Substituted dihydropyrazolones and their use
View Patent ↗The present application relates to novel substituted dihydropyrazolone derivatives, processes for their preparation, their use for treatment and/or prophylaxis of diseases and their use for the preparation of medicaments for treatment and/or prophylaxis of diseases, in particular cardiovascular and haematological diseases and kidney diseases, and for promoting wound healing.
1. A method for treating cardiac insufficiency, coronary heart disease, myocardial infarction, or stroke in a subject comprising administering a therapeutically effective amount of a compound of the formula
in which
X represents N or CH;
R 1 represents hydrogen or cyano; and
R 2 represents a saturated 4- to 7-membered heterocyclyl radical which is attached via a nitrogen atom,
where the heterocyclyl radical may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino and C 3 -C 6 -cycloalkyl,
or
where the heterocyclyl radical may be substituted by 1 to 4 fluorine substituents, or a salt thereof.
2. A method for increasing the haematocrit in a subject comprising administering a therapeutically effective amount of a compound of the formula
in which
X represents N or CH;
R 1 represents hydrogen or cyano; and
R 2 represents a saturated 4- to 7-membered heterocyclyl radical which is attached via a nitrogen atom,
where the heterocyclyl radical may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino and C 3 -C 6 -cycloalkyl,
or
where the heterocyclyl radical may be substituted by 1 to 4 fluorine substituents, or a salt thereof.
3. A method for treating acute renal failure or for promoting wound healing in a subject comprising administering a therapeutically effective amount of a compound of the formula
in which
X represents N or CH;
R 1 represents hydrogen or cyano; and
R 2 represents a saturated 4- to 7-membered heterocyclyl radical which is attached via a nitrogen atom,
where the heterocyclyl radical may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino and C 3 -C 6 -cycloalkyl,
or
where the heterocyclyl radical may be substituted by 1 to 4 fluorine substituents, or a salt thereof.
4. A method for treating retinopathy in premature babies (retinopathia prematurorum) in a subject comprising administering a therapeutically effective amount of a compound of the formula
in which
X represents N or CH;
R 1 represents hydrogen or cyano; and
R 2 represents a saturated 4- to 7-membered heterocyclyl radical which is attached via a nitrogen atom,
where the heterocyclyl radical may be substituted by a substituent, where the substituent is selected from the group consisting of hydroxyl, hydroxycarbonyl, C 1 -C 3 -alkyl, C 1 -C 3 -alkylamino and C 3 -C 6 -cycloalkyl,
or
where the heterocyclyl radical may be substituted by 1 to 4 fluorine substituents, or a salt thereof.
5. The method of claim 1 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula
or a salt thereof.
6. The method of claim 1 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl }-1H-imidazole-4-carbonitrile, as represented by the formula
7. The method of claim 1 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula
or a salt thereof.
8. The method of claim 1 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula
9. The method of claim 1 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
or a salt thereof.
10. The method of claim 1 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
11. The method of claim 1 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pryrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula:
or a salt thereof.
12. The method of claim 1 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula:
13. The method of claim 2 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula
or a salt thereof.
14. The method of claim 2 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula
15. The method of claim 2 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula
or a salt thereof.
16. The method of claim 2 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula
17. The method of claim 2 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
or a salt thereof.
18. The method of claim 2 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
19. The method of claim 2 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula:
or a salt thereof.
20. The method of claim 3 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula:
21. The method of claim 3 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula
or a salt thereof.
22. The method of claim 3 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula
23. The method of claim 3 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine -3-carboxylic acid, as represented by the formula
or a salt thereof.
24. The method of claim 3 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula
25. The method of claim 3 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
or a salt thereof.
26. The method of claim 3 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
27. The method of claim 3 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula:
or a salt thereof.
28. The method of claim 3 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula:
29. The method of claim 4 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula
or a salt thereof.
30. The method of claim 4 , wherein the compound of formula (I) is 1-{2-[6-(4-Cyclobutylpiperazin-1-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-imidazole-4-carbonitrile, as represented by the formula
31. The method of claim 4 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula
or a salt thereof.
32. The method of claim 4 , wherein the compound of formula (I) is 1-{6-[5-Oxo-4-(1H-1,2,3-triazol-1-yl)-2,5-dihydro-1H-pyrazol-1-yl]pyrimidin-4-yl}azetidine-3-carboxylic acid, as represented by the formula
33. The method of claim 4 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
or a salt thereof.
34. The method of claim 4 , wherein the compound of formula (I) is 2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-4-(1H-1,2,3-triazol-1-yl)-1,2-dihydro-3H-pyrazol-3-one, as represented by the formula
35. The method of claim 4 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula:
or a salt thereof.
36. The method of claim 4 , wherein the compound of formula (I) is 1-{2-[6-(1,2-Oxazinan-2-yl)pyrimidin-4-yl]-3-oxo-2,3-dihydro-1H-pyrazol-4-yl}-1H-1,2,3-triazole-4-carbonitrile, as represented by the formula: