IP Library › Granted Patent US 7,501,412

Granted Patent B2

US 7,501,412 · App. 10/536,173 · Granted Mar 10, 2009

Isoquinoline compounds and medicinal use thereof

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Quick Facts

Patent No.: US 7,501,412
App. No.: 10/536,173
Granted: Mar 10, 2009
Kind: B2

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Abstract

The present invention relates to an isoquinoline compound represented by the following formula (I) or (II), an optically active form thereof, a pharmaceutically acceptable salt thereof, a water adduct thereof, a hydrate thereof and a solvate thereof, as well as an agent for the prophylaxis and/or treatment of a disease caused by hyperreactivity of poly(ADP-ribose)polymerase, containing the compound, and a poly(ADP-ribose)polymerase inhibitor containing the compound. In addition, this compound is useful as an agent for the prophylaxis and/or treatment of cerebral infarction, particularly as an agent for the prophylaxis and/or treatment of acute cerebral infarction.

Claims (394)

1. An isoquinoline compound represented by the following formula (I)

wherein

R 1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, alkylamino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy;

R 2 is a hydrogen atom, alkyl or amino;

D is void, —C(O)—(CH 2 ) n — wherein n is an integer of 0 to 7, or straight chain or branched chain alkylene having 1 to 8 carbon atoms, provided that when D is methylene, then R 2 is alkyl and when D is void, then R 2 is a hydrogen atom; and

R 3 is amino, monoalkylamino, dialkylamino, or a group selected from the following formulas (a), (b), (c) and (d), provided that when D is void, then R 3 is (a) or (d) and when n is 0, then R 3 is (a),

wherein

m is an integer of 1 to 3,

l is an integer of 1 to 3,

R 4 is void, a hydrogen atom, alkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, aryl optionally having substituent(s), heteroaryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroarylalkyl optionally having substituent(s), sulfamoyl or alkylsulfonylamino,

R 5 is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl or ketone, and

M is —CH—, —C═C—, a nitrogen atom, an oxygen atom or a sulfur atom;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

2. The isoquinoline compound of claim 1 , wherein, in the formula (I),

R 2 is a hydrogen atom, alkyl having 1 to 4 carbon atoms or amino;

D is void, —C(O)—(CH 2 ) n — wherein n is an integer of 0 to 7, or straight chain or branched chain alkylene having 1 to 8 carbon atoms, provided that when D is methylene, then R 2 is alkyl having 1 to 4 carbon atoms and when D is void, then R 2 is a hydrogen atom; and

R 3 is amino, monoalkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms, or a group selected from the formulas (a), (b), (c) and (d), provided that when D is void, then R 3 is (a) or (d) and when n is 0, then R 3 is (a),

wherein

m is an integer of 1 to 3,

l is an integer of 1 to 3,

R 4 is a hydrogen atom, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, amino, monoalkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms, alkoxycarbonyl having 1 to 4 carbon atoms, alkylsulfonyl having 1 to 4 carbon atoms, acyl, acylamino, aryl optionally having substituent(s), heteroaryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroarylalkyl optionally having substituent(s), sulfamoyl or alkylsulfonylamino,

R 5 is a hydrogen atom, a hydroxyl group, alkyl having 1 to 4 carbon atoms, hydroxyalkyl or ketone, and

M is —CH—, —C═C—, a nitrogen atom, an oxygen atom or a sulfur atom;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

3. The isoquinoline compound of claim 1 , wherein, in the formula (I),

R 1 is a hydrogen atom, a halogen atom, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms;

R 2 is a hydrogen atom or alkyl having 1 to 4 carbon atoms;

D is void or straight chain or branched chain alkylene having 1 to 5 carbon atoms, provided that when D is methylene, then R 2 is alkyl having 1 to 4 carbon atoms and when D is void, then R 2 is a hydrogen atom; and

R 3 is dialkylamino having 1 to 4 carbon atoms or a group selected from the formulas (a), (b) and (d), provided that when D is void, then R 3 is (a) or (d),

wherein

m is an integer of 1 to 3,

R 4 is a hydrogen atom, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, aryl optionally having substituent(s), heteroaryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroarylalkyl optionally having substituent(s),

R 5 is a hydrogen atom, a hydroxyl group, alkyl having 1 to 4 carbon atoms or hydroxyalkyl, and

M is —CH—, a nitrogen atom or oxygen atom;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

4. The isoquinoline compound of claim 1 , wherein, in the formula (I),

R 1 is a hydrogen atom, a halogen atom, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms;

R 2 is a hydrogen atom;

D is void; and

R 3 is the formula (a) or (d),

wherein

m is an integer of 1 to 3,

l is an integer of 1 to 3,

R 5 is a hydrogen atom, a hydroxyl group, alkyl having 1 to 4 carbon atoms or hydroxyalkyl having 1 to 4 carbon atoms;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

5. The isoquinoline compound of claim 1 , wherein, in the formula (I),

R 1 is a hydrogen atom, a halogen atom, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms;

R 2 is a hydrogen atom;

D is void; and

R 3 is a group represented by the formula (a),

wherein

m is an integer of 1 to 3,

R 4 is a hydrogen atom, alkyl having 1 to 4 carbon atoms or hydroxyalkyl having 1 to 4 carbon atoms, and

R 5 is a hydrogen atom, a hydroxyl group, alkyl having 1 to 4 carbon atoms or hydroxyalkyl having 1 to 4 carbon atoms;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

6. The isoquinoline compound of claim 1 , wherein, in the formula (I),

R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, methyl or methoxy;

R 2 is a hydrogen atom;

D is void; and

R 3 is a group represented by the formula (a),

wherein

m is 2,

R 4 is a hydrogen atom, methyl, ethyl or 2-hydroxyethyl, and

R 5 is a hydrogen atom;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

7. The isoquinoline compound of claim 1 , which is selected from

(196) 8-fluoro-4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(197) 6-fluoro-4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(198) 4-(1-methylpiperidin-4-yl)-7-trifluoromethyl-2H-isoquinolin-1-one,

(201) 7-methoxy-4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(202) 4-(1-methyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-isoquinolin-1-one,

(203) 7-methyl-4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(204) 7-dimethylamino-4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(205) 4-(1,2,3,6-tetrahydropyridin-4-yl)-2H-isoquinolin-1-one,

(206) 4-(1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-isoquinolin-1-one,

(207) 4-(1-isopropyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-isoquinolin-1-one,

(208) 4-(1-ethyl-1,2,3,6-tetrahydropyridin-4-yl)-2H-isoquinolin-1-one,

(212) 7-fluoro-4-(1-ethylpiperidin-4-yl)-2H-isoquinolin-1-one, and

(213) 7-fluoro-4-(1-isopropylpiperidin-4-yl)-2H-isoquinolin-1-one,

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

8. The isoquinoline compound of claim 1 , wherein, in the formula (I),

R 1 is a hydrogen atom, a fluorine atom or a chlorine atom;

R 2 is a hydrogen atom;

D is void; and

R 3 is a group represented by the formula (a),

wherein

m is 2,

R 4 is a hydrogen atom, methyl, ethyl or 2-hydroxyethyl, and

R 5 is a hydrogen atom;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

9. The isoquinoline compound of claim 1 , which is selected from

(31) 4-(piperidin-4-yl)-2H-isoquinolin-1-one,

(32) 4-(1-(2-hydroxyethyl)piperidin-4-yl)-2H-isoquinolin-1-one,

(33) 4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(44) 7-chloro-4-(piperidin-4-yl)-2H-isoquinolin-1-one,

(45) 7-fluoro-4-(piperidin-4-yl)-2H-isoquinolin-1-one,

(46) 7-chloro-4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(47) 7-fluoro-4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(48) 7-fluoro-4-(1-(2-hydroxyethyl)piperidin-4-yl)-2H-isoquinolin-1-one,

(74) 4-(1-ethylpiperidin-4-yl)-2H-isoquinolin-1-one,

(192) 7-chloro-4-(1-(2-hydroxyethyl)piperidin-4-yl)-2H-isoquinolin-1-one, and

(212) 7-fluoro-4-(1-ethylpiperidin-4-yl)-2H-isoquinolin-1-one,

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

10. The isoquinoline compound of claim 1 , wherein, in the formula (I),

R 1 is a hydrogen atom, a halogen atom, alkyl, alkoxy, haloalkyl, a hydroxyl group, amino, dialkylamino, nitro, cyano, acyl, carboxyl, alkoxycarbonyl, carbamoyl, N-alkylcarbamoyl, N,N-dialkylcarbamoyl, acylamino, diacylamino, thiol, alkylthio, alkoxycarbonylamino, sulfamoyl, N-alkylsulfamoyl, N,N-dialkylsulfamoyl or alkoxyalkyloxy;

R 2 is a hydrogen atom, alkyl or amino;

D is void, —C(O)—(CH 2 ) n — wherein n is an integer of 0 to 7, or straight chain or branched chain alkylene chain having 1 to 8 carbon atoms, provided that when D is methylene, then R 2 is alkyl and when D is void, then R 2 is a hydrogen atom; and

R 3 is amino, monoalkylamino, dialkylamino, or a group selected from the above-mentioned formulas (a), (b) and (c), provided that when D is void, then R 3 is (a) and when n is 0, then R 3 is (a),

wherein

m is an integer of 1 to 3,

l is an integer of 1 to 3,

R 4 is a hydrogen atom, alkyl, hydroxyalkyl, amino, monoalkylamino, dialkylamino, alkoxycarbonyl, alkylsulfonyl, acyl, acylamino, aryl optionally having substituent(s), heteroaryl optionally having substituent(s), arylalkyl optionally having substituent(s), heteroarylalkyl optionally having substituent(s), sulfamoyl or alkylsulfonylamino,

R 5 is a hydrogen atom, a hydroxyl group, alkyl, hydroxyalkyl or ketone, and

M is —CH—, —C═C—, a nitrogen atom, an oxygen atom or a sulfur atom;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

11. The isoquinoline compound of claim 10 , wherein, in the formula (I),

R 1 is a hydrogen atom, a halogen atom, alkyl having 1 to 4 carbon atoms, alkoxy having 1 to 4 carbon atoms, haloalkyl having 1 to 4 carbon atoms, a hydroxyl group, amino, dialkylamino having 1 to 4 carbon atoms, nitro, cyano, acyl having 1 to 4 carbon atoms, carboxyl, alkoxycarbonyl having 1 to 4 carbon atoms, carbamoyl, N-alkylcarbamoyl having 1 to 4 carbon atoms, N,N-dialkylcarbamoyl having 1 to 4 carbon atoms, acylamino having 1 to 4 carbon atoms, diacylamino having 1 to 4 carbon atoms, thiol, alkylthio having 1 to 4 carbon atoms, alkoxycarbonylamino having 1 to 4 carbon atoms, sulfamoyl, N-alkylsulfamoyl having 1 to 4 carbon atoms, N,N-dialkylsulfamoyl having 1 to 4 carbon atoms or alkoxyalkyloxy having 1 to 4 carbon atoms;

R 2 is a hydrogen atom, alkyl having 1 to 4 carbon atoms or amino;

D is void, —C(O)—(CH 2 ) n — wherein n is an integer of 0 to 7, or alkylene chain having 1 to 5 carbon atoms, provided that when D is methylene, then R 2 is alkyl having 1 to 4 carbon atoms and when D is void, then R 2 is a hydrogen atom; and

R 3 is amino, monoalkylamino having 1 to 4 carbon atoms, dialkylamino having 1 to 4 carbon atoms, or a group selected from the formulas (a), (b) and (c), provided that when D is void, then R 3 is a group represented by the formula (a) and when n is 0, then R 3 is a group represented by the formula (a),

wherein

m is an integer of 1 to 3,

l is an integer of 1 to 3,

R 4 is a hydrogen atom, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, arylalkyl optionally having substituent(s) or aryl optionally having substituent(s),

R 5 is a hydrogen atom, a hydroxyl group, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, and

M is —CH—, —C═C—, a nitrogen atom or oxygen atom;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

12. The isoquinoline compound of claim 10 , wherein, in the formula (I),

R 1 is a hydrogen atom, a halogen atom, alkyl having 1 to 4 carbon atoms or alkoxy having 1 to 4 carbon atoms;

R 2 is a hydrogen atom, alkyl having 1 to 4 carbon atoms or amino;

D is void, —C(O)—(CH 2 ) n — wherein n is an integer of 0 to 5, or alkylene chain having 1 to 5 carbon atoms, provided that when D is methylene, then R 2 is alkyl having 1 to 4 carbon atoms and when D is void, then R 2 is a hydrogen atom; and

wherein

m is an integer of 1 to 3,

l is an integer of 1 to 3,

R 4 is a hydrogen atom, alkyl having 1 to 4 carbon atoms, hydroxyalkyl having 1 to 4 carbon atoms, arylalkyl optionally having substituent(s) or aryl optionally having substituent(s),

R 5 is a hydrogen atom, a hydroxyl group, alkyl having 1 to 4 carbon atoms or hydroxyalkyl having 1 to 4 carbon atoms, and

M is —CH—, —C═C— or a nitrogen atom or an oxygen atom;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

13. The isoquinoline compound of claim 10 , wherein, in the formula (I),

R 1 is a hydrogen atom, a fluorine atom, a chlorine atom, methyl, or methoxy;

R 2 is a hydrogen atom, methyl, ethyl, isopropyl or amino;

D is void, —C(O)—(CH 2 ) n — wherein n is an integer of 0 to 3, or methylene, provided that when D is methylene, then R 2 is methyl, ethyl or isopropyl and when D is void, then R 2 is a hydrogen atom; and

R 3 is dimethylamino, diethylamino, diisopropylamino or a group selected from the following formulas (a), (b) and (c), provided that when D is void, then R 3 is (a) and when n is 0, then R 3 is (a),

wherein

m is an integer of 1 to 2,

l is an integer of 1 to 2,

R 4 is a hydrogen atom, methyl, ethyl, 2-hydroxyethyl, phenyl or benzyl,

R 5 is a hydrogen atom, a hydroxyl group or hydroxymethyl, and

M is —CH—, —C═C—, a nitrogen atom or an oxygen atom;

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

14. The isoquinoline compound of claim 10 , which is selected from

(1) 3-amino-4-(2-(dimethylamino)acetyl)-2H-isoquinolin-1-one,

(2) 3-amino-4-(2-(piperidin-1-yl)acetyl)-2H-isoquinolin-1-one,

(3) 3-amino-4-(2-(dimethylamino)acetyl)-5-methyl-2H-isoquinolin-1-one,

(4) 3-amino-4-(3-(dimethylamino)propionyl)-2H-isoquinolin-1-one,

(5) 3-amino-4-(4-(dimethylamino)butyryl)-2H-isoquinolin-1-one,

(6) (R)-3-amino-4-((1-methylpyrrolidin-2-yl)carbonyl)-2H-isoquinolin-1-one,

(8) (S)-3-amino-4-((1-methylpyrrolidin-2-yl)carbonyl)-2H-isoquinolin-1-one,

(9) 3-amino-4-(3-(pyrrolidin-1-yl)propionyl)-2H-isoquinolin-1-one,

(10) 3-amino-7-methyl-4-((dimethylamino)acetyl)-2H-isoquinolin-1-one,

(11) 3-amino-7-methyl-4-((pyrrolidin-1-yl)acetyl)-2H-isoquinolin-1-one,

(12) 3-amino-4-(3-(dimethylamino)propionyl)-7-methyl-2H-isoquinolin-1-one,

(13) 3-amino-4-((pyrrolidin-1-yl)acetyl)-2H-isoquinolin-1-one,

(14) 3-amino-4-(2-(dimethylamino)acetyl)-7-fluoro-2H-isoquinolin-1-one,

(15) 3-amino-7-fluoro-4-((pyrrolidin-1-yl)acetyl)-2H-isoquinolin-1-one,

(16) 3-amino-4-(3-(dimethylamino)propionyl)-7-fluoro-2H-isoquinolin-1-one,

(18) 3-amino-4-(2-(dimethylamino)acetyl)-7-chloro-2H-isoquinolin-1-one,

(19) 3-amino-4-(3-(dimethylamino)propionyl)-7-chloro-2H-isoquinolin-1-one,

(20) 3-amino-4-(2-(pyrrolidin-1-yl)acetyl)-7-chloro-2H-isoquinolin-1-one,

(25) 3-methyl-4-(pyrrolidin-1-yl)methyl-2H-isoquinolin-1-one,

(26) 3-amino-6-chloro-4-(2-(dimethylamino)acetyl)-2H-isoquinolin-1-one,

(27) 7-chloro-3-methyl-4-((pyrrolidin-1-yl)methyl)-2H-isoquinolin-1-one,

(28) 7-fluoro-3-methyl-4-((pyrrolidin-1-yl)methyl)-2H-isoquinolin-1-one,

(29) 4-((pyrrolidin-1-yl)methyl)-2H-isoquinolin-1-one,

(30) 3-methyl-4-(dimethylaminomethyl)-2H-isoquinolin-1-one,

(31) 4-(piperidin-4-yl)-2H-isoquinolin-1-one,

(32) 4-(1-(2-hydroxyethyl)piperidin-4-yl)-2H-isoquinolin-1-one,

(33) 4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(34) 3-methyl-4-(piperidin-1-yl)methyl-2H-isoquinolin-1-one,

(35) 4-dimethylaminomethyl-3-isopropyl-2H-isoquinolin-1-one,

(36) 4-(pyrrolidin-1-yl)methyl-3-isopropyl-2H-isoquinolin-1-one,

(37) 3-methyl-4-((4-phenylpiperidin-1-yl)methyl)-2H-isoquinolin-1-one,

(40) 3-methyl-4-((4-phenylpiperazin-1-yl)methyl)-2H-isoquinolin-1-one,

(41) 3-methyl-4-diethylaminomethyl-2H-isoquinolin-1-one,

(42) 3-methyl-4-(morpholin-4-yl)methyl-2H-isoquinolin-1-one,

(43) 4-(4-phenylpiperazin-1-yl)methyl-3-isopropyl-2H-isoquinolin-1-one,

(44) 7-chloro-4-(piperidin-4-yl)-2H-isoquinolin-1-one,

(45) 7-fluoro-4-(piperidin-4-yl)-2H-isoquinolin-1-one,

(46) 7-chloro-4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(47) 7-fluoro-4-(1-methylpiperidin-4-yl)-2H-isoquinolin-1-one,

(48) 7-fluoro-4-(1-(2-hydroxyethyl)piperidin-4-yl)-2H-isoquinolin-1-one,

(49) 4-dimethylaminomethyl-3-ethyl-2H-isoquinolin-1-one,

(50) 4-(pyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(74) 4-(1-ethylpiperidin-4-yl)-2H-isoquinolin-1-one,

(75) 4-(piperidin-4-yl)-3-methyl-2H-isoquinolin-1-one,

(76) 4-(1-methylpiperidin-4-yl)-3-methyl-2H-isoquinolin-1-one,

(77) 4-(1-(2-hydroxyethyl)piperidin-4-yl)-3-methyl-2H-isoquinolin-1-one,

(78) 4-(1-ethylpiperidin-4-yl)-3-methyl-2H-isoquinolin-1-one,

(79) 4-(piperidin-4-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(80) 4-(1-methylpiperidin-4-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(81) 4-(1-(2-hydroxyethyl)piperidin-4-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(82) 4-(1-ethylpiperidin-4-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(83) 4-(piperidin-4-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(84) 4-(1-methylpiperidin-4-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(85) 4-(1-(2-hydroxyethyl)piperidin-4-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(86) 4-(1-ethylpiperidin-4-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(87) 4-(piperidin-4-yl)-3,7-dimethyl-2H-isoquinolin-1-one,

(88) 4-(1-methylpiperidin-4-yl)-3,7-dimethyl-2H-isoquinolin-1-one,

(89) 4-(1-(2-hydroxyethyl)piperidin-4-yl)-3,7-dimethyl-2H-isoquinolin-1-one,

(90) 4-(1-ethylpiperidin-4-yl)-3,7-dimethyl-2H-isoquinolin-1-one,

(91) 4-(pyrrolidin-3-yl)-2H-isoquinolin-1-one,

(92) 4-(1-methylpyrrolidin-3-yl)-2H-isoquinolin-1-one,

(93) 4-(1-ethylpyrrolidin-3-yl)-2H-isoquinolin-1-one,

(94) 4-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-2H-isoquinolin-1-one,

(95) 4-(pyrrolidin-3-yl)-7-chloro-2H-isoquinolin-1-one,

(96) 4-(1-methylpyrrolidin-3-yl)-7-chloro-2H-isoquinolin-1-one,

(97) 4-(1-ethylpyrrolidin-3-yl)-7-chloro-2H-isoquinolin-1-one,

(98) 4-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-7-chloro-2H-isoquinolin-1-one,

(99) 4-(pyrrolidin-3-yl)-7-fluoro-2H-isoquinolin-1-one,

(100) 4-(1-methylpyrrolidin-3-yl)-7-fluoro-2H-isoquinolin-1-one,

(101) 4-(1-ethylpyrrolidin-3-yl)-7-fluoro-2H-isoquinolin-1-one,

(102) 4-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-7-fluoro-2H-isoquinolin-1-one,

(103) 4-(pyrrolidin-3-yl)-3-methyl-2H-isoquinolin-1-one,

(104) 4-(1-methylpyrrolidin-3-yl)-3-methyl-2H-isoquinolin-1-one,

(105) 4-(1-ethylpyrrolidin-3-yl)-3-methyl-2H-isoquinolin-1-one,

(106) 4-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-3-methyl-2H-isoquinolin-1-one,

(107) 4-(pyrrolidin-3-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(108) 4-(1-methylpyrrolidin-3-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(109) 4-(1-ethylpyrrolidin-3-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(110) 4-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(111) 4-(pyrrolidin-3-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(112) 4-(1-methylpyrrolidin-3-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(113) 4-(1-ethylpyrrolidin-3-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(114) 4-(1-(2-hydroxyethyl)pyrrolidin-3-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(115) 4-(pyrrolidin-2-yl)-3-methyl-2H-isoquinolin-1-one,

(116) 4-(1-methylpyrrolidin-2-yl)-3-methyl-2H-isoquinolin-1-one,

(117) 4-(1-(2-hydroxyethyl)pyrrolidin-2-yl)-3-methyl-2H-isoquinolin-1-one,

(118) 4-(pyrrolidin-2-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(119) 4-(1-methylpyrrolidin-2-yl)-7-chloro-3-methyl-2H-isoquinolin-1-one,

(120) 4-(pyrrolidin-2-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(121) 4-(1-methylpyrrolidin-2-yl)-7-fluoro-3-methyl-2H-isoquinolin-1-one,

(122) 3-methyl-4-[(4-methylpiperazin-1-yl)methyl]-2H-isoquinolin-1-one,

(123) 3-methyl-4-[4-(2-hydroxyethyl)piperazin-1-yl]methyl-2H-isoquinolin-1-one,

(124) 3-methyl-4-(4-benzylpiperidin-1-yl)methyl-2H-isoquinolin-1-one,

(125) 3-methyl-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-2H-isoquinolin-1-one,

(126) 3-methyl-4-(indolin-1-yl)methyl-2H-isoquinolin-1-one,

(127) 3-methyl-4-(diisopropylamino)methyl-2H-isoquinolin-1-one,

(128) (S)-3-methyl-4-(3-hydroxypyrrolidin-1-yl)methyl-2H-isoquinolin-1-one,

(129) (R)-3-methyl-4-(3-hydroxypyrrolidin-1-yl)methyl-2H-isoquinolin-1-one,

(130) (R)-3-methyl-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-2H-isoquinolin-1-one,

(131) (S)-3-methyl-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-2H-isoquinolin-1-one,

(132) 3-methyl-4-(4-hydroxypiperidin-1-yl)methyl-2H-isoquinolin-1-one,

(133) 3-methyl-4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl-2H-isoquinolin-1-one,

(134) 7-chloro-4-dimethylaminomethyl-3-methyl-2H-isoquinolin-1-one,

(135) 7-chloro-4-diethylaminomethyl-3-methyl-2H-isoquinolin-1-one,

(136) 7-chloro-4-(4-phenylpiperidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(137) 7-chloro-4-(4-phenylpiperazin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(138) 7-chloro-4-(morpholin-4-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(139) 7-chloro-4-(4-methylpiperazin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(140) 7-chloro-4-(4-(2-hydroxyethyl)piperazin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(141) 7-chloro-4-(4-benzylpiperidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(142) 7-chloro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(143) 7-chloro-4-(indolin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(144) 7-chloro-4-diisopropylaminomethyl-3-methyl-2H-isoquinolin-1-one,

(145) (S)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(146) (R)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(147) (R)-7-chloro-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(148) (S)-7-chloro-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(149) 7-chloro-4-(4-hydroxypiperidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(150) 7-chloro-4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(151) 7-fluoro-4-dimethylaminomethyl-3-methyl-2H-isoquinolin-1-one,

(152) 7-fluoro-4-diethylaminomethyl-3-methyl-2H-isoquinolin-1-one,

(153) 7-fluoro-4-(4-phenylpiperidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(154) 7-fluoro-4-(4-phenylpiperazin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(155) 7-fluoro-4-(morpholin-4-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(156) 7-fluoro-4-(4-methylpiperazin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(157) 7-fluoro-4-(4-(2-hydroxyethyl)piperazin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(158) 7-fluoro-4-(4-benzylpiperidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(159) 7-fluoro-4-(1,2,3,4-tetrahydroisoquinolin-2-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(160) 7-fluoro-4-(indolin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(161) 7-fluoro-4-diisopropylaminomethyl-3-methyl-2H-isoquinolin-1-one,

(162) (S)-7-fluoro-4-(3-hydroxypyrrolidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(163) (R)-7-fluoro-4-(3-hydroxypyrrolidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(164) (R)-7-fluoro-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(165) (S)-7-fluoro-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(166) 7-fluoro-4-(4-hydroxypiperidin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(167) 7-fluoro-4-(4-phenyl-1,2,3,6-tetrahydropyridin-1-yl)methyl-3-methyl-2H-isoquinolin-1-one,

(168) (S)-4-(3-hydroxypyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(169) (R)-4-(3-hydroxypyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(170) (R)-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(171) (S)-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(172) 4-(4-hydroxypiperidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(173) (S)-4-(3-hydroxypyrrolidin-1-yl)methyl-3-isopropyl-2H-isoquinolin-1-one,

(174) (R)-4-(3-hydroxypyrrolidin-1-yl)methyl-3-isopropyl-2H-isoquinolin-1-one,

(175) (R)-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-isopropyl-2H-isoquinolin-1-one,

(176) (S)-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-isopropyl-2H-isoquinolin-1-one,

(177) 4-(4-hydroxypiperidin-1-yl)methyl-3-isopropyl-2H-isoquinolin-1-one,

(178) 7-chloro-4-dimethylaminomethyl-3-ethyl-2H-isoquinolin-1-one,

(179) 7-chloro-4-(pyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(180) (S)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(181) (R)-7-chloro-4-(3-hydroxypyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(182) (R)-7-chloro-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(183) (S)-7-chloro-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(184) 7-chloro-3-ethyl-4-(4-hydroxypiperidin-1-yl)methyl-2H-isoquinolin-1-one,

(185) 7-fluoro-4-dimethylaminomethyl-3-ethyl-2H-isoquinolin-1-one,

(186) 7-fluoro-4-(pyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(187) (S)-7-fluoro-4-(3-hydroxypyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(188) (R)-7-fluoro-4-(3-hydroxypyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(189) (R)-7-fluoro-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(190) (S)-7-fluoro-4-(2-hydroxymethylpyrrolidin-1-yl)methyl-3-ethyl-2H-isoquinolin-1-one,

(191) 7-fluoro-3-ethyl-4-(4-hydroxypiperidin-1-yl)methyl-2H-isoquinolin-1-one, and

(192) 7-chloro-4-(1-(2-hydroxyethyl)piperidin-4-yl)-2H-isoquinolin-1-one,

an optically active form thereof, a pharmaceutically acceptable salt thereof, a hydrate thereof, a water adduct thereof or a solvate thereof.

15. The isoquinoline compound of claim 10 , which is selected from

(1) 3-amino-4-(2-(dimethylamino)acetyl)-2H-isoquinolin-1-one,

(2) 3-amino-4-(2-(piperidin-1-yl)acetyl)-2H-isoquinolin-1-one,

(3) 3-amino-4-(2-(dimethylamino)acetyl)-5-methyl-2H-isoquinolin-1-one,

(4) 3-amnino-4-(3-(dimethylamino)propionyl)-2H-isoquinolin-1-one,