Substituted 2-(chroman-6-yloxyl)-thiazoles and their use as pharmaceuticals

Abstract

The present invention relates to substituted 2-(chroman-6-yloxy)-thiazoles of the formula I, in which Ar, R2, R3 and R4 are as defined in the claims. The compounds of the formula I are inhibitors of the sodium-calcium exchanger (NCX), especially of the sodium-calcium exchanger of subtype 1 (NCX1), and are suitable for the treatment of diverse disorders in which intracellular calcium homeostasis is disturbed, such as arrhythmias, heart failure and stroke. The invention furthermore relates to processes for the preparation of the compounds of the formula I, their use as pharmaceuticals, and pharmaceutical compositions comprising them.

1 - 22 . (canceled) 
     
     
         23 . A compound of the formula IVa or of the formula VI, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a salt thereof, 
       
         
           
           
               
               
           
         
         wherein 
         R50 is (C 1 -C 4 )-alkyl; 
         Ar is selected from the series consisting of phenyl and a 5-membered or 6-membered monocyclic aromatic heterocycle, which are all unsubstituted or substituted by one or more identical or different substituents R1, wherein the heterocycle comprises 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur and is bonded via a ring carbon atom; 
         R1 is selected from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, phenyl, Het1, HO—, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O—, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-O—, phenyl-O—, Het1-O— and (C 1 -C 6 )-alkyl-S(O) n —, and two groups R1 bonded to adjacent ring carbon atoms in Ar, together with the carbon atoms carrying them, can form a 5-membered to 7-membered mono-unsaturated ring which comprises 0, 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, and which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
         R3 is selected from the series consisting of hydrogen, halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—; 
         R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—; 
         Het1 is a 5-membered or 6-membered monocyclic aromatic heterocycle comprising 1 or 2 identical or different ring heteroatoms selected from the series consisting of nitrogen, oxygen and sulfur, which is unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and (C 1 -C 4 )-alkyl-O—; 
         n is selected from the series consisting of 0, 1 and 2, wherein all numbers n are independent of one another; 
         wherein all phenyl groups, unless specified otherwise, are unsubstituted or substituted by one or more identical or different substituents selected from the series consisting of halogen, (C 1 -C 4 )-alkyl and —O—(C 1 -C 4 )-alkyl; 
         wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl; 
         wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents. 
       
     
     
         24 . A compound of the formula IVa or of the formula VI, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a salt thereof, according to  claim 23 , wherein
 Ar is selected from the series consisting of phenyl, thiophenyl, pyridinyl and pyrazinyl, which are all unsubstituted or substituted by one or more identical or different substituents R1;   R1 is selected from the series consisting of halogen, (C 1 -C 6 )-alkyl, (C 3 -C 7 )-cycloalkyl, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-, HO—, (C 1 -C 6 )-alkyl-O—, (C 3 -C 7 )-cycloalkyl-O—, (C 3 -C 7 )-cycloalkyl-(C 1 -C 4 )-alkyl-O— and (C 1 -C 6 )-alkyl-S(O) n —;   R3 is selected from the series consisting of hydrogen, halogen and (C 1 -C 4 )-alkyl;   R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen and (C 1 -C 4 )-alkyl;   n is selected from the series consisting of 0, 1 and 2, wherein all numbers n are independent of one another;   wherein all cycloalkyl groups, independently of any other substituents which can be present on a cycloalkyl group, can be substituted by one or more identical substituents selected from the series consisting of fluorine and (C 1 -C 4 )-alkyl;   wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.   
     
     
         25 . A compound of the formula IVa or of the formula VI, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a salt thereof, according to  claim 23 , wherein
 Ar is selected from the series consisting of phenyl, thiophenyl, pyridinyl and pyrazinyl, which are all unsubstituted or substituted by one or more identical or different substituents R1;   R1 is selected from the series consisting of halogen, (C 1 -C 6 )-alkyl, HO— and (C 1 -C 6 )-alkyl-O—;   R3 is selected from the series consisting of hydrogen, halogen and (C 1 -C 4 )-alkyl;   R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen and (C 1 -C 4 )-alkyl;   wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents.   
     
     
         26 . A compound of the formula IVa or of the formula VI, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a salt thereof, according to  claim 23 , which is a compound of the formula IVe or of the formula VIa. 
       
         
           
           
               
               
           
         
       
     
     
         27 . A compound of the formula IVa or of the formula VI, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a salt thereof, according to  claim 23 , which is a compound of the formula IVe or of the formula VIa, 
       
         
           
           
               
               
           
         
         wherein 
         R50 is (C 1 -C 4 )-alkyl; 
         Ar is phenyl which is unsubstituted or substituted by one or more identical or different substituents R1; 
         R1 is selected from the series consisting of halogen, (C 1 -C 6 )-alkyl, HO— and (C 1 -C 6 )-alkyl-O—; 
         R3 is selected from the series consisting of hydrogen, halogen and (C 1 -C 4 )-alkyl; 
         R4 is hydrogen or one or more identical or different substituents selected from the series consisting of halogen and (C 1 -C 4 )-alkyl; 
         wherein all alkyl groups, independently of any other substituents which can be present on an alkyl group, can be substituted by one or more fluorine substituents. 
       
     
     
         28 . A compound of the formula IVa, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a salt thereof, according to  claim 23 . 
       
         
           
           
               
               
           
         
       
     
     
         29 . A compound of the formula VI, in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a salt thereof, according to  claim 23 . 
       
         
           
           
               
               
           
         
       
     
     
         30 . A compound according to  claim 23 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a-salt thereof, which is selected from the series consisting of:
 2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester;   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester;   4-Chloro-2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester;   4-Methyl-2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester;   2-(2-Phenyl-chroman-6-yloxy)-4-trifluoromethyl-thiazole-5-carboxylic acid methyl ester;   2-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-[2-(4-Methanesulfonyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   4-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester;   2-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester;   2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-[2-(2,5-Difluoro-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-[2-(5-Fluoro-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-[2-(2-Ethyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-(2-Thiophen-3-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester;   2-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-[2-(6-Chloro-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-(2-Pyrazin-2-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester;   2-[2-(6-Methyl-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-[2-(3-Isopropoxy-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-4-carboxylic acid methyl ester;   2-((S)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester;   2-[2-(2-Fluoro-3-methoxy-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester;   2-(7-Methyl-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester; and   2-(3-Methyl-2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester.   
     
     
         31 . A compound according to  claim 23 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, or a salt thereof, which is selected from the series consisting of:
 2-(2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid;   2-(2-Phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid;   4-Chloro-2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid;   4-Methyl-2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid;   2-(2-Phenyl-chroman-6-yloxy)-4-trifluoromethyl-thiazole-5-carboxylic acid;   2-[2-(3-Fluoro-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   2-[2-(4-Methanesulfonyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   4-Methyl-2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid;   2-(2-Pyridin-3-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid;   2-[2-(5-Fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   2-[2-(2,5-Difluoro-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   2-[2-(5-Fluoro-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   2-[2-(2-Ethyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   2-(2-Thiophen-3-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid;   2-[2-(2,6-Dimethyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   2-[2-(6-Chloro-pyridin-3-yl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   2-(2-Pyrazin-2-yl-chroman-6-yloxy)-thiazole-5-carboxylic acid;   2-[2-(3-Isopropoxy-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   2-((S)-2-Phenyl-chroman-6-yloxy)-thiazole-4-carboxylic acid;   2-((S)-2-o-Tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid;   2-[2-(2-Fluoro-3-methoxy-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid;   2-(7-Methyl-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid; and   2-(3-Methyl-2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid.   
     
     
         32 . A compound according to  claim 23 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester. 
     
     
         33 . A compound according to  claim 23 , which is 2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester. 
     
     
         34 . A compound according to  claim 23 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is 2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid methyl ester. 
     
     
         35 . A compound according to  claim 23 , which is 2-((S)-2-phenyl-chroman-6-yloxy)-thiazole-4-carboxylic acid methyl ester. 
     
     
         36 . A compound according to  claim 23 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is 2-[2-(5-fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid methyl ester. 
     
     
         37 . A compound according to  claim 23 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is 2-(2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid, or a salt thereof. 
     
     
         38 . A compound according to  claim 23 , which is 2-((S)-2-o-tolyl-chroman-6-yloxy)-thiazole-5-carboxylic acid, or a salt thereof. 
     
     
         39 . A compound according to  claim 23 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is 2-(2-phenyl-chroman-6-yloxy)-thiazole-5-carboxylic acid, or a salt thereof. 
     
     
         40 . A compound according to  claim 23 , which is 2-((S)-2-phenyl-chroman-6-yloxy)-thiazole-4-carboxylic acid, or a salt thereof. 
     
     
         41 . A compound according to  claim 23 , in any of its stereoisomeric forms or a mixture of stereoisomeric forms in any ratio, which is 2-[2-(5-fluoro-2-methyl-phenyl)-chroman-6-yloxy]-thiazole-5-carboxylic acid, or a salt thereof.