2-acylaminothiazole derivative or salt thereof

1. A pharmaceutical composition comprising a 2-acylaminothiazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient

wherein

A is methylene;

R 1 is a group represented by the formula (II), or cyclic amino which may be substituted

 wherein

R 11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when A represents methylene, R 11 may be present as methylene which is bridged to thienyl or phenyl represented by R 2 or when A represents methylene, R 11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A; and

R 12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R 2 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting, of a lower alkyl which may be substituted with one or more halogens, and a halogen; and

R 3 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted.

2. The pharmaceutical composition according to claim 1 , which is a thrombocytopenia treating agent.

3. The pharmaceutical composition according to claim 1 , which is a c-Mpl ligand.

4. A compound of formula (III) or a pharmaceutically acceptable salt thereof

wherein

B is a lower alkylene;

R 4 is a group represented by the formula (II), or cyclic amino which may be substituted

wherein

R 11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when B represents methylene, R 11 may be present as methylene which is bridged to thienyl or phenyl represented by R 5 or when B represents methylene, R 11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by B; and

R 12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R 5 is thienyl or phenyl, each of which may be substituted; and

R 6 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted provided that unsubstituted phenyl and indole which may be substituted are excluded.

5. The compound according to claim 4 or a pharmaceutically acceptable salt thereof, wherein B is methylene.

6. The compound according to claim 5 or a pharmaceutically acceptable salt thereof, wherein R 5 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting of a lower alkyl which may be substituted with one or more halogens, and a halogen.

7. The compound according to claim 6 or a pharmaceutically acceptable salt thereof, wherein R 6 is pyridyl which may be substituted, or phenyl which is substituted.

8. The compound according to claim 7 or a pharmaceutically acceptable salt thereof, wherein R 6 is pyridin-3-yl whose 5-position is substituted with a group selected from the group consisting of chloro and fluoro, and whose 6-position is substituted, or phenyl whose 3-position is substituted with a group selected from the group consisting of chloro and fluoro, whose 5-position is 5 substituted with a group selected from the member consisting of —H, chloro and fluoro, and whose 4-position is substituted.

9. The compound of claim 4 , wherein the compound is

1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[cyclobutyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl)piperidine-4-carboxylic acid,

1-(5-([5-{(butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]carbamoyl}-3-chloro-2-pyridyl)piperidine-4-carboxylic acid,

1-{5-[(4-(4-chlorothiophen-2-yl)-5-{[(2R)-2-methylpyrrolidin-1-yl]methyl}thiazol-2yl)carbamoyl]-3-fluoro-2-pyridyl)piperidin-4-carboxylic acid,

1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(2S)-2-methylpyrrolidin-1yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,

1-(3-chloro-5-{[4-(4-chlorothiophen-2-yl)-5-(dimethylaminomethyl)thiazol-2-yl]carbamoyl}-2-pyridyl)piperidine-4-carboxylic acid,

1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[isopropyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,

4-[{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-[isopropyl(methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}(methyl)amino]butyric acid,

1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[(3S)-3-methylpyrrolidin-1-yl]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl}piperidine-4-carboxylic acid,

1-{3-chloro-5-[(4-(4-chlorothiophen-2-yl)-5-{[[(2S)-2-methoxypropyl](methyl)amino]methyl}thiazol-2-yl)carbamoyl]-2-pyridyl)piperidine-4-carboxylic acid,

N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-[(3-hydroxypropyl)amino]nicotinamide,

N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-(3-oxopiperazin-1-yl)nicotinamide or

N-[5-{[butyl(methyl)amino]methyl}-4-(4-chlorothiophen-2-yl)thiazol-2-yl]-5-chloro-6-[4-(hydroxymethyl)piperidino]nicotinamide, or

a pharmaceutically acceptable salt thereof.

10. A pharmaceutical composition comprising the compound according to any one of claims 4 to 9 as an active ingredient.

11. The pharmaceutical composition according to claim 10 , which is a platelet increasing agent.

12. The pharmaceutical composition according to claim 10 , which is a thrombocytopenia treating agent.

13. The pharmaceutical composition according to claim 10 , which is a c-Mpl ligand.

14. A method of increasing platelets in a patient comprising administering to the patient a pharmaceutical composition comprising a 2-acylaminothiazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient

wherein

A: a lower alkylene;

R 1 is a group represented by the formula (II), or cyclic amino which may be substituted

wherein

R 11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when A represents methylene, R 11 may be present as methylene which is bridged to thienyl or phenyl represented by R 2 or when A represents methylene, R 11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A; and

R 12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R 2 is thienyl or phenyl, each of which may be is substituted; and

R 3 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted.

15. The method according to claim 14 , wherein A is methylene.

16. The method according to claim 15 , wherein R 2 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting, of a lower alkyl which may be substituted with one or more halogens, and a halogen.

17. The method according to claim 14 , wherein the pharmaceutical composition is administered orally in a daily amount of 0.0001 mg/kg body weight to 50 mg/kg body weight, 0.001 mg/kg body weight to 10 mg/kg body weight, or 0.01 mg/kg body weight to 1 mg/kg body weight.

18. The method according to claim 17 , wherein the daily amount is administered in one, two, three, or four doses.

19. The method according to claim 14 , wherein the pharmaceutical composition is administered intravenously in a daily amount of 0.0001 mg/kg body weight to 1 mg/kg body weight or 0.0001 mg/kg body weight to 0.1 mg/kg body weight.

20. A method of treating thrombocytopenia in a patient comprising administering to the patient a pharmaceutical composition comprising a 2-acylaminothiazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient

wherein

A: a lower alkylene;

R 1 is a group represented by the formula (II), or cyclic amino which may be substituted

wherein

R 11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when A represents methylene, R 11 may be present as methylene which is bridged to thienyl or phenyl represented by R 2 or when A represents methylene, R 11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A; and

R 12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R 2 is thienyl or phenyl, each of which may be is substituted; and

R 3 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted.

21. The method according to claim 20 , wherein A is methylene.

22. The method according to claim 21 , wherein R 2 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting, of a lower alkyl which may be substituted with one or more halogens, and a halogen.

23. The method according to claim 20 , wherein the pharmaceutical composition is administered orally in a daily amount of 0.0001 mg/kg body weight to 50 mg/kg body weight, 0.001 mg/kg body weight to 10 mg/kg body weight, or 0.01 mg/kg body weight to 1 mg/kg body weight.

24. The method according to claim 23 , wherein the daily amount is administered in one, two, three, or four doses.

25. The method according to claim 20 , wherein the pharmaceutical composition is administered intravenously in a daily amount of 0.0001 mg/kg body weight to 1 mg/kg body weight or 0.0001 mg/kg body weight to 0.1 mg/kg body weight.

26. The method according to claim 20 , wherein the thrombocytopenia is caused by one or more of anemia, myelodysplastic syndrome, chemotherapy, radiotherapy, idiopathic thrombocytopenic purpura, hepatic diseases, and human immunodeficiency virus (HIV).

27. A method of regulating c-Mpl activity for the treatment of thrombocytopenia comprising administering a c-Mpl ligand to a patient, wherein the c-Mpl ligand comprises a 2-acylaminothiazole derivative represented by formula (I) or a pharmaceutically acceptable salt thereof as an active ingredient

wherein

A: a lower alkylene;

R 1 is a group represented by the formula (II), or cyclic amino which may be substituted

wherein

R 11 is a hydrogen atom, a lower alkyl which may be substituted, or a cycloalkyl which may be substituted such that when A represents methylene, R 11 may be present as methylene which is bridged to thienyl or phenyl represented by R 2 or when A represents methylene, R 11 may be present as a lower alkylene which may be substituted and which forms a ring closed at the methylene represented by A; and

R 12 is a lower alkyl, a cycloalkyl or a non-aromatic heterocycle, each of which may be substituted;

R 2 is thienyl or phenyl, each of which may be is substituted; and

R 3 is an aromatic heterocycle, an aryl or cyclic amino, each of which may be substituted.

28. The method according to claim 27 , wherein A is methylene.

29. The method according to claim 28 , wherein R 2 is thienyl or phenyl, each of which is substituted with one or more groups selected from the group consisting, of a lower alkyl which may be substituted with one or more halogens, and a halogen.

30. The method according to claim 27 , wherein the pharmaceutical composition is administered orally in a daily amount of 0.0001 mg/kg body weight to 50 mg/kg body weight, 0.001 mg/kg body weight to 10 mg/kg body weight, or 0.01 mg/kg body weight to 1 mg/kg body weight.

31. The method according to claim 30 , wherein the daily amount is administered in one, two, three, or four doses.

32. The method according to claim 27 , wherein the pharmaceutical composition is administered intravenously in a daily amount of 0.0001 mg/kg body weight to 1 mg/kg body weight or 0.0001 mg/kg body weight to 0.1 mg/kg body weight.