Aminoalkylbenzothiazepine derivatives and uses thereof

1. A compound represented by Formula 1 below, or a pharmaceutically acceptable salt thereof:

wherein

R 1 is hydroxy, carboxy, or hydroxysulfonyl(C 1-4 alkyl);

R 2 and R 3 are each independently hydrogen, C 1-4 alkyl, hydroxy (C 1-4 alkyl);

carbamoyl(C 1-4 alkyl), carboxy, carboxy(C 1-4 alkyl), (C 5-10 heteroaryl)(C 1-4 alkyl), or (C 5-10 aryl)(C 1-4 alkyl), or R 2 and R 3 , taken together with the respective carbon atom to which they are attached, form C 3-7 cycloalkylene;

R 4 is hydrogen or carboxy(C 1-4 alkyl);

R 5 is hydrogen, halogen, (C 1-4 alkyl)thio, (C 1-4 alkyl)amino, or di(C 1-4 alkyl)amino;

R 6 and R 7 are each independently C 1-6 alkyl;

R 8 and R 9 are each independently hydrogen, hydroxy, C 1-4 alkoxy, C 1-4 alkyl, halogen, nitro, cyano, amino, (C 1-4 alkyl)amino, di(C 1-4 alkyl)amino, acetamido, formyl, C 1-4 alkanoyl, carboxy, carbamoyl, (C 1-4 alkyl)carbamoyl, di(C 1-4 alkyl)carbamoyl, carbamoyloxy, (C 1-4 alkyl)carbamoyloxy, di(C 1-4 alkyl)carbamoyloxy, (C 1-4 alkyl)sulfonyloxy, sulfamoyloxy, (C 1-4 alkyl)sulfamoyloxy, or di(C 1-4 alkyl)sulfamoyloxy;

Q is C 5-10 aryl or C 5-10 heteroaryl; and

n is an integer of 0 to 3.

2. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein

R 1 is hydroxy, carboxy, or hydroxysulfonyl(C 1-4 alkyl);

R 2 and R 3 are each independently hydrogen, C 1-4 alkyl, hydroxy(C 1-4 alkyl), carbamoyl(C 1-4 alkyl), carboxy, carboxy(C 1-4 alkyl), or (C 5-10 heteroaryl)(C 1-4 alkyl), or R 2 and R 3 , taken together with the respective carbon atom to which they are attached, form C 3-7 cycloalkylene;

R 4 is hydrogen or carboxy(C 1-4 alkyl);

R 5 is (C 1-4 alkyl)thio;

R 6 and R 7 are each independently C 1-6 alkyl;

R 8 and R 9 are each independently hydrogen, hydroxy, halogen, or C 1-4 alkoxy;

Q is C 5-10 aryl; and

n is an integer of 0 to 3.

3. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 1 is hydroxy, carboxy, or hydroxysulfonylmethyl.

4. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 2 and R 3 are each independently hydrogen, carboxy, methyl, isobutyl, carbamoylmethyl, carboxymethyl, carboxyethyl, hydroxymethyl, imidazolylmethyl, indolylmethyl, or ethyl, or R 2 and R 3 , taken together with the respective carbon atom to which they are attached, form cyclopropylene.

5. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is hydrogen, carboxymethyl, or carboxyethyl.

6. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 5 is methylthio, ethylthio, or dimethylamino.

7. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 6 and R 7 are both butyl or both ethyl.

8. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein R 8 and R 9 are each independently hydrogen, hydroxy, methoxy, methyl, ethyl, fluoro, chloro, nitro, cyano, amino, methylamino, ethylamino, dimethylamino, acetyl, carboxy, carbamoyl, methylcarbamoyl, dimethylcarbamoyl, carbamoyloxy, methylcarbamoyloxy, dimethylcarbamoyloxy, methylsulfonyloxy, sulfamoyloxy, methylsulfamoyloxy, or dimethylsulfamoyloxy.

9. The compound of claim 1 or a pharmaceutically acceptable salt thereof, wherein Q is phenyl, pyridinyl, pyrimidinyl, or thiophenyl.

10. The compound or a pharmaceutically acceptable salt thereof of claim 1 , wherein the compound is selected from the group consisting of:

1) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid;

2) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid;

3) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)succinic acid;

4) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid;

5) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid;

6) 4-amino-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-4-oxobutanoic acid;

7) (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid;

8) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-methylpropanoic acid;

9) (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-(1H-imidazol-4-yl)propanoic acid;

10) (R)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-(1H-indol-2-yl)propanoic acid;

11) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-4-methylpentanoic acid;

12) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid;

13) (S)-2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic acid;

14) 3-((carboxymethyl)((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid;

15) 3-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)pentanedioic acid;

16) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid;

17) 1-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid;

18) 2-(((3,3-dibutyl-7-methylthio-1,1-dioxido-5-phenyl-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic acid;

19) 2-4(3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid;

20) 2-(((3,3-dibutyl-5-(4-hydroxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid;

21) 2-(((3,3-dibutyl-5-(3-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid;

22) 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid;

23) 2-(((3,3-dibutyl-5-(3-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid;

24) 2-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)acetic acid;

25) 2-(((3,3-dibutyl-5-(4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoethanesulfonic acid;

26) 1-(((3,3-dibutyl-5-(3-fluoro-4-methoxyphenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid;

27) 2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-2-oxoacetic acid;

28) (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)propanoic acid;

29) (S)-2-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)-3-hydroxypropanoic acid; and

30) 1-(((3,3-dibutyl-5-(4-fluorophenyl)-7-methylthio-1,1-dioxido-2,3,4,5-tetrahydrobenzo[b][1,4]thiazepine-8-yl)methyl)amino)cyclopropanecarboxylic acid.

11. A pharmaceutical composition comprising the compound according to claim 1 or a pharmaceutically acceptable salt thereof.

12. A pharmaceutical composition comprising the compound according to claim 10 or a pharmaceutically acceptable salt thereof.

13. A method for treating constipation in a subject in need thereof, the method comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to the subject, thereby treating constipation.

14. A method for treating constipation in a subject in need thereof, the method comprising administering an effective amount of the compound according to claim 10 or a pharmaceutically acceptable salt thereof to the subject, thereby treating constipation.