2,3-diaryl- or heteroaryl-substituted 1,1,1-trifluoro-2-hydroxypropyl compounds

Abstract

The present invention relates to compounds of formula I wherein R 1a to R 1e , R 2 , R 3 and R 5 are as defined in the description and claims and R 4 signifies a bicyclic heteroaryl group or a cyanophenyl group, as well as pharmaceutically acceptable salts thereof. The compounds are glucocorticoid receptor antagonists useful for the treatment and/or prevention of diseases such as diabetes, dyslipidemia, obesity, hypertension, cardiovascular diseases, adrenal imbalance or depression.

1 . A compound of formula I, 
       
         
           
           
               
               
           
         
       
       wherein
 A is C—R 1b  or N; 
 R 1a , R 1b , R 1c , R 1d  and R 1e  independently from each other are selected from the group consisting of: 
 hydrogen; C 1-7 -alkyl; C 2-7 -alkenyl; C 3-7 -cycloalkyl-C 1-7 -alkyl; halogen; halogen-C 1-7 -alkyl; halogen-C 1-7 -alkoxy; halogen-C 1-7 -alkyl-sulfonyloxy; hydroxy; hydroxy-C 1-7 -alkyl; C 1-7 -alkoxy; C 1-7 -alkoxy-C 1-7 -alkoxy; hydroxy-C 1-7 -alkoxy; amino-C 1-7 -alkoxy; cyano; carboxyl; carboxyl-C 1-7 -alkyl; carboxyl-C 1-7 -alkoxy; C 1-7 -alkoxycarbonyl; C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy; C 1-7 -alkoxycarbonylamino-C 1-7 -alkoxy; C 1-7 -alkylcarbonyloxy-C 1-7 -alkoxy; aminocarbonyl-C 1-7 -alkoxy; di-C 1-7 -alkylamino; di-C 2-7 -alkenylamino; C 1-7 -alkylsulfonyl-amino; carboxyl-C 1-7 -alkylaminocarbonyl;
 phenyl, said phenyl being substituted by a group selected from carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, 
 Cl 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and aminocarbonyl, and, in addition, optionally substituted by one or two substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy and halogen-C 1-7 -alkoxy; 
 phenyloxy, wherein the phenyl ring is unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy; carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and aminocarbonyl; 
 heteroaryl selected from the group consisting of pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, said heteroaryl being unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl- 
 C 1-7 -alkoxy and aminocarbonyl; 
 heteroaryloxy, wherein heteroaryl is selected from the group consisting of pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and is unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy; carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and aminocarbonyl; 
 phenyl-C 1-7 -alkoxy, wherein the phenyl ring is unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkyl, hydroxy, cyano, C 1-7 -alkylsulfonyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxy-carbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy; and 
 heterocyclyl or heterocyclylcarbonyl, wherein heterocyclyl is selected from the group consisting of pyrrolidine, piperidine and azepine and is substituted by carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy; 
 
 R 2  is selected from the group consisting of C 1-7 -alkyl, C 3-7 -cycloalkyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, triazolyl-C 1-7 -alkyl and phenyl, said phenyl being unsubstituted or substituted by one, two or three halogen groups; 
 R 3  is hydrogen or C 1-7 -alkyl; 
 or R 2  and R 3  together with the carbon atom they are attached to form a C 3 -C 5 -cycloalkyl ring; 
 R 4  is phenyl substituted by cyano and, in addition, optionally substituted by one or two substituents selected from the group consisting of halogen, halogen-C 1-7 -alkyl, C 1-7 -alkyl, C 1-7 -alkoxy and halogen-C 1-7 -alkoxy; and 
 R 5  is hydrogen or methyl; 
 
       or a pharmaceutically acceptable salt thereof. 
     
     
         2 . A compound according to  claim 1 , wherein A is C—R 1b . 
     
     
         3 . A compound according to  claim 1 , wherein one of R 1c  and R 1d  is selected from the group consisting of:
 phenyl, said phenyl being substituted by a group selected from carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl,   C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and aminocarbonyl, and, in addition, optionally substituted by one or two substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy and halogen-C 1-7 -alkoxy;   phenyloxy, wherein the phenyl ring is unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy; carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and aminocarbonyl, heteroaryl selected from the group consisting of pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, said heteroaryl being unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-   C 1-7 -alkoxy and aminocarbonyl;   heteroaryloxy, wherein heteroaryl is selected from the group consisting of pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and is unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy; carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and aminocarbonyl,   phenyl-C 1-7 -alkoxy, wherein the phenyl ring is unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkyl, hydroxy, cyano, C 1-7 -alkylsulfonyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxy-carbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy; and heterocyclyl or heterocyclylcarbonyl, wherein heterocyclyl is selected from the group consisting of pyrrolidine, piperidine and azepine and is substituted by carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy.   
     
     
         4 . A compound according to  claim 1 , wherein one of R 1c  and R 1d  is selected from the group consisting of:
 phenyl, said phenyl being substituted by a group selected from carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl,   C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and aminocarbonyl, and, in addition, optionally substituted by one or two substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy and halogen-C 1-7 -alkoxy;   phenyloxy, wherein the phenyl ring is unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy; carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and aminocarbonyl; and   
       phenyl-C 1-7 -alkoxy, wherein the phenyl ring is unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkyl, hydroxy, cyano, C 1-7 -alkylsulfonyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxy-carbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy. 
     
     
         5 . A compound according to  claim 1 , wherein one of R 1c  and R 1d  is selected from the group consisting of
 heteroaryl selected from the group consisting of pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, said heteroaryl being unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-   C 1-7 -alkoxy and aminocarbonyl;   heteroaryloxy, wherein heteroaryl is selected from the group consisting of pyridyl, pyridazinyl, pyrimidinyl and pyrazinyl, and is unsubstituted or substituted by one, two or three substituents selected from the group consisting of C 1-7 -alkyl, halogen, halogen-C 1-7 -alkyl, C 1-7 -alkoxy, halogen-C 1-7 -alkoxy, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and aminocarbonyl, and   heterocyclyl or heterocyclylcarbonyl, wherein heterocyclyl is selected from the group consisting of pyrrolidine, piperidine and azepine and is substituted by carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkyl and C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy.   
     
     
         6 . A compound according to  claim 1 , wherein one of R 1c  and R 1d  is selected from the group consisting of hydroxy, C 1-7 -alkoxy, carboxyl, carboxyl-C 1-7 -alkyl, carboxyl-C 1-7 -alkoxy, C 1-7 -alkoxycarbonyl, C 1-7 -alkoxycarbonyl-C 1-7 -alkoxy and carboxyl-C 1-7 -alkylaminocarbonyl. 
     
     
         7 . A compound according to  claim 1 , wherein R 1a  is halogen or halogen-C 1-7 -alkyl. 
     
     
         8 . A compound according to  claim 1 , wherein three of R 1a , R 1b , R 1c , R 1d  and R 1e  are hydrogen. 
     
     
         9 . A compound according to  claim 1 , wherein R 2  is C 1-7 -alkyl. 
     
     
         10 . A compound according to  claim 1 , wherein R 3  is hydrogen. 
     
     
         11 . A compound according to  claim 1 , wherein R 5  is hydrogen. 
     
     
         12 . A compound according to  claim 1 , wherein said compound is selected from the group consisting of:
 4-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-fluoro-benzoic acid methyl ester,   4-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-fluoro-benzoic acid,   2-chloro-4-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-benzoic acid methyl ester,   2-chloro-4-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-benzoic acid,   6-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-4-trifluoromethyl-nicotinic acid methyl ester,   6-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-4-trifluoromethyl-nicotinic acid,   6-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid methyl ester,   6-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid,   5-chloro-6-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid methyl ester,   5-chloro-6-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid,   and pharmaceutically acceptable salts thereof.   
     
     
         13 . A compound according to  claim 1 , wherein said compound is selected from the group consisting of:
 3′-chloro-4′-[2-(4-cyano-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-4-fluoro-biphenyl-3-carboxylic acid,   3′-chloro-4′-[2-(4-cyano-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-3-fluoro-biphenyl-4-carboxylic acid,   3′-chloro-4′-[2-(3-cyano-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-3-fluoro-biphenyl-4-carboxylic acid,   3′-chloro-4′-[2-(3-cyano-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-4-fluoro-biphenyl-3-carboxylic acid,   5-chloro-6-{3-chloro-4-[2-(4-cyano-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid,   2-chloro-4-{3-chloro-4-[2-(4-cyano-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-benzoic acid,   6-{3-chloro-4-[2-(4-cyano-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid,   and pharmaceutically acceptable salts thereof.   
     
     
         14 . A compound according to  claim 1 , selected from the group consisting of
 4-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-2-fluoro-benzoic acid,   2-chloro-4-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-benzoic acid,   6-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid,   5-chloro-6-{3-chloro-4-[2-(4-cyano-3,5-dimethyl-phenyl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenoxy}-nicotinic acid,   and pharmaceutically acceptable salts thereof.   
     
     
         15 . A pharmaceutical composition comprising a compound according to  claim 1  and a pharmaceutically acceptable carrier and/or adjuvant.