Substituted triazole derivatives and uses thereof

Patent metadata

Field	Value
Publication number	US-11230540-B2
Application number	US-201816758744-A
Country	US
Kind code	B2
Filing date	Oct 17, 2018
Priority date	Oct 24, 2017
Publication date	Jan 25, 2022
Grant date	Jan 25, 2022

Abstract

The present invention relates to novel substituted 1,2,4-triazole derivatives, to processes for the preparation of such compounds, to pharmaceutical compositions containing such compounds, and to the use of such compounds or compositions for the treatment and/or prevention of diseases, in particular for the treatment and/or prevention of renal and cardiovascular diseases.

First claim

The invention claimed is:

1. A compound of formula (I)

in which
R 1 represents hydrogen or methyl,
R 2 represents amino, C 1 -C 5 -alkyl, methoxy, cyclopropyl or a 5- or 6-membered heterocyclyl,
where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of fluorine, hydroxy, amino, aminocarbonyl, aminosulfonyl, difluoromethyl, trifluoromethyl, methoxy, ethoxy, C 3 -C 6 -cycloalkyl, 4- to 7-membered heterocyclyl, methylsulfonyl, methylcarbonylamino, 2,2,2-trifluoroethylaminocarbonyl, methylsulfonylamino and C 1 -C 4 -alkoxycarbonyl,
wherein heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, formyl, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C 1 -C 4 -alkoxycarbonyl, and
wherein cycloalkyl may be substituted by one substituent hydroxyl, and

where heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, formyl, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C 1 -C 4 -alkoxycarbonyl, or

R 1 and R 2 together with the nitrogen atom to which they are attached form a 4- to 6-membered heterocyclyl,
where heterocyclyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, chlorine, fluorine, hydroxy, aminocarbonyl, methyl, methoxy, trifluoromethyl, methylcarbonyl, methylsulfonyl and C 1 -C 4 -alkoxycarbonyl,

R 3 represents phenyl, pyridinyl or 3,3,3-trifluoroprop-1-yl,
where phenyl may be substituted by one substituent selected from the group consisting of chlorine, fluorine, methoxy and trifluoromethyl, and
where pyridinyl may be substituted by one substituent selected from the group consisting of chlorine, bromine, fluorine, methoxy, trifluoromethyl and trifluoromethoxy, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

2. A compound of formula (I) according to claim 1 , wherein
R 1 represents hydrogen or methyl,
R 2 represents amino, C 1 -C 5 -alkyl, methoxy, cyclopropyl or pyrrolidin-3-yl,
where alkyl may be substituted by 1 to 2 substituents independently of one another selected from the group consisting of hydroxy, amino, trifluoromethyl, methoxy, C 3 -C 6 -cycloalkyl and oxetan-3-yl,
wherein oxetan-3-yl may be substituted by one substituent methyl, and
wherein cycloalkyl may be substituted by one substituent hydroxyl, and

where pyrrolidin-3-yl may be substituted by one substituent formyl, or

R 1 and R 2 together with the nitrogen atom to which they are attached form a pyrrolidinyl, piperazinyl or morpholinyl,
where pyrrolidinyl, piperazinyl and morpholinyl may be substituted by 1 to 3 substituents independently of one another selected from the group consisting of oxo, hydroxy, methyl, trifluoromethyl and C 1 -C 4 -alkoxycarbonyl,

R 3 represents phenyl, pyridinyl or 3,3,3-trifluoroprop-1-yl, where phenyl may be substituted by one substituent selected from the group consisting of chlorine, fluorine, methoxy and trifluoromethyl, and
where pyridinyl may be substituted by one substituent selected from the group consisting of chlorine, bromine, methoxy, trifluoromethyl and trifluoromethoxy, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

3. A compound of formula (I) according to claim 1 , wherein
R 1 represents hydrogen,
R 2 represents 2,2,2-trifluoroeth-1-yl, 2-hydroxy-2-methyl-prop-1-yl, 2-amino-2-methyl-prop-1-yl or (3-methyloxetan-3-yl)methyl, or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-hydroxy-3-methylpyrrolidinyl,
R 3 represents 3-chloropyridin-2-yl, 3-(trifluoromethoxy)pyridin-2-yl or 4-chloropyridin-3-yl, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

4. A compound of formula (I) according to claim 1 wherein
R 1 represents hydrogen,
R 2 represents 2-hydroxy-2-methyl-prop-1-yl or 2-amino-2-methyl-prop-1-yl, or
R 1 and R 2 together with the nitrogen atom to which they are attached form a 3-hydroxy-3-methylpyrrolidinyl,
R 3 represents 3-chloropyridin-2-yl, 3-(trifluoromethoxy)pyridin-2-yl or 4-chloropyridin-3-yl, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

5. The compound of formula (I) according to claim 1 , wherein
R 1 represents hydrogen or methyl,
R 2 represents methyl or cyclopropyl, or
R 1 and R 2 together with the nitrogen atom to which they are attached form a morpholinyl,
R 3 represents 2-chlorophenyl, 3-chlorophenyl or 3-fluorophenyl, and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof.

6. Process for preparing a compound of formula (I) and/or a pharmaceutically acceptable salt thereof, solvate thereof and/or solvate of a salt thereof according to claim 1 , comprising reacting
[A] a compound of formula

in which
R 4 represents methyl or ethyl, with a compound of formula

to give a compound of formula (I) or
[B] reacting a compound of formula

in which
R 5 represents methyl or ethyl, in the presence of an at least stoichiometric amount of a base with a compound of formula

to give an intermediate compound, which is then allowed to react with a compound of formula (VI) or a respective salt thereof

to give a compound of formula (I) or
[C] reacting a compound of formula

with a compound of formula

in which
X 1 represents bromine or chlorine,
to give a compound of formula (I),
each [A], [B] and [C] optionally followed, where appropriate, by (i) separating the compound of formula (I) thus obtained into a respective diastereomer, and/or (ii) converting the compound of formula (I) into a respective pharmaceutically acceptable salt thereof, solvate thereof and/or a solvate of a salt thereof by treatment with a corresponding solvent and/or acid or base.

7. Compound as defined in claim 1 for treatment and/or prevention of one or more diseases.

8. Compound as defined in claim 1 for use in a method for the treatment and/or prevention of acute and chronic kidney diseases including diabetic nephropathy, acute and chronic heart failure, preeclampsia, peripheral arterial disease (PAD), coronary microvascular dysfunction (CMD), Raynaud' s syndrome, dysmenorrhea, cardiorenal syndrome, hypervolemic and euvolemic hyponatremia, liver cirrhosis, ascites, edema and the syndrome of inadequate ADH secretion (SIADH).

9. A product comprising a compound as defined in claim 1 for the manufacture of a pharmaceutical composition for the treatment and/or prevention of acute and chronic kidney diseases in

Assignees

• Bayer Pharma AG

Inventors

• Collin-Kroepelin Marie-Pierre
• Kolkhof Peter
• Neubauer Thomas
• Fuerstner Chantal
• Pook Elisabeth
• Tinel Hanna
• Schmeck Carsten
• Wasnaire Pierre
• Schirmer Heiko
• Lustig Klemens

Classifications

• A61P13/00

  Drugs for disorders of the urinary system · CPC title

• C07D401/14 Primary

  containing three or more hetero rings · CPC title

• C07D403/14 Primary

  containing three or more hetero rings · CPC title

• A61K31/4196

  1,2,4-Triazoles · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title