Benzoxazinone derivative
[PROBLEMS] To provide a compound useful as an agent for the treatment of circulatory diseases, nervous system diseases, metabolic diseases, reproductive system diseases, and digestive tract diseases. [MEANS FOR SOLVING PROBLEMS] The compound, which is for use as an active ingredient, is represented by the formula (I): [wherein R 1 represents optionally halogenated C 1-6 alkyl, etc.; R 2 represents, e.g., a group represented by the formula (II-1) or (II-4) (wherein W represents C 1-6 alkylene, etc. and R represents C 1-6 alkyl, etc.); R 3 represents hydrogen, C 1-6 alkyl, etc.; X represents —O—, —NH—, etc.; and Y 1 , Y 2 , Y 3 , and Y 4 each independently represents —CH—, —N—, etc.].
1. A compound represented by the formula (I) or a pharmaceutically acceptable salt thereof:
wherein R 1 represents optionally halogenated C 1-6 alkyl or optionally halogenated C 3-8 cycloalkyl;
R 2 represents a substituent selected from a group consisting of the following groups:
wherein W represents C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene or C 3-6 cycloalkylene, wherein the alkylene, alkenylene, alkynylene or cycloalkylene may be substituted by optionally halogenated C 1-3 alkyl, optionally halogenated C 1-3 alkyloxy, hydroxyl or halogen;
R represents C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl may be substituted by halogen, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, cyano, phenyl, C 1-6 alkylthio, hydroxyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkyl, di-C 1-6 alkylaminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, C 1-6 alkylsulfonylamino or C 1-6 alkylaminosulfonyl;
R 3 represents a hydrogen atom, C 1-6 alkyl, aryl or heteroaryl;
X represents —O—, —C(R 4a )(R 4b )— or —NR 5 —;
R 4a , R 4b and R 5 each independently represent hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl may be substituted by halogen, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, cyano, aryl or heteroaryl;
Y 1 represents —CR 6 — or —N—;
Y 2 represents —CR 7 — or —N—;
Y 3 represents —CR 8 — or —N—;
Y 4 represents —CR 9 — or —N—;
R 6 , R 7 , R 8 and R 9 each independently represent a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, hydroxyl, hydroxy-C 1-6 alkyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkyl, di-C 1-6 alkylamino-(C 1-6 )alkyl, C 1-6 alkoxy-C 1-6 alkyl, heterocyclyl, aryl, heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio, arylsulfonyl, heteroarylsulfonyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, C 1-6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C 1-6 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, heterocyclylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, C 1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C 1-6 alkylsulfamoyl, arylsulfamoyl or heteroarylsulfamoyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be substituted by a group selected from the group consisting of halogen, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, carboxyl and cyano.
2. A compound of claim 1 , represented by the formula (I-1) or a pharmaceutically acceptable salt thereof:
wherein R 1 represents optionally halogenated C 1-6 alkyl or optionally halogenated C 3-8 cycloalkyl;
R 2 represents a substituent selected from a group consisting of the following groups:
wherein W represents C 1-6 alkylene, C 2-6 alkenylene, C 2-6 alkynylene or C 3-6 cycloalkylene, wherein the alkylene, alkenylene, alkynylene or cycloalkylene may be substituted by optionally halogenated C 1-3 alkyl, optionally halogenated C 1-3 alkyloxy, hydroxyl or halogen;
R represents C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl may be substituted by halogen, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, cyano, phenyl, C 1-6 alkylthio, hydroxyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkyl, di-C 1-6 alkylaminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, C 1-6 alkylsulfonylamino or C 1-6 alkylaminosulfonyl;
R 3 represents a hydrogen atom, C 1-6 alkyl, aryl or heteroaryl;
X represents —O—, —C(R 4a )(R 4b )— or —NR 5 —;
R 4a , R 4b and R 5 each independently represent hydrogen, C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl, wherein the C 1-6 alkyl, C 3-8 cycloalkyl, aryl or heteroaryl may be substituted by halogen, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, cyano, aryl or heteroaryl;
Y 1 represents —CR 6 — or —N—;
Y 2 represents —CR 7 — or —N—;
Y 3 represents —CR 8 — or —N—;
Y 4 represents —CR 9 — or —N—;
R 6 , R 7 , R 8 and R 9 each independently represent a hydrogen atom, halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, hydroxyl, hydroxy-C 1-6 alkyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkyl, di-C 1-6 alkylamino-(C 1-6 )alkyl, C 1-6 alkoxy-C 1-6 alkyl, heterocyclyl, aryl, heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio, arylsulfonyl, heteroarylsulfonyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, C 1-6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C 1-6 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, heterocyclylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, C 1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C 1-6 alkylsulfamoyl, arylsulfamoyl or heteroarylsulfamoyl, wherein the alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl may be substituted by a group selected from the group consisting of halogen, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, carboxyl and cyano.
3. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 1 is trifluoromethyl.
4. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 2 is a substituent represented by the formula (II-1), (II-4) or (II-6).
5. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R in R 2 is phenyl or heteroaryl, which may be substituted by a substituent selected from the group consisting of halogen, cyano, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, hydroxyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkyl, di-C 1-6 alkylamino-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, C 1-6 alkylsulfonylamino and C 1-6 alkylsulfamoyl.
6. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein R 3 is a hydrogen atom.
7. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein in the case where Y 1 , Y 2 , Y 3 and Y 4 are —CR 6 —, —CR 7 —, —CR 8 — and —CR 9 —, respectively, at least one of R 6 , R 7 , R 8 and R 9 is selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, hydroxyl, hydroxy-C 1-6 alkyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkyl, di-C 1-6 alkylaminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, heterocyclyl, aryl, heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio, arylsulfonyl, heteroarylsulfonyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, C 1-6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C 1-6 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, heterocyclylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, C 1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C 1-6 alkylsulfamoyl, arylsulfamoyl and heteroarylsulfamoyl, wherein the aryl or heteroaryl may be substituted by a group selected from the substituent consisting of halogen, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, carboxyl and cyano, and the rest are each a hydrogen atom.
8. The compound or a pharmaceutically acceptable salt thereof according to claim 1 , wherein X is —O— or —NR 5 —.
9. The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein R 1 is trifluoromethyl.
10. The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein R 2 is a substituent represented by the formula (II-1), (II-4) or (II-6).
11. The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein R in R 2 is phenyl or heteroaryl, which may be substituted by a substituent selected from the group consisting of halogen, cyano, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, C 1-6 alkylthio, hydroxyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, hydroxy-C 1-6 alkyl, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkyl, di-C 1-6 alkylamino-C 1-6 alkyl, C 1-6 alkoxy-C 1-6 alkyl, C 1-6 alkylcarbonyl, C 1-6 alkylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, C 1-6 alkylsulfonylamino and C 1-6 alkylsulfamoyl.
12. The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein R 3 is a hydrogen atom.
13. The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein in the case where Y 1 , Y 2 , Y 3 and Y 4 are —CR 6 —, —CR 7 —, —CR 8 — and —CR 9 —, respectively, at least one of R 6 , R 7 , R 8 and R 9 is selected from the group consisting of halogen, cyano, C 1-6 alkyl, C 3-8 cycloalkyl, C 1-6 alkoxy, hydroxyl, hydroxy-C 1-6 alkyl, amino, C 1-6 alkylamino, di-C 1-6 alkylamino, amino-C 1-6 alkyl, C 1-6 alkylamino-C 1-6 alkyl, di-C 1-6 alkylaminoalkyl, C 1-6 alkoxy-C 1-6 alkyl, heterocyclyl, aryl, heteroaryl, C 1-6 alkylsulfonyl, C 1-6 alkylsulfinyl, C 1-6 alkylthio, arylsulfonyl, heteroarylsulfonyl, arylsulfinyl, heteroarylsulfinyl, arylthio, heteroarylthio, C 1-6 alkylcarbonyl, arylcarbonyl, heteroarylcarbonyl, C 1-6 alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C 1-6 alkylcarbamoyl, C 3-8 cycloalkylcarbamoyl, heterocyclylcarbamoyl, arylcarbamoyl, heteroarylcarbamoyl, C 1-6 alkylsulfonylamino, arylsulfonylamino, heteroarylsulfonylamino, C 1-6 alkylsulfamoyl, arylsulfamoyl and heteroarylsulfamoyl, wherein the aryl or heteroaryl may be substituted by a group selected from the substituent consisting of halogen, optionally halogenated C 1-6 alkyl, optionally halogenated C 1-6 alkyloxy, C 1-6 alkylsulfonyl, carboxyl and cyano, and the rest are each a hydrogen atom.
14. The compound or a pharmaceutically acceptable salt thereof according to claim 2 , wherein X is —O— or —NR 5 —.
15. An inhibitor of a long-chain fatty acyl elongase (LCE) comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.
16. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 and a pharmaceutically acceptable additive.
17. A therapeutic treatment agent for metabolic syndrome, fatty liver, hyperlipidemia, dyslipidemia, non-alcoholic fatty liver, obesity, diabetes or bulimia, comprising the compound or a pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.