

[0078] Step B-4: Dehydration condensation reaction [wherein each symbol is the same as defined above] (Step B-4: (1) + (3-4) → [I-4]) The compound of formula [I-4] can be obtained, for example, by amidating compound (1) with compound (3-4). Specifically, compound (I-4) can be produced by reacting compound (1) or a salt thereof with a reactive derivative at the carboxy group of compound (3-4).

[0079] Suitable reactive derivatives at the carboxy group of compound (3-4) include, for example, acid halides, acid azides, acid anhydrides, activated amides, activated esters, etc. More preferred reactive derivatives include acid chlorides; acid azides; mixed acid anhydrides with acids such as substituted phosphoric acids (e.g., dialkyl phosphoric acid, phenyl phosphoric acid, diphenyl phosphoric acid, dibenzyl phosphoric acid, halogenated phosphoric acids, etc.), dialkyl phosphorous acids, sulfurous acid, thiosulfuric acid, sulfonic acids (e.g., methanesulfonic acid, etc.), aliphatic carboxylic acids (e.g., acetic acid, propionic acid, butyric acid, isobutyric acid, pivalic acid, pentanoic acid, isopentanoic acid, 2-ethylbutyric acid, trichloroacetic acid, etc.), or aromatic carboxylic acids (e.g., benzoic acid, etc.); symmetrical acid anhydrides; imidazole, 4-substituted imidazoles, dimethylpyrazole, trimethylsilyl phosphate, methylpyrazole ... Examples include activated amides with azole or tetrazole; activated esters (e.g., cyanomethyl ester, methoxymethyl ester, dimethyliminomethyl ester, vinyl ester, propargyl ester, p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester, pentachlorophenyl ester, mesylphenyl ester, etc.); and esters with N-hydroxy compounds (e.g., N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone, N-hydroxysuccinimide, N-hydroxyphthalimide, HOBt, etc.). These reactive derivatives can be arbitrarily selected from among them depending on the type of compound (3-4) to be used.

[0080] When compound (3-4) is used in the form of a free acid or a salt thereof in step B-4, the reaction may be carried out in the presence of a condensing agent. Examples of the condensing agent include the above-mentioned condensing agents. HATU is preferred as the condensing agent in step B-4. Furthermore, the reaction may be carried out in the presence of the above-mentioned condensing agent in the coexistence of an active esterifying agent such as N-hydroxysuccinimide, N-hydroxyphthalimide, or HOBt.

[0081] Examples of the inert solvent used in Step B-4 include the above-mentioned inert solvents, preferably dimethylformamide. Examples of the base used in Step B-4 include the above-mentioned bases, preferably DIPEA. The proportions of compound (1) and compound (3-4) used in Step B-4 are usually 1 mole of the former and at least 1 mole, preferably about 1 to 5 moles, of the latter. The reaction temperature is not particularly limited, and the reaction usually proceeds under cooling, room temperature, or heating. The reaction is preferably carried out at a temperature of room temperature to 100°C for 30 minutes to 30 hours, preferably 30 minutes to 5 hours.

[0082] Synthesis of phosphonate represented by formula [I-10] Among the compounds of formula [I], the compound represented by formula [I-10] can be synthesized more specifically by the method shown in the following step A-10.

[0083] Step A-10: Phosphoric acid coupling reaction [wherein each symbol is the same as above] (Step A-10: (1) + (2-10) → [I-10]) The compound of formula [I-10] can be obtained by reacting compound (1) with compound (2-10) in an inert solvent in the presence of a base. Examples of the leaving group include the above-mentioned leaving groups. Examples of the inert solvent include the above-mentioned inert solvents, preferably halogenated hydrocarbon solvents such as dichloromethane. Examples of the base include the above-mentioned bases, preferably DIPEA. The reaction conditions are not particularly limited, and the reaction can usually proceed under cooling, at room temperature, or under heating. Preferably, the reaction is carried out at room temperature to 100°C for 30 minutes to 30 hours, preferably 1 hour to 18 hours.

[0084] Production of carboxylic acids or amine compounds [wherein each symbol is the same as above] In the compound of formula [I], when R contains a carboxylic acid, the carboxylic acid group may be protected with an appropriate protecting group to form an ester or the like, and after carrying out any of the above methods, the protecting group may be deprotected to synthesize the compound of formula [I] as the final product. Furthermore, in the compound of formula [I], when R contains an amine, the amine group may be protected with an appropriate protecting group, and after carrying out any of the above methods, the protecting group may be deprotected to synthesize the compound of formula [I] as the final product. Here, there may be a plurality of carboxylic acids or amines in R, and preferably 1 to 2 carboxylic acids or amines are present.

[0085] Among the compounds of formula [I], the compound represented by formula [I-2'] can be synthesized by deprotecting the hydroxy-protecting group in intermediate (6) using, for example, the method shown in the following step E-2. Step E-2: Deprotection of hydroxy-protecting group (hydrolysis reaction) [In the formula, PG １ represents a protecting group for a hydroxy group, and the structure: represents any group obtained by excluding the structure represented by the above formula from the -X-R group, n is any integer from 1 to 3, and the other symbols are the same as above. (Step E-2: (6) → [I-2']) Compound [I-2'] can be obtained by subjecting intermediate (6) to a deprotection reaction. The deprotection reaction may be carried out using a known reaction, or a known hydrolysis reaction may be used. For example, PG １When is a silyl group, intermediate (6) can be deprotected in an inert solvent in the presence of a fluoride source or an acid to obtain compound [I-2']. Alternatively, the deprotection reaction may be performed using a known hydrolysis reaction in the presence of a base. Examples of fluoride sources include tetrabutylammonium fluoride, hydrofluoric acid, and cesium fluoride. The amount of the fluoride source used is usually 1 to 10 molar equivalents, preferably 1 to 5 molar equivalents, relative to intermediate (6). Examples of acids include inorganic acids such as hydrochloric acid, sulfuric acid, nitric acid, hydrobromic acid, and phosphoric acid; and organic acids such as acetic acid, trifluoroacetic acid, oxalic acid, phthalic acid, fumaric acid, tartaric acid, maleic acid, citric acid, succinic acid, methanesulfonic acid, p-toluenesulfonic acid, and 10-camphorsulfonic acid. Two or more of these acids may be mixed and used in an appropriate ratio. The amount of acid used is usually 1 molar equivalent to an excess amount relative to intermediate (6). Examples of the base include inorganic bases such as alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide), alkaline earth metal hydroxides (e.g., magnesium hydroxide, calcium hydroxide), alkali metal carbonates (e.g., sodium carbonate, potassium carbonate), alkaline earth metal carbonates (e.g., magnesium carbonate, calcium carbonate), and alkali metal bicarbonates (e.g., sodium bicarbonate, potassium bicarbonate); and organic bases such as trialkylamines (e.g., trimethylamine, triethylamine), picoline, DBN, DABCO, and DBU. Two or more of these may be mixed and used in an appropriate ratio. The amount of the acid used is usually 1 molar equivalent to an excess amount relative to the intermediate (6). Examples of the inert solvent include hydrocarbons, halogenated hydrocarbons, water, alcohols, ethers, esters, ketones, amides, nitriles, sulfoxides, and the like. Two or more of these may be mixed and used in an appropriate ratio. The reaction temperature is usually −80 to 150° C. The reaction time is usually from 0.1 to 200 hours.

[0086] Examples of "hydroxy-protecting groups" or "hydroxy-protecting groups" are not particularly limited as long as they are protecting groups for hydroxy groups used in the field of organic synthetic chemistry, and include, for example, alkyl groups (e.g., methyl, ethyl, isopropyl, tert-butyl, trifluoromethyl, hydroxymethyl, 2-hydroxyethyl, acetylmethyl); alkenyl groups (e.g., ethenyl, 1-propenyl, 2-propenyl, 1-methyl-2-propenyl); alkynyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl); formyl groups (e.g., ethynyl, 1-propynyl, 2-propynyl, 1-methyl-2-propynyl); alkyl(alkenyl)carbonyl groups (e.g., acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, methoxyacetyl, acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E)-2-methyl-2-butenoyl); arylcarbonyl groups (e.g., benzoyl, α-naphthoyl, β-naphthoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trifluorobenzoyl, methylbenzoyl, 4-toluoyl, 4-anisoyl, 4-nitrobenzoyl, 2-nitrobenzoyl, 2-(methoxycarbonyl)benzoyl, 4-phenylbenzoyl); alkoxycarbonyl groups (e.g., methoxycarbonyl, tert-butoxycarbonyl, 2,2,2-trichloroethoxycarbonyl, 2-trimethylsilylethoxycarbonyl, 9-fluorenylmethyloxycarbonyl); tetrahydro(thio)pyranyl (furanyl) groups (e.g., tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, 4-methylbenzo ... tetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl, tetrahydrofuran-2-yl, tetrahydrothiofuran-2-yl); silyl groups (e.g., trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, tert-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-tert-butylsilyl, triisopropylsilyl, diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl, phenyldiisopropylsilyl);Alkoxymethyl groups (e.g., methoxymethyl, 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl, tert-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl, bis(2-chloroethoxy)methyl); alkoxyethyl groups (e.g., 1-ethoxyethyl, 1-(isopropoxy)ethyl); halogenated ethyl groups (e.g., 2,2,2-trichloroethyl); aralkyl groups (e.g., benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9-anthrylmethyl, alkyl, 4-methylbenzyl, 2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-cyanobenzyl); alkenyloxycarbonyl groups (e.g., vinyloxycarbonyl, allyloxycarbonyl); aralkyloxycarbonyl groups (e.g., benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl). Preferred examples of the protecting group for a hydroxy group include alkyl groups.

[0087] Among the compounds of formula [I], the compound represented by formula [I-2″] can be synthesized by deprotecting the amine protecting group in intermediate (7) using, for example, the method shown in the following step F-2. Step F-2: Deprotection of the amine protecting group [In the formula, PG ２ represents an amine-protecting group, and the other symbols are the same as above.] Compound [I-2″] can be obtained by subjecting intermediate (7) to a deprotection reaction. The deprotection reaction may be carried out using a known reaction, for example, ２When is a tert-butoxycarbonyl group (Boc), intermediate (7) can be deprotected in the presence of an acid (e.g., hydrochloric acid, trifluoroacetic acid, etc.) in an inert solvent or without a solvent to obtain compound [I-2″]. Examples of the inert solvent include hydrocarbons, halogenated hydrocarbons, water, alcohols, ethers (e.g., cyclopentyl methyl ether), esters, ketones, amides, nitriles, sulfoxides, etc., and two or more of these may be mixed in an appropriate ratio. The reaction temperature is usually −80 to 150° C. The reaction time is usually 0.1 to 200 hours.

[0088] Examples of "amine group-protecting groups" or "amine protecting groups" are not particularly limited as long as they are protecting groups for amino groups used in the field of organic synthetic chemistry, and include, for example, groups similar to "alkyl(alkenyl)carbonyl groups," "arylcarbonyl groups," "alkoxycarbonyl groups," "silyl groups," "aralkyl groups," "alkenyloxycarbonyl groups," and "aralkyloxycarbonyl groups" in the above-mentioned "hydroxy group-protecting groups." A preferred example of an amine protecting group is the Boc group.

[0089] Among the compounds of [I], the compound represented by formula [I-4'] can be synthesized by deprotecting the amine protecting group in the intermediate (8) using, for example, the method shown in the following step F-4. Step F-4: Deprotection of the amine protecting group [wherein each symbol is the same as defined above] Compound [I-4'] can be obtained by subjecting intermediate (8) to a deprotection reaction. This reaction can be carried out, for example, under the same reaction conditions as in the above-mentioned step F-2.

[0090] In this specification, the compounds of formula [I], starting compounds, and intermediate compounds include chemically acceptable geometric isomers, stereoisomers, optical isomers, and tautomers. Various isomers can be separated by a general optical resolution method, or can be produced from the corresponding optically active starting compounds.

[0091] In this specification, the compound of formula [I], the starting compound, and the intermediate compound may be in the form of a salt, and the target compound obtained in each reaction may also form a salt. When the compound obtained in each reaction is a free compound, it can be converted into the target salt by a method known per se, and when the compound is a salt, it can be converted into the free form or another target salt by a method known per se. Examples of such salts include the salts exemplified below.

[0092] The salts referred to herein include pharmaceutically acceptable acid addition salts or base addition salts. Examples of acids in acid addition salts include inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid, and phosphoric acid; organic acids such as formic acid, propionic acid, oxalic acid, carbonic acid, picric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, acetic acid, citric acid, tartaric acid, malonic acid, succinic acid, maleic acid, fumaric acid, malic acid, and lactic acid; and amino acids such as aspartic acid and glutamic acid. Examples of the base in the base addition salt include metals such as alkali metals (e.g., sodium, potassium, etc.) and alkaline earth metals (e.g., calcium, magnesium, etc.); inorganic bases such as alkali metal carbonates (e.g., lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, etc.), alkali metal hydrogencarbonates (e.g., lithium hydrogencarbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, etc.), and alkali metal hydroxides (e.g., lithium hydroxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, cesium hydroxide, etc.); and organic bases such as methylamine, diethylamine, trimethylamine, triethylamine, N-ethyldiisopropylamine, ethanolamine, diethanolamine, triethanolamine, ethylenediamine, tris(hydroxymethyl)methylamine, dicyclohexylamine, N,N'-dibenzylethylenediamine, guanidine, pyridine, quinoline, piperidine, imidazole, dimethylaminopyridine, dimethylaniline, picoline, choline, N-methylmorpholine, DBN, DBU, DABCO, etc.; amino acids such as lysine and arginine; and ammonia.

[0093] The compound of formula [I] also includes various hydrates, solvates and crystalline polymorphs of the compound represented by formula [I] and its salts. The compound of formula [I] includes compounds in which any one or more atoms of formula [I] are substituted with one or more isotope atoms. Examples of isotope atoms include deuterium ( ２ H), tritium ( ３ H), １３ C. １４ N. １８ Examples include O.

[0094] The compound of formula [I] can be used in combination with various therapeutic or prophylactic agents for diseases that can be treated by the compound of formula [I]. The combination may be administered simultaneously, or separately, consecutively, or at a desired time interval. The simultaneous administration preparation may be a combined preparation or may be formulated separately.

[0095] Next, a medical preparation (hereinafter also referred to as a "pharmaceutical composition") containing the compound of formula [I] as an active ingredient will be described.

[0096] The above-mentioned medical preparation is a formulation of the compound of formula [I] in the form of a conventional medical preparation, and is prepared using the compound of formula [I] or a salt thereof and a pharmaceutically acceptable carrier, which may include commonly used diluents or excipients such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, lubricants, etc.

[0097] Such medical preparations can be selected from a variety of forms depending on the purpose of treatment, and examples include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, and injections (liquids, suspensions, etc.).

[0098] A wide variety of known carriers can be used when forming tablets, including excipients such as lactose, sucrose, sodium chloride, glucose, urea, starch, calcium carbonate, kaolin, and crystalline cellulose; binders such as water, ethanol, propanol, simple syrup, glucose solution, starch solution, gelatin solution, carboxymethylcellulose, shellac, methylcellulose, potassium phosphate, and polyvinylpyrrolidone; and dry starch, sodium alginate, agar powder, laminaran powder, and sodium bicarbonate. disintegrants such as calcium carbonate, polyoxyethylene sorbitan fatty acid esters, sodium lauryl sulfate, stearic acid monoglyceride, starch, lactose; disintegration inhibitors such as sucrose, stearin, cocoa butter, hydrogenated oil; absorption promoters such as quaternary ammonium bases, sodium lauryl sulfate; humectants such as glycerin, starch; adsorbents such as starch, lactose, kaolin, bentonite, colloidal silicic acid; and lubricants such as purified talc, stearates, boric acid powder, polyethylene glycol.

[0099] Furthermore, the tablets may be coated with conventional tablets as needed, for example, sugar-coated tablets, gelatin-coated tablets, enteric-coated tablets, film-coated tablets, double-layered tablets, or multi-layered tablets.

[0100] A wide range of known carriers can be used when forming the tablets into pills, including excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oil, kaolin, and talc; binders such as powdered gum arabic, powdered tragacanth, gelatin, and ethanol; and disintegrants such as laminaran and agar.

[0101] As the carrier used for forming into suppositories, a wide variety of known carriers can be used, including, for example, polyethylene glycol, cacao butter, higher alcohols, esters of higher alcohols, gelatin, semi-synthetic glycerides, etc.

[0102] When prepared as an injection, the solution, emulsion, and suspension are preferably sterilized and isotonic with blood. Diluents used in forming these solutions, emulsions, and suspensions can be any known and widely used diluent, such as water, ethanol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, and polyoxyethylene sorbetan fatty acid esters. In this case, the medical preparation may contain sufficient amounts of salt, glucose, amino acids, or glycerin to prepare an isotonic solution. It may also contain conventional solubilizers, buffers, soothing agents, and, if necessary, colorants, preservatives, fragrances, flavors, sweeteners, and other pharmaceuticals.

[0103] As used herein, the term "therapeutically effective amount" refers to an amount effective to provide a therapeutic benefit, such as alleviation of symptoms, when administered to a human or non-human. The specific dose of a substance administered to provide a therapeutic benefit will, of course, be determined by specific circumstances, such as the specific substance administered, the route of administration, the condition being treated, and the individual being treated. For example, the amount of the compound of formula [I] contained in a medical preparation may be 1 to 70% by weight of the compound of formula [I] in the medical preparation.

[0104] For example, dosages that may provide satisfactory results in oral administration include dosages on the order of about 0.01 to 20 mg / kg. A recommended daily dosage for oral administration ranges from about 0.75 mg to 2000 mg, and may be administered suitably once or in 2 to 4 divided doses daily. Thus, a unit dosage form for oral administration may contain, for example, about 0.2 mg to 100 mg or 500 mg, e.g., about 0.2 mg, 2.0 mg, 50 mg, 75 mg, or 100 mg to 200 mg or 500 mg, of a compound of formula [I], together with a pharmaceutically acceptable diluent or carrier.

[0105] As used herein, the term "pharmaceutically acceptable" refers to a compound, a composition containing the compound, or an administration form thereof that does not cause excessive toxicity, irritation, allergic response, etc., and has a reasonable benefit / risk ratio appropriate for application to humans or animals.

[0106] The present invention will be further explained in detail by the following Reference Examples, Examples and Test Examples, but these do not limit the present invention and may be modified within the scope of the present invention.

[0107] The following abbreviations may be used in this specification. REX: Reference Example Number EX: Example Number STR: Structural Formula RProp: Production Method (wherein the number shown in the relevant item indicates that the compound was produced using the corresponding raw material in the same manner as in the Reference Example with the given number as the Reference Example Number) Prop: Production Method (wherein the number shown in the relevant item indicates that the compound was produced using the corresponding raw material in the same manner as in the Example with the given number as the Example Number) Data: Physical property data (NMR1: dimethyl sulfoxide-d ６ During １ δ (ppm) in H-NMR; NMR2: CDCl ３ During １ δ (ppm) in H-NMR; NMR3: CD ３ During OD １ δ (ppm) in H-NMR, or MS: mass spectrum)

[0108] Furthermore, the following abbreviations may be used for compound and reagent names:

[0109] In the following examples, "room temperature" generally refers to about 10°C to about 35°C. Ratios shown for mixed solvents are by volume unless otherwise specified. % refers to % by weight unless otherwise specified. 1HNMR (proton nuclear magnetic resonance spectrum) was measured by Fourier transform NMR (either Bruker AVANCE III 400 (400 MHz) or Bruker AVANCE III HD (500 MHz)). MS (mass spectrum) was measured by LC / MS (Waters Acquity SQD / LC: Waters Acquity UPLC H-Class or Thermo Fisher Scientific ITQ 1100). The data shown are the actual values ​​(found). Usually, the molecular ion peak of the free form ([M+H] + , [MH] - etc.), free molecular ion peak [M] + Or fragment ion peak, or free sodium adduct ion peak [M+Na] + The absolute configuration of the compound was determined by known X-ray crystal structure analysis methods (e.g., Shigeru Ohba and Shigenobu Yano, "Basic Lectures for Chemists 12: X-Ray Crystal Structure Analysis" (1st ed., 1999)) or estimated from the empirical rules of asymmetric epoxidation (Waldemar Adam, Rainer T. Fell, Chantu R. Saha-Moller and Cong-Gui Zhao: Tetrahedron: Asymmetry 1998, 9, 397-401; Yuanming Zhu, Yong Tu, Hongwu Yu, Yian Shi: Tetrahedron Lett. 1988, 29, 2437-2440).

[0110] Reference Example 1 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (2 g) and triethylamine (3.4 mL) were dissolved in DCM (40 mL), and chloromethyl chloroformate (0.91 mL) was slowly added under ice-cooling and stirring. The temperature was returned to room temperature and the mixture was stirred for an additional hour. Water was added to the reaction mixture and the mixture was stirred. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Hexane-AcOEt) to give chloromethyl (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (2.37 g).

[0111] Reference Example 3 Sebacic acid (10 g) was suspended in DCM (200 mL), and DMF (0.38 mL) was added and stirred. Oxalyl chloride (13 mL) was slowly added dropwise to this solution, and after the addition was complete, the mixture was stirred at room temperature. The reaction mixture was concentrated under reduced pressure and azeotroped twice with DCM. The residue was dissolved in DCM (100 mL), and a solution of 4-methoxybenzyl alcohol (6.78 mL) in DCM (5 mL) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 3 hours. The reaction mixture was stirred under ice cooling, and 5 mol / L HCl was added dropwise, followed by stirring overnight at room temperature. Insoluble matter was removed by filtration, and the organic layer was separated from the filtrate. The organic layer was concentrated under reduced pressure, and the residue was dissolved in AcOEt. This organic layer was washed twice with water, then separated and concentrated under reduced pressure. The resulting solid was recrystallized from diethyl ether-hexane, and the crystals were collected by filtration. After drying under reduced pressure, 10-((4-methoxybenzyl)oxy)-10-oxodecanoic acid (2.72 g) was obtained.

[0112] Reference Example 4 4-Methoxybenzyl alcohol (5.99 mL) and oxepane-2,7-dione (80% purity, 5.0 g) were dissolved in DCM (200 mL), and DMAP (0.38 g, 3.1 mmol) and pyridine (6.82 mL) were added, followed by stirring overnight at room temperature. 67 mL of 2 mol / L aqueous HCl was added to the reaction solution, and the mixture was stirred for a while. The organic layer was then separated and washed with saturated brine. The organic layer was separated, and the solvent was evaporated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (Hexane-AcOEt) to give 6-((4-methoxybenzyl)oxy)-6-oxo-oxohexanoic acid (3.21 g).

[0113] Reference Example 5 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (737 mg), N-(tert-butoxycarbonyl)-N-methylglycine (624 mg), HATU (1.26 g), DIPEA (1.10 mL), and DMF (7.5 mL) were mixed and stirred at room temperature for 18 hours. Water was added to the reaction mixture, and the mixture was extracted with AcOEt. The mixture was then washed with 1 mol / L aqueous HCl, water, and saturated NaHCO ３ The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane / AcOEt), and then the solvent was concentrated under reduced pressure to give tert-butyl methyl(2-((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)carbamate (0.97 g).

[0114] Reference Example 6 tert-Butyl methyl (2-((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)carbamate (0.97 g) was dissolved in CPME, and 4 mol / L HCl CPME solution was added at room temperature, followed by stirring overnight. The solvent was concentrated under reduced pressure. EtOH and AcOEt were added to the residue, followed by trituration, and the precipitated solid was collected by filtration. The solid was washed with AcOEt and dried to give 2-(methylamino)-1-((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)ethan-1-one hydrochloride.

[0115] Example 1 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (0.5 g) and TEA (0.85 mL) were dissolved in DCM (10 mL), and butyryl chloride (0.32 mL) was slowly added while stirring and ice-cooling. The temperature was returned to room temperature and the mixture was stirred for an additional 1 hour. Water was added to the reaction mixture and the mixture was stirred. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Hexane-AcOEt) to give 1-((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)butan-1-one (550 mg).

[0116] Example 5 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (0.5 g) and TEA (0.85 mL) were dissolved in DCM (10 mL), and ethyl chloroformate (0.29 mL) was slowly added under ice-cooling and stirring. The temperature was returned to room temperature and the mixture was stirred for an additional 1 hour. Water was added to the reaction mixture and the mixture was stirred. The organic layer was separated and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Hexane-AcOEt). The resulting solid was recrystallized from diethyl ether-hexane and dried under reduced pressure to give ethyl (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (320 mg).

[0117] Example 8 Chloromethyl (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (the product of Reference Example 1) (0.50 g) was dissolved in 5 mL of DMF, and the solution was diluted with AcOH (0.19 mL) and Cs ２ CO ３ (1.62 g) was added and stirred at room temperature for 1 hour. Water and AcOEt were added to the reaction mixture and stirred, and the organic layer was separated and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (Hexane-AcOEt) to obtain acetoxymethyl (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (510 mg).

[0118] Example 17 TFA (1.74 mL) was added to 4-methoxybenzyl ((((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)oxy)methyl) adipate (1.2 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure and then azeotroped twice with DCE. The obtained crude product was purified by silica gel column chromatography (Hexane-AcOEt) to give 6-(((((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carbonyl)oxy)methoxy)-6-oxohexanoic acid (463 mg).

[0119] Example 21 TFA (1.16 mL) was added to 1-((tert-butoxycarbonyl)amino)cyclopropane-1-carbonyl)oxy)methyl (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (0.70 g), and the mixture was stirred at room temperature for 1 hour. DCM was added to the reaction mixture, and the mixture was concentrated under reduced pressure twice. The resulting residue was dissolved in a small amount of DCM and stirred, and a 4 mol / L HCl solution in AcOEt was added and the mixture was stirred. Hexane and diethyl ether were further added, and the resulting solid was collected by filtration. After drying under reduced pressure, ((1-aminocyclopropane-1-carbonyl)oxy)methyl (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane-3-carboxylate hydrochloride (580 mg) was obtained.

[0120] Example 24 N ２ , N ６ 1.45 g of 1-bis(tert-butoxycarbonyl)-L-lysine and 0.94 g of HOBt were dissolved in 20 mL of DCM, and then 1.0 g of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride and 1.2 g of WSC.HCl were added and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction mixture and the mixture was stirred. The organic layer was separated and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane-AcOEt) to give di-tert-butyl ((S)-6-((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-6-oxohexane-1,5-diyl)dicarbonate (1.81 g).

[0121] Example 27 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (123 mg), 3-(2-acetoxy-4,6-dimethylphenyl)-3-methylbutanoic acid (145 mg), HATU (209 mg), DIPEA (0.183 mL), and DMF (1.5 mL) were mixed and stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with AcOEt. The mixture was then washed with 1N HCl, water, saturated NaHCO ３ The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane-AcOEt) to give 3,5-dimethyl-2-(2-methyl-4-((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-4-oxobutan-2-yl)phenyl acetate (189 mg).

[0122] Example 28 (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane hydrochloride (246 mg) and DIPEA (0.367 mL) were dissolved in DCM (2.5 mL). Diethyl phosphorochloridate (0.159 mL) was added and the mixture was stirred at room temperature for 18 hours. Water was added to the reaction mixture, which was then extracted with DCM. The mixture was then washed with 1N aqueous HCl, water, saturated NaHCO ３The organic layer was dried over anhydrous magnesium sulfate and filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Hexane-AcOEt) to give diethyl ((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)phosphonate (149 mg).

[0123] Example 29 A mixture of tert-butyl tert-butyl(2-(methyl(2-((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)amino)-2-oxoethyl)carbamate (0.47 g) and a 4 N HCl CPME (2.4 mL) solution was stirred at room temperature for 15 hours. The solvent was concentrated under reduced pressure, and then IPE was added and the mixture was triturated. The solid was collected by filtration and washed with hexane to give 2-(tert-butylamino)-N-methyl-N-(2-((1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexan-3-yl)-2-oxoethyl)acetamide hydrochloride (363 mg).

[0124] The structures and physical property data of the Reference Example compounds (Reference Examples 1 to 8) and Example compounds (Examples 1 to 30) obtained by methods similar to those described above, as well as the compounds (Examples 31 to 114) obtained by similar methods, are shown in the following table.

[0125]

[0126]

[0127]

[0128]

[0129] [Test Examples] Test Example 1: Test to confirm conversion to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane (1) In vitro metabolic reaction The reaction system described below was prepared, and the conversion of the evaluation compound to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in 9000 g human liver supernatant fraction (S9) and buffer was evaluated. Human liver S9 was purchased from Sekisui XenoTech and used. The evaluation compound was dissolved in DMSO to a concentration of 10 mM and further diluted with acetonitrile to a concentration of 100 μM before use. The evaluation compound solution was prepared immediately before use. <Reaction System> Final Concentrations: Test Compound 1 μM, Human Liver S9 1 mg / mL, Coenzymes (NADPH / NADH) 1 mM each, Magnesium Chloride 5 mM, 100 mM Phosphate Buffer (pH 7.4). Number of Samples: n = 2. <Reaction Method> The reaction system without the test compound was preincubated at 37°C for 5 minutes, after which the test compound solution was added to initiate the reaction. After the coenzyme addition, the system was incubated for 0 and 60 minutes. An acetonitrile solution containing an internal standard was added at the specified intervals to terminate the reaction and prepare the measurement sample. Calibration curve samples (0.01, 0.1, and 1 μM) with the same composition were prepared. (2) Analysis Method: The measurement sample and calibration curve sample were centrifuged, and the supernatant was injected into a liquid chromatograph-tandem mass spectrometer to measure (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in the reaction system. Ionization was performed using electrospray ionization (ESI) with positive ionization detection, and selective reaction detection was performed using set precursor and product ions. (3) Data analysis: Regarding the conversion of the evaluation compound to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane, the production of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane in the 0-minute reaction sample and the 60-minute reaction sample was compared, and samples that met all of the following criteria were judged to have "converted from the evaluation compound to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane."・In a reaction system using human liver S9, no production of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane was observed in the 0-minute reaction sample, but production of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane was observed in the 60-minute reaction sample. ・In a reaction system using buffer, no production of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane was observed in the 0-minute and 60-minute reaction samples. The test results are shown in the table below. The concentration of (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane produced (μM) is the average of n = 2.

[0130] The compounds of formula [I] are converted chemically or enzymatically to (1R,5S)-1-(naphthalen-2-yl)-3-azabicyclo[3.1.0]hexane under physiological conditions and are useful for treating or preventing central nervous system (CNS) disorders.

Claims

1. Formula [I]: 【Chemistry 1】 [In the formula, X is, 1) -C(=O)-O-, 2)-C(=O)-O-C(X １１ａ )(X １２ａ )-O-C(=O)-、 3)-C(=O)-O-C(X １１ｂ )(X １２ｂ )-O-P(=O)(-OR ２ｂ )-O-、 4) -C(=O)-, 5)-C(=O)-C(X １１ｃ )(X １２ｃ )-N(X １３ｃ )-C(=O)-、 6)-C(X １１ｄ )(X １２ｄ )-O-C(=O)-、 7)-C(X １１ｅ )(X １２ｅ )-N(X １３ｅ )-C(=O)-、 8)-C(X １１ｆ )(X １２ｆ )-O-P(=O)(-OR ２ｆ )-O-、 )(︉ １１ｇ )(︸ １２ｇ ) ２ｇ )? １１ｈ )(︸ １２ｈ )、または 10)-P(=O)(-OR ２ｉ ) —O—; X １１ａ , X １１ｂ , X １１ｃ , X １１ｄ , X １１ｅ , X １１ｆ , X １１ｇ , X １１ｈ , X １２ａ , X １２ｂ , X １２ｃ , X １２ｄ , X １２ｅ , X １２ｆ , X １２ｇ , and X １２ｈ are each independently H or optionally substituted C １ -C ６ is alkyl, or X １１ａ and X １２ａ , X １１ｂ and X １２ｂ , X １１ｃ and X １２ｃ , X １１ｄ and X １２ｄ , X １１ｅ and X １２ｅ , X １１ｆ and X １２ｆ , X １１ｇ and X １２ｇ , and X １１ｈ and X １２ｈ Each of them, together with the carbon atom to which they are attached, is C ３ -C ６ may form a cycloalkane ring or a 3- to 6-membered heterocycloalkane ring; X １３ｃ and X １３ｅ are each independently H or optionally substituted C １ -C ６ is alkyl; R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ are each independently i) H, ii) optionally substituted C １ -C １８ Alkyl, iii) optionally substituted C ２ -C １８ Alkenyl, iv) optionally substituted C ２ -C １８ Alkynyl, v) an optionally substituted 3- to 15-membered hydrocarbon ring group, or vi) an optionally substituted 3- to 15-membered heterocyclic group. A compound represented by the formula:

2. R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ are each independently, if substituted, 1) C １ -C ６ Alkyl, 2) Hydroxy C １ -C ６ Alkyl, 3) optionally substituted C ３ -C ６ Cycloalkyl, 4)-C(=O)-O-R １１ａ 、 5)-O-C(=O)-R １１ｂ 、 6)-C(=O)-N(R １２ａ )-R １３ａ 、 7)-N(R １２ｂ )-C(=O)-R １３ｂ 、 8)-N(R １２ｃ )-C(=O)-O-R ２０ 、 9)-SR １４ 、 10)-OR １５ 、 11)-N(R １２ｄ )-R １６ 、 12)-S(=O)(=O)-OR １７ 、 13)-O-P(=O)(OR １８ )-OR １９ 、 14) optionally substituted 6- to 14-membered aryl, 15) an optionally substituted 3- to 15-membered heterocyclic group, 16) Halogens, and 17) Cyano may be substituted with one or more groups, the same or different, selected from the group consisting of: R １１ａ , R １１ｂ , R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １３ａ , R １３ｂ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ are each independently H, optionally substituted C １ -C ６ an alkyl group, an optionally substituted 3- to 15-membered hydrocarbon ring group, or an optionally substituted 3- to 15-membered heterocyclic group; The compound according to claim 1 or a salt thereof.

3. R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ are each independently i) H, ii) optionally substituted C １ -C １８ Alkyl, iii) optionally substituted C ２ -C ６ Alkenyl, iv) optionally substituted C ２ -C ６ Alkynyl, v) optionally substituted C ３ -C ６ Cycloalkyl, vi) an optionally substituted 6- to 10-membered aryl; or vii) an optionally substituted 5- to 10-membered heterocyclic group; Here, R, R ２ｂ , R ２ｆ , R ２ｇ and R ２ｉ are each independently, if substituted, 1) C １ -C ６ Alkyl, 2) Hydroxy C １ -C ６ Alkyl, 3) 1 to 3 C of the same or different species １ -C ６ C optionally substituted with alkyl ３ -C ６ Cycloalkyl, 4)-C(=O)-O-R １１ａ 、 5)-O-C(=O)-R １１ｂ 、 6)-C(=O)-N(R １２ａ )-R １３ａ 、 7)-N(R １２ｂ )-C(=O)-R １３ｂ 、 8)-N(R １２ｃ )-C(=O)-O-R ２０ 、 9)-SR １４ 、 10)-OR １５ 、 11)-N(R １２ｄ )-R １６ 、 12)-S(=O)(=O)-OR １７ 、 13)-O-P(=O)(OR １８ )-OR １９ 、 14) Optionally substituted 6- to 10-membered aryl (wherein the optionally substituted 6- to 10-membered aryl is C １ -C ６ Alkyl, Hydroxy C １ -C ６ Alkyl and C １ -C ６ alkanoyloxy; 15) Optionally substituted 5- to 10-membered heterocyclic group (wherein the optionally substituted 5- to 10-membered heterocyclic group is C １ -C ６ Alkyl and C １ -C ６ alkanoyloxy; and a 5- to 10-membered heterocyclic group optionally substituted with 1 to 3 identical or different groups selected from the group consisting of alkanoyloxy. 16) Halogens, and 17) Cyano may be substituted with 1 to 3 groups, the same or different, selected from the group consisting of: R １１ａ , R １１ｂ , R １２ａ , R １２ｂ , R １２ｃ , R １２ｄ , R １３ａ , R １３ｂ , R １４ , R １５ , R １６ , R １７ , R １８ , R １９ , and R ２０ are each independently H, optionally substituted C １ -C ６ alkyl, optionally substituted 6- to 10-membered aryl, or optionally substituted 5- to 10-membered heteroaryl; wherein the optionally substituted C １ -C ６ The alkyl may be optionally substituted with 1 to 2 groups, the same or different, selected from the group consisting of optionally substituted phenyl and amino; The optionally substituted 6- to 10-membered aryl is hydroxyC １ -C ６ Alkyl and C １ -C ６ alkoxy may be substituted with 1 to 3 groups, the same or different, selected from the group consisting of: The optionally substituted 5- to 10-membered heteroaryl is selected from the group consisting of 1 to 3 hydroxyl groups, which may be the same or different. １ -C ６ The compound or salt thereof according to claim 1, which is optionally substituted with alkyl.

4. X is, -C(=O)-O-, -C(=O)-O-C(X １１ａ )(X １２ａ )-O-C(=O)-、 -C(=O)-, -C(=O)-C(X １１ｃ )(X １２ｃ )-N(X １３ｃ )-C(=O)-、または -P(=O)(-OR ２ｉ ) —O—; X １１ａ , X １１ｃ , X １２ａ and X １２ｃ are each independently H or C １ -C ６ is alkyl; X １３ｃ is C １ -C ６ is alkyl; R and R ２ｉ each independently represents an optionally substituted C １ -C １８ Alkyl or optionally substituted C ３ -C ６ is cycloalkyl, where R and R ２ｉ When substituted, it is —C(═O)—O—R １１ａ , -NH-C(=O)-OR ２０ , -NH-R １６ and optionally substituted 6- to 10-membered aryl, wherein the optionally substituted 6- to 10-membered aryl is selected from the group consisting of C １ -C ６ Alkyl and C １ -C ６ alkanoyloxy; R １１ａ is H or optionally substituted C １ -C ６ alkyl, wherein the optionally substituted C １ -C ６ The alkyl group may be selected from the group consisting of 1 to 3 C １ -C ６ optionally substituted with phenyl, which may be substituted with alkoxy; R １６ is H or C １ -C ６ is alkyl; R ２０ is C １ -C ６ is alkyl, 2. The compound according to claim 1 or a salt thereof.

5. X is -C(=O)-O-, -C(=O)-OC(X １１ａ ) (X １２ａ ) —O—C(═O)—, or —C(═O)—; X １１ａ and X １２ａ are each independently H or methyl; The compound according to claim 4 or a salt thereof.

6. A pharmaceutical composition comprising a compound according to any one of claims 1 to 5 or a salt thereof, and a pharma- ceutically acceptable carrier.

7. 7. A pharmaceutical composition according to claim 6 for use in the treatment of a central nervous system (CNS) disorder.

8. 6. A therapeutic and / or prophylactic agent for a central nervous system (CNS) disorder, comprising the compound according to any one of claims 1 to 5 or a salt thereof.

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