Morphinan derivative

Abstract

To provide a compound useful as an active ingredient of an anxiolytic drug or antidepressant, and a pharmaceutical comprising the same.SOLUTION: The invention provides a morphinan derivative represented by general formula (I) in the figure.SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to morphinan derivatives having opioid δ receptor agonistic activity. [Background technology]

[0002] Opioids exert their effects by binding to opioid receptors, which have three subtypes: μ, δ, and κ. Agonists for all three subtypes are known to have analgesic effects. However, while morphine, an agonist with high affinity for the opioid μ receptor, has a strong analgesic effect, it also has side effects such as dependence, drug abuse, tolerance, respiratory depression, constipation due to inhibition of gastrointestinal motility, nausea and vomiting, decreased blood pressure, bradycardia, suppression of the cough reflex, and drowsiness. Eptazocine, a selective agonist of the opioid kappa receptor, has a strong analgesic effect, but causes dependence, tolerance, drowsiness, constipation, and mild respiratory depression, while also causing sweating, nausea, vomiting, and dry mouth. On the other hand, activation of the opioid δ receptor is known to produce analgesic, antidepressant, and anxiolytic effects. For example, enkephalin, an endogenous ligand of the opioid δ receptor, is known to have analgesic properties. Furthermore, receptor-deficient mice exhibit increased anxiety-like and depressive-like behaviors (Non-Patent Document 1), and enhancement of the enkephalin-δ receptor system is known to be involved in emotional regulation (Non-Patent Document 2). Furthermore, the antidepressant and anxiolytic effects of various δ receptor agonists are antagonized by δ receptor antagonists in various anxiety and depression models in rats and mice, demonstrating the usefulness of selective δ receptor agonists as antidepressant and anxiolytic drugs (Non-Patent Documents 3-7, Patent Document 1, Patent Document 2). Agonists that selectively activate the opioid δ receptor are expected to have little or no side effects that manifest through activation of the opioid μ receptor or opioid κ receptor. In addition, activation of the δ receptor has been suggested to have an ameliorative effect on neurodegenerative diseases such as Parkinson's disease and Alzheimer's disease, ischemia, stroke, dysuria, HIV infection, alcoholism, diabetes, etc. (Non-Patent Document 8). Various compounds have been reported as opioid δ agonists, and their analgesic, antidepressant, and anxiolytic effects have been demonstrated (Patent Documents 1 to 6, Non-Patent Document 9). Some opioid δ agonists, such as SNC80 and BW373U86, have been reported to induce convulsions (Non-Patent Documents 5, 6, and 10). In addition to the classic tricyclic antidepressants and monoamine oxidase inhibitors, tetracyclic antidepressants and triazolopyridine antidepressants have been developed. In recent years, selective serotonin reuptake inhibitors (SSRIs), serotonin-noradrenaline reuptake inhibitors (SNRIs), and noradrenergic and specific serotonergic antidepressants (NaSSAs) have become popular. However, none of these antidepressants are particularly effective in terms of remission rates. Furthermore, their usefulness is limited by the risk of increased aggression early after initiation of treatment and an increased risk of suicidal ideation and suicide attempts in younger patients. Benzodiazepines are widely used as anti-anxiety drugs, but these drugs have unresolved issues, such as dependency at normal doses, hypnotic effects, muscle relaxation, sedation, and cognitive impairment, making them difficult to use in elderly people and patients with poor general health. Recently, SSRIs and SNRIs, which were developed as antidepressants, have been expanded to treat various anxiety disorders, but they do not provide immediate relief and can have adverse effects. Furthermore, anesthetics such as barbiturates also have anxiolytic effects, but are dangerous because their effective doses are close to the lethal dose. Therefore, there is a need for the development of anti-anxiety drugs and anti-depressants that exert their effects through a mechanism of action different from that of currently used drugs and that have improved side effects and safety.

Prior Technology Literature

[0003]

Patent Document 1

Patent document 2

Patent document 3

Patent document 4

Patent document 5

Patent document 6

Non-licensed literature

[0004] [Non-licensed document 1] Nature Genetics 2000, 25, 195 [Non-licensed document 2] Neuroscience 2005,135,305 [Non-licensed document 3] J.Pharmacol.Exp.Ther.2011,338,195

Non-licensed Document 4

Non-licensed Document 5

Non-licensed Document 6

Non-licensed Document 7

Non-licensed literature 9

[0005] An object of the present invention is to provide safe anti-anxiety drugs, antidepressants, analgesics, drugs for treating Parkinson's disease, and drugs for treating frequent urination and urinary incontinence that are highly effective and have few adverse effects such as dependence, tolerance, respiratory depression, constipation, nausea and vomiting, decreased blood pressure, bradycardia, cough reflex inhibition, hypnotic effect, muscle relaxation, sedation, cognitive decline, sweating, and dry mouth.An object of the present invention is to provide safe drugs that can simultaneously exert antidepressant, anxiolytic, and analgesic effects, thereby providing relief to patients suffering from depression, anxiety, and pain.Another object of the present invention is to provide a drug that can simultaneously treat depression, anxiety, and pain with a single drug, that is safe, and can be administered orally or by injection (e.g., subcutaneous injection). [Means for solving the problem]

[0006] (1) The present invention relates to a compound represented by the following general formula (I):

[0007] [ka]

[0008] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Aryl;C 2-6 Alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; C 3-6cycloalkyl; or heteroarylalkyl in which the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and the alkylene portion has 1 to 5 carbon atoms; R 2 represents a heterocycle containing 1 to 4 heteroatoms selected from N, O and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group; where R 2 is R 2 is bonded to Y through a carbon atom which is a ring atom of R 3 , R 4 and R 5 are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C 1-6 Alkoxy;C 6-10 Aryloxy;C 1-6 Alkanoyloxy;Nitro;Amino;C 1-8 Alkylamino;C 6-10 represents an arylamino or acylamino having 2 to 6 carbon atoms in the acyl moiety, R 6a and R 6b are the same or different and represent hydrogen, fluorine or hydroxy, or R 6a and R 6b together represent =O, R 7 and R 8 are the same or different and represent hydrogen, fluorine or hydroxy; R 9 and R 10 are the same or different and are hydrogen; C 1-6 Alkyl; C 6-10Aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; heteroarylalkyl having 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene moiety; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; 2-6 represents alkenyl, X represents O or CH2; And Y represents C(=O). However, R 1 C 1-10 alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; the alkylene portion of aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; and the alkylene portion of heteroarylalkyl having 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene portion. 1 to 6 halogens; hydroxy; C 1-6 Alkoxy;C 6-10 Aryloxy;C 1-6 Alkanoyl; C 1-6 Alkanoyloxy; Carboxyl; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; Carbamoyl; Alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; Dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; Alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; Aminosulfonyl; Alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; Alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens 1-6 alkoxy; and arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety, And R1 C 6-10 Aryl; aryl moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; R 3 , R 4 and R 5 C 6-10 the aryl portion of aryloxy; and C 6-10 the aryl portion of arylamino; and R 9 and R 10 C 6-10 Aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; aryl moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and heteroaryl moiety of heteroarylalkyl having 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene moiety, C 1-6 Alkyl; C 1-6 Alkoxy;C 1-6 Alkanoyloxy; Hydroxy; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; Carbamoyl; Alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; Dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; Halogen; Nitro; Cyano; C substituted with 1 to 3 halogens 1-6 Alkyl; C substituted with 1 to 3 halogens 1-6 and optionally substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having an alkyl group with 1 to 3 carbon atoms; and methylenedioxy. R 2 The heterocycle of the formula (I) can be an oxo group or any of the above-mentioned R 1 C 6-10 The aryl may have a substituent, Further R 1 C 1-10 For alkyl, NR 11 R 12where R 11 and R 12 are the same or different and are hydrogen; C 1-10 alkyl; or aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, or 11 and R 12 and R 11 and R 12 may be bonded to a nitrogen atom, and optionally, together with one or two heteroatoms, form a 5- to 7-membered ring, And also R 1 The alkylene portion of the aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion is phenyl or C substituted with 1 to 3 halogens. 1-6 It may be substituted with at least one substituent selected from alkyl. The present invention relates to a compound represented by the formula: Figure US08122960-20130323-C00002, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

[0009] The present invention also relates to a pharmaceutical comprising a compound represented by the above general formula (I), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also relates to a pharmaceutical composition containing, as an active ingredient, a compound represented by the above general formula (I), a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also relates to an analgesic containing, as an active ingredient, a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. The present invention also relates to an antidepressant containing, as an active ingredient, a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. The present invention also relates to an anxiolytic agent containing, as an active ingredient, a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. The present invention also relates to a method for alleviating, preventing, or treating depression, which comprises administering an effective amount of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. The present invention also relates to a method for alleviating, preventing, or treating anxiety, which comprises administering an effective amount of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. The present invention also relates to a method for alleviating, preventing or treating pain, which comprises administering an effective amount of a compound represented by the above general formula (I), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof. The present invention also relates to use of a compound represented by the above general formula (I), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the alleviation, prevention, or treatment of pain, depression, or anxiety. The present invention also relates to a method for alleviating, preventing, or treating pain, depression, or anxiety in a human, which method comprises administering to a human an effective amount of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate of the compound. The present invention also relates to a therapeutic agent for Parkinson's disease, which comprises, as an active ingredient, a compound represented by the above general formula (I), a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also relates to a method for alleviating, preventing, or treating Parkinson's disease, which comprises administering an effective amount of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. The present invention also relates to the use of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the alleviation, prevention, or treatment of Parkinson's disease. The present invention also relates to a method for alleviating, preventing, or treating Parkinson's disease in humans, which method comprises administering to humans an effective amount of a compound represented by the above general formula (I), a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also relates to a therapeutic agent for urinary frequency or urinary incontinence, which contains, as an active ingredient, a compound represented by the above general formula (I), a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. The present invention also relates to a method for alleviating, preventing, or treating frequent urination or urinary incontinence, which comprises administering an effective amount of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. The present invention also relates to the use of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the relief, prevention, or treatment of frequent urination or urinary incontinence. The present invention also relates to a method for alleviating, preventing, or treating urinary frequency or urinary incontinence in a human, which method comprises administering to a human an effective amount of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate of the compound. The present invention also relates to a therapeutic agent for glaucoma, which contains, as an active ingredient, a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. The present invention also relates to a method for alleviating, preventing, or treating glaucoma, which comprises administering an effective amount of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. The present invention also relates to the use of a compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, for the alleviation, prevention, or treatment of glaucoma. The present invention also relates to a method for alleviating, preventing, or treating glaucoma in humans, which method comprises administering to humans an effective amount of a compound represented by the above general formula (I), a tautomer, a stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. [Effects of the Invention]

[0010] The compounds of the present invention, represented by general formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts or solvates thereof, have potent agonist activity at opioid δ receptors and show no or only weak activation at μ and κ receptors. Therefore, they exhibit excellent antidepressant, anxiolytic, and analgesic effects, as well as therapeutic effects for Parkinson's disease and urinary incontinence, due to activation of the opioid δ receptor. Because the compounds of the present invention show no or only weak activation at opioid μ and κ receptors, they are free of or have very little side effects such as dependence, drug abuse, tolerance, respiratory depression, constipation due to gastrointestinal motility inhibition, nausea and vomiting, hypotension, bradycardia, cough reflex inhibition, drowsiness, sweating, and dry mouth. Furthermore, as far as investigations have shown, the compounds of the present invention show no or only slight effects on other receptors, channels, and enzymes. Therefore, the compounds of the present invention are expected to have no or very little adverse effects such as convulsions, muscle relaxation, sedation, and cognitive impairment. The compound of the present invention can be administered orally or by injection (for example, subcutaneous injection) and exhibits high blood concentration and brain penetration, and can therefore be used by oral administration or injection. The compounds of the present invention are excellent in terms of drug metabolism because they are hardly metabolized in hepatocyte-derived microsomes, and there is little concern about side effects due to metabolic products. The compounds of the present invention have no or negligibly weak inhibitory activity against Kv11.1 (or hERG; human Ether-a-go-go Related Gene), a potassium ion channel responsible for repolarization of cardiac action potentials, and are therefore safe drugs in terms of the risk of sudden death due to prolongation of the QT interval. The compounds of the present invention are highly effective and safe drugs. The compound of the present invention can simultaneously relieve depression, anxiety, and pain with a single drug. [Brief explanation of the drawings]

[0011] [Figure 1] FIG. 1 shows the results of the elevated plus maze test on Compound 1 in mice. [Figure 2] FIG. 2 shows the results of the elevated plus maze test on Compound 7 in mice. [Figure 3] FIG. 3 shows the results of the elevated plus maze test on Compound 3 in mice. [Figure 4] FIG. 4 shows the results of the mouse elevated plus maze test for Compound 9. [Figure 5] FIG. 5 shows the results of the mouse elevated plus maze test for Compound 10. [Figure 6] FIG. 6 shows the results of the rat elevated plus maze test for Compounds 3, 7, and 10. DETAILED DESCRIPTION OF THE INVENTION

[0012] The present invention will now be described in more detail. Among the compounds represented by the general formula (I) in (1) above, tautomers, stereoisomers of the compounds, or pharmaceutically acceptable salts thereof, or solvates thereof, preferred are the following. (2) R 1 C 1-10 a compound represented by the above general formula (I) of (1), which is alkyl; a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; or an aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (3) R 1is a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to the above (1) or (2). (4) R 1 C substituted with hydroxy 2-6 Alkyl; C substituted with 1 to 6 halogens 1-6 Alkyl; or C 1-6 Alkoxy-substituted C 2-6 A compound represented by the above general formula (I) of (1), which is alkyl, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (5) R 1 is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (6) R 2 is a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group, or a heterocycle in which a benzene ring is fused to the heterocycle, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, according to any one of (1) to (5). (7) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) to (6), which is pyridine 1-oxide optionally substituted by 1 to 4 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (8) R2 The compound according to any one of the above (1) to (7), wherein is pyridine 1-oxide, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (9) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) to (6), which is pyridin-2(1H)-one optionally substituted by 1 to 4 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (10) R 2 Pyridin-2(1H)-one; 1-C 1-6 Alkylpyridin-2(1H)-one; or 6-C 1-6 The compound according to any one of (1) to (6) or (9), which is alkylpyridin-2(1H)-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (11) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 and pyridin-4(1H)-one, which may be substituted with 1 to 4 substituents selected from alkyl. The compound according to any one of the above (1) to (6), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (12) R 2 is pyridin-4(1H)-one or 1-C 1-6 The compound according to any one of (1) to (6) or (11), which is alkylpyridin-4(1H)-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (13) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C1-10 The compound according to any one of the above (1) to (6), which is pyridazin-3(2H)-one optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (14) R 2 is pyridazin-3(2H)-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to any one of (1) to (6) or (13) above. (15) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) to (6), which is pyrazin-2(1H)-one optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (16) R 2 is pyrazin-2(1H)-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to any one of (1) to (6) above. (17) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) to (6), which is 4H-pyran-4-one or 2H-pyran-2-one optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (18) R 2 is 4H-pyran-4-one or 2H-pyran-2-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to any one of (1) to (6) or (17) above. (19) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) to (6), which is quinolin-2(1H)-one optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (20) R 2 is quinolin-2(1H)-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to any one of (1) to (6) above. (twenty one) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) to (6), which is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (twenty two) R 2 is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to any one of (1) to (6) or (21) above. (twenty three) The compound according to any one of the above (1) to (22), wherein X is CH2, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof. (twenty four) R 3 and R 4 wherein one is hydroxy and the other is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to any one of (1) to (23) above. (twenty five) R 3is halogen; cyano; carbamoyl; C 1-6 Alkoxy;C 1-6 Alkanoyloxy; amino; or acylamino, where the acyl moiety has 2 to 6 carbon atoms; 4 is hydrogen or hydroxy, and R 5 is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof according to any one of the above (1) to (23). (26) R 3 is hydroxy; carbamoyl; or C 1-6 Alkanoyloxy, R 4 is hydrogen and R 5 is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof according to any one of the above (1) to (23). (27) R 3 is hydroxy and R 4 is hydrogen and R 5 is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof according to any one of the above (1) to (23). (28) R 3 , R 4 and R 5 are all hydrogen, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof according to any one of (1) to (23) above. (29) R 6a , R 6b , R 7 , R 8 , R 9 and R 10 are all hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to any one of (1) to (28) above.

[0013] (30) R 5 , R 6a , R 6b, R 7 , R 8 , R 9 and R 10 is hydrogen, R 1 is hydrogen; C 1-6 Alkyl; C 2-6 alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; or aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; R 2 represents a 5- to 7-membered heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group, or a heterocycle in which a benzene ring is fused to the heterocycle; where R 2 is R 2 is bonded to Y through a carbon atom which is a ring atom of R 3 and R 4 are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C 1-6 Alkoxy;C 6-10 Aryloxy;C 1-6 Alkanoyloxy; amino; or acylamino, the acyl moiety of which has 2 to 6 carbon atoms; X is CH2, And Y is C(=O), However, R 1 C 1-6 Alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl, in which the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; or the alkylene portion of aralkyl, in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms, 1 to 6 halogens; hydroxy; C 1-6 Alkoxy;C 6-10 Aryloxy;C 1-6 Alkanoyl; C 1-6Alkanoyloxy; Carboxyl; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; Carbamoyl; Alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; Dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; Alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; Aminosulfonyl; Alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; Alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens 1-6 alkoxy; and arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety, And R 1 an aralkyl aryl moiety in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; R 3 and R 4 C 6-10 The aryl part of aryloxy is C 1-6 Alkyl; C 1-6 Alkoxy;C 1-6 Alkanoyloxy; Hydroxy; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; Carbamoyl; Alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; Dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; Halogen; Nitro; Cyano; C substituted with 1 to 3 halogens 1-6 Alkyl; C substituted with 1 to 3 halogens 1-6 and optionally substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having an alkyl group with 1 to 3 carbon atoms; and methylenedioxy. R 2 The heterocycle of the formula (I) can be an oxo group or any of the above-mentioned R 1 the aryl portion of the aralkyl has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms, and the aryl portion of the aralkyl may have a substituent that the aryl portion may have, Further R 1The alkylene portion of the aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion is phenyl or C substituted with 1 to 3 halogens. 1-6 A compound represented by the above general formula (I) (1), which may be substituted with at least one substituent selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (31) R 1 C 1-6 The compound according to (1) or (30), which is alkyl; cycloalkylalkyl in which the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; or aralkyl in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (32) R 1 is a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to (1), (30), or (31). (33) R 1 C substituted with hydroxy 2-6 Alkyl; C substituted with 1 to 6 halogens 1-6 Alkyl; or C 1-6 Alkoxy-substituted C 2-6 The compound according to (1) or (30), wherein R is alkyl, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof of the compound. (34) R 1 is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl, or a tautomer, stereoisomer, or pharmaceutically acceptable salt of the compound according to (1) or (30), or a solvate thereof. (35) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (34), which is pyridine 1-oxide, pyridin-2(1H)-one, pyridin-4(1H)-one, pyridazin-3(2H)-one, pyrazin-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one, quinolin-2(1H)-one, pyrimidin-4(3H)-one, or pyrimidin-2,4(1H,3H)-dione, each of which may be substituted by a substituent selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (36) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (35), which is pyridine 1-oxide optionally substituted by 1 to 4 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (37) R 2 is pyridine 1-oxide, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof of the compound according to any one of (1) or (30) to (36). (38) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (35), which is pyridin-2(1H)-one optionally substituted by 1 to 4 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (39) R 2 Pyridin-2(1H)-one; 1-C 1-6 Alkylpyridin-2(1H)-one; or 6-C 1-6The compound according to any one of (1) or (30) to (35), which is alkylpyridin-2(1H)-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (40) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (35), which is pyridin-4(1H)-one optionally substituted by 1 to 4 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (41) R 2 is pyridin-4(1H)-one or 1-C 1-6 The compound according to any one of (1), (30) to (35), or (40), which is alkylpyridin-4(1H)-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (42) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (35), which is pyridazin-3(2H)-one optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (43) R 2 is pyridazin-3(2H)-one, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof of the compound according to any one of (1), (30) to (35), or (42). (44) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10The compound according to any one of (1) or (30) to (35), which is pyrazin-2(1H)-one optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (45) R 2 is pyrazin-2(1H)-one, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof of the compound according to any one of (1), (30) to (35), or (44). (46) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (35), which is 4H-pyran-4-one or 2H-pyran-2-one, optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (47) R 2 is 4H-pyran-4-one or 2H-pyran-2-one, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof according to any one of (1), (30) to (35), or (46). (48) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (35), which is quinolin-2(1H)-one optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (49) R 2 is quinolin-2(1H)-one, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof of the compound according to any one of (1), (30) to (35), or (48). (50) R 2 C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (35), which is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, optionally substituted by 1 to 3 substituents selected from alkyl, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (51) R 2 is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof according to any one of (1), (30) to (35), or (50). (52) R 3 and R 4 wherein one of the groups is hydroxy and the other is hydrogen, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof of the compound according to any one of (1) or (30) to (51). (53) R 3 is halogen; cyano; carbamoyl; C 1-6 Alkoxy;C 1-6 Alkanoyloxy; amino; or acylamino, where the acyl moiety has 2 to 6 carbon atoms; 4 is hydrogen or hydroxy, a tautomer, a stereoisomer, a pharmaceutically acceptable salt, or a solvate thereof of the compound according to any one of (1) or (30) to (51). (54) R 3 is hydroxy; carbamoyl; or C 1-6 Alkanoyloxy, R 4 is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to any one of (1) or (30) to (51). (55) R 3is hydroxy and R 4 is hydrogen, A compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (56) R 3 and R 4 is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, according to any one of (1), (30) to (51). (57) 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one and A compound selected from 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof. (58) 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one, 5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione and A compound selected from 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof.

[0014] In the present specification: C 1-6Examples of the alkyl include methyl, ethyl, propyl, i-propyl, butyl, tert-butyl, pentyl, neopentyl, and hexyl. C 1-10 As alkyl, the above C 1-6 In addition to the alkyls exemplified above, heptyl, octyl, etc. are also included. C substituted with 1 to 3 halogens 1-6 Examples of alkyl include 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl, and 3,3,3-trifluoropropyl. C 2-6 Alkenyl includes 2-propenyl or 3-methyl-2-butenyl. Examples of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion include C 1 , C 2 , C 3 , C 4 , C 5 , C 6 , C 7 , C 8 , C 9 , C 10 , C 11 , C 12 , C 13 , C 14 , C 15 , C 16 , C 17 , C 18 , C 19 , C 20 , C 21 , C 22 , C 23 , C 24 , C 25 , C 26 , C 27 , C 28 , C 29 , C 30 , C 31 , C 32 , C 33 , C 34 , C 35 , C 36 , C 37 , C 38 , C 39 ... 3-6 Examples include methyl, ethyl, and the like substituted with cycloalkyl. Examples of aralkyl groups in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms include benzyl and phenethyl groups. C 3-6 Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. C 6-10 The aryl includes phenyl, naphthyl, and the like. Examples of heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms include pyridyl, furyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl and thiazolyl. The heteroaryl contains 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms, and the alkylene portion has 1 to 5 carbon atoms. Examples of the heteroarylalkyl include (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, (furan-2-yl)methyl, (furan-3-yl)methyl, (imidazol-2-yl)methyl, (imidazol-4-yl)methyl, (imidazol-5-yl)methyl, (thiazol-2-yl)methyl, (thiazol-4-yl)methyl, (thiazol-5-yl)methyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(pyrazol-1-yl)ethyl, 2-(thiophen-2-yl)ethyl, and 2-(thiophen-3-yl)ethyl. C 1-6 Alkanoyl includes acetyl and propionyl. C 1-6 Alkoxy includes methoxy, ethoxy, propoxy, and the like. C 1-6 Alkanoyloxy includes acetoxy and the like. Examples of the alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety include methoxycarbonyl and ethoxycarbonyl. Examples of halogen include fluorine, chlorine, bromine, and iodine. C substituted with 1 to 3 halogens 1-6 Alkoxy includes fluoromethoxy or trifluoromethoxy and the like. C substituted with 1 to 6 halogens 1-6 Alkoxy includes C substituted with 1 to 3 halogen atoms as described above. 1-6 In addition to alkoxy, examples include tetrafluoroethoxy and the like. Examples of phenylalkyl in which the alkyl has 1 to 3 carbon atoms include benzyl. C 6-10 Aryloxy includes phenoxy and the like. C 1-8 Examples of alkylamino include methylamino and ethylamino. Examples of acylamino in which the acyl moiety has 2 to 6 carbon atoms include acetylamino. C 6-10 Arylamino includes phenylamino and the like. Examples of alkylcarbamoyl groups in which the alkyl moiety has 1 to 6 carbon atoms include ethylcarbamoyl groups. Examples of dialkylcarbamoyl in which the alkyl moiety has 1 to 6 carbon atoms include diethylcarbamoyl. Examples of alkylsulfonyl groups in which the alkyl moiety has 1 to 6 carbon atoms include methylsulfonyl groups. Examples of alkylsulfinyl groups in which the alkyl moiety has 1 to 6 carbon atoms include methylsulfinyl groups. Examples of alkylthio in which the alkyl moiety has 1 to 6 carbon atoms include methylthio. Examples of arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety include benzoyl. R 11 and R 12 and R 11 and R 12 Examples of the 5- to 7-membered ring which may be formed by combining with the nitrogen atom to which is bonded and, if desired, one or two heteroatoms include pyrrolidine, piperidine, and morpholine. R 2 and at least one carbon atom and 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms, and at least one pair of adjacent ring-constituting atoms has a double bond. and heterocycles further substituted with at least one oxo group include: (A) C substituted with 1 to 3 fluorines, such as pyridine 1-oxide and 2-methylpyridine 1-oxide 1-10 Alkyl and unsubstituted C 1-10 pyridine 1-oxide optionally substituted by 1 to 4 substituents selected from alkyl; (B) C substituted with 1 to 3 fluorines, such as pyridin-2(1H)-one, 1-methylpyridin-2(1H)-one, 1-ethylpyridin-2(1H)-one, 6-methylpyridin-2(1H)-one, 6-ethylpyridin-2(1H)-one, or 6-trifluoromethylpyridin-2(1H)-one 1-10 Alkyl and unsubstituted C 1-10 pyridin-2(1H)-one optionally substituted by 1 to 4 substituents selected from alkyl; (C) C substituted with 1 to 3 fluorines, such as pyridin-4(1H)-one, 1-methylpyridin-4(1H)-one, 1-ethylpyridin-4(1H)-one, or 1-(fluoroethyl)pyridin-4(1H)-one 1-10 Alkyl and unsubstituted C 1-10 pyridin-4(1H)-one optionally substituted by 1 to 4 substituents selected from alkyl; (D) C substituted with 1 to 3 fluorines such as pyridazin-3(2H)-one, 2-methylpyridazin-3(2H)-one, etc. 1-10 Alkyl and unsubstituted C 1-10 pyridazin-3(2H)-one optionally substituted by 1 to 3 substituents selected from alkyl; (E) C substituted with 1 to 3 fluorines such as pyrazin-2(1H)-one, 1-methylpyrazin-2(1H)-one, etc. 1-10 Alkyl and unsubstituted C 1-10 Pyrazin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl (F) C substituted with 1 to 3 fluorines, such as 4H-pyran-4-one, 3-methyl-4H-pyran-4-one, 2H-pyran-2-one, and 5-methyl-2H-pyran-2-one 1-10 Alkyl and unsubstituted C 1-10 4H-pyran-4-one and 2H-pyran-2-one optionally substituted with 1 to 3 substituents selected from alkyl (G) C substituted with 1 to 3 fluorines, such as quinolin-2(1H)-one, 6-methylquinolin-2(1H)-one, quinolin-1-oxide, and 4-methylquinolin-1-oxide1-10 Alkyl and unsubstituted C 1-10 quinolin-2(1H)-one and quinolin-1-oxide each optionally substituted by 1 to 3 substituents selected from alkyl; (H) C substituted with 1 to 3 fluorines such as pyrimidin-4(3H)-one and pyrimidin-2,4(1H,3H)-dione 1-10 Alkyl and unsubstituted C 1-10 Examples thereof include pyrimidin-4(3H)-one and pyrimidin-2,4(1H,3H)-dione, each of which may be substituted with 1 to 3 substituents selected from alkyl. The tautomers of the compound represented by the general formula (I) include the above R 2 and at least one carbon atom and 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms, and at least one pair of adjacent ring-constituting atoms has a double bond, and is further substituted with at least one oxo group, and examples thereof include tautomers in heterocycles such as R 2 These include the 2-pyridone (lactam) and the corresponding 2-hydroxypyridine (lactim type). With regard to the compound represented by the above general formula (I), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof, the pharmaceutically acceptable salt is preferably an acid addition salt, and examples of the acid addition salt include salts with organic acids or inorganic acids such as hydrochloride, sulfate, fumaric acid, oxalate, methanesulfonate, and camphorsulfonate. In the compound represented by the above general formula (I), a tautomer of the compound, a stereoisomer, a pharmaceutically acceptable salt thereof, or a solvate thereof, examples of the stereoisomer include cis- and trans-isomers, racemates, optically active substances, etc. In the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt of the compound, or a solvate thereof, the solvate is a pharmaceutically acceptable solvate of the compound of the present invention or a salt thereof, and also includes a hydrate. Furthermore, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof may be a prodrug that has been chemically modified so as to be converted into a pharmacologically active substance and exert (activate) a pharmacological effect after reaching the body or a target site. Examples of such prodrugs include, for example, when the group constituting the prodrug is present at a hydroxyl group, conventional hydroxyl-protecting groups such as lower acyl groups and lower alkoxycarbonyl groups; when the group constituting the prodrug is present at a nitrogen atom, conventional amino-protecting groups such as lower acyl groups and lower alkoxycarbonyl groups; and prodrug groups introduced into the carboxylic acid moiety, such as pivaloyloxymethyl (tBu-C(O)O—CH—), medoxomil, and cilexitil groups. Furthermore, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof may be substituted with a stable isotope such as deuterium.

[0015] Next, methods for producing the compound represented by the above general formula (I), a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof will be described below. The abbreviations used in this specification are as follows: Abbreviations Boc: tert-butoxycarbonyl CPM: cyclopropylmethyl DMA: N,N-dimethylacetamide DMAP: N,N-dimethyl-4-aminopyridine DMF: N,N-dimethylformamide DMSO: dimethyl sulfoxide HATU: 1-[bis(dimethylamino)methylene]-1H-1,2,3- Triazolo[4,5-b]pyridinium 3-oxide Hexafluorophosphate HOAt: 1-hydroxy-7-azabenzotriazole HOBT: 1-hydroxybenzotriazole Me: Methyl Ms: Mesir Ph: Phenyl TBS: tert-butyldimethylsilyl THF: tetrahydrofuran TLC: thin layer chromatography Ts: Tosil WSC: 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (Manufacturing method) In the compound represented by the above general formula (I), R 5 、R 6a 、R 6b 、R 7 、R 8 、R 9 and R 10 The compound of the present invention is The following compound (I), which is a compound provided by the present invention, can be obtained, for example, by a deprotection reaction from the following compound (IA) to compound (I).

[0016] [ka]

[0017] [In the formula, R 1a , R 2a , R 3a and R 4a are converted by deprotection reaction into R 1 , R 2 , R 3 and R 4 and R 1a is itself R 1 and R 2a is itself R 2 and R 3a is itself R 3 and R 4a is itself R 4Other symbols have the same meanings as above.] In the above-mentioned production method, the compound (I) can be deprotected by a suitable known general deprotection reaction to give the compound (IA) R 1a R 1 Convert to R 2a R 2 Convert to R 3a R 3 Convert to R 4a R 4 For example, R in the above compound (IA) can be obtained by converting 1a , R 2a , R 3a Or R 4a When the compound (IA) contains a hydroxyl group protected by a methyl group, the protecting methyl group can be removed by (1) reacting the compound (IA) with boron tribromide in dichloromethane, or (2) heating the compound (IA) with a large excess of pyridine hydrochloride in the absence of a solvent, thereby converting the compound (IA) to the compound (I). In addition, R in the above compound (IA) 1a , R 2a , R 3a Or R 4a When compound (IA) contains a hydroxyl group protected with a tert-butyldimethylsilyl (TBS) group, the protecting TBS group can be removed by (3) reacting compound (IA) with ammonia dissolved in an appropriate solvent, or (4) reacting compound (IA) with hydrogen chloride dissolved in an appropriate solvent, or (5) reacting compound (IA) with tetrabutylammonium fluoride in THF, thereby converting compound (IA) to compound (I). R 1a , R 2a , R 3a Or R 4aWhen each of the groups contains a functional group protected by another protecting group, compound (IA) can be converted to compound (I) by general deprotection conditions explained in, for example, "Green's Protective Groups in Organic Synthesis" by Peter G.M. Wuts (5th edition; A John Wiley & Sons, Inc., Publication). These R 1a , R 2a , R 3a and R 4a have different protecting groups and need to be removed under different conditions, the above compound (IA) may be converted to the above compound (I) as a multi-step deprotection reaction by successively carrying out different conditions suitable for removing each protecting group. The compound (IA) can be obtained, for example, by a general acylation reaction of the following compound (IB) in the reaction scheme shown below.

[0018] [ka]

[0019] [In the formula, R 1a , R 2a , R 3a and R 4a are converted by deprotection reaction into R 1 , R 2 , R 3 and R 4 and R 1a is itself R 1 and R 2a is itself R 2 and R 3a is itself R 3 and R 4a is itself R 4 It may also be the case that 1 represents a leaving group of a general acylating agent. Other symbols are as defined above.] In the above-mentioned production method, the compound (IB), the carboxylic acid (R 2a COOH) and a condensing agent such as HATU or WSC to give the compound (IA). In addition, the compound (IB) and the carboxylic acid chloride (R 2a COCl; L in the formula 1 =Cl) or carboxylic acid anhydride (L in the formula 1 =-OC(O)R 2a The compound (IA) can be obtained by reacting the compound (IA) with 2-(2-methyl-2-propanol)-2-one in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine. R 3a When R is a hydroxyl group (OH), in addition to the desired amidation reaction in the acylation reaction in the above scheme, 3a Acylation of the hydroxyl group proceeds as a side reaction, and R 3a = -OC(O)R 2a However, by treating the reaction solution with a 2N ammonia / methanol solution, etc., R 3a As a result, the compound (IB) is selectively amidated to a secondary amine to give the compound (IA). In addition, the above compound (IB) and the corresponding carboxylic acid (R 2a The compound (IA) can be synthesized from the compound (—COOH). The compound (IB) can be prepared, for example, by the compound 8 (Example 4: R 1a =CPM,X=O,R 3a =OMe,R 4a =H), Compound 33 (Example 29: R 1a =Me,X=O,R 3a=OMe,R 4a =H), Compound 67 (Example 60:R 1a =CPM,X=O,R 3a =H,R 4a =OH), Compound 77 (Example 67:R 1a =CPM,X=CH2,R 3a =OMe,R 4a =H), Compound 116 (Example 101:R 1a =CPM,X=CH2,R 3a =H,R 4a =OH), Compound 130 (Example 106:R 1a =PhCF2CH2,X=CH2,R 3a =OMe,R 4a =H), Compound 185 (Example 143:R 1a =TBSOCH2CH2,X=CH2,R 3a =OMe,R 4a =H), Compound 189 (Example 144:R 1a =(R)-MeCH(OH)CH2, X=CH2, R 3a =OMe,R 4a =H), Compound 350 (Example 261:R 1a =(S)-MeCH(OH)CH2, X=CH2, R 3a =OMe,R 4a =H), Compound 291 (Example 224:R 1a =CPM,X=CH2,R 3a =H,R 4a =OMe), Compound 297 (Example 228:R 1a =CPM,X=CH2,R 3a =H,R 4a =H), compound 29 (Example 27:R 1a =BocNHCH2CH2,X=CH2,R 3a =OTBS,R 4a =H), or compound 68 (Example 34: R 1a =Boc, X=CH2, R 3a =OMe,R 4a Alternatively, the desired compound (IA) can be synthesized by combining known functional group transformation and deprotection reactions according to the methods described in the above patent documents. The following compound (IA) can also be obtained, for example, by a general alkylation reaction of the following compound (IC) in the reaction scheme shown below.

[0020] [ka]

[0021] [In the formula, in the formula, R 1a , R 2a , R 3a and R 4a are converted by deprotection reaction into R 1 , R 2 , R 3 and R 4 and R 1a is itself R 1 and R 2a is itself R 2 and R 3a is itself R 3 and R 4a is itself R 4 It may also be the case that 2 R represents a leaving group in a general alkylation reaction. 1’a is R 1’a -CH2=R 1a The other symbols are as defined above.] In the above production method, the compound (IC) is reacted with the corresponding aldehyde (R 1’a -CHO;R 1’a is R 1’a -CH2=R 1a The compound (IA) can be synthesized by reacting the compound (IA) with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent. In addition, the above compound (IC) can be reacted with the corresponding alkylating agent (R 1a -L 2 : L 2represents a halogen such as Cl, Br, I, or an appropriate leaving group such as OMs or OTs.) in the presence of a base such as potassium carbonate to synthesize the compound (IA). In addition, R for the above compound (IC) 1a The introduction of the group is not limited to the reaction described above, and the compound (IC) can be converted to the compound (IA) by applying a known general reaction for introducing an alkyl group into an amino group, including a multi-step reaction. The compound (IC) can be prepared, for example, from compound 11 (Example 7: R 2a =Ph,X=O,R 3a =OMe,R 4a =H), Compound 81 (Example 71:R 2a =Ph,X=CH2,R 3a =OMe,R 4a =H), Compound 121 (Example 104:R 2a =Ph,X=CH2,R 3a =OTBS,R 4a =H), Compound 149 (Example 120:R 2a =2-pyridil, X=CH2, R 3a =OMe,R 4a =H), Compound 116 (Example 101:R 1a =CPM,X=CH2,R 3a =OMe,R 4a =H), Compound 217 (Example 163:R 2a =CF3,X=CH2,R 3a =OMe,R 4a =H) from suitable starting materials described in the above literature, by combining known functional group conversion and deprotection reactions. Compounds other than the compounds represented by the above general formula (I), which are compounds provided by the present invention, can also be produced by combining the above production method, the method described in the Examples below, and further, the above Patent Documents 4 to 6, Non-Patent Document 11, etc.

[0022] The compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof exhibited excellent agonistic activity and selectivity for the opioid δ receptor in tests for functional activity against μ, δ, and κ opioid receptors (see Table 6 in Example 40). Furthermore, the compound represented by the general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof significantly increased the time spent in the wall-free lane in an elevated plus maze test in mice and rats, thereby exerting anxiolytic-like effects (see Figures 1 to 6 in Examples 41 and 42). The elevated plus maze test was performed according to the method described in Non-Patent Document 6. Furthermore, it was revealed that the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, had an excellent antidepressant effect in a test for suppressing hyperemotional responses in olfactory bulbectomized (OBX) rats (Example 44). Furthermore, the compound represented by the general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof was shown to have therapeutic effects on Parkinson's disease in a mouse model of reserpine-induced Parkinson's disease (Example 45). Furthermore, in a test using a rat model of cerebral infarction-induced overactive bladder, the compound represented by the above general formula (I), its tautomer, stereoisomer, or pharmaceutically acceptable salt, or solvate thereof, tended to increase the urination interval and single urination volume in a dose-dependent manner, suggesting that the test substance has an effect of improving frequent urination (Example 46, Table 8). Furthermore, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, showed only a weak inhibitory effect in a hERG (human ether-a-go-go related gene) potassium channel inhibition test, as described later in Example 43. This indicates that the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, has a low risk of delaying ventricular repolarization and prolonging the QT interval in humans. In addition, the compounds represented by the general formula (I), their tautomers, stereoisomers, or pharmaceutically acceptable salts or solvates thereof exhibit sufficient central transport to exert their pharmacological effects. A metabolic stability test using human liver microsomes revealed that the compounds of the present invention exhibit high stability, demonstrating that they are orally administrable compounds with anxiolytic, antidepressant, analgesic, antiparkinsonian, and urinary frequency / urinary incontinence-improving effects. Metabolic stability using human liver microsomes can be evaluated by adding a known amount of the test compound to human liver microsomes, incubating for a certain period of time, and then quantifying the amount of compound using liquid chromatography (LC) or the like (Example 47, Table 9). Therefore, in consideration of the above-mentioned Patent Documents 1 to 6 and Non-Patent Documents 1 to 10, etc., the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used for the treatment and prevention of depression or anxiety, and can be used as a prophylactic or therapeutic drug (antidepressant, anti-anxiety drug, etc.) for psychiatric disorders included in the depressive disorders, anxiety disorders, bipolar disorders, obsessive-compulsive disorders and related disorders, trauma- and stress-related disorders, etc., described in DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition, American Psychiatric Association), as well as a prophylactic or therapeutic drug for neurodegenerative diseases such as urinary incontinence, myocardial ischemia, cerebral ischemia, chronic cough, hypertension, Parkinson's disease, and epilepsy. Furthermore, the application of opioid δ agonists to glaucoma has been proposed, as described in IOVS, March 2013, Vol. 54, No. 3; J. Neurochem. (2009) 108, 741-754, etc. Therefore, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof of the compound can be used as a prophylactic or therapeutic agent for glaucoma. As used herein, depression may refer to mood disorders such as feelings of depression, sadness, and loneliness, as well as a combination of decreased motivation to do things, mental congestion, pessimistic thoughts, and autonomic nervous disorders such as sleep disorders and decreased appetite. Furthermore, as used herein, anxiety may refer to a state of feeling danger or fear accompanied by restlessness, tension, tachycardia, difficulty breathing, and the like, even without any clearly identifiable stimulus. Depression and anxiety include the depression and anxiety symptoms seen in the psychiatric disorders described in the DSM-5 (e.g., depressive symptoms seen in bipolar disorder, depression and anxiety symptoms seen in PTSD), a depressive state that persists to a certain extent but with symptoms milder than those of the depressive disorders described in the DSM-5, and a state in which symptoms milder than those of the anxiety disorders described in the DSM-5 persist to a certain extent. Furthermore, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate of the compound may be used as a drug to assist in the treatment of the above diseases. Furthermore, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof can be used as a drug for the treatment of pain in diseases accompanied by acute pain and chronic pain, as well as for the prophylaxis and treatment of cancer pain accompanied by severe pain such as rheumatoid arthritis, osteoarthritis, and bone tumor pain, diabetic neuropathic pain, postherpetic neuralgia, and visceral pain. Preferably, the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof is expected to be an antidepressant or an anxiolytic. The compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof can be administered to humans by an appropriate administration method such as oral administration or parenteral administration. In addition, it can also be used in combination with other anxiolytics, antidepressants, or analgesics. For preparation, the composition can be manufactured into dosage forms such as tablets, granules, powders, capsules, suspensions, injections, suppositories, etc., by a conventional method in the technical field of pharmaceutical preparations. In the preparation of these, for example, in the case of tablets, usual excipients, disintegrants, binders, lubricants, pigments, etc. are used. Here, examples of excipients include lactose, D-mannitol, crystalline cellulose, glucose, etc.; examples of disintegrants include starch, carboxymethylcellulose calcium (CMC-Ca), etc.; examples of lubricants include magnesium stearate, talc, etc.; and examples of binders include hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP), etc. In the preparation of injections, examples of solvents, stabilizers, solubilizers, suspending agents, emulsifiers, soothing agents, buffers, preservatives, etc. are used. The dosage for adults is usually 0.1 μg to 1 g / day, preferably 0.001 to 200 mg / day, for the compound represented by the general formula (I) above, which is the active ingredient, or a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof, for injection, or 1 μg to 10 g / day, preferably 0.01 to 2000 mg / day, for oral administration, but this can be increased or decreased depending on age, symptoms, etc. Next, the present invention will be explained in more detail with reference to Reference Examples and Examples, but the present invention is not limited to these. The compounds of the examples and reference examples were named by converting the structural formulas drawn using ChemDraw ver. 14 manufactured by Cambridge Soft into English names using the naming algorithm built into the software, and then translating them into Japanese. The NMR data and mass spectrometry measurements (ESI+ or ESI-) for Examples 1 to 34 are shown in Tables 1 to 5. [Example]

[0023] Reference example 1-1 Synthesis of (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol

[0024] [ka]

[0025] (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (372 mg, 1.02 mmol) synthesized by the method of Example 67 of Patent Document WO2013 / 035833 was added to a 300 mL round-bottom flask, dissolved in dichloromethane (5 mL), and stirred vigorously at 0 ° C for 20 minutes. After that, 1.0 M boron tribromide / dichloromethane solution (5 mL, 5 mmol) was added and stirred at room temperature for 30 minutes. Methanol (10 mL) was added to the reaction solution at 0 ° C and stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the residue was suspended in chloroform (50 mL) and washed with 6% aqueous ammonia (20 mL). The aqueous layer was extracted twice with chloroform (30 mL). The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (356 mg, 100%) as a brown foam. [Alternative method] (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (3.58 g, 9.82 mmol) and pyridine hydrochloride (87 g, 753 mmol) were added to a 500 mL round-bottom flask and stirred at 200 ° C for 1 hour. After the reaction, the mixture was returned to room temperature, and the resulting solid was dissolved in saturated aqueous potassium carbonate, extracted with ethyl acetate and chloroform, and the combined organic layer was dried over anhydrous sodium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure to give the title compound (3.30 g, 96%) as a brown foam. 1 H NMR(CDCl3,400MHz):δ6.94 (d, 1H, J = 8.2 Hz), 6.70 (dd, 1H, J = 8.2, 2.8 Hz), 6.50 (d, 1H, J = 2.3 Hz), 3.73-3.76 (m, 1H), 3.23-3.31 (m, 2H), 3.05-3.12 (m, 2H), 2.77-2.99 (m, 4H), 2.55 (dd, 1H, J = 11.0, 5.0 Hz), 2.31 (d, 1H, J = 6.4 Hz), 1.91-2.11 (m, 2H), 1.69-1.74 (m, 1H), 1.20-1.45 (m, 3H), 0.93-1.10 (m, 3H), 0.77-0.83 (m, 1H), 0.42-0.51 (m, 2H), 0.05-0.14 (m, 2H). Reference example 1-2 Synthesis of (1S,3aR,5aS,6R,11bR,11cS)-10-((tert-butyldimethylsilyl)oxy)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole

[0026] [ka]

[0027] (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (694 mg, 1.98 mmol) synthesized by the method of Reference Example 1-1 was added to a 200 mL round-bottom flask and dissolved in DMF (20 mL). Imidazole (241 mg, 3.54 mmol) and tert-butyldimethylchlorosilane (498 mg, 3.31 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. Since raw materials remained in the reaction solution, imidazole (529 mg, 7.77 mmol) and tert-butyldimethylchlorosilane (503 mg, 3.34 mmol) were added and the mixture was stirred at room temperature for 18 hours. Water (150 ml) was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane (1:1, 100 mL). The aqueous layer was made basic with 6% aqueous ammonia (30 mL), and then extracted twice with a mixed solvent of ethyl acetate and hexane (1:1, 100 mL). The combined organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 25 g) using methanol / chloroform (concentration gradient 0-50%) followed by methanol / chloroform containing 10% concentrated aqueous ammonia (concentration gradient 20-50%) as the eluent to give the title compound (456 mg, 50%) as a yellow syrup and the starting material (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (265 mg, 38%). 1H NMR(CDCl3,400MHz):δ6.94 (d, 1H, J = 8.2 Hz), 6.65 (d, 1H, J = 2.8 Hz), 6.59 (dd, 1H, J = 8.2, 2.8 Hz), 3.49-3.53 (m, 1H), 3.33 (dd, 1H, J = 8.2, 7.8 Hz), 3.08-3.18 (m, 2H), 2.77-2.96 (m, 4H), 2.71 (t, 1H, J = 7.3 Hz), 2.51-2.55 (m, 1H), 2.30 (d, 2H, J = 6.4 Hz), 1.90-2.03 (m, 2H), 1.63-1.68 (m, 1H), 1.35-1.43 (m, 1H), 0.91-1.13 (m, 14H), 0.77-0.83 (m, 1H), 0.42-0.51 (m, 2H), 0.16 (s, 6H), 0.08-0.10 (m, 2H). Example 1 Synthesis of 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide

[0028] [ka]

[0029] In a 50 mL round-bottom flask, (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (31 mg, 87 μmol), 2-carboxypyridine 1-oxide (32 mg, 0.23 mmol), and HATU (125 mg, 0.33 mmol) synthesized in Reference Example 1 were added, and the mixture was suspended in THF (1.5 mL). Then, triethylamine (70 μL, 0.50 mmol) and DMA (200 μL) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction mixture was added 2N ammonia / methanol solution (2 mL), and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was suspended in 6% aqueous ammonia and extracted with ethyl acetate. The combined organic layer was washed with saturated brine and then dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform (concentration gradient: 0%-50%) as eluent to yield the title compound (18 mg, 44%) as a white solid. Example 2 Synthesis of 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide

[0030] [ka]

[0031] The reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (36 mg, 0.10 mmol), 4-carboxypyridine 1-oxide (42 mg, 0.30 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (108 mg, 0.28 mmol) in a similar manner as in Example 1. The reaction solution was purified by column chromatography (silica gel, 10 g) using methanol and 5% triethylamine in ethyl acetate (gradient: 10%-50%) as the eluent. The resulting syrup was dissolved in methanol, and then chloroform and tert-butyl methyl ether were added to turn the solution into powder, which was then collected by filtration to give the title compound (30 mg, 62%) as a slightly brown solid. Example 3 Synthesis of 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0032] [ka]

[0033] The reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (39 mg, 0.11 mmol), 2-oxo-1,2-dihydropyridine-3-carboxylic acid (39 mg, 0.28 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (130 mg, 0.34 mmol). The reaction mixture was quenched by adding 2N ammonia / methanol solution, concentrated under reduced pressure, and the residue was purified by column chromatography (silica gel, 10 g) using methanol and ethyl acetate containing 5% triethylamine (concentration gradient: 10%-50%) as the eluent. The resulting residue was powdered with 6% aqueous ammonia to give the title compound (13 mg, 25%) as a pale yellow powder. Example 4 Synthesis of 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide

[0034] [ka]

[0035] The reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (34 mg, 97 μmol), 3-carboxypyridine 1-oxide (40 mg, 0.29 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (125 mg, 0.33 mmol) according to the same procedure as in Example 1. The reaction was quenched by adding 2 N ammonia / methanol solution to the reaction solution, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 25 g) using 0.1 N ammonia / methanol solution and chloroform (concentration gradient: 0%-50%) as eluent. The resulting syrup was dissolved in methanol, and then tert-butyl methyl ether was added to turn the mixture into powder, which was then collected by filtration to give the title compound (14 mg, 31%) as a slightly brown amorphous substance. Example 5 Synthesis of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0036] [ka]

[0037] The reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (34 mg, 96 μmol), 6-oxo-1,6-dihydropyridine-3-carboxylic acid (40 mg, 0.29 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (132 mg, 0.35 mmol) in the same manner as in Example 1. 2N ammonia / methanol solution was added to the reaction solution to terminate the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10 g) using 0.1 N ammonia / methanol solution and chloroform (concentration gradient: 1%-50%) as eluents. The resulting compound was suspended in chloroform to remove impurities and then washed with 6% aqueous ammonia. The aqueous layer was extracted with chloroform, and the combined organic layers were dried over anhydrous sodium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to give the title compound (14 mg, 30%) as a pale yellow powder. Reference example 2 Synthesis of 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0038] [ka]

[0039] This compound was synthesized according to the method described in WO2006 / 107254. 2-Oxo-1,2-dihydropyridine-3-carboxylic acid (500 mg, 3.59 mmol) was added to a 50 mL round-bottom flask and suspended in methanol (5 mL) and water (0.8 mL). Potassium hydroxide (400 mg, 7.13 mmol) was then added and the mixture was stirred at 100°C for 15 minutes. The reaction solution was returned to room temperature, iodomethane (2.6 mL, 41.8 mmol) was added, and the mixture was stirred at 100°C for 45 minutes. The mixture was then concentrated under reduced pressure until the solvent volume was reduced by half. 3N hydrochloric acid (20 mL) was added to the reaction solution, and the resulting solid was filtered, washed with water and acetonitrile, and dried under reduced pressure to yield the title compound (64.9 mg, 12%) as a white powder. 1 H NMR(CD3OD,400MHz):δ8.43 (dd, 1H, J = 6.9, 2.3 Hz), 8.05 (dd, 1H, J = 6.9, 2.3 Hz), 6.65 (t, 1H, J = 6.9 Hz), 3.70 (s, 3H). Example 6 Synthesis of 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

[0040] [ka]

[0041] The reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 86 μmol), 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (29 mg, 0.19 mmol) synthesized in Reference Example 2, diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72 mg, 0.19 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. The reaction solution was quenched by adding 1.4 N ammonia / methanol solution, and then concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC using 1.4 N ammonia / methanol solution-chloroform (concentration: 5%) as a developing solvent to give the title compound (26.2 mg, 63%) as a pale yellow amorphous solid. Example 7 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0042] [ka]

[0043] The reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (66 mg, 0.19 mmol), 6-oxo-1,6-dihydropyridine-2-carboxylic acid (83 mg, 0.59 mmol), triethylamine (150 μL, 1.10 mmol), and HATU (262 mg, 0.69 mmol) in the same manner as in Example 1. 2N ammonia / methanol solution was added to the reaction solution to terminate the reaction, and the mixture was concentrated under reduced pressure. The residue was purified by column chromatography (amino silica gel, 10 g) using methanol and chloroform (concentration gradient: 0%-30%) as eluents. The resulting syrup was dissolved in methanol and triturated with tert-butyl methyl ether to give the title compound (83 mg, 94%) as a brown solid. Example 8 Synthesis of 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one

[0044] [ka]

[0045] The reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (19 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg, 0.13 mmol). However, DMF was used as the solvent instead of THF and DMA. The reaction solution was quenched by adding 1.4 N ammonia / methanol solution, and then concentrated under reduced pressure. The residue was purified by preparative TLC using 1.4 N ammonia / methanol solution-chloroform (concentration: 10%) as the developing solvent. To further remove impurities, the resulting solid was suspended in saturated aqueous potassium carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and inorganic matter was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound. The resulting compound was converted into a hydrochloride salt according to Example 32 for use in biological activity testing. Example 9 Synthesis of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

[0046] [ka]

[0047] The reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 86 μmol), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (29 mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72 mg, 0.19 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. The reaction solution was quenched by adding 1.4 N ammonia / methanol solution, and then concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC using methanol and chloroform (concentration: 10%) as a developing solvent to give the title compound (31.1 mg, 75%) as a white amorphous solid. Reference example 3 Synthesis of 1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0048] [ka]

[0049] 6-Oxo-1,6-dihydropyridine-2-carboxylic acid (500 mg, 3.59 mmol) was added to a 50 mL round-bottom flask and suspended in methanol (5 mL) and water (0.8 mL). Potassium hydroxide (400 mg, 7.13 mmol) was then added and the mixture was stirred at 100°C for 15 minutes. The reaction solution was returned to room temperature, iodomethane (2.6 mL, 41.8 mmol) was added, and the mixture was stirred at 100°C for 1 hour. The mixture was then concentrated under reduced pressure until the solvent volume was reduced to half. 3N hydrochloric acid was added to the reaction solution, and the resulting solid was filtered, washed with water and acetonitrile, and dried under reduced pressure to give the title compound (339 mg, 62%) as a white powder. 1H NMR(DMSO-d6,400MHz):δ7.45 (dd, 1H, J = 9.2, 6.9 Hz), 6.72 (dd, 1H, J = 6.9, 1.4 Hz), 6.59 (dd, 1H, J = 9.2, 1.4 Hz), 3.51 (s, 3H). Example 10 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

[0050] [ka]

[0051] The reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 86 μmol), 1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (29 mg, 0.19 mmol) synthesized by the method of Reference Example 3, diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72 mg, 0.19 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. The reaction solution was quenched by adding 1.4 N ammonia / methanol solution, and then concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC using methanol and chloroform (concentration: 10%) as a developing solvent to give the title compound (32.7 mg, 79%) as a white amorphous solid. Example 11 Synthesis of 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0052] [ka]

[0053] The reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (54 mg, 0.15 mmol), 2-methoxyisonicotinic acid (54 mg, 0.35 mmol), triethylamine (140 μL, 1.00 mmol), and HATU (195 mg, 0.51 mmol) according to the same procedure as in Example 1. The reaction was terminated by adding 2N ammonia / methanol solution to the reaction solution, followed by concentration under reduced pressure. The residue was suspended in chloroform and washed with 6% aqueous ammonia. The aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was then filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (amino silica gel, 16 g) using 10% concentrated aqueous ammonia in methanol and chloroform as eluents to give ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(2-methoxypyridin-4-yl)methanone (61 mg, 82%) as a white solid. 1H NMR(DMSO-d6,400MHz):δ8.20 (d, 0.6H, J = 6.0 Hz), 8.15 (d, 0.4H, J = 5.0 Hz), 6.88-6.97 (m, 2H), 6.80 (s, 0.6H), 6.74 (s, 0.4H), 6.64 (d, 0.6H, J = 2.8 Hz), 6.56 (dd, 0.6H, J = 8.2, 2.3 Hz), 6.45-6.51 (m, 0.8H), 4.06-4.16 (m, 1H), 3.92 (s, 1.8H), 3.88 (s, 1.2H), 3.64-3.69 (m, 0.6H), 3.43-3.37 (m, 2H), 3.14-3.17 (m, 1H), 2.97-3.09 (m, 1H), 2.82-2.91 (m, 2H), 2.52-2.56 (m, 1H), 2.29-2.31 (m, 2H), 1.88-2.08 (m, 2H), 1.66-1.80 (m, 1H), 1.42-1.57 (m, 1.6H), 1.02-1.23 (m, 2.4H), 0.75-0.96 (m, 2H), 0.42-0.49 (m, 2H), 0.05-0.14 (m, 2H). The ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(2-methoxypyridin-4-yl)methanone (48 mg, 98 μmol) obtained above and pyridine hydrochloride (2.88 g, 25 mmol) were added to a 100 mL round-bottom flask and stirred at 200°C for 10 minutes. The reaction solution was cooled to room temperature, suspended in 6% aqueous ammonia, and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (concentration gradient: 0% to 30%) as an eluent to give the title compound (35 mg, 75%) as a white solid. Example 12 Synthesis of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione

[0054] [ka]

[0055] A reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 90 μmol), 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid monohydrate (35 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (114 mg, 0.30 mmol). 2N ammonia / methanol solution was added to the reaction solution to quench the reaction. The mixture was then concentrated under reduced pressure. The resulting residue was suspended in saturated aqueous sodium bicarbonate and extracted three times with a 5:1 mixture of chloroform and methanol. The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC using 10% concentrated aqueous ammonia in methanol and chloroform (concentration: 25%) as a developing solvent to give the title compound (16 mg, 35%) as a white solid. Example 13 Synthesis of 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one

[0056] [ka]

[0057] A reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 90 μmol), 4-oxo-1,4-dihydropyridine-3-carboxylic acid (28 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (114 mg, 0.30 mmol) in a similar manner as in Example 1. The reaction was quenched by adding 2N ammonia / methanol solution to the reaction solution, which was then suspended in saturated aqueous sodium bicarbonate and extracted three times with ethyl acetate. The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol containing 10% concentrated aqueous ammonia and chloroform (concentration: 15%) as a developing solvent to give the title compound (19 mg, 44%) as a white solid. Example 14 Synthesis of 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one

[0058] [ka]

[0059] A reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 90 μmol), 4-oxo-1,4-dihydropyridine-2-carboxylic acid (28 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (114 mg, 0.30 mmol). The reaction was quenched by adding 2N ammonia / methanol solution to the reaction solution, and the mixture was suspended in saturated aqueous sodium bicarbonate and extracted three times with a 5:1 mixture of chloroform and methanol. The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC using 10% concentrated aqueous ammonia in methanol and chloroform (concentration: 15%) as a developing solvent to give the title compound (8 mg, 20%) as a white solid. Example 15 Synthesis of 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

[0060] [ka]

[0061] A reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 90 μmol), 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (31 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (114 mg, 0.30 mmol). The reaction was quenched by adding 2N ammonia / methanol solution to the reaction solution, and the mixture was then suspended in saturated aqueous sodium bicarbonate and extracted three times with chloroform. The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC using methanol and chloroform (concentration: 5%) as a developing solvent to give the title compound (41 mg, 94%) as a white solid. Example 16 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one

[0062] [ka]

[0063] The reaction was carried out using the same procedure as in Example 1, using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 85.9 μmol), 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (31 mg, 0.22 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (129 mg, 0.34 mmol). The reaction solution was quenched by adding 2N ammonia / methanol solution and then concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform (concentration gradient: 0% to 30%) as an eluent to give the title compound (27 mg, 66%) as a white solid. Example 17 Synthesis of 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one

[0064] [ka]

[0065] A reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (33 mg, 95 μmol), 2-oxo-1,2-dihydroquinoline-4-carboxylic acid (50 mg, 0.26 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (128 mg, 0.34 mmol) in the same manner as in Example 1. The reaction was terminated by adding 2N ammonia / methanol solution to the reaction solution, followed by concentration under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform (concentration gradient: 0% to 30%) as an eluent to give the title compound (28 mg, 56%) as a white solid. Example 18 Synthesis of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one

[0066] [ka]

[0067] The reaction was carried out using the same procedure as in Example 1, using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 2-oxo-2H-pyran-5-carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg, 0.13 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. One hour after the start of the reaction, 1N hydrochloric acid was added to the reaction solution and further stirred. The reaction mixture was quenched by adding aqueous potassium carbonate solution, extracted with chloroform, dried over sodium sulfate, filtered to remove insoluble matter, and concentrated under reduced pressure. The residue was subjected to preparative TLC using methanol and chloroform (concentration: 5%) as a developing solvent to give the title compound (4.0 mg, 15%) as a brown amorphous solid. Example 19 Synthesis of 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one

[0068] [ka]

[0069] The reaction was carried out using the same procedure as in Example 1, using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 4-oxo-4H-pyran-2-carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg, 0.13 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. The reaction solution was quenched by adding 2N methylamine / methanol solution (0.3 mL, 0.6 mmol), and then concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC using methanol and chloroform (concentration: 10%) as a developing solvent to give the title compound (4.4 mg, 16%) as a brown amorphous solid. Example 20 Synthesis of 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one

[0070] [ka]

[0071] The reaction was carried out using the same procedure as in Example 1, with (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 4-oxo-4H-pyran-2-carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg, 0.13 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. The reaction solution was quenched by adding 2N methylamine / methanol solution (3.0 mL, 6.0 mmol), and then concentrated under reduced pressure. The residue was suspended in saturated aqueous potassium carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (concentration gradient: 0%-10%) as an eluent to give the title compound (19 mg, 68%) as a slightly brown amorphous solid. Example 21 Synthesis of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one

[0072] [ka]

[0073] The reaction was carried out using the same procedure as in Example 1, using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 5-oxo-4,5-dihydropyrazine-2-carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU (48 mg, 0.13 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. The reaction solution was quenched by adding 1.4 N ammonia / methanol solution, and then concentrated under reduced pressure. The residue was suspended in aqueous potassium carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient: 5%-30%) as an eluent to give the title compound (12.2 mg, 45%) as a slightly brown amorphous solid. Example 22 Synthesis of 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide

[0074] [ka]

[0075] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (52 mg, 0.11 mmol) synthesized in Example 1 was added to a 10 mL test tube and suspended in THF (1 mL). Triethylamine (45 μL, 0.32 mmol) and acetyl chloride (15 μL, 0.21 mmol) were then added and the mixture was stirred at room temperature for 1 hour. Since it was confirmed that starting materials remained in the reaction mixture, triethylamine (45 μL, 0.32 mmol) and acetyl chloride (15 μL, 0.21 mmol) were added again and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium bicarbonate and ethyl acetate were added to the reaction solution, and the mixture was stirred vigorously for 20 minutes. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (51 mg, 89%) as a yellow amorphous solid. Example 23 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0076] [ka]

[0077] The reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (27 mg, 79 μmol), 6-oxo-1,6-dihydropyridine-2-carboxylic acid (18 mg, 0.16 mmol), triethylamine (50 μL, 0.36 mmol), and HATU (70 mg, 0.18 mmol), prepared by the method of compound 297 (Example 228) described in Patent Document WO2013 / 035833. 2N ammonia / methanol solution was added to the reaction solution to terminate the reaction, and the mixture was concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. After filtering off the insoluble material, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (concentration gradient: 0%-20%) as the eluent. The resulting compound was dissolved in methanol and triturated with tert-butyl methyl ether to obtain the title compound (24 mg, 67%) as a white solid. Reference example 4 Synthesis of 3-oxo-3,4-dihydropyrazine-2-carboxylic acid

[0078] [ka]

[0079] This compound was synthesized by the method described in Patent Document WO2009 / 033084, and the 1H NMR spectrum was consistent with the data described in the literature Syn. Commun. 2010.40(20).2988-2999. 3-Aminopyrazine-2-carboxylic acid (300 mg, 2.17 mmol) and concentrated sulfuric acid (1.3 mL) were added to a 50 mL round-bottom flask, and sodium nitrite (149 mg, 2.16 mmol) dissolved in concentrated sulfuric acid (1.6 mL) was added dropwise in an ice bath, followed by stirring for 1 hour. The reaction solution was added to ice water, stirred vigorously, and the resulting solid was collected by filtration. The resulting solid was dried under reduced pressure at 60 °C for 1 hour to yield the title compound (166 mg, 55%) as pale yellow crystals. 1 H NMR (DMSO-d6,400MHz): δ7.80 (d, 1H, J = 3.7 Hz), 7.64 (d, 1H, J = 3.7 Hz). Example 24 Synthesis of 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one

[0080] [ka]

[0081] The reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol) and 3-oxo-3,4-dihydropyrazine-2-carboxylic acid (20 mg, 0.14 mmol) synthesized in Reference Example 4. However, HOAt (17 mg, 0.13 mmol) was used instead of triethylamine, WSC (24 mg, 0.13 mmol) was used instead of HATU, and DMF was used instead of THF as the solvent. The reaction mixture was quenched by adding 1.4 N ammonia / methanol solution, extracted with chloroform, and washed with saturated aqueous ammonium chloride and then saturated aqueous sodium bicarbonate. The organic layer was dried over anhydrous sodium sulfate, and insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 20%) as a developing solvent to obtain the title compound (5.9 mg, 22%) as a pale yellow amorphous solid. Example 25 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione

[0082] [ka]

[0083] The reaction was carried out using the same procedure as in Example 1, except that (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol) and 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (20 mg, 0.13 mmol). However, HOAt (17 mg, 0.13 mmol) was used instead of triethylamine, WSC (24 mg, 0.13 mmol) was used instead of HATU, and DMF was used instead of THF as the solvent. The reaction solution was quenched by adding 1.4 N ammonia / methanol solution, and then concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient: 5%-30%) as eluent. To remove impurities, the resulting compound was suspended in chloroform and aqueous ammonia, and then filtered to give the title compound (2.5 mg, 9%) as a slightly brown amorphous solid. Reference example 5 Synthesis of 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0084] [ka]

[0085] 6-Oxo-1,6-dihydropyridine-2-carboxylic acid (129 mg, 925 μmol) and 1,1-diethoxy-N,N-dimethylmethanamine (1.5 mL) were added to a 30 mL round-bottom flask and stirred at 100°C for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient 0%-20%) as eluent to obtain ethyl 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylate (104 mg, 58%) as a colorless oil. The ethyl 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylate (104 mg, 533 μmol) obtained above was added to a 50 mL round-bottom flask and dissolved in ethanol (3 mL). 5 N aqueous sodium hydroxide solution (200 μL, 1.0 mmol) was added and stirred at 55°C for 2 hours. The reaction solution was allowed to cool to room temperature, acidified with 5 N hydrochloric acid (400 μL, 2.0 mmol), and then concentrated under reduced pressure. Ethanol (3 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was suspended in ethanol (3 mL), and the insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure to give the title compound (48 mg, 54%) as a colorless crystalline solid. 1 H NMR (DMSO-d6,400MHz):δ7.41 (dd, 1H, J = 9.2, 6.0 Hz), 6.65 (d, 1H, J = 6.4 Hz), 6.53 (d, 1H, J = 8.7 Hz), 4.06 (q, 2H, J = 6.9Hz), 1.17 (t, 3H, J = 6.9 Hz). Example 26 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one

[0086] [ka]

[0087] A reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 92 μmol), 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (33 mg, 0.19 mmol) synthesized in Reference Example 5, triethylamine (70 μL, 0.50 mmol), and HATU (136 mg, 0.36 mmol) in the same manner as in Example 1. The reaction was terminated by adding 2N ammonia / methanol solution to the reaction solution, followed by concentration under reduced pressure. The residue was suspended in 6% aqueous ammonia and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate. After filtering off the insoluble material, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (concentration gradient: 0%-20%) as the eluent. The resulting compound was dissolved in methanol and triturated with tert-butyl methyl ether to obtain the title compound (35 mg, 76%) as a white solid. Example 27 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one

[0088] [ka]

[0089] The reaction was carried out in the same manner as in Example 1, except that (1S,3aR,5aS,6R,11bR,11cS)-10-((tert-butyldimethylsilyl)oxy)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (30 mg, 65 μmol) and 6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (20 mg, 0.14 mmol) were used. However, HOAt (19 mg, 0.14 mmol) was used instead of triethylamine, WSC (27 mg, 0.14 mmol) was used instead of HATU, and DMF was used instead of THF as the solvent. The residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient: 0%-10%) as the eluent. The solid obtained above, methanol (2 mL), and aqueous ammonia were added to a 100 mL round-bottom flask and stirred at room temperature for 3 days. The reaction solution was concentrated, and the residue was suspended in chloroform. Insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 20%) as a developing solvent to obtain the title compound (1.7 mg, 6%) as a white amorphous solid. Reference example 6 Synthesis of 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

[0090] [ka]

[0091] To 2-oxo-2H-pyran-5-carboxylic acid (200 mg, 1.43 mmol) and DMAP (17.5 mg, 143 μmol) dissolved in dichloromethane (3.3 mL) and THF (3.3 mL), WSC (274 mg, 1.43 mmol) and benzyl alcohol (148 μL, 1.43 mmol) were added and stirred at room temperature for 2 hours. Water was added to the reaction solution, and the insoluble material was filtered off. The mixture was then extracted with hexane and washed with saturated aqueous sodium bicarbonate. The combined organic layer was dried over sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methanol (10 mL) along with ethylamine hydrochloride (112 mg, 1.37 mmol), and triethylamine (520 μL, 3.73 mmol) was added. The mixture was stirred at room temperature for 16 hours. After the reaction, the mixture was concentrated under reduced pressure. The resulting residue was added with saturated aqueous sodium bicarbonate, extracted with chloroform, and washed with saturated brine. The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (10 g) using ethyl acetate and hexane (concentration gradient 10%-60%) as eluent to obtain benzyl 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (126 mg, 34% in two steps) as a pale yellow amorphous solid. The 1-ethyl-6-oxo-1,6-dihydropyridine-3-benzyl carboxylate obtained above was dissolved in methanol (2 mL) and ethyl acetate (2 mL), and 10% palladium on carbon was added. The mixture was stirred under a hydrogen atmosphere at room temperature for 2 hours. After the reaction, insoluble matter was filtered through Celite, and the resulting solution was concentrated to give the title compound (73 mg, 89%) as a pale yellow amorphous solid. 1 H NMR(CH3OD,400MHz):δ8.43 (d, 1H, J = 2.3 Hz), 7.95 (dd, 1H, J = 9.6, 2.3 Hz), 6.51 (d, 1H, J = 9.6 Hz), 4.07 (q, 2H, J = 7.3 Hz), 1.34 (t, 3H, J = 7.3 Hz). Example 28 Synthesis of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one

[0092] [ka]

[0093] The reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (15 mg, 43 μmol), 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (16 mg, 94 μmol) synthesized in Reference Example 6, diisopropylethylamine (37 μL, 0.21 mmol), and HATU (36 mg, 94 μmol). However, only THF was used as the solvent. The reaction was terminated by adding 1.4 N ammonia / methanol solution to the reaction solution, and then concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient: 0%-30%) as eluent to give the title compound (13.3 mg, 62%) as a white amorphous solid. Example 29 Synthesis of 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide hydrochloride

[0094] [ka]

[0095] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (79 mg, 0.17 mmol) synthesized in Example 1 was added to a 50 mL round-bottom flask and dissolved in ethanol (2 mL). 2 N hydrochloric acid (1 mL) was then added, and the resulting solution was concentrated under reduced pressure. The resulting residue was dried under reduced pressure at 80°C for 18 hours to give the title compound (85 mg, 99%) as a white amorphous solid. Example 30 Synthesis of 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one hydrochloride

[0096] [ka]

[0097] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (44 mg, 93 μmol) synthesized in Example 3 was added to a 50 mL round-bottom flask and dissolved in 2 N hydrochloric acid (2 mL). The resulting solution was concentrated under reduced pressure. The resulting residue was dried under reduced pressure at 100° C. for 18 hours to give the title compound (40 mg, 84%) as a yellow solid. Example 31 Synthesis of 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one hydrochloride

[0098] [ka]

[0099] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (26 mg, 54 μmol) synthesized in Example 6 and ethyl acetate were added to a 10 mL test tube, followed by extraction with 1 N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The resulting residue was dried under reduced pressure at 60°C for 1 hour to give the title compound (23 mg, 83%) as a pale yellow amorphous solid. Example 32 Synthesis of 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one hydrochloride

[0100] [ka]

[0101] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one synthesized in Example 8 and ethyl acetate were added to a 10 mL test tube, followed by extraction with 1 N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The resulting residue was dried under reduced pressure to give the title compound (11 mg, 39% over two steps from Example 8) as a pale yellow amorphous solid. Example 33 Synthesis of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one hydrochloride

[0102] [ka]

[0103] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (31 mg, 64 μmol) synthesized in Example 9 and ethyl acetate were added to a 10 mL test tube, followed by extraction with 1 N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The resulting residue was dried under reduced pressure at 60°C for 2 hours to give the title compound (22 mg, 67%) as a pale yellow amorphous solid. Example 34 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one hydrochloride

[0104] [ka]

[0105] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (33 mg, 67 μmol) synthesized in Example 10 and ethyl acetate were added to a 10 mL test tube, followed by extraction with 1 N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The resulting residue was dried under reduced pressure at 60°C for 2 hours to give the title compound (33 mg, 94%) as a slightly brown amorphous solid.

[0106] [Table 1]

[0107] [Table 2]

[0108] [Table 3]

[0109] [Table 4]

[0110] [Table 5]

[0111] Reference example 7-1 Synthesis of 2,2,2-trichloroethyl (1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate

[0112] [ka]

[0113] 2,2,2-trichloroethyl (1S,3aR,5aS,6R,11bR,11cS)-10-methoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate (972.7 mg, 2.00 mmol) synthesized by the method described in WO2014136305, Example 34 (1) was added to a 100 mL eggplant-shaped flask and dissolved in methylene chloride (20 mL). After cooling the reaction solution to 0 ° C, 1 M boron tribromide / methylene chloride solution (6 mL) was added with vigorously stirring, and the mixture was stirred for 1 hour while warming to room temperature. Saturated aqueous sodium bicarbonate (30 mL) was added to the reaction solution, followed by extraction with chloroform (20 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (1.04 g, >100%) as a white foam. The crude product was used directly in the next reaction without further purification. Reference example 7-2 Synthesis of 2,2,2-trichloroethyl (1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate

[0114] [ka]

[0115] 2,2,2-trichloroethyl (1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate (1.04 g), synthesized in Reference Example 7-1, was added to a 100 mL eggplant-shaped flask and dissolved in THF (20 mL). Triethylamine (2.79 mL, 20 mmol) and trifluoroacetic anhydride (1.41 mL, 10 mmol) were added to the resulting solution and stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was diluted with saturated aqueous sodium bicarbonate (50 mL) and then extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to give the title compound (1.46 g, >100%) as a white foam. The crude product was used in the next reaction without further purification. Reference example 7-3 Synthesis of 2,2,2-trifluoro-1-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-14-yl)ethan-1-one

[0116] [ka]

[0117] 2,2,2-trichloroethyl (1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylate (1.46 g), synthesized in Reference Example 7-2, was placed in a 100 mL eggplant-shaped flask and dissolved in acetic acid (25 mL). Zinc powder (1.31 g, 20 mmol) was added to the resulting solution and stirred at room temperature for 2 hours. The reaction solution was filtered through Celite, and excess zinc powder was removed by distillation. The filtrate was concentrated under reduced pressure and then azeotroped with toluene. The residue was diluted with saturated aqueous sodium bicarbonate (30 mL) and extracted with chloroform (30 mL x 3). The combined organic layer was dried over anhydrous sodium sulfate, insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (amino silica gel: 16 g) using ethyl acetate and methanol (concentration gradient 0%-30%) as eluent to give the title compound (215 mg, overall yield for three steps: 27%) as a pale yellow foam. 1H NMR CDCl3,6.96-7.06(m,1H),6.64-6.72(m,1H),6.52-6.58(m,1H),5.90(br s,1H),4.90(d,0.5H,J=6.8Hz),4.34(dd,0.5H,J=6.5,13.8Hz),4.18-4.24(m,0.5 H),2.72-3.81(m,8.5H),2.21-2.45(m,1H),1.46-2.00(m,3H),0.99-1.43(m,4H). Reference example 8-1 Synthesis of ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate

[0118] [ka]

[0119] This compound was synthesized according to the method described in WO2011 / 090935. A 20% sodium ethoxide / ethanol solution (60 mL) and ethyl 2-(ethoxymethylene)malonate (10.5 mL, 524 mmol) were added to a 500 mL eggplant-shaped flask and stirred at room temperature for 10 minutes. Hydrazine monohydrate (5.1 mL, 104 mmol) was added to the resulting mixture, which was then heated and stirred at 80°C for 18 hours. The resulting yellow suspension was then cooled to 0°C. To the vigorously stirred reaction mixture, 1N hydrochloric acid (180 mL) was slowly added at the same temperature to give a yellow solution. Ethyl acetate (150 mL) was added to the resulting solution and stirred at room temperature for 1 hour. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layer was dried over anhydrous sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was crystallized from ethyl acetate and hexane to give the title compound (2.82 g, 35%) as yellow crystals (a mixture of tautomers). Mass spectrometry ES MH=155 Reference example 8-2 Synthesis of 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid

[0120] [ka]

[0121] Ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (200 mg, 1.28 mmol), iodomethane (397 μL, 6.40 mmol), and DMF (5 mL) were added to a 50 mL round-bottom flask. Sodium hydride (60%, dispersed in liquid paraffin) (256 mg, 6.40 mmol) was added and stirred at room temperature for 22 hours. Under ice cooling, water was added to the reaction solution, which was then extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (25 g) using ethyl acetate and hexane (concentration gradient 5%-60%) as eluent to afford ethyl 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (51 mg, 22%) as a white solid. The ethyl 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (51 mg, 0.279 mmol) obtained above was added to a 50 mL round-bottom flask and dissolved in ethanol (1 mL). 5 N aqueous sodium hydroxide solution (0.5 mL, 2.50 mmol) was added and stirred at room temperature for 3 days. 1 N hydrochloric acid (2.7 mL) was added to the reaction solution, and the solution was concentrated under reduced pressure. The resulting residue was dissolved in THF, and insoluble matter was filtered off using Celite. The filtrate was concentrated under reduced pressure to give the title compound (43 mg, 100%) as a white powder. 1H NMR DMSO-d6,11.91(brs,1H),7.99(s,1H),3.80(s,3H),3.69(s,3H). Example 35 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0122] [ka]

[0123] 2,2,2-trifluoro-1-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-14-yl)ethan-1-one (54 mg, 136 μmol), 6-oxo-1,6-dihydropyridine-2-carboxylic acid (67 mg, 0.48 mmol), and HATU (197 mg, 0.52 mmol) synthesized in Reference Example 7-3 were added to a 10 mL test tube, and the mixture was suspended in THF (2 mL). Then, triethylamine (100 μL, 0.72 mmol) and DMA (100 μL) were added and stirred at room temperature for 1.5 hours. Ethanolamine (100 μL) and methanol (2 mL) were added to the reaction mixture, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the resulting residue was dissolved in chloroform (30 mL) and washed with 6% aqueous ammonia (10 mL x 3). The combined aqueous layer was extracted with chloroform (20 mL). The combined organic layer was dried over anhydrous magnesium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (amino silica gel, 16 g) using methanol and chloroform (concentration gradient: 10%-30%) as eluent to give 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (M+H = 514.26) as a white foam. The 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one obtained above was dissolved in methanol (5 mL) in a 100 mL eggplant-shaped flask, and sodium borohydride (124 mg, 3.26 mmol) was added and stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the residue was suspended in 6% aqueous ammonia (20 mL) and washed with chloroform (20 mL × 2). The aqueous layer was concentrated under reduced pressure, and the residue was purified by column chromatography (amino silica gel, 12 g) using methanol and chloroform (concentration gradient: 10%-30%) as eluents to obtain 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)- A mixture of 1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one and the title compound 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one was obtained. The above obtained mixture was dissolved in concentrated aqueous ammonia (3 mL) in a 50 mL recovery flask, and the flask was sealed with a rubber stopper and heated with stirring at 80° C. for 18 hours. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (amino silica gel, 7 g) using methanol and chloroform (concentration gradient: 10%-50%) as eluent. The resulting crude product was triturated with methanol (0.2 mL) and t-butyl methyl ether (3 mL) to give the title compound (23 mg, 41%). 1H NMR DMSO-d6,9.08(s,1H),7.53(dd,0.7H,J=6.9,8.7Hz),7.47(dd,0.3H,J=7.3,9.2Hz),6.92(d,0.7H,J=8.2Hz),6.87(d,0.3 H,J=7.8Hz),6.39-6.58(m,4H),4.42-4.45(m,0.7H),4.13-4.17(m,0.3H),3.89-3.94(m,0.3H),3.71-3.76(m,0.7H),3.61 (d,0.7H,J=11.0Hz),3.45-3.48(m,0.3H),3.15-3.27(m,1H),2.80-3.09(m,5H),2.64-2.73(m,1H),2.13-2.44(m,2H),1. 63-1.70(m,1H),1.25-1.59(m,2H),1.12-1.15(d,1H,J=11.0Hz),1.01-1.07(m,1H),0.88-0.94(m,1H),0.66-0.74(m,1H). Example 36 Synthesis of 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one

[0124] [ka]

[0125] The reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 86 μmol), 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (29 mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72 mg, 0.19 mmol). However, only THF (2 mL) was used as the solvent. The reaction was terminated by adding 1.4 N ammonia / methanol solution to the reaction solution, which was then concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 10 g) using methanol and ethyl acetate (concentration gradient: 0%-30%) to give ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(3-methoxy-1-methyl-1H-pyrazol-4-yl)methanone (33.3 mg, 80%) as a pale yellow amorphous solid. 1H NMR CD3OD 7.69(s,0.7H),7.55(s,0.3H),6.90-6.96(m,1H),6.63(d,0.7H,J=2.8Hz),6.53-6.58(m,1.3H ),2.78-5.02(m,8H),3.90(s,3H),3.73(s,2.1H),3.68(s,0.9H),2.53-2.57(m,1H),2.31-2.33 (m,2H),1.90-2.09(m,2H),1.66-1.76(m,1H),1.51-0.78(m,7H),0.45-0.48(m,2H),0.09-0.12(m,2H). The ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(3-methoxy-1-methyl-1H-pyrazol-4-yl)methanone (15 mg, 31 μmol) obtained above was added to a 30 mL round-bottom flask and dissolved in methylene chloride (1 mL). A 1.0 M boron tribromide / methylene chloride solution (153 μL, 0.15 mmol) was added under ice cooling, and the mixture was stirred at room temperature for 1 hour. The reaction was quenched by adding 1.4 N ammonia / methanol solution, and the mixture was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over sodium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The residue was subjected to preparative TLC using ammonia water-containing methanol and chloroform (concentration: 10%) as a developing solvent to give the title compound (10.6 mg, 73%) as a pale yellow amorphous solid. 1H NMR DMSO-d6 11.47(s,0.1H),11.37(s,0.9H),9.11(s,1H),8.09(s,0.9H),7.48(s,0.1H) ,6.94(d,1H,J=8.2Hz),6.60(d,1H,J=2.3Hz),6.54(dd,1H,J=8.2,2.3Hz),4 .33-4.50(m,1H),2.50-4.07(m,12H),2.19-2.34(m,2H),1.80-2.00(m,2H), 1.58-1.65(m,1H),0.70-1.43(m,6H),0.38-0.53(m,2H),0.02-0.16(m,2H). Example 37 Synthesis of 5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0126] [ka]

[0127] The reaction was carried out in the same manner as in Example 1 using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 5-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid (22 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol), and HATU (72 mg, 0.13 mmol). However, only THF (1 mL) was used as the solvent. The reaction was terminated by adding 1.4 N ammonia / methanol solution to the reaction solution, which was then concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate and extracted with chloroform. The organic layer was dried over sodium sulfate, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (amino silica gel, 8 g) using methanol and ethyl acetate (concentration gradient: 0%-80%) as eluents to give the title compound (11.6 mg, 40%) as a brown amorphous solid. 1H NMR DMSO-d6 11.99(br s,1H),9.06(br s,1H),7.68(s,0.7H),7.59(s,0.3H),7.48(d,1H,J=2.3Hz),6.89(d,0.7H,J=8.2H z),6.85(d,0.3H,J=8.2Hz),6.40-6.56(m,2H),4.25-4.32(m,0.7H),3.93-3.98(m, 0.3H),3.78-3.84(m,0.3H),2.11-3.62(m,10.7H),1.68-1.91(m,2H),1.48-1.63( m,1H),0.87-1.46(m,4H),0.50-0.79(m,2H),0.29-0.47(m,2H),0.06-0.12(m,2H). Example 38 Synthesis of 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione

[0128] [ka]

[0129] A reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (35 mg, 98 μmol), 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (35 mg, 0.19 mmol), triethylamine (70 μL, 0.50 mmol), and HATU (145 mg, 0.38 mmol) in a similar manner as in Example 1. The reaction was quenched by adding 2N ammonia / methanol solution and then concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia (20 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layer was washed with saturated brine (10 mL) and then dried over anhydrous magnesium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (amino silica gel, 10 g) using methanol and ethyl acetate (concentration gradient: 0%-30%) as the eluent. The resulting syrup was dissolved in methanol (0.2 mL), powdered with t-butyl methyl ether (3 mL), and filtered to give the title compound (39 mg, 76%) as a white powder. 1H NMR CD3OD 7.82(s,1H),6.92-6.98(m,1H),6.52-6.65(m,2H),4.53-4.62(m,1H),4.02-4.18(m,1H ),3.50-3.80(m,2H),3.42(s,2H),3.37(s,1H),3.33(s,2H),3.31(s,1H),2.81-3.18(m, 5H),2.57-2.59(m,1H),2.30-2.38(m,2H),1.93-2.09(m,2H),1.67-1.78(m,1H),1.43-1 .59(m,2H),1.10-1.29(m,2H),0.81-0.95(m,2H),0.44-0.53(m,2H),0.08-0.17(m,2H). Example 39 Synthesis of 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0130] [ka]

[0131] The experiment was carried out in the same manner as in Example 1. (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (82 mg, 0.23 mmol), triethylamine (200 μL, 1.43 mmol), and HATU (167 mg, 0.44 mmol) were used to react the product. The reaction was quenched by adding ethanolamine (200 μL) and methanol (1 mL). The mixture was then diluted with ethyl acetate (50 mL) and washed with 6% aqueous ammonia (50 mL). The aqueous layer was extracted with chloroform (30 mL x 2), and the combined organic layer was dried over anhydrous sodium sulfate. After filtering off the insoluble material, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (amino silica gel, 7 g) using methanol and ethyl acetate (concentration gradient: 10%-50%) as the eluent. The resulting syrup-like substance was dissolved in methanol (0.2 mL) and powdered with t-butyl methyl ether (3 mL). The resulting powder was dried under reduced pressure at 100°C for 16 hours to give the title compound (87 mg, 100%) as a white amorphous substance. 1H NMR DMSO-d6 7.5(br s,1H),6.97-7.03(m,1H),6.45-6.73(m,4H),4.40-4.45(m,0.7H),3.84-3.89 (m,0.3H),3.69(s,3H),3.55-3.62(m,1H),2.95-3.22(m,4H),2.79-2.84(m,2 H),2.13-2.62(m,4H),1.79-1.87(m,2H),1.26-1.60(m,3H),0.99-1.14(m,3H ),0.70-0.74(m,1H),0.54-0.61(m,1H),0.39-0.40(m,2H),0.00-0.07(m,2H). Example 40 Opioid receptor function test The functional activity of the compounds provided by the present invention at μ, δ, and κ opioid receptors was examined. Methods: The Lance Ultra cAMP kit (PerkinElmer) was used and assays were performed according to the prescribed method. To evaluate agonist activity, CHO cells expressing each human opioid receptor (δ, μ, and κ; accession numbers and catalog numbers are listed below) were incubated with the test compound in the presence of 10 μM forskolin in assay buffer (1×HBSS, 1 M HEPES, pH 7.4, 250 mM IBMX (Isobutylmethylxanthine), 7.5% BSA) for 30 minutes. The cAMP detection reagent included in the kit was then added, and time-resolved fluorescence measurements were performed one hour later using an EnVision plate reader (PerkinElmer). The test compound and each control drug (δ: SNC80, μ: DAMGO, κ: U-69593) were incubated for 10 min. -12 ~10 -5 The test compound was evaluated over a range of concentrations, and the dose-response curve was calculated from the fluorescence value at 665 nm. 50 value and E max The value was calculated. max The values ​​were calculated as the percentage of the maximum response of the test compound when the maximum response of each control drug was taken as 100%. SNC80: (+)-4-[(αR)-α-((2S,5R)-4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl]-N,N-diethylbenzamide DAMGO: [D-Ala 2 ,N-MePhe 4 ,Gly-ol]enkephalin U-69593: (+)-(5α,7α,8β)-N-methyl-N-[7-(1-pyrrolidinyl)-1-oxaspiro[4.5]dec-8-yl]benzeneacetamide Accession number and catalog number δ:Catalog No.CT4607,accession No.NM_000911.2 μ:Catalog No.CT4605,accession No.NM_000914 κ:Catalog No.CT4606,accession No.NM_000912 (ChanTest Corporation)

[0132] [Table 6]

[0133] NC: Maximum response was not achieved at the highest concentration (10 μM), so ED 50 The value was not calculated. * : Because the maximum response was not achieved at the highest concentration, the response rate at the highest concentration is shown as a reference value. As shown in Table 6, it was confirmed that the compounds of the present invention have potent agonist activity against opioid δ receptors, and have no or only very weak agonist activity against μ and κ receptors. Example 41 Mouse elevated plus maze test (Test Method) Male C57BL / 6N mice aged 5-6 weeks were used for the study. A 40-cm-high plus-maze apparatus was used, consisting of an open-ended runway (6 cm wide, 30 cm long) and a walled runway (6 cm wide, 30 cm long, with walls 15 cm high). Mice were placed facing the walled runway and allowed to enter the plus-maze spontaneously. The test substance was dissolved in saline or 0.005 N HCl-saline and administered subcutaneously to the back 30 minutes before the start of the test. A video camera was started to record the mouse's exploratory behavior at the start of the test, and the test began when the mouse entered the plus-maze. The video footage was used to determine the time spent in each runway, and the percentage of time spent in the open-ended runway (%) was calculated. (Test results) As shown in Figures 1 and 2, in this experiment, Compounds 1 (compound described in Example 1) and 7 (compound described in Example 7) significantly increased the percentage of time spent in the wall-free lane at subcutaneous administration of 3 mg / kg and 10 mg / kg, respectively, demonstrating anxiolytic effects. Furthermore, Compounds 3 (compound described in Example 3), 9 (compound described in Example 9), and 10 (compound described in Example 10) tended to increase the percentage of time spent in the wall-free lane (Figures 3 to 5).

[0134] Example 42 Rat elevated plus maze test The anxiolytic effect of the compounds of the present invention was examined using the rat elevated plus maze test. (Test Method) Male Wistar rats aged 7-9 weeks were used in this study. A 50-cm-high plus-maze apparatus consisted of an open-walled runway (10 cm wide, 50 cm long) and a walled runway (10 cm wide, 50 cm long, with walls 30 cm high). Rats were placed facing the walled runway and allowed to enter the plus-maze spontaneously. Exploratory behavior was observed for 5 minutes. The test substance was dissolved in a 4.5% cyclodextrin solution and orally administered 2 hours before the start of the study. Test data were automatically analyzed using video image behavioral analysis software (PanLab Smart 3.0, PanLab SL), and the percentage of time spent in the open runway (%) was calculated. (Test results) As shown in Figure 6, in this experiment, compounds 7 (compound described in Example 7), 3 (compound described in Example 3), and 10 (compound described in Example 10) significantly increased the percentage of time spent in the wall-free lane when administered orally at 3 mg / kg, demonstrating anxiolytic-like effects. Example 43 hERG (human ether-a-go-go related gene) potassium channel inhibition test (Test Method) Tests were performed using CHO cells stably expressing the hERG channel (purchased from the Channelopathy Foundation) using a Port-a-Patch autopatch clamp apparatus (Nanion Technologies). hERG currents were measured by holding the cell membrane potential at -80 mV and then administering a +20 mV depolarizing pulse for 1.5 seconds followed by a -50 mV test pulse for 1.5 seconds every 10 seconds. The tail currents induced by the test pulses were monitored. Test compounds were dissolved in extracellular solution (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM D(+)-glucose, 10 mM HEPES, pH 7.4) and perfused for 5 minutes at room temperature. Percent inhibition was calculated as the percentage of the tail current after compound application relative to the maximum tail current before compound application (100%). For the test, cells with a peak tail current of 300 pA or more, a tail current run-down of less than 10% of the initial current value, and a leak current of less than 200 pA were used. (Test results) Table 7 shows the test results. In the table, compounds 1, 3, 7, 9, and 10 are compounds described in Examples 1, 3, 7, 9, and 10, respectively. As is clear from Table 7, all of the test compounds exhibited only weak inhibitory effects. On the other hand, it was found that the compounds described in WO 2013 / 35833 (Patent Document 4) include compounds with strong hERG inhibitory activity.

[0135] [Table 7]

[0136] Comparative Compound 1: Example 93 (Compound 104) of WO 2013 / 35833 Comparative Compound 2: Example 205 (Compound 267) of WO 2013 / 35833 Example 44 Hyperemotional response inhibition test in olfactory bulbectomized (OBX) rats (Test Method) Saitoh et al.'s method (Saitoh A, Yamada M, Yamada M, Takahashi K, Yamaguchi K, Murasawa H, Nakatani A, Tatsumi Y, Hirose N, Kamei J: Antidepressant-like effects of the delta-opioid receptor agonist SNC80 ([(+)-4-[(alphaR)-alpha-[(2S,5R)-2,5-dimethyl-4-(2-propenyl)-1-piperazinyl] -(3-methoxyphenyl)methyl]-N,N-diethylbenzamide) in an olfactory bulbectomized rat model. Brain Res. 2008 OBX rats were generated by surgically removing the olfactory bulb and then rearing them in isolation according to the [1208:160-169] standard. Emotional hyperactivity was assessed 14 days after surgery before group allocation and 2 hours after administration on days 1, 4, 7, 10, and 14 according to the criteria for evaluating emotional hyperactivity established by Gomidata et al. (Gomida et al.: Behavioral pharmacological and electroencephalographic studies of 7-chloro-1-methyl-5-phenyl-1H-1, 5-benzodiazepine-2, 4-(3H, 5H:)-dione (clobazam). Japanese Journal of Pharmacology 82, 267 (1983)). The drug was administered subcutaneously once daily for 14 consecutive days. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was used as a positive control. 1% cyclodextrin (CD) was used as the vehicle. (Test results) Administration of 0.1 mg / kg of the test substance (the compound described in Example 7 above) significantly reduced the emotional hyperreactivity of OBX rats compared to the vehicle-treated group from day 4 of administration, and by day 7 of administration, the level had recovered to the same level as that of the sham-operated rats. Administration of 1 mg / kg of the test substance significantly reduced the emotional hyperreactivity of OBX rats compared to the vehicle-treated group from day 1 of administration, and by day 4 of administration, the level had recovered to the same level as that of the sham-operated rats. These effects were sustained until day 14. On the other hand, administration of 10 mg / kg of fluoxetine significantly reduced the emotional hyperreactivity of OBX rats compared to the vehicle-treated group on day 14 of administration. These findings suggest that the test substance, unlike SSRIs, may exhibit antidepressant-like effects from a single dose. Furthermore, it is possible that tolerance to the antidepressant-like effects of the test substance may not develop.

[0137] Example 45 Reserpine-induced Parkinson's disease model mouse (Test Method) ICR male mice (5 weeks old: Japan SLC) were obtained and used after an acclimation period (5-12 days). The PD model was created based on the report by Hille et al. (Exp Neurol. 2001, 172:189). Reserpine (5 mg / kg) was administered intraperitoneally 18-24 hours before the start of the test. On the day of the test, the test compound was administered subcutaneously, and the animals were immediately placed in a locomotor activity cage and the distance traveled was measured for 60 minutes. (Test results) Administration of 10 mg / kg of the test substance (the compound described in Example 7 above) showed a significant increase in exploratory behavior and also showed a tendency to increase rearing behavior, although this was not significant (P=0.16), suggesting that the test substance has a therapeutic effect on Parkinson's disease.

[0138] Example 46 Evaluation using a rat model of cerebral infarction-induced overactive bladder (Test Method) A transient middle cerebral artery occlusion model was created using 8-week-old male SD rats under isoflurane inhalation anesthesia. The next day, a small neck incision was made again under isoflurane inhalation anesthesia, and a catheter for administration was placed in the jugular vein and guided to the back. Cystometry surgery was also performed, and the other end of the cannula inserted into the bladder was guided to the back and connected to a sieve. Four days after cerebral ischemic surgery, cystometry measurements were performed without anesthesia and without restraint. After a stable period of measurement, vehicle was intravenously administered to the bladder, and pre-administration values ​​for the test substance were measured for approximately 30 minutes. Subsequently, the test substance was administered intravenously at approximately 30-minute intervals, starting with the lowest dose, and post-administration values ​​were measured for approximately 30 minutes. Animals that were determined to have frequent urination (urination intervals of 10 minutes or less) in the pre-administration measurements were used, and resting pressure, micturition pressure, micturition interval, and single voided volume at each time point were calculated. (Test results) The measurement results are shown in Table 8. As is clear from Table 8, the test substance (the compound described in Example 7 above) did not affect the resting pressure or micturition pressure at any dose. On the other hand, the micturition interval and the single micturition volume tended to increase in a dose-dependent manner, suggesting that the test substance has an effect of improving frequent urination.

[0139] [Table 8]

[0140] Mean ±SE (n=5)

[0141] Example 47 Metabolic Stability Test (Test Method) Human liver microsomes and the test substance were reacted for a fixed time (0-60 min), and the amount of unchanged test substance remaining in the reaction sample was measured to calculate the residual rate. The residual rate at 0 hours of reaction was set to 100%, and the residual rate after incubation was plotted log-linearly against time, and the regression line (y = 100e -kt , k = linear slope: elimination rate constant) was calculated and metabolic clearance CL was calculated using the following formula: int(mL / min / kg) was calculated. CL int * = k (-min) × 52.5 (mg MS protein / g liver) × 26 (g liver / kg) / MS protein (mg MS protein / mL) *: Davies, B. and Morris, T.: Physiological parameters in laboratory animals and humans. Pharm. Res., 10(7): 1093-1095, 1993. (Test results) The test results are shown in Table 9.

[0142] [Table 9]

[0143] Comparative Compound 1: Example 93 (Compound 104) of WO 2013 / 35833 As is clear from Table 9, the compounds of the present invention have excellent metabolic stability. On the other hand, it was found that some of the compounds described in WO 2013 / 35833 (Patent Document 4) have poor metabolic stability. [Explanation of symbols]

[0144] In Figures 1 to 6, the vertical axis indicates the proportion of time spent in the wall-less lane, and the horizontal axis indicates the test drug and its administered dose.

Claims

[Claim 1] The following general formula (I): 【Chemical 1】 (In the formula, R １ is hydrogen; C １－１０ Alkyl; C ６－１０ Aryl; C ２－６ Alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; C ３－６ cycloalkyl; or heteroarylalkyl in which the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and the alkylene portion has 1 to 5 carbon atoms; R ２ represents a heterocycle containing 1 to 4 heteroatoms selected from N, O and S and at least one carbon atom as ring-constituting atoms, wherein at least one pair of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group; Here, R ２ is R ２ is bonded to Y via a carbon atom which is a ring-constituting atom of R ３ , R ４ and R ５ are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C １－６ Alkoxy; C ６－１０ Aryloxy; C １－６ Alkanoyloxy; Nitro; Amino; C １－８ Alkylamino; C ６－１０ represents an arylamino or acylamino having 2 to 6 carbon atoms in the acyl moiety; R ６ａ and R ６ｂ are the same or different and represent hydrogen; fluorine or hydroxy; or R ６ａ and R ６ｂ together represent =0, R ７ and R ８ are the same or different and represent hydrogen, fluorine or hydroxy; R ９ and R １０ are the same or different and are hydrogen; C １－６ Alkyl; C ６－１０ Aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; heteroarylalkyl having 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene moiety; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; ２－６ represents alkenyl, X is O or CH ２ represents And Y represents C(=O). However, R １ C １－１０ Alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyl, in which the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; the alkylene portion of aralkyl, in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; and the alkylene portion of heteroarylalkyl, in which the heteroaryl portion has 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and the alkylene portion has 1 to 5 carbon atoms, Halogen; Hydroxy; C １－６ Alkoxy; C 6－１０ Aryloxy; C １－６ Alkanoyl; C １－６ Alkanoyloxy; carboxyl; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens １－６ alkoxy; and arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety; And R １ C ６－１０ Aryl; an aryl portion of an aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; R ３ , R ４ and R ５ C ６－１０ the aryl portion of the aryloxy; and C ６－１０ the aryl portion of arylamino; and R ９ and R １０ C ６－１０ Aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; aryl moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and heteroaryl moiety of heteroarylalkyl having 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene moiety. C １－６ Alkyl; C １－６ Alkoxy; C １－６ Alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; halogen; nitro; cyano; C substituted with 1 to 3 halogens １－６ Alkyl; C substituted with 1 to 3 halogens １－６ and optionally substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; and methylenedioxy. R ２ The heterocycle of the formula (I) can be an oxo group or any of the above-mentioned R １ C ６－１０ The aryl may have a substituent, Further R １ is C １－１０ In the case of alkyl, NR １１ R １２ where R １１ and R １２ are the same or different and are hydrogen; C １－１０ alkyl; or aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, or １１ and R １２ And, R １１ and R １２ may be joined together with the nitrogen atom to which R is attached and optionally one or two heteroatoms to form a 5- to 7-membered ring, and R １ The alkylene portion of the aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion is phenyl or C substituted with 1 to 3 halogens. １－６ It may be substituted with at least one substituent selected from alkyl. A compound represented by the formula: Figure imgf000016_0001, a tautomer or stereoisomer of the compound, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

Images