KR20190053228A

KR20190053228A - Use of a morphinan derivative for the treatment of opioid δ receptor agonist-related disorders

Info

Publication number: KR20190053228A
Application number: KR1020197010645A
Authority: KR
Inventors: 히로시 나가세; 히데아키 후지이; 아키요시 사이토; 에리코 나카타; 마사아키 히로세; 이사오 오오이; 고헤이 하야시다
Original assignee: 닛뽕 케미파 가부시키가이샤
Priority date: 2016-09-16
Filing date: 2017-09-15
Publication date: 2019-05-17

Abstract

The present invention relates to a pharmaceutical composition comprising a morphinan derivative exhibiting an opioid δ receptor agonist action. By administering the medicinal composition provided by the present invention, an opioid-δ receptor-related disease (eg, headache) can be treated or prevented.

Description

Use of a morphinan derivative for the treatment of opioid δ receptor agonist-related disorders

The present invention relates to the use of morphinan derivatives having an opioid δ receptor agonist action, for example for the treatment of headache.

The present application claims priority based on Japanese Patent Application No. 2016-203925 filed on September 16, 2016, the entirety of which is hereby incorporated by reference.

The opioid binds to the opioid receptor and exerts its effects, and there are three subtypes of opioid receptors, mu, delta and kappa. It is known that in all three subtypes of μ, δ, and κ, the agonist has analgesic action.

Among these, agonists selectively activating opioid δ receptors are expected to have little or no side effects caused by activation of opioid receptors or opioid κ receptors.

To date, various compounds have been reported as opioid δ receptor agonists, and their analgesic action, antidepressant action and anti-anxiety action 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 in preventing headaches in that they are effective for chronic and acute headaches, and suppress the onset of headache (Non-Patent Document 4).

Japanese Patent Application Publication No. 2006-522775 WO 2001/046192 WO 2008/001859 WO 2013/035833 WO 2014/021273 WO 2014/136305

Tetrahedron, 2011, 67, 6682 European Journal of Pharmacology 276 (1995) 131-135 European Journal of Pharmacology 322 (1997) 27-30 British Journal of Pharmacology 171 (2014) 2375-2384

It is an object of the present invention to provide a medicament useful for the treatment or prevention of an opioid-δ receptor-related disease (for example, headache).

The present inventors have intensively studied to achieve the above object and found out that a pharmaceutical composition containing a morphinan derivative is useful for the treatment or prevention of an opioid-δ receptor-related disease (for example, headache) Completed.

The invention relates, in one aspect, to a compound of formula (I):

[Chemical Formula 1]

Wherein R ¹ is hydrogen, C _1-10 alkyl, C _6-10 aryl, C _2-6 alkenyl, the number of carbon atoms of the cycloalkyl moiety is 3 to 6, the number of carbon atoms of the alkylene moiety is 1 to 5 Aralkyl wherein the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; C _3-6 cycloalkyl; Represents a heteroarylalkyl having 1 to 4 hetero atoms as ring constituting atoms and having 1 to 5 carbon atoms in the alkylene moiety,

R ² contains 1 to 4 hetero atoms 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 , A heterocycle substituted with at least one oxo group,

Wherein, R ² is through a carbon atom of the ring constituent atoms of R ² bonded to a Y,

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 are hydrogen; Fluorine or hydroxy, or R < ^6a > and R < ^6b >

R ⁷ and R ⁸ are the same or different and are 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 a ring constituent atom; 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; Heteroarylalkyl wherein the heteroaryl moiety comprises 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; Cycloalkylalkyl or C _2-6 alkenyl 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,

X represents O or CH ₂ ,

And Y represents C (= O).

Provided that C _1-10 alkyl of R ¹ ; An alkylene moiety and a cycloalkyl moiety of a 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; An 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 an alkylene moiety of a heteroarylalkyl wherein the heteroaryl moiety contains 1 to 4 heteroatoms selected from N, O and S as a ring constituent atom and the number of carbon atoms of the alkylene moiety is 1 to 5,

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; An alkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; A dialkylcarbamoyl group 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 _1-6 alkoxy substituted with 1 to 6 halogens; And arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety,

And C _6-10 aryl of R ¹ ; An aryl moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; Aryl moieties of C _6-10 aryloxy of R ³ , R ⁴ and R ⁵ ; And aryl moieties of C _6-10 arylamino; And C _6-10 aryl of R ⁹ and R ¹⁰ ; Heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as a ring constituent atom; An aryl moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; And the heteroaryl moiety of the heteroarylalkyl wherein 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,

C _1-6 alkyl; C _1-6 alkoxy; C _1-6 alkanoyloxy; Hydroxy; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; Carbamoyl; An alkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; A dialkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; Halogen; Nitro; Cyano; C _1-6 alkyl substituted with one to three halogens; C _1-6 alkoxy substituted by one to three halogens; Phenyl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as a ring constituent atom; Phenoxy; Phenylalkyl having 1 to 3 carbon atoms in the alkyl; Methylenedioxy, < / RTI >< RTI ID = 0.0 >

The heterocycle of R ² may have a substituent which the C _6-10 aryl of R ¹ described above may have in addition to the oxo group,

And when R ¹ is C _1-10 alkyl, it may be substituted with NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are the same or different and are hydrogen; C _1-10 alkyl; Or an aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety or a nitrogen atom to which R ¹¹ and R ¹² and R ¹¹ and R ¹² are bonded, One or two hetero atoms may be taken together to form a 5-7 membered ring,

And the alkylene moiety of the aralkyl in which the number of carbon atoms in the aryl moiety of R ¹ is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5 is phenyl or C _1-6 alkyl substituted with 1 to 3 halogens May be substituted with at least one substituent selected from the group consisting of < RTI ID = 0.0 >

, A tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

The present invention also provides, in one aspect, an opioid δ receptor-related compound comprising the compound represented by the general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof of the compound And a pharmaceutical composition for the treatment or prevention of a disease (e.g., headache).

The present invention provides medicaments useful for the treatment or prevention of opioid-δ receptor-related diseases (for example, headache) and the like.

Brief Description of the Drawings Fig. 1 is a diagram showing the results of a mouse hyperbolic cruciate test on Compound 1. Fig. The ordinate axis represents the ratio of staying time in the runway without a wall, and the abscissa axis represents the drug to be tested and its dose.
Fig. 2 is a diagram showing the results of a mouse hyperbolic cruciate test on Compound 7. Fig. The ordinate axis represents the ratio of staying time in the runway without a wall, and the abscissa axis represents the drug to be tested and its dose.
Fig. 3 is a diagram showing the results of a mouse hyperbolic cruciate test on Compound 3. Fig. The ordinate axis represents the ratio of staying time in the runway without a wall, and the abscissa axis represents the drug to be tested and its dose.
4 is a graph showing the results of a mouse hyperbolic cruciate test on Compound 9. Fig. The ordinate axis represents the ratio of staying time in the runway without a wall, and the abscissa axis represents the drug to be tested and its dose.
5 is a diagram showing the results of a mouse hyperbolic cruciate test on Compound 10. Fig. The ordinate axis represents the ratio of staying time in the runway without a wall, and the abscissa axis represents the drug to be tested and its dose.
6 is a diagram showing the results of a rat elevated cruciate test on compounds 3, 7, and 10. FIG. The ordinate axis represents the ratio of staying time in the runway without a wall, and the abscissa axis represents the drug to be tested and its dose.

Next, the present invention will be described in more detail.

(One)

The invention relates, in one aspect, to a compound of formula (I):

(2)

R ² contains 1 to 4 hetero atoms 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 at least 1 Lt; / RTI > represents a heterocycle substituted with one to three oxo groups,

X represents O or CH ₂ ,

And Y represents C (= O).

Provided that C _1-10 alkyl of R ¹ ; An alkylene moiety and a cycloalkyl moiety of a 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; An 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 heteroaryl moiety contains 1 to 4 heteroatoms selected from N, O and S as a ring constituent atom and the alkylene moiety of the heteroarylalkyl having 1 to 5 carbon atoms in the alkylene moiety is 1 to 6 Halogen; Hydroxy; C _1-6 alkoxy; C _6-10 aryloxy; C _1-6 alkanoyl; C _1-6 alkanoyloxy; Carboxyl; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; Carbamoyl; An alkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; A dialkylcarbamoyl group 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 _1-6 alkoxy substituted with 1 to 6 halogens; And arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety,

And when R ¹ is C _1-10 alkyl, it may be substituted with NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are the same or different and are hydrogen; C _1-10 alkyl; Or an aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety or a nitrogen atom to which R ¹¹ and R ¹² and R ¹¹ and R ¹² are bonded, An alkyl of 1 to 5 carbon atoms of an alkylene moiety having 1 to 5 carbon atoms and having 1 to 2 hetero atoms united to form a 5- to 7-membered ring, and the number of carbon atoms of the aryl moiety of R ¹ is 6 to 10, And the phenylene group or the C _1-6 alkyl substituted with 1 to 3 halogens may be substituted with at least one substituent.

In one embodiment, there is provided a compound represented by the general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvent thereof used in a pharmaceutical composition provided by the present invention of (1) The cargoes are as follows (2) to (58):

(2)

R ¹ is C _1-10 alkyl; Cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is from 3 to 6 and the number of carbon atoms in the alkylene moiety is from 1 to 5; Or an 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 mixture of the compound represented by the above general formula (I) A pharmaceutically acceptable salt or solvate thereof;

(3)

The compound according to (1) or (2) above, wherein R ¹ is cycloalkyl alkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety, tautomers of the compounds, stereoisomers , Or a pharmaceutically acceptable salt or solvate thereof;

(4)

C _2-6 alkyl, wherein R < ¹ > is substituted with hydroxy; C _1-6 alkyl substituted with one to six halogens; Or a C _2-6 alkyl substituted by C _1-6 alkoxy, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof (1) ;

(5)

(1) wherein R ¹ is allyl, fluoropropyl, 2- (pyridin-3-yl) ethyl, 2- (methylsulfonyl) ethyl or 2- Compounds, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or solvates thereof;

(6)

R ² contains 1 to 4 hetero atoms 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 at least 1 The compound according to any one of (1) to (5), a tautomer, a stereoisomer, a stereoisomer, a stereoisomer or a mixture thereof, wherein the compound is a 5- to 7-membered heterocyclic ring substituted with two oxo groups or a heterocyclic ring in which a benzene ring is condensed, Or a pharmaceutically acceptable salt or solvate thereof;

(7)

R ² has 1 to 3 fluorine substituted C _1-10 alkyl, and is substituted with 1-4 substituents selected from C _1-10 alkyl is not substituted pyridine 1-oxide, which may in the above (1) to (6), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound;

(8)

The compound according to any one of (1) to (7), wherein R ² is pyridine 1-oxide, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(9)

R ² is one to three fluorine-C _1-10 alkyl, and pyridin-2 that may be substituted with 1-4 substituents selected from C _1-10 alkyl is not substituted with (1H) - is on, the ( A compound represented by any one of (1) to (6), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(10)

R ² is pyridin -2 (1H) - one; 1-C _1-6 alkylpyridin-2 (1H) -one; Or 6-C _1-6 alkylpyridin-2 (1H) -one, the compound according to any one of (1) to (6) or (9) above, a tautomer, a stereoisomer, Acceptable salts or solvates thereof;

(11)

Pyridin -4 optionally R ² is substituted with one to three one to four substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with fluorine (1H) - is on, the ( A compound represented by any one of (1) to (6), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(12)

(1) to (6) or (11), wherein R ² is pyridin-4 (1H) -one or 1-C _1-6 alkylpyridin-4 A tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(13)

(2H) -one which may be substituted with 1 to 3 substituents selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl, and R ² is pyridazin-3 A compound according to any one of (1) to (6), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(14)

The compound according to any one of (1) to (6) or (13), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R ² is pyridazin-3 Their solvates;

(15)

Pyrazin-2 which may be substituted with R ² is a C _1-10 alkyl, and 1-3 substituents selected from C _1-10 alkyl is not substituted with one to three fluorine (1H) - is on, the ( A compound represented by any one of (1) to (6), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(16)

The compound according to any one of (1) to (6), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is pyrazin-2 (1H) -one;

(17)

R ² is one to three fluorine pyran which may be optionally substituted with one to three substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, it is not substituted by 4H- 2H- pyran-4-one or A compound represented by any one of the above (1) to (6), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(18)

(1) to (6) or (17), wherein R ² is 4H-pyran-4-one or 2H-pyran-2-one, tautomers, stereoisomers, Acceptable salts or solvates thereof;

(19)

Wherein R ² is quinolin-2 (1H) -one which may be substituted with 1 to 3 substituents selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl; A compound represented by any one of (1) to (6), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(20)

The compound according to any one of (1) to (6) above, wherein R ² is quinolin-2 (1H) -one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(21)

R ² is one to three C _1-10 alkyl and the fluorine-pyrimidine-4, that is not a substituted C _1-10 optionally substituted with 1 to 3 substituents selected from alkyl substituted with (3H) - one or The compound according to any one of (1) to (6) above, wherein the compound is a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvent thereof, wherein the compound is a pyrimidine-2,4 (1H, freight ;

(22)

The compound according to any one of (1) to (6) or (21), wherein R ² is pyrimidin-4 (3H) -one or pyrimidine- A tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(23)

The compound according to any one of (1) to (22) above, wherein X is CH ₂ , a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(24)

The compound according to any one of (1) to (23) above, wherein one of R ³ and R ⁴ is hydroxy and the other is hydrogen, a tautomer, a stereoisomer, or a 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 a compound according to any one of (1) to (23) above, wherein the number of carbon atoms of the acyl moiety is 2 to 6, R ⁴ is hydrogen or hydroxy, and R ⁵ is hydrogen, An isomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(26)

R ³ is hydroxy; Carbamoyl; Or a C _1-6 alkanoyloxy, R ⁴ is hydrogen, R ⁵ is a compound according to any one of hydrogen, the above (1) to 23, a tautomer thereof, a stereoisomer of the compound, or a pharmaceutically Or a solvate thereof;

(27)

The compound according to any one of (1) to (23) above, wherein R ³ is hydroxy, R ⁴ is hydrogen and R ⁵ is hydrogen, a tautomer of the compound, a stereoisomer or a pharmaceutically acceptable salt thereof Salts or solvates thereof;

(28)

The compound according to any one of (1) to (23) above, wherein R ³ , R ⁴ and R ⁵ are both hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(29)

The compound according to any one of (1) to (28) above, wherein R ^6a , R ^6b , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are both hydrogen, a tautomer, a stereoisomer, Or a solvate thereof;

(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; Cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is from 3 to 6 and the number of carbon atoms in the alkylene moiety is from 1 to 5; Or 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 ² contains 1 to 4 hetero atoms 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 at least 1 A 5- to 7-membered heterocyclic ring substituted with an oxo group or a heterocyclic ring condensed with a benzene ring on the heterocyclic ring,

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 an acylamino group having 2 to 6 carbon atoms in the acyl moiety,

X is CH ₂ ,

When Y is C (= O)

However, C _1-6 alkyl for R ^1; An alkylene moiety and a cycloalkyl moiety of a 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 an alkylene moiety of an aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety,

An aryl moiety of an aralkyl wherein the number of carbon atoms of the aryl moiety of R ¹ is 6 to 10 and the number of carbon atoms of the alkylene moiety is 1 to 5; The aryl moiety of the C _6-10 aryloxy of R ³ and R ⁴ ,

The heterocycle of R ² may have a substituent which the aryl moiety of the above-mentioned R ^{1 may have in} the aryl moiety of the aralkyl moiety having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms, You may have,

The alkylene moiety of the aralkyl in which the number of carbon atoms in the aryl moiety of R ¹ is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5 is selected from phenyl or C _1-6 alkyl substituted with 1 to 3 halogens A compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof of the compound (1) which may be substituted with at least one substituent selected;

(31)

R ¹ is C _1-6 alkyl; Cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is from 3 to 6 and the number of carbon atoms in the alkylene moiety is from 1 to 5; Or a compound according to (1) or (30) 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, a tautomer, a stereoisomer, Or a solvate thereof;

(32)

The compound according to (1), (30) or (31), wherein R ¹ is cycloalkyl alkyl having 3 to 6 carbon atoms in the alkylene moiety and 1 to 5 carbon atoms in the alkylene moiety, An isomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(33)

C _2-6 alkyl, wherein R < ¹ > is substituted with hydroxy; C _1-6 alkyl substituted with one to six halogens; (1) or (30), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is a C _2-6 alkyl substituted with C _1-6 alkoxy;

(34)

The compound according to (1) or (30), wherein R ¹ is allyl, fluoropropyl, 2- (pyridin-3-yl) ethyl, 2- (methylsulfonyl) A tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(35)

R ² is pyridin-1-oxide, pyridin-2 (1H) -one which may be substituted with a substituent selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl, pyridine 4H-pyran-2-one, quinolin-2 (lH) -one, (1) or (30) to (34), the tautomer of the compound, the tautomer of the compound, and the compound represented by the formula (1) or the pyrimidine A stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(36)

R ² has 1 to 3 fluorine substituted C _1-10 alkyl, and is substituted with 1-4 substituents selected from C _1-10 alkyl is not substituted pyridine 1-oxide, which may by, (1) or ( 30) to (35), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(37)

The compound according to any one of (1) or (30) to (36), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, wherein R ² is pyridine 1-oxide;

(38)

Pyridin-2 which may optionally R ² is substituted with 1-4 substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with one to three fluorine (1H) - is on, (1 ) Or a compound according to any one of (30) to (35), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(39)

R ² is pyridin -2 (1H) - one; 1-C _1-6 alkylpyridin-2 (1H) -one; Or a compound according to any one of (1) or (30) to (35), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is 6-C _1-6 alkylpyridin-2 (1H) Or a solvate thereof;

(40)

Pyridin -4 optionally R ² is substituted with one to three one to four substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with fluorine (1H) - is on, (1 ) Or a compound according to any one of (30) to (35), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(41)

The compound according to any one of (1), (30) to (35), or (40), wherein R ² is pyridin-4 (1H) -one or 1-C _1-6 alkylpyridin- A tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(42)

Pyridazin-3 which may optionally R ² is substituted with 1-3 substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with one to three fluorine (2H) - is on, ( 1) or (30) to (35), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(43)

The compound according to any one of (1), (30) to (35) or (42) wherein R ² is pyridazin-3 (2H) -one, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof Or a solvate thereof;

(44)

(1 H) -one, wherein R ² is optionally substituted with 1 to 3 substituents selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl, (1 ) Or a compound according to any one of (30) to (35), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(45)

The compound according to any one of (1), (30) to (35), or (44) wherein R ² is pyrazin-2 (1H) -one, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof Salts or solvates thereof;

(46)

R ² is optionally substituted by 1 to 3 fluorine a C _1-10 alkyl and substituted C _1-10 that is not one to three substituents selected from alkyl substituted by, 4H- pyran-4-one or 2H- A compound represented by any one of (1) or (30) to (35), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(47)

The compound according to any one of (1), (30) to (35) or (46), wherein R ² is 4H-pyran-4-one or 2H-pyran-2-one, tautomers, stereoisomers, Or a pharmaceutically acceptable salt or solvate thereof;

(48)

R ² is quinolin-2 (1H) -one which may be substituted with 1 to 3 substituents selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl, 1 ) Or a compound according to any one of (30) to (35), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(49)

A compound according to any one of (1), (30) to (35) or (48), wherein R ² is quinolin-2 (1H) -one, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof Salts or solvates thereof;

(50)

R ² is one to three C _1-10 alkyl and the fluorine-pyrimidine-4, that is not a substituted C _1-10 optionally substituted with 1 to 3 substituents selected from alkyl substituted with (3H) - one or (1) or (30) to (35), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the compound is a pyrimidine-2,4 (1H, Or a solvate thereof;

(51)

The compound according to any one of (1), (30) to (35) or (50), wherein R ² is pyrimidin-4 (3H) -one or pyrimidine- A tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof;

(52)

The compound according to any one of (1) or (30) to (51), wherein one of R ³ and R ⁴ is hydroxy and the other is hydrogen, a tautomer, a stereoisomer, Acceptable salts or solvates thereof;

(53)

R ³ is halogen; Cyano; Carbamoyl; C _1-6 alkoxy; C _1-6 alkanoyloxy; Amino; Or a compound according to any one of (1) or (30) to (51), wherein the number of carbon atoms of the acyl moiety is 2 to 6, and R ⁴ is hydrogen or hydroxy, a tautomer of the compound, Isomer, or a pharmaceutically acceptable salt or solvate thereof;

(54)

R ³ is hydroxy; Carbamoyl; Or a C _1-6 alkanoyloxy, R ⁴ is hydrogen, (1) or (30) - (51) which in the compound, the compound tautomers, stereoisomers, or pharmaceutically acceptable according to any one of Salts or solvates thereof;

(55)

The compound according to any one of (1) or (30) to (51), wherein R ³ is hydroxy and R ⁴ is hydrogen, a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof, Solvate;

(56)

A compound represented by any one of (1), (30) to (51) wherein R ³ and R ⁴ are hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or a solvate thereof;

(57)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridine 1-oxide,

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridine 1-oxide,

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridine 1-oxide,

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, Carbonyl) -1-methylpyridin-2 (1H) -one, 1,6-bis- (epiaminoethano)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, -6,11b- (epiaminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -6-methylpyridin-

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, Carbonyl) -1-methylpyridin-2 (1H) -one, 1,6-bis- (epiaminoethano)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) Carbonyl) -1-methylpyridin-2 (1H) -one, 1,6-bis- (epiaminoethano)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, (LH, 3H) -dione, < / RTI > 6,11b- (epiaminoethano)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-4 (1H)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-4 (1H)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) Carbonyl) -1-methylpyridin-2 (1H) -one, 1,6-bis- (epiaminoethano)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridazin-3 (2H)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) quinolin-2 (1H)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonaphtho [1,2-e] indole-3-carbonyl) -2H-

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -4H-

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -1- methylpyridin-

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrazin-2 (1H)

(Cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro-1H (1, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridine 1-oxide,

(Cyclopropylmethyl) -2,3,3a, 4,5,6,7, llc-octahydro-lH-6, llb- (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrazin-2 (1H)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (LH, 3H) -dione, < / RTI > 6,11b- (epiaminoethano)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -1-ethylpyridin-

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrimidin-4 (3H)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, (1H) -one, wherein the compound is selected from the group consisting of: A tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of said compound; or

(58)

6 - ((1S, 3aR, 5aS, 6R, llbR, llcS) -10-hydroxy-2,3,3a, 4,5,6,7, llc-octahydro- Ethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) -6,11b- (epiminoethano) -1,5a-methanonaphtho [1,2-e] indole-3-carbonyl) -1-methyl-1,2- dihydro- 3-one,

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7, llc- < RTI ID = 0.0 & (LH-indole-3-carbonyl) pyridin-2 (lH) -one,

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, -2,3-dimethylpyrimidine-2,4 (1H, 3H) -dicyclohexylcarbamoyl) -6,11b- (epiaminoethano) - Dion and

(Cyclopropylmethyl) -10-methoxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1S, 3aR, 5aS, 6R, llbR, llcS) -1, 5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H) -one, the taut of the compound Isomer, stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof.

In the present specification,

_{Examples of} C _1-6 alkyl include methyl, ethyl, propyl, i-propyl, butyl, tert-butyl, pentyl, neopentyl and hexyl.

Examples of C _1-10 alkyl include heptyl, octyl and the like, in addition to those exemplified above for C _1-6 alkyl.

Examples of C _1-6 alkyl substituted with 1 to 3 halogens include 2-chloroethyl, 2-fluoroethyl, 3-fluoropropyl, 2,2-difluoroethyl, trifluoromethyl or 3,3 , 3-trifluoropropyl, and the like.

_{Examples of} C _2-6 alkenyl include 2-propenyl and 3-methyl-2-butenyl.

Examples of the cycloalkylalkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety are substituted with C _3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl Methyl, ethyl and the like.

Examples of the 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 and a phenethyl group.

_{Examples of} C _3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

_{Examples of} C _6-10 aryl include phenyl and naphthyl.

The heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as a ring constituting atom includes pyridyl, furyl, imidazolyl, pyrazolyl, pyrimidinyl, pyrazinyl, pyridazinyl or thia Zolyl, and the like.

Heteroaryl includes 1 to 4 heteroatoms selected from N, O and S as ring constituting atoms and heteroarylalkyl having 1 to 5 carbon atoms in the alkylene moiety includes (pyridin-2-yl) Methyl, (imidazol-2-yl) methyl, (pyridin-4-yl) methyl, Yl) methyl, (thiazol-5-yl) methyl, (thiazol-4-yl) methyl, (Thiophen-2-yl) ethyl, 2- (pyridin-3-yl) ethyl, 2- Yl) ethyl, and the like.

_{Examples of} C _1-6 alkanoyl include acetyl and propionyl.

_{Examples of} C _1-6 alkoxy include methoxy, ethoxy or propoxy.

Examples of C _1-6 alkanoyloxy include acetoxy and the like.

Examples of alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety include methoxycarbonyl or ethoxycarbonyl.

Examples of the halogen include fluorine, chlorine, bromine and iodine.

Examples of C _1-6 alkoxy substituted by 1 to 3 halogens include fluoromethoxy, trifluoromethoxy, and the like.

With 1 to 6 halogen substituted C _1-6 alkoxy is, in addition to the substituted C _1-6 alkoxy with one to three of the halogens, and the like in tetrafluoro-ethoxy.

Examples of the phenylalkyl having 1 to 3 carbon atoms of the alkyl include benzyl and the like.

_{Examples of} C _6-10 aryloxy include phenoxy and the like.

_{Examples of} C _1-8 alkylamino include methylamino and ethylamino.

Examples of acylamino having 2 to 6 carbon atoms in the acyl moiety include acetylamino and the like.

_{Examples of} C _6-10 arylamino include phenylamino and the like.

Examples of the alkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety include ethylcarbamoyl and the like.

Examples of dialkylcarbamoyl having 1 to 6 carbon atoms in the alkyl moiety include diethylcarbamoyl and the like.

Examples of the alkylsulfonyl having 1 to 6 carbon atoms in the alkyl moiety include methylsulfonyl and the like.

Examples of the alkylsulfinyl having 1 to 6 carbon atoms in the alkyl moiety include methylsulfinyl and the like.

Examples of the alkylthio having 1 to 6 carbon atoms in the alkyl portion include methylthio and the like.

Examples of the arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety include benzoyl and the like.

In R ¹¹ and R ¹² and, R ¹¹ and R ¹² is a nitrogen atom linking, and 5 ~ 7 membered ring which may be formed is a single one or two hetero atoms, as desired, the pyrrolidine, piperidine, And morpholine.

At least one heteroatom selected from N, O and S of R ² and at least one carbon atom as ring constituting atoms and at least one pair of adjacent ring constituting atoms has a double bond,

As the heterocyclic ring substituted with at least one oxo group,

Substituted with (A) pyridine 1-oxide, 2-methyl-pyridine 1-oxide, such as 1 to 4 substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with one to three fluorine of Pyridine 1-oxide,

(1 H) -one, 6-methylpyridin-2 (1H) -one, 6-methylpyridin- ethylpyridine -2 (1H) - one, or 6-trifluoromethyl-pyridin -2 (1H) - from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with one to three fluorine, such as on- Pyridin-2 (1H) -one which may be optionally substituted with 1 to 4 substituents selected from

(1H) -one, (C) pyridin-4 (1H) -one, 1- methylpyridin- -4 pyridine optionally substituted with 1-4 substituents selected from C _1-10 alkyl that is not a C _1-10 alkyl, and substituted with one to three fluorine on such (1H) - one,

(D) pyridazin -3 (2H) - one, 2-methyl-pyridazin -3 (2H) - that is a C _1-10 alkyl, and is not substituted with one to three fluorine, such as on-C _1-10 alkyl, (2H) -one which may be substituted with 1 to 3 substituents selected from the group consisting of halogen,

(E) pyrazin -2 (1H) - one, 1-methyl-pyrazin -2 (1H) - are selected from C _1-10 alkyl and the C _1-10 alkyl is not substituted with one to three fluorine, such as on- Pyrazine-2 (1H) -one which may be substituted with 1 to 3 substituents selected from

(F) 1 to 3 fluorines such as 4H-pyran-4-one, 3-methyl-4H-pyran-4-one, 2H- 4H-pyran-4-one which may be substituted with 1 to 3 substituents selected from substituted C _1-10 alkyl and unsubstituted C _1-10 alkyl, 2H-pyran-2-one

(G) quinolin -2 (1H) - one, 6-Methyl-quinolin -2 (1H) - one, quinoline-1-oxide, a C _{1-substituted} 4-methyl-quinoline-1-one to three fluorine oxide, etc. -2-quinoline which may be substituted with 1 to 3 substituents selected from _-10 alkyl and C _1-10 alkyl is not substituted (1H) - one, quinoline-1-oxide,

(H) pyrimidin -4 (3H) - one, pyrimidine -2,4 (1H, 3H) - substituted with 1-3 fluorine, such as dione C _1-10 alkyl and substituted C _1-10 that are not (3H) -one, pyrimidine-2,4 (1H, 3H) -dione which may be substituted with 1 to 3 substituents selected from the group consisting of halogen,

The tautomer of the compound represented by the above general formula (I) includes 1 to 4 hetero atoms selected from N, O and S of R ² and at least one carbon atom as ring constituting atoms, At least one of the ring constituting atoms may be a tautomer in a heterocycle having a double bond and being substituted with at least one oxo group. For example, a tautomer corresponding to the 2-pyridone (lactam) of R ² 2-hydroxypyridine (Rock team type).

The pharmaceutically acceptable salt of the compound represented by the above general formula (I), the tautomer, stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound is preferably an acid addition salt, Examples of the acid addition salts include salts with organic acids or inorganic acids such as hydrochloride, sulfate, fumaric acid, oxalate, methanesulfonate, camphorsulfonate and the like.

In the compound represented by the above general formula (I), a tautomer, a stereoisomer or a pharmaceutically acceptable salt or a solvate thereof of the compound, the stereoisomer includes a cis, a trans isomer, a racemate, .

In the compound represented by the above general formula (I), the tautomer, the stereoisomer, the pharmaceutically acceptable salt or the solvate thereof of the compound, the solvate may be a pharmaceutically acceptable salt of the compound of the present invention or a salt thereof Solvate, and hydrate.

The compound represented by the general formula (I), the tautomer, stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound is converted into a pharmacologically active substance after reaching the body or target site, It may be a chemically modified prodrug to exert its effect (activation).

Examples of such a prodrug include a typical protecting group for a hydroxyl group such as a lower acyl group and a lower alkoxycarbonyl group when the group constituting the prodrug is present in the hydroxyl group. When the prodrug is present in the nitrogen atom, a lower acyl group , A lower alkoxycarbonyl group, or a prodrug group introduced into a carboxylic acid moiety such as pivaloyloxymethyl (tBu-C (O) O-CH2-) group, Medoxomil ) Group, and a silexethyl group.

The compound represented by the general formula (I), the tautomer, stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound may be substituted with a stable isotope such as deuterium.

A method for producing the compound represented by the above general formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or a solvate thereof is described below.

The abbreviations used in this specification are as follows.

About

Boc: tert-Butoxycarbonyl

CPM: Cyclopropylmethyl

DMA: N, N-dimethylacetamide

DMAP: N, N-dimethyl-4-aminopyridine

DMF: N, N-dimethylformamide

DMSO: dimethylsulfoxide

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: Messy

Ph: phenyl

TBS: tert-butyldimethylsilyl

THF: tetrahydrofuran

TLC: Thin layer chromatography

Ts: Toilets

WSC: 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride

(Manufacturing method)

Is a compound represented by the above general formula (I), R ⁵ , R ^6a , R ^6b , R ⁷ , R ⁸ , R ⁹ And R ¹⁰ The compound provided by the present invention which is hydrogen

The compound (I), which is a compound provided by the present invention, can be obtained, for example, by deprotection from the following compound (I-A) to the compound (I).

(3)

^Wherein R ^1a , R ^2a , R ^3a and R ^4a are arbitrary functional groups convertible to R ¹ , R ² , R ³ and R ⁴ of the general formula (I) by a deprotection reaction, and R ^1a itself is R ¹ , R ^2a is itself R ² , R ^3a is itself R ³ , and R ^4a may itself be R ⁴ . Other symbols are the same as above.]

In the above production process, the compound (I) can be obtained by converting R ^1a into R ¹ , converting R ^2a into R ² , R ^3a into a compound represented by the formula R ³ , or by converting R ^4a to R ⁴ . For example, when R ^1a , R ^2a , R ^3a or R ^4a in the compound (IA) contains a hydroxyl group protected by a methyl group, the compound (IA) can be obtained by (1) Or (2) the methyl group as a protecting group can be removed by heating the compound (IA) in excess in the absence of a solvent together with the pyridine hydrochloride salt, so that the compound (I) can be derived.

When R ^1a , R ^2a , R ^3a or R ^4a in the compound (IA) contains a hydroxyl group protected by a tert-butyldimethylsilyl (TBS) group, the compound (IA) (4) a method of reacting hydrogen chloride dissolved in an appropriate solvent, or (5) a method of reacting tetrabutylammonium fluoride in THF to remove the TBS group as a protecting group, (I). &Lt; / RTI >

In the case where R ^1a , R ^2a , R ^3a or R ^4a each contain a functional group protected by other protecting groups, for example, see Peter GM Wuts, Green's Protective Groups in Organic Synthesis (5th edition; A John Wiley &Son's, Inc , The compound (IA) can be derivatized to the compound (I) by the general deprotection conditions described in the literature.

When these R ^1a , R ^2a , R ^3a and R ^4a each have different protecting groups and they need to be removed under different conditions, different conditions suitable for the removal of the respective protecting groups are successively carried out, As the deprotection reaction, the compound (IA) may be derived to the compound (I).

The compound (I-A) can be obtained, for example, by a general acylation reaction for the following compound (I-B) in the reaction formula shown below.

[Chemical Formula 4]

^Wherein R ^1a , R ^2a , R ^3a and R ^4a are arbitrary functional groups convertible to R ¹ , R ² , R ³ and R ⁴ of the general formula (I) by a deprotection reaction, and R ^1a itself is R ¹ , R ^2a is itself R ² , R ^3a is itself R ³ , and R ^4a may itself be R ⁴ . L ¹ represents a leaving group of a general acylating agent. Other symbols are the same as above.]

(IB), carboxylic acid (R ^2a COOH), HATU, WSC and the like in the presence of a base such as HOBT or DMAP or a base such as triethylamine or diisopropylethylamine, The compound (IA) can be obtained by reacting a condensing agent of the formula

The compound (IB), the carboxylic acid chloride (R ^2a COCl; L ¹ = Cl in the formula) or the carboxylic acid anhydride (L ¹ = -OC (O) R ^{2a in the} formula) In the presence of a base such as isopropylamine, pyridine or the like, to obtain the compound (IA).

In the case where R ^3a is a hydroxyl group (OH), the acylation with respect to the R ^3a hydroxyl group proceeds as a side reaction in addition to the desired amidation reaction in the acylation reaction in the above scheme, and R ^The product which becomes ^3a = -OC (O) R ^2a is transiently produced as a by-product, but the reaction solution is recycled to R ^3a = OH in a post-treatment by treating with a 2N ammonia / methanol solution or the like, IB) can be obtained by selectively amidating the compound (IA) with a secondary amine in the presence of a base.

In addition, Christian AGN Montalbetti, et al., Tetrahedron, 61 (46), 2005, 10827-10852. The compound (IA) can also be synthesized from the compound (IB) and the corresponding carboxylic acid (R ^2a -COOH) by the condensation reaction described above.

The compound (IB) can be obtained, for example, by compound 8 (Example 4: R ^1a = CPM, X = O, R ^3a = OMe, R ^4a = H) described in patent document WO2013 / 035833, : 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 = (example ^{67: R 1a = CPM, X} = CH 2, R 3a = OMe, R 4a = H), compound 116 (example ^{101: R 1a = CPM, X} = CH 2, R 3a = H, R 4a = OH), compound 130 (example ^{_{106: R 1a = PhCF 2 CH}} 2, X = CH 2, R 3a = OMe, R 4a = H), compound 185 (example ^{_{143: R 1a = TBSOCH 2 CH}} 2, _{^{X = CH 2, R 3a =}} OMe, R 4a = H), compound 189 (example ^{144: R 1a = (R)} -MeCH (OH) CH 2, X = CH 2, R 3a = OMe, R 4a = H), compound 350 (example ^{261: R 1a = (S)} -MeCH (OH) CH 2, X = CH 2, R 3a = OMe, R 4a = H), compound 291 (example 224: R ^1a = for ^{R 1a = CPM, X = CH} 2, R 3a = H, R 4a = H), WO2014 / 136305: CPM, X = CH 2, R 3a = H, R 4a = OMe), compound 297 (example 228 The described compound 29 (conducted ^{_{27: R 1a = BocNHCH 2 CH}} 2, X = CH 2, R 3a = OTBS, R 4a = H), or compound 68 (Example ^{34: R 1a = Boc, X} = CH 2, R 3a = OMe, R ^4a = H), or by combining known functional group conversion and deprotection reactions by the methods described in the above patent documents, the desired compound (IA) can be synthesized.

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

[Chemical Formula 5]

^Wherein R ^1a , R ^2a , R ^3a and R ^4a are arbitrary functional groups convertible to R ¹ , R ² , R ³ and R ⁴ of the general formula (I) by a deprotection reaction, and R ^1a itself is 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 of a general alkylation reaction. R ^1'a represents a substituent which is R ^1'a -CH ₂ = R ^1a . Other symbols are the same as above.]

(R ^1'a -CHO, where R ^1'a is R ^1'a -CH ₂ ^═R (R ^1'a) -CH ₂ ^O in the presence of an additive such as acetic acid in the presence of an additive such as acetic acid, ^1a ), a reducing agent such as sodium triacetoxyborohydride or sodium cyanoborohydride in an appropriate solvent, to thereby synthesize the compound (IA).

The corresponding alkylating agent (R ^1a -L ² : L ² represents a halogen such as Cl, Br or I or a suitable eliminator such as OMs or OTs) for the compound (IC) in a polar solvent such as DMF or alcohol. ) In the presence of a base such as potassium carbonate can be used to synthesize the compound (IA).

In addition, introduction of the R &^lt; ^1a ^> group into the compound (IC) is not limited to the above-described reaction, but the introduction of an alkyl group to a known general amino group including multi- (IA). &Lt; / RTI >

The compound (IC) can be obtained, for example, by reacting compound 11 (Example 7: R ^2a = Ph, X = O, R ^3a = OMe, R ^4a = H), compound 81 (Example 71 ^{: R 2a = Ph, X =} CH 2, R 3a = OMe, R 4a = H), compound 121 (example ^{104: R 2a = Ph, X} = CH 2, R 3a = OTBS, R 4a = H), compound 149 (example ^{120: R 2a = 2-pyridil} , X = CH 2, R 3a = OMe, R 4a = H), compound 116 (example ^{101: R 1a = CPM, X} = CH 2, R 3a = OMe, R ^4a = H), Compound 217 (Example 163: R ^2a = CF ₃ , X = CH ₂ , R ^3a = OMe, R ^4a = H) Can be synthesized by combining known functional group conversion and deprotection reactions from raw materials.

With respect to other compounds of the compound represented by the general formula (I), which is a compound provided by the present invention, the methods described in the above-mentioned production methods and later examples, and further, the above-described Patent Documents 4 to 6 and non- .

The compound represented by the above general formula (I), the tautomer, the stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound has excellent working activity against the opioid delta receptor Lt; / RTI >

Accordingly, the compound represented by the above general formula (I), the tautomer, the stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound can be used in a pharmaceutical composition exhibiting an opioid δ receptor agonist action .

The compound represented by the above-mentioned general formula (I), the tautomer, the stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound may be a hERG (human ether-a-go-go related gene) , Only a weak inhibitory action is shown.

Accordingly, the compound represented by the above-mentioned general formula (I), the tautomer, the stereoisomer, the pharmaceutically acceptable salt thereof or the solvate thereof of the compound has a risk of delaying the ventricular repolarization in the human and prolonging the QT interval And can be used in low pharmaceutical compositions.

In addition, the compound represented by the above general formula (I), the tautomer, stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound exhibits excellent stability against metabolism by human liver microsomes.

Accordingly, the compound represented by the above-mentioned general formula (I), the tautomer, stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound can be used in a pharmaceutical composition for oral administration.

The compound represented by the above general formula (I), the tautomer, stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound acts in the brain in an animal model such as depression, anxiety, , It is considered that the in-brain migration is good.

The pharmaceutical composition provided by the present invention is orally or parenterally administered to a human or other mammal, and examples of the parenteral administration include intravenous administration, subcutaneous administration, intramuscular administration, intraarticular administration, transmucosal administration, transdermal administration , Prophylactic administration, rectal administration, and intrathecal administration.

The medicinal composition provided by the present invention is a composition which comprises a compound represented by the above general formula (I), a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof or a solvate thereof, (E.g., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a binder, such as an excipient, for example, excipients such as lactose, D-mannitol, crystalline cellulose, glucose, (E.g., magnesium stearate, talc), a disintegrant (e.g. starch, carboxymethylcellulose calcium (CMC-Ca)), a diluent (e.g. water for injection, physiological saline) May be mixed with additives (for example, a pH adjuster, a surfactant, a solubilizer, a preservative, an emulsifier, an isotonizing agent, a stabilizer) and may be formulated into tablets, granules, powders, capsules, suspensions, It can be the best. For example, in the case of a tablet, a compound represented by the above-mentioned general formula (I), a tautomer, stereoisomer or pharmaceutically acceptable salt thereof or a solvate thereof may be mixed with an excipient (for example, lactose, D (E.g. starch, carboxymethylcellulose calcium (CMC-Ca)), binders (e.g., hydroxypropylcellulose (HPC), gelatin, polyvinylpyrrolidone (PVP)), a lubricant (e.g., magnesium stearate, talc), or the like. For example, in order to prepare an injection, the compound represented by the general formula (I), the tautomer, stereoisomer or pharmaceutically acceptable salt thereof or a solvate thereof may be mixed with a dispersant (for example, (E.g. sodium chloride, mannitol, sorbitol, glucose), preservatives (e.g., methylparaben, propylparaben), isotonic agents (for example, sodium chloride, mannitol, sorbitol, glucose), polysaccharides such as carboxymethylcellulose, sodium alginate, and hyaluronic acid, or may be mixed with a pH adjusting agent (for example, sodium phosphate, potassium phosphate) or the like.

The medicinal composition provided by the present invention is a compound represented by the above general formula (I) in an amount effective for the treatment or prevention of an opioid δ receptor-related disease (for example, headache), a tautomer, a stereoisomer, Pharmaceutically acceptable salts or solvates thereof.

The dose of the compound represented by the above-mentioned general formula (I), the tautomer, stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound depends on the kind of salt, administration method, symptom to be administered, Can be appropriately determined. For example, when a compound represented by the above general formula (I), a tautomer, a stereoisomer or a pharmaceutically acceptable salt thereof or a solvate thereof is orally administered to a human, 1 to 10 g / Day, preferably 0.01 to 2000 mg / day, more preferably 0.1 to 100 mg / day, and in the case of intravenous administration to humans, 0.1 to 1 g / day, preferably 0.001 to 200 mg / / Day. It may be administered one to three times a day.

The compound represented by the above general formula (I), the tautomer, stereoisomer or pharmaceutically acceptable salt or solvate thereof of the compound may be used in combination with other medicines (for example, analgesics (for example, (Eg, a nonsteroidal anti-inflammatory drug), an antidepressant drug, an anxiolytic drug (eg, selective serotonin reuptake inhibitor), etc. The combination may be administered simultaneously (eg, as a compounding agent) (For example, by administering a separately formulated one) at a desired time.

In the present specification, the opioid-δ receptor-related disease is a disease which can be treated or prevented by an opioid δ receptor agonist and is, for example, a disease described below and includes, but is not limited to, depression, anxiety, Diabetes, functional gastrointestinal disorders, or neurodegenerative diseases (for example, Parkinson's disease, Parkinson's disease, diabetes mellitus), glaucoma, urinary incontinence, myocardial ischemia, cerebral ischemia, chronic cough, hypertension, drug dependence, alcohol dependence, gastritis, Epilepsy, Alzheimer's disease).

In one embodiment, the medicinal compositions provided by the present invention may be used for the treatment and / or prevention of depression or anxiety, and may be used in DSM-5 (American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, fifth edition) (Eg, social anxiety disorder (social fear), panic disorder, agoraphobia, generalized anxiety disorder), bipolar disorder group, compulsive disorder and related disorder group, mental trauma and stress (Antidepressants, anxiolytics, etc.), which are included in the group of psychotic disorders (for example, post-traumatic stress disorder), and the like, as well as urinary incontinence, myocardial ischemia, cerebral ischemia, chronic cough, , And can be used as a prophylactic and / or therapeutic agent for drug dependence, alcohol dependence, gastritis, premature ejaculation, diarrhea, functional gastrointestinal disorder, or neurodegenerative diseases (for example, Parkinson's disease, epilepsy and Alzheimer's disease).

In one embodiment, the medicinal composition provided by the present invention is a medicinal composition for the treatment of depression, which is a medicinal composition having a fast onset of drug efficacy (onset). In one embodiment, the medicinal composition provided by the present invention is a medicinal composition for treating depression, which is a medicinal composition that does not cause resistance by continuous administration.

In one embodiment, the pharmaceutical composition provided by the present invention can be used as a preventive and therapeutic agent for depression, which is a symptom of Alzheimer's disease.

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. Accordingly, in one embodiment, the pharmaceutical composition provided by the present invention can be used as a preventive or therapeutic agent for glaucoma.

In the present specification, the term "depression" refers to a state having a disorder of autonomic nervous system such as mood disorder such as mood disorder, mood, loneliness, deterioration of activity desire, stagnation of accident, pessimistic notion, . In the present specification, anxiety is not associated with a stimulus that can be clearly identified, and may be a state of feeling danger or fear accompanied by insomnia, tension, tachycardia, difficulty in breathing, and the like. Depression, anxiety includes symptoms of depression, anxiety (such as depressive symptoms seen in the bipolar disorder group, depression seen in PTSD, anxiety symptoms), as seen in the DSM-5 mental illness described above, A condition in which the symptoms are mild but persistent for some time, and a condition in which the symptoms are milder than those in the DSM-5 anxiety disorder group.

In one embodiment, the medicinal composition provided by the present invention is useful as an analgesic agent for the treatment and / or prevention of pain in general.

There are several categories of pain, but in terms of duration and quality, it is divided into acute pain and chronic pain. Acute pain is the most important biological signal for the severity or extent of injury. Examples of acute pain include invasive pain caused by painful substances released by tissue injury or inflammation, . Chronic pain is a pain that lasts for more than a reasonable period of time required for the normal course of acute disease or wound healing, and examples of chronic pain include neuropathic pain such as postherpetic pain, pain associated with diabetic neuropathy Pain, and fibromyalgia. From the viewpoint of cause, pain is divided into invasive water-soluble pain, neuropathic pain, and psychogenic pain. Inflammatory water-soluble pain may include periarticularitis, hay fever, rheumatoid arthritis, headache, toothache, bruises, and stab wounds. Neuropathic pain is a pain caused by nerve impairment, and is associated with peripheral neuropathic pain such as postherpetic neuralgia, pain accompanied by diabetic neuropathy, sciatica, and pain accompanied by peripheral neuropathy due to anticancer drugs , Post-stroke pain, pain after spinal cord injury, pain associated with multiple sclerosis, and the like. Psychogenic pain is pain caused by psychological and social factors such as anxiety and stress in social life.

Specific examples of diseases associated with pain and pain which are useful for the treatment and / or prevention of the medicinal compositions provided by the present invention include the following: painful epilepsy, short stiffness, complex local pain syndrome, polynuropathy, accompanied by diabetic neuropathy Neuralgia injury, neuron injury, post-operative scar syndrome, visceral pain, burns (including sunburn), throat pain, swelling or intercostal neuralgia Pain associated with arthritic rheumatism, pain accompanied by degenerative arthropathy, headache, migraine, oral cavity pain, toothache, tongue pain, pain accompanied by arthritis, trigeminal neuralgia, shoulder pain, intervertebral disc herniation Pain associated with degenerative scoliosis, pain associated with spinal stenosis, pain associated with thoracic outlet syndrome, cognitive impairment Pain accompanied by total joint syndrome, Alzheimer's syndrome, pain accompanied by cervical sprain, chest pain, abdominal pain, pain associated with gallstones, gallstone pain, pain accompanied by pancreatitis, urinary incontinence, pain associated with irritable bowel syndrome, Pain associated with osteoporosis, pain accompanied by arthralgia, gout, pain accompanied by dysmenorrhoea, pain accompanied by ankylosing spondylitis, muscular pain, herpes zoster, fibromyalgia, fibromyalgia, Complex pain associated with occlusive arteriosclerosis, pain accompanied by bladder disease, pain accompanied by Raynaud's phenomenon, postherpetic neuralgia, coursalia, pain accompanied by diabetic neuropathy, carpal tunnel syndrome Pain, diabetes-associated pain, pain associated with Guillain-Barre syndrome, pain associated with leprosy, pain associated with medication , Pain accompanied by radiotherapy, pain after spinal cord injury, pain accompanied by spinal cord synostosis, post-stroke pain (including sagittal), centripetal block, sympathetic-dependent pain, ABC syndrome, multiple sclerosis, skin disease Pain accompanied by trauma, pain accompanied by necrosis, pain accompanied by somatic expressive disorder, pain accompanied by somatization disorder, pain accompanied by depression, Parkinson ' s disease Pain associated with arthritis, cramps, mediastinum, analgesia, labor, inflammatory pain, invasive water-soluble pain, cardiogenic pain, overactive bladder, cystitis, prostatitis, prostatitis, back pain.

Preferably, the medicinal composition provided by the present invention is used for the treatment of pain associated with diabetic peripheral neuropathy, postherpetic pain, post-spinal cord injury, post-stroke pain, pain accompanied by multiple sclerosis, Pain and fibromyalgia, and for the treatment and / or prevention of headache. Headache includes chronic headache, acute headache, and the headache is preferably a migraine, for example a migraine with episodic migraine or ovulation. Further, the medicinal composition provided by the present invention is useful for the treatment of symptoms of depression and / or anxiety accompanying headache.

The medicinal composition provided by the present invention is useful for remedying symptoms of depression and / or anxiety accompanying pain as well as relieving and / or alleviating the pain in that it has an antidepressant and / or anxiolytic effect Do. Accordingly, the medicinal composition provided by the present invention may be a medicinal composition for treating or preventing the symptoms of depression and / or anxiety accompanying pain.

For example, fibromyalgia is a major symptom of chronic pain that can not be tolerated by the whole body, and it involves emotional disturbances such as depression and anxiety. The medicinal composition provided by the present invention is useful in remedying the symptoms of depression and / or anxiety accompanying pain, in addition to relieving and / or alleviating the pain of fibromuscular pain. Accordingly, the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for treating or preventing the symptoms of depression and / or anxiety of fibromyalgia.

In addition, the medicinal composition provided by the present invention is effective for the treatment or prevention of the central symptoms of Parkinson's disease and overactive bladder, but is also effective for the treatment or prevention of pain accompanying these diseases. Accordingly, the pharmaceutical composition provided by the present invention may be a pharmaceutical composition for treating or preventing pain associated with Parkinson's disease or overactive bladder.

In one embodiment, the present invention provides a method of preventing or treating a disease as described above, which comprises administering a pharmaceutical composition provided by the present invention.

In one embodiment, the present invention provides the use of a medicinal composition provided by the present invention for the prevention or treatment of the above-mentioned diseases.

In one embodiment, the present invention provides a method for the prevention or treatment of the above-mentioned diseases, which comprises administering any of the compounds described in (1) to (58) above.

In one embodiment, the present invention provides the use of any of the compounds described in (1) to (58) above for the preparation of a pharmaceutical composition for preventing or treating the above-mentioned diseases.

The invention also provides embodiments of the following 1) to 88):

One)

A method of treating or preventing a disease involving pain or pain in a mammalian subject (e.g., a human), comprising administering to a subject in need thereof a therapeutically or prophylactically effective amount of a compound of formula (I):

[Chemical Formula 6]

X represents O or CH ₂ ,

And Y represents C (= O).

Provided that C _1-10 alkyl of R ¹ ; An alkylene moiety and a cycloalkyl moiety of a 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; An 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 heteroaryl moiety contains 1 to 4 heteroatoms selected from N, O and S as a ring constituent atom and the alkylene moiety of the heteroarylalkyl having 1 to 5 carbon atoms in the alkylene moiety is 1 to 6 doggy

Halogen; Hydroxy; C _1-6 alkoxy; C _6-10 aryloxy; C _1-6 alkanoyl; C _1-6 alkanoyloxy; Carboxyl; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; Carbamoyl; An alkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; A dialkylcarbamoyl group 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 _1-6 alkoxy substituted with 1 to 6 halogens; And arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety,

A tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof;

2)

Pain, or pain associated with diabetic neuropathy, headache, fibromyalgia, post-spinal cord injury, post-stroke pain (including sagittal), multiple sclerosis, post-operative pain or back pain, 1 &Lt; / RTI >

3)

The method according to 1) or 2), wherein the disease involving pain or pain is a headache;

4)

Headache, migraine, 3);

5)

The method according to 3) or 4), wherein the headache is migraine with migraine or transient migraine of transient;

6)

The method according to 1) or 2), wherein the disease involving pain or pain is fibromyalgia.

7)

A method for treating or preventing depression or anxiety accompanying pain in a mammalian subject (e.g., human), comprising administering to a subject in need of treatment or prevention of depression or anxiety accompanying pain an effective amount of a compound of formula (I):

(7)

X represents O or CH ₂ ,

And Y represents C (= O).

8)

Depression or anxiety accompanying pain, depression or anxiety accompanying headache, or depression or anxiety accompanied by fibromyalgia;

9)

(I) for use in the treatment or prevention of a disease involving pain or pain,

[Chemical Formula 8]

X represents O or CH ₂ ,

And Y represents C (= O).

The heterocycle of R ₂ may have a substituent which the C _6-10 aryl of R ¹ described above may have in addition to the oxo group,

The use of a pharmaceutical composition comprising a compound represented by formula (I), a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound;

10)

Pain, or pain associated with diabetic neuropathy, headache, fibromyalgia, post-spinal cord injury, post-stroke pain (including sagittal), multiple sclerosis, post-operative pain or back pain, );

11)

Use according to 9) or 10), wherein the disease involving pain or pain is a headache;

12)

Headache, migraine, 11);

13)

Use described in 11) or 12), wherein the headache is a migraine with migraine or transient migraine of transient;

14)

A disease associated with pain or pain is fibromyalgia, 9) use as described in 10) or 10);

15)

For use in the treatment or prevention of depression or anxiety associated with pain,

[Chemical Formula 9]

X represents O or CH ₂ ,

And Y represents C (= O).

16)

Depression or anxiety accompanying pain, depression or anxiety accompanying headache, or depression or anxiety accompanying fibromuscular symptoms;

17)

(I): < RTI ID = 0.0 > (I) < / RTI > for the manufacture of a medicinal composition for the treatment or prophylaxis of diseases,

[Chemical formula 10]

X represents O or CH ₂ ,

And Y represents C (= O).

18)

Pain, or pain associated with diabetic neuropathy, headache, fibromyalgia, post-spinal cord injury, post-stroke pain (including sagittal), multiple sclerosis, post-operative pain or back pain, 17 );

19)

Use according to 17) or 18), wherein the disease involving pain or pain is a headache;

20)

Headache, migraine, 19);

21)

19) or 20), wherein the headache is migraine with migraine or transient migraine of transient;

22)

17) or 18), wherein the disease associated with pain or pain is fibromyalgia;

23)

For the preparation of a medicinal composition for the treatment or prevention of depression or anxiety associated with pain,

(11)

X represents O or CH ₂ ,

And Y represents C (= O).

24)

Depression or anxiety associated with pain, depression or anxiety accompanying headache, or depression or anxiety accompanying fibromuscular symptoms;

25)

A medicinal composition for the treatment or prevention of diseases accompanied by pain or pain, comprising a compound represented by formula (I):

[Chemical Formula 12]

X represents O or CH ₂ ,

And Y represents C (= O).

, A tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof or a solvate thereof;

26)

Pain, or pain associated with diabetic neuropathy, headache, fibromyalgia, post-spinal cord injury, post-stroke pain (including sagittal), multiple sclerosis, post-operative pain or back pain, 25 A medicinal composition according to the present invention;

27)

A medicinal composition according to 25) or 26), wherein the disease accompanied by pain or pain is a headache;

28)

Headache, migraine, 27);

29)

27) or 28), wherein the headache is migraine with migraine or transient migraine of transient;

30)

Wherein the disease associated with pain or pain is fibromyalgia, 25) or 26);

31)

A medicinal composition for the treatment or prevention of depression or anxiety accompanying pain, comprising a compound represented by the general formula (I):

[Chemical Formula 13]

X represents O or CH ₂ ,

And Y represents C (= O).

32)

A medicinal composition according to item 31), wherein depression or anxiety accompanying pain is depression or anxiety accompanying headache, or depression or anxiety accompanied by fibromyalgia;

33)

In formula (I), R ¹ is C _1-10 alkyl; Cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is from 3 to 6 and the number of carbon atoms in the alkylene moiety is from 1 to 5; Or an aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety.

34)

The method according to any one of 1) to 33), wherein R ¹ in the general formula (I) is a cycloalkyl alkyl having 3 to 6 carbon atoms in the cycloalkyl moiety and 1 to 5 carbon atoms in the alkylene moiety , Use or composition;

35)

In the general formula (I), C _2-6 alkyl wherein R ¹ is substituted with hydroxy; C _1-6 alkyl substituted with one to six halogens; Or C _1-6 alkoxy substituted by C _2-6 alkyl, 1) to 32) of the method according to any one, or a use composition;

36)

(1) to (3), wherein R ¹ is allyl, fluoropropyl, 2- (pyridin-3-yl) ethyl, 2- (methylsulfonyl) ethyl or 2- 32) according to any one of the preceding claims;

37)

In formula (I), R ² comprises 1 to 4 heteroatoms selected from N, O and S and at least one carbon atom as ring constituent atoms, and at least one pair of adjacent ring constituent atoms comprises 2 1] to [36], wherein the heterocyclic ring is a 5- to 7-membered heterocyclic ring having at least one oxo group or a condensed ring thereof, or a heterocyclic ring in which the benzene ring is condensed with the heterocyclic ring, .

38)

In the general formula (I), R ² is pyridin-1-yl optionally substituted with 1 to 4 substituents selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl; A method, a use or a composition as described in any one of (1) to (37), wherein

39)

The method, use or composition according to any one of 1) to 38), wherein in the general formula (I), R ² is pyridine 1-oxide;

40)

In the formula (I), R ² is one to three fluorine, and C _1-10 alkyl optionally substituted with 1-4 substituents selected from C _1-10 alkyl is not substituted pyridin-2 is substituted with (1H) -one, 1) to 37);

41)

In the general formula (I), R ² is pyridin-2 (1H) -one; 1-C _1-6 alkylpyridin-2 (1H) -one; Or 6-C _1-6 alkylpyridin-2 (1H) -one according to any one of 1) to 37), 40);

42)

In the formula (I), R ² is 1-pyridine which may be substituted with three 1-4 substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, it is not substituted by fluorine -4 (1H) -one, 1) to 37);

43)

The method according to any one of 1) to 37) and 42), wherein in the general formula (I), R ² is pyridin-4 (1H) -one or 1-C _1-6 alkylpyridin- , Use or composition;

44)

In the formula (I), R ² is one to three fluorine are substituted by 1-3 substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, it is not substituted by optionally substituted pyridazine is - 3 (2H) -one, wherein 1) to 37);

45)

The method, use or composition according to any one of 1) to 37), 44), wherein in the general formula (I), R ² is pyridazin-3 (2H) -one;

46)

In the formula (I), R ² is pyrazin-2 which may be substituted with 1 to 3 substituents selected from a C _1-10 alkyl substituted with C _1-10 alkyl, and one to three fluorine (1H) - Use, or composition according to any one of 1) to 37);

47)

The method, use or composition according to any one of 1) to 37) and 46), wherein in the general formula (I), R ² is pyrazin-2 (1H) -one;

48)

In the formula (I), R ² is one to three fluorine are substituted by 1-3 substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with an optionally 4H- pyran 4-one or 2H-pyran-2-one, wherein the method, use or composition according to any one of 1) to 37)

49)

The method, use or composition according to any one of 1) to 37), 48), wherein in the general formula (I), R ² is 4H-pyran-4-one or 2H-pyran-2-one.

50)

In the formula (I), R ² is one to three fluorine, and C _1-10 alkyl optionally substituted with 1-3 substituents selected from C _1-10 alkyl is not substituted quinoline -2 is substituted with (1H) -one, 1) to 37);

51)

The method, use or composition according to any one of 1) to 37) and 50), wherein in the general formula (I), R ² is quinolin-2 (1H) -one;

52)

In the formula (I), R ² is optionally substituted with 1 to 3 is one to three substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, it is not substituted by fluorine, pyrimidine -4) (3H) -one or pyrimidine-2,4 (1H, 3H) -dione.

53)

The method according to any one of 1) to 37) and 52), wherein R ² is pyrimidine-4 (3H) -one or pyrimidine-2,4 (1H, 3H) -dione in the general formula (I) Use or composition;

54)

The method, use or composition according to any one of 1) to 53), wherein X in the general formula (I) is CH ₂ ;

55)

The method, use or composition according to any one of 1) to 54), wherein in the general formula (I), one of R ³ and R ⁴ is hydroxy and the other is hydrogen;

56)

In formula (I), R < ³ > is halogen; Cyano; Carbamoyl; C _1-6 alkoxy; C _1-6 alkanoyloxy; Amino; Or a compound according to any one of 1) to 54), wherein the number of carbon atoms of the acyl moiety is 2 to 6, R ⁴ is hydrogen or hydroxy, and R ⁵ is hydrogen.

57)

In formula (I), R < ³ > is hydroxy; Carbamoyl; Or C _1-6 alkanoyloxy; R ⁴ is hydrogen; and R ⁵ is hydrogen. The method, use or composition according to any one of 1) to 54);

58)

The method, use or composition according to any one of 1) to 54), wherein in the general formula (I), R ³ is hydroxy, R ⁴ is hydrogen and R ⁵ is hydrogen.

59)

The method, use or composition according to any one of 1) to 54), wherein in the general formula (I), R ³ , R ⁴ and R ⁵ are all hydrogen.

60)

The method, use or composition according to any one of 1) to 59), wherein in the general formula (I), R ^6a , R ^6b , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are both hydrogen.

61)

R ⁵ , R ^6a , R ^6b , R ⁷ , R ⁸ , R ⁹ and R ¹⁰ are hydrogen,

X is CH ₂ ,

When Y is C (= O)

However, C _1-6 alkyl for R ^1; An alkylene moiety and a cycloalkyl moiety of a 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 an alkylene 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 is 1 to 6

The alkylene moiety of the aralkyl in which the number of carbon atoms in the aryl moiety of R ¹ is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5 is selected from phenyl or C _1-6 alkyl substituted with 1 to 3 halogens The method, use or composition according to any one of 1) to 32), which may be substituted with at least one substituent selected.

62)

In formula (I), R ¹ is C _1-6 alkyl; Cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is from 3 to 6 and the number of carbon atoms in the alkylene moiety is from 1 to 5; Or an aralkyl group having 6 to 10 carbon atoms in the aryl moiety and having 1 to 5 carbon atoms in the alkylene moiety;

63) 1) to 32), wherein R ¹ is cycloalkylalkyl, the number of carbon atoms in the cycloalkyl moiety is from 3 to 6, and the number of carbon atoms in the alkylene moiety is from 1 to 5, ), 61), 62) according to any one of the preceding claims;

64)

In the general formula (I), C _2-6 alkyl wherein R ¹ is substituted with hydroxy; C _1-6 alkyl substituted with one to six halogens; Or C _1-6 alkoxy substituted by C _2-6 alkyl, 1) to 32), 61) of the method according to any one, or a use composition;

65)

(1) to (3), wherein R ¹ is allyl, fluoropropyl, 2- (pyridin-3-yl) ethyl, 2- (methylsulfonyl) ethyl or 2- 32), < RTI ID = 0.0 > 61) < / RTI >

66)

In the formula (I), R ² is one to three fluorine substituted with C _1-10 alkyl and C _1-10 that are not substituted pyridine which may be substituted with substituents selected from alkyl, 1-oxide, pyridine- Pyran-2 (1H) -one, 4H-pyran-4-one, 2H-pyran- , 1) to 32), 61) to 65), which is at least one selected from the group consisting of quinolin-2 (1H) Methods, uses or compositions described herein;

67)

_Wherein R < ² > is pyridine 1-oxide optionally substituted with 1 to 4 substituents selected from C _1-10 alkyl and C _1-10 alkyl substituted with 1 to 3 fluorine, ) To 32), 61) to 66);

68)

The method, use or composition according to any one of 1) to 32), 61) to 67), wherein R ² in the general formula (I) is pyridine 1-oxide.

69)

In the formula (I), R ² is pyridin-2 which may be substituted with 1 to 4 substituents selected from a C _1-10 alkyl substituted with C _1-10 alkyl, and one to three fluorine (1H) - Use, or composition according to any one of 1) to 32), 61) to 66);

70)

In the general formula (I), R ² is pyridin-2 (1H) -one; 1-C _1-6 alkylpyridin-2 (1H) -one; Or 6-C _1-6 alkylpyridin-2 (1H) -one according to any one of 1) to 32), 61) to 66);

71)

In the formula (I), R ² is 1-pyridine which may be substituted with three 1-4 substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, it is not substituted by fluorine -4 (1H) -one, 1) to 32), 61) to 66);

72)

Any one of 1) to 32), 61) to 66) wherein R ² is pyridin-4 (1H) -one or 1-C _1-6 alkylpyridin- Use or composition according to any one of claims 1 to 5;

73)

In the formula (I), R ² is one to three fluorine are substituted by 1-3 substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, it is not substituted by optionally substituted pyridazine is - 3 (2H) -one, 1) to 32), 61) to 66)

74)

The method, use or composition according to any one of 1) to 32), 61) to 66) and 73), wherein R ² in the general formula (I) is pyridazin-3 (2H) -one;

75)

In the formula (I), R ² is optionally substituted with one to three one to three substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with the fluorine-pyrazin-2 (1H) -one, 1) to 32), 61) to 66);

76)

The method, use or composition according to any one of 1) to 32), 61) to 66) and 75), wherein R ² in the general formula (I) is pyrazin-2 (1H) -one;

77)

In the general formula (I), R < ² > is 4H-cyclopentyl, which may be substituted with 1 to 3 substituents selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl, Pyran-4-one or 2H-pyran-2-one, which comprises the steps of: 1) to 32), 61) to 66);

78)

The method according to any one of 1) to 32), 61) to 66), 77), wherein R ² is 4H-pyran-4-one or 2H-pyran-2-one in the general formula (I) Composition;

79)

In the formula (I), R ² is one to three fluorine, and C _1-10 alkyl optionally substituted with 1-3 substituents selected from C _1-10 alkyl is not substituted quinoline -2 is substituted with (1H) -one, 1) to 32), 61) to 66);

80)

The method, use or composition according to any one of 1) to 32), 61) to 66) and 79), wherein R ² in the general formula (I) is quinolin-2 (1H) -one;

81)

In the formula (I), R ² is optionally substituted with 1 to 3 is one to three substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, it is not substituted by fluorine, pyrimidine Or a composition or a composition according to any one of 1) to 32), 61) to 66), wherein the compound is selected from the group consisting of 4,4'-dihydroxy-4 (3H) -one or pyrimidine-2,4 (1H, 3H) -dione.

82)

1) to 32), 61) to 66), 81) in which R ² in the general formula (I) is pyrimidin-4 (3H) -one or pyrimidine- Or composition according to any one of claims 1 to 5;

83)

The method, use or composition according to any one of 1) to 32) and 61) to 82), wherein one of R ³ and R ⁴ in the general formula (I) is one of hydroxy and the other is hydrogen.

84)

In formula (I), R < ³ > is halogen; Cyano; Carbamoyl; C _1-6 alkoxy; C _1-6 alkanoyloxy; Amino; Or a method, a use or composition according to any one of 1) to 32), 61) to 82), wherein the number of carbon atoms in the acyl moiety is 2 to 6 and R ⁴ is hydrogen or hydroxy.

85)

In formula (I), R < ³ > is hydroxy; Carbamoyl; Or C _1-6 alkanoyloxy, and R ⁴ is hydrogen. The method, use or composition according to any one of 1) to 32), 61) to 82)

86)

The method, use or composition according to any one of 1) to 32), 61) to 82), wherein in the general formula (I), R ³ is hydroxy and R ⁴ is hydrogen.

87)

The method, use or composition according to any one of 1) to 32), 61) to 82), wherein in the general formula (I), R ³ and R ⁴ are hydrogen;

88)

When the compound represented by the general formula (I)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, -1,2,3,4-tetrahydroisoquinoline-6,11b- (epiaminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -1-ethylpyridin- , 1) to 32).

Next, the present invention will be described in more detail with reference to the following Reference Examples and Examples, but the present invention is not limited thereto.

The names of the compound of the Example and the compound of the Reference Example were converted into English names by the naming algorithm on which the same software was loaded, and then translated into Japanese by the structural formula drawn using ChemDraw ver.14 manufactured by Cambridge Soft.

In addition, the NMR data and measured values (ESI + or ESI-) of the mass spectrometry of Examples 1 to 34 are shown in Tables 1 to 5.

Example

Reference Example 1-1

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro-lH- Ethano) -1,5a-methanonaphtho [1,2-e] indol-10-ol

[Chemical Formula 14]

(1S, 3aR, 5aS, 6R, 11bR, llcS) -14- (cyclopropylmethyl) -10-methoxy-2,3- (Epiminoethano) -1,5a-methanaphtho [l, 2-e] indole (372 mg, 1.02 mmol) Was dissolved in dichloromethane (5 mL), stirred vigorously at 0 ° C for 20 minutes, and then 1.0 M boron trichloride / dichloromethane solution (5 mL, 5 mmol) was added and stirred at room temperature for 30 minutes Respectively. Methanol (10 mL) was added to the reaction solution at 0 占 폚, 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% ammonia aqueous solution (20 mL). The aqueous layer was extracted twice with chloroform (30 mL), and the combined organic layers were dried over anhydrous sodium sulfate. The insoluble material was separated by filtration and the filtrate was concentrated under reduced pressure to give the title compound (356 mg, 100%) as a brown foam .

[Alternative method]

(1S, 3aR, 5aS, 6R, 11bR, llcS) -14- (cyclopropylmethyl) -10-methoxy-2,3,4,5- (Epiminoethano) -l, 5a-methanaphtho [l, 2-e] indole (3.58 g, 9.82 mmol) And pyridine hydrochloride (87 g, 753 mmol) were added, and the mixture was stirred at 200 占 폚 for 1 hour. After the reaction, the reaction mixture was returned to room temperature, and a saturated aqueous solution of potassium carbonate was added to dissolve the resulting solid. The mixture was extracted with ethyl acetate and chloroform, and the combined organic layer was dried over anhydrous sodium sulfate. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure to obtain the title compound (3.30 g, 96%) as a brown foam.

Reference Example 1-2

(1S, 3aR, 5aS, 6R, llbR, llcS) -10 - ((tert- butyldimethylsilyl) oxy) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c Synthesis of octahydro-1H-6,11b- (epiminoethano) -1,5a-methanonaphtho [1,2-e] indole

[Chemical Formula 15]

(1S, 3aR, 5aS, 6R, 11bR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7- (694 mg, 1.98 mmol) was added to the solution, and the mixture was stirred at < RTI ID = 0.0 > Was dissolved in DMF (20 mL), imidazole (241 mg, 3.54 mmol) and tert-butyldimethylchlorosilane (498 mg, 3.31 mmol) were added at room temperature, and the mixture was stirred at room temperature for 2 hours. Imidazole (529 mg, 7.77 mmol) and tert-butyldimethylchlorosilane (503 mg, 3.34 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 18 hours. Water (150 m) was added to the reaction solution, and the mixture was extracted with a mixed solvent of ethyl acetate and hexane (1: 1, 100 mL). The aqueous layer was made basic by adding 6% aqueous ammonia (30 mL), and then extracted twice with a mixed solvent of ethyl acetate and hexane (1: 1, 100 mL). The combined organic layers were dried over anhydrous magnesium sulfate, the insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, 25 g) using methanol / chloroform (concentration gradient 0-50%) followed by methanol / chloroform (concentration gradient 20-50%) containing 10% concentrated aqueous ammonia as elution solvent The title compound (456 mg, 50%) was obtained as yellow syrup, and (1S, 3aR, 5aS, 6R, 11bR, 11cS) -14- (cyclopropylmethyl) -2,3,3a, 4,5, 6,7,11c-octahydro-1H-6,11b- (epiminoethano) -1,5a- methanaphtho [l, 2-e] indol-10-ol (265 mg, 38% .

Example 1

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonaphto [1,2-e] indole-3-carbonyl) pyridine 1-oxide

[Chemical Formula 16]

In a 50 mL round-bottomed flask, (1S, 3aR, 5aS, 6R, 11bR, 11cS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c- (31 mg, 87 μmol), 2-carboxypyridine 1-oxide (31 mg, 87 μmol) and 2-carboxypyridine 1-oxide (70 μL, 0.50 mmol) and DMA (200 μL) were added to the reaction mixture, which was then dissolved in THF (1.5 mL), and the mixture was stirred at room temperature Lt; / RTI > for 1 hour.

To the reaction mixture was added 2N ammonia / methanol solution (2 mL), and the mixture was stirred at the same temperature for 1 hour.

The reaction solution was concentrated under reduced pressure, and the obtained residue was suspended in 6% aqueous ammonia and extracted with ethyl acetate. The combined organic layers were washed with saturated brine, dried over anhydrous magnesium sulfate, and the insoluble materials were separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform (gradient: 0% -50%) as elution solvent to give the title compound (18 mg, 44%) as a white solid .

Example 2

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) (Epiminoethano) -1,5a-methanonaphto [1,2-e] indole-3-carbonyl) pyridine 1-oxide

[Chemical Formula 17]

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (36 mg, 0.10 mmol) and 4-carboxypyridine 1-oxide (42 mg, 0.10 mmol) were added to a solution of 1H-6,11b- (epiminoethano) , 0.30 mmol), triethylamine (70 L, 0.50 mmol) and HATU (108 mg, 0.28 mmol). The reaction solution was purified by column chromatography (silica gel, 10 g) using methanol and ethyl acetate (concentration gradient: 10% -50%) containing 5% triethylamine as elution solvent. The obtained syrup was dissolved in methanol, followed by addition of chloroform and tert-butyl methyl ether, followed by pulverization and filtration to obtain the title compound (30 mg, 62%) as a brownish solid.

Example 3

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H)

[Chemical Formula 18]

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (39 mg, 0.11 mmol), 2-oxo-1,2-dihydro-1H-6,11b- (epiminoethano) The reaction was carried out using pyridine-3-carboxylic acid (39 mg, 0.28 mmol), triethylamine (70 L, 0.50 mmol) and HATU (130 mg, 0.34 mmol). The reaction was terminated by the addition of 2N ammonia / methanol solution to the reaction solution, and the reaction mixture was concentrated under reduced pressure. The residue was purified directly by using methanol and ethyl acetate (gradient: 10% -50%) containing 5% triethylamine The product was purified by column chromatography (silica gel, 10 g) used as an elution solvent. The obtained residue was powdered from 6% aqueous ammonia to obtain the title compound (13 mg, 25%) as a pale yellow powder.

Example 4

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonaphto [1,2-e] indole-3-carbonyl) pyridine 1-oxide

[Chemical Formula 19]

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (34 mg, 97 [mu] mol), 3-carboxypyridine 1-oxide (40 mg, , 0.29 mmol), triethylamine (70 L, 0.50 mmol) and HATU (125 mg, 0.33 mmol). The reaction was terminated by adding 2N ammonia / methanol solution to the reaction solution, and the reaction mixture was concentrated under reduced pressure to obtain a residue. The residue was directly purified by column chromatography using 0.1% ammonia / methanol solution and chloroform (concentration gradient: 0% -50% Purification by chromatography (silica gel, 25 g). The obtained syrup was dissolved in methanol, followed by addition of tert-butyl methyl ether to obtain a powder, which was collected by filtration to obtain the title compound (14 mg, 31%) as slightly brown amorphous.

Example 5

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H)

[Chemical Formula 20]

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (34 mg, 96 占 퐉 ol), 6-oxo-1,6-dihydropyridine (18 mg, -3-carboxylic acid (40 mg, 0.29 mmol), triethylamine (70 L, 0.50 mmol) and HATU (132 mg, 0.35 mmol). The reaction was terminated by adding 2 N ammonia / methanol solution to the reaction solution, and then concentrated under reduced pressure. The residue was purified directly by column chromatography (silica gel, 10 g) using a 0.1 N ammonia / methanol solution and chloroform (gradient: 1% -50%) directly as elution solvent. The compound thus obtained was suspended in chloroform to remove impurities and then washed with 6% ammonia water. The aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous sodium sulfate. The insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (14 mg, 30%) as a pale yellow powder.

Reference Example 2

Synthesis of 1-methyl-2-oxo-1,2-dihydropyridine-3-carboxylic acid

[Chemical Formula 21]

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) Potassium hydroxide (400 mg, 7.13 mmol) was added and the mixture was stirred at 100 占 폚 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, and then concentrated under reduced pressure until the amount of the solvent became half. 3N hydrochloric acid (20 mL) was added to the reaction solution, and the resulting solid was filtered, washed with water and acetonitrile, and dried under reduced pressure to give the title compound (64.9 mg, 12%) as a white powder.

Example 6

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, Carbonyl) -1-methylpyridin-2 (1H) -one was synthesized in the same manner as in Synthesis example 1,

[Chemical Formula 22]

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (30 mg, 86 占 퐉 ol), 1-methyl-1 H-indole-10-ol synthesized in Referential Example 2 and 1-methyl- The reaction was carried out using 2-oxo-1,2-dihydropyridine-3-carboxylic acid (29 mg, 0.19 mmol), diisopropylethylamine (75 L, 0.43 mmol) and HATU (72 mg, 0.19 mmol) Respectively. However, dichloromethane was used instead of THF and DMA as solvents. To the reaction solution was added 1.4 N ammonia / methanol solution, the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was suspended in a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using 1.4 ammonia / methanol / methanol solution - chloroform (concentration: 5%) as a developing solvent to give the title compound (26.2 mg, 63%) as pale yellow amorphous.

Example 7

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H)

(23)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (66 mg, 0.19 mmol), 6-oxo-1,6-dihydro-1H-6,11b- (epiminoethano) The reaction was carried out using pyridine-2-carboxylic acid (83 mg, 0.59 mmol), triethylamine (150 L, 1.10 mmol) and HATU (262 mg, 0.69 mmol). The reaction was terminated by adding 2 N ammonia / methanol solution to the reaction solution, and then concentrated under reduced pressure. The residue was purified by providing directly to column chromatography (amino silica gel, 10 g) using methanol and chloroform (gradient: 0% -30%) as eluting solvent. The obtained syrup was dissolved in methanol, and tert-butyl methyl ether was added thereto to give a powder, which was obtained as a brown solid (83 mg, 94%).

Example 8

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -6-methylpyridin-2 (1H)

&Lt; EMI ID =

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (20 mg, 57 μmol), 6-methyl-2-oxo-1, 5-dicarboxylic acid The reaction was carried out using 2-dihydropyridine-3-carboxylic acid (19 mg, 0.13 mmol), diisopropylethylamine (50 L, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, THF and DMF were used instead of DMA as solvents. The reaction was stopped by adding 1.4 N ammonia / methanol solution to the reaction solution, and the reaction mixture was concentrated under reduced pressure, and the residue was subjected to preparative TLC using ammonia / methanol solution-chloroform (concentration: 10% After the purification, the resulting solid was suspended in a saturated aqueous solution of potassium carbonate and extracted with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the inorganic substance was separated by filtration. The filtrate was concentrated under reduced pressure to give the title compound &Lt; / RTI > The obtained compound was converted into the hydrochloride salt according to Example 32 to provide for biological activity test.

Example 9

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, Carbonyl) -1-methylpyridin-2 (1H) -one was synthesized in the same manner as in Synthesis example 1,

(25)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (30 mg, 86 占 퐉 ol), 1-methyl-6-oxo-1, The reaction was carried out using 6-dihydropyridine-3-carboxylic acid (29 mg, 0.19 mmol), diisopropylethylamine (75 L, 0.43 mmol) and HATU (72 mg, 0.19 mmol). However, dichloromethane was used instead of THF and DMA as solvents. To the reaction solution was added 1.4 N ammonia / methanol solution, the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was suspended in a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 10%) as a developing solvent to give the title compound (31.1 mg, 75%) as white amorphous.

Reference Example 3

Synthesis of 1-methyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

(26)

Oxo-1,6-dihydropyridine-2-carboxylic acid (500 mg, 3.59 mmol) was added to a 50 mL round bottom flask and suspended in methanol (5 mL) and water (0.8 mL) Potassium hydroxide (400 mg, 7.13 mmol) was added and the mixture was stirred at 100 占 폚 for 15 minutes. The reaction solution was returned to room temperature, and iodomethane (2.6 mL, 41.8 mmol) was added thereto. The mixture was stirred at 100 ° C for 1 hour and then concentrated under reduced pressure to half the amount of the solvent. 3N hydrochloric acid was added to the reaction solution, and the resulting solid was filtered, washed with water and acetonitrile, and dried under reduced pressure to give the title compound (339 mg, 62%) as a white powder.

Example 10

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) Carbonyl) -1-methylpyridin-2 (1H) -one was synthesized in the same manner as in Synthesis example 1,

(27)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (30 mg, 86 占 퐉 ol), and 1- (4-fluorobenzyl) -2,3-dimethyl-l, Dihydro-pyridine-2-carboxylic acid (29 mg, 0.19 mmol), diisopropylethylamine (75 μL, 0.43 mmol) and HATU (72 mg, 0.19 mmol) And the reaction was carried out. However, dichloromethane was used instead of THF and DMA as solvents. To the reaction solution was added 1.4 N ammonia / methanol solution, the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was suspended in a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 10%) as a developing solvent to give the title compound (32.7 mg, 79%) as white amorphous.

Example 11

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H)

(28)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (54 mg, 0.15 mmol) and 2-methoxyisonicotinic acid (54 mg, 0.15 mmol) in the same manner as in Reference Example 1, except that 1H-6,11b- (epiminoethano) 0.35 mmol), triethylamine (140 L, 1.00 mmol) and HATU (195 mg, 0.51 mmol). The reaction was terminated by adding 2 N ammonia / methanol solution to the reaction solution, and then concentrated under reduced pressure. The residue was suspended in chloroform, and then washed with 6% ammonia water. The aqueous layer was extracted with chloroform, and the combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform as an eluting solvent containing 10% of concentrated ammonia water to obtain ((1S, 3aR, 5aS, 6R, - (cyclopropylmethyl) -10-hydroxy-1,2,3a, 4,5,6,7,11c-octahydro-3H-6,11b- (epiminoethano) (2-methoxypyridin-4-yl) methanone (61 mg, 82%) as a white solid.

To a 100 mL round bottom flask was added ((1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -10- (2-methoxypyridin-4-yl) methane (2-methoxypyridin-4-yl) (48 mg, 98 μmol) and pyridine hydrochloride (2.88 g, 25 mmol) were added and the mixture was heated and stirred at 200 ° C. for 10 minutes. The reaction solution was cooled to room temperature, suspended in 6% ammonia water, and extracted with ethyl acetate. The combined organic layers were dried over anhydrous magnesium sulfate, the insoluble materials were separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (gradient: 0% -30%) as eluent to give the title compound (35 mg, 75%) as a white solid.

Example 12

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, -6,11b- (epiaminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrimidine-2,4 (1H, 3H) -dione

[Chemical Formula 29]

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (32 mg, 90 μmol), 2,4-dioxo-1,2-dihydroxybenzoic acid (35 mg, 0.20 mmol), triethylamine (70 [mu] L, 0.50 mmol) and HATU (114 mg, 0.30 mmol) in anhydrous THF After the reaction was stopped by adding 2N ammonia / methanol solution to the reaction solution, the reaction mixture was concentrated under reduced pressure, and the resulting residue was suspended in a saturated aqueous solution of sodium hydrogencarbonate and washed three times with a 5: 1 mixed solution of chloroform and methanol And extracted. The collected organic layer was dried over anhydrous sodium sulfate, insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol and chloroform (concentration: 25%) containing 10% concentrated aqueous ammonia as a developing solvent to give the title compound (16 mg, 35%) as a white solid.

Example 13

(30)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (32 mg, 90 μmol), 4-oxo-1,4-dihydro-1H-6,11b- (epiminoethano) The reaction was carried out using pyridine-3-carboxylic acid (28 mg, 0.20 mmol), triethylamine (70 L, 0.50 mmol) and HATU (114 mg, 0.30 mmol), and 2N ammonia / methanol After the reaction was stopped by adding the solution, it was suspended in a saturated aqueous sodium hydrogencarbonate solution and extracted three times with ethyl acetate. The collected organic layer was dried over anhydrous sodium sulfate, insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 15%) containing 10% concentrated aqueous ammonia as eluent to give the title compound (19 mg, 44%) as a white solid.

Example 14

(31)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (32 mg, 90 μmol), 4-oxo-1,4-dihydro-1H-6,11b- (epiminoethano) The reaction was carried out using pyridine-2-carboxylic acid (28 mg, 0.20 mmol), triethylamine (70 L, 0.50 mmol) and HATU (114 mg, 0.30 mmol) and 2N ammonia / methanol After the reaction was stopped by adding the solution, it was suspended in a saturated aqueous solution of sodium hydrogencarbonate and extracted three times with a 5: 1 mixed solution of chloroform and methanol. The collected organic layer was dried over anhydrous sodium sulfate, insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 15%) containing 10% concentrated aqueous ammonia as eluent to give the title compound (8 mg, 20%) as a white solid.

Example 15

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) Carbonyl) -1-methylpyridin-2 (1H) -one was synthesized in the same manner as in Synthesis example 1,

(32)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (32 mg, 90 占 퐉 ol), 1-methyl-2-oxo-1, The reaction was carried out using 2-dihydropyridine-4-carboxylic acid (31 mg, 0.20 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (114 mg, 0.30 mmol) After the reaction was stopped by adding a prescribed ammonia / methanol solution, it was suspended in a saturated aqueous solution of sodium hydrogencarbonate and extracted three times with chloroform. The collected organic layer was dried over anhydrous sodium sulfate, insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 5%) as a developing solvent to give the title compound (41 mg, 94%) as a white solid.

Example 16

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (Epiminoethano) -1,5a-methanonaphtho [1,2-e] indole-3-carbonyl) pyridazin-3 (2H)

(33)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (30 mg, 85.9 占 퐉 ol), 6-oxo-1,6-dihydro-1H-6,11b- (epiminoethano) The reaction was carried out using pyridazine 3-carboxylic acid (31 mg, 0.22 mmol), triethylamine (70 L, 0.50 mmol) and HATU (129 mg, 0.34 mmol). The reaction was terminated by adding 2 N ammonia / methanol solution to the reaction solution, and then concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform (concentration gradient: 0% -30%) as an elution solvent to give the title compound (27 mg, 66%) as a white solid .

Example 17

(34)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (33 mg, 95 占 퐉 ol), 2-oxo-1,2-dihydro-1H-6,11b- (epiminoethano) 4-carboxylic acid (50 mg, 0.26 mmol), triethylamine (70 L, 0.50 mmol) and HATU (128 mg, 0.34 mmol). The reaction was terminated by adding 2 N ammonia / methanol solution to the reaction solution, and then concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform (concentration gradient: 0% -30%) as an elution solvent to give the title compound (28 mg, 56%) as a white solid .

Example 18

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -2H-pyran-

(35)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (20 mg, 57 μmol), 2-oxo-2H-pyran-5-ylmethanol The reaction was carried out using carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 L, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, dichloromethane was used instead of THF and DMA as solvents. After 1 hour from the start of the reaction, 1N hydrochloric acid was added to the reaction solution and further stirred. After the reaction was stopped by adding an aqueous potassium carbonate solution to the reaction solution, the reaction mixture was extracted with chloroform, and the organic layer was dried over sodium sulfate. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 5%) as a developing solvent to give the title compound (4.0 mg, 15%) as brown amorphous.

Example 19

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, Synthesis of 6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -4H-pyran-

(36)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (20 mg, 57 μmol), 4-oxo-4H-pyran-2-ylmethyl] -1H-6,11b- (epiminoethano) The reaction was carried out using carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 L, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, dichloromethane was used instead of THF and DMA as solvents. To the reaction solution was added 2N methylamine / methanol solution (0.3 mL, 0.6 mmol), the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was suspended in a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol and chloroform (concentration: 10%) as a developing solvent to give the title compound (4.4 mg, 16%) as brown amorphous.

Example 20

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, Carbonyl) -1-methylpyridin-4 (1H) -one Synthesis of 2- (4-fluoropyridin-

(37)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (20 mg, 57 μmol), 4-oxo-4H-pyran-2-ylmethyl] -1H-6,11b- (epiminoethano) The reaction was carried out using carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 L, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, dichloromethane was used instead of THF and DMA as solvents. To the reaction solution was added 2N methylamine / methanol solution (3.0 mL, 6.0 mmol), the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was suspended in a saturated aqueous potassium carbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, and the insoluble matter was separated by filtration. The filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (concentration gradient: 0% -10%) as elution solvent to give the title compound (19 mg, 68% It was obtained as Perth.

Example 21

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrazin-2 (1H)

(38)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (20 mg, 57 μmol), 5-oxo-4,5-dihydro-1H-6,11b- (epiminoethano) The reaction was carried out using pyrazine-2-carboxylic acid (18 mg, 0.13 mmol), diisopropylethylamine (50 L, 0.29 mmol) and HATU (48 mg, 0.13 mmol). However, dichloromethane was used instead of THF and DMA as solvents. To the reaction solution was added 1.4 N ammonia / methanol solution, the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was suspended in an aqueous potassium carbonate solution, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient: 5% -30%) as elution solvent to give the title compound (12.2 mg, 45%) as a brown amorphous .

Example 22

(Cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro-1H (1, (Epiminoethano) -1,5a-methanonaphto [1,2-e] indole-3-carbonyl) pyridine 1-oxide

[Chemical Formula 39]

To a 10 mL test tube was added 2 - ((1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5 , 6,7,11c-octahydro-1H-6,11b- (epiminoethano) -1,5a-methanaphtho [l, 2 -e] indole- 3- carbonyl) pyridine 1-oxide (45 μL, 0.32 mmol) and acetyl chloride (15 μL, 0.21 mmol) were added to the solution, which was stirred for 1 hour at room temperature. Triethylamine (45 μL, 0.32 mmol) and acetyl chloride (15 μL, 0.21 mmol) were added to the reaction solution, and the mixture was stirred at room temperature for 1 hour. A saturated aqueous sodium hydrogen carbonate solution and ethyl acetate were added to the reaction solution, and the mixture was stirred vigorously for 20 minutes. The aqueous layer was separated and extracted with ethyl acetate. The combined organic layer was dried over anhydrous magnesium sulfate. The insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (51 mg, 89%) as yellow amorphous.

Example 23

(40)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) - lH-pyrrolo [2,3-d] pyrimidine, prepared by the method of Compound 297 (Example 228) described in Patent Document WO2013 / 035833, 2,3,3a, 4,5,6,7,11c-octahydro-lH-6,11b- (epiminoethano) -l, 5a-methanaphtho [l, 2-e] indole , 18 mg, 0.16 mmol), triethylamine (50 μL, 0.36 mmol) and HATU (70 mg, 0.18 mmol) were used as the starting materials And the reaction was carried out. The reaction was terminated by adding 2 N ammonia / methanol solution to the reaction solution, and then concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (gradient: 0% -20%) as an elution solvent. The resulting compound was dissolved in methanol, and tert-butyl methyl ether was added to the mixture to obtain the title compound (24 mg, 67%) as a white solid.

Reference Example 4

Synthesis of 3-oxo-3,4-dihydropyrazine-2-carboxylic acid

(41)

This compound was synthesized by the method of patent publication WO2009 / 033084 and the 1H NMR spectrum was obtained from literature Syn. Commun. 2010. 40 (20). 2988-2999.

3-aminopyrazine-2-carboxylic acid (300 mg, 2.17 mmol) and concentrated sulfuric acid (1.3 mL) were added to a 50 mL round bottom flask, and sodium nitrite (149 mg , 2.16 mmol) was added dropwise, followed by stirring for 1 hour. The reaction solution was added to iced water and vigorously stirred, and the resulting solid was filtered. The obtained solid was dried under reduced pressure at 60 占 폚 for 1 hour to give the title compound (166 mg, 55%) as pale yellow crystals.

Example 24

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrazin-2 (1H)

(42)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (20 mg, 57 [mu] mol), 3-oxo-indole-10-ol synthesized in Referential Example 4, The reaction was carried out using 3,4-dihydropyrazine-2-carboxylic acid (20 mg, 0.14 mmol). Except that HOAt (17 mg, 0.13 mmol) was used instead of triethylamine, WSC (24 mg, 0.13 mmol) was used instead of HATU, and DMF was used instead of THF as a solvent. The reaction was terminated by the addition of 1.4 N ammonia / methanol solution to the reaction solution, extracted with chloroform, washed with a saturated aqueous ammonia solution and then with a saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over anhydrous sodium sulfate, insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using methanol and chloroform (concentration: 20%) as eluent to give the title compound (5.9 mg, 22%) as pale yellow amorphous.

Example 25

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) -6,11b- (epiaminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrimidine-2,4 (1H, 3H) -dione

(43)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (20 mg, 57 μmol), 2,6-dioxo-1,2 (2,6-dioxo-1,2,3,4-tetrahydroisoquinolin- , 3,6-tetrahydropyrimidine-4-carboxylic acid (20 mg, 0.13 mmol). Except that HOAt (17 mg, 0.13 mmol) was used instead of triethylamine, WSC (24 mg, 0.13 mmol) was used instead of HATU, and DMF was used instead of THF as a solvent. To the reaction solution was added 1.4 N ammonia / methanol solution, the reaction was stopped, and the mixture 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 an elution solvent. The resulting compound was suspended in chloroform and aqueous ammonia to remove impurities and then filtered to obtain the title compound (2.5 mg, 9%) as slightly brown amorphous.

Reference Example 5

Synthesis of 1-ethyl-6-oxo-1,6-dihydropyridine-2-carboxylic acid

(44)

6-dihydro-pyridine-2-carboxylic acid (129 mg, 925 μmol) and 1,1-diethoxy-N, N-dimethylmethanamine (1.5 mL) were added to a 30 mL round- And the mixture was stirred at 100 ° C for 2 hours. The reaction solution was cooled to room temperature and then concentrated under reduced pressure. The residue was subjected to column chromatography (silica gel, 10 g) using methanol and chloroform (concentration gradient 0% -20%) as elution solvent to give 1-ethyl-6-oxo-1,6-dihydropyridin- -Carboxylate (104 mg, 58%) as a colorless oily substance.

Ethyl-6-oxo-1,6-dihydropyridine-2-carboxylate (104 mg, 533 μmol) obtained above was added to a 50 mL round bottom flask and dissolved in ethanol (3 mL) 5N aqueous sodium hydroxide solution (200 L, 1.0 mmol) was added, and the mixture was stirred at 55 deg. C for 2 hours. The reaction solution was cooled to room temperature, acidified with 5 N hydrochloric acid (400 L, 2.0 mmol), and then concentrated under reduced pressure. Ethanol (3 mL) was added to the residue, and the mixture was concentrated under reduced pressure. The residue was suspended in ethanol (3 mL), insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (48 mg, 54%) as a colorless crystalline solid.

Example 26

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) Carbonyl) -1-ethylpyridin-2 (1H) -one To a solution of 1- (2-aminoethyl)

[Chemical Formula 45]

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (32 mg, 92 [mu] mol), 1-ethyl-indole-10-ol synthesized in Referential Example 5, The reaction was carried out using 6-oxo-1,6-dihydropyridine-2-carboxylic acid (33 mg, 0.19 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (136 mg, 0.36 mmol) Respectively. The reaction was terminated by adding 2 N ammonia / methanol solution to the reaction solution, and then concentrated under reduced pressure. The residue was suspended in 6% aqueous ammonia, extracted with ethyl acetate, and the organic layer was dried over anhydrous magnesium sulfate. The insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 8 g) using methanol and chloroform (gradient: 0% -20%) as an elution solvent. The resulting compound was dissolved in methanol, and tert-butyl methyl ether was added to the mixture to obtain the title compound (35 mg, 76%) as a white solid.

Example 27

(46)

(Cyclopropylmethyl) -2,3,3a, 4,6,7,8-tetramethyluronium hexafluorophosphate was obtained in the same manner as in Example 1, except that (1S, 3aR, 5aS, 6R, (30 mg, 65 [mu] mol), 6, 11b- (epiminoethano) -1,5a-methanaphtho [ -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 instead of THF as a solvent. The residue was suspended in water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and insolubles were separated by filtration. 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 an elution solvent.

To the 100 mL round bottom flask was added the solid obtained above, methanol (2 mL), and aqueous ammonia solution, and the mixture was stirred at room temperature for 3 days. After concentrating the reaction solution, the residue was suspended in chloroform, the insoluble matter was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to preparative TLC using methanol and chloroform (concentration: 20%) as eluent to give the title compound (1.7 mg, 6%) as white amorphous.

Reference Example 6

Synthesis of 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid

(47)

(200 mg, 1.43 mmol) and DMAP (17.5 mg, 143 [mu] mol) dissolved in dichloromethane (3.3 mL) and THF mg, 1.43 mmol) and benzyl alcohol (148 L, 1.43 mmol) were added, and the mixture was stirred at room temperature for 2 hours. Water was added to the reaction solution, the insoluble matter was separated by filtration, extracted with hexane, and washed with a saturated aqueous solution of sodium hydrogencarbonate. The combined organic layers were dried over sodium sulfate, and the insolubles were separated by filtration 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 L, 3.73 mmol) was added, and the mixture was stirred at room temperature for 16 hours. After the reaction, the reaction mixture was concentrated under reduced pressure, and to the obtained residue was added a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform, followed by washing with saturated brine. The combined organic layers were dried over anhydrous sodium sulfate, the insoluble materials were separated by filtration, 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 an elution solvent to give 1-ethyl-6-oxo-1,6-dihydropyridin- (126 mg, 2 steps, 34%) was obtained as pale yellow amorphous.

The obtained benzyl 1-ethyl-6-oxo-1,6-dihydropyridine-3-carboxylate was dissolved in methanol (2 mL) and ethyl acetate (2 mL), 10% palladium carbon was added , And the mixture was stirred under hydrogen atmosphere at room temperature for 2 hours. After the reaction, the insolubles were filtered through celite and the resulting solution was concentrated to obtain the title compound (73 mg, 89%) as pale yellow amorphous.

Example 28

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, Carbonyl) -1-ethylpyridin-2 (1H) -one To a solution of 1- (2-aminoethyl)

(48)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (15 mg, 43 [mu] mol) and 1-ethyl-2-ethyl-l, The reaction was carried out using 6-oxo-1,6-dihydropyridine-3-carboxylic acid (16 mg, 94 μmol), diisopropylethylamine (37 μL, 0.21 mmol) and HATU (36 mg, Respectively. Only THF was used as the solvent. To the reaction solution was added 1.4 N ammonia / methanol solution, the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was suspended in a saturated aqueous solution of sodium hydrogencarbonate, followed by extraction with chloroform. The organic layer was dried over anhydrous sodium sulfate, the insoluble matter was separated by filtration, 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% -30%) as an elution solvent to give the title compound (13.3 mg, 62%) as white amorphous .

Example 29

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, 1,2-e] indole-3-carbonyl) pyridine 1-oxide hydrochloride The title compound was obtained as a white amorphous solid

(49)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,6-tetrahydropyrimidin-2-one synthesized in Example 1 was added to a 50 mL round- (Epiminoethano) -1,5a-methanaphtho [1,2-e] indole-3-carbonyl) pyridine 1-oxide 79 mg, 0.17 mmol) was dissolved in ethanol (2 mL), and 2N hydrochloric acid (1 mL) was added to the solution. The resulting solution was concentrated under reduced pressure. The obtained residue was dried under reduced pressure at 80 占 폚 for 18 hours to give the title compound (85 mg, 99%) as white amorphous.

Example 30

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, 1,2-e] indole-3-carbonyl) pyridin-2 (1H) -one hydrochloride Synthesis of

(50)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,6-tetrahydropyrimidin-2-one synthesized in Example 3 was added to a 50 mL round- (Epiminoethano) -1,5a-methanaphtho [1,2-e] indole-3-carbonyl) pyridin-2 ) -One (44 mg, 93 mol) was added to dissolve in 2 N hydrochloric acid (2 mL), and the resulting solution was concentrated under reduced pressure. The obtained residue was dried under reduced pressure at 100 ° C for 18 hours to give the title compound (40 mg, 84%) as a yellow solid.

Example 31

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, Carbonyl) -1-methylpyridin-2 (1H) -one hydrochloride The title compound was synthesized in the same manner as in Synthesis example 1,

(51)

10 ml of a solution of 3 - ((1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5 , 6,7,11c-octahydro-1H-6,11b- (epiminoethano) -1,5a- methanaphtho [l, 2-e] indole-3-carbonyl) 2 (1H) -one (26 mg, 54 μmol) and ethyl acetate were added, extraction was performed using 1N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The obtained residue was dried under reduced pressure at 60 ° C for 1 hour to give the title compound (23 mg, 83%) as pale yellow amorphous.

Example 32

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, -6,11b- (epiaminoethano) -1,5a-methanonaphtho [1,2-e] indole-3-carbonyl) -6-methylpyridin-2 (1H) -one hydrochloride

(52)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5-trideoxy-2, 3,3a, 4,5 , 6,7,11c-octahydro-1H-6,11b- (epiminoethano) -1,5a-methanaphtho [1,2-e] indole-3- 2 (1H) -one and ethyl acetate were added, extraction was performed using 1N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The obtained residue was dried under reduced pressure to give the title compound (11 mg, 39% for 2 steps in Example 8) as pale yellow amorphous.

Example 33

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, Carbonyl) -1-methylpyridin-2 (1H) -one hydrochloride The title compound was synthesized in the same manner as in Synthesis example 1,

(53)

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6-tetrahydropyrimidinedione synthesized in Example 9 was added to a 10-mL test tube. , 6,7,11c-octahydro-1H-6,11b- (epiminoethano) -1,5a- methanaphtho [l, 2-e] indole-3-carbonyl) 2 (1H) -one (31 mg, 64 μmol) and ethyl acetate were added thereto. The mixture was extracted with 1N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The obtained residue was dried under reduced pressure at 60 占 폚 for 2 hours to give the title compound (22 mg, 67%) as pale yellow amorphous.

Example 34

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) Carbonyl) -1-methylpyridin-2 (1H) -one hydrochloride The title compound was synthesized in the same manner as in Synthesis example 1,

(54)

To a 10 mL test tube was added 6 - ((1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5 , 6,7,11c-octahydro-1H-6,11b- (epiminoethano) -1,5a- methanaphtho [l, 2-e] indole-3-carbonyl) 2 (1H) -one (33 mg, 67 μmol) and ethyl acetate were added, extraction was performed using 1N hydrochloric acid, and the aqueous layer was concentrated under reduced pressure. The obtained residue was dried under reduced pressure at 60 ° C for 2 hours to give the title compound (33 mg, 94%) as slightly brown amorphous.

Reference Example 7-1

(1S, 3aR, 5aS, 6R, llbR, llcS) -10-hydroxy-1,2,3a, 4,5,6,7,11c-octahydro-3H-6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carboxylic acid 2,2,2-trichloroethyl

(55)

(1S, 3aR, 5aS, 6R, llbR, llcS) -10-methoxy-l, 2,3a, 4,5, 6,7,11c-octahydro-3H-6,11b- (epiminoethano) -1,5a-methanaphtho [l, 2-e] indole-3-carboxylic acid 2,2,2- Ethyl (972.7 mg, 2.00 mmol) was added and dissolved in methylene chloride (20 mL). After the reaction solution was cooled to 0 ° C, a 1 M boron-boron-methylene chloride solution (6 mL) was added with vigorous stirring, and the mixture was stirred for 1 hour while raising the temperature to room temperature.

To the reaction solution was added a saturated aqueous solution of sodium hydrogencarbonate (30 mL) and extracted with chloroform (20 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, and the insoluble material was separated by filtration. The filtrate was concentrated under reduced pressure to give the title compound (1.04 g,> 100%) as a white foamy substance. The crude product was used for the next reaction without further purification.

Reference Example 7-2

(1S, 3aR, 5aS, 6R, llbR, llcS) -10-hydroxy-14- (2,2,2-trifluoroacetyl) -1,2,3a, 4,5,6,7,11c- Synthesis of 2,2,2-trichloroethyl 3H-6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carboxylic acid

(56)

(1S, 3aR, 5aS, 6R, 11bR, 11cS) -10-hydroxy-1,2,3a, 4,5,6,7,11c- (2,2,2-trichloroethyl) (1.04 g) in tetrahydrofuran was added dropwise to a solution of 3-amino-2- Was added and dissolved in THF (20 mL). Triethylamine (2.79 mL, 20 mmol) and trifluoroacetic anhydride (1.41 mL, 10 mmol) were added to the resulting solution, and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure. The residue was diluted with a saturated aqueous sodium bicarbonate solution (50 mL) and extracted with ethyl acetate (30 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate, the insoluble materials were separated by filtration, and the filtrate was concentrated under reduced pressure to give the title compound (1.46 g,> 100%) as a white foam. The crude product was used for the next reaction without further purification.

Reference Example 7-3

2,2,2-Trifluoro-1 - ((1S, 3aR, 5aS, 6R, llbR, llcS) -10-hydroxy-2,3,3a, 4,5,6,7, llc-octahydro -1H-6,11b- (epiminoethano) -1,5a-methanaphtho [1,2-e] indol-14-yl) ethan-

(57)

10-hydroxy-14- (2,2,2-trifluoroacetyl) -1 (4-fluoropyridin-2-yl) , 2,3a, 4,5,6,7,11c-octahydro-3H-6,11b- (epiminoethano) -1,5a-methanonaphtho [ 2,2,2-trichloroethyl acetate (1.46 g) was added and dissolved in acetic acid (25 mL). To the resulting solution was added zinc powder (1.31 g, 20 mmol), which was stirred for 2 hours at room temperature. The reaction solution was filtered through celite to remove an excessive amount of zinc powder. The filtrate was concentrated under reduced pressure, and azeotropically with toluene. The residue was diluted with a saturated aqueous sodium hydrogen carbonate solution (30 mL) and extracted with chloroform (30 mL x 3). The combined organic layers were dried over anhydrous sodium sulfate, the insoluble materials were separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel: 16 g) using ethyl acetate and methanol (concentration gradient 0% -30%) as elution solvent to give the title compound (215 mg, yield of 27% As a pale yellow foam material.

Reference Example 8-1

Synthesis of ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate

(58)

The synthesis of this compound was carried out according to the method described in WO2011 / 090935.

A 20% sodium ethoxide / ethanol solution (60 mL) and ethyl 2- (ethoxymethylene) malonate (10.5 mL, 524 mmol) were added to a 500 mL eggplant type flask and stirred at room temperature for 10 minutes. Hydrazine monohydrate (5.1 mL, 104 mmol) was added to the resulting mixture, which was stirred and heated at 80 占 폚 for 18 hours, and the resulting yellow suspension was cooled to 0 占 폚. To the vigorously stirred reaction solution was slowly added 1 N hydrochloric acid (180 mL) at the same temperature to obtain a yellow solution. To the resulting solution was added ethyl acetate (150 mL), and the mixture was stirred at room temperature for 1 hour. After the organic layer was separated, the aqueous layer was extracted with ethyl acetate (100 mL x 2). The combined organic layers were dried over anhydrous sodium sulfate and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the resulting residue was crystallized from ethyl acetate and hexane to give the title compound (2.82 g, 35%) as yellow crystals (mixture of tautomers). Mass spectroscopy ES M-H = 155

Reference Example 8-2

Synthesis of 3-methoxy-1-methyl-1H-pyrazole-4-carboxylic acid

[Chemical Formula 59]

To a 50 mL round bottom flask was added ethyl 3-oxo-2,3-dihydro-1H-pyrazole-4-carboxylate (200 mg, 1.28 mmol), iodomethane (397 μL, 6.40 mmol) and DMF ) Was added and sodium hydride (60%, dispersed in liquid paraffin) (256 mg, 6.40 mmol) was added thereto, followed by stirring at room temperature for 22 hours. Water was added to the reaction solution and extracted three times with ethyl acetate. The combined organic layer was dried over sodium sulfate, and the insoluble material was separated by filtration, 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 an elution solvent to give 3-methoxy-1-methyl-1H-pyrazol- Ethyl acetate (51 mg, 22%) as a white solid.

Methyl-1H-pyrazole-4-carboxylate (51 mg, 0.279 mmol) was added to a 50 mL round-bottomed flask and dissolved in ethanol (1 mL) 5N aqueous sodium hydroxide solution (0.5 mL, 2.50 mmol) was added thereto, followed by stirring at room temperature for 3 days. To the reaction solution was added 1N hydrochloric acid (2.7 mL) and the solution was concentrated under reduced pressure. The obtained residue was dissolved in THF, insoluble matters were separated by filtration using celite, and the filtrate was concentrated under reduced pressure to give the title compound (43 mg, 100%) as a white powder.

Example 35

(60)

10 mL of a test tube was charged with 2,2,2-trifluoro-1 - ((1S, 3aR, 5aS, 6R, llbR, llcS) -10-hydroxy-2,3,3a , 4,5,6,7,11c-octahydro-1H-6,11b- (epiminoethano) -1,5a-methanaphtho [l, 2-e] indol- (67 mg, 0.48 mmol), and HATU (197 mg, 0.52 mmol) 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 L) 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 combined aqueous layers were extracted with chloroform (20 mL). The combined organic layer was dried over anhydrous magnesium sulfate, the insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was subjected to column chromatography (amino silica gel, 16 g) using methanol and chloroform (concentration gradient: 10% -30%) as an elution solvent to obtain 6 - ((1S, 3aR, 5aS, 6R, , 11cS) -10-hydroxy-14- (2,2,2-trifluoroacetyl) -2,3,3a, 4,5,6,7,11c-octahydro-1H- -1,2-e] indole-3-carbonyl) pyridin-2 (1H) -one (M + H = 514.26) as a white foam.

The obtained 6 - ((1S, 3aR, 5aS, 6R, llbR, llcS) -10-hydroxy-14- (2,2,2-trifluoroacetyl) -2,3,3a, 4,5, (LH-indol-3-yl) -pyridin-2-yl] -6,7,11c-octahydro-1H-6,11b- (epiminoethano) The warm was dissolved in methanol (5 mL) in a 100 mL eggplant type 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 purified by column chromatography (amino silica gel, 12 g) eluting with methanol and chloroform (gradient: 10% -30%) to give 6 - ((1S, 3aR, 5aS, 6R, llbR, llcS) -10-Hydroxy-14- (2,2,2-trifluoroacetyl) -2,3,3a, 4,5,6,7, llc-octahydro- (1H) -thiophene-1, 5a-methanonaphtho [1,2-e] indole-3-carbonyl) pyridin- , 3aR, 5aS, 6R, 11bR, llcS) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-lH-6,11b- (epiminoethano) , 5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H) -one.

The obtained mixture was dissolved in concentrated ammonia water (3 mL) in a 50 mL eggplant type flask, and the mixture was stirred under heating at 80 DEG C for 18 hours in a sealed state using a rubber stopper.

The reaction mixture was concentrated under reduced pressure and the residue was subjected to column chromatography (amino silica gel, 7 g) with methanol and chloroform (gradient: 10% -50%) as elution solvent. 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%).

Example 36

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) -6,11b- (epiminoethano) -1,5a-methanonaphtho [1,2-e] indole-3-carbonyl) -1-methyl-1,2- dihydro- Synthesis of 3-one

(61)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (30 mg, 86 μmol), 3-methoxy-1-methyl-1H-indole-10-ol 4-carboxylic acid (29 mg, 0.19 mmol), diisopropylethylamine (75 L, 0.43 mmol) and HATU (72 mg, 0.19 mmol). Only THF (2 mL) was used as a solvent. To the reaction solution was added 1.4 N ammonia / methanol solution, the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium hydrogencarbonate, extracted with chloroform, and the organic layer was dried over sodium sulfate. The insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by column chromatography (silica gel, 10 g) using methanol and ethyl acetate (concentration gradient: 0% -30%) as an elution solvent to obtain ((1S, 3aR, 5aS, 6R, 11cS) -14- (cyclopropylmethyl) -10-hydroxy-1,2,3a, 4,5,6,7,11c-octahydro-3H-6,11b- (epiminoethano) Yl) methanone (33.3 mg, 80%) was obtained as a pale yellow amorphous substance from 3-methoxy-1-methyl-1H-pyrazol- .

A solution of ((1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -10- (3-methoxy-1-methyl-1H-6,11b- (epiminoethano) -1,5a-methanaphtho [ Yl) methanone (15 mg, 31 μmol) was dissolved in methylene chloride (1 mL), and 1.0 M boron-boron-methylene chloride solution (153 μL, 0.15 mmol) And the mixture was stirred at room temperature for 1 hour. After the reaction was stopped by adding 1.4 ammonia / methanol solution, the mixture was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium hydrogencarbonate, extracted with chloroform, and the organic layer was dried over sodium sulfate. The insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to preparative TLC using ammonia water-containing methanol and chloroform (concentration: 10%) as a developing solvent to give the title compound (10.6 mg, 73%) as pale yellow amorphous.

Example 37

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7, llc- < RTI ID = 0.0 & Synthesis of octahydro-1H-6,11b- (epiminoethano) -1,5a-methanaphtho [1,2-e] indole-3-carbonyl) pyridin-2 (1H)

(62)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (20 mg, 57 μmol), 5-chloro-2-oxo-1, The reaction was carried out using 2-dihydropyridine-3-carboxylic acid (22 mg, 0.13 mmol), diisopropylethylamine (50 L, 0.29 mmol) and HATU (72 mg, 0.13 mmol). Only THF (1 mL) was used as a solvent. To the reaction solution was added 1.4 N ammonia / methanol solution, the reaction was stopped, and the mixture was concentrated under reduced pressure. The residue was suspended in saturated aqueous sodium hydrogencarbonate, extracted with chloroform, and the organic layer was dried over sodium sulfate. The insoluble material was separated by filtration, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by column chromatography (amino silica gel, 8 g) using methanol and ethyl acetate (gradient: 0% -80%) to give the title compound (11.6 mg, 40% It was obtained as amorphous.

Example 38

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, -2,3-dimethylpyrimidine-2,4 (1H, 3H) -dicyclohexylcarbamoyl) -6,11b- (epiaminoethano) - Synthesis of Dione

(63)

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro- (35 mg, 98 占 퐉 ol), 1,3-dimethyl-2,4-dihydro-1H-6,11b- (epiminoethano) (35 mg, 0.19 mmol), triethylamine (70 μL, 0.50 mmol) and HATU (145 mg, 0.38 mmol) were used as starting materials After the reaction was completed, the reaction was terminated by the addition of a 2N ammonia / methanol solution to the reaction solution, followed by concentration under reduced pressure. The residue was suspended in 6% aqueous ammonia (20 mL) and extracted with ethyl acetate (15 mL x 2). The combined organic layers were washed with saturated brine (10 mL) and dried over anhydrous magnesium sulfate. Insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (amino silica gel, 10 g) using methanol and ethyl acetate (gradient: 0% -30%) as elution solvent. The resulting syrupy material was dissolved in methanol (0.2 mL), t-butyl methyl ether (3 mL) was added to the mixture, which was powdered and collected by filtration to obtain the title compound (39 mg, 76%) as a white powder.

Example 39

(Cyclopropylmethyl) -10-methoxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1S, 3aR, 5aS, 6R, llbR, llcS) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H)

&Lt; EMI ID =

The experiment was carried out in the same manner as in Example 1.

(1S, 3aR, 5aS, 6R, llbR, llcS) -14- (cyclopropylmethyl) -10-methoxy-2,3,3a, 4,5,6 , 5,11c-octahydro-lH-6,11b- (epiminoethano) -l, 5a-methanaphtho [l, 2 -e] indole (82 mg, 0.23 mmol), triethylamine The reaction was terminated by adding ethanolamine (200 μL) and methanol (1 mL) to the reaction solution. Ethyl acetate (50 mL) was added to the reaction mixture, , And then washed with 6% aqueous ammonia (50 mL). The aqueous layer was extracted with chloroform (30 mL x 2) and the combined organic layers were dried over anhydrous sodium sulfate. Insolubles were separated by filtration, and the filtrate was concentrated under reduced pressure. The residue was purified by column chromatography (amino silica gel, 7 g) using methanol and ethyl acetate (gradient: 10% -50%) as elution solvent. The resulting syrupy material was dissolved in methanol (0.2 mL), and t-butyl methyl ether (3 mL) was added to the mixture to be powdered. The obtained powder was dried under reduced pressure at 100 ° C for 16 hours to give the title compound (87 mg, 100%) as a white amorphous substance.

Example 40

Opioid receptor function test

The functional activity of the compounds provided by the present invention on the mu, delta and kappa opioid receptors was examined.

Method: Using Lance Ultra cAMP kit (Perkin Elmer), the method was performed according to a predetermined method. In the evaluation of agonist activity, CHO cells expressing each human opioid receptor (δ, μ and κ: liquid session number and catalog number are shown below) and test compound were dissolved in assay buffer (1 × HBSS, 1M HEPES, pH 7.4, 250 mM IBMX (Isobutylmethylxanthine), 7.5% BSA) for 30 minutes. Subsequently, the cAMP detection reagent in the kit was added, and 1 hour later, time-resolved fluorescence measurement was performed using an EnVision plate reader (Perkin Elmer). The test compound and each control (δ: SNC80, μ: DAMGO, κ: U-69593) were evaluated in the concentration range of 10 ^-12 to 10 ^-5 M and the dose response of the test compound from the fluorescence value of 665 nm The curves were obtained, and EC ₅₀ value and E _max value were calculated. The _Emax value was determined as the ratio of the maximum reaction of the test compound when the maximum response of each reference drug was taken as 100%.

SNC80:

(2S, 5R) -4-allyl-2,5-dimethyl-1-piperazinyl) -3-methoxybenzyl] -N, N-diethyl Benzamide

DAMGO:

^{[D-Ala 2, N-} MePhe 4, Gly-ol] enkephalin

U-69593:

Methyl-N- [7- (1-pyrrolidinyl) -1-oxaspiro [4.5] dec-8-yl] benzeneacetamide

Access session number and catalog number

?: Catalog No. CT4607, accession No. NM_000911.2

μ: Catalog No. CT4605, accession No. NM_000914

K: Catalog No. CT4606, accession No. NM_000912

(ChanTest Corporation)

NC: 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 maximum concentration, the reaction rate at the maximum concentration was shown as a reference value.

As shown in Table 6, it was confirmed that the compound of the present invention had strong agonistic activity against the opioid delta receptor and no agonist activity or only very weak agonist activity for the mu and kappa receptors .

Example 41

Mouse elevated crucifix test

(Test Methods)

For the test, 5-5 week old C57BL / 6N male mice were used. In a 40 cm height cruciform device consisting of a wall-less runway (6 cm wide, 30 cm long) and a runway with walls (6 cm wide, 30 cm long, 15 cm wall height) , And then spontaneously infiltrated into the cross maze. The test substance was dissolved in saline or 0.005 N HCl-saline and administered subcutaneously 30 minutes before the start of the test. At the start of the test, recording of the video camera was started, and the time when the mouse entered the cross maze was set as the start of the test. Based on the images, the residence time in each runway was obtained, and the residence time rate (%) in the run without a wall was calculated.

(Test result)

As shown in Figs. 1 and 2, Compound 1 (compound described in Example 1) and 7 (compound described in Example 7) were administered with subcutaneous administration of 3 mg / kg and 10 mg / kg, respectively , It was confirmed that the residence time rate was increased by running without a wall, and it showed anti-anxiety-like action. Further, with respect to the compound 3 (the compound described in Example 3), 9 (the compound described in Example 9), and 10 (the compound described in Example 10), there was a tendency to prolong the wall-free running time ratio 3-5).

Example 42

Rat elevated crucifix test

The anti-anxiety effects of the compounds provided by the present invention were investigated using the rat hypercalcimetry test.

(Test Methods)

Wistar male rats of 7-9 weeks of age were used for the test. In a 50 m high cruciform device consisting of a wall-less runway (10 cm wide, 50 cm long) and a runway with a wall (10 cm wide, 50 cm long, 30 cm high wall) , And then spontaneously infiltrated into the crossmaze and observed for 5 minutes of search behavior. The test substance was dissolved in a 4.5% aqueous solution of cyclodextrin and orally administered 2 hours before the start of the test. The test data was automatically analyzed by using video image behavior analysis software (Smart3.0, PanLab S.L., manufactured by PanLab), and the time ratio (%) of staying on the road without a wall was calculated.

(Test result)

As shown in FIG. 6, Compound 7 (compound described in Example 7), 3 (compound described in Example 3), and 10 (compound described in Example 10) were administered at a dose of 3 mg / kg orally , And it was confirmed that anti - anxiety - like action was exhibited by increasing the stay time ratio in the running without wall.

Example 43

hERG (human ether-a-go-go related gene) potassium channel inhibition test

(Test Methods)

The test was performed by the Port-a-Patch auto-patch clamp device (Nanion Technologies) using hERG channel stable expression CHO cells (purchased from Channelopathy Foundation). The hERG current was maintained at -80 mV after the cell membrane potential was maintained at -80 mV for 1.5 seconds, followed by a test pulse for -50 mV for 1.5 seconds following the depolarization pulse for 1.5 seconds at a frequency of once every 10 seconds, Lt; / RTI > The test compound was dissolved in an extracellular solution (137 mM NaCl, 4 mM KCl, 1.8 mM CaCl ₂ , 1 mM MgCl ₂ , 10 mM D (+) - glucose, 10 mM HEPES, pH 7.4) Lt; / RTI > The inhibition rate was obtained from the ratio of the tail current value after application of the compound when the maximum tail current value before application of the compound was taken as 100%. For the test, cells with a tail current peak value of 300 pA or more, a tail current run-down of less than 10% of the initial value of the current, and a leakage current of less than 200 pA were used.

(Test result)

Table 7 shows the test results.

In the table, the compounds 1, 3, 7, 9, and 10 are the compounds described in Examples 1, 3, 7, 9,

As evident from Table 7, all of the test compounds showed only weak inhibitory action.

On the other hand, it has been found that the compound described in WO 2013/35833 (Patent Document 4) has a compound having a strong hERG inhibitory action.

Comparative Compound 1: Example 93 of WO 2013/35833 (Compound 104)

Comparative Compound 2: Example 205 of WO 2013/35833 (Compound 267)

Example 44

Suppression of excessive hyperactivity in rats with cadaver extraction model (OBX) rats

(Test Methods)

Saito 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 -1-piperazinyl] - (3-methoxyphenyl) methyl] -N, N-dibenzylamino- OBX rats were prepared by isolation of the rat crown after excision of the rats, according to the method of Dietz, et al. 7-Chloro-1-methyl-L-glutamyl-L-carnitine (Gomita et al. Behavioral and epileptic studies of 5-phenyl-1H-1,5-benzodiazepine-2,4- (3H, 5H) -dione (Clobazam) were evaluated according to the Japanese Pharmacological Journal 82,267 (1983) , Once daily, subcutaneously for 14 consecutive days As a positive control, fluoxetine, which is a selective serotonin reuptake inhibitor (SSRI), was used, and 1% cyclodextrin (CD) was used as the solvent.

(Test result)

At the dose of 0.1 mg / kg of the test substance (the compound described in Example 7 above), the excessive hyperactivity of the OBX rats was significantly lowered from the 4th day after the administration compared with the solvent administration group, And recovered to the same level as the rat. In the case of 1 mg / kg of the test substance, the excessive hyperactivity of the OBX rats was significantly lowered from the first day of administration compared with the solvent administration group, and was recovered to the same level as that of the gastric operation group rats on the fourth day of administration. These effects continued until day 14. On the other hand, in the case of 10 mg / kg of fluoxetine, the excessive hyperactivity of the OBX rats was significantly lowered compared to the solvent administration group on the 14th day of administration.

From the above examinations, it was suggested that the test substance showed an antidepressant similar action from a single administration, unlike the SSRI. In addition, it was suggested that the antidepressant-like action of the test substance would not cause resistance.

Example 45

Reserpine-induced Parkinson's disease model mice

(Test Methods)

ICR male mice (5 weeks old: Japanese SLC) were obtained and used after setting the purging period (5-12 days).

The PD model was fabricated with reference to Hille et al. (Exp Neurol. 2001, 172: 189). (5 mg / kg) intraperitoneally 18-24 hours before the start of the test. The test was carried out by subcutaneously administering the test compound on the same day and immediately placing it in the spontaneous locomotor activity cage and measuring the moving distance for 60 minutes.

(Test result)

The administration of 10 mg / kg of the test substance (the compound described in Example 7 above) showed a significant increase in the search behavior, but not significant (P = 0.16) The therapeutic effect of Parkinson's disease was suggested.

Example 46

Assessment of induced cerebral infarction and activity using active bladder model

(Test Methods)

Using SD male rats aged 8 weeks, a transient mesial cerebral artery occlusion model was prepared under isoflurane inhalation anesthesia. On the next day, the neck was subcutaneously rescued under isoflurane inhalation anesthesia, and a catheter for administration was introduced into the jugular vein and introduced into the abdomen. In addition, a cystometry operation was performed, and the other end of the cannula inserted into the bladder was guided to the drain and connected to the sibil.

Four days after the cerebral ischemic surgery, cystometry was performed under no anesthesia and no restraint. The bladder pressure was measured after the stabilization period, the medium was administered intravenously, and the value before administration of the test substance was measured for about 30 minutes. Thereafter, the test substance was administered in the order of cumulative intravenous injection from the lower dose every about 30 minutes, and the value after each administration was measured for about 30 minutes. In the measurements before the administration, the animals judged to have frequency of urination (the urination interval of 10 minutes or less) were employed and the pressure at the time of stopping at each time point, the pressure at the time of urination, the interval between urination and the amount of urination one time were calculated.

(Test result)

The measurement results are shown in Table 8.

As is apparent from Table 8, the test substance (the compound described in Example 7 above) did not affect the pressure at the time of stopping and the pressure at the time of urination at any dose. On the other hand, the urination interval and the single void volume showed a tendency to increase in a dose-dependent manner, suggesting the action of improving the frequency of the test substance.

Mean ± S.E. (n = 5)

Example 47

Metabolic stability test

(Test Methods)

The human liver microsomes and the test substance were allowed to react for a certain period of time (0 to 60 minutes), and the remaining amount of unchanged test substance in the test sample was measured, and the residual rate was determined. The residual ratio after incubation was plotted log-linearly with respect to time, and the regression line (y = 100e- ^kt , k = slope of the straight line: disappearance rate constant ), And the metabolic clearance CL _int (mL / min / kg) was calculated using the following equation.

CL _int * = k (-min) x 52.5 (mg MS protein / g liver) x 26 (g liver / kg) / MS protein (mg MS protein /

*: Davies, B. and Morris, T.: Physiological parameters in laboratory animals and humans. Pharm. Res., 10 (7): 1093-1095, 1993.

(Test result)

The test results are shown in Table 9.

Comparative Compound 1: Example 93 of WO 2013/35833 (Compound 104)

As evident from Table 9, the compounds of the present invention were found to have excellent metabolic stability. On the other hand, it has been found that compounds having poor metabolic stability exist in the compounds described in WO 2013/35833 (Patent Document 4).

Claims

The following general formula (I):

Wherein R ¹ is hydrogen, C _1-10 alkyl, C _6-10 aryl, C _2-6 alkenyl, the number of carbon atoms of the cycloalkyl moiety is 3 to 6, the number of carbon atoms of the alkylene moiety is 1 to 5 Aralkyl wherein the aryl moiety has 6 to 10 carbon atoms and the alkylene moiety has 1 to 5 carbon atoms; C _3-6 cycloalkyl; Represents a heteroarylalkyl having 1 to 4 hetero atoms as ring constituting atoms and having 1 to 5 carbon atoms in the alkylene moiety,
R ² contains 1 to 4 hetero atoms 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 at least 1 Lt; / RTI > represents a heterocycle substituted with one to three oxo groups,
Wherein, R ² is through a carbon atom of the ring constituent atoms of R ² bonded to a Y,
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 are hydrogen; Fluorine or hydroxy, or R < ^6a > and R < ^6b >
R ⁷ and R ⁸ are the same or different and are 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 a ring constituent atom; 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; Heteroarylalkyl wherein the heteroaryl moiety comprises 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; Cycloalkylalkyl or C _2-6 alkenyl 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,
X represents O or CH ₂ ,
And Y represents C (= O).
Provided that C _1-10 alkyl of R ¹ ; An alkylene moiety and a cycloalkyl moiety of a 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; An 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 heteroaryl moiety contains 1 to 4 heteroatoms selected from N, O and S as a ring constituent atom and the alkylene moiety of the heteroarylalkyl having 1 to 5 carbon atoms in the alkylene moiety is 1 to 6 Halogen; Hydroxy; C _1-6 alkoxy; C _6-10 aryloxy; C _1-6 alkanoyl; C _1-6 alkanoyloxy; Carboxyl; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; Carbamoyl; An alkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; A dialkylcarbamoyl group 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 _1-6 alkoxy substituted with 1 to 6 halogens; And arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety,
And C _6-10 aryl of R ¹ ; An aryl moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; Aryl moieties of C _6-10 aryloxy of R ³ , R ⁴ and R ⁵ ; And aryl moieties of C _6-10 arylamino; And C _6-10 aryl of R ⁹ and R ¹⁰ ; Heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as a ring constituent atom; An aryl moiety of aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety; And the heteroaryl moiety of the heteroarylalkyl wherein 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,
C _1-6 alkyl; C _1-6 alkoxy; C _1-6 alkanoyloxy; Hydroxy; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; Carbamoyl; An alkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; A dialkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; Halogen; Nitro; Cyano; C _1-6 alkyl substituted with one to three halogens; C _1-6 alkoxy substituted by one to three halogens; Phenyl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as a ring constituent atom; Phenoxy; Phenylalkyl having 1 to 3 carbon atoms in the alkyl; Methylenedioxy, < / RTI >< RTI ID = 0.0 >
The heterocycle of R ² may have a substituent which the C _6-10 aryl of R ¹ described above may have in addition to the oxo group,
And when R ¹ is C _1-10 alkyl, it may be substituted with NR ¹¹ R ¹² , wherein R ¹¹ and R ¹² are the same or different and are hydrogen; C _1-10 alkyl; Or an aralkyl having 6 to 10 carbon atoms in the aryl moiety and 1 to 5 carbon atoms in the alkylene moiety or a nitrogen atom to which R ¹¹ and R ¹² and R ¹¹ and R ¹² are bonded, An alkyl of 1 to 5 carbon atoms of an alkylene moiety having 1 to 5 carbon atoms and having 1 to 2 hetero atoms united to form a 5- to 7-membered ring, and the number of carbon atoms of the aryl moiety of R ¹ is 6 to 10, And the phenylene group or the C _1-6 alkyl substituted with 1 to 3 halogens may be substituted with at least one substituent.
, A tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

The method according to claim 1,
R ¹ is C _1-10 alkyl; Cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is from 3 to 6 and the number of carbon atoms in the alkylene moiety is from 1 to 5; Or 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, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof &Lt; / RTI >

3. The method according to claim 1 or 2,
Wherein R ¹ is cycloalkylalkyl having 3 to 6 carbon atoms in the alkyl moiety and 1 to 5 carbon atoms in the alkylene moiety, tautomers, stereoisomers, or pharmaceutically acceptable salts thereof, or And a solvate thereof.

The method according to claim 1,
C _2-6 alkyl, wherein R < ¹ > is substituted with hydroxy; C _1-6 alkyl substituted with one to six halogens; Or C _2-6 alkyl substituted with C _1-6 alkoxy, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

The method according to claim 1,
Compounds wherein R ¹ is allyl, fluoropropyl, 2- (pyridin-3-yl) ethyl, 2- (methylsulfonyl) ethyl or 2- (aminosulfonyl) ethyl, tautomers, stereoisomers, A pharmaceutically acceptable salt thereof or a solvate thereof.

6. The method according to any one of claims 1 to 5,
R ² contains 1 to 4 hetero atoms 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 at least 1 A 5- to 7-membered heterocyclic ring substituted with an oxo group or a heterocyclic ring in which a benzene ring is condensed on the heterocyclic ring, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof &Lt; / RTI >

7. The method according to any one of claims 1 to 6,
R ² is one to three fluorine, and C _1-10 alkyl optionally substituted with 1-4 substituents selected from C _1-10 alkyl is not substituted pyridine 1-oxides of the compounds to be substituted, the tautomer of the compound An isomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

8. The method according to any one of claims 1 to 7,
R ² is pyridine 1-oxide, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

7. The method according to any one of claims 1 to 6,
Pyridin-2 which may optionally R ² is substituted with 1-4 substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with one to three fluorine (1H) - is on the compound, the A tautomer of a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

10. The method according to any one of claims 1 to 6 or 9,
R ² is pyridin -2 (1H) - one; 1-C _1-6 alkylpyridin-2 (1H) -one; Or 6-C _1-6 alkylpyridin-2 (1H) -one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

7. The method according to any one of claims 1 to 6,
Pyridin -4 optionally R ² is substituted with one to three one to four substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with fluorine (1H) - is on the compound, the A tautomer of a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

12. The method according to any one of claims 1 to 6 or 11,
Compounds wherein R ² is pyridin-4 (1H) -one or 1-C _1-6 alkylpyridin-4 (1H) -one, tautomers, stereoisomers or pharmaceutically acceptable salts thereof or solvates thereof &Lt; / RTI >

7. The method according to any one of claims 1 to 6,
R ² is one to three flutes which may be substituted with fluorine, the C _1-10 alkyl and substituted C _1-10 that is not from 1 to 3 substituents selected from alkyl substituted with chopped -3 (2H) - is on the compound, A tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof of the compound.

The method according to any one of claims 1 to 6 or 13,
And R ² is pyridazin-3 (2H) -one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

7. The method according to any one of claims 1 to 6,
R ² is C _1-10 alkyl and one to three 1-pyrazin-2 that may be substituted by 3 substituents selected from a C _1-10 alkyl substituted with fluorine (1H) - is on the compounds, tautomers of the compounds , A stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

16. The method according to any one of claims 1 to 6 or 15,
R ² is pyrazin -2 (1H) - is on the compounds, pharmaceutical compositions comprising the compound of the tautomer, stereoisomer, or salt or solvate its pharmaceutically acceptable.

7. The method according to any one of claims 1 to 6,
R ² is one to three fluorine pyran which may be optionally substituted with one to three substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, it is not substituted by 4H- 2H- pyran-4-one or -2-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

18. The method according to any one of claims 1 to 6 or 17,
R ² is 4H-pyran-4-one or 2H-pyran-2-one, tautomers, stereoisomers, or pharmaceutically acceptable salts or solvates thereof.

7. The method according to any one of claims 1 to 6,
2 (1H) -one, wherein R ² is optionally substituted with 1 to 3 substituents selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl, A tautomer of a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

20. The method according to any one of claims 1 to 6 or 19,
R ² is quinolin-2 (1H) -one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

7. The method according to any one of claims 1 to 6,
R ² is one to three C _1-10 alkyl and the fluorine-pyrimidine-4, that is not a substituted C _1-10 optionally substituted with 1 to 3 substituents selected from alkyl substituted with (3H) - one or Pyrimidine-2,4 (1H, 3H) -dione, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

22. The method according to any one of claims 1 to 6 or 21,
Compounds of formula I wherein R ² is pyrimidin-4 (3H) -one or pyrimidine-2,4 (1H, 3H) -dione, tautomers, stereoisomers or pharmaceutically acceptable salts or solvates thereof &Lt; / RTI >

23. The method according to any one of claims 1 to 22,
A pharmaceutical composition comprising a compound wherein X is CH ₂ , a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

24. The method according to any one of claims 1 to 23,
R ³ and R ⁴ , one of which is hydroxy and the other is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

24. The method according to any one of claims 1 to 23,
R ³ is halogen; Cyano; Carbamoyl; C _1-6 alkoxy; C _1-6 alkanoyloxy; Amino; Or acylamino wherein the number of carbon atoms of the acyl moiety is 2 to 6, R ⁴ is hydrogen or hydroxy and R ⁵ is hydrogen, a tautomer, stereoisomer or pharmaceutically acceptable salt thereof or And a solvate thereof.

24. The method according to any one of claims 1 to 23,
R ³ is hydroxy; Carbamoyl; Or C _1-6 alkanoyloxy, R ⁴ is hydrogen and R ⁵ is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

24. The method according to any one of claims 1 to 23,
R ³ is hydroxy, R ⁴ is hydrogen, and R ⁵ is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

24. The method according to any one of claims 1 to 23,
R ³ , R ⁴ and R ⁵ are both hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

29. The method according to any one of claims 1 to 28,
R ^6a , R ^6b , R ⁷ , R ⁸ , R ^9, and R ¹⁰ are all hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

The method according to claim 1,
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; Cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is from 3 to 6 and the number of carbon atoms in the alkylene moiety is from 1 to 5; Or 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 ² contains 1 to 4 hetero atoms 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 at least 1 A 5- to 7-membered heterocyclic ring substituted with an oxo group or a heterocyclic ring condensed with a benzene ring on the heterocyclic ring,
Wherein, R ² is through a carbon atom of the ring constituent atoms of R ² bonded to a Y,
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 an acylamino group having 2 to 6 carbon atoms in the acyl moiety,
X is CH ₂ ,
When Y is C (= O)
However, C _1-6 alkyl for R ^1; An alkylene moiety and a cycloalkyl moiety of a 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 an alkylene moiety of an 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 is 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; An alkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; A dialkylcarbamoyl group 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 _1-6 alkoxy substituted with 1 to 6 halogens; And arylcarbonyl having 6 to 10 carbon atoms in the aryl moiety,
An aryl moiety of an aralkyl wherein the number of carbon atoms of the aryl moiety of R ¹ is 6 to 10 and the number of carbon atoms of the alkylene moiety is 1 to 5; The aryl moiety of the C _6-10 aryloxy of R ³ and R ⁴ ,
C _1-6 alkyl; C _1-6 alkoxy; C _1-6 alkanoyloxy; Hydroxy; Alkoxycarbonyl having 1 to 6 carbon atoms in the alkoxy moiety; Carbamoyl; An alkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; A dialkylcarbamoyl group having 1 to 6 carbon atoms in the alkyl moiety; Halogen; Nitro; Cyano; C _1-6 alkyl substituted with one to three halogens; C _1-6 alkoxy substituted by one to three halogens; Phenyl; Heteroaryl containing 1 to 4 heteroatoms selected from N, O and S as a ring constituent atom; Phenoxy; Phenylalkyl having 1 to 3 carbon atoms in the alkyl; Methylenedioxy, < / RTI >< RTI ID = 0.0 >
The heterocycle of R ² may have a substituent which the aryl moiety of the above-mentioned R ^{1 may have in} the aryl moiety of the aralkyl moiety having 6 to 10 carbon atoms and the alkylene moiety having 1 to 5 carbon atoms, You may have,
The alkylene moiety of the aralkyl in which the number of carbon atoms in the aryl moiety of R ¹ is 6 to 10 and the number of carbon atoms in the alkylene moiety is 1 to 5 is selected from phenyl or C _1-6 alkyl substituted with 1 to 3 halogens A tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, which may be substituted with at least one substituent selected.

32. The method of claim 1 or 30,
R ¹ is C _1-6 alkyl; Cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is from 3 to 6 and the number of carbon atoms in the alkylene moiety is from 1 to 5; Or 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, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof &Lt; / RTI >

32. The method of claim 1, 30, or 31,
R ¹ is cycloalkylalkyl, cycloalkylalkyl wherein the number of carbon atoms in the cycloalkyl moiety is from 3 to 6 and the number of carbon atoms in the alkylene moiety is from 1 to 5, tautomers, stereoisomers, or pharmacological &Lt; / RTI > or a solvate thereof.

32. The method of claim 1 or 30,
C _2-6 alkyl, wherein R < ¹ > is substituted with hydroxy; C _1-6 alkyl substituted with one to six halogens; Or C _2-6 alkyl substituted with C _1-6 alkoxy, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

32. The method of claim 1 or 30,
Compounds wherein R ¹ is allyl, fluoropropyl, 2- (pyridin-3-yl) ethyl, 2- (methylsulfonyl) ethyl or 2- (aminosulfonyl) ethyl, tautomers, stereoisomers, A pharmaceutically acceptable salt thereof or a solvate thereof.

35. The method according to any one of claims 1 to 30,
R ² is pyridin-1-oxide, pyridin-2 (1H) -one which may be substituted with a substituent selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl, pyridine 4H-pyran-2-one, quinolin-2 (lH) -one, (3H) -one or pyrimidine-2,4 (1H, 3H) -dione, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof &Lt; / RTI >

37. The method according to any one of claims 1 to 30,
R ² is C _1-10 alkyl, and C _1-10 alkyl substituted with 1 to 3 fluorine, or a pyridine 1-oxide which may be substituted with 1 to 4 substituents selected from C _1-10 alkyl substituted with 1 to 3 fluorine, a tautomer of the compound, a stereoisomer , Or a pharmaceutically acceptable salt thereof or a solvate thereof.

36. The method according to any one of claims 1 or 30 to 36,
R ² is pyridine 1-oxide, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

37. The method according to any one of claims 1 to 30,
R ² is C _1-10 alkyl, 1-3 optionally substituted pyridin-2 as a C _1-10 1 ~ 4 substituents selected from alkyl substituted by fluorine (1H) - is on the compounds, tautomers of the compounds , A stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

37. The method according to any one of claims 1 to 30,
R ² is pyridin -2 (1H) - one; 1-C _1-6 alkylpyridin-2 (1H) -one; Or 6-C _1-6 alkylpyridin-2 (1H) -one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

37. The method according to any one of claims 1 to 30,
Pyridin -4 optionally R ² is substituted with one to three one to four substituents selected from C _1-10 alkyl that is a C _1-10 alkyl, and is not substituted with fluorine (1H) - is on the compound, the A tautomer of a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

41. The method according to any one of claims 1, 30 to 35 or 40,
Compounds wherein R ² is pyridin-4 (1H) -one or 1-C _1-6 alkylpyridin-4 (1H) -one, tautomers, stereoisomers or pharmaceutically acceptable salts thereof or solvates thereof &Lt; / RTI >

37. The method according to any one of claims 1 to 30,
R ² is one to three flutes which may be substituted with fluorine, the C _1-10 alkyl and substituted C _1-10 that is not from 1 to 3 substituents selected from alkyl substituted with chopped -3 (2H) - is on the compound, A tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof of the compound.

43. The method according to any one of claims 1, 30 to 35 or 42,
And R ² is pyridazin-3 (2H) -one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

37. The method according to any one of claims 1 to 30,
2 (1H) -one, wherein R ² is optionally substituted with 1 to 3 substituents selected from C _1-10 alkyl substituted with 1 to 3 fluorine and unsubstituted C _1-10 alkyl, A tautomer of a compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

44. The method according to any one of claims 1, 30 to 35 or 44,
R ² is pyrazin -2 (1H) - is on the compounds, pharmaceutical compositions comprising the compound of the tautomer, stereoisomer, or salt or solvate its pharmaceutically acceptable.

37. The method according to any one of claims 1 to 30,
R ² is optionally substituted by 1 to 3 fluorine a C _1-10 alkyl and substituted C _1-10 that is not one to three substituents selected from alkyl substituted by, 4H- pyran-4-one or 2H- Pyran-2-one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

The method according to any one of claims 1, 30 to 35 or 46,
R ² is 4H-pyran-4-one or 2H-pyran-2-one, tautomers, stereoisomers, or pharmaceutically acceptable salts or solvates thereof.

49. A method according to any one of claims 1, 30 to 35 or 48,
R ² is quinolin-2 (1H) -one, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

37. The method according to any one of claims 1 to 30,
R ² is one to three C _1-10 alkyl and the fluorine-pyrimidine-4, that is not a substituted C _1-10 optionally substituted with 1 to 3 substituents selected from alkyl substituted with (3H) - one or Pyrimidine-2,4 (1H, 3H) -dione, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

The method according to any one of claims 1, 30 to 35 or 50,
Compounds of formula I wherein R ² is pyrimidin-4 (3H) -one or pyrimidine-2,4 (1H, 3H) -dione, tautomers, stereoisomers or pharmaceutically acceptable salts or solvates thereof &Lt; / RTI >

52. The method according to any one of claims 1 to 50,
R ³ and R ⁴ , one of which is hydroxy and the other is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

52. The method according to any one of claims 1 to 50,
R ³ is halogen; Cyano; Carbamoyl; C _1-6 alkoxy; C _1-6 alkanoyloxy; Amino; Or acylamino wherein the number of carbon atoms of the acyl moiety is 2 to 6 and R ⁴ is hydrogen or hydroxy, a tautomer, stereoisomer, or pharmaceutically acceptable salt thereof, or a solvate thereof, &Lt; / RTI >

52. The method according to any one of claims 1 to 50,
R ³ is hydroxy; Carbamoyl; Or C _1-6 alkanoyloxy, and R ⁴ is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

52. The method according to any one of claims 1 to 50,
R ³ is hydroxy, and R ⁴ is hydrogen, a tautomer, a stereoisomer, or a pharmaceutically acceptable salt or solvate thereof, of the compound.

52. The method according to any one of claims 1 to 50,
R ³ and R ⁴ are hydrogen, a tautomer of the compound, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof.

(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridine 1-oxide,
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridine 1-oxide,
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridine 1-oxide,
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, Carbonyl) -1-methylpyridin-2 (1H) -one, 1,6-bis- (epiaminoethano)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, -6,11b- (epiaminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -6-methylpyridin-
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, Carbonyl) -1-methylpyridin-2 (1H) -one, 1,6-bis- (epiaminoethano)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) Carbonyl) -1-methylpyridin-2 (1H) -one, 1,6-bis- (epiaminoethano)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, (LH, 3H) -dione, < / RTI > 6,11b- (epiaminoethano)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-4 (1H)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-4 (1H)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) Carbonyl) -1-methylpyridin-2 (1H) -one, 1,6-bis- (epiaminoethano)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridazin-3 (2H)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) quinolin-2 (1H)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonaphtho [1,2-e] indole-3-carbonyl) -2H-
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -4H-
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (1R, 3aR, 5aS, 6R, -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -1- methylpyridin-
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrazin-2 (1H)
(Cyclopropylmethyl) -2,3,3a, 4,5,6,7,11c-octahydro-1H (1, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridine 1-oxide,
(Cyclopropylmethyl) -2,3,3a, 4,5,6,7, llc-octahydro-lH-6, llb- (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyridin-2 (1H)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (3S, 3aR, 5aS, 6R, (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrazin-2 (1H)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (LH, 3H) -dione, < / RTI > 6,11b- (epiaminoethano)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) (Epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) -1-ethylpyridin-
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 6R) -6,11b- (epiminoethano) -1,5a-methanonato [1,2-e] indole-3-carbonyl) pyrimidin-4 (3H)
(Cyclopropylmethyl) -10-hydroxy-2,3,3a, 4,5,6,7,11c-octahydro-1H (4H, 3R, 5aS, 6R, (1H) -one, wherein the compound is selected from the group consisting of: A tautomer, a stereoisomer, or a pharmaceutically acceptable salt thereof, or a solvate thereof, of the compound.

57. The method according to any one of claims 1 to 57,
A medicinal composition for treating or preventing pain.

59. The method of claim 58,
Wherein the pain is a headache.

60. The method of claim 59,
Headache, migraine.

59. The method of claim 58,
Wherein the pain is fibromyalgia.

62. The method of claim 61,
A medicament composition for treating or preventing depression or anxiety symptoms of fibromyalgia.