Use of morphinan derivatives for the treatment of opioid δ receptor agonist-related diseases

Abstract

To provide a pharmaceutical product useful for the treatment or prevention of opioid δ receptor-related diseases. [Solution] The present invention relates to a pharmaceutical composition comprising a morphinan derivative that exerts opioid δ receptor agonist activity. By administering the pharmaceutical composition provided by the present invention, opioid δ receptor-related diseases (e.g., headaches) may be treated or prevented.

Description

[Technical Field]

[0001] The present invention relates to the use of morphinan derivatives having opioid δ receptor agonist activity, for example, for the treatment of headaches. This application claims priority pursuant to Japanese Patent Application No. 2016-203925, filed in Japan on September 16, 2016, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Opioids exert their effects by binding to opioid receptors, and there are three subtypes of opioid receptors: μ, δ, and κ. It is known that the agonists of all three subtypes (μ, δ, and κ) have analgesic effects. Among these, agonists that selectively activate opioid δ receptors are expected to have little to no side effects that occur through the activation of opioid μ receptors and opioid κ receptors. To date, various compounds have been reported as opioid δ receptor agonists, and their analgesic, antidepressant, and anxiolytic effects have been demonstrated (Patent Documents 1-6, Non-Patent Documents 1-3). Regarding headaches, opioid δ receptor agonists have been shown to be effective for chronic and acute headaches, and to be effective in preventing headaches by suppressing headache auras (Non-Patent Document 4). [Prior art documents] [Patent Documents]

[0003] [Patent Document 1] Special Publication 2006-522775 [Patent Document 2] WO 2001 / 046192 [Patent Document 3] WO 2008 / 001859 [Patent Document 4] WO 2013 / 035833 [Patent Document 5] WO 2014 / 021273 [Patent Document 6] WO 2014 / 136305 [Non-patent literature]

[0004] [Non-Patent Document 1] Tetrahedron, 2011, 67, 6682 [Non-Patent Document 2] European Journal of Pharmacology 276 (1995) 131-135 [Non-Patent Document 3] European Journal of Pharmacology 322 (1997) 27-30 [Non-Patent Document 4] British Journal of Pharmacology 171 (2014) 2375-2384 [Overview of the Initiative] [Problems that the invention aims to solve]

[0005] The object of the present invention is to provide a pharmaceutical agent useful for the treatment or prevention of opioid δ receptor-related diseases (e.g., headaches). [Means for solving the problem]

[0006] The inventors of the present invention conducted diligent research to achieve the above objectives and discovered that a pharmaceutical composition containing a morphinan derivative is useful for the treatment or prevention of opioid δ receptor-related diseases (e.g., headaches), thus completing the present invention. In one aspect, the present invention relates to the following general formula (I):

[0007] [ka]

[0008] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10Aryl; C 2-6 Alkenyl; cycloalkylalkyl in which the cycloalkyl part has 3 to 6 carbon atoms and the alkylene part has 1 to 5 carbon atoms; aralkyl in which the aryl part has 6 to 10 carbon atoms and the alkylene part has 1 to 5 carbon atoms; C 3-6 Cycloalkyl; or heteroarylalkyl in which the heteroaryl part contains 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms and the alkylene part has 1 to 5 carbon atoms, R 2 represents a heterocycle that contains 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, and at least one set of adjacent ring-constituting atoms has a double bond and is further substituted with at least one oxo group, Here, R 2 is bonded to Y via a carbon atom that is a ring-constituting atom of R 2 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 arylamino or acylamino in which the acyl part has 2 to 6 carbon atoms, 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 constituent atoms; Aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; Heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms in the heteroaryl portion and 1 to 5 carbon atoms in the alkylene portion; Cycloalkylalkyl or C having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion. 2-6 Representing Alkenil, X represents O or CH2, And Y represents C (=O). However, R 1 C 1-10 Alkyl; The alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the alkyl / cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; The alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and The alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5. 1-6 halogens; hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6 Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R1 C 6-10 Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring. And again R 1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) The present invention provides a pharmaceutical composition comprising a compound represented by [formula], a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.

[0009] Furthermore, in one aspect, the present invention provides a pharmaceutical composition for the treatment or prevention of opioid δ receptor-related disorders (e.g., headache) comprising a compound represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof. [Effects of the Invention]

[0010] The present invention provides a pharmaceutical product useful for the treatment or prevention of opioid δ receptor-related diseases (e.g., headaches). [Brief explanation of the drawing]

[0011] [Figure 1] Figure 1 shows the results of a mouse elevated cruciform maze test for compound 1. The vertical axis represents the percentage of time spent in the wall-free maze, and the horizontal axis represents the test drug and its dosage. [Figure 2]Figure 2 shows the results of a mouse elevated cruciform maze test for compound 7. The vertical axis represents the percentage of time spent in the wall-free labyrinth, and the horizontal axis represents the test drug and its dosage. [Figure 3] Figure 3 shows the results of a mouse elevated cruciform maze test for compound 3. The vertical axis represents the percentage of time spent in the wall-less labyrinth, and the horizontal axis represents the test drug and its dosage. [Figure 4] Figure 4 shows the results of a mouse elevated cruciform maze test for compound 9. The vertical axis represents the percentage of time spent in the wall-less labyrinth, and the horizontal axis represents the test drug and its dosage. [Figure 5] Figure 5 shows the results of a mouse elevated cruciform maze test for compound 10. The vertical axis represents the percentage of time spent in the wall-free labyrinth, and the horizontal axis represents the test drug and its dosage. [Figure 6] Figure 6 shows the results of the elevated cruciform maze test in rats for compounds 3, 7, and 10. The vertical axis represents the percentage of time spent on the wall-less labyrinth, and the horizontal axis represents the test drug and its dosage. [Modes for carrying out the invention]

[0012] Next, the present invention will be described in more detail. (1) In one aspect, the present invention relates to the following general formula (I): [ka] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Ariel; C 2-6 Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms. 3-6 This represents a cycloalkyl or heteroaryl alkyl group in which the cycloalkyl or heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R2 represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom 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, where R 2 is bonded to Y via a carbon atom that is a ring-constituting atom of R 2 , R 3 , R 4 and R 5 are the same or different and represent hydrogen; hydroxy; halogen; cyano; carbamoyl; C 1-6 alkoxy; C 6-10 [[ID=?]]aryloxy; C 1-6 alkanoyloxy; nitro; amino; C 1-8 alkylamino; C 6-10 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 represent 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 in the heteroaryl moiety 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 or C 2-6 alkenyl, X represents O or CH2, (注:原文中“ 6-10 ”处的翻译存疑,原文此处为“アリールオキシ;C”,推测可能是表述有误,翻译时按“aryloxy; C”处理,但不确定是否准确反映原文意图。)And Y represents C(=O). However, R 1 of C 1-10 alkyl; the cycloalkyl part has 3 to 6 carbon atoms, and the alkylene part has 1 to 5 carbon atoms in the cycloalkylalkyl; the alkylene part of aralkyl where the aryl part has 6 to 10 carbon atoms and the alkylene part has 1 to 5 carbon atoms; and the heteroaryl part contains 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms, and the alkylene part of heteroarylalkyl where the alkylene part has 1 to 5 carbon atoms has 1 to 6 halogen; hydroxy; C 1-6 alkoxy; C 6-10 aryloxy; C 1-6 alkanoyl; C 1-6 alkanoyloxy; carboxyl; alkoxycarbonyl where the alkoxy part has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoyl where the alkyl part has 1 to 6 carbon atoms; dialkylcarbamoyl where the alkyl part has 1 to 6 carbon atoms; alkylsulfonyl where the alkyl part has 1 to 6 carbon atoms; aminosulfonyl; alkylsulfinyl where the alkyl part has 1 to 6 carbon atoms; alkylthio where the alkyl part has 1 to 6 carbon atoms; C 1-6 alkoxy; may be substituted with at least one substituent selected from arylcarbonyl where the aryl part has 6 to 10 carbon atoms, and R 1 of C 6-10 aryl; the aryl part of aralkyl where the aryl part has 6 to 10 carbon atoms and the alkylene part has 1 to 5 carbon atoms; R 3 , R 4 and R 5 of C 6-10 the aryl part of aryloxy; and C 6-10 the aryl part of arylamino; and R 9 and R 10 of C 6-10Aryl; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12 It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) The present invention provides a pharmaceutical composition comprising a compound represented by [formula], a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.

[0013] As one embodiment, a compound represented by general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof used in the pharmaceutical composition provided by the present invention as described in (1) above, is as follows (2) to (58): (2) R 1 C 1-10 A compound represented by the above general formula (I) of (1), wherein the alkyl; cycloalkyl alkyl has 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl has 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvates thereof; (3) R 1 The compound described in (1) or (2) above, wherein the cycloalkyl group has 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of the said compound; (4) R 1 C is substituted with hydroxyl 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) that is alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or solvates thereof; (5) R 1 Compounds represented by the above general formula (I) of (1), wherein is allyl, fluoropropyl, 2-(pyridine-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl; tautomers, stereoisomers, or pharmaceutically acceptable salts thereof of the said compound; (6) R 2 A compound according to any of (1) to (5) above, wherein the compound comprises a 5-7 membered heterocycle or a heterocycle in which a benzene ring is fused to the heterocycle, wherein the heterocycle comprises 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring constituent atoms, and at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvates thereof; (7) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine 1-oxide which may be substituted with 1 to 4 substituents selected from alkyl groups, any of the compounds described in (1) to (6) above, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of said compound, or a solvate thereof; (8) R 2 A compound according to any of (1) to (7) above, wherein the compound is pyridine 1-oxide, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (9) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine-2(1H)-one which may be substituted with 1 to 4 substituents selected from alkyl groups, any of the compounds described in (1) to (6) above, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (10) R 2Pyridine-2(1H)-one; 1-C 1-6 Alkylpyridine-2(1H)-one; or 6-C 1-6 A compound that is alkylpyridine-2(1H)-one, as described in any of (1) to (6) or (9) above, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof;

[0014] (11) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine-4(1H)-one which may be substituted with 1 to 4 substituents selected from alkyl groups, any of the compounds described in (1) to (6) above, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (12) R 2 is pyridine-4(1H)-one or 1-C 1-6 A compound that is alkylpyridine-4(1H)-one, as described in any of (1) to (6) or (11) above, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (13) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridazine-3(2H)-one which may be substituted with 1 to 3 substituents selected from alkyl groups, a compound according to any one of items (1) to (6) above, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of said compound, or a solvate thereof; (14) R 2 A compound described in any of (1) to (6) or (13) above, wherein the compound is pyridazine-3(2H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (15) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10Alkyl and unsubstituted C 1-10 A pyrazine-2(1H)-one which may be substituted with 1 to 3 substituents selected from alkyl groups, any of the compounds described in (1) to (6) above, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (16) R 2 A compound according to any of (1) to (6) above, wherein the compound is pyrazine-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (17) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A compound according to any of (1) to (6) above, which is 4H-pyran-4-one or 2H-pyran-2-one, which may be substituted with 1 to 3 substituents selected from alkyl groups; a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of said compound; (18) R 2 A compound according to any of (1) to (6) or (17) above, wherein the compound is 4H-pyran-4-one or 2H-pyran-2-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (19) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A compound according to any of (1) to (6) above, which is a quinoline-2(1H)-one that may be substituted with 1 to 3 substituents selected from alkyl groups, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of said compound, or a solvate thereof; (20) R 2 A compound according to any of (1) to (6) above, wherein the compound is quinoline-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof;

[0015] (twenty one) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A compound according to any of (1) to (6) above, which is a pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione, which may be substituted with one to three substituents selected from alkyl groups, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvates thereof; (twenty two) R 2 A compound described in any of (1) to (6) or (21) above, wherein the compound is pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of the said compound, or a solvate thereof; (twenty three) A compound described in any of (1) to (22) above, wherein X is CH2, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (twenty four) R 3 and R 4 Of which, one is hydroxyl and the other is hydrogen, one of the compounds described in (1) to (23) above, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (twenty five) R 3 is halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 1-6 Alkanoyloxy; amino; or acylamino, where the number of carbon atoms in the acyl moiety is 2 to 6, R 4 is hydrogen or hydroxyl, R 5 A compound described in any of (1) to (23) above, wherein the compound is hydrogen, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (26) R 3 is hydroxy; carbamoyl; or C 1-6 With alkanoyloxy, R 4is hydrogen, R 5 A compound described in any of (1) to (23) above, wherein the compound is hydrogen, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (27) R 3 is hydroxy, R 4 is hydrogen, R 5 A compound described in any of (1) to (23) above, wherein the compound is hydrogen, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (28) R 3 , R 4 and R 5 A compound described in any of (1) to (23) above, in which all atoms are hydrogen, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (29) R 6a , R 6b , R 7 , R 8 , R 9 and R 10 A compound described in any of (1) to (28) above, in which all atoms are hydrogen, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof;

[0016] (30) R 5 , R 6a , R 6b , R 7 , R 8 , R 9 and R 10 It is hydrogen, R 1 is hydrogen; C 1-6 Alkyl; C 2-6 Alkenyl; cycloalkylalkyl, where the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; or aralkyl, where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms. R 2This represents a 5-7 membered heterocycle or a heterocycle in which a benzene ring is fused to the heterocycle, comprising 1-4 heteroatoms selected from N, O, and S and at least one carbon atom as ring constituent atoms, and at least one pair of adjacent ring constituent atoms having a double bond and further substituted with at least one oxo group. Here, R 2 is R 2 It is bonded to Y via the carbon atoms that make up the ring, R 3 and R 4 These are the same or different: hydrogen; hydroxyl; halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyloxy; amino; or acylamino, where the number of carbon atoms in the acyl portion is 2 to 6. X is CH2, And Y is C (=O), However, R 1 C 1-6 Alkyl; The alkylene and cycloalkyl portions of a cycloalkylalkyl group have 3 to 6 carbon atoms in the alkyl or cycloalkyl group, and the alkylene portion has 1 to 5 carbon atoms in the alkyl or cycloalkyl group, or the alkylene portion of an aralkyl group has 6 to 10 carbon atoms in the aryl group, and the alkylene portion has 1 to 5 carbon atoms in the alkylene group. 1-6 halogens; hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 The aryl portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 The aryl portion of the aralkyl may have substituents such that the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms. Furthermore, R 1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 Compounds represented by the above general formula (I) which may be substituted with at least one substituent selected from alkyl groups, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof of the compound, or solvates thereof; (31) R 1 C 1-6A compound described in (1) or (30), wherein the alkyl; 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, stereoisomer, or pharmaceutically acceptable salt thereof or solvates thereof; (32) R 1 The compound described in (1), (30), or (31), wherein the cycloalkyl group has 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion; a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of the compound; (33) R 1 C is substituted with hydroxyl 2-6 Alkyl; C substituted with 1 to 6 halogens 1-6 Alkyl; or C 1-6 alkoxy-substituted C 2-6 A compound described in (1) or (30) that is alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (34) R 1 The compounds described in (1) or (30), wherein allyl, fluoropropyl, 2-(pyridine-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof; (35) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10A compound described in (1) or any of (30) to (34), which is pyridine 1-oxide, pyridine-2(1H)-one, pyridine-4(1H)-one, pyridazine-3(2H)-one, pyrazine-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one, quinoline-2(1H)-one, pyrimidine-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvates thereof; (36) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine 1-oxide which may be substituted with 1 to 4 substituents selected from alkyl groups, the compound described in (1) or any of (30) to (35), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of said compound, or a solvate thereof; (37) R 2 A compound according to (1) or any of (30) to (36), wherein the compound is pyridine 1-oxide, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (38) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine-2(1H)-one which may be substituted with 1 to 4 substituents selected from alkyl groups, a compound according to (1) or any of (30) to (35), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of said compound, or a solvate thereof; (39) R 2 Pyridine-2(1H)-one; 1-C 1-6 Alkylpyridine-2(1H)-one; or 6-C 1-6A compound that is alkylpyridine-2(1H)-one, as described in (1) or any of (30) to (35), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (40) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine-4(1H)-one which may be substituted with 1 to 4 substituents selected from alkyl groups, a compound according to (1) or any of (30) to (35), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of said compound, or a solvate thereof;

[0017] (41) R 2 is pyridine-4(1H)-one or 1-C 1-6 A compound that is alkylpyridine-4(1H)-one, as described in any of (1), (30) to (35) or (40), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (42) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridazine-3(2H)-one which may be substituted with 1 to 3 substituents selected from alkyl groups, the compound described in (1) or any of (30) to (35), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of the said compound, or a solvate thereof; (43) R 2 A compound according to any of (1), (30) to (35) or (42), wherein the compound is pyridazine-3(2H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (44) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10A pyrazine-2(1H)-one which may be substituted with 1 to 3 substituents selected from alkyl groups, the compound described in (1) or any of (30) to (35), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of the said compound, or a solvate thereof; (45) R 2 A compound according to any of (1), (30) to (35) or (44), wherein the compound is pyrazine-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (46) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A compound according to (1) or any of (30) to (35), which is 4H-pyran-4-one or 2H-pyran-2-one, which may be substituted with 1 to 3 substituents selected from alkyl groups; a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvates thereof; (47) R 2 Compounds according to any of (1), (30) to (35) or (46), wherein is 4H-pyran-4-one or 2H-pyran-2-one, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof or solvates thereof; (48) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A quinoline-2(1H)-one which may be substituted with 1 to 3 substituents selected from alkyl groups, a compound according to (1) or any of (30) to (35), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of said compound, or a solvate thereof; (49) R 2 A compound according to any of (1), (30) to (35) or (48), wherein is quinoline-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of said compound, or a solvate thereof; (50) R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A compound according to (1) or any of (30) to (35), which is a pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione, which may be substituted with one to three substituents selected from alkyl groups; a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvates thereof;

[0018] (51) R 2 A compound according to any of (1), (30) to (35) or (50), wherein the compound is pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvates thereof; (52) R 3 and R 4 A compound described in (1) or any of (30) to (51), wherein one of the compounds is hydroxyl and the other is hydrogen; a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof of the said compound; (53) R 3 is halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 1-6 Alkanoyloxy; amino; or acylamino, where the number of carbon atoms in the acyl moiety is 2 to 6, R 4 Compounds described in (1) or any of (30) to (51), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, wherein the compound is hydrogen or hydroxyl; (54) R 3 is hydroxy; carbamoyl; or C 1-6 With alkanoyloxy, R 4 A compound according to (1) or any of (30) to (51), wherein the compound is hydrogen, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (55) R 3 is hydroxy, R 4 (1) or (30) to (51) is hydrogen as described in either (1) or (30) to (51). Compounds, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof; (56) R 3 and R 4 A compound according to any of (1), (30) to (51), wherein the compound is hydrogen, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof;

[0019] (57) 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinoline-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-(epiminoetano)-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazine-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazine-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-4(3H)-one and Compounds 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof or solvates thereof; or

[0020] (58) 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazole-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione and The compound may be 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvates thereof.

[0021] In this specification, C 1-6 Examples of alkyl groups include methyl, ethyl, propyl, i-propyl, butyl, tert-butyl, pentyl, neopentyl, or hexyl. C 1-10 As for alkyl groups, the above C 1-6 In addition to the alkyl groups exemplified above, other examples include heptyl and octyl groups. C substituted with 1 to 3 halogens 1-6 Examples of alkyl groups include 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl, or 3,3,3-trifluoropropyl. C 2-6 Examples of alkenyls include 2-propenyl or 3-methyl-2-butenyl. Examples of cycloalkylalkyls where the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. 3-6 Examples include methyl and ethyl substituted with cycloalkyl groups. Aralkyl groups in which the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms include the benzyl group and the phenethyl group. C 3-6 Examples of cycloalkyl compounds include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. C 6-10 Examples of aryl compounds include phenyl and naphthyl. Examples of heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms include pyridyl, furyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridadinyl, or thiazolyl. Heteroaryls contain 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the number of carbon atoms in the alkylene portion is 1 to 5. Examples of heteroarylalkyls include (pyridine-2-yl)methyl, (pyridine-3-yl)methyl, (pyridine-4-yl)methyl, (furan-2-yl)methyl, (furan-3-yl)methyl, (imidazole-2-yl)methyl, (imidazole-4-yl)methyl, (imidazole-5-yl)methyl, (thiazole-2-yl)methyl, (thiazole-4-yl)methyl, (thiazole-5-yl)methyl, 2-(pyridine-2-yl)ethyl, 2-(pyridine-3-yl)ethyl, 2-(pyrazole-1-yl)ethyl, 2-(thiophene-2-yl)ethyl, or 2-(thiophene-3-yl)ethyl.

[0022] C 1-6 Examples of alkanoyls include acetyl and propionyl. C 1-6 Examples of alkoxys include methoxy, ethoxy, or propoxy. C 1-6 Examples of alkanoyloxys include acetoxy. Examples of alkoxycarbonyls with 1 to 6 carbon atoms in the alkoxy portion include methoxycarbonyl and ethoxycarbonyl. Examples of halogens include fluorine, chlorine, bromine, or iodine. C substituted with 1 to 3 halogens 1-6 Examples of alkoxys include fluoromethoxy or trifluoromethoxy. C substituted with 1 to 6 halogens 1-6 As alkoxy, C is substituted with the 1 to 3 halogens mentioned above. 1-6 Examples include alkoxy compounds and tetrafluoroethoxy compounds. Examples of phenylalkyl groups with 1 to 3 carbon atoms include benzyl. C 6-10 Examples of aryloxys include phenoxy. C 1-8 Examples of alkylaminos include methylamino and ethylamino. Examples of acylaminos with 2 to 6 carbon atoms in the acyl portion include acetylaminos. C 6-10 Examples of arylaminos include phenylamino acids. Examples of alkylcarbamoyls, where the number of carbon atoms in the alkyl portion is 1 to 6, include ethylcarbamoyl. Examples of dialkylcarbamoyls, where the alkyl portion has 1 to 6 carbon atoms, include diethylcarbamoyl. Examples of alkylsulfonyls with 1 to 6 carbon atoms in the alkyl portion include methylsulfonyl. Examples of alkyl sulfinyls with 1 to 6 carbon atoms in the alkyl portion include methyl sulfinyl. Examples of alkylthios in which the alkyl portion has 1 to 6 carbon atoms include methylthio. Examples of arylcarbonyls with 6 to 10 carbon atoms in the aryl portion include benzoyl. R 11 and R 12 And, R 11 and R 12 Examples of 5-7 membered rings that may be formed by the nitrogen atom to which the compound is bonded, and optionally by the addition of 1-2 heteroatoms, include pyrrolidine, piperidine, and morpholine.

[0023] R 2 A heteroring comprising 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group, is: (A) C substituted with 1 to 3 fluorine atoms, such as pyridine 1-oxide and 2-methylpyridine 1-oxide. 1-10 Alkyl and unsubstituted C 1-10 Pyridine 1-oxide may be substituted with 1 to 4 substituents selected from alkyl groups. (B) C substituted with 1 to 3 fluorines, such as pyridine-2(1H)-one, 1-methylpyridine-2(1H)-one, 1-ethylpyridine-2(1H)-one, 6-methylpyridine-2(1H)-one, 6-ethylpyridine-2(1H)-one, or 6-trifluoromethylpyridine-2(1H)-one. 1-10 Alkyl and unsubstituted C 1-10 Pyridine-2(1H)-one may be substituted with 1 to 4 substituents selected from alkyl groups. (C) C substituted with 1 to 3 fluorine atoms, such as pyridine-4(1H)-one, 1-methylpyridine-4(1H)-one, 1-ethylpyridine-4(1H)-one, or 1-(fluoroethyl)pyridine-4(1H)-one. 1-10 Alkyl and unsubstituted C 1-10 Pyridine-4(1H)-one may be substituted with 1 to 4 substituents selected from alkyl groups. (D) C substituted with 1 to 3 fluorines, such as pyridazine-3(2H)-one and 2-methylpyridazine-3(2H)-one. 1-10 Alkyl and unsubstituted C 1-10 Pyridazine-3(2H)-one may be substituted with 1 to 3 substituents selected from alkyl groups. (E) C substituted with 1 to 3 fluorines, such as pyrazine-2(1H)-one and 1-methylpyrazine-2(1H)-one. 1-10 Alkyl and unsubstituted C 1-10 Pyrazine-2(1H)-one may be substituted with 1 to 3 substituents selected from alkyl groups. (F) C substituted with 1 to 3 fluorine atoms, such as 4H-pyran-4-one, 3-methyl-4H-pyran-4-one, 2H-pyran-2-one, 5-methyl-2H-pyran-2-one, etc. 1-10 Alkyl and unsubstituted C 1-104H-pyran-4-one, 2H-pyran-2-one, which may be substituted with 1 to 3 substituents selected from alkyl groups. (G) C substituted with 1 to 3 fluorine atoms, such as quinoline-2(1H)-one, 6-methylquinoline-2(1H)-one, quinoline-1-oxide, and 4-methylquinoline-1-oxide. 1-10 Alkyl and unsubstituted C 1-10 Quinoline-2(1H)-one, quinoline-1-oxide, which may be substituted with 1 to 3 substituents selected from alkyl groups. (H) C substituted with 1 to 3 fluorine atoms, such as pyrimidine-4(3H)-one and pyrimidine-2,4(1H,3H)-dione. 1-10 Alkyl and unsubstituted C 1-10 Examples include pyrimidine-4(3H)-one and pyrimidine-2,4(1H,3H)-dione, which may be substituted with 1 to 3 substituents selected from alkyl groups.

[0024] As a tautomer of the compound represented by the above general formula (I), the above R 2 Examples of tautomers in a heterocycle include those comprising 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group, for example R 2 This includes 2-pyridone (lactam) and its corresponding 2-hydroxypyridine (lactim type). In compounds represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, pharmaceutically acceptable salts are preferably acid addition salts, and examples of acid addition salts include salts with organic or inorganic acids such as hydrochloride, sulfate, fumaric acid, oxalate, methanesulfonate, and camphorsulfonate. The compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, include cis, trans, racemic, and optically active stereoisomers. A compound represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof, wherein the solvate is a pharmaceutically acceptable solvate of the compound or salt thereof of the present invention, including hydrates. Furthermore, the compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or their solvates, may also be prodrugs that are chemically modified to be converted into pharmacologically active substances and exert (activate) pharmacological effects after reaching the body or target site. Examples of such prodrugs include, when the prodrug group is located on a hydroxyl group, ordinary hydroxyl group protecting groups such as lower acyl groups and lower alkoxycarbonyl groups; when located on a nitrogen atom, ordinary amino group protecting groups such as lower acyl groups and lower alkoxycarbonyl groups; or prodrug groups introduced into the carboxylic acid moiety, such as pivaloyloxymethyl (tBu-C(O)O-CH2-) group, medoxomil group, and silexityl group. Furthermore, the compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or their solvates may be substituted with stable isotopes such as deuterium.

[0025] The following describes a method for producing the compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof. 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: Mesil Ph: Phenylen TBS: tert-butyldimethylsilyl THF: Tetrahydrofuran TLC: Thin-layer chromatography Ts: Tosil WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0026] (Manufacturing method) 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 provided by the present invention, in which hydrogen is present The compound (I) provided by the present invention can be obtained, for example, by a deprotection reaction from the compound (IA) to compound (I).

[0027] [ka]

[0028] [In the formula, R 1a , R 2a , R 3a and R 4a These are R's of the general formula (I) above, respectively, due to the deprotection reaction. 1 , R 2 , R3 and R 4 It is any functional group that can be converted to R, and also R 1a is R 1 And R 2a is R 2 And R 3a is R 3 And also, R 4a is R 4 This may also be the case. Other symbols are considered to have the same meaning as above.

[0029] In the above manufacturing method, compound (I) is subjected to a suitable known general deprotection reaction with compound (IA) as needed. 1a to R 1 Convert to R 2a to R 2 Convert to R 3a to R 3 Convert to R 4a to R 4 This can be derived by converting to R in the above compound (IA). For example, R 1a , R 2a , R 3a Or R 4a If the compound (IA) contains a hydroxyl group protected by a methyl group, the protecting methyl group can be removed from the compound (IA) by (1) reacting it with boron tribromide in dichloromethane, or (2) heating the compound (IA) with a large excess of pyridine hydrochloride in a solvent-free environment, thereby leading to the compound (I). Furthermore, R in the above compound (IA) 1a , R 2a , R 3a Or R 4a If the compound (IA) contains a hydroxyl group protected by a tert-butyldimethylsilyl (TBS) group, the protecting TBS group can be removed from the compound (IA) by (3) reacting it with ammonia dissolved in a suitable solvent, (4) reacting it with hydrogen chloride dissolved in a suitable solvent, or (5) reacting it with tetrabutylammonium fluoride in THF, thereby leading to the compound (I). R1a , R 2a , R 3a Or R 4a If each of these compounds contains a functional group protected by another protecting group, the above compound (IA) can be converted to the above compound (I) by general deprotection conditions described, for example, in "Green's Protective Groups in Organic Synthesis (5th edition; A John Wiley & Son's, Inc., Pubication)" by Peter GM Wuts. These R 1a , R 2a , R 3a and R 4a If each compound has a different protecting group and these need to be removed under different conditions, it is possible to proceed to compound (IA) as a multi-step deprotection reaction by successively applying different conditions appropriate for the removal of each protecting group.

[0030] The above compound (IA) can be obtained, for example, by a general acylation reaction with the following compound (IB) in the reaction formula shown below.

[0031] [ka]

[0032] [In the formula, R 1a , R 2a , R 3a and R 4a These are R's of the general formula (I) above, respectively, due to the deprotection reaction. 1 , R 2 , R 3 and R 4 It is any functional group that can be converted to R, and also R 1a is R 1 And R 2a is R 2 And R 3a is R 3 And also, R 4a is R 4This could also be the case. L 1 The symbol represents the leaving group of a common acylating agent. Other symbols have the same meaning as above.

[0033] In the above manufacturing method, if necessary, additives such as HOBT and DMAP, and bases such as triethylamine and diisopropylethylamine are used to produce the above compound (IB) and carboxylic acid (R 2a The above compound (IA) can be obtained by reacting it with COOH and a condensing agent such as HATU or WSC. Furthermore, the above compound (IB) and 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 above compound (IA) can be obtained by reacting with ) in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine. R 3a If is a hydroxyl group (OH), then in addition to the desired amidation reaction in the acylation reaction shown in the diagram above, R 3a Acylation of the hydroxyl group proceeds as a side reaction, and in the reaction system, R of the above compound (IA) 3a = -OC(O)R 2a Although a by-product is temporarily formed, by treating the reaction solution with a 2 N ammonia / methanol solution, R can be removed during the post-treatment process. 3a The compound is converted back to =OH, and as a result, compound (IA) is obtained in which selective amidation to the secondary amine in compound (IB) has been carried out. In addition, the above compound (IB) and the corresponding carboxylic acid (R) can also be produced by the condensation reaction described in Christian AGN Montalbetti, et al, Tetrahedron, 61(46), 2005, 10827-10852. 2a The above compound (IA) can be synthesized from -COOH.

[0034] The above compound (IB) is, for example, compound 8 (Example 4:R) described in Patent Document WO2013 / 035833. 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 described in WO2014 / 136305 (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 The desired compound (IA) can be synthesized by using (=H) or by combining known functional group transformation and deprotection reactions according to the methods described in the above patent document.

[0035] The compound (IA) below can also be obtained, for example, by a general alkylation reaction of the compound (IC) below in the reaction formula shown below.

[0036] [ka]

[0037] [In the formula, in the formula, R 1a , R 2a , R 3a and R 4a These are R's of the general formula (I) above, respectively, due to the deprotection reaction. 1 , R 2 , R 3 and R 4 It is any functional group that can be converted to R, and also R 1a is R 1 And R 2a is R 2 And R 3a is R 3 And also, R 4a is R 4 This could also be the case. L 2 R represents the leaving group in a typical alkylation reaction. 1’a is R 1’a -CH2=R 1a This represents substituents such that [the above]. Other symbols have the same meaning as above.

[0038] In the above manufacturing method, the above compound (IC) is subjected to the corresponding aldehyde (R) in the presence of additives such as acetic acid as needed. 1’a -CHO;R 1’a is R 1’a -CH2=R 1aThe substituents are such that the above compound (IA) can be synthesized by reacting it with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent. Furthermore, in a polar solvent such as DMF or an alcohol, the above compound (IC) is subjected to the corresponding alkylating agent (R 1a -L 2 : L 2 The above compound (IA) can be synthesized by reacting ) in the presence of a base such as potassium carbonate.

[0039] In addition, R for the above compound (IC) 1a The introduction of the group is not limited to the reaction described above; known general alkyl group introduction reactions to amino groups, including multi-step reactions, can be applied to convert the above compound (IC) to the above compound (IA).

[0040] The above compound (IC) is, for example, compound 11 (Example 7:R) described in Patent Document WO2013 / 035833. 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 4aIt can be synthesized by combining known functional group transformations and deprotection reactions from appropriate starting materials described in the above-mentioned literature, following a method similar to the synthesis method of (=H). Other compounds of the compound represented by the above general formula (I), which is provided by the present invention, can also be produced by combining the above production method, the method used in the examples described below, and the above-mentioned Patent Documents 4-6 and Non-Patent Document 1, etc.

[0041] The compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, exhibit superior activating activity and selectivity for opioid δ receptors compared to μ and κ opioid receptors. Therefore, compounds represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, can be used in pharmaceutical compositions that exert opioid δ receptor agonist activity. Furthermore, the compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or their solvates, exhibit only weak inhibitory activity against the hERG (human ether-a-go-go related gene) potassium channel. Therefore, compounds represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, can be used in pharmaceutical compositions that have a low risk of delayed ventricular repolarization and QT interval prolongation in humans. Furthermore, the compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, exhibit excellent stability against metabolism by human liver microsomes. Therefore, compounds represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, can be used in pharmaceutical compositions for oral administration. Furthermore, compounds represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, exert their medicinal effects by acting on the brain in animal models of depression, anxiety, etc., suggesting good brain penetration.

[0042] The pharmaceutical compositions provided by the present invention are administered orally or parenterally to humans or other mammals. Examples of parenteral administration include intravenous, subcutaneous, intramuscular, intra-articular, transmucosal, transdermal, nasal, rectal, and intrathecal administration. The pharmaceutical compositions provided by the present invention may be prepared by mixing a compound represented by the above general formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, either as is, or with a pharmaceutically acceptable carrier, such as an excipient (e.g., lactose, D-mannitol, crystalline cellulose, glucose), a binder (e.g., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), a disintegrant (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), a diluent (e.g., water for injection, physiological saline), and, if necessary, an additive (e.g., pH adjuster, surfactant, solubilizer, preservative, emulsifier, isotonic agent, stabilizer), and may be in the form of tablets, granules, powders, capsules, suspensions, injections, suppositories, etc. For example, to form tablets, 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 may be formulated by mixing it with an excipient (e.g., lactose, D-mannitol, crystalline cellulose, glucose), a disintegrant (e.g., starch, carboxymethylcellulose calcium (CMC-Ca)), a binder (e.g., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), etc. For example, to prepare an injectable preparation, the compound represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof may be formulated by mixing it with a dispersant (e.g., surfactants such as Tween 80, polysaccharides such as carboxymethylcellulose, sodium alginate, hyaluronic acid, or polysorbate), a preservative (e.g., methylparaben, propylparaben), an isotonic agent (e.g., sodium chloride, mannitol, sorbitol, glucose), a pH adjuster (e.g., sodium phosphate, potassium phosphate), etc.

[0043] The pharmaceutical compositions provided by the present invention may contain an amount effective for the treatment or prevention of opioid δ receptor-related disorders (e.g., headaches), a compound represented by the above general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.

[0044] The dosage of the compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, can be appropriately determined depending on the type of salt, the method of administration, the symptoms of the recipient, age, etc. For example, when the compound represented by the above general formula (I), its tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof are administered orally to humans, the dosage may be 1 μg to 10 g / day, preferably 0.01 to 2000 mg / day, more preferably 0.1 to 100 mg / day. When administered intravenously to humans, the dosage may be 0.1 μg to 1 g / day, preferably 0.001 to 200 mg / day. It may also be administered in 1 to 3 divided doses per day.

[0045] Furthermore, compounds represented by the above general formula (I), tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof, can be used in combination with other drugs (e.g., analgesics (e.g., nonsteroidal anti-inflammatory drugs), antidepressants / anxiolytics (e.g., selective serotonin reuptake inhibitors)). Combination therapy may be achieved by simultaneous administration (e.g., administration as a combination drug), or by administration separately, consecutively, or at desired intervals (e.g., administration of separately formulated drugs).

[0046] In this specification, opioid δ receptor-related diseases are diseases that can be treated or prevented by opioid δ receptor agonists, and include, but are not limited to, the following diseases: depression, anxiety, pain (e.g., headache, fibromyalgia), glaucoma, urinary incontinence, myocardial ischemia, cerebral ischemia, chronic cough, hypertension, drug addiction, alcoholism, gastritis, premature ejaculation, diarrhea, functional gastrointestinal disorders, or neurodegenerative diseases (e.g., Parkinson's disease, epilepsy, Alzheimer's disease). In one embodiment, the pharmaceutical composition provided by the present invention can be used for the treatment and / or prevention of depression or anxiety, and can be used as a preventive and / or therapeutic agent (antidepressant, anxiolytic, etc.) for mental disorders included in the DSM-5 (Diagnostic and Statistical Manual of Mental Disorders, 5th Edition), such as depressive disorders, anxiety disorders (e.g., social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder), bipolar disorders, obsessive-compulsive disorder and related disorders, and trauma and stressor-related disorders (e.g., post-traumatic stress disorder). It can also be used as a preventive and / or therapeutic agent (antidepressant, anxiolytic, etc.) for urinary incontinence, myocardial ischemia, cerebral ischemia, chronic cough, hypertension, drug addiction, alcoholism, gastritis, premature ejaculation, diarrhea, functional gastrointestinal disorders, or neurodegenerative diseases (e.g., Parkinson's disease, epilepsy, Alzheimer's disease). In one embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for the treatment of depression, and is a pharmaceutical composition that exhibits a rapid onset of efficacy. In another embodiment, the pharmaceutical composition provided by the present invention is a pharmaceutical composition for the treatment of depression, and is a pharmaceutical composition that does not cause tolerance with continuous administration. In one embodiment, the pharmaceutical composition provided by the present invention can be used as a preventive and therapeutic agent for depression, which is an accompanying symptom of Alzheimer's disease. Furthermore, as described in IOVS, March 2013, Vol. 54, No. 3; J. Neurochem. (2009) 108, 741-754, etc., opioid δ receptor agonists have been proposed for use in treating glaucoma. Therefore, in one embodiment, the pharmaceutical composition provided by the present invention can be used as a preventive or therapeutic agent for glaucoma. In this specification, depression can be a state that includes mood disorders such as feelings of depression, sadness, and loneliness, as well as autonomic nervous system disorders such as decreased motivation, mental congestion, pessimistic thoughts, sleep disturbances, and decreased appetite. In this specification, anxiety can be a state in which a person feels danger or fear, accompanied by restlessness, tension, rapid heartbeat, and shortness of breath, even though there is no clearly identifiable stimulus. Depression and anxiety include symptoms of depression and anxiety seen in the mental disorders described in the DSM-5 (e.g., depressive symptoms seen in the bipolar disorder group, depressive and anxiety symptoms seen in PTSD), depressive states that are milder than those in the depressive disorders group described in the DSM-5 but persist to some extent, and states that are milder than those in the anxiety disorders group described in the DSM-5 but persist to some extent. In one embodiment, the pharmaceutical composition provided by the present invention is useful as an analgesic for the treatment and / or prevention of pain in general. Pain can be classified in various ways, but in terms of duration and nature, it can be divided into acute pain and chronic pain. Acute pain is the most important biological signal regarding the severity and extent of injury. Examples of acute pain include nociceptive pain, which is caused by pain-inducing substances released by tissue injury or inflammation and is relieved as the injury is treated. Chronic pain is pain that persists beyond the normal course of an acute disease or the reasonable time required for wound healing. Examples of chronic pain include postherpetic pain, neuropathic pain such as pain associated with diabetic neuropathy, and fibromyalgia. In terms of cause, pain can be divided into nociceptive pain, neuropathic pain, and psychogenic pain. Examples of nociceptive pain include periarthritis of the shoulder, tenosynovitis, rheumatoid arthritis, headaches, toothaches, bruises, and cuts. Neuropathic pain is pain caused by nerve damage and includes peripheral neuropathic pain such as postherpetic neuralgia, diabetic neuropathy, sciatica, and peripheral neuropathy caused by anticancer drug use, as well as central nervous system pain such as post-stroke pain, spinal cord injury pain, and pain associated with multiple sclerosis. Psychogenic pain is pain caused by psychological and social factors such as anxiety and stress experienced in social life.

[0047] The following are specific examples of pain and pain-related diseases for which the pharmaceutical compositions provided by the present invention are useful for treatment and / or prevention: phantom limb pain, stump pain, complex regional pain syndrome, polyneuropathy, pain associated with diabetic neuropathy, pain due to HIV infection, paraneoplastic pain, glossopharyngeal neuralgia, occipital neuralgia, nerve root injury, nerve plexus injury, postoperative scar syndrome, visceral pain, burns (including sunburn), angina pectoris, spinal segment or intercostal neuralgia, pain resulting from chemotherapy-induced neuropathy, pain associated with rheumatoid arthritis, and osteoarthritis. Pain associated with: headaches, migraines, orofacial pain, toothaches, glossodynia, temporomandibular joint disorders, trigeminal neuralgia, shoulder pain, pain associated with herniated discs, pain associated with degenerative cervical spondylosis, pain associated with spinal stenosis, pain associated with thoracic outlet syndrome, pain associated with brachial plexus avulsion syndrome, shoulder-hand syndrome, whiplash, chest pain, abdominal pain, colic, pain associated with gallstones, pain associated with pancreatitis, urinary tract stones, pain associated with irritable bowel syndrome, lower back pain, sciatica, pain associated with fractures, pain associated with osteoporosis, joint pain, and pain associated with gout. Pain, pain associated with cauda equina syndrome, pain associated with ankylosing spondylitis, muscle pain, painful spasms, myofascial pain syndrome, fibromyalgia, complex regional pain syndrome, pain associated with arteriosclerosis obliterans, pain associated with Buerger's disease, pain associated with Raynaud's phenomenon, postherpetic pain, causalgia, pain associated with compressive neuropathy, pain associated with carpal tunnel syndrome, pain associated with diabetes, pain associated with Guillain-Barré syndrome, pain associated with leprosy, pain associated with drug therapy, pain associated with radiation therapy, pain after spinal cord injury, syringomyelia Pain associated with [unspecified conditions], post-stroke pain (including thalamic pain), afferent pathway deprivation pain, sympathetic nerve-dependent pain, ABC syndrome, multiple sclerosis, pain associated with skin diseases, cancer pain, surgical pain, postoperative pain, pain associated with trauma, pain associated with gangrene, pain associated with somatoform disorder, pain associated with somatization disorder, pain associated with depression, pain associated with Parkinson's disease, knee pain, pain associated with arthritis, menstrual cramps, mid-course pain, labor pains, delivery pains, inflammatory pain, nociceptive pain, psychogenic pain, overactive bladder, cystitis, prostatitis, prostatitis, and lower back pain.

[0048] Preferably, the pharmaceutical compositions provided by the present invention are used for the treatment and / or prevention of pain associated with diabetic peripheral neuropathy, postherpetic pain, post-spinal cord injury pain, post-stroke pain, pain associated with multiple sclerosis, pain associated with chronic lower back pain and fibromyalgia, and headaches. Headaches include chronic headaches and acute headaches, and headaches are preferably migraines, such as transient migraines (episodic migraines) or migraines with aura. The pharmaceutical compositions provided by the present invention are also useful for treating symptoms of depression and / or anxiety associated with headaches.

[0049] The pharmaceutical composition provided by the present invention has antidepressant and / or anxiolytic effects, and therefore, in addition to reducing and / or alleviating the above-mentioned pain, it is also useful for the remission of depressive and / or anxiety symptoms associated with pain. Thus, the pharmaceutical composition provided by the present invention can be a pharmaceutical composition for the treatment or prevention of depressive and / or anxiety symptoms associated with pain. For example, fibromyalgia is characterized by unbearable chronic pain throughout the body as its core symptom, accompanied by emotional disorders such as depression and anxiety. The pharmaceutical composition provided by the present invention is useful not only for reducing and / or alleviating the pain of fibromyalgia, but also for the remission of depressive and / or anxious symptoms associated with the pain. Therefore, the pharmaceutical composition provided by the present invention can be a pharmaceutical composition for the treatment or prevention of depressive and / or anxious symptoms of fibromyalgia. Furthermore, the pharmaceutical composition provided by the present invention is effective in treating or preventing the core symptoms of Parkinson's disease and overactive bladder, and in addition, it is also effective in treating or preventing pain associated with these diseases. Therefore, the pharmaceutical composition provided by the present invention can be a pharmaceutical composition for treating or preventing pain associated with Parkinson's disease or overactive bladder.

[0050] In one embodiment, the present invention provides a method for preventing or treating the diseases described above, comprising administering a pharmaceutical composition provided by the present invention. In one embodiment, the present invention provides a use of a pharmaceutical composition provided by the present invention for the prevention or treatment of the diseases described above. As one embodiment, the present invention provides a method for preventing or treating the diseases described above, comprising administering any of the compounds described in (1) to (58) above. As one embodiment, the present invention provides the use of any of the compounds described in (1) to (58) above for the manufacture of pharmaceutical compositions for the prevention or treatment of the diseases described above.

[0051] The present invention also provides the following embodiments 1) to 88): 1) A method for treating or preventing pain or painful diseases in mammals (e.g., humans), wherein an effective amount of general formula (I) is provided to a subject requiring treatment or prevention of pain or painful diseases: [ka] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Ariel; C 2-6 Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms. 3-6 This represents a cycloalkyl or heteroaryl alkyl group in which the cycloalkyl or heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R 2 This represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group. Here, R 2 is R 2 It is bonded to Y via the carbon atoms that make up the ring, R 3 , R 4 and R 5 These are the same or different: hydrogen; hydroxyl; halogen; cyano; carbamoyl; C1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyloxy; Nitro; Amino; C 1-8 Alkylamino; C 6-10 This represents an arylamino or acylamino compound in which the acyl moiety has 2 to 6 carbon atoms. R 6a and R 6b is the same or different, representing hydrogen; fluorine or hydroxyl, or R 6a and R 6b Together they represent = O, R 7 and R 8 These are identical or different, representing hydrogen; fluorine or hydroxyl, R 9 and R 10 They are the same or different, hydrogen; C 1-6 Alkyl; C 6-10 Aryl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; Heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms in the heteroaryl portion and 1 to 5 carbon atoms in the alkylene portion; Cycloalkylalkyl or C having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion. 2-6 Representing Alkenil, X represents O or CH2, And Y represents C (=O). However, R 1 C 1-10 Alkyl; The alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the alkyl / cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; The alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and The alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5, has 1 to 6 Halogen; Hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6 Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 C 6-10 Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and 1 to 5 carbon atoms in the alkylene moiety, C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6Alkanoyloxy;hydroxy;alkoxycarbonyl;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12 It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R 1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) A method comprising administering a compound represented by, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; 2) The method according to 1), wherein the pain or pain-related disease is pain associated with diabetic neuropathy, headache, fibromyalgia, post-spinal cord injury pain, post-stroke pain (including thalamic pain), multiple sclerosis, postoperative pain, or lower back pain. 3) The method according to 1) or 2) wherein the pain or painful condition is a headache; 4) The headache is a migraine, as described in 3); 5) The method according to 3) or 4), wherein the headache is transient migraine or migraine with aura; 6) The method according to 1) or 2) wherein the pain or painful disease is fibromyalgia; 7) A method for treating or preventing depression or anxiety associated with pain in mammals (e.g., humans), wherein the general formula (I) is effective in providing a sufficient amount to subjects requiring treatment or prevention of depression or anxiety associated with pain: [ka] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Ariel; C 2-6 Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms. 3-6 This represents a cycloalkyl or heteroaryl alkyl group in which the cycloalkyl or heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R 2 This represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group. Here, R 2 is R 2 It is bonded to Y via the carbon atoms that make up the ring, R3 , R 4 and R 5 These are the same or different: hydrogen; hydroxyl; halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyloxy; Nitro; Amino; C 1-8 Alkylamino; C 6-10 This represents an arylamino or acylamino compound in which the acyl moiety has 2 to 6 carbon atoms. R 6a and R 6b is the same or different, representing hydrogen; fluorine or hydroxyl, or R 6a and R 6b Together they represent = O, R 7 and R 8 These are identical or different, representing hydrogen; fluorine or hydroxyl, R 9 and R 10 They are the same or different, hydrogen; C 1-6 Alkyl; C 6-10 Aryl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; Heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms in the heteroaryl portion and 1 to 5 carbon atoms in the alkylene portion; Cycloalkylalkyl or C having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion. 2-6 Representing Alkenil, X represents O or CH2, And Y represents C (=O). However, R 1 C 1-10Alkyl; The alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the alkyl / cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; The alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and The alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5, has 1 to 6 Halogen; Hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6 Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 C 6-10 Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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 6-10Aryl; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12 It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) A method comprising administering a compound represented by, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; 8) The method described in 7), wherein the depression or anxiety associated with pain is depression or anxiety associated with headache, or depression or anxiety associated with fibromyalgia; 9) General formula (I) for use in the treatment or prevention of pain or painful diseases: [ka] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Ariel; C 2-6 Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms. 3-6 This represents a cycloalkyl or heteroaryl alkyl group in which the cycloalkyl or heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R 2 This represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group. Here, R 2 is R 2 It is bonded to Y via the carbon atoms that make up the ring, R 3 , R 4 and R 5These are the same or different: hydrogen; hydroxyl; halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyloxy; Nitro; Amino; C 1-8 Alkylamino; C 6-10 This represents an arylamino or acylamino compound in which the acyl moiety has 2 to 6 carbon atoms. R 6a and R 6b is the same or different, representing hydrogen; fluorine or hydroxyl, or R 6a and R 6b Together they represent = O, R 7 and R 8 These are identical or different, representing hydrogen; fluorine or hydroxyl, R 9 and R 10 They are the same or different, hydrogen; C 1-6 Alkyl; C 6-10 Aryl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; Heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms in the heteroaryl portion and 1 to 5 carbon atoms in the alkylene portion; Cycloalkylalkyl or C having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion. 2-6 Representing Alkenil, X represents O or CH2, And Y represents C (=O). However, R 1 C 1-10Alkyl; The alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the alkyl / cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; The alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and The alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5, has 1 to 6 Halogen; Hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6 Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 C 6-10 Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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 6-10Aryl; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12 It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) Use of pharmaceutical compositions comprising a compound represented by, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or solvates thereof; 10) Use as described in 9) when the pain or painful condition is associated with diabetic neuropathy, headache, fibromyalgia, post-spinal cord injury pain, post-stroke pain (including thalamic pain), multiple sclerosis, postoperative pain, or lower back pain; 11) The use described in 9) or 10) for pain or a painful condition being headache; 12) If the headache is a migraine, use as described in 11); 13) The use described in 11) or 12) for headaches that are transient migraines or migraines with aura; 14) Use as described in 9) or 10) when the pain or painful condition is fibromyalgia; 15) General formula (I) for use in the treatment or prevention of depression or anxiety associated with pain: [ka] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Ariel; C 2-6 Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms. 3-6 This represents a cycloalkyl or heteroaryl alkyl group in which the cycloalkyl or heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R 2 This represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group. Here, R 2 is R 2 It is bonded to Y via the carbon atoms that make up the ring, R 3 , R 4 and R 5 These are the same or different: hydrogen; hydroxyl; halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyloxy; Nitro; Amino; C 1-8 Alkylamino; C 6-10 This represents an arylamino or acylamino compound in which the acyl moiety has 2 to 6 carbon atoms. R 6a and R 6b is the same or different, representing hydrogen; fluorine or hydroxyl, or R 6a and R 6b Together they represent = O, R 7 and R 8 These are identical or different, representing hydrogen; fluorine or hydroxyl, R 9 and R 10 They are the same or different, hydrogen; C 1-6 Alkyl; C 6-10 Aryl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; Heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms in the heteroaryl portion and 1 to 5 carbon atoms in the alkylene portion; Cycloalkylalkyl or C having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion. 2-6 Representing Alkenil, X represents O or CH2, And Y represents C (=O). However, R 1 C 1-10 Alkyl; The alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the alkyl / cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; The alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and The alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5, has 1 to 6 Halogen; Hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6 Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 C 6-10 Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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 6-10Aryl; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12 It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) Use of pharmaceutical compositions containing compounds represented by, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof; 16) Use as described in 15) for depression or anxiety associated with pain, which is depression or anxiety associated with headache, or depression or anxiety associated with fibromyalgia; 17) A general formula (I) for manufacturing pharmaceutical compositions for the treatment or prevention of pain or painful diseases: [ka] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Ariel; C 2-6 Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms. 3-6 This represents a cycloalkyl or heteroaryl alkyl group in which the cycloalkyl or heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R 2 This represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group. Here, R 2 is R 2 It is bonded to Y via the carbon atoms that make up the ring, R 3 , R 4 and R 5These are the same or different: hydrogen; hydroxyl; halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyloxy; Nitro; Amino; C 1-8 Alkylamino; C 6-10 This represents an arylamino or acylamino compound in which the acyl moiety has 2 to 6 carbon atoms. R 6a and R 6b is the same or different, representing hydrogen; fluorine or hydroxyl, or R 6a and R 6b Together they represent = O, R 7 and R 8 These are identical or different, representing hydrogen; fluorine or hydroxyl, R 9 and R 10 They are the same or different, hydrogen; C 1-6 Alkyl; C 6-10 Aryl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; Heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms in the heteroaryl portion and 1 to 5 carbon atoms in the alkylene portion; Cycloalkylalkyl or C having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion. 2-6 Representing Alkenil, X represents O or CH2, And Y represents C (=O). However, R 1 C 1-10Alkyl; The alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the alkyl / cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; The alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and The alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5, has 1 to 6 Halogen; Hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6 Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 C 6-10 Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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 6-10Aryl; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12 It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) Use of compounds represented by, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof; 18) Use as described in 17) when the pain or painful condition is associated with diabetic neuropathy, headache, fibromyalgia, post-spinal cord injury pain, post-stroke pain (including thalamic pain), multiple sclerosis, postoperative pain, or lower back pain; 19) The use described in 17) or 18) for pain or a painful condition being headache; 20) If the headache is a migraine, use as described in 19); twenty one) Use as described in 19) or 20) for headaches that are transient migraines or migraines with aura; twenty two) Use as described in 17) or 18) when the pain or painful condition is fibromyalgia; twenty three) A general formula (I) for manufacturing a pharmaceutical composition for the treatment or prevention of depression or anxiety associated with pain: [ka] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Ariel; C 2-6 Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms. 3-6 This represents a cycloalkyl or heteroaryl alkyl group in which the cycloalkyl or heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R 2 This represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group. Here, R 2 is R 2 It is bonded to Y via the carbon atoms that make up the ring, R 3 , R 4 and R 5 These are the same or different: hydrogen; hydroxyl; halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyloxy; Nitro; Amino; C 1-8 Alkylamino; C 6-10 This represents an arylamino or acylamino compound in which the acyl moiety has 2 to 6 carbon atoms. R 6a and R 6b is the same or different, representing hydrogen; fluorine or hydroxyl, or R 6a and R 6b Together they represent = O, R 7 and R 8 These are identical or different, representing hydrogen; fluorine or hydroxyl, R 9 and R 10 They are the same or different, hydrogen; C 1-6 Alkyl; C 6-10 Aryl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; Heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms in the heteroaryl portion and 1 to 5 carbon atoms in the alkylene portion; Cycloalkylalkyl or C having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion. 2-6 Representing Alkenil, X represents O or CH2, And Y represents C (=O). However, R 1 C 1-10 Alkyl; The alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the alkyl / cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; The alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and The alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5, has 1 to 6 Halogen; Hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6 Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 C 6-10 Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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 6-10Aryl; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12 It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) Use of compounds represented by, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof; twenty four) Use as described in 23) for depression or anxiety associated with pain, which is depression or anxiety associated with headache, or depression or anxiety associated with fibromyalgia; twenty five) A pharmaceutical composition for the treatment or prevention of pain or painful diseases, comprising general formula (I): [ka] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Ariel; C 2-6 Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms. 3-6 This represents a cycloalkyl or heteroaryl alkyl group in which the cycloalkyl or heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R 2 This represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S, and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group. Here, R 2 is R 2 It is bonded to Y via the carbon atoms that make up the ring, R 3 , R 4 and R 5are 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 aryl amino or acylamino where the acyl moiety has 2 to 6 carbon atoms, 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 6-10 aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring - forming atoms; aralkyl where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; heteroarylalkyl where the heteroaryl moiety contains 1 to 4 heteroatoms selected from N, O and S as ring - forming atoms and the alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms or C 2-6 alkenyl, X represents O or CH2, and Y represents C(=O). However, the C of R 1 of 1-10Alkyl; The alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the alkyl / cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; The alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and The alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5, has 1 to 6 Halogen; Hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6 Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 C 6-10 Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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 6-10Aryl; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12 It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) Pharmaceutical compositions comprising a compound represented by , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or solvates thereof; 26) The pharmaceutical composition according to 25), wherein the pain or painful disease is pain associated with diabetic neuropathy, headache, fibromyalgia, pain after spinal cord injury, pain after stroke (including thalamic pain), multiple sclerosis, postoperative pain, or lower back pain; 27) The pharmaceutical composition according to 25) or 26), wherein the pain or painful disorder is a headache; 28) The headache is a migraine, as described in 27); 29) The use described in 27) or 28) for headaches that are transient migraines or migraines with aura; 30) The pharmaceutical composition according to 25) or 26), wherein the pain or painful disease is fibromyalgia; 31) A pharmaceutical composition for the treatment or prevention of depression or anxiety associated with pain, comprising general formula (I): [ka] (In the formula, R 1 is hydrogen; C 1-10 Alkyl; C 6-10 Ariel; C 2-6 Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms. 3-6 This represents a cycloalkyl or heteroaryl alkyl group in which the cycloalkyl or heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R 2 represents a heterocyclic ring containing 1 to 4 heteroatoms selected from N, O and S and at least one carbon atom 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, wherein R 2 is bonded to Y via a carbon atom which is a ring-constituting atom of R 2 ; R 3 ,R 4 and R 5 are the same or different and represent 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 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 represent 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 in the heteroaryl moiety 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 or C 2-6 alkenyl, X represents O or CH2, And Y represents C (=O). However, R 1 C 1-10 Alkyl; The alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the alkyl / cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; The alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and The alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5, has 1 to 6 Halogen; Hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6 Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 C 6-10 Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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 6-10Aryl; Heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl aryl moiety having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and Heteroarylalkyl heteroaryl moiety having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 C 6-10 The aryl may have substituents that it may have, Furthermore, R 1 C 1-10 In the case of alkyl, NR 11 R 12 It may be replaced with R 11 and R 12 They are the same or different, hydrogen; C 1-10 Alkyl; or aryl moiety has 6 to 10 carbon atoms and alkylene moiety has 1 to 5 carbon atoms, or R 11 and R 12 And, R 11 and R 12 The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 (It may be substituted with at least one substituent selected from alkyl groups.) Pharmaceutical compositions comprising a compound represented by , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or solvates thereof; 32) The pharmaceutical composition according to 31), wherein the depression or anxiety associated with pain is depression or anxiety associated with headache, or depression or anxiety associated with fibromyalgia; 33) In general formula (I), R 1 C 1-10 A cycloalkylalkyl having 3 to 6 carbon atoms in the alkyl or cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or an aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, as described in any of 1) to 32); 34) In general formula (I), R 1 A cycloalkylalkyl group having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion, as described in any of 1) to 33); 35) In general formula (I), R 1 C is substituted with hydroxyl 2-6 Alkyl; C substituted with 1 to 6 halogens 1-6 Alkyl; or C 1-6 alkoxy-substituted C 2-6 Alkyl, method, use, or composition as described in any of 1) to 32); 36) In general formula (I), R 1 The method, use, or composition described in any of 1) to 32) is allyl, fluoropropyl, 2-(pyridine-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl; 37) In general formula (I), R 2 The method, use, or composition according to any one of 1) to 36), wherein is a 5-7 membered heterocycle or a heterocycle in which a benzene ring is fused to the heterocycle, wherein the heterocycle comprises 1-4 heteroatoms selected from N, O, and S and at least one carbon atom as ring constituent atoms, and at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group. 38) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine 1-oxide which may be substituted with 1 to 4 substituents selected from alkyl groups, according to any of the methods, uses, or compositions described in 1) to 37); 39) In general formula (I), R 2 The method, use, or composition according to any of 1) to 38) wherein the compound is pyridine 1-oxide; 40) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine-2(1H)-one, which may be substituted with 1 to 4 substituents selected from alkyl groups, as described in any of 1) to 37); 41) In general formula (I), R 2 Pyridine-2(1H)-one; 1-C 1-6 Alkylpyridine-2(1H)-one; or 6-C 1-6 Alkylpyridine-2(1H)-one, as described, used, or composed according to any of methods 1) to 37), 40); 42) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10A pyridine-4(1H)-one, which may be substituted with 1 to 4 substituents selected from alkyl groups, as described, used, or composed in any of the methods 1) to 37); 43) In general formula (I), R 2 is pyridine-4(1H)-one or 1-C 1-6 Alkylpyridine-4(1H)-one, as described, used, or composed according to any of methods 1) to 37), 42); 44) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 Pyridazine-3(2H)-one, which may be substituted with 1 to 3 substituents selected from alkyl groups, as described, used, or composed according to any of 1) to 37); 45) In general formula (I), R 2 The method, use, or composition according to any of 1) to 37), 44), wherein pyridazine-3(2H)-one; 46) In general formula (I), R 2 C 1-10 Alkyl and fluorine-substituted C 1-10 A pyrazine-2(1H)-one, which may be substituted with 1 to 3 substituents selected from alkyl groups, according to any of the methods, uses, or compositions described in 1) to 37); 47) In general formula (I), R 2 The method, use, or composition according to any of 1) to 37), 46), wherein pyrazine-2(1H)-one; 48) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A 4H-pyran-4-one or 2H-pyran-2-one, which may be substituted with 1 to 3 substituents selected from alkyl groups, as described in any of 1) to 37); use or composition according to any of 1) to 37); 49) In general formula (I), R 2 The method, use, or composition according to any of 1) to 37), 48), wherein is 4H-pyran-4-one or 2H-pyran-2-one; 50) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A quinoline-2(1H)-one, which may be substituted with 1 to 3 substituents selected from alkyl groups, according to any of the methods, uses, or compositions described in 1) to 37); 51) In general formula (I), R 2 The method, use, or composition according to any of 1) to 37), 50), wherein is quinoline-2(1H)-one; 52) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione, which may be substituted with 1 to 3 substituents selected from alkyl groups, as described in any of 1) to 37); use or composition according to any of 1) to 37); 53) In general formula (I), R 2 The method, use, or composition described in any of 1) to 37), 52) wherein pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione; 54) The method, use, or composition according to any of 1) to 53) in which X is CH2 in general formula (I); 55) In general formula (I), R 3 and R 4 The method, use, or composition according to any of 1) to 54), wherein one of the atoms is hydroxyl and the other is hydrogen; 56) In general formula (I), R 3 is halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 1-6Alkanoyloxy; amino; or acylamino, where the number of carbon atoms in the acyl moiety is 2 to 6, R 4 is hydrogen or hydroxyl, R 5 A method, use, or composition according to any of 1) to 54), wherein the hydrogen is hydrogen; 57) In general formula (I), R 3 is hydroxy; carbamoyl; or C 1-6 With alkanoyloxy, R 4 is hydrogen, R 5 A method, use, or composition according to any of 1) to 54), wherein the hydrogen is hydrogen; 58) In general formula (I), R 3 is hydroxy, R 4 is hydrogen, R 5 A method, use, or composition according to any of 1) to 54), wherein the hydrogen is hydrogen; 59) In general formula (I), R 3 , R 4 and R 5 A method, use, or composition according to any of 1) to 54), wherein all atoms are hydrogen; 60) In general formula (I), R 6a , R 6b , R 7 , R 8 , R 9 and R 10 A method, use, or composition according to any of 1) to 59), wherein all atoms are hydrogen; 61) R 5 , R 6a , R 6b , R 7 , R 8 , R 9 and R 10 It is hydrogen, R 1 is hydrogen; C 1-6 Alkyl; C 2-6 Alkenyl; cycloalkylalkyl, where the cycloalkyl portion has 3 to 6 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; or aralkyl, where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms. R 2 This represents a 5-7 membered heterocycle or a heterocycle in which a benzene ring is fused to the heterocycle, comprising 1-4 heteroatoms selected from N, O, and S and at least one carbon atom as ring constituent atoms, and at least one pair of adjacent ring constituent atoms having a double bond and further substituted with at least one oxo group. Here, R 2 is R 2 It is bonded to Y via the carbon atoms that make up the ring, R 3 and R 4 These are the same or different: hydrogen; hydroxyl; halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyloxy; amino; or acylamino, where the number of carbon atoms in the acyl portion is 2 to 6. X is CH2, And Y is C (=O), However, R 1 C 1-6 Alkyl; The alkylene and cycloalkyl portions of a cycloalkylalkyl group have 3 to 6 carbon atoms in the alkyl or cycloalkyl group, and the alkylene portion has 1 to 5 carbon atoms in the alkyl or aryl portion has 6 to 10 carbon atoms in the alkylene portion, and the alkylene portion has 1 to 5 carbon atoms in the alkyl or cycloalkyl group, which has 1 to 6 carbon atoms. Halogen; Hydroxyl; C 1-6 Alkoxy; C 6-10 Aryloxy; C 1-6 Alkanoyl; C 1-6 Alkanoyloxy;carboxyl;alkoxycarbonyl;carbamoyl;alkylcarbamoyl;dialkylcarbamoyl;alkylsulfonyl;aminosulfonyl;alkylsulfinyl;alkylthio;Cylthio;Cylthio;Cylthio(1-6)Cylamino 1-6Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And, R 1 The aryl portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; 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;carbamoyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;alkoxycarbonyl;dialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyano;Cyano;Cyanocarbonyl;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;Hydroxycarbonyl;alkdialkylcarbamoyl;alkoxycarbonyl;halogen;nitro;cyanocarbon;Cyanocarbonyl;Cyanocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;halogen;nitro;cyanocarbonyl;Cyanocarbonyl;Cynocarbonyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;dialkylcarbamoyl;Hydroxycarbonyl;H 1-6 Alkyl; C substituted with 1-3 halogens 1-6 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl; phenoxy; alkyl; phenylalkyl; and methylenedioxy, which have 1 to 3 carbon atoms. R 2 The heterocycle has, in addition to the oxo group, the R mentioned above. 1 The aryl portion of the aralkyl may have substituents such that the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms. Furthermore, R 1 The alkylene portion of an aralkyl molecule has 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion, and is substituted with phenyl or 1 to 3 halogens. 1-6 The method, use, or composition according to any one of 1) to 32), which may be substituted with at least one substituent selected from alkyl groups; 62) In general formula (I), R 1 C 1-6A cycloalkylalkyl having 3 to 6 carbon atoms in the alkyl or cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or an aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; the method, use, or composition according to any of 1) to 32), 61); 63) In general formula (I), R 1 A cycloalkylalkyl is a cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion, as described in any of 1) to 32), 61), 62); 64) In general formula (I), R 1 C is substituted with hydroxyl 2-6 Alkyl; C substituted with 1 to 6 halogens 1-6 Alkyl; or C 1-6 alkoxy-substituted C 2-6 Alkyl, the method, use, or composition according to any of 1) to 32), 61); 65) In general formula (I), R 1 The method, use, or composition according to any of 1) to 32), 61), wherein is allyl, fluoropropyl, 2-(pyridine-3-yl)ethyl, 2-(methylsulfonyl)ethyl, or 2-(aminosulfonyl)ethyl; 66) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine 1-oxide, pyridine-2(1H)-one, pyridine-4(1H)-one, pyridazine-3(2H)-one, pyrazine-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one, quinoline-2(1H)-one, pyrimidine-4(3H)-one, or pyrimidine-2,4(1H,3H)-dione, as described, used, or composed according to any of 1) to 32), 61) to 65); 67) In general formula (I), R 2 C 1-10 Alkyl and fluorine-substituted C 1-10 A pyridine 1-oxide which may be substituted with 1 to 4 substituents selected from alkyl groups, according to any of the methods, uses, or compositions described in 1) to 32), 61) to 66); 68) In general formula (I), R 2 The method, use, or composition according to any of 1) to 32), 61) to 67), wherein the compound is pyridine 1-oxide; 69) In general formula (I), R 2 C 1-10 Alkyl and fluorine-substituted C 1-10 A pyridine-2(1H)-one which may be substituted with 1 to 4 substituents selected from alkyl groups, according to any of the methods, uses, or compositions described in 1) to 32), 61) to 66); 70) In general formula (I), R 2 Pyridine-2(1H)-one; 1-C 1-6 Alkylpyridine-2(1H)-one; or 6-C 1-6 Alkylpyridine-2(1H)-one, as described, used, or composed according to any of methods 1) to 32), 61) to 66); 71) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyridine-4(1H)-one which may be substituted with 1 to 4 substituents selected from alkyl groups, as described, used, or composed according to any of 1) to 32), 61) to 66); 72) In general formula (I), R 2 is pyridine-4(1H)-one or 1-C 1-6 Alkylpyridine-4(1H)-one, as described, used, or composed according to any of methods 1) to 32), 61) to 66); 73) In general formula (I), R2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 Pyridazine-3(2H)-one, which may be substituted with 1 to 3 substituents selected from alkyl groups, according to any of the methods, uses, or compositions described in 1) to 32), 61) to 66); 74) In general formula (I), R 2 The method, use, or composition according to any of 1) to 32), 61) to 66), or 73), wherein pyridazine-3(2H)-one; 75) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyrazine-2(1H)-one which may be substituted with 1 to 3 substituents selected from alkyl groups, according to any of the methods, uses, or compositions described in 1) to 32), 61) to 66); 76) In general formula (I), R 2 The method, use, or composition according to any of 1) to 32), 61) to 66), or 75), wherein pyrazine-2(1H)-one; 77) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A 4H-pyran-4-one or 2H-pyran-2-one, which may be substituted with 1 to 3 substituents selected from alkyl groups, as described, used, or composed according to any of 1) to 32), 61) to 66); 78) In general formula (I), R 2 The method, use, or composition according to any of 1) to 32), 61) to 66), or 77), wherein is 4H-pyran-4-one or 2H-pyran-2-one; 79) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10A quinoline-2(1H)-one, which may be substituted with 1 to 3 substituents selected from alkyl groups, according to any of the methods, uses, or compositions described in 1) to 32), 61) to 66); 80) In general formula (I), R 2 The method, use, or composition according to any of 1) to 32), 61) to 66), or 79), wherein the compound is quinoline-2(1H)-one; 81) In general formula (I), R 2 C is substituted with 1 to 3 fluorine atoms. 1-10 Alkyl and unsubstituted C 1-10 A pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione, which may be substituted with 1 to 3 substituents selected from alkyl groups, as described, used, or composed according to any of 1) to 32), 61) to 66); 82) In general formula (I), R 2 The method, use, or composition according to any of 1) to 32), 61) to 66), or 81), wherein is pyrimidine-4(3H)-one or pyrimidine-2,4(1H,3H)-dione; 83) In general formula (I), R 3 and R 4 Of these, one is hydroxyl and the other is hydrogen, the method, use, or composition according to any of 1) to 32), 61) to 82); 84) In general formula (I), R 3 is halogen; cyano; carbamoyl; C 1-6 Alkoxy; C 1-6 Alkanoyloxy; amino; or acylamino, where the number of carbon atoms in the acyl moiety is 2 to 6, R 4 The method, use, or composition according to any one of 1) to 32), 61) to 82), wherein is hydrogen or hydroxyl; 85) In general formula (I), R 3 is hydroxy; carbamoyl; or C 1-6 With alkanoyloxy, R 4The method, use, or composition according to any of 1) to 32), 61) to 82), wherein the hydrogen is hydrogen; 86) In general formula (I), R 3 is hydroxy, R 4 The method, use, or composition according to any of 1) to 32), 61) to 82), wherein the hydrogen is hydrogen; 87) In general formula (I), R 3 and R 4 The method, use, or composition according to any of 1) to 32), 61) to 82), wherein the hydrogen is hydrogen; 88) Compounds represented by general formula (I) 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinoline-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-(epiminoetano)-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazine-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazine-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-(epiminoetano)-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one, as described, used, or composed in any of methods 1) to 32).

[0052] Next, the present invention will be described in more detail with reference to examples and embodiments, but the present invention is not limited to these. The names of the example compounds and reference example compounds were derived by first plotting the structural formulas using CambridgeSoft's ChemDraw ver.14, then converting them to English names using the software's built-in naming algorithm, and finally translating them into Japanese. The NMR data and measured mass spectrometry values ​​(ESI+ or ESI-) for Examples 1-34 are shown in Tables 1-5. [Examples]

[0053] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-10-ol

[0054] [ka]

[0055] (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole (372 mg, 1.02 mmol), synthesized by the method of Patent Document WO2013 / 035833 Example 67, was added to a 300 mL round-bottom flask, dissolved in dichloromethane (5 mL), and vigorously stirred at 0°C for 20 minutes. Then, 1.0 M boron tribromide / dichloromethane solution (5 mL, 5 mmol) was added and the mixture was stirred at room temperature for 30 minutes. Methanol (10 mL) was added to the reaction solution at 0°C and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, 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 collected organic layer was dried on anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (356 mg, 100%) as a brown foam.

[0056] [Alternative method] (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole (3.58 g, 9.82 mmol) and pyridine hydrochloride (87 g, 753 mmol), synthesized by the method of Patent Document WO2013 / 035833, Example 67, 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 potassium carbonate aqueous solution. The mixture was extracted with ethyl acetate and chloroform, and the collected organic layer was dried on anhydrous sodium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure to obtain 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).

[0057] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole

[0058] [ka]

[0059] (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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, 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 for 2 hours at room temperature. Since residual starting materials were found 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 it was extracted with a mixed solvent of ethyl acetate and hexane (1:1,100 mL). 6% aqueous ammonia (30 mL) was added to the aqueous layer to make it basic, and then it was extracted twice with a mixed solvent of ethyl acetate and hexane (1:1,100 mL). The collected organic layer was dried on anhydrous magnesium sulfate, insoluble materials were filtered off, and 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 obtain 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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).

[0060] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide

[0061] [ka]

[0062] (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-10-ol (31 mg, 87 μmol), 2-carboxypyridine 1-oxide (32 mg, 0.23 mmol), and HATU (125 mg, 0.33 mmol) were added to a 50 mL round-bottom flask. After suspension in THF (1.5 mL), triethylamine (70 μL, 0.50 mmol) and DMA (200 μL) were added and the mixture was stirred at room temperature for 1 hour. 2 mL of 2 N ammonia / methanol solution was added to the reaction mixture and 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 collected organic layer was washed with saturated brine, dried on anhydrous magnesium sulfate, and after filtering off insoluble matter, 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 eluents to obtain the title compound (18 mg, 44%) as a white solid.

[0063] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide

[0064] [ka]

[0065] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). The reaction solution was purified by column chromatography (silica gel, 10 g) using methanol and ethyl acetate containing 5% triethylamine (concentration gradient: 10%–50%) as the elution solvent. The obtained syrup was dissolved in methanol, then chloroform and tert-butyl methyl ether were added to form a powder, and the resulting mixture was filtered to obtain the title compound (30 mg, 62%) as a slightly brown solid.

[0066] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one

[0067] [ka]

[0068] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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) in the same manner as in Example 1. After stopping the reaction by adding a 2 N ammonia / methanol solution to the reaction solution, the mixture was 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 using 6% aqueous ammonia to obtain the title compound (13 mg, 25%) as a pale yellow powder.

[0069] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide

[0070] [ka]

[0071] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, the solution was concentrated under reduced pressure, and the residue was purified by direct column chromatography (silica gel, 25 g) using 0.1 N ammonia / methanol solution and chloroform (concentration gradient: 0%–50%) as the eluent. The obtained syrup was dissolved in methanol, then tert-butyl methyl ether was added and the mixture was powdered. The resulting liquid was then filtered to obtain the title compound (14 mg, 31%) as a slightly brown amorphous material.

[0072] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one

[0073] [ka]

[0074] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was purified by direct column chromatography (silica gel, 10 g) using a 0.1 N ammonia / methanol solution and chloroform (concentration gradient: 1%–50%) as the eluent. To remove impurities, the obtained compound was suspended in chloroform and washed with 6% aqueous ammonia. After extracting the aqueous layer with chloroform, the combined organic layers were dried on anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (14 mg, 30%) as a pale yellow powder.

[0075] Reference example 2 Synthesis of 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[0076] [ka]

[0077] This compound was synthesized by a method in accordance with 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, suspended in methanol (5 mL) and water (0.8 mL), then potassium hydroxide (400 mg, 7.13 mmol) was added and the mixture was stirred at 100°C for 15 minutes. The reaction solution was allowed to return to room temperature, iodomethane (2.6 mL, 41.8 mmol) was added and the mixture was stirred at 100°C for 45 minutes, after which it was concentrated under reduced pressure until the solvent volume was halved. 3 N hydrochloric acid (20 mL) was added to the reaction solution, the resulting solid was filtered, washed with water and acetonitrile, and then dried under reduced pressure to obtain 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).

[0078] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one

[0079] [ka]

[0080] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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. After stopping the reaction by adding a 1.4 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in a saturated aqueous sodium bicarbonate solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC with a 1.4 N ammonia / methanol solution-chloroform (concentration: 5%) as the developing solvent, and the title compound (26.2 mg, 63%) was obtained as a pale yellow amorphous material.

[0081] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one

[0082] [ka]

[0083] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was purified by direct column chromatography (amino silica gel, 10 g) using methanol and chloroform (concentration gradient: 0%–30%) as eluents. The resulting syrup was dissolved in methanol, tert-butyl methyl ether was added, and the mixture was powdered to obtain the title compound (83 mg, 94%) as a brown solid.

[0084] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridine-2(1H)-one

[0085] [ka]

[0086] The reaction was carried out using the same method 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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. After stopping the reaction by adding a 1.4 N ammonia / methanol solution to the reaction solution, the mixture was concentrated under reduced pressure. The residue was purified by preparative TLC using a 1.4 N ammonia / methanol solution-chloroform (concentration: 10%) as the developing solvent. To further remove impurities, the resulting solid was suspended in saturated potassium carbonate aqueous solution and extracted with chloroform. The organic layer was dried on anhydrous sodium sulfate, and inorganic materials were filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound. The obtained compound was prepared as a hydrochloride salt according to Example 32 for use in biological activity testing.

[0087] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one

[0088] [ka]

[0089] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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) in the same manner as in Example 1. However, dichloromethane was used as the solvent instead of THF and DMA. After stopping the reaction by adding a 1.4 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in a saturated aqueous sodium bicarbonate solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC with methanol and chloroform (concentration: 10%) as the developing solvent to obtain the title compound (31.1 mg, 75%) as a white amorphous material.

[0090] Reference example 3 Synthesis of 1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0091] [ka]

[0092] 6-oxo-1,6-dihydropyridine-2-carboxylic acid (500 mg, 3.59 mmol) was added to a 50 mL round-bottom flask, suspended in methanol (5 mL) and water (0.8 mL), then potassium hydroxide (400 mg, 7.13 mmol) was added and the mixture was stirred at 100°C for 15 minutes. The reaction solution was allowed to return to room temperature, iodomethane (2.6 mL, 41.8 mmol) was added and the mixture was stirred at 100°C for 1 hour, after which it was concentrated under reduced pressure until the solvent volume was halved. 3 N hydrochloric acid was added to the reaction solution, the resulting solid was filtered, washed with water and acetonitrile, and then dried under reduced pressure to obtain 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).

[0093] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one

[0094] [ka]

[0095] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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. After stopping the reaction by adding a 1.4 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in a saturated aqueous sodium bicarbonate solution, extracted with chloroform, and the organic layer was dried over anhydrous sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC with methanol and chloroform (concentration: 10%) as the developing solvent to obtain the title compound (32.7 mg, 79%) as a white amorphous material.

[0096] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one

[0097] [ka]

[0098] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, it was concentrated 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 layers were dried on anhydrous magnesium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (aminosilica gel, 16 g) using methanol and chloroform containing 10% concentrated ammonia water as the eluent solvent to obtain ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-yl)(2-methoxypyridine-4-yl)methanone (61 mg, 82%) as a white solid.

[0099] 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). To a 100 mL round-bottom flask, the above-mentioned ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-yl)(2-methoxypyridine-4-yl)methanone (48 mg, 98 μmol) and pyridine hydrochloride (2.88 g, 25 mmol) were added and heated and stirred at 200 °C for 10 minutes. After the reaction solution cooled to room temperature, it was suspended in 6% aqueous ammonia and extracted with ethyl acetate. The collected organic layer was dried on anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (amino silica gel, 8g) using methanol and chloroform (concentration gradient: 0%–30%) as eluents to obtain the title compound (35mg, 75%) as a white solid.

[0100] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione

[0101] [ka]

[0102] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding a 2 N ammonia / methanol solution to the reaction solution, the mixture was concentrated under reduced pressure, and the resulting residue was suspended in saturated sodium bicarbonate aqueous solution and extracted three times with a 5:1 mixed solution of chloroform and methanol. The collected organic layer was dried on anhydrous sodium sulfate, and after filtering off insoluble matter, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 25%) containing 10% concentrated aqueous ammonia as the developing solvent, and the title compound (16 mg, 35%) was obtained as a white solid.

[0103] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one

[0104] [ka]

[0105] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, the mixture was suspended in saturated sodium bicarbonate aqueous solution and extracted three times with ethyl acetate. The collected organic layer was dried on anhydrous sodium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol and chloroform (concentration: 15%) containing 10% concentrated aqueous ammonia as the developing solvent, and the title compound (19 mg, 44%) was obtained as a white solid.

[0106] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-4(1H)-one

[0107] [ka]

[0108] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, the solution was suspended in saturated sodium bicarbonate aqueous solution and extracted three times with a 5:1 mixed solution of chloroform and methanol. The collected organic layer was dried on anhydrous sodium sulfate, and after filtering off insoluble matter, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 15%) containing 10% concentrated aqueous ammonia as the developing solvent, and the title compound (8 mg, 20%) was obtained as a white solid.

[0109] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one

[0110] [ka]

[0111] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, the mixture was suspended in saturated sodium bicarbonate aqueous solution and extracted three times with chloroform. The collected organic layer was dried on anhydrous sodium sulfate, and after filtering off insoluble matter, the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC with methanol and chloroform (concentration: 5%) as the developing solvent to obtain the title compound (41 mg, 94%) as a white solid.

[0112] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazine-3(2H)-one

[0113] [ka]

[0114] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried on anhydrous magnesium sulfate. After filtering off the insoluble material, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform (concentration gradient: 0%–30%) as the elution solvent to obtain the title compound (27 mg, 66%) as a white solid.

[0115] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinoline-2(1H)-one

[0116] [ka]

[0117] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried on anhydrous magnesium sulfate. After filtering off the insoluble material, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform (concentration gradient: 0%–30%) as the elution solvent to obtain the title compound (28 mg, 56%) as a white solid.

[0118] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one

[0119] [ka]

[0120] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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) in the same manner as in Example 1. However, dichloromethane was used as the solvent instead of THF and DMA. One hour after the start of the reaction, 1 N hydrochloric acid was added to the reaction solution and the mixture was further stirred. After stopping the reaction by adding an aqueous potassium carbonate solution to the reaction solution, the mixture was extracted with chloroform, the organic layer was dried on sodium sulfate, and the insoluble material was filtered off. The filtrate was then concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 5%) as the developing solvent to obtain the title compound (4.0 mg, 15%) as a brown amorphous material.

[0121] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one

[0122] [ka]

[0123] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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. After stopping the reaction by adding 2 N methylamine / methanol solution (0.3 mL, 0.6 mmol) to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in a saturated aqueous sodium bicarbonate solution, extracted with chloroform, and the organic layer was dried on anhydrous sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC with methanol and chloroform (concentration: 10%) as the developing solvent to obtain the title compound (4.4 mg, 16%) as a brown amorphous material.

[0124] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-4(1H)-one

[0125] [ka]

[0126] The reaction was carried out using the same method 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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. After stopping the reaction by adding 2 N methylamine / methanol solution (3.0 mL, 6.0 mmol) to the reaction solution, the solution was concentrated under reduced pressure. The residue was suspended in a saturated potassium carbonate aqueous solution, extracted with chloroform, and the organic layer was dried on anhydrous sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (concentration gradient: 0%–10%) as eluents to obtain the title compound (19 mg, 68%) as a light brown amorphous material.

[0127] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one

[0128] [ka]

[0129] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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) in the same manner as in Example 1. However, dichloromethane was used as the solvent instead of THF and DMA. After stopping the reaction by adding a 1.4 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in an aqueous potassium carbonate solution, extracted with chloroform, and the organic layer was dried on anhydrous sodium sulfate. Insoluble materials were filtered off, and 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: 5%–30%) as eluents to obtain the title compound (12.2 mg, 45%) as a light brown amorphous material.

[0130] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide

[0131] [ka]

[0132] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-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). Then, triethylamine (45 μL, 0.32 mmol) and acetyl chloride (15 μL, 0.21 mmol) were added and the mixture was stirred at room temperature for 1 hour. Since residual starting material was confirmed 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. A saturated sodium bicarbonate aqueous solution and ethyl acetate were added to the reaction solution and vigorously stirred for 20 minutes. The aqueous layer was then separated and extracted with ethyl acetate. The collected organic layer was dried on anhydrous magnesium sulfate, and the insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (51 mg, 89%) as a yellow amorphous material.

[0133] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one

[0134] [ka]

[0135] Following the same procedure as in Example 1, 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-(epiminoetano)-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia and extracted with ethyl acetate, and the organic layer was dried on anhydrous magnesium sulfate. After filtering off the insoluble material, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (concentration gradient: 0%–20%) as eluents. The resulting compound was dissolved in methanol, tert-butyl methyl ether was added, and the mixture was powdered to obtain the title compound (24 mg, 67%) as a white solid.

[0136] Reference example 4 Synthesis of 3-oxo-3,4-dihydropyrazine-2-carboxylic acid

[0137] [ka]

[0138] This compound was synthesized using the method described in Patent Document WO2009 / 033084, and its 1H NMR spectrum matched the data described in the reference 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. Sodium nitrite (149 mg, 2.16 mmol) dissolved in concentrated sulfuric acid (1.6 mL) was added dropwise under ice bath conditions, and the mixture was stirred for 1 hour. The reaction solution was added to ice water and stirred vigorously, and the resulting solid was collected by filtration. The obtained solid was dried under reduced pressure at 60°C for 1 hour to obtain 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).

[0139] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazine-2(1H)-one

[0140] [ka]

[0141] The reaction was carried out using the same method 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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) instead of HATU, and DMF was used instead of THF as the solvent. The reaction was stopped by adding a 1.4 N ammonia / methanol solution to the reaction solution, then extracted with chloroform and washed with saturated ammonium chloride aqueous solution followed by saturated sodium bicarbonate aqueous solution. The organic layer was dried on anhydrous sodium sulfate, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC with methanol and chloroform (concentration: 20%) as the developing solvent to obtain the title compound (5.9 mg, 22%) as a pale yellow amorphous material.

[0142] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione

[0143] [ka]

[0144] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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) instead of HATU, and DMF was used instead of THF as the solvent. After stopping the reaction by adding a 1.4 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient: 5%–30%) as eluents. To remove impurities, the obtained compound was suspended in chloroform and aqueous ammonia, then filtered to obtain the title compound (2.5 mg, 9%) as a slightly brown amorphous material.

[0145] Reference example 5 Synthesis of 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

[0146] [ka]

[0147] 6-oxo-1,6-dihydropyridine-2-carboxylic acid (129 mg, 925 μmol) and 1,1-diethoxy-N,N-dimethylmethaneamine (1.5 mL) were added to a 30 mL round-bottom flask and stirred at 100 °C for 2 hours. After cooling the reaction solution to room temperature, it was concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient 0%-20%) as eluents to obtain ethyl 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (104 mg, 58%) as a colorless oily substance. 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). Then, 200 μL, 1.0 mmol, aqueous sodium hydroxide solution (5 N) was added, and the mixture was stirred at 55 °C for 2 hours. After the reaction solution was allowed to cool to room temperature, 400 μL, 2.0 mmol, 5 N hydrochloric acid was added to make it acidic, and the mixture was concentrated under reduced pressure. Ethanol (3 mL) was added to the residue, and the mixture was concentrated under reduced pressure. After suspending the residue in ethanol (3 mL), insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain 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).

[0148] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one

[0149] [ka]

[0150] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After stopping the reaction by adding 2 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried on anhydrous magnesium sulfate. After filtering off the insoluble matter, 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 eluents. The obtained compound was dissolved in methanol, tert-butyl methyl ether was added, and the mixture was powdered to obtain the title compound (35 mg, 76%) as a white solid.

[0151] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-4(3H)-one

[0152] [ka]

[0153] The reaction was carried out using the same method as in Example 1, with (1S,3aR,5aS,6R,11bR,11cS)-10-((tert-butyldimethylsilyl)oxy)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-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). However, HOAt (19 mg, 0.14 mmol) was used instead of triethylamine, WSC (27 mg, 0.14 mmol) instead of HATU, and DMF was used instead of THF as the solvent. The residue was suspended in water, extracted with ethyl acetate, and the organic layer was dried on anhydrous sodium sulfate. Insoluble materials were filtered off, and 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 eluents. The solid obtained above, methanol (2 mL), and aqueous ammonia solution were added to a 100 mL round-bottom flask and stirred at room temperature for 3 days. After concentrating the reaction solution, the residue was suspended in chloroform, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC with methanol and chloroform (concentration: 20%) as the developing solvent to obtain the title compound (1.7 mg, 6%) as a white amorphous material.

[0154] Reference example 6 Synthesis of 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

[0155] [ka]

[0156] To a mixture of 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 the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, and the insoluble matter was filtered off. The mixture was then extracted with hexane and washed with saturated sodium bicarbonate aqueous solution. The collected organic layer was dried on sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methanol (10 mL) with ethylamine hydrochloride (112 mg, 1.37 mmol), triethylamine (520 μL, 3.73 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction, the mixture was concentrated under reduced pressure, and the resulting residue was extracted with saturated sodium bicarbonate aqueous solution and chloroform, and washed with saturated brine. The collected organic layer was dried on anhydrous sodium sulfate, and insoluble matter 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 eluents to obtain 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid benzyl (126 mg, 2-step 34%) as a pale yellow amorphous material. The 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid benzyl obtained above was dissolved in methanol (2 mL) and ethyl acetate (2 mL), and 10% palladium carbon was added. The mixture was then stirred at room temperature under a hydrogen atmosphere for 2 hours. After the reaction, the insoluble material was filtered through Celite, and the resulting solution was concentrated to obtain the title compound (73 mg, 89%) as a pale yellow amorphous material. 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).

[0157] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridine-2(1H)-one

[0158] [ka]

[0159] The reaction was carried out using the same method 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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. After stopping the reaction by adding a 1.4 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in a saturated aqueous sodium bicarbonate solution, extracted with chloroform, and the organic layer was dried on anhydrous sodium sulfate. Insoluble materials were filtered off, and 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%–30%) as eluents to obtain the title compound (13.3 mg, 62%) as a white amorphous material.

[0160] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide hydrochloride

[0161] [ka]

[0162] 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-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, dissolved in ethanol (2 mL), and then 2 N hydrochloric acid (1 mL) was added to obtain the resulting solution, which was concentrated under reduced pressure. The resulting residue was dried under reduced pressure at 80°C for 18 hours to obtain the title compound (85 mg, 99%) as a white amorphous material.

[0163] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one hydrochloride

[0164] [ka]

[0165] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (44 mg, 93 μmol) synthesized in Example 3 was added to a 50 mL round-bottom flask and dissolved in 2 mL of 2 N hydrochloric acid. The resulting solution was concentrated under reduced pressure. The resulting residue was dried under reduced pressure at 100 °C for 18 hours to obtain the title compound (40 mg, 84%) as a yellow solid.

[0166] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one hydrochloride

[0167] [ka]

[0168] 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one (26 mg, 54 μmol) synthesized in Example 6 and ethyl acetate were added to a 10 mL test tube. Extraction was performed using 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 obtain the title compound (23 mg, 83%) as a pale yellow amorphous material.

[0169] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridine-2(1H)-one hydrochloride

[0170] [ka]

[0171] To a 10 mL test tube, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridine-2(1H)-one and ethyl acetate were added, and the mixture was extracted with 1 N hydrochloric acid. The aqueous layer was concentrated under reduced pressure. The resulting residue was dried under reduced pressure to obtain the title compound (11 mg, 39% from Example 8, 2 steps) as a pale yellow amorphous material.

[0172] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one hydrochloride

[0173] [ka]

[0174] 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one (31 mg, 64 μmol) synthesized in Example 9 and ethyl acetate were added to a 10 mL test tube. Extraction was performed using 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 obtain the title compound (22 mg, 67%) as a pale yellow amorphous material.

[0175] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one hydrochloride

[0176] [ka]

[0177] 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one (33 mg, 67 μmol) synthesized in Example 10 and ethyl acetate were added to a 10 mL test tube. Extraction was performed using 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 obtain the title compound (33 mg, 94%) as a light brown amorphous material.

[0178] [Table 1]

[0179] [Table 2]

[0180] [Table 3]

[0181] [Table 4]

[0182] [Table 5]

[0183] Reference example 7-1 Synthesis of (1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid 2,2,2-trichloroethyl

[0184] [ka]

[0185] (1S,3aR,5aS,6R,11bR,11cS)-10-methoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid 2,2,2-trichloroethyl (972.7 mg, 2.00 mmol), synthesized by the method described in WO2014136305, Example 34(1), was added to a 100 mL round-bottom 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 while vigorously stirring, and the mixture was stirred for 1 hour while raising the temperature to room temperature. After adding saturated sodium bicarbonate aqueous solution (30 mL) to the reaction solution, it was extracted with chloroform (20 mL x 3). The collected organic layer was dried on anhydrous sodium sulfate, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (1.04 g, >100%) as a white foam. The crude product was used directly in the next reaction without further purification.

[0186] Reference example 7-2 (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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid synthesis of 2,2,2-trichloroethyl

[0187] [ka]

[0188] (1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid, synthesized in Reference Example 7-1, was added to a 100 mL round-bottom 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 sodium bicarbonate aqueous solution (50 mL) and then extracted with ethyl acetate (30 mL x 2). The collected organic layer was dried over anhydrous sodium sulfate, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure to obtain the title compound (1.46 g, >100%) as a white foam. The crude product was used directly in the next reaction without further purification.

[0189] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-14-yl)ethane-1-one

[0190] [ka]

[0191] To a 100 mL round-bottom flask, (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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid, 2,2,2-trichloroethyl (1.46 g) was added 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 azeotropically mixed with toluene. The residue was diluted with saturated sodium bicarbonate aqueous solution (30 mL) and extracted with chloroform (30 mL x 3). The collected organic layer was dried on anhydrous sodium sulfate, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography (aminosilica gel: 16 g) using ethyl acetate and methanol (concentration gradient 0%-30%) as eluents to obtain the title compound (215 mg, 3 steps, total yield 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).

[0192] Reference example 8-1 Synthesis of ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate

[0193] [ka]

[0194] This compound was synthesized according to the method described in WO2011 / 090935. 60 mL of 20% sodium ethoxide / ethanol solution and 10.5 mL, 524 mmol of ethyl 2-(ethoxymethylene)malonate were added to a 500 mL round-bottom flask and stirred at room temperature for 10 minutes. 5.1 mL, 104 mmol of hydrazine monohydrate was added to the resulting mixture and heated at 80°C for 18 hours with stirring. The resulting yellow suspension was then cooled to 0°C. 180 mL of 1N hydrochloric acid was slowly added to the vigorously stirred reaction mixture at the same temperature to obtain a yellow solution. 150 mL of ethyl acetate was added to the solution and stirred at room temperature for 1 hour. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL x 2). The collected organic layer was dried over anhydrous sodium sulfate, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was crystallized using ethyl acetate and hexane to obtain the title compound (2.82 g, 35%) as yellow crystals (a mixture of tautomers). Mass spectrometry ES MH=155

[0195] Reference example 8-2 Synthesis of 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid

[0196] [ka]

[0197] 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate ethyl (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 the mixture was stirred at room temperature for 22 hours. Under ice cooling, water was added to the reaction solution, and it was extracted three times with ethyl acetate. The collected organic layer was dried on 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 eluents to obtain 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate ethyl (51 mg, 22%) as a white solid.

[0198] 51 mg, 0.279 mmol of ethyl 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (prepared as described above) was added to a 50 mL round-bottom flask and dissolved in ethanol (1 mL). Then, 0.5 mL, 2.50 mmol of 5 N aqueous sodium hydroxide solution was added and the mixture was stirred at room temperature for 3 days. 2.7 mL of 1 N hydrochloric acid 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 obtain 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).

[0199] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one

[0200] [ka]

[0201] To a 10 mL test tube, 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]indole-14-yl)ethane-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) were added. After suspension in THF (2 mL), triethylamine (100 μL, 0.72 mmol) and DMA (100 μL) were added and the mixture was stirred at room temperature for 1.5 hours. Ethanolamine (100 μL) and methanol (2 mL) were added to the reaction mixture and 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 collected aqueous layer was extracted with chloroform (20 mL). The collected organic layer was dried on anhydrous magnesium sulfate, insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 16 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one (M+H=514.26) as a white foamy substance. 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one obtained above was dissolved in methanol (5 mL) in a 100 mL round-bottom flask, sodium borohydride (124 mg, 3.26 mmol) was added, and the mixture was stirred at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, the residue was suspended in 6% aqueous ammonia (20 mL), and washed with chloroform (20 mL x 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. The result was 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)pyridine-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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one was obtained. The resulting mixture was dissolved in 3 mL of concentrated ammonia water in a 50 mL round-bottom flask, sealed with a rubber stopper, and heated and stirred 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 eluents. The resulting crude product was powdered using methanol (0.2 mL) and t-butyl methyl ether (3 mL) to obtain the title compound (23 mg, 41%).

[0202] 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).

[0203] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazole-3-one

[0204] [ka]

[0205] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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), except that only THF (2 mL) was used as the solvent. After stopping the reaction by adding a 1.4 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in saturated sodium bicarbonate solution, extracted with chloroform, and the organic layer was dried over sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (silica gel, 10 g) using methanol and ethyl acetate (concentration gradient: 0%–30%) as eluents to obtain ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-yl)(3-methoxy-1-methyl-1H-pyrazole-4-yl)methanone (33.3 mg, 80%) as a pale yellow amorphous material. 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).

[0206] To a 30 mL round-bottom flask, the ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-yl)(3-methoxy-1-methyl-1H-pyrazole-4-yl)methanone (15 mg, 31 μmol) obtained above was added, dissolved in methylene chloride (1 mL), and under ice cooling, 1.0 M boron tribromide / methylene chloride solution (153 μL, 0.15 mmol) was added and the mixture was stirred at room temperature for 1 hour. After stopping the reaction by adding 1.4 N ammonia / methanol solution, the mixture was concentrated under reduced pressure. The residue was suspended in saturated sodium bicarbonate solution, extracted with chloroform, and the organic layer was dried over sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol containing ammonia water and chloroform (concentration: 10%) as the developing solvent, and the title compound (10.6 mg, 73%) was obtained as a pale yellow amorphous material. 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).

[0207] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one

[0208] [ka]

[0209] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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) according to the same procedure as in Example 1. However, only THF (1 mL) was used as the solvent. After stopping the reaction by adding a 1.4 N ammonia / methanol solution to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in saturated sodium bicarbonate solution, extracted with chloroform, and the organic layer was dried over sodium sulfate. Insoluble materials were filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (amino silica gel, 8 g) using methanol and ethyl acetate (concentration gradient: 0%-80%) as eluents to obtain the title compound (11.6 mg, 40%) as a brown amorphous material. 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).

[0210] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione

[0211] [ka]

[0212] Following the same procedure as in Example 1, 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-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). After adding 2 N ammonia / methanol solution to the reaction solution to stop the reaction, the solution was concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia (20 mL) and extracted with ethyl acetate (15 mL x 2). The collected organic layer was washed with saturated brine (10 mL) and dried on anhydrous magnesium sulfate. After filtering off insoluble matter, 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 eluents. The resulting syrup-like substance was dissolved in methanol (0.2 mL), t-butyl methyl ether (3 mL) was added to powderize it, and the resulting liquid was filtered to obtain 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).

[0213] 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-(epiminoetano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one

[0214] [ka]

[0215] The experiment was conducted using the same method as in Example 1. The reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoetano)-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). After adding ethanolamine (200 μL) and methanol (1 mL) to the reaction solution to stop the reaction, the solution was 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 collected organic layer was dried on anhydrous sodium sulfate. After filtering off insoluble matter, 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 eluents. The resulting syrup-like substance was dissolved in methanol (0.2 mL), and then t-butyl methyl ether (3 mL) was added to powderize it. The resulting powder was dried under reduced pressure at 100°C for 16 hours to obtain 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).

[0216] Example 40 Opioid receptor function test The functional activity of the compounds provided by this invention against μ, δ, and κ opioid receptors was investigated. Methods: The Lance Ultra cAMP kit (PerkinElmer) was used, and the procedure was followed according to the specified method. For evaluation of agonist activity, CHO cells expressing each human opioid receptor (δ, μ, and κ: accession numbers and catalog numbers are listed below) and the test compound were reacted for 30 minutes in assay buffer (1×HBSS, 1M HEPES, pH 7.4, 250 mM IBMX (Isobutylmethylxanthine), 7.5% BSA) in the presence of 10 μM forskolin. Subsequently, the cAMP detection reagent from the kit was added, and time-resolved fluorescence measurements were performed after 1 hour using an EnVision plate reader (PerkinElmer). The test compound and each control drug (δ: SNC80, μ: DAMGO, κ: U-69593) were 10 -12 ~10 -5 The evaluation was performed within the concentration range of M, and the dose-response curve of the test compound was determined from the fluorescence value at 665 nm, and the EC 50 Value and E max The value was calculated. E max The value was determined as the percentage of the maximum reaction of the test compound compared to the maximum reaction of each control drug, which was set to 100%. SNC80: (+)-4-[(α R)-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]decy-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)

[0217] [Table 6]

[0218] NC: The maximum reaction was not reached at the highest concentration (10 μM), therefore ED 50 The value was not calculated. * Since the maximum reaction was not achieved at the highest concentration, the reaction rate at the highest concentration is shown as a reference value. As shown in Table 6, the compounds of the present invention were confirmed to have potent agonist activity against opioid δ receptors, and to have no agonist activity or only very weak agonist activity against μ and κ receptors.

[0219] Example 41 Mouse elevated cross maze test (Test method) Male C57BL / 6N mice aged 5-6 weeks were used in the study. A 40 cm high cross maze device consisting of an open path (6 cm wide, 30 cm long) and a walled path (6 cm wide, 30 cm long, wall height 15 cm) was used. Mice were placed facing the walled path and allowed to enter the cross maze voluntarily. 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 study. Video recording was started at the beginning of the study, and the start of the study was defined as the moment the mouse entered the cross maze. Five minutes of exploratory behavior was recorded. Based on the video footage, the time spent in each path was determined, and the percentage of time spent in the open path 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 time spent on the wallless running path when administered subcutaneously at 3 mg / kg and 10 mg / kg, respectively, confirming an anxiolytic-like effect. Furthermore, compounds 3 (compound described in Example 3), 9 (compound described in Example 9), and 10 (compound described in Example 10) showed a tendency to extend the time spent on the wallless running path (Figures 3-5).

[0220] Example 42 Rat elevated cruciform maze test The anxiolytic effect of the compounds provided in this invention was investigated using a rat elevated cusp maze test. (Test method) Male Wistar rats aged 7-9 weeks were used in the study. A 50cm high cross maze device consisting of an open path (10cm wide, 50cm long) and a walled path (10cm wide, 50cm long, wall height 30cm) was used. Rats were placed facing the walled path and allowed to enter the cross maze voluntarily, and their exploratory behavior was observed for 5 minutes. The test substance was dissolved in a 4.5% cyclodextrin aqueous solution and administered orally 2 hours before the start of the study. The test data was automatically analyzed using video image behavior analysis software (PanLab Smart3.0, PanLab SL), and the percentage of time spent in the open path 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 rate of time spent on the wallless running path when administered orally at 3 mg / kg, confirming that they exhibit anxiolytic-like effects.

[0221] Example 43 hERG (human ether-a-go-go related gene) potassium channel inhibition test (Test method) The tests were performed using hERG channel-stable expressing CHO cells (purchased from the Channelopathy Foundation) with a Port-a-Patch autopatch clamp device (Nanion Technologies). The hERG current was confirmed by maintaining the cell membrane potential at -80 mV, followed by a +20 mV depolarization pulse for 1.5 seconds, and then a -50 mV test pulse for 1.5 seconds, applied every 10 seconds. The tail current induced by the test pulse was then measured. The test compound was dissolved in extracellular fluid (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM gCl2, 10 mM D(+)-glucose, 10 mM HEPES, pH 7.4) and perfused at room temperature for 5 minutes. The inhibition rate was calculated as the ratio of the tail current value after compound application to the maximum tail current value before compound application (set as 100%). The study used cells with a peak tail current of 300 pA or higher, a tail current run-down of less than 10% of the initial current value, and a leakage current of less than 200 pA.

[0222] (Test results) Table 7 shows the test results. In the table, compounds 1, 3, 7, 9, and 10 are the compounds described in Examples 1, 3, 7, 9, and 10, respectively. As is clear from Table 7, all of the test compounds showed only weak inhibitory activity. On the other hand, it was found that some compounds described in WO 2013 / 35833 (Patent Document 4) exhibit strong hERG inhibitory activity.

[0223] [Table 7]

[0224] Comparative compound 1: Example 93 of WO 2013 / 35833 (compound 104) Comparative compound 2: Example 205 (compound 267) of WO 2013 / 35833

[0225] Example 44 Emotional hyperresponse suppression test in olfactory bulbectomy model (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 prepared by surgically removing the rat olfactory bulb and then housing the rats in isolation, according to [1208:160-169.]. Emotional hyperresponsiveness was evaluated before group division on postoperative day 14, and 2 hours after administration on days 1, 4, 7, 10, and 14, according to the emotional hyperresponsiveness evaluation criteria developed by Gomita et al. (Gomita 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 solvent. (Test results) Administration of 0.1 mg / kg of the test substance (compound described in Example 7 above) significantly reduced the emotional hyperresponsiveness of OBX rats compared to the solvent-administered group from day 4 of administration, and restored it to a level comparable to that of the sham surgery group rats by day 7. Administration of 1 mg / kg of the test substance significantly reduced the emotional hyperresponsiveness of OBX rats compared to the solvent-administered group from day 1 of administration, and restored it to a level comparable to that of the sham surgery group rats by day 4 of administration. These effects persisted until day 14. On the other hand, administration of 10 mg / kg of fluoxetine significantly reduced the emotional hyperresponsiveness of OBX rats compared to the solvent-administered group on day 14 of administration. Based on the above analysis, it was suggested that the test substance may exhibit antidepressant-like effects from a single dose, unlike SSRIs, suggesting that the test substance has a faster onset of antidepressant effects compared to SSRIs. Furthermore, it was suggested that tolerance to the test substance's antidepressant-like effects may not develop.

[0226] Example 45 Reserpine-induced Parkinson's disease model mouse (Test method) ICR male mice (5 weeks old: Japanese SLC) were obtained and used after an acclimatization 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 study. The study was conducted by subcutaneously administering the test compound on the day of the study, immediately placing the subjects in a spontaneous motility activity cage, and measuring the distance traveled over 60 minutes. (Test results) Administration of 10 mg / kg of the test substance (compound described in Example 7 above) showed a significant increase in exploratory behavior, and also a non-significant (P=0.16) tendency towards increased standing behavior, suggesting that the test substance has a therapeutic effect on Parkinson's disease.

[0227] Example 46 Evaluation using a rat stroke-induced overactive bladder model (Test method) A transient middle cerebral artery occlusion model was created using 8-week-old male SD rats under isoflurane inhalation anesthesia. The following day, under isoflurane inhalation anesthesia again, a small incision was made in the neck, and a catheter for administration was placed in the jugular vein and guided to the back. Cystometry was also performed, and the other end of a cannula inserted into the bladder was guided to the back and connected to a sieve. Cystometry was performed four days after cerebral ischemia surgery under unanesthetized and unrestrained conditions. After measuring bladder pressure for a stable period, the medium was administered intravenously, and the pre-administration value was measured for approximately 30 minutes. Subsequently, the test substance was administered intravenously in increasing and decreasing doses at approximately 30-minute intervals, and the post-administration value was measured for approximately 30 minutes. Animals judged to have frequent urination (voiding interval of 10 minutes or less) in the pre-administration measurements were selected, and resting pressure, voiding pressure, voiding interval, and single void volume were calculated at each time point. (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 resting pressure or voiding pressure at any dose. On the other hand, the voiding interval and the amount of urine per void tended to increase in a dose-dependent manner, suggesting that the test substance has an effect on improving frequent urination.

[0228] [Table 8] Mean ± SE (n=5)

[0229] Example 47 Metabolic stability test (Test method) Human liver microsomes and the test substance were reacted for a set period of time (0-60 min), and the amount of unchanged test substance remaining in the reaction sample was measured to determine the retention rate. The retention rate of the unchanged substance at reaction time 0 was set to 100%, and the retention rate after incubation was plotted log-linearly against time, and the regression line (y=100e) was used. -kt , where k = slope of the line: elimination rate constant, is determined, and metabolic clearance CL is calculated using the following formula. int The (mL / min / kg) was calculated. CLint * = 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.

[0230] [Table 9]

[0231] Comparative compound 1: Example 93 of WO 2013 / 35833 (compound 104) As is clear from Table 9, the compounds of the present invention have demonstrated excellent metabolic stability. On the other hand, it was found that some compounds described in WO 2013 / 35833 (Patent Document 4) exhibit poor metabolic stability.

Claims

[Claim 1] The following general formula (I): 【Chemistry 1】 (In the formula, R １ is hydrogen; C １－１０ Alkyl; C ６－１０ Ariel; C ２－６ Alkenyl; Cycloalkylalkyl, where the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; Aralkyl, where the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; C ３－６ This represents a cycloalkyl or heteroaryl alkyl group in which the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms, and the alkylene portion has 1 to 5 carbon atoms. R ２ This represents a heterocycle comprising 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring constituent atoms, wherein at least one pair of adjacent ring constituent atoms has a double bond and is further substituted with at least one oxo group. Here, R ２ is R ２ It is bonded to Y via the carbon atoms that make up the ring, R ３ , R ４ and R ５ are the same or different and represent 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 arylamino or acylamino having 2 to 6 carbon atoms in the acyl moiety, R ６ａ and R ６ｂ is the same or different, representing hydrogen; fluorine or hydroxyl, or R ６ａ and R ６ｂ Together they represent = O, R ７ and R ８ These are identical or distinct, representing hydrogen; fluorine or hydroxyl, R ９ and R １０ are the same or different, hydrogen; C １－６ Alkyl; C ６－１０ Aryl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; Aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; Heteroarylalkyl having 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms in the heteroaryl portion and 1 to 5 carbon atoms in the alkylene portion; Cycloalkylalkyl or C having 3 to 6 carbon atoms in the cycloalkyl portion and 1 to 5 carbon atoms in the alkylene portion. ２－６ Representing Alkenil, X is O or CH ２ This represents, And Y represents C (=O). However, R １ C １－１０ Alkyl; the alkylene and cycloalkyl portions of cycloalkylalkyls where the number of carbon atoms in the cycloalkyl portion is 3 to 6 and the number of carbon atoms in the alkylene portion is 1 to 5; the alkylene portion of aralkyls where the number of carbon atoms in the aryl portion is 6 to 10 and the number of carbon atoms in the alkylene portion is 1 to 5; and the alkylene portion of heteroarylalkyls where the heteroaryl portion contains 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms and the number of carbon atoms in the alkylene portion is 1 to 5, has 1 to 6 Halogen; Hydroxyl; C １－６ Alkoxy; C 6－１０ Aryloxy; C １－６ Alkanoyl; C １－６ Alkanoyloxy; carboxyl; alkoxycarbonyl with 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl; alkylcarbamoyl with 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl with 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl with 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl; alkylsulfinyl with 1 to 6 carbon atoms in the alkyl moiety; alkylthio with 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens １－６ Alkoxy; may be substituted with at least one substituent selected from arylcarbonyls having 6 to 10 carbon atoms in the aryl portion. And R １ C ６－１０ Aryl; the aryl portion of an aralkyl molecule where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms; 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; heteroaryls containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; aryl moieties of aralkyls having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and heteroaryl alkyls having 1 to 4 heteroatoms selected from N, O, and S as ring constituent 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 with 1 to 6 carbon atoms in the alkoxy portion; Carbamoyl; Alkylcarbamoyl with 1 to 6 carbon atoms in the alkyl portion; Dialkylcarbamoyl with 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 It may also be substituted with at least one substituent selected from alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring constituent atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; or methylenedioxy. R ２ The heterocycle has an oxo group, as well as the R group mentioned above. １ C ６－１０ The aryl may have substituents that it may have, Furthermore R １ C １－１０ In the case of alkyl, NR １１ R １２ It may be replaced with R here １１ and R １２ are the same or different, hydrogen; C １－１０ Alkyl; or aryl moiety with 6 to 10 carbon atoms and alkylene moiety with 1 to 5 carbon atoms, or R １１ and R １２ And, R １１ and R １２ The nitrogen atom to which it is bonded, and optionally one or two heteroatoms, may come together to form a 5-7 membered ring, and also R １ The alkylene portion of the aralkyl, where the aryl portion has 6 to 10 carbon atoms and the alkylene portion has 1 to 5 carbon atoms, is substituted with phenyl or 1 to 3 halogens. １－６ (It may be substituted with at least one substituent selected from alkyl groups.) A pharmaceutical composition comprising a compound represented by , a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.

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