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

Abstract

The present invention relates to a pharmaceutical composition comprising a morphinan derivative that exhibits opioid δ receptor agonist activity. By administering the pharmaceutical composition provided by the present invention, opioid δ receptor-related disorders (e.g., headache) can be treated or prevented.

Description

Technical Field

[0001] The present invention relates to the use of a morphinan derivative having an opioid δ receptor agonist action, for example, for the treatment of headache. This application claims priority based on Japanese Patent Application No. 2016-203925 filed in Japan on September 16, 2016, the entire disclosure of which is incorporated herein by reference.

Background Art

[0002] Opioids exert effects by binding to opioid receptors, and there are three subtypes of opioid receptors: μ, δ, and κ. It is known that agonists of any of the three subtypes of μ, δ, and κ have analgesic effects. Among these, agonists that selectively activate the opioid δ receptor are expected to have few or no side effects that appear through the activation of the opioid μ receptor or the opioid κ receptor. 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 to 6, Non-Patent Documents 1 to 3). Regarding headache, it has been shown that opioid δ receptor agonists are effective for chronic and acute headaches and are effective for preventing headache because they suppress the prodrome of headache (Non-Patent Document 4).

Prior Art Documents

Patent Documents

[0003]

Patent Document 1

Patent Document 2

Patent Document 3

Patent Document 4

Patent Document 5

Patent Document 6

Non-Patent Document

[0004]

Non-Patent Document 1

Non-Patent Document 2

Non-Patent Document 3

Non-Patent Document 4

Summary of the Invention

Problems to be Solved by the Invention

[0005] An object of the present invention is to provide a medicament useful for the treatment or prevention of opioid δ receptor-related diseases (for example, headache).

Means for Solving the Problems

[0006] The present inventors earnestly studied to achieve the above object, and found that a pharmaceutical composition containing a morphinan derivative is useful for the treatment or prevention of opioid δ receptor-related diseases (for example, headache), and completed the present invention. In one aspect, the present invention provides the following general formula (I):

[0007]

Chemical Formula

[0008] (In the formula, R 1 is hydrogen; C 1-10 alkyl; C 6-10Aryl; C 2-6 Alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; C 3-6 Cycloalkyl; or heteroarylalkyl having 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and 1 to 5 carbon atoms in the alkylene moiety, 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 having at least one set of adjacent ring-constituting atoms having a double bond and being 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 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 having 2 to 6 carbon atoms in the acyl moiety, R 6a and R 6b are the same or different and represent hydrogen; fluorine or hydroxy, or R 6a and R 6b together represent =O, R 7 and R 8 are the same or different and represent hydrogen; fluorine or hydroxy, R 9 and R 10 are the same or different and are hydrogen; C 1-6 alkyl; C 6-10Aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; aralkyl in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; heteroarylalkyl in which the heteroaryl moiety contains 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms and the alkylene moiety has 1 to 5 carbon atoms; cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms or C 2-6 represents alkenyl, X represents O or CH2, and Y represents C(=O). However, R 1 's C 1-10 alkyl; the alkylene moiety and cycloalkyl moiety of cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; the alkylene moiety of aralkyl in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; and the alkylene moiety of heteroarylalkyl in which the heteroaryl moiety contains 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms and the alkylene moiety has 1 to 5 carbon atoms are 1 to 6 halogens; hydroxy; C 1-6 alkoxy; C 6-10 aryloxy; C 1-6 alkanoyl; C 1-6 alkanoyloxy; carboxyl; alkoxycarbonyl in which the alkoxy moiety has 1 to 6 carbon atoms; carbamoyl; alkylcarbamoyl in which the alkyl moiety has 1 to 6 carbon atoms; dialkylcarbamoyl in which the alkyl moiety has 1 to 6 carbon atoms; alkylsulfonyl in which the alkyl moiety has 1 to 6 carbon atoms; aminosulfonyl; alkylsulfinyl in which the alkyl moiety has 1 to 6 carbon atoms; alkylthio in which the alkyl moiety has 1 to 6 carbon atoms; C substituted with 1 to 6 halogens 1-6 alkoxy; may be substituted with at least one substituent selected from arylcarbonyl in which the aryl moiety has 6 to 10 carbon atoms, and R1 C of 6-10 aryl; the aryl portion of an aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; R 3 R 4 and R 5 C of 6-10 the aryl portion of aryloxy; and C 6-10 the aryl portion of arylamino; and R 9 and R 10 C of 6-10 aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; the aryl portion of an aralkyl having 6 to 10 carbon atoms in the aryl portion and 1 to 5 carbon atoms in the alkylene portion; and the heteroaryl portion of a heteroarylalkyl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms and having 1 to 5 carbon atoms in the alkylene portion is C 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkanoyloxy; hydroxy; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy portion; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl portion; halogen; nitro; cyano; C 1-6 alkyl substituted with 1 to 3 halogens; C 1-6 alkoxy substituted with 1 to 3 halogens; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl having 1 to 3 carbon atoms in the alkyl; may be substituted with at least one substituent selected from methylenedioxy R 2 The heterocycle of R 1 C of 6-10 aryl may optionally have a substituent that the above-mentioned R Furthermore, when R 1 is C 1-10 alkyl, NR 11 R 12may be replaced here, where R 11 and R 12 are the same or different and are hydrogen; C 1-10 alkyl; or aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, or R 11 and R 12 and R 11 and R 12 may combine with the nitrogen atom to which they are attached and, optionally, one or two heteroatoms to form a 5- to 7-membered ring, and also the alkylene moiety of the aralkyl where the aryl moiety of R 1 has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms may be substituted with at least one substituent selected from phenyl or C 1-6 alkyl substituted with 1 to 3 halogens.) There is provided a pharmaceutical composition comprising a compound represented by formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof of the compound.

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

Advantages of the Invention

[0010] The present invention provides a medicament useful for the treatment or prevention of opioid δ receptor-related diseases (e.g., headache).

Brief Description of the Drawings

[0011]

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

Figure 6

Mode for Carrying Out the Invention

[0012] Next, the present invention will be described in more detail. (1) In one aspect, the present invention provides the following general formula (I):

Chemical formula

[0013] In one embodiment, the compound represented by the general formula (I) used in the pharmaceutical composition provided by the present invention of the above (1), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof are as follows (2) to (58): (2) R 1 is C 1-10 alkyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound represented by the general formula (I) of the above (1); (3) R 1 is cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound according to the above (1) or (2); (4) R 1 is C 2-6 alkyl substituted with hydroxy; C 1-6 alkyl substituted with 1 to 6 halogen atoms; or C 1-6 alkyl substituted with C 2-6 alkoxy, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound represented by the general formula (I) of the above (1); (5) R 1 is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl or 2-(aminosulfonyl)ethyl, a compound represented by the above general formula (I) of (1), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (6) R 2 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 pair of adjacent ring-constituting atoms has a double bond, and is further substituted with at least one oxo group, a 5- to 7-membered heterocycle or a heterocycle condensed with a benzene ring to the heterocycle, a compound according to any one of the above (1) to (5), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (7) R 2 is pyridine 1-oxide optionally substituted with 1 to 4 substituents selected from C 1-10 alkyl substituted with 1 to 3 fluorines and unsubstituted C 1-10 alkyl, a compound according to any one of the above (1) to (6), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (8) R 2 is pyridine 1-oxide, a compound according to any one of the above (1) to (7), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (9) R 2 is pyridin-2(1H)-one optionally substituted with 1 to 4 substituents selected from C 1-10 alkyl substituted with 1 to 3 fluorines and unsubstituted C 1-10 alkyl, a compound according to any one of the above (1) to (6), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (10) R 2is pyridin-2(1H)-one; 1-C 1-6 alkylpyridin-2(1H)-one; or 6-C 1-6 A compound according to any one of (1) to (6) or (9) above, which is alkylpyridin-2(1H)-one, a tautomer, stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof;

[0014] (11) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 A compound according to any one of (1) to (6) above, which is pyridin-4(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl and unsubstituted C alkyl, a tautomer, stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof; (12) R 2 is pyridin-4(1H)-one or 1-C 1-6 alkylpyridin-4(1H)-one, a compound according to any one of (1) to (6) or (11) above, a tautomer, stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof; (13) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 A compound according to any one of (1) to (6) above, which is pyridazin-3(2H)-one optionally substituted with 1 to 3 substituents selected from alkyl and unsubstituted C alkyl, a tautomer, stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof; (14) R 2 is pyridazin-3(2H)-one, a compound according to any one of (1) to (6) or (13) above, a tautomer, stereoisomer of the compound, or a pharmaceutically acceptable salt or solvate thereof; (15) R 2 is C substituted with 1 to 3 fluorines 1-10Alkyl and unsubstituted C 1-10 The compound according to any one of the above (1) to (6), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof, which is pyrazin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl; (16) R 2 The compound according to any one of the above (1) to (6), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof, wherein R is pyrazin-2(1H)-one; (17) R 2 is C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of the above (1) to (6), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof, which is 4H-pyran-4-one or 2H-pyran-2-one optionally substituted with 1 to 3 substituents selected from alkyl; (18) R 2 The compound according to any one of the above (1) to (6) or (17), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof, wherein R is 4H-pyran-4-one or 2H-pyran-2-one; (19) R 2 is C substituted with 1 to 3 fluorines 1-10 Alkyl and unsubstituted C 1-10 The compound according to any one of the above (1) to (6), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof, which is quinolin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl; (20) R 2 The compound according to any one of the above (1) to (6), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof, wherein R is quinolin-2(1H)-one;

[0015] (21) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, which may be substituted with 1 to 3 substituents selected from alkyl and unsubstituted Calkyl, the tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof, of the compound according to any one of (1) to (6) above; (22) R 2 is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, the compound according to any one of (1) to (6) or (21) above, the tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (23) X is CH2, the compound according to any one of (1) to (22) above, the tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (24) R 3 and R 4 wherein one of them is hydroxy and the other is hydrogen, the compound according to any one of (1) to (23) above, the tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (25) R 3 is halogen; cyano; carbamoyl; C 1-6 alkoxy; C 1-6 alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, R 4 is hydrogen or hydroxy, R 5 is hydrogen, the compound according to any one of (1) to (23) above, the tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (26) R 3 is hydroxy; carbamoyl; or C 1-6 alkanoyloxy, R 4is hydrogen, R 5 is hydrogen, the compound according to any one of the above (1) to (23), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof; (27) R 3 is hydroxy, R 4 is hydrogen, R 5 is hydrogen, the compound according to any one of the above (1) to (23), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof; (28) R 3 、R 4 and R 5 are all hydrogen, the compound according to any one of the above (1) to (23), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof; (29) R 6a 、R 6b 、R 7 、R 8 、R 9 and R 10 are all hydrogen, the compound according to any one of the above (1) to (28), a tautomer, stereoisomer, or a 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 are hydrogen, R 1 is hydrogen; C 1-6 alkyl; C 2-6 alkenyl; cycloalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, R 2It represents a 5- to 7-membered heterocyclic ring containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, with at least one pair of adjacent ring-constituting atoms having a double bond and being further substituted with at least one oxo group, or a heterocyclic ring condensed with a benzene ring to the said heterocyclic ring. Here, R 2 is bonded to Y via a carbon atom that is a ring-constituting atom of R 2 . R 3 and R 4 are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C 1-6 alkoxy; C 6-10 aryloxy; C 1-6 alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety. When X is CH2 and Y is C(=O). However, the C 1 of R 1-6 alkyl; the alkylene moiety and cycloalkyl moiety of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or the alkylene moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety are 1 to 6 halogens; hydroxy; C 1-6 alkoxy; C 6-10 aryloxy; C 1-6 alkanoyl; C 1-6 alkanoyloxy; carboxyl; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens 1-6It may be substituted with at least one substituent selected from an alkoxy group; an arylcarbonyl group in which the number of carbon atoms in the aryl moiety is 6 to 10, and R 1 the aryl moiety of the aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; R 3 and R 4 the C 6-10 aryl moiety of the aryloxy group is C 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkanoyloxy; hydroxy; alkoxycarbonyl in which the number of carbon atoms in the alkoxy moiety is 1 to 6; carbamoyl; alkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; dialkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; halogen; nitro; cyano; C 1-6 alkyl substituted with 1 to 3 halogen atoms; C 1-6 alkoxy substituted with 1 to 3 halogen atoms; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms; phenoxy; phenylalkyl in which the number of carbon atoms in the alkyl moiety is 1 to 3; It may be substituted with at least one substituent selected from methylenedioxy, R 2 In addition to the oxo group, the heterocyclic ring of R 1 may have a substituent that the aryl moiety of the aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety of R Furthermore, R 1 the alkylene moiety of the aralkyl group having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety may be substituted with at least one substituent selected from phenyl or C 1-6 alkyl substituted with 1 to 3 halogen atoms, and the compound represented by the above general formula (I) of (1), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof; (31) R 1 is C 1-6An alkyl; a cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; or an aralkyl in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms, the compound according to (1) or (30), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (32) R 1 is a cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms, the compound according to (1), (30) or (31), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (33) R 1 is C substituted with hydroxy 2-6 alkyl; C substituted with 1 to 6 halogens 1-6 alkyl; or C 1-6 alkyl substituted with alkoxy 2-6 alkyl, the compound according to (1) or (30), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (34) R 1 is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl or 2-(aminosulfonyl)ethyl, the compound according to (1) or (30), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (35) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10A compound according to any one of (1) or (30) to (34), which may be substituted with a substituent selected from alkyl, a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof, which is pyridine 1-oxide, pyridin-2(1H)-one, pyridin-4(1H)-one, pyridazin-3(2H)-one, pyrazin-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one, quinolin-2(1H)-one, pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione; (36) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 A compound according to any one of (1) or (30) to (35), which may be substituted with 1 to 4 substituents selected from alkyl, a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof, which is pyridine 1-oxide; (37) R 2 is pyridine 1-oxide, a compound according to any one of (1) or (30) to (36), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof; (38) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 A compound according to any one of (1) or (30) to (35), which may be substituted with 1 to 4 substituents selected from alkyl, a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof, which is pyridin-2(1H)-one; (39) R 2 is pyridin-2(1H)-one; 1-C 1-6 alkylpyridin-2(1H)-one; or 6-C 1-6The compound according to any one of (1) or (30) to (35), which is alkylpyridin-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (40) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (35), which is pyridin-4(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl and unsubstituted C alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof;

[0017] (41) R 2 is pyridin-4(1H)-one or 1-C 1-6 The compound according to any one of (1), (30) to (35) or (40), which is alkylpyridin-4(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (42) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 The compound according to any one of (1) or (30) to (35), which is pyridazin-3(2H)-one optionally substituted with 1 to 3 substituents selected from alkyl and unsubstituted C alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (43) R 2 is pyridazin-3(2H)-one, the compound according to any one of (1), (30) to (35) or (42), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof; (44) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10A compound according to any one of (1) or (30) to (35), which is pyrazin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof; (45) R 2 A compound according to any one of (1), (30) to (35) or (44), wherein R is pyrazin-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof; (46) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 A compound according to any one of (1) or (30) to (35), which is 4H-pyran-4-one or 2H-pyran-2-one optionally substituted with 1 to 3 substituents selected from alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof; (47) R 2 A compound according to any one of (1), (30) to (35) or (46), wherein R is 4H-pyran-4-one or 2H-pyran-2-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof; (48) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 A compound according to any one of (1) or (30) to (35), which is quinolin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof; (49) R 2 A compound according to any one of (1), (30) to (35) or (48), wherein R is quinolin-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or a solvate thereof; (50) R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 alkyl, a pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione optionally substituted with 1 to 3 substituents selected therefrom, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvate thereof, a compound according to any of (1) or (30) to (35);

[0018] (51) R 2 is a pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, a compound according to any of (1), (30) to (35) or (50), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvate thereof; (52) R 3 and R 4 wherein one of them is hydroxy and the other is hydrogen, a compound according to any of (1) or (30) to (51), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvate thereof; (53) R 3 is halogen; cyano; carbamoyl; C 1-6 alkoxy; C 1-6 alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, and R 4 is hydrogen or hydroxy, a compound according to any of (1) or (30) to (51), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvate thereof; (54) R 3 is hydroxy; carbamoyl; or C 1-6 alkanoyloxy, and R 4 is hydrogen, a compound according to any of (1) or (30) to (51), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvate thereof; (55) R 3 is hydroxy and R 4 is hydrogen, the compound according to any one of (1) or (30) to (51), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof; compound, a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof; (56) R 3 and R 4 are hydrogen, the compound according to any one of (1), (30) to (51), a tautomer, stereoisomer, or a 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 4 - ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 3 - ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3 - ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-10-Acetoxy-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one and A compound selected from 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof or solvate 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one, 5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione and A compound selected from 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof, may be any of them.

[0021] In this specification, C 1-6 Examples of alkyl include methyl, ethyl, propyl, i-propyl, butyl, tert-butyl, pentyl, neopentyl, or hexyl. C 1-10 Examples of alkyl include, in addition to those exemplified above for C 1-6 alkyl, heptyl, octyl, and the like. C alkyl substituted with 1 to 3 halogens 1-6 Examples of alkyl include 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl, or 3,3,3-trifluoropropyl. C 2-6 Examples of alkenyl include 2-propenyl or 3-methyl-2-butenyl. Examples of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety include methyl, ethyl, etc. substituted with cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. 3-6 Examples include methyl, ethyl, etc. substituted with cycloalkyl. Examples of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety include a benzyl group or a phenethyl group. C 3-6 Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. C 6-10 Examples of aryl include phenyl or naphthyl. Examples of heteroaryl containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms include pyridyl, furyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, or thiazolyl, etc. Heteroarylalkyl contains 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms, and the number of carbon atoms in the alkylene moiety is 1 to 5. Examples of heteroarylalkyl include (pyridin-2-yl)methyl, (pyridin-3-yl)methyl, (pyridin-4-yl)methyl, (furan-2-yl)methyl, (furan-3-yl)methyl, (imidazol-2-yl)methyl, (imidazol-4-yl)methyl, (imidazol-5-yl)methyl, (thiazol-2-yl)methyl, (thiazol-4-yl)methyl, (thiazol-5-yl)methyl, 2-(pyridin-2-yl)ethyl, 2-(pyridin-3-yl)ethyl, 2-(pyrazol-1-yl)ethyl, 2-(thiophen-2-yl)ethyl, or 2-(thiophen-3-yl)ethyl, etc.

[0022] C 1-6 Examples of alkanoyl include acetyl or propionyl, etc. C 1-6 Examples of alkoxy include methoxy, ethoxy, or propoxy, etc. C 1-6 Examples of alkanoyloxy include acetoxy, etc. Examples of alkoxycarbonyl with the number of carbon atoms in the alkoxy moiety being 1 to 6 include methoxycarbonyl or ethoxycarbonyl, etc. Examples of halogen include fluorine, chlorine, bromine, or iodine, etc. C substituted with 1 to 3 halogens 1-6 Examples of alkoxy include fluoromethoxy or trifluoromethoxy, etc. C substituted with 1 to 6 halogens 1-6 Examples of alkoxy include the above C substituted with 1 to 3 halogens 1-6 In addition to the above alkoxy, examples include tetrafluoroethoxy, etc. Examples of phenylalkyl in which the alkyl group has 1 to 3 carbon atoms include benzyl and the like. C 6-10 Examples of aryloxy include phenoxy and the like. C 1-8 Examples of alkylamino include methylamino, ethylamino and the like. Examples of acylamino in which the acyl moiety has 2 to 6 carbon atoms include acetylamino and the like. C 6-10 Examples of arylamino include phenylamino and the like. Examples of alkylcarbamoyl in which the alkyl moiety has 1 to 6 carbon atoms include ethylcarbamoyl and the like. Examples of dialkylcarbamoyl in which the alkyl moiety has 1 to 6 carbon atoms include diethylcarbamoyl and the like. Examples of alkylsulfonyl in which the alkyl moiety has 1 to 6 carbon atoms include methylsulfonyl and the like. Examples of alkylsulfinyl in which the alkyl moiety has 1 to 6 carbon atoms include methylsulfinyl and the like. Examples of alkylthio in which the alkyl moiety has 1 to 6 carbon atoms include methylthio and the like. Examples of arylcarbonyl in which the aryl moiety has 6 to 10 carbon atoms include benzoyl and the like. R 11 and R 12 and R 11 and R 12 Examples of a 5- to 7-membered ring that may be formed by combining the nitrogen atom to which R, R, R, and R are attached, and, if desired, 1 to 2 heteroatoms together include pyrrolidine, piperidine, morpholine and the like.

[0023] R 2 Containing 1 to 4 heteroatoms selected from N, O and S of R and at least one carbon atom as ring-constituting atoms, and at least one pair of adjacent ring-constituting atoms having a double bond Examples of a heterocyclic ring further substituted with at least one oxo group include (A) Pyridine 1-oxide, pyridine 1-oxide substituted with 1 to 3 fluorines such as 2-methylpyridine 1-oxide, etc., and C 1-10 alkyl and unsubstituted C 1-10 pyridine 1-oxide which may be substituted with 1 to 4 substituents selected from alkyl (B) Pyridin-2(1H)-one, 1-methylpyridin-2(1H)-one, 1-ethylpyridin-2(1H)-one, 6-methylpyridin-2(1H)-one, 6-ethylpyridin-2(1H)-one or 6-trifluoromethylpyridin-2(1H)-one, etc., and C 1-10 alkyl and unsubstituted C 1-10 pyridin-2(1H)-one which may be substituted with 1 to 4 substituents selected from alkyl (C) Pyridin-4(1H)-one, 1-methylpyridin-4(1H)-one, 1-ethylpyridin-4(1H)-one or 1-(fluoroethyl)pyridin-4(1H)-one, etc., and C 1-10 alkyl and unsubstituted C 1-10 pyridin-4(1H)-one which may be substituted with 1 to 4 substituents selected from alkyl (D) Pyridazin-3(2H)-one, 2-methylpyridazin-3(2H)-one, etc., and C 1-10 alkyl and unsubstituted C 1-10 pyridazin-3(2H)-one which may be substituted with 1 to 3 substituents selected from alkyl (E) Pyrazin-2(1H)-one, 1-methylpyrazin-2(1H)-one, etc., and C 1-10 alkyl and unsubstituted C 1-10 pyrazin-2(1H)-one which may be substituted with 1 to 3 substituents selected from alkyl (F) 4H-Pyran-4-one, 3-methyl-4H-pyran-4-one, 2H-pyran-2-one, 5-methyl-2H-pyran-2-one, etc., and C 1-10 alkyl and unsubstituted C 1-104H-Pyran-4-one and 2H-pyran-2-one, which may be substituted with 1 to 3 substituents selected from alkyl (G) C substituted with 1 to 3 fluorines such as quinolin-2(1H)-one, 6-methylquinolin-2(1H)-one, quinoline 1-oxide, 4-methylquinoline 1-oxide, etc. 1-10 Alkyl and unsubstituted C 1-10 Quinolin-2(1H)-one, quinoline 1-oxide, which may be substituted with 1 to 3 substituents selected from alkyl (H) C substituted with 1 to 3 fluorines such as pyrimidin-4(3H)-one, pyrimidine-2,4(1H,3H)-dione, etc. 1-10 Alkyl and unsubstituted C 1-10 Examples include pyrimidin-4(3H)-one, pyrimidine-2,4(1H,3H)-dione, etc., which may be substituted with 1 to 3 substituents selected from alkyl.

[0024] Tautomers of the compound represented by the above general formula (I) include those containing 1 to 4 heteroatoms selected from N, O, and S of R above and at least one carbon atom as ring-constituting atoms, and at least one pair of adjacent ring-constituting atoms having a double bond, and further substituted with at least one oxo group in a heterocycle. For example, 2-pyridone (lactam) of R 2 corresponds to the corresponding 2-hydroxypyridine (lactim form). 2 In the compound represented by the above general formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, pharmaceutically acceptable salts preferably include acid addition salts, and examples of acid addition salts include salts with organic acids or inorganic acids such as hydrochloride, sulfate, fumaric acid, oxalate, methanesulfonate, camphorsulfonate, etc. In the compound represented by the above general formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, stereoisomers include cis, trans isomers, racemates, optically active forms, etc. ​In the compound represented by the above general formula (I), its tautomer, stereoisomer, or its pharmaceutically acceptable salt or solvate thereof, the solvate is a pharmaceutically acceptable solvate of the compound of the present invention or its salt, including hydrates. Further, the compound represented by the above general formula (I), its tautomer, stereoisomer, or its pharmaceutically acceptable salt or solvate thereof may be a prodrug that is converted into a pharmacologically active substance after reaching the body or the target site and is chemically modified to exhibit (activate) a pharmacological effect. Examples of such prodrugs include, when the group constituting the prodrug is present in a hydroxyl group, ordinary protecting groups for hydroxyl groups such as lower acyl groups and lower alkoxycarbonyl groups; when present in a nitrogen atom, ordinary protecting groups for amino 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 silyl group. Furthermore, the compound represented by the above general formula (I), its tautomer, stereoisomer, or its pharmaceutically acceptable salt or solvate thereof may be substituted with stable isotopes such as deuterium.

[0025] The method for producing the compound represented by the above general formula (I), its tautomer, stereoisomer, or its pharmaceutically acceptable salt or solvate thereof is shown below. The abbreviations used in this specification are as follows. Abbreviation Table 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: Mesyl Ph: Phenyl TBS: tert-Butyldimethylsilyl THF: Tetrahydrofuran TLC: Thin layer chromatography Ts: Tosyl WSC: 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride

[0026] (Production method) The compound represented by the above general formula (I), wherein R 5 、R 6a 、R 6b 、R 7 、R 8 、R 9 and R 10 are hydrogen, provided by the present invention The following compound (I), which is a compound provided by the present invention, can be obtained, for example, by a deprotection reaction from the following compound (I-A) to compound (I).

[0027] [Chemical formula]

[0028] [In the formula, R 1a , R 2a , R 3a and R 4a are, respectively, by the deprotection reaction, R 1 , R 2 , R3 and R 4 is any functional group convertible to R 1a and R 1 is itself R 2a and R 2 is itself R 3a and R 3 is itself R 4a and R 4 may also be the case. Other symbols shall have the same meaning as described above.]

[0029] In the above production method, the above compound (I) can be led to by converting R 1a to R 1 converting R 2a to R 2 converting R 3a to R 3 or converting R 4a to R 4 as appropriate. For example, when R 1a , R 2a , R 3a or R 4a in the above compound (I-A) contains a hydroxyl group protected by a methyl group, for the above compound (I-A), (1) a method of reacting boron tribromide in dichloromethane, or (2) a method of heating the above compound (I-A) in the absence of a solvent with a large excess of pyridine hydrochloride can be used to remove the methyl group which is a protecting group and lead to the above compound (I). Also, when R 1a , R 2a , R 3a or R 4a in the above compound (I-A) contains a hydroxyl group protected by a tert-butyldimethylsilyl (TBS) group, for the above compound (I-A), (3) a method of reacting ammonia dissolved in an appropriate solvent, or (4) a method of reacting hydrogen chloride dissolved in an appropriate solvent, or (5) a method such as reacting tetrabutylammonium fluoride in THF can be used to remove the TBS group which is a protecting group and lead to the above compound (I). R1a , R 2a , R 3a Or R 4a When each of them contains a functional group protected by another protecting group, for example, the above compound (I-A) can be led to the above compound (I) by the general deprotection conditions described in "Green's Protective Groups in Organic Synthesis (5th edition; A John Wiley & Son’s, Inc, Pubication)" written by Peter G.M. Wuts. These Rs 1a , R 2a , R 3a And R 4a Each have different protecting groups, and when they need to be removed under different conditions respectively, different conditions appropriate for the removal of each protecting group can be carried out continuously, and in some cases, the above compound (I-A) can be led to the above compound (I) as a multi-step deprotection reaction.

[0030] The above compound (I-A) can be obtained, for example, by a general acylation reaction with respect to the following compound (I-B) in the reaction formula shown below.

[0031]

Chemical formula

[0032] [In the formula, R 1a , R 2a , R 3a And R 4a Are each an arbitrary functional group that can be converted to R 1 , R 2 , R 3 And R 4 In the general formula (I) by a deprotection reaction, and R 1a Is itself R 1 , R 2a Is itself R 2 , R 3a Is itself R 3 , and R 4a Is itself R 4It may also be the case. L 1 represents a leaving group of a general acylating agent. Other symbols have the same meanings as described above.]

[0033] In the above production method, if necessary, in the presence of additives such as HOBT and DMAP, and bases such as triethylamine and diisopropylethylamine, the above compound (I-B), carboxylic acid (R 2a COOH), and a condensing agent such as HATU or WSC are allowed to act to obtain the above compound (I-A). Further, the above compound (I-A) can be obtained by allowing the above compound (I-B) and carboxylic acid chloride (R 2a COCl; L 1 in the formula = Cl) or carboxylic anhydride (L 1 in the formula = -OC(O)R 2a ) to act in the presence of a base such as triethylamine, diisopropylethylamine, or pyridine. R 3a is a hydroxyl group (OH), in addition to the desired amidation reaction in the acylation reaction in the above reaction scheme, acylation of the R 3a hydroxyl group proceeds as a side reaction, and in the reaction system, R 3a in the above compound (I-A) becomes = -OC(O)R 2a and a by-product is temporarily formed. However, by treating the reaction solution with a 2N ammonia / methanol solution or the like, in the post-treatment process, R 3a is reconverted to = OH, and as a result, the above compound (I-A) in which selective amidation to the secondary amine in the above compound (I-B) has proceeded can be obtained. In addition, the above compound (I-A) can also be synthesized from the above compound (I-B) and the corresponding carboxylic acid (R 2a -COOH) by the condensation reaction described in Christian A.G.N. Montalbetti, et al, Tetrahedron, 61(46), 2005, 10827-10852.

[0034] The above compound (I-B) is, for example, Compound 8 described in Patent Document WO2013 / 035833 (Example 4: R 1a = CPM, X = O, R 3a = OMe, R 4a = H), Compound 33 (Example 29: R 1a = Me, X = O, R 3a = OMe, R 4a = H), Compound 67 (Example 60: R 1a = CPM, X = O, R 3a = H, R 4a = OH), Compound 77 (Example 67: R 1a = CPM, X = CH2, R 3a = OMe, R 4a = H), Compound 116 (Example 101: R 1a = CPM, X = CH2, R 3a = H, R 4a = OH), Compound 130 (Example 106: R 1a = PhCF2CH2, X = CH2, R 3a = OMe, R 4a = H), Compound 185 (Example 143: R 1a = TBSOCH2CH2, X = CH2, R 3a = OMe, R 4a = H), Compound 189 (Example 144: R 1a = (R)-MeCH(OH)CH2, X = CH2, R 3a = OMe, R 4a = H), Compound 350 (Example 261: R 1a = (S)-MeCH(OH)CH2, X = CH2, R 3a = OMe, R 4a = H), Compound 291 (Example 224: R 1a = CPM, X = CH2, R 3a = H, R 4a = OMe), Compound 297 (Example 228: R 1a = CPM, X = CH2, R 3a = H, R 4a = H), Compound 29 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 =H) is used, or the desired compound (I-A) can be synthesized by combining known functional group transformation and deprotection reactions according to the methods described in the above patent documents.

[0035] The following compound (I-A) can also be obtained, for example, by a general alkylation reaction of the following compound (I-C) in the reaction formula shown below.

[0036] [Chemical formula]

[0037] [In the formula, in the formula, R 1a , R 2a , R 3a and R 4a are each an arbitrary functional group that can be converted to R 1 , R 2 , R 3 and R 4 of the general formula (I) by a deprotection reaction, and R 1a is itself R 1 , R 2a is itself R 2 , R 3a is itself R 3 , and R 4a may itself be R 4 . L 2 represents a leaving group for a general alkylation reaction. R 1’a represents a substituent such that R 1’a -CH2 = R 1a . Other symbols have the same meanings as described above.]

[0038] In the above production method, for the above compound (I-C), in the presence of an additive such as acetic acid if necessary, the corresponding aldehyde (R 1’a -CHO; R 1’a is R 1’a -CH2 = R 1arepresents a substituent such that). By reacting the above compound (I-A) with a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in a suitable solvent, the above compound (I-A) can be synthesized. Also, in a polar solvent such as DMF or alcohol, the corresponding alkylating agent (R 1a -L 2 : L 2 represents a halogen such as Cl, Br, I or a suitable leaving group such as OMs, OTs). By reacting the above compound (I-A) in the presence of a base such as potassium carbonate, the above compound (I-A) can be synthesized.

[0039] In addition, the introduction of the R 1a group into the above compound (I-C) is not limited to the reactions described above, and a known general reaction for introducing an alkyl group into an amino group including a multi-step reaction can be applied to lead the above compound (I-C) to the above compound (I-A).

[0040] The above compound (I-C) is, for example, compound 11 described in Patent Document WO2013 / 035833 (Example 7: R 2a = Ph, X = O, R 3a = OMe, R 4a = H), compound 81 (Example 71: R 2a = Ph, X = CH2, R 3a = OMe, R 4a = H), compound 121 (Example 104: R 2a = Ph, X = CH2, R 3a = OTBS, R 4a = H), compound 149 (Example 120: R 2a = 2-pyridil, X = CH2, R 3a = OMe, R 4a = H), compound 116 (Example 101: R 1a = CPM, X = CH2, R 3a = OMe, R 4a = H), compound 217 (Example 163: R 2a = CF3, X = CH2, R 3a = OMe, R 4aIt can be synthesized by combining known functional group conversion and deprotection reactions from the appropriate starting materials described in the above literature according to the method according to the synthesis method of =H). Regarding other compounds of the compound represented by the above general formula (I), which is a compound provided by the present invention, they can also be produced by combining the above production method, the method described in the following examples, and further the above Patent Documents 4 to 6 and Non-Patent Document 1, etc.

[0041] The compound represented by the above general formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound exhibits excellent agonistic activity and selectivity for the opioid δ receptor as compared with the μ and κ opioid receptors. Therefore, the compound represented by the above general formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound can be used in a pharmaceutical composition that exerts an opioid δ receptor agonist action. In addition, the compound represented by the above general formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound shows only a weak inhibitory action on the hERG (human ether-a-go-go related gene) potassium channel. Therefore, the compound represented by the above general formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound can be used in a pharmaceutical composition with a low risk of delay in ventricular repolarization and prolongation of the QT interval in humans. Furthermore, the compound represented by the above general formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound exhibits excellent stability against metabolism by human liver microsomes. Therefore, the compound represented by the above general formula (I), a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof of the compound can be used in a pharmaceutical composition for oral administration. In addition, the compound represented by the general formula (I), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof, acts in the brain in animal models of depression, anxiety, etc. to exhibit a medicinal effect, and thus is considered to have good brain transferability.

[0042] The pharmaceutical composition provided by the present invention is administered orally or parenterally to humans or other mammals. Examples of parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intra-articular administration, transmucosal administration, transdermal administration, nasal administration, rectal administration, and intrathecal administration. The pharmaceutical composition provided by the present invention contains the compound represented by the above general formula (I), its tautomer, stereoisomer, or its pharmaceutically acceptable salt or solvate thereof, either as it is or mixed with a pharmaceutically acceptable carrier, such as excipients (e.g., lactose, D-mannitol, crystalline cellulose, glucose), binders (e.g., hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricants (e.g., magnesium stearate, talc), disintegrants (e.g., starch, carboxymethyl cellulose calcium (CMC-Ca)), diluents (e.g., water for injection, physiological saline), and, if necessary, additives (e.g., pH adjusters, surfactants, solubilizing agents, preservatives, emulsifiers, isotonic agents, stabilizers), and can be prepared in the form of tablets, granules, powders, capsules, suspensions, injections, suppositories, etc. For example, to prepare tablets, the compound represented by the above general formula (I), its tautomer, stereoisomer, or its pharmaceutically acceptable salt or solvate thereof can be formulated by mixing with excipients (e.g., lactose, D-mannitol, crystalline cellulose, glucose), disintegrants (e.g., starch, carboxymethyl cellulose calcium (CMC-Ca)), binders (e.g., hydroxypropyl cellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), lubricants (e.g., magnesium stearate, talc), etc. For example, to prepare injections, the compound represented by the above general formula (I), its tautomer, stereoisomer, or its pharmaceutically acceptable salt or solvate thereof can be formulated by mixing with dispersants (e.g., surfactants such as Tween80, polysaccharides such as carboxymethyl cellulose, sodium alginate, hyaluronic acid, polysorbate), preservatives (e.g., methyl paraben, propyl paraben), isotonic agents (e.g., sodium chloride, mannitol, sorbitol, glucose), pH adjusters (e.g., sodium phosphate, potassium phosphate), etc.

[0043] The pharmaceutical composition provided by the present invention can contain a compound represented by the above general formula (I) in an amount effective for the treatment or prevention of opioid δ receptor-related diseases (for example, headache), a tautomer, stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof.

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

[0045] In addition, the compound represented by the above general formula (I), a tautomer, stereoisomer of the compound, or a pharmaceutically acceptable salt thereof or a solvate thereof can be used in combination with other drugs (for example, analgesics (for example, non-steroidal anti-inflammatory drugs), antidepressants and anxiolytics (for example, selective serotonin reuptake inhibitors)). The combination can be achieved by co-administration (for example, administration as a formulation), or separately and continuously, or at a desired time interval (for example, administration of separately formulated products).

[0046] In this specification, an opioid δ receptor-related disease is a disease that can be treated or prevented by an opioid δ receptor agonist, for example, the diseases described below, including but not limited to, depression, anxiety, pain (for example, headache, fibromyalgia), glaucoma, urinary incontinence, myocardial ischemia, cerebral ischemia, chronic cough, hypertension, drug dependence, alcohol dependence, gastritis, premature ejaculation, diarrhea, functional gastrointestinal disorders, or neurodegenerative diseases (for example, 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 is a medicament for the prevention and / or treatment (such as antidepressants, anxiolytics, etc.) of mental disorders included in the depressive disorder group, anxiety disorder group (such as social anxiety disorder (social phobia), panic disorder, agoraphobia, generalized anxiety disorder), bipolar disorder group, obsessive-compulsive disorder and related disorder group, mental trauma and stressor-related disorder group (such as post-traumatic stress disorder), etc. described in DSM-5 (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, 5th Edition). Additionally, it can be used as a medicament for the prevention and / or treatment of urinary incontinence, myocardial ischemia, cerebral ischemia, chronic cough, hypertension, drug dependence, alcohol dependence, gastritis, premature ejaculation, diarrhea, functional gastrointestinal disorders, or neurodegenerative diseases (such as 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 with a rapid onset of drug efficacy. Also, 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 does not develop tolerance upon continuous administration. In one embodiment, the pharmaceutical composition provided by the present invention can be used as a medicament for the prevention and treatment of depression, which is an accompanying symptom of Alzheimer's disease. Also, 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 application to glaucoma. Therefore, in one embodiment, the pharmaceutical composition provided by the present invention can be used as a medicament for the prevention or treatment of glaucoma. As used herein, depression may be a state accompanied by mood disorders such as feelings of depression, sadness, and loneliness, decreased activity motivation, sluggish thinking, pessimistic ideas, and furthermore autonomic nerve disorders such as sleep disorders and decreased appetite. Also, as used herein, anxiety may be a state of feeling danger or fear, accompanied by uneasiness, tension, tachycardia, dyspnea, etc., without being associated with clearly identifiable stimuli. Depression and anxiety include symptoms of depression and anxiety (for example, depressive symptoms seen in bipolar disorder, depressive and anxiety symptoms seen in PTSD) as described in the above DSM-5, depressive states with somewhat milder symptoms than the depressive disorder group described in DSM-5 but persisting to some extent, and states with somewhat milder symptoms than the anxiety disorder group described in DSM-5 but persisting to some extent. In one embodiment, the pharmaceutical composition provided by the present invention is useful for the treatment and / or prevention of all types of pain as an analgesic. Pain can be classified in various ways. From the perspective of duration and nature, it can be divided into acute pain and chronic pain. Acute pain is the most important biological signal for the intensity and extent of injury. Examples of acute pain include nociceptive pain caused by pain substances released by tissue injury, inflammation, etc., and relieved along with the treatment of the injury. 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 neuropathic pain such as postherpetic neuralgia and pain associated with diabetic neuropathy, and fibromyalgia. From the perspective of cause, pain can be divided into nociceptive pain, neuropathic pain, and psychogenic pain. Nociceptive pain includes periarthritis of shoulder, tenosynovitis, rheumatoid arthritis, headache, toothache, contusion, cut, etc. Neuropathic pain is pain caused by nerve damage, including peripheral neuropathic pain such as postherpetic neuralgia, pain associated with diabetic neuropathy, sciatica, pain associated with peripheral neuropathy caused by taking anticancer drugs, and central neuropathic pain such as pain after stroke, pain after spinal cord injury, and pain associated with multiple sclerosis. Psychogenic pain is pain caused by psychological and social factors such as anxiety and stress received in social life.

[0047] Specific examples of pain and diseases accompanied by pain for which the pharmaceutical composition provided by the present invention is useful for treatment and / or prevention are as follows: 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, plexus injury, postoperative scar syndrome, visceral pain, burns (including sunburn), angina pectoris, spinal joint or intercostal neuralgia, pain resulting from chemotherapy-induced neuropathy, pain associated with rheumatoid arthritis, pain associated with osteoarthritis, headache, migraine, orofacial pain, toothache, glossodynia, pain associated with temporomandibular joint disorder, trigeminal neuralgia, shoulder pain, pain associated with lumbar disc herniation, pain associated with cervical spondylosis, pain associated with spinal stenosis, pain associated with thoracic outlet syndrome, pain associated with brachial plexus avulsion syndrome, shoulder-hand syndrome, pain associated with whiplash, chest pain, abdominal pain, colic, pain associated with cholelithiasis, pain associated with pancreatitis, urolithiasis, pain associated with irritable bowel syndrome, low back pain, sciatica, pain associated with fracture, pain associated with osteoporosis, joint pain, pain associated with gout, pain associated with cauda equina syndrome, pain associated with ankylosing spondylitis, muscle pain, painful spasm, myofascial pain syndrome, fibromyalgia, complex regional pain syndrome, pain associated with atherosclerotic obliterans, pain associated with Buerger's disease, pain associated with Raynaud's phenomenon, postherpetic neuralgia, causalgia, pain associated with entrapment 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 radiotherapy, pain after spinal cord injury, pain associated with syringomyelia, pain after stroke (including thalamic pain), deafferentation pain, sympathetically maintained 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 somatic symptom disorder, pain associated with somatization disorder, pain associated with depression, pain associated with Parkinson's disease, knee joint pain, pain associated with arthritis, dysmenorrhea, intermediate pain, labor pain, delivery pain, inflammatory pain, nociceptive pain, psychogenic pain, overactive bladder, cystitis, prostatitis, prostatodynia, low back pain.

[0048] Preferably, the pharmaceutical composition provided by the present invention is used for the treatment and / or prevention of pain associated with diabetic peripheral neuropathy, postherpetic neuralgia, pain after spinal cord injury, pain after stroke, pain associated with multiple sclerosis, pain associated with chronic low back pain, fibromyalgia, and headache. Headache includes chronic headache and acute headache, and the headache is preferably migraine, for example, episodic migraine or migraine with aura. In addition, the pharmaceutical composition provided by the present invention is useful for the treatment of symptoms of depression and / or anxiety associated with headache.

[0049] Since the pharmaceutical composition provided by the present invention has antidepressant and / or anxiolytic effects, in addition to reducing and / or alleviating the above-mentioned pain, it is also useful for remission of symptoms of depression and / or anxiety associated with pain. Therefore, the pharmaceutical composition provided by the present invention can be a pharmaceutical composition for the treatment or prevention of symptoms of depression and / or anxiety associated with pain. For example, fibromyalgia has intractable chronic pain throughout the body as a core symptom and accompanying symptoms such as mood disorders such as depression and anxiety. The pharmaceutical composition provided by the present invention is useful for remission of symptoms of depression and / or anxiety associated with pain in addition to reducing and / or alleviating the pain of fibromyalgia. Therefore, the pharmaceutical composition provided by the present invention can be a pharmaceutical composition for the treatment or prevention of symptoms of depression and / or anxiety in fibromyalgia. In addition, the pharmaceutical composition provided by the present invention is effective for the treatment or prevention of the core symptoms in Parkinson's disease and overactive bladder, and in addition, it is also effective for the treatment or prevention of pain associated with these diseases. Therefore, the pharmaceutical composition provided by the present invention can be a pharmaceutical composition for the treatment or prevention of pain associated with Parkinson's disease or overactive bladder.

[0050] As one embodiment, the present invention provides a method for preventing or treating the diseases described above, which includes administering the pharmaceutical composition provided by the present invention. As one embodiment, the present invention provides the use of the 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, which comprises 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 a pharmaceutical composition for preventing or treating 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 a disease accompanied by pain in a mammalian subject (e.g., human), the method comprising administering an effective amount of a compound of general formula (I) to a subject in need of treating or preventing pain or a disease accompanied by pain:

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

Chemical formula

[0052] Next, reference examples and examples are given to explain the present invention in more detail, but the present invention is not limited thereto. The names of the example compounds and reference example compounds were translated into Japanese after converting the structural formulas drawn using ChemDraw ver.14 manufactured by CambridgeSoft into English names by the naming algorithm installed in the same software. The NMR data and measured values of mass spectrometry (ESI+ or ESI-) of Examples 1 to 34 are shown in Tables 1 to 5.

Example

[0053] Reference Example 1-1 (1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol synthesis

[0054]

Chemical formula

[0055] (1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (372 mg, 1.02 mmol) synthesized by the method of Example 67 of Patent Document WO2013 / 035833 was added to a 300 mL round-bottom flask, dissolved in dichloromethane (5 mL), and vigorously stirred at 0 °C for 20 minutes. Then, a 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, and the residue was suspended in chloroform (50 mL) and washed with 6% aqueous ammonia solution (20 mL). The aqueous layer was extracted twice with chloroform (30 mL), and the collected organic layer was dried over anhydrous sodium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure to obtain the title compound (356 mg, 100%) as a brown foam.

[0056] [Alternative method] To a 500 mL round-bottomed flask were added (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (3.58 g, 9.82 mmol) synthesized by the method of Example 67 of Patent Document WO2013 / 035833 and pyridinium hydrochloride (87 g, 753 mmol), and the mixture was stirred at 200 °C for 1 hour. After the reaction, the mixture was returned to room temperature, and saturated aqueous potassium carbonate solution was added to the resulting solid to dissolve it. The mixture was extracted with ethyl acetate and chloroform, and the collected organic layer was dried over 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 1H NMR (CDCl3, 400 MHz): δ 6.94 (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 (1S,3aR,5aS,6R,11bR,11cS)-10-((tert-butyldimethylsilyl)oxy)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole synthesis

[0058]

Chem.

[0059] (1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (694 mg, 1.98 mmol) synthesized by the method of Reference Example 1-1 was added to a 200 mL round-bottom flask, dissolved in DMF (20 mL), and imidazole (241 mg, 3.54 mmol) and tert-butyldimethylchlorosilane (498 mg, 3.31 mmol) were added at room temperature, followed by stirring at room temperature for 2 hours. Since the remaining raw material was confirmed in the reaction solution, imidazole (529 mg, 7.77 mmol) and tert-butyldimethylchlorosilane (503 mg, 3.34 mmol) were added, and the mixture was stirred at room temperature for 18 hours. Water (150 mL) was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane (1:1, 100 mL). After adding 6% aqueous ammonia (30 mL) to the aqueous layer to make it basic, the mixture was extracted twice with a mixed solvent of ethyl acetate and hexane (1:1, 100 mL). The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble matter was 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%) and then methanol / chloroform (concentration gradient 20 - 50%) containing 10% concentrated aqueous ammonia as the elution solvent to obtain the title compound (456 mg, 50%) as a yellow syrup, and also the raw material (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (265 mg, 38%). 11H NMR (CDCl3, 400 MHz): δ 6.94 (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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide

[0061] [Chemical Structure]

[0062] To a 50 mL round-bottom flask, (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (31 mg, 87 μmol) synthesized in Reference Example 1, 2-carboxypyridine 1-oxide (32 mg, 0.23 mmol), and HATU (125 mg, 0.33 mmol) were added, and the mixture was suspended in THF (1.5 mL). Then, triethylamine (70 μL, 0.50 mmol) and DMA (200 μL) were added, and the mixture was stirred at room temperature for 1 hour. To the reaction solution, 2 N ammonia / methanol solution (2 mL) was added, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained residue was suspended in 6% aqueous ammonia and extracted with ethyl acetate. The collected organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered to remove insoluble matters, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (aminosilica gel, 16 g) using methanol and chloroform (concentration gradient: 0% - 50%) as elution solvents 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyridine 1-oxide

[0064]

Chemical formula

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (36 mg, 0.10 mmol), 4-carboxypyridine 1-oxide (42 mg, 0.30 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (108 mg, 0.28 mmol). The reaction solution was directly subjected to column chromatography (silica gel, 10 g) using methanol and ethyl acetate containing 5% triethylamine (concentration gradient: 10% - 50%) as the elution solvent for purification. The obtained syrup was dissolved in methanol, chloroform and tert-butyl methyl ether were added, and after powdering, it was collected by filtration to obtain the title compound (30 mg, 62%) as a light 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyridin-2(1H)-one

[0067]

Chemical Structure

[0068] 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (39 mg, 0.11 mmol), 2-oxo-1,2-dihydropyridine-3-carboxylic acid (39 mg, 0.28 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (130 mg, 0.34 mmol). After adding 2 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure, and the residue was directly subjected to column chromatography (silica gel, 10 g) using ethyl acetate containing methanol and 5% triethylamine (concentration gradient: 10% - 50%) as the elution solvent for purification. The obtained residue was powdered from 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyridine 1-oxide

[0070]

Chemical Structure

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (34 mg, 97 μmol), 3-carboxypyridine 1-oxide (40 mg, 0.29 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (125 mg, 0.33 mmol). After adding 2 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure, and the residue was directly subjected to column chromatography (silica gel, 25 g) using 0.1 N ammonia / methanol solution and chloroform (concentration gradient: 0% - 50%) as elution solvents for purification. The obtained syrup was dissolved in methanol, tert-butyl methyl ether was added to powder it, and then it was collected by filtration to obtain the title compound (14 mg, 31%) as a slightly brown amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyridin-2(1H)-one

[0073]

Chemical Structure

[0074] According to the same method 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (34 mg, 96 μmol), 6-oxo-1,6-dihydropyridine-3-carboxylic acid (40 mg, 0.29 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (132 mg, 0.35 mmol). After adding a 2N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was directly subjected to column chromatography (silica gel, 10 g) using a 0.1N ammonia / methanol solution and chloroform (concentration gradient: 1% - 50%) as elution solvents for purification. The obtained compound was suspended in chloroform and washed with 6% aqueous ammonia to remove impurities. After extracting the aqueous layer with chloroform, the combined organic layers were dried over anhydrous sodium sulfate, the 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] [Chemical formula]

[0077] This compound was synthesized by a method according to the method described in WO2006 / 107254. 2-Oxo-1,2-dihydropyridine-3-carboxylic acid (500 mg, 3.59 mmol) was added to a 50 mL round-bottom flask and suspended in methanol (5 mL) and water (0.8 mL). 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 returned to room temperature, iodomethane (2.6 mL, 41.8 mmol) was added and the mixture was stirred at 100 °C for 45 minutes. Then, it was concentrated under reduced pressure until the solvent volume was reduced by half. 3 N hydrochloric acid (20 mL) was added to the reaction solution, and the resulting solid was filtered, washed with water and acetonitrile, and dried under reduced pressure to obtain the title compound (64.9 mg, 12%) as a white powder. 1 1H NMR (CD3OD, 400 MHz): δ 8.43 (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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

[0079]

Chemical formula

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 86 μmol), 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid synthesized in Reference Example 2 (29 mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol), and HATU (72 mg, 0.19 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using 1.4 N ammonia / methanol solution-chloroform (concentration: 5%) as the developing solvent to obtain the title compound (26.2 mg, 63%) as a pale yellow amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyridin-2(1H)-one

[0082]

Chemical Structure

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (66 mg, 0.19 mmol), 6-oxo-1,6-dihydropyridine-2-carboxylic acid (83 mg, 0.59 mmol), triethylamine (150 μL, 1.10 mmol) and HATU (262 mg, 0.69 mmol). After adding 2 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was directly subjected to column chromatography (aminosilica gel, 10 g) using methanol and chloroform (concentration gradient: 0% - 30%) as elution solvents for purification. The obtained syrup was dissolved in methanol, tert-butyl methyl ether was added, and it 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)-6-methylpyridin-2(1H)-one

[0085]

Chemical Structure

[0086] 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 6-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid (19 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, DMF was used as the solvent instead of THF and DMA. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure, and the residue was subjected to preparative TLC using 1.4 N ammonia / methanol solution-chloroform (concentration: 10%) as the developing solvent for purification. Then, in order to remove impurities further, the obtained solid was suspended in saturated aqueous potassium carbonate solution, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, the inorganic substances were filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound. The obtained compound was converted to the hydrochloride salt according to Example 32 for use in the biological activity test.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)-1-methylpyridin-2(1H)-one

[0088]

Chemical Structure

[0089] 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 86 μmol), 1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (29 mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol) and HATU (72 mg, 0.19 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium hydrogen carbonate solution, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, the 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: 10%) as the developing solvent to obtain the title compound (31.1 mg, 75%) as a white amorphous solid.

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

[0091] [Chemical formula]

[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 stirred at 100 °C for 15 minutes. The reaction solution was returned to room temperature, iodomethane (2.6 mL, 41.8 mmol) was added and stirred at 100 °C for 1 hour, then concentrated under reduced pressure until the solvent volume was reduced by half. 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. 11H NMR (DMSO-d6, 400 MHz): δ 7.45 (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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one

[0094]

Chemical Structure

[0095] Following the same procedure as in Example 1, (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 86 μmol), 1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid (29 mg, 0.19 mmol) synthesized by the method of Reference Example 3, diisopropylethylamine (75 μL, 0.43 mmol) and HATU (72 mg, 0.19 mmol) were used for the reaction. However, dichloromethane was used as the solvent instead of THF and DMA. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol and chloroform (concentration: 10%) as the developing solvent to obtain the title compound (32.7 mg, 79%) as a white amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0097]

Chemical formula

[0098] Following the same procedure as in Example 1, (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (54 mg, 0.15 mmol), 2-methoxyisonicotinic acid (54 mg, 0.35 mmol), triethylamine (140 μL, 1.00 mmol) and HATU (195 mg, 0.51 mmol) were used for the reaction. After adding 2 N ammonia / methanol solution to the reaction solution to stop the reaction, 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 over anhydrous magnesium sulfate. The insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (aminosilica gel, 16 g) using methanol containing 10% concentrated ammonia and chloroform as eluting solvents to give ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(2-methoxypyridin-4-yl)methanone (61 mg, 82%) as a white solid.

[0099] 11H NMR (DMSO-d6, 400 MHz): δ 8.20 (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 were added ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(2-methoxypyridin-4-yl)methanone (48 mg, 98 μmol) obtained above, and pyridine hydrochloride (2.88 g, 25 mmol), and the mixture was heated with stirring at 200 °C for 10 minutes. After the reaction solution was cooled to room temperature, it was suspended in 6% aqueous ammonia and extracted with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (aminosilica gel, 8 g) using methanol and chloroform (concentration gradient: 0% - 30%) as elution solvents to obtain the title compound (35 mg, 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione

[0101] [Chemical formula]

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 90 μmol), 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid monohydrate (35 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (114 mg, 0.30 mmol). After adding 2 N ammonia / methanol solution to the reaction solution to stop the reaction, the resulting residue was concentrated under reduced pressure, suspended in an aqueous solution of saturated sodium hydrogen carbonate, and extracted three times with a 5:1 mixed solution of chloroform and methanol. The collected organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol containing 10% concentrated ammonia water and chloroform (concentration: 25%) as the developing solvent to obtain the title compound (16 mg, 35%) 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one

[0104]

Chem.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 90 μmol), 4-oxo-1,4-dihydropyridine-3-carboxylic acid (28 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (114 mg, 0.30 mmol). After adding a 2N ammonia / methanol solution to the reaction solution to stop the reaction, the mixture was suspended in an aqueous saturated sodium hydrogen carbonate solution and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol containing 10% concentrated ammonia water and chloroform (concentration: 15%) as the developing solvents to give the title compound (19 mg, 44%) 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyridin-4(1H)-one

[0107]

Chem.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 90 μmol), 4-oxo-1,4-dihydropyridine-2-carboxylic acid (28 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (114 mg, 0.30 mmol). After adding a 2 N ammonia / methanol solution to the reaction solution to stop the reaction, the mixture was suspended in an aqueous saturated sodium hydrogen carbonate solution and extracted three times with a 5:1 mixed solution of chloroform and methanol. The collected organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol containing 10% concentrated ammonia water and chloroform (concentration: 15%) as the developing solvent to obtain the title compound (8 mg, 20%) 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)-1-methylpyridin-2(1H)-one

[0110]

Chemical formula

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 90 μmol), 1-methyl-2-oxo-1,2-dihydropyridine-4-carboxylic acid (31 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (114 mg, 0.30 mmol). After adding a 2 N ammonia / methanol solution to the reaction solution to stop the reaction, the mixture was suspended in an aqueous saturated sodium hydrogen carbonate solution and extracted three times with chloroform. The collected organic layers were dried over anhydrous sodium sulfate, the 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: 5%) as the developing solvents to give 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyridazin-3(2H)-one

[0113]

Chemical Structure

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 85.9 μmol), 6-oxo-1,6-dihydropyridazine-3-carboxylic acid (31 mg, 0.22 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (129 mg, 0.34 mmol). After adding 2 N ammonia / methanol solution to the reaction solution to stop the reaction, 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 over anhydrous magnesium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (aminosilica gel, 16 g) using methanol and chloroform (concentration gradient: 0% - 30%) as elution solvents 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)quinolin-2(1H)-one

[0116]

Chemical Structure

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (33 mg, 95 μmol), 2-oxo-1,2-dihydroquinoline-4-carboxylic acid (50 mg, 0.26 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (128 mg, 0.34 mmol). After adding 2 N ammonia / methanol solution to the reaction solution to stop the reaction, 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 over anhydrous magnesium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (aminosilica gel, 16 g) using methanol and chloroform (concentration gradient: 0% - 30%) as elution solvents 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)-2H-pyran-2-one

[0119]

Chemical Structure

[0120] 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 2-oxo-2H-pyran-5-carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. After 1 hour from the start of the reaction, 1 N hydrochloric acid was added to the reaction solution and further stirred. An aqueous potassium carbonate solution was added to the reaction solution to stop the reaction, followed by extraction with chloroform. The organic layer was dried over sodium sulfate, insolubles were filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol and chloroform (concentration: 5%) as the developing solvents, and the title compound (4.0 mg, 15%) was obtained as a brown amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)-4H-pyran-4-one

[0122]

Chemical Structure

[0123] Following the same method 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 4-oxo-4H-pyran-2-carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. After adding 2 N methylamine / methanol solution (0.3 mL, 0.6 mmol) to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol and chloroform (concentration: 10%) as the developing solvent, and the title compound (4.4 mg, 16%) was obtained as a brown amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)-1-methylpyridin-4(1H)-one

[0125]

Chemical Structure

[0126] 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 4-oxo-4H-pyran-2-carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. After adding 2 N methylamine / methanol solution (3.0 mL, 6.0 mmol) to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in saturated aqueous potassium carbonate solution, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (aminosilica gel, 8 g) using methanol and chloroform (concentration gradient: 0% - 10%) as the elution solvent to obtain the title compound (19 mg, 68%) as a slightly brown amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyrazin-2(1H)-one

[0128]

Chemical Structure

[0129] 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 5-oxo-4,5-dihydropyrazine-2-carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, dichloromethane was used as the solvent instead of THF and DMA. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in an aqueous potassium carbonate solution, extracted with chloroform, the organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate 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 the elution solvent to obtain the title compound (12.2 mg, 45%) as a slightly brown amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyridine 1-oxide

[0131]

Chemical Structure

[0132] To a 10 mL test tube, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (52 mg, 0.11 mmol) synthesized in Example 1 was added 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 the remaining raw material was confirmed in the reaction solution, triethylamine (45 μL, 0.32 mmol) and acetyl chloride (15 μL, 0.21 mmol) were added again, and the mixture was stirred at room temperature for 1 hour. Saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the mixture was vigorously stirred for 20 minutes. Then, the aqueous layer was separated and extracted with ethyl acetate. The collected organic layer was dried over anhydrous magnesium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (51 mg, 89%) as a yellow amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0134]

Chemical Structure

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (27 mg, 79 μmol), 6-oxo-1,6-dihydropyridine-2-carboxylic acid (18 mg, 0.16 mmol), triethylamine (50 μL, 0.36 mmol) and HATU (70 mg, 0.18 mmol), which were prepared by the method of Compound 297 (Example 228) described in Patent Document WO2013 / 035833. After adding a 2 N ammonia / methanol solution to the reaction solution to stop the reaction, 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 over anhydrous magnesium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (aminosilica gel, 8 g) using methanol and chloroform (concentration gradient: 0% - 20%) as elution solvents. The obtained compound was dissolved in methanol, tert-butyl methyl ether was added, and it 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]

Chemical Structure

[0138] This compound was synthesized by the method of Patent Document WO2009 / 033084, and the 1H NMR spectrum was consistent with the data described in Syn.Commun.2010.40(20).2988-2999. To a 50 mL round-bottom flask were added 3-aminopyrazine-2-carboxylic acid (300 mg, 2.17 mmol) and concentrated sulfuric acid (1.3 mL). While under an ice bath, sodium nitrite (149 mg, 2.16 mmol) dissolved in concentrated sulfuric acid (1.6 mL) was added dropwise, and then the mixture was stirred for 1 hour. The reaction solution was added to ice water, and the resulting solid was collected by filtration with vigorous stirring. 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 1H NMR (DMSO-d6, 400 MHz): δ 7.80 (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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one

[0140]

Chemical Structure

[0141] Following the same procedure as in Example 1, a reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol) and 3-oxo-3,4-dihydropyrazine-2-carboxylic acid (20 mg, 0.14 mmol) synthesized in Reference Example 4. However, HOAt (17 mg, 0.13 mmol) was used instead of triethylamine, WSC (24 mg, 0.13 mmol) was used instead of HATU, and DMF was used as the solvent instead of THF. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, the mixture was extracted with chloroform and washed successively with saturated aqueous ammonium chloride and saturated aqueous sodium hydrogen carbonate. The organic layer was dried over anhydrous sodium sulfate, the 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: 20%) as the developing solvents to give the title compound (5.9 mg, 22%) as a pale yellow amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyrimidine-2,4(1H,3H)-dione

[0143]

Chemical Structure

[0144] 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol) and 2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxylic acid (20 mg, 0.13 mmol). However, HOAt (17 mg, 0.13 mmol) was used instead of triethylamine, WSC (24 mg, 0.13 mmol) was used instead of HATU, and DMF was used as the solvent instead of THF. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, 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 the elution solvent. The obtained compound was suspended in chloroform and aqueous ammonia to remove impurities and then collected by filtration to obtain the title compound (2.5 mg, 9%) as a slightly brown amorphous substance.

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

[0146] [Chemical formula]

[0147] To a 30 mL round-bottom flask, 6-oxo-1,6-dihydropyridine-2-carboxylic acid (129 mg, 925 μmol) and 1,1-diethoxy-N,N-dimethylmethanamine (1.5 mL) were added 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 the elution solvent to obtain ethyl 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylate (104 mg, 58%) as a colorless oily substance. 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, dissolved in ethanol (3 mL), then 5 N aqueous sodium hydroxide solution (200 μL, 1.0 mmol) was added, and the mixture was stirred at 55 °C for 2 hours. After allowing the reaction solution to cool to room temperature, 5 N hydrochloric acid (400 μL, 2.0 mmol) was added to make it acidic, and then it was concentrated under reduced pressure. Ethanol (3 mL) was added to the residue, and it was concentrated under reduced pressure. The residue was suspended in ethanol (3 mL), the 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 1H NMR (DMSO-d6, 400 MHz): δ 7.41 (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 = 6.9 Hz), 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one

[0149]

Chemical formula

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (32 mg, 92 μmol), 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid synthesized in Reference Example 5 (33 mg, 0.19 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (136 mg, 0.36 mmol). After adding a 2N ammonia / methanol solution to the reaction solution to stop the reaction, 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 over anhydrous magnesium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (aminosilica gel, 8 g) using methanol and chloroform (concentration gradient: 0% - 20%) as elution solvents. The obtained compound was dissolved in methanol, tert-butyl methyl ether was added and 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyrimidin-4(3H)-one

[0152]

Chemical Structure

[0153] Following the same procedure as in Example 1, the reaction was carried out using (1S,3aR,5aS,6R,11bR,11cS)-10-((tert-butyldimethylsilyl)oxy)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (30 mg, 65 μmol) and 6-oxo-1,6-dihydropyrimidine-4-carboxylic acid (20 mg, 0.14 mmol). However, HOAt (19 mg, 0.14 mmol) was used instead of triethylamine, WSC (27 mg, 0.14 mmol) was used instead of HATU, and DMF was used as the solvent instead of THF. After the residue was suspended in water, it was extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient: 0% - 10%) as the elution solvent. 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 the reaction solution was concentrated, 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 using methanol and chloroform (concentration: 20%) as the developing solvent, and the title compound (1.7 mg, 6%) was obtained as a white amorphous solid.

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

[0155]

Chemical formula

[0156] 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) were treated with WSC (274 mg, 1.43 mmol) and benzyl alcohol (148 μL, 1.43 mmol), and the mixture was stirred at room temperature for 2 h. Water was added to the reaction solution, and the insoluble material was filtered off. The filtrate was extracted with hexane and washed with a saturated aqueous sodium hydrogen carbonate solution. The collected organic layer was dried over sodium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The resulting residue was dissolved in methanol (10 mL) together 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 h. After the reaction, the mixture was concentrated under reduced pressure. Saturated aqueous sodium hydrogen carbonate solution was added to the resulting residue, and the mixture was extracted with chloroform and washed with saturated brine. The collected organic layer was dried over anhydrous sodium sulfate, the insoluble material was filtered off, and 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 elution solvents to give benzyl 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate (126 mg, 34% over 2 steps) as a pale yellow amorphous solid. Benzyl 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate obtained above was dissolved in methanol (2 mL) and ethyl acetate (2 mL), 10% palladium on carbon was added, and the mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. After the reaction, the insoluble material was filtered through celite, and the resulting solution was concentrated to give the title compound (73 mg, 89%) as a pale yellow amorphous solid. 1 H NMR (CH3OD, 400 MHz): δ 8.43 (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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one

[0158]

Chem.

[0159] According to the same method as in Example 1, (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (15 mg, 43 μmol), 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (16 mg, 94 μmol) synthesized in Reference Example 6, diisopropylethylamine (37 μL, 0.21 mmol) and HATU (36 mg, 94 μmol) were used for the reaction. However, only THF was used as the solvent. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium hydrogen carbonate solution and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient: 0% - 30%) as the elution solvent to obtain the title compound (13.3 mg, 62%) as a white amorphous solid.

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

[0161]

Chem.

[0162] To a 50 mL round-bottom flask was added 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide (79 mg, 0.17 mmol) synthesized in Example 1. After dissolving in ethanol (2 mL), 2 N hydrochloric acid (1 mL) was added, and the resulting solution was concentrated under reduced pressure. The obtained residue was dried at 80 °C for 18 hours under reduced pressure to obtain the title compound (85 mg, 99%) as a white amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one hydrochloride

[0164]

Chem.

[0165] To a 50 mL round-bottom flask was added 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one (44 mg, 93 μmol) synthesized in Example 3. It was dissolved in 2 N hydrochloric acid (2 mL), and the resulting solution was concentrated under reduced pressure. The obtained residue was dried at 100 °C for 18 hours under reduced pressure 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one hydrochloride

[0167]

Chemical formula

[0168] 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (26 mg, 54 μmol) synthesized in Example 6 and ethyl acetate were added, extracted with 1 N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The obtained residue was dried at 60 °C for 1 hour under reduced pressure to obtain the title compound (23 mg, 83%) as a pale yellow amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one hydrochloride

[0170]

Chemical formula

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one synthesized in Example 8 and ethyl acetate were added, and extraction was carried out using 1 N hydrochloric acid. The aqueous layer was concentrated under reduced pressure. The obtained residue was dried under reduced pressure to obtain the title compound (11 mg, 39% from 2 steps of Example 8) as a pale yellow amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one hydrochloride

[0173]

Chemical formula

[0174] To a 10 mL test tube, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (31 mg, 64 μmol) synthesized in Example 9 and ethyl acetate were added, and extraction was carried out using 1 N hydrochloric acid. The aqueous layer was concentrated under reduced pressure. The obtained residue was dried at 60 °C under reduced pressure for 2 hours to obtain the title compound (22 mg, 67%) as a pale yellow amorphous solid.

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one hydrochloride

[0176]

Chem.

[0177] To a 10 mL test tube, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one (33 mg, 67 μmol) synthesized in Example 10 and ethyl acetate were added, extracted with 1 N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The obtained residue was dried at 60 °C for 2 hours under reduced pressure to obtain the title compound (33 mg, 94%) as a slightly brown amorphous solid.

[0178]

Table 1

[0179]

Table 2

[0180]

Table 3

[0181]

Table 4

[0182]

Table 5

[0183] Reference Example 7-1 (1S,3aR,5aS,6R,11bR,11cS)-10-Hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid 2,2,2-trichloroethyl ester synthesis

[0184] [Chemical formula]

[0185] (1S,3aR,5aS,6R,11bR,11cS)-10-Methoxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid 2,2,2-trichloroethyl ester (972.7 mg, 2.00 mmol) synthesized by the method described in Example 34(1) of WO2014136305 was added to a 100 mL eggplant-shaped flask and dissolved in methylene chloride (20 mL). After cooling the reaction solution to 0 °C, a 1 M boron tribromide / methylene chloride solution (6 mL) was added while stirring vigorously, and then the mixture was stirred for 1 hour while warming to room temperature. After adding a saturated aqueous sodium hydrogen carbonate solution (30 mL) to the reaction solution, the mixture was extracted with chloroform (20 mL × 3). The collected organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure to obtain the title compound (1.04 g, >100%) as a white foamy substance. The crude product was used in the next reaction as it was 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid 2,2,2-trichloroethyl ester synthesis

[0187]

Chem.

[0188] Add (1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid 2,2,2-trichloroethyl ester (1.04 g) synthesized in Reference Example 7-1 to a 100 mL eggplant-shaped flask, and dissolve it in THF (20 mL). Add triethylamine (2.79 mL, 20 mmol) and trifluoroacetic anhydride (1.41 mL, 10 mmol) to the resulting solution, and stir at room temperature for 1 hour. Concentrate the reaction solution under reduced pressure. Dilute the residue with saturated aqueous sodium hydrogen carbonate solution (50 mL), and then extract with ethyl acetate (30 mL x 2). Dry the collected organic layer over anhydrous sodium sulfate, filter off the insoluble matter, and concentrate the filtrate under reduced pressure to obtain the title compound (1.46 g, >100%) as a white foamy substance. The crude product was used in the next reaction as it was 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-14-yl)ethan-1-one

[0190]

Chem.

[0191] (1S,3aR,5aS,6R,11bR,11cS)-10-Hydroxy-14-(2,2,2-trifluoroacetyl)-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carboxylic acid 2,2,2-trichloroethyl ester (1.46 g) synthesized in Reference Example 7-2 was added to a 100 mL eggplant-shaped flask and dissolved in acetic acid (25 mL). Zinc powder (1.31 g, 20 mmol) was added to the resulting solution, and the mixture was stirred at room temperature for 2 hours. The reaction solution was filtered through celite to remove the excess zinc powder. The filtrate was concentrated under reduced pressure and then azeotroped with toluene. The residue was diluted with a saturated aqueous sodium hydrogen carbonate solution (30 mL) and then extracted with chloroform (30 mL x 3). The collected organic layer was dried over anhydrous sodium sulfate, the insoluble matter was filtered off, and 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 elution solvents to obtain the title compound (215 mg, overall yield of 3 steps 27%) as a pale yellow foam. 1H NMR CDCl3, 6.96 - 7.06 (m, 1H), 6.64 - 6.72 (m, 1H), 6.52 - 6.58 (m, 1H), 5.90 (br s, 1H), 4.90 (d, 0.5H, J = 6.8 Hz), 4.34 (dd, 0.5H, J = 6.5, 13.8 Hz), 4.18 - 4.24 (m, 0.5H), 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]

Chemical Structure

[0194] The synthesis of this compound was carried out according to the method described in WO2011 / 090935. To a 500 mL eggplant-shaped flask were added 20% sodium ethoxide / ethanol solution (60 mL) and ethyl 2-(ethoxymethylene)malonate (10.5 mL, 524 mmol), and the mixture was stirred at room temperature for 10 minutes. Hydrazine monohydrate (5.1 mL, 104 mmol) was added to the resulting mixture, and the mixture was heated and stirred at 80 °C for 18 hours. Then, the resulting yellow suspension was cooled to 0 °C. 1N hydrochloric acid (180 mL) was slowly added to the vigorously stirred reaction solution at the same temperature to obtain a yellow solution. Ethyl acetate (150 mL) was added to the resulting solution, and the mixture was stirred at room temperature for 1 hour. After separating the organic layer, the aqueous layer was extracted with ethyl acetate (100 mL × 2). The collected organic layers were dried over anhydrous sodium sulfate, and the insoluble matters were 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 M-H = 155

[0195] Reference Example 8-2 Synthesis of 3-Methoxy-1-methyl-1H-pyrazole-4-carboxylic Acid

[0196] [Chemical formula]

[0197] Ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (200 mg, 1.28 mmol), iodomethane (397 μL, 6.40 mmol) and DMF (5 mL) were added to a 50 mL round-bottomed flask, and sodium hydride (60%, dispersed in liquid paraffin) (256 mg, 6.40 mmol) was added. The mixture was stirred at room temperature for 22 hours. Under ice-cooling, water was added to the reaction solution, and the mixture was extracted three times with ethyl acetate. The collected organic layer was dried over sodium sulfate, the insoluble matter was filtered off, and 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 elution solvents to obtain ethyl 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (51 mg, 22%) as a white solid.

[0198] Ethyl 3-methoxy-1-methyl-1H-pyrazole-4-carboxylate (51 mg, 0.279 mmol) obtained above was added to a 50 mL round-bottomed flask, dissolved in ethanol (1 mL), and then 5 N aqueous sodium hydroxide solution (0.5 mL, 2.50 mmol) was added. The mixture was stirred at room temperature for 3 days. 1 N hydrochloric acid (2.7 mL) was added to the reaction solution, and the solution was concentrated under reduced pressure. The obtained residue was dissolved in THF, the insoluble matter was filtered off using celite, and 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 (br s, 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0200]

Chemical Structure

[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]indol-14-yl)ethan-1-one (54 mg, 136 μmol) synthesized in Reference Example 7-3, 6-oxo-1,6-dihydropyridine-2-carboxylic acid (67 mg, 0.48 mmol), and HATU (197 mg, 0.52 mmol) were added. After suspending 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 solution, and the mixture was stirred at the same temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the obtained 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 over anhydrous magnesium sulfate, the insoluble matter was 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 (concentration gradient: 10% - 30%) as elution solvents to obtain 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-carbonyl)pyridin-2(1H)-one (M + H = 514.26) as a white foam-like substance. 6-((1S,3aR,5aS,6R,11bR,11cS)-10-Hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one obtained above was dissolved in methanol (5 mL) in a 100 mL eggplant-shaped flask, 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, and 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 subjected to column chromatography (aminosilica gel, 12 g) using methanol and chloroform (concentration gradient: 10% - 30%) as elution solvents for purification to obtain a mixture of 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-14-(2,2,2-trifluoroacetyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one and the title compound 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one. The above-obtained mixture was dissolved in concentrated aqueous ammonia (3 mL) in a 50 mL eggplant flask, sealed with a rubber stopper, and heated with stirring at 80 °C for 18 hours in a sealed tube state. The reaction mixture was concentrated under reduced pressure, and the residue was subjected to column chromatography (aminosilica gel, 7 g) using methanol and chloroform (concentration gradient: 10% - 50%) as elution solvents. The obtained 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 in DMSO-d6, 9.08 (singlet, 1H), 7.53 (doublet of doublets, 0.7H, J = 6.9, 8.7 Hz), 7.47 (doublet of doublets, 0.3H, J = 7.3, 9.2 Hz), 6.92 (doublet, 0.7H, J = 8.2 Hz), 6.87 (doublet, 0.3H, J = 7.8 Hz), 6.39 - 6.58 (multiplet, 4H), 4.42 - 4.45 (multiplet, 0.7H), 4.13 - 4.17 (multiplet, 0.3H), 3.89 - 3.94 (multiplet, 0.3H), 3.71 - 3.76 (multiplet, 0.7H), 3.61 (doublet, 0.7H, J = 11.0 Hz), 3.45 - 3.48 (multiplet, 0.3H), 3.15 - 3.27 (multiplet, 1H), 2.80 - 3.09 (multiplet, 5H), 2.64 - 2.73 (multiplet, 1H), 2.13 - 2.44 (multiplet, 2H), 1.63 - 1.70 (multiplet, 1H), 1.25 - 1.59 (multiplet, 2H), 1.12 - 1.15 (doublet, 1H, J = 11.0 Hz), 1.01 - 1.07 (multiplet, 1H), 0.88 - 0.94 (multiplet, 1H), 0.66 - 0.74 (multiplet, 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one

[0204] [Chemical Structure]

[0205] 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (30 mg, 86 μmol), 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid (29 mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol) and HATU (72 mg, 0.19 mmol). However, only THF (2 mL) was used as the solvent. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate, extracted with chloroform, the organic layer was dried over sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (silica gel, 10 g) using methanol and ethyl acetate (concentration gradient: 0% - 30%) as the elution solvent for purification to obtain ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(3-methoxy-1-methyl-1H-pyrazol-4-yl)methanone (33.3 mg, 80%) as a pale yellow amorphous solid. 1H NMR CD3OD 7.69(s,0.7H),7.55(s,0.3H),6.90 - 6.96(m,1H),6.63(d,0.7H,J = 2.8Hz),6.53 - 6.58(m,1.3H),2.78 - 5.02(m,8H),3.90(s,3H),3.73(s,2.1H),3.68(s,0.9H),2.53 - 2.57(m,1H),2.31 - 2.33 (m,2H),1.90 - 2.09(m,2H),1.66 - 1.76(m,1H),1.51 - 0.78(m,7H),0.45 - 0.48(m,2H),0.09 - 0.12(m,2H).

[0206] To a 30 mL round-bottom flask was added ((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-1,2,3a,4,5,6,7,11c-octahydro-3H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-3-yl)(3-methoxy-1-methyl-1H-pyrazol-4-yl)methanone (15 mg, 31 μmol) obtained above, 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, followed by stirring at room temperature for 1 hour. After adding 1.4 N ammonia / methanol solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate, extracted with chloroform, the organic layer was dried over sodium sulfate, the insoluble matter was filtered off, and then the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol containing aqueous ammonia and chloroform (concentration: 10%) as the developing solvent to obtain the title compound (10.6 mg, 73%) as a pale yellow amorphous solid. 1H NMR DMSO-d6 11.47(s,0.1H),11.37(s,0.9H),9.11(s,1H),8.09(s,0.9H),7.48(s,0.1H),6.94(d,1H,J=8.2Hz),6.60(d,1H,J=2.3Hz),6.54(dd,1H,J=8.2,2.3Hz),4.33-4.50(m,1H),2.50-4.07(m,12H),2.19-2.34(m,2H),1.80-2.00(m,2H),1.58-1.65(m,1H),0.70-1.43(m,6H),0.38-0.53(m,2H),0.02-0.16(m,2H).

[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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one

[0208] [Chemical formula]

[0209] Following the same method 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (20 mg, 57 μmol), 5-chloro-2-oxo-1,2-dihydropyridine-3-carboxylic acid (22 mg, 0.13 mmol), diisopropylethylamine (50 μL, 0.29 mmol) and HATU (72 mg, 0.13 mmol). However, only THF (1 mL) was used as the solvent. After adding 1.4 N ammonia / methanol solution to the reaction solution to stop the reaction, it was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium bicarbonate, extracted with chloroform, the organic layer was dried over sodium sulfate, the insoluble matter was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (aminosilica gel, 8 g) using methanol and ethyl acetate (concentration gradient: 0% - 80%) as the elution solvent for purification to obtain the title compound (11.6 mg, 40%) as a brown amorphous solid. 1H NMR DMSO-d6 11.99(br s,1H),9.06(br s,1H),7.68(s,0.7H),7.59(s,0.3H),7.48(d,1H,J=2.3Hz),6.89(d,0.7H,J=8.2Hz),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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione

[0211]

Chem.

[0212] Following the same procedure as in Example 1, after reacting using (1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indol-10-ol (35 mg, 98 μmol), 1,3-dimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylic acid (35 mg, 0.19 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (145 mg, 0.38 mmol), a 2 N ammonia / methanol solution was added to the reaction solution to stop the reaction, and then it 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 then dried over anhydrous magnesium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (aminosilica gel, 10 g) using methanol and ethyl acetate (concentration gradient: 0% - 30%) as the elution solvent for purification. The obtained syrupy substance was dissolved in methanol (0.2 mL), t-butyl methyl ether (3 mL) was added to powder it, and then it was collected by filtration 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-(epiminoethano)-1,5a - methanonaphtho[1,2 - e]indole - 3 - carbonyl)pyridin - 2(1H)-one

[0214]

Chemical Structure

[0215] The experiment was carried out according to 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-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole (82 mg, 0.23 mmol), triethylamine (200 μL, 1.43 mmol) and HATU (167 mg, 0.44 mmol) adjusted according to the method of Example 67 described in WO2013035833. After the reaction, ethanolamine (200 μL) and methanol (1 mL) were added to the reaction solution to stop the reaction. After dilution with ethyl acetate (50 mL), it was washed with 6% aqueous ammonia (50 mL). The aqueous layer was extracted with chloroform (30 mL x 2), and the collected organic layers were dried over anhydrous sodium sulfate. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (aminosilica gel, 7 g) using methanol and ethyl acetate (concentration gradient: 10% - 50%) as elution solvents. The obtained syrupy substance was dissolved in methanol (0.2 mL), and t-butyl methyl ether (3 mL) was added to powder it. The obtained 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, 2H), 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 activities of the compounds provided by the present invention against μ, δ and κ opioid receptors were examined. Method: It was carried out according to a predetermined method using the Lance Ultra cAMP kit (PerkinElmer). In the evaluation of agonist activity, each human opioid receptor (δ, μ, and κ; accession numbers and catalog numbers are as follows) - expressing CHO cells and the test compound were each reacted in assay buffer (1×HBSS, 1 M HEPES, pH 7.4, 250 mM IBMX (Isobutylmethylxanthine), 7.5% BSA) in the presence of 10 μM forskolin for 30 minutes. Subsequently, the cAMP detection reagent in the kit was added, and time - resolved fluorescence measurement was performed using an EnVision plate reader (PerkinElmer) 1 hour later. The test compound and each control drug (δ: SNC80, μ: DAMGO, κ: U - 69593) were evaluated in the concentration range of 10 -12 ~10 -5 M. A dose - response curve of the test compound was obtained from the fluorescence value at 665 nm, and the EC 50 value and E max value were calculated. The E max value was determined as the ratio of the maximum response of the test compound when the maximum response of each control drug was set to 100%. SNC80: (+)-4 - [(αR)-α - ((2S,5R)-4 - allyl - 2,5 - dimethyl - 1 - piperazinyl)-3 - methoxybenzyl]-N,N - diethylbenzamide DAMGO: [D - Ala 2 ,N - MePhe 4 ,Gly - ol]enkephalin U - 69593: (+)-(5α,7α,8β)-N - methyl - N - [7 - (1 - pyrrolidinyl)-1 - oxaspiro[4.5]decan - 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] N.C.: Since the maximum reaction was not reached at the highest concentration (10 μM), the ED 50 value was not calculated. * : Since the maximum reaction was not reached at the highest concentration, the reaction rate at the highest concentration was shown as a reference value. As shown in Table 6, it was confirmed that the compound of the present invention has strong agonist activity against the opioid δ receptor and has no agonist activity or only very weak agonist activity against the μ and κ receptors.

[0219] Example 41 Mouse elevated plus-maze test (Test method) Five- to six-week-old male C57BL / 6N mice were used in the test. The mice were placed facing the side with a wall in a 40-cm-high plus maze apparatus consisting of an open arm (width 6 cm, length 30 cm) and a closed arm (width 6 cm, length 30 cm, wall height 15 cm), and were spontaneously allowed to enter the plus maze. The test substance was dissolved in saline or 0.005 N HCl-saline and administered subcutaneously to the back 30 minutes before the start of the test. The video camera recording was started at the start of the test, and the time when the mouse entered the plus maze was defined as the start of the test, and the exploratory behavior for 5 minutes was recorded by shooting. Based on the video, the residence time in each arm was determined, and the open arm residence time rate (%) was calculated. (Test results) As shown in FIGS. 1 and 2, in this experiment, compound 1 (the compound described in Example 1) and compound 7 (the compound described in Example 7) were confirmed to significantly increase the residence time rate in the open - field path and exhibit an anxiolytic - like effect at subcutaneous administrations of 3 mg / kg and 10 mg / kg, respectively. Also, for compound 3 (the compound described in Example 3), compound 9 (the compound described in Example 9), and compound 10 (the compound described in Example 10), a tendency to extend the residence time rate in the open - field path was observed (FIGS. 3 - 5).

[0220] Example 42 Rat elevated plus-maze test The anxiolytic effect of the compounds provided by the present invention was investigated using the rat elevated plus - maze test. (Test method) Wistar male rats at 7 - 9 weeks of age were used in the test. The rats were placed facing the walled path side in an elevated plus - maze apparatus consisting of an open - field path (width 10 cm, length 50 cm) and a walled path (width 10 cm, length 50 cm, wall height 30 cm) with a height of 50 cm, and were spontaneously allowed to enter the plus - maze, and their exploratory behavior was observed for 5 minutes. The test substance was dissolved in a 4.5% aqueous cyclodextrin solution and orally administered 2 hours before the start of the test. The test data were automatically analyzed using video image behavior analysis software (Smart 3.0 manufactured by PanLab, PanLab S.L.), and the residence time rate (%) in the open - field path was calculated. (Test results) As shown in FIG. 6, in this experiment, compound 7 (the compound described in Example 7), compound 3 (the compound described in Example 3), and compound 10 (the compound described in Example 10) were confirmed to significantly increase the residence time rate in the open - field path and exhibit an anxiolytic - like effect at an oral administration of 3 mg / kg.

[0221] Example 43 hERG (human ether-a-go-go related gene) potassium channel inhibition test (Test method) The test was performed using hERG channel stably expressing CHO cells (purchased from Channelopathy Foundation) with a Port-a-Patch automated patch clamp device (Nanion Technologies). The hERG current was measured by applying a test pulse of -50 mV for 1.5 seconds following a depolarizing pulse of +20 mV for 1.5 seconds at a frequency of once every 10 seconds after holding the cell membrane potential at -80 mV, and was confirmed by the tail current induced by the test pulse. The test compound was dissolved in the extracellular solution (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl2, 1 mM MgCl2, 10 mM D(+)-glucose, 10 mM HEPES, pH 7.4) and refluxed at room temperature for 5 minutes. The inhibition rate was determined from the ratio of the tail current value after application of the compound to the maximum tail current value before application of the compound, with the maximum tail current value before application of the compound set as 100%. Cells with a peak value of the tail current of 300 pA or more, a run-down of the tail current of less than 10% of the initial current value, and a leak current of less than 200 pA were used for the test.

[0222] (Test results) The test results are shown in Table 7. 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 effects. On the other hand, it was found that among the compounds described in WO 2013 / 35833 (Patent Document 4), there are compounds with strong hERG inhibitory effects.

[0223] [Table 7]

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

[0225] Example 44 Test for suppressing hyperemotional response in olfactory bulbectomy model (OBX) rats (Test method) According to the method of Saitoh et al. (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 1208:160-169.), OBX rats were prepared by isolating and raising them after removing the rat olfactory bulb region. The evaluation of hyperemotional reactivity was performed according to the hyperemotional reactivity 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). Yakuri to Chiryo 82, 267 (1983)) before grouping on the 14th day after the operation and 2 hours after administration on the 1st, 4th, 7th, 10th, and 14th days of administration. The drug was administered subcutaneously once a day for 14 consecutive days. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI), was used as the positive control drug. In addition, 1% cyclodextrin (CD) was used as the solvent. (Test Results) Administration of the test substance (the compound described in Example 7 above) at 0.1 mg / kg significantly reduced the hyperemotional reactivity of OBX rats compared to the vehicle administration group from the 4th day of administration, and restored it to the level comparable to that of sham-operated rats on the 7th day of administration. Administration of the test substance at 1 mg / kg significantly reduced the hyperemotional reactivity of OBX rats compared to the vehicle administration group from the 1st day of administration, and restored it to the level comparable to that of sham-operated rats on the 4th day of administration. Moreover, these effects persisted until the 14th day. On the other hand, administration of fluoxetine at 10 mg / kg significantly reduced the hyperemotional reactivity of OBX rats compared to the vehicle administration group on the 14th day of administration. From the above examinations, since the test substance was shown to potentially exhibit antidepressant-like effects from a single administration, different from SSRI, it was suggested that the onset of the antidepressant effect of the test substance was faster compared to SSRI. Furthermore, it was suggested that the antidepressant-like effect of the test substance was unlikely to cause tolerance.

[0226] Example 45 Reserpine-induced Parkinson's disease model mice (Test method) ICR male mice (5 weeks old: Japan SLC) were obtained and used after a domestication period (5 - 12 days). The PD model was prepared with reference to the report by Hille et al. (Exp Neurol. 2001, 172:189). It was prepared by intraperitoneal administration of reserpine (5 mg / kg) 18 - 24 hours before the start of the test. The test was conducted by subcutaneously administering the test compound on the same day and immediately placing the mice in an open-field activity cage to measure the moving distance for 60 minutes. (Test results) Administration of the test substance (the compound described in Example 7 above) at 10 mg / kg showed a significant increasing effect on exploratory behavior and also showed a tendency to increase rearing behavior, although not significantly (P = 0.16), suggesting a therapeutic effect of the test substance on Parkinson's disease.

[0227] Example 46 Evaluation using a rat cerebral infarction-induced overactive bladder model (Test method) Eight-week-old male Sprague-Dawley rats were used to establish a transient middle cerebral artery occlusion model under isoflurane inhalation anesthesia. On the next day, the neck was incised again under isoflurane inhalation anesthesia, a catheter for administration was placed in the jugular vein, and it was led to the back. In addition, a cystometry operation was performed, and the other end of the cannula inserted into the bladder was led to the back and connected to a Sieber. Four days after the cerebral ischemia surgery, cystometry measurement was performed under anesthesia-free and restraint-free conditions. After measuring the bladder pressure during the stable period, the vehicle was intravenously administered, and the pre-dose value was measured for about 30 minutes. Thereafter, the test substance was cumulatively intravenously administered in order from a low dose at intervals of about 30 minutes, and the post-dose value was measured for about 30 minutes. In the pre-dose measurement, animals judged to have frequent urination (urination interval of 10 minutes or less) were adopted, and the resting pressure, micturition pressure, urination interval, and single micturition volume at each time point were calculated. (Test results) The measurement results are shown in Table 8. As is clear from Table 8, the test substance (the compound described in Example 7 above) did not affect the resting pressure and micturition pressure at any dose. On the other hand, since the urination interval and single micturition volume showed a tendency to increase in a dose-dependent manner, an effect of improving frequent urination of the test substance was suggested.

[0228] [Table 8] Mean ± S.E. (n = 5)

[0229] Example 47 Metabolic stability test (Test method) Human liver microsomes and the test substance were reacted for a certain period of time (0 to 60 min), the remaining amount of the unchanged form of the test substance in the reaction sample was measured, and the residual rate was determined. The residual rate of the unchanged form at 0 hour of the reaction time was set to 100%, and the residual rate after incubation was plotted as log-linear against time, and the regression line (y = 100e -kt , k = slope of the straight line: disappearance rate constant) was obtained, and the metabolic clearance CL int (mL / min / kg) was calculated using the following formula. 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, it was revealed that the compounds of the present invention have excellent metabolic stability. On the other hand, it was found that there are compounds with poor metabolic stability among the compounds described in WO 2013 / 35833 (Patent Document 4).

Claims

1. The following general formula (I): 【Chemical Formula 1】 (wherein, R 1 is hydrogen; C 1-10 alkyl; C 6-10 aryl; C 2-6 alkenyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; C 3-6 cycloalkyl; or heteroarylalkyl having 1 to 5 carbon atoms in the alkylene moiety and containing 1 to 4 heteroatoms selected from N, O, and S as ring-constituting atoms, R 2 represents a heterocycle containing 1 to 4 heteroatoms selected from N, O, and S and at least one carbon atom as ring-constituting atoms, and having at least one set of adjacent ring-constituting atoms having a double bond and being 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 having 2 to 6 carbon atoms in the acyl moiety, R 6a and R 6b are the same or different and represent hydrogen; fluorine or hydroxy, or R 6a and R 6b together represent =O, R 7 and R 8 are the same or different and represent hydrogen; fluorine or hydroxy, R 9 and R 10 are the same or different and are hydrogen; C 1-6 alkyl; C 6-10 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 is O or CH 2 represents, and Y represents C(=O). However, the C 1 of R 1-10 alkyl; the alkylene moiety and cycloalkyl moiety of cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; the alkylene moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; and the alkylene moiety of 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 have 1 to 6 halogens; hydroxy; C 1-6 alkoxy; C 6-10 aryloxy; C 1-6 alkanoyl; C 1-6 alkanoyloxy; carboxyl; alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; carbamoyl; alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety; alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety; aminosulfonyl; alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety; alkylthio having 1 to 6 carbon atoms in the alkyl moiety; C substituted with 1 to 6 halogens 1-6 optionally substituted with at least one substituent selected from alkoxy; arylcarbonyl in which the number of carbon atoms in the aryl moiety is 6 to 10, and R 1 's C 6-10 aryl; the aryl moiety of aralkyl in which the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5; R 3 , R 4 and R 5 's C 6-10 the aryl moiety of aryloxy; and C 6-10 the aryl moiety of arylamino; and R 9 and R 10 's C 6-10 aryl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; the aryl moiety of aralkyl in which the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5; and the heteroaryl moiety of heteroarylalkyl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms and having 1 to 5 carbon atoms in the alkylene moiety is C 1-6 alkyl; C 1-6 alkoxy; C 1-6 alkanoyloxy; hydroxy; alkoxycarbonyl in which the number of carbon atoms in the alkoxy moiety is 1 to 6; carbamoyl; alkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; dialkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; halogen; nitro; cyano; C substituted with 1 to 3 halogens 1-6 alkyl; C substituted with 1 to 3 halogens 1-6 alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; phenoxy; phenylalkyl in which the number of carbon atoms in the alkyl is 1 to 3; optionally substituted with at least one substituent selected from methylenedioxy, R 2 's heterocycle, in addition to the oxo group, the above-mentioned R 1 's C 6-10It may have a substituent that an aryl may have, and further R 1 is C 1-10 In the case of alkyl, NR 11 R 12 may be substituted with, where R 11 and R 12 are the same or different and are hydrogen; C 1-10 alkyl; or aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, or R 11 and R 12 and, R 11 and R 12 the nitrogen atom to which is bonded, and further optionally 1 to 2 heteroatoms may together form a 5- to 7-membered ring, and also the alkylene moiety of the aralkyl of R 1 having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety may be substituted with at least one substituent selected from phenyl or C 1-6 alkyl substituted with 1 to 3 halogens. ) A pharmaceutical composition comprising a compound represented by, a tautomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof.

2. R 1 is C 1-10 alkyl; cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety; or aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety, the pharmaceutical composition according to claim 1.

3. R 1 is cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety, the pharmaceutical composition according to claim 1 or 2.

4. R 1 is C substituted with hydroxy 2-6 alkyl; C substituted with 1 to 6 halogens 1-6 alkyl; or C 1-6 C substituted with alkoxy 2-6 The pharmaceutical composition according to claim 1, wherein it is alkyl.

5. R 1 The pharmaceutical composition according to claim 1, wherein R is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl or 2-(aminosulfonyl)ethyl.

6. R 2 The pharmaceutical composition according to any one of claims 1 to 5, wherein R 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 pair of adjacent ring-constituting atoms has a double bond, and is further substituted with at least one oxo group, and is a 5- to 7-membered heterocycle or a heterocycle condensed with a benzene ring to the heterocycle.

7. R 2 C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 The pharmaceutical composition according to any one of claims 1 to 6, which is pyridine 1-oxide optionally substituted with 1 to 4 substituents selected from alkyl.

8. R 2 The pharmaceutical composition according to any one of claims 1 to 7, wherein R is pyridine 1-oxide.

9. R 2 C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 The pharmaceutical composition according to any one of claims 1 to 6, which is pyridin-2(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl.

10. R 2 is pyridin-2(1H)-one; 1-C 1-6 alkylpyridin-2(1H)-one; or 6-C 1-6 The pharmaceutical composition according to any one of claims 1 to 6 or claim 9, which is alkylpyridin-2(1H)-one.

11. R 2 is a C substituted with 1 to 3 fluorines 1-10 alkyl and an unsubstituted C 1-10 pyridin-4(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl, and the pharmaceutical composition according to any one of claims 1 to 6.

12. R 2 is pyridin-4(1H)-one or 1-C 1-6 alkylpyridin-4(1H)-one, and the pharmaceutical composition according to any one of claims 1 to 6 or claim 11.

13. R 2 is a C substituted with 1 to 3 fluorines 1-10 alkyl and an unsubstituted C 1-10 pyridazin-3(2H)-one optionally substituted with 1 to 3 substituents selected from alkyl, and the pharmaceutical composition according to any one of claims 1 to 6.

14. R 2 is pyridazin-3(2H)-one, and the pharmaceutical composition according to any one of claims 1 to 6 or claim 13.

15. R 2 is C 1-10 alkyl and a C substituted with 1 to 3 fluorines 1-10 pyrazin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl, and the pharmaceutical composition according to any one of claims 1 to 6.

16. R 2 is pyrazin-2(1H)-one, and the pharmaceutical composition according to any one of claims 1 to 6 or claim 15.

17. R 2 is a C substituted with 1 to 3 fluorines 1-10 alkyl and an unsubstituted C 1-10The pharmaceutical composition according to any one of claims 1 to 6, which is 4H-pyran-4-one or 2H-pyran-2-one optionally substituted with 1 to 3 substituents selected from alkyl.

18. R 2 The pharmaceutical composition according to any one of claims 1 to 6 or claim 17, wherein R is 4H-pyran-4-one or 2H-pyran-2-one.

19. R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 The pharmaceutical composition according to any one of claims 1 to 6, which is quinolin-2(1H)-one optionally substituted with 1 to 3 substituents selected from alkyl.

20. R 2 The pharmaceutical composition according to any one of claims 1 to 6 or claim 19, wherein R is quinolin-2(1H)-one.

21. R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 The pharmaceutical composition according to any one of claims 1 to 6, which is pyrimidin-4(3H)-one or pyrimidine-2,4(1H,3H)-dione optionally substituted with 1 to 3 substituents selected from alkyl.

22. R 2 The pharmaceutical composition according to any one of claims 1 to 6 or claim 21, wherein R is pyrimidin-4(3H)-one or pyrimidine-2,4(1H,3H)-dione.

23. X is CH 2 The pharmaceutical composition according to any one of claims 1 to 22.

24. R 3 and R 4 Of these, one is hydroxy and the other is hydrogen, according to any one of claims 1 to 23.

25. R 3 is halogen; cyano; carbamoyl; C 1-6 alkoxy; C 1-6 alkanoyloxy; amino; or acylamino in which the number of carbon atoms of the acyl moiety is 2 to 6, R 4 is hydrogen or hydroxy, R 5 is hydrogen, the pharmaceutical composition according to any one of claims 1 to 23.

26. R 3 is hydroxy; carbamoyl; or C 1-6 alkanoyloxy, R 4 is hydrogen, R 5 is hydrogen, the pharmaceutical composition according to any one of claims 1 to 23.

27. R 3 is hydroxy, R 4 is hydrogen, R 5 is hydrogen, the pharmaceutical composition according to any one of claims 1 to 23.

28. R 3 , R 4 and R 5 are all hydrogen, the pharmaceutical composition according to any one of claims 1 to 23.

29. R 6a , R 6b , R 7 , R 8 , R 9 and R 10 are all hydrogen, the pharmaceutical composition according to any one of claims 1 to 28.

30. R 5 , R 6a , R 6b , R 7 , R 8 , R 9 and R 10 are hydrogen, R 1 is hydrogen; C 1-6 alkyl; C 2-6Alkenyl; cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; or aralkyl in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms, R 2 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 pair of adjacent ring-constituting atoms has a double bond, and is further substituted with at least one oxo group, representing a 5- to 7-membered heterocycle or a heterocycle condensed with a benzene ring to the heterocycle, Here, R 2 is bonded to Y via a carbon atom which is a ring-constituting atom of R 2 R 3 and R 4 are the same or different and are hydrogen; hydroxy; halogen; cyano; carbamoyl; C 1-6 alkoxy; C 6-10 aryloxy; C 1-6 alkanoyloxy; amino; or acylamino in which the acyl moiety has 2 to 6 carbon atoms, X is CH 2 and and Y is C(=O), provided that the C 1 alkyl of R 1-6 ; the alkylene moiety and the cycloalkyl moiety of cycloalkylalkyl in which the cycloalkyl moiety has 3 to 6 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; or the alkylene moiety of aralkyl in which the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety 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 1-6Alkanoyloxy; carboxyl; alkoxycarbonyl in which the number of carbon atoms in the alkoxy moiety is 1 to 6; carbamoyl; alkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; dialkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; alkylsulfonyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; aminosulfonyl; alkylsulfinyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; alkylthio in which the number of carbon atoms in the alkyl moiety is 1 to 6; C substituted with 1 to 6 halogens 1-6 Optionally substituted with at least one substituent selected from alkoxy; arylcarbonyl in which the number of carbon atoms in the aryl moiety is 6 to 10 and R 1 The aryl moiety of the aralkyl in which the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5; R 3 and R 4 The C of 6-10 The aryl moiety of aryloxy may be C 1-6 Alkyl; C 1-6 Alkoxy; C 1-6 Alkanoyloxy; hydroxy; alkoxycarbonyl in which the number of carbon atoms in the alkoxy moiety is 1 to 6; carbamoyl; alkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; dialkylcarbamoyl in which the number of carbon atoms in the alkyl moiety is 1 to 6; halogen; nitro; cyano; C substituted with 1 to 3 halogens 1-6 Alkyl; C substituted with 1 to 3 halogens 1-6 Alkoxy; phenyl; heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as ring-constituting atoms; phenoxy; phenylalkyl in which the number of carbon atoms in the alkyl is 1 to 3; Optionally substituted with at least one substituent selected from methylenedioxy R 2 In addition to the oxo group, the heterocycle of R 1 May have a substituent that the aryl moiety of the aralkyl in which the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5 may have Furthermore, R 1The alkylene moiety of the aralkyl, wherein the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5, is phenyl or C substituted with 1 to 3 halogens 1-6 The pharmaceutical composition according to claim 1, which may be substituted with at least one substituent selected from C

31. R 1 is C 1-6 alkyl; cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is 3 to 6 and the number of carbon atoms in the alkylene moiety is 1 to 5; or aralkyl wherein the number of carbon atoms in the aryl moiety is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5, which is the pharmaceutical composition according to claim 1 or claim 30.

32. R 1 is cycloalkylalkyl, wherein the number of carbon atoms in the cycloalkyl moiety is 3 to 6 and the number of carbon atoms in the alkylene moiety is 1 to 5, which is the pharmaceutical composition according to claim 1, claim 30, or claim 31.

33. R 1 is C substituted with hydroxy 2-6 alkyl; C substituted with 1 to 6 halogens 1-6 alkyl; or C 1-6 alkyl substituted with alkoxy 2-6 which is the pharmaceutical composition according to claim 1 or claim 30.

34. R 1 is allyl, fluoropropyl, 2-(pyridin-3-yl)ethyl, 2-(methylsulfonyl)ethyl or 2-(aminosulfonyl)ethyl, which is the pharmaceutical composition according to claim 1 or claim 30.

35. R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10The pharmaceutical composition according to any one of claims 1 or 30 to 34, which is pyridine 1-oxide, pyridin-2(1H)-one, pyridin-4(1H)-one, pyridazin-3(2H)-one, pyrazin-2(1H)-one, 4H-pyran-4-one, 2H-pyran-2-one, quinolin-2(1H)-one, pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, optionally substituted with a substituent selected from alkyl.

36. R 2 is C 1-10 alkyl and C substituted with 1 to 3 fluorines 1-10 The pharmaceutical composition according to any one of claims 1 or 30 to 35, which is pyridine 1-oxide optionally substituted with 1 to 4 substituents selected from alkyl.

37. R 2 The pharmaceutical composition according to any one of claims 1 or 30 to 36, wherein R is pyridine 1-oxide.

38. R 2 is C 1-10 alkyl and C substituted with 1 to 3 fluorines 1-10 The pharmaceutical composition according to any one of claims 1 or 30 to 35, which is pyridin-2(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl.

39. R 2 is pyridin-2(1H)-one; 1-C 1-6 alkylpyridin-2(1H)-one; or 6-C 1-6 The pharmaceutical composition according to any one of claims 1 or 30 to 35, which is alkylpyridin-2(1H)-one.

40. R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 The pharmaceutical composition according to any one of claims 1 or 30 to 35, which is pyridin-4(1H)-one optionally substituted with 1 to 4 substituents selected from alkyl.

41. R 2 is pyridin-4(1H)-one or 1-C 1-6 alkylpyridin-4(1H)-one, and the pharmaceutical composition according to any one of Claims 1, 30 to 35 or Claim 40.

42. R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 alkyl, and is pyridazin-3(2H)-one which may be substituted with 1 to 3 substituents selected therefrom, and the pharmaceutical composition according to any one of Claims 1 or 30 to 35.

43. R 2 is pyridazin-3(2H)-one, and the pharmaceutical composition according to any one of Claims 1, 30 to 35 or Claim 42.

44. R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 alkyl, and is pyrazin-2(1H)-one which may be substituted with 1 to 3 substituents selected therefrom, and the pharmaceutical composition according to any one of Claims 1 or 30 to 35.

45. R 2 is pyrazin-2(1H)-one, and the pharmaceutical composition according to any one of Claims 1, 30 to 35 or Claim 44.

46. R 2 is C substituted with 1 to 3 fluorines 1-10 alkyl and unsubstituted C 1-10 alkyl, and is 4H-pyran-4-one or 2H-pyran-2-one which may be substituted with 1 to 3 substituents selected therefrom, and the pharmaceutical composition according to any one of Claims 1 or 30 to 35.

47. R 2 is 4H-pyran-4-one or 2H-pyran-2-one, and the pharmaceutical composition according to any one of Claims 1, 30 to 35 or Claim 46.

48. R 2 is a quinolin-2(1H)-one optionally substituted with 1 to 3 substituents selected from C alkyl substituted with 1 to 3 fluorines and unsubstituted C alkyl, according to any one of claims 1 or 30 to 35. 1-10 alkyl and the pharmaceutical composition according to any one of claims 1 or 30 to 35 which may be substituted with 1 to 3 substituents selected from C alkyl and unsubstituted C alkyl. 1-10 alkyl, the pharmaceutical composition according to any one of claims 1 or 30 to 35 which may be substituted with 1 to 3 substituents selected from C alkyl and unsubstituted C alkyl.

49. R 2 is quinolin-2(1H)-one, the pharmaceutical composition according to any one of claims 1, 30 to 35 or claim 48.

50. R 2 is a pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione optionally substituted with 1 to 3 substituents selected from C alkyl substituted with 1 to 3 fluorines and unsubstituted C alkyl, according to any one of claims 1 or 30 to 35. 1-10 alkyl and the pharmaceutical composition according to any one of claims 1 or 30 to 35 which may be substituted with 1 to 3 substituents selected from C alkyl and unsubstituted C alkyl. 1-10 alkyl, the pharmaceutical composition according to any one of claims 1 or 30 to 35 which may be substituted with 1 to 3 substituents selected from C alkyl and unsubstituted C alkyl.

51. R 2 is pyrimidin-4(3H)-one or pyrimidin-2,4(1H,3H)-dione, the pharmaceutical composition according to any one of claims 1, 30 to 35 or claim 50.

52. R 3 and R 4 wherein one of them is hydroxy and the other is hydrogen, the pharmaceutical composition according to any one of claims 1 or 30 to 51.

53. R 3 is halogen; cyano; carbamoyl; C 1-6 alkoxy; C 1-6 alkanoyloxy; amino; or acylamino having 2 to 6 carbon atoms in the acyl moiety, R 4 is hydrogen or hydroxy, the pharmaceutical composition according to any one of claims 1 or 30 to 51.

54. R 3 is hydroxy; carbamoyl; or C 1-6Alkanoyloxy, R 4 The pharmaceutical composition according to any one of claims 1 or 30 to 51, wherein R is hydrogen.

55. R 3 is hydroxy and R 4 is hydrogen, the pharmaceutical composition according to any one of claims 1 or 30 to 51.

56. R 3 and R 4 are hydrogen, the pharmaceutical composition according to any one of claims 1 or 30 to 51.

57. 2 - ((1S,3aR,5aS,6R,11bR,11cS) - 14 - (cyclopropylmethyl) - 10 - hydroxy - 2,3,3a,4,5,6,7,11c - octahydro - 1H - 6,11b - (epiminoethano) - 1,5a - methanonaphtho[1,2 - e]indole - 3 - carbonyl)pyridine 1 - oxide, 4 - ((1S,3aR,5aS,6R,11bR,11cS) - 14 - (cyclopropylmethyl) - 10 - hydroxy - 2,3,3a,4,5,6,7,11c - octahydro - 1H - 6,11b - (epiminoethano) - 1,5a - methanonaphtho[1,2 - e]indole - 3 - carbonyl)pyridine 1 - oxide, 3 - ((1S,3aR,5aS,6R,11bR,11cS) - 14 - (cyclopropylmethyl) - 10 - hydroxy - 2,3,3a,4,5,6,7,11c - octahydro - 1H - 6,11b - (epiminoethano) - 1,5a - methanonaphtho[1,2 - e]indole - 3 - carbonyl)pyridin - 2(1H) - one, 3 - ((1S,3aR,5aS,6R,11bR,11cS) - 14 - (cyclopropylmethyl) - 10 - hydroxy - 2,3,3a,4,5,6,7,11c - octahydro - 1H - 6,11b - (epiminoethano) - 1,5a - methanonaphtho[1,2 - e]indole - 3 - carbonyl)pyridine 1 - oxide, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-6-methylpyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-4(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridazin-3(2H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)quinolin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-2H-pyran-2-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-4H-pyran-4-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-4(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(Cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 2-((1S,3aR,5aS,6R,11bR,11cS)-10-acetoxy-14-(Cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrazin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidine-2,4(1H,3H)-dione, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyrimidin-4(3H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, 6-((1S,3aR,5aS,6R,11bR,11cS)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 4-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methyl-1,2-dihydro-3H-pyrazol-3-one, 5-chloro-3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione and 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-methoxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, a pharmaceutical composition comprising a compound selected from the group consisting of the compound, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof.

58. A pharmaceutical composition comprising a compound that is 2-(((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.

59. A pharmaceutical composition comprising a compound that is 3-(((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.

60. A pharmaceutical composition comprising a compound that is 6-(((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine-2(1H)-one), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.

61. A pharmaceutical composition comprising a compound that is 5-(((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridine-2(1H)-one), a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof.

62. A pharmaceutical composition comprising a compound which is 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof. **Claim 63** A pharmaceutical composition comprising a compound which is 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof. **Claim 64** A pharmaceutical composition comprising a compound which is 2-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridine 1-oxide, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a solvate of a pharmaceutically acceptable salt of the compound. **Claim 65** A pharmaceutical composition comprising a compound which is 3-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a solvate of a pharmaceutically acceptable salt of the compound. **Claim 66** A pharmaceutical composition comprising a compound which is 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)pyridin-2(1H)-one, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a solvate of the pharmaceutically acceptable salt of the compound.

67. A pharmaceutical composition comprising a compound which is 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a solvate of the pharmaceutically acceptable salt of the compound.

68. A pharmaceutical composition comprising a compound which is 6-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-methylpyridin-2(1H)-one, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a solvate of the pharmaceutically acceptable salt of the compound.

69. A pharmaceutical composition comprising a compound which is 5-((1S,3aR,5aS,6R,11bR,11cS)-14-(cyclopropylmethyl)-10-hydroxy-2,3,3a,4,5,6,7,11c-octahydro-1H-6,11b-(epiminoethano)-1,5a-methanonaphtho[1,2-e]indole-3-carbonyl)-1-ethylpyridin-2(1H)-one, a pharmaceutically acceptable salt of the compound, a solvate of the compound, or a solvate of the pharmaceutically acceptable salt of the compound.

70. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing pain.

71. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing headache.

72. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing fibromyalgia.

73. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing depression or anxiety symptoms in fibromyalgia.

74. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing depression.

75. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing anxiety.

76. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing Parkinson's disease.

77. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing overactive bladder.

78. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing urinary incontinence.

79. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing frequent urination.

80. The pharmaceutical composition according to any one of claims 1 to 69, which is a pharmaceutical composition for treating or preventing glaucoma.

81. The pharmaceutical composition according to any one of claims 1 to 80, which is for oral administration.

82. The pharmaceutical composition for oral administration according to any one of claims 1 to 81, wherein the compound, a tautomer, stereoisomer thereof, or a pharmaceutically acceptable salt or solvate thereof is orally administered at 0.1 to 100 mg / day.

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